fhe Interagency Committee on New Therapies for Pain and Discomfort Report to the White House May 1979 S. 'ARTMENT OF HEALTH, EDUCATION, Public Health Service Nati 5 The Interagency Committee on New Therapies - for Pain and Discomfort Report to the White House ) _ May 1979 U.S. DEPARTMENT OF National Institutes of Health HM 2,9 PUBLIC HEALTH TABLE OF CONTENTS LIBRARY FOREWORD I COMMITTEE AND SUBCOMMITTEE MEMBERS IT EXECUTIVE SUMMARY ITI REPORTS AND RECOMMENDATIONS: IV A. Terminal Illness B. Research Needs and Opportunities in the Control of Pain and Discomfort a. Program and Report of Conference on Pain, Discomfort, and Humani- tarian Care held at NIH on February 15-16, 1979 C. Investigational New Drug (IND) Process for Schedule I Drugs APPENDIX: Supplementary articles cited in the Report of the Interagency Committee, commissioned scien- tific papers and other relevant material FOREWORD The Interagency Committee on New Therapies for Pain and Discomfort, composed of Federal physicians and scientists, was created late in 1977 to assess the status of research on intractable pain and humane care of dying patients and to develop recommendations in these two areas. A primary objective of the Committee is to promote research on the mecha- nisms and appropriate treatment of severe pain and discomfort experienced by terminally ill patients. The Committee was formed in response to the expressed interest of the White House and Dr. Peter Bourne, then Director, Office of Drug Abuse Policy, in the problems of pain and other discomforts of the dying and in fostering research on the possible pain-relieving characteristics of abused substances not approved for treatment in the United States. Attention was focused on the subject of pain relief as a result of reports from England regarding the use of heroin for terminally ill patients, as well as largely anecdotal reports that heroin, marijuana, and other drugs in the so-called "dangerous drug' category may be effective as anti-nausea drugs for cancer patients undergoing therapy and in treatment of glaucoma. In general, the Interagency Committee's charges were: e Develop recommendations on expediting the process whereby heroin, marijuana, and other Schedule I drugs (those with the highest abuse potential and not approved for marketing ‘in this country) are made readily available to investigators for therapeutic research purposes. e Examine the state of the art concerning the mechanisms of pain and its relief and make recommendations to fill the gaps in knowledge and to intensify research in this area. Subcommittees were formed to address the charges to the parent committee as follows: 1. The Subcommittee on Terminal Illness. This group was responsible for identifying the public health issues related to terminal illness and for developing recommendations on pertinent areas for continued study or action. The report of the subcommittee deals with a variety of psychosocial and other problems of the terminally ill including the effects of illness and death of one member of a family on other members; the ethics of terminal care; and the clinical care of the terminally ill, control of pain and other discomfort and educational needs of health professionals. 2. The Subcommittee for Research Needs and Opportunities in the Control of Pain and Discomfort. This group examined current research efforts dealing with fundamental knowledge of the mechanism of pain and its management and developed a series of recommendations. To complement the report of this sub- committee the Interagency Committee sponsored a national meeting on "Pain, Discomfort, and Humanitarian Care" in February 1979, which included a consensus I-1 development panel on management of pain and discomfort in the termi- nally ill. The panel issued a series of conclusions and recommendations about the special care needed for dying patients and that information was widely distributed to physicians, researchers, medical students, the press, and the public. A summary of this conference is attached to the report of the subcommittee on Research Needs and Opportunities in the Control of Pain and Discomfort but the entire conference proceedings will be published at a later date. 3. The Subcommittee on the IND (Investigational New Drugs) Process for Schedule I Drugs. This subcommittee reviewed the then existing procedures and made recommendations aimed at expediting the access to Schedule I drugs by research scientists interested in evaluating these agents and facilitating controlled clinical trials for assessing. the potential medical utility of these substances. Beginning with its first meeting in January 1978, the Committee has met monthly for one-half day and engaged in a variety of activities designed to assist the Committee in its deliberations. These activities included: e Reports by clinical scientists engaged in therapeutic research with marijuana, tetrahydrocannibinol (THC), and heroin. e Presentations by the directors of various types of hospices in the United States, Canada, and the United Kingdom. @ Discussion with representatives of State legislatures on pending legislation dealing with Schedule I substances. e Commissioned leading investigators to write technical papers on the preclinical and clinical research on heroin, marijuana, and THC for dissemination to physicians and scientists with the ob- jective of stimulating research interest in these agents. e Development and distribution of fact sheets dealing with the clini- cal research status of heroin, THC and marijuana and including the locations of research studies, These fact sheets are aimed at assisting practicing physicians in patient referral. An issue of concern to the Interagency Committee is the potential impact of the endorsement of marijuana and heroin by medical societies and of legalization by State legislatures. The Committee has distributed infor- mation to State officials, State legislatures, State medical societies, community leaders, researchers, and practicing physicians providing details about the current legal status of Schedule I drugs. It has also offered technical assistance on proposed State legislative actions. This document is a compilation of the reports and recommendations adopted by the Interagency Committee in carrying out its mandate to assess the status of research on chronic pain and the humane care of the chronically I-2 ill. The executive summary containing the major recommendations is followed by the reports of the three Subcommittees. It should be noted that certain aspects of the charges to the Committee were considered by more than one Subcommittee, and that there is thus some overlap in the recommendations. The report also includes a summary of the national conference on pain sponsored by the Committee, commissioned papers on heroin and marijuana, copies of informational material distributed to State medical societies and State legislatures for guidance when considering the need for legislation, and an article ''developed for" practicing physicians which appeared in the Journal of the American Medical Association. The latter materials are to be found in the Appendix. Finally, I want to express my deep appreciation to the members of the Committee for their commitment and hard work. It has been a privilege and a pleasure for me to be associated with this group. Seymour Perry, M.D. Chairman Associate Director, OMAR, NIH INTERAGENCY COMMITTEE ON NEW THERAPIES FOR PAIN AND DISCOMFORT Seymour Perry, M.D., CHAIRMAN Associate Director for Office of Medical Applications of Research (OMAR), NIH George W. Shaffer, M.D., EXECUTIVE SECRETARY Assistant to the Associate Director, OMAR, NIH DEPARTMENT OF HEALTH, EDUCATION, AND WELFARE National Institutes of Health, NIH National Institute on Aging (NIA) Dr. Robert Butler, Director Dr. Richard Greulich, Scientific Director National Cancer Institute (NCI) Dr. Arthur C. Upton, Director Dr. Vincent DeVita, Director, DCT Dr. Diane Fink, Associate Director, Medical Applications of Cancer Research Ms. Janet Lunceford, DCCR Dr. Jane Henney, DCT Mr. Lawrence D. Burke, Program Director for Rehabilitation, DCCR Dr. Michael Jensen-Akula, Special Assistant to Chief, Investigational Drug Branch National Institute of Dental Research (NIDR) Dr. Ronald Dubner, Chief, Neurobiology and Anesthesiology Branch National Eye Institute (NEI) Dr. Douglas Gaasterland, Senior Staff Ophthalmologist National Institute of Neurological and Communicative Disorders and Stroke (NINCDS) Dr. Donald Calne, Clinical Director, Intramural Research Program Dr. Murray Goldstein, Director, Stroke and Trauma Program Office of the Secretary, OS Mr. Joel Mangel, Deputy Assistant General Counsel II-1 Office of the Assistant Secretary for Health, OASH Dr. Faye Abdellah, Assistant Surgeon General Alcohol, Drug Abuse, and Mental Health Administration (ADAMHA) National Institute of Mental Health (NIMH) Dr. William Bunney, Chief, Biological Psychiatry Branch National Institute on Drug Abuse (NIDA) Dr. William Pollin, Director Dr. Larry Ng, Research Physician, Clinical Behavioral Branch, Division of Research Dr. Robert Willette, Acting Chief, Research Technology Branch, Division of Research Food and Drug Administration (FDA) Dr. Stuart Nightingale, Assistant to the Director, Bureau of Drugs Dr. Ronald Kartzinel, Director, Division of Neuropharmacological Drug Products, Bureau of Drugs Dr. Edward Tocus, Chief, Drug Abuse Staff, Division of Neuropharma- cological Drug Products, Bureau of Drugs Dr. John Scigliano, Executive Secretary, Drug Abuse Advisory Committee Health Care Financing Administration (HCFA) Mrs. Bernice Harper, Special Assistant to the Director, HSQB for Long Term Care Issues Health Resources Administration (HRA) Dr. Ken Moritsugu, Deputy Director, Division of Medicine THE WHITE HOUSE Mr. Robert Angarola, Esq., Assistant Director, Domestic Policy Staff DEPARTMENT OF JUSTICE Drug Enforcement Administration (DEA) Mr. Kenneth Durrin, Director, Office of Compliance and Regulatory Affairs Dr. Judith Lawrence, Pharmacologist II-2 VETERANS ADMINISTRATION (VA) Dr. Marguerite Hays, Director, Medical Research Service DEPARTMENT OF DEFENSE (DOD) Captain Peter A. Flynn, M.C., USN, Special Assistant for Professional Activities II-3 SUBCOMMITTEES Subcommittee on the IND Process for Schedule I Drugs Dr. Vincent DeVita, NCI - CHAIRPERSON Dr. Douglas Gaasterland - NEI Dr. William Pollin, NIDA Dr. Stuart Nightingale, FDA Dr. Edward Tocus, FDA Dr. Ronald Kartzinel, FDA Dr. Brian Lewis, NCI Subcommittee on Guidelines for Research in Pain, etc. Dr. Ronald Dubner, NIDR - CHAIRPERSON Dr. Richard C. Greulich, NIA Dr. Diane Fink, NCI Dr. Brian Lewis, NCI Dr. William Pollin, NIDA Subcommittee on the Terminally Ili Dr. Diane Fink, NCI - CHAIRPERSON Dr. William Pollin, NIDA Dr. Larry Ng, NIMH Mr. Lawrence Burke, NCI Ms. Janet Lunceford, NCI Dr. George W. Shaffer, OMAR Subcommittee on National Conference Dr. William Bunney, NIMH - CHAIRPERSON Dr. Ronald Dubner, NIDR Dr. Diane Fink, NCI Dr. Larry Ng, NIMH Mr. Larry Burke, NHLBI Dr. Robert Ringler, NIA Dr. Glen Davis, NIMH Dr. Agu Pert, NIMH Dr. George Shaffer, OMAR II-4 REPORT TO THE WHITE HOUSE INTERAGENCY COMMITTEE ON NEW THERAPIES FOR PAIN AND DISCOMFORT EXECUTIVE SUMMARY The following briefly summarizes the recommendations of the Interagency Committee on New Therapies for Pain and Discomfort. These recommenda- tions have been reviewed and approved by the agencies represented on the Committee. TERMINAL ILLNESS 1. Steps should be taken by governmental and private groups to institute and carry out a vigorous educational program for health professionals on the care of the terminally ill. Further study should be given to related issues such as ethical prob- lems, bereavement care, symptom control, appropriate facilities, and the role of volunteers. Research should be undertaken to define more clearly the terminal state and the associated psychosocial and attitudinal questions; to address reimbursement issues; and to develop operational models for the optimal care of the terminally ill. Principles for the care of the terminally ill should include:* o Administration of medication so as to avoid or minimize the onset of pain (rather than use of analgesics "as needed"); e Employment of drugs that maximize patient comfort; e Avoidance of unnecessary diagnostic studies and therapies that may cause discomfort; and e Treatment of the patient and family as a unit. The optimal team for the care of the dying patient should include nurses, social workers, rehabilitation specialists, nutritionists, pharmacists, spiritual counselors, volunteer aids and health admin- istrators as well as physicians.* *From recommendations issued by a consensus development panel at the National Conference on Pain, Discomfort and Humanitarian Care, February 15-16, 1979, and subsequently adopted by the Interagency Committee on New Therapies for Pain and Discomfort. ITI-1 The role of health care providers and hospitals should be re- assessed in the light of the hospice experience, emphasizing the hospice concept as distinguished from the hospice as an institu- tional entity.* Clinical research should be focused on the experience of aging and death, and on the efficacy of bereavement counseling.* Instruction on the diagnosis and management of pain should be incorporated into the curricula of medical, dental nursing and other paramedical schools.* RESEARCH NEEDS AND OPPORTUNITIES IN THE CONTROL OF PAIN AND DISCOMFORT 1. Special attention should be given to research on the mechanisms of pain, particularly its neural basis and its psychological aspects and to studies of the incidence of chronic refractory pain. New drugs must be developed, particularly derivatives of existing drugs for pain control and studied within the framework of improved guidelines for clinical trials, taking into account the special prob- lems of such research. Greater emphasis should be placed on non-pharmacological therapies for pain. Research on pain should receive increased funding, its coordination among involved Federal agencies improved, and information regarding such research more effectively disseminated. A new NIH/ADAMHA initial review group should be established to serve as a focus for reviewing proposals for studies on pain. Greater numbers of investigators should be trained for research on pain, as recruitment of young researchers is essential for continuec progress. Physicians should ado . the credo that ''caring'" is as important as "curing.''* Pain should be recognized as multidimensional and treatment should be directed toward the patients' mental, social and spiritual as well as physical needs.* *From recommendations issued by a consensus development panel at the National Conference on Pain, Discomfort and Humanitarian Care, February 15-16, 1979, and subsequently adopted by the Interagency Committee on New Therapies for Pain and Discomfort. III-2 THE INVESTIGATIONAL NEW DRUG PROCESS FOR SCHEDULE I DRUGS** 1. The National Cancer Institute should lead in investigating the potential benefits of: 1) heroin for analgesia; and 2) tetrahydro- cannabinol (THC) or other agents for nausea and vomiting secondary to cancer chemotherapy. 2. To expedite clinical trials, data previously obtained by NIDA and NCI on drug chemistry and toxicology should be disseminated to investigators. 3. The NCI distribution system for evaluating anticancer drugs should be used for distributing THC to bona fide researchers investigating the drug's safety and efficacy for relieving nausea and vomiting associated with cancer therapy. Other NIH Institutes as appropri- ate should facilitate research on promising uses of THC, marijuana and heroin, using distribution systems similar to that developed by NCI. 4. Schedule I drugs should be available only for use under valid research protocols. Requests for these drugs for therapeutic use should be referred to institutions conducting clinical trials of these agents. **These recommendations have been or are in process of being imple- mented. I1I-3 TERMINAL ILLNESS The Subcommittee on Terminal Illness met seven times during the period of March through September 1978. The Subcommittee's objectives were to identify the public health issues related to terminal illness, and to provide recommendations on pertinent areas for continued study and/or action to its parent committee, Interagency Committee on New Therapies for Pain and Discomfort. While the Subcommittee recognizes that a number of groups within the Federal Government are concerned with issues of hospice and terminal care, the Subcommittee offers this report to fulfill its charge to its parent committee.* The Subcommittee reinforced its deliberations through the following activities: A. Literature review by individual Subcommittee members with reports and group discussions organized to seek a consensus on major issues. B. Written reports by Subcommittee members on designated topics as specifically assigned by the Subcommittee chairman. C. Presentations to the Subcommittee by a number of persons with experience in the field: Dr. William Elliott —- Methodist Hospital, Indianapolis, IN Dr. John Fletcher - Assistant for Bioethics to the Director, Clinical Center, NIH Dr. Richard Geltman - St. Luke's Hospital, New York, NY Dr. Sylvia Lack - Hospice, Inc., New Haven, CT Dr. William Lamers - Hospice of Marin, San Rafael, CA Dr. Ida Martinson - University of Minnesota, Minneapolis, MN Father James McCartney - Georgetown School of Medicine, Washington, DC Dr. Balfour Mount - McGill University, Quebec, Canada D. Participation by Subcommittee members, as participants or expert consultants, in a number of national and international meetings, workshops, planning groups, and conferences on various aspects of terminal illness. *As this report was going to the printer, the HEW Secretary's Task Force on Hospice submitted its report. This Task Force had been asked by the Secretary to examine current activities within the Department and outside relating to hospice and to make recommendations on the appropriate Federal role. Iv-1 SUBCOMMITTEE ON TERMINAL ILLNESS: REPORT AND RECOMMENDATIONS Background In the past ten years there has been a particular interest in the issues of terminal illness, death and dying. The 1960's and 1970's saw the rise of highly developed medical technology and significant medical treatment advances for many diseases. There has been a increasing tread toward patients dying in hospitals and similar institutions rather than at home. According to recent statistics in the United States and Canada, 70 to 80% of people dying, die in acute care facilities. The health care delivery. system of today is geared to episodic, acute, and curative interventions, usually of a sophisticated technical nature. Some believe that the modern hospital is highly depersonalized. Many authors have pointed out that the terminally ill patient in the modern acute hospital may encounter uncontrolled physical symptoms, iso- lation, and depersonalization instead of receiving sympathetic understanding and expertise in meeting his medical and emotional needs. The family may have limited access to the dying patient in the acute care hospital. Anec- dotal reports suggest that the proper use of analgesics by the medical and nursing profession may need updating. Finally, traditional nursing home care has been described as spotty and episodic. Another variable relating to the management of terminal illness has been a shift in the family structure of the Western culture. Research has shown that the patient and his family constitute the optimal unit of care during the terminal phase of life. Due to increased mobility and technologic progress, the Western family has shifted from the extended family of old to the smaller, nuclear family of today. In the last two to three years, the public has shown its concern about terminal illness by its enthusiastic interest in the hospice movement. The hospice movement has its origins in the English and Canadian approach to terminal care, especially the thorough work of Dr. Cicely Saunders and her associates at the St. Christopher's Hospice. St. Christopher's Hospice (and other English and Canadian hospices) primarily deals with symptomatic dying cancer patients (85 to 90% of the patients are cancer patients) and much of our information on hospice care relates to cancer patients. The hospice movement in the United States is quite new and it is difficult to generalize United States experiences. The original, freestanding English hospice idea has been extended to other care settings which range from separate wards within an acute care hospital to the intermingling of terminally ill patients on all acute hospital wards managed by special teams to home care programs. Examples of a number of the alternatives in organizational structure were presented to the Subcommittee Iv-2 but no final conclusions can be drawn as to which organizational setting can be recommended as best for use throughout the United States. Definition of Terminal Illness Perhaps the most difficult task of the Subcommittee was to develop an operational definition of terminal illness. Everyone knows intuitively which is meant, but to focus the deliberations, the following operational definition of terminal illness was adopted. "A state of disease characterized by a progressive deterioration with impairment of function and survival limited in time, usually from several days to a few months." The Subcommittee recognized that there are some experts who believe that a specific definition of terminal illness is not possible. The details of the terminal state may vary according to the basic under- lying disease process. For example, terminal illness may not be a homo- geneous entity but may have different degrees of physical impairment due to the underlying disease, all of which may reflect in the emotional state of the patient and his family. Different age groups of patients may represent different care problems. For purposes of this report, the basic disease entity must not be amenable to cure or long-term control. (For example, a number of diseases, i.e., diabetes and neurological disorders are chronic diseases which are not curable but the course of these diseases may go on for many years.) The Subcommittee did not address its discussion to the issues of long term, chronic care or custodial care. Therefore, the Subcommittee concerned itself with the several days to months preceeding death. Principles for Terminal Care In this report care for the terminally ill will be termed terminal care (TC) and does not focus on so-called hospice care. 1. Several important principles relate to the current interest in TC: a. The patient and the family, not the disease, is the unit of care. b. Treatment of symptoms (including psychological and social) of terminal illness is of prime importance in patient comfort. c. Followup of survivors (bereavement care) has benefit and should be included in all programs of terminal care. Iv-3 d. Home care as well as institutional care must be part of program for the terminally ill and must be avilable 24 hours a day. e. TC requires a multidisciplinary approach involving physicians, nurses, social workers, dietitians, clergy, volunteers, etc. f. Regular medical evaluation is required to determine if disease- oriented treatment would be of value to the patient and to provide necessary management of symptoms. Terminal care looks to the comfort of the patient and the family. Significant symptoms of terminal illness, such as pain, require sophisti- cated medical and nursing care. A coordinated in-patient and home care component must be available to the patient with emphasis on keeping the patient in the familiar surroundings of his home as long as possible. Selection of Patients for Terminal Care (TC) The decision for the selection of patients for TC presents a responsible challenge to the medical profession. The English hospice normally admits severely symptomatic patients (with serious symptoms such as pain, nausea, depression) who are not thought to be amenable to curative treatment for their disease, are not responding to disease palliation, and have limited life expectancy. Some questions raised by United States physicians are: Will patients be deprived of curative treatment by premature referral to such a program? Can no disease-oriented, palliative treatment be given when a patient is in a terminal care program? Does the oncologist or other disease-oriented physician have a role in such programs?. Will these programs become ''death houses"? Terminal care program admission cannot be viewed as a one-way "ticket." Disease-oriented treatment ¢an and should be given when appropriate to assist in the relief of disease symptoms. The patient's physician should be a valuable member of the TC team. The selection of admission to a TC program will, of course, require judgment on the part of the physician because there is no specific test that determines precise life expectancy. The patient, of course, must participate in the selection decision process with the physician and decide with his/her family if a TC program is an approach for him/her and their family unit. Medical Symptom Control Must Be Carefully and Expertly Administered 1. Pain in the terminally ill a. Pain relief medication for the termimally ill may range from mild analgesics such as aspirin to narcotics such as oral morphine, methadone, and others. IV-4 b. Several basic precepts must apply to pain management in the terminally ill. 1) Pain must be carefully mapped for each patient and followed closely for change. 2) Pain medication for chronic pain must be given on a regular basis and not on a patient request basis. 3) Pain medication must be given in adequate oral doses to relieve symptoms. 4) Currently available narcotics, if properly used, can control pain in terminal patients. For example, oral morphine has been shown to be as effective as heroin for pain relief and cocaine may not be a necessary ingredient in the Brompton's Mix. 5) Addiction to narcotics is not a problem in the terminally ill. c. Relief of pain may be achieved by the following practices: 1) Modification of the disease process--occasionally radiation, drugs, hormones, even surgery aimed at the disease may be helpful. 2) Elevation of pain threshold--honest reassurance, anti- depressants, analgesics, anti-inflammatory drugs, corticosteriods, narcotics. 3) Interruption. of pain pathways--nerve blocks or stimulation. 4) Modification of life style--change in habits may relieve symptoms (sitting vs. standing for shaving), casts, and internal fixation. 2. Other important symptoms in terminal illness are anorexia, nausea, vomiting, depression, insomnia, fungating growths, urinary or bowel incontinence, dysphagia, sore mouth, dyspnea, anxiety, and mental confusion, etc. The intensity of these symptoms vary in appearance and intensity among dying patients. A detailed discussion of such symptoms appears later in this report. Staffing | Terminal care requires a multidisciplinary team approach. Physicians, nurses, clergy, social workers, volunteers, etc., are all required to care for dying patients. IV-5 During the in-patient phase, the family has free access to the patient with special provisions made for family comfort, but families provide only the care they can and wish to provide. In fact, the family may be given a routine "day off" per week to tend to its business. Lay volunteers are also used in TC. These lay volunteers need not be used in place of skilled professional staff but add to the spectrum of support provided to the patient and family. Not only is recruitment and training of TC staff important, but staff need ongoing support to more effectively deal with their own stress that results from the constant proximity to dying. Professional training does not automatically prepare physicians, nurses, physical therapists, etc., to cope with their own feelings about death and dying patients. Psychiatric consultation, supportive interactions at work and home, group feedback sessions and other mechanisms for staff support should be regularly employed. Staff is a highly developed, essential resource in TC and must be maintained at an effective functional level. Use of Experimental Drugs for Symptom Control Care of the terminally ill does not preclude use of experimental drugs for symptom control provided that such drugs are used in a well-designed research study with informed consent, and all the assurances for protection of human subjects provided. Indiscriminate use of experimental drugs in these patients is not to be condoned. Psychological Impact of Terminal Illness and Bereavement Care Classical psychosocial support in TC is important. Dr. Cicely Saunders said recently that warm human caring of one human being to another was perhaps more important at St. Christopher's than psychiatric consultation. Preparation of the patient and family for death and bereavement followup of the family after death cannot be overemphasized. (A further discussion of psychologic implications and of bereavement followup appears elsewhere in this report.) Medical Profession Acceptance The primary care physician can and should be a valuable member of the TC team. Some TC units have been well accepted by local community physicians. It is not clear whether such units will be accepted throughout the United States. Since the primary care physician can maintain his role in the care of his terminally ill patients, there will be less worry by the physician about abandonment of his patient. IV-6 Ethical Issues A number of ethical issues have been raised by the current interest in care of the terminally ill. They include, for example, the decision to accept a patient into a TC program. Indeed, even the definition of "terminally 111" has ethical implications. Further, the very recognition of TC raises the issue of passive euthanasia. (Further considerations on these issues can be found in the Appendix material.) Reimbursement of Terminal Care While recognizing the importance of reimbursement and costs, the Subcommittee did not draw definitive conclusions. Summary Recommendations 1. Action Recommendations -- While the Subcommittee recognized the need for additional research in the area of TC, it believed that a number of action recommendations could be implemented immediately. Each of the following recommendations was deemed to be of equal importance. a. Education of Practicing Health Professionals All practicing physicians should be informed of the principles of TC. The important role of nurses, social workers and other health-related professions in the management of terminal illness is recognized, and the informational needs of these health professionals must be considered in the detailed planning for professional educatiom. Care of the terminally ill must be integrated into the health care delivery system of the United States. To assure rapid and widespread dissemination of conclusions to the health profession, a summary of the principles of TC could be prepared and distributed to all physicians as a Physician Advisory from the Surgeon General. The summary should be distrib- uted to widely read medical journals, such as the Journal of the American Medical Association, and bulletins of professional societies. Educational information for nurses, social workers, and other health professionals also can follow a similar pattern to assure that essential information on TC is disseminated. Other steps that should be taken by both governmental and non- governmental bodies to communicate information on TC to health professionals include the following: 1) Short courses should be offered by professional organizations to demonstrate to physicians the concepts of TC, especially symptom control such as pain. Iv-7 2) Information on TC should be included in appropriate programs of continuing medical education offered for Category 1, American Medical Association credit. 3) Medical, nursing, etc., professional societies should consider identifying a national list of professionals from whom consultation could be obtained on problems of terminal illness. 4) Professional societies such as colleges and academies should include special seminars on terminal illness at their major professional meetings. 5) State and local Health Departments, as well as voluntary health organizations (e.g., the American Cancer Society), should assess the role they can play in disseminating in- formation concerning terminal illness to the health professions. 6) A few TC education resource units geographically situated across the United States should be designed to provide practicing health professionals training in the concepts of TC. Patient /Public Information The stage of terminal illness needs complete and full information for both the patient and the family. Patient education materials should be developed emphasizing control, of symptoms, and the psychologic, social, and spiritual preparation of the patient and his family. All patients and their families entering this state of disease should be provided access to relevant educational materials. The Subcommittee was concerned that full information should be given to the involved persons. The patient and his family may be particularly vulnerable to possibilities of fraud or profiteering. Undergraduate and Graduate Training Undergraduate and post graduate training for health professionals must . take into account the problems of TC. Medical, nursing, and other health professional schools should take this aspect of care into account in curriculum development for students and residents, etc. The Subcommittee did not believe that it was necessary to train large numbers of subspecialists in terminal illness but felt that all health professionals must receive a proper foundation in the principles of TC. Iv-8 Ethical Aspects of Terminal Illness The ethical aspects of terminal illness must be carefully considered for every patient. The rights and choices of the individual are of paramount importance. Experimental studies require the use of informed consent with careful explanation of risks and benefits. Some investigators, including Dr. Balfour Mount, caution that professionals dealing with terminally ill patients must be concerned about the needless repetition of studies already performed simply for the purpose of clarifying the possible place for heroin. Bereavement Care The bereaved constitute a high risk population. Health professionals dealing with terminal illness must be aware of the principles of bereavement followup. Appropriate followup is a requirement of TC programs. In situations of unusual family disruption, referral for special help should be considered by those dealing with bereavement followup. Staff Support Stress on staff working with terminal patients must be recognized. Support must be provided to staff in dealing with problems of coping with terminal illness. Organizational Structure The organizational structure for TC in the United States has not been fully defined. The institutional format for TC can be carried out in a number of settings, i.e., separate institutions, separate wards or wings, special teams of professionals serving special wards and general ward patients, and care as part of regular hospital ward. Many believe that separate institutional wards are best due to possibility of allowing unlimited family access, special privileges in cooking, etc. Others argue that a separate institution is required. This point of view is challenged by still others as wasteful in view of large numbers of empty hospital beds. While no definite organizational recom- mendation is possible now, all possibilities must be given consideration by communities or groups planning TC programs before any is chosen. Evaluation of various organizational units must be undertaken as soon as possible. There must be recognition of the importance of care in the home among familiar surroundings. Both adult and pediatric patients Iv-9 h. even with serious disease diagnosis, can be successfully managed at home for significant periods during the terminal stage. Home care must be an aspect of all programs in TC. Symptom Control Careful attention must be given to the monitoring and control of the symptoms of the terminally ill patient. All health professional education must include the importance of the psychosocial aspects of TC. Volunteer Education Considering the important role of volunteers in TC programs, guidance can be given to development of appropriate education programs for TC volunteers. Research Recommendations —- These research recommendations can be implemented by a variety of mechanisms already available within the Public Health Service, namely grants, contracts, intramural activities and collaborative studies among Federal agencies. Full discussion of research needs are to be found in the attached reports. a. Studies are required to-- 1) Characterize aspects of terminal illness due to many disease processes, including cancer, and identify special problems which may be presented by different age groups of patients. 2) Determine improved methods of symptom control and characterize such symptoms through epidemiologic studies. 3) Evaluate psychological and social patterns of terminal illness on the patient and family--especially the identifi- cation of high risk family groups, and the use of different modes of psychological and social intervention. 4) Determine economic aspects of terminal care and relate these economic issues to current reimbursement plans. 5) Evaluate the various organizational possibilities for TC within the context of the current health care delivery system. Community health planners, administrators, health professionals, and the public need this information for crucial decisions on resource allocation. IV-10 6) Define health professional (especially physician and nurse) attitudes toward terminal illness. Such studies must develop the characteristics required for the staff recruit- ment and staff retention in TC programs. b. A special NIH study section may be required to review grant and contract applications for studies in TC. This study section would require multidisciplinary expertise not only in medicine and nursing but also in behavioral, biostatistical, study design, sociology, economics, educational fields, etc. c. Appropriate funds must be made available within the Public Health Service to assure that high quality research programs are supported. Exact levels would be purely guesses by the Subcommittee. However, adequate funds should be available for high quality approved research grants (and comparable contract proposals) with priorities of 100 to 250 at a minimum. Appropriate NIH institutes and other agencies must consider problems of terminal illness in their budgetary planning and allocate funds for needed activities. Identified Areas of Clinical Management of Terminal Care Other Than Pain Control Terminal illness presents unique and special problems for the patient and his family, as well as for the health care specialists who are responsible for their physical and emotional care. Because the needs of terminally ill patients and their families are so unique and individualized, care requires a more complete and responsive approach than traditional, cure- oriented acute care facilities have allowed. The process of dying from ter- minal illness is a stressful experience, especially during the transitory phas of the patient's illness when a diagnosis is made that curative treatment will no longer affect a meaningful change in ultimate prognosis. During this stage of terminal illness, many patients encounter an attitude from the supporting medical staff that nothing more can be done. Such an attitude all to frequently results in the patient's isolation due to the medical staff's failure to shift their much needed attentions and efforts from the disease process to the dying process. The isolated patient is left very much alone to cope with many and varied distressing symptoms which could and should be treated. The primary objective of palliative care is to alleviate all of the distressing symptoms which occur during the advanced stages of terminal disease, including not only the clinical treatment of physical symptoms, but serious and equal attention to the patient's emotional, spiritual, and social needs. IV-11 The principles of aggressive palliative care are based upon a holistic clinical approach which is maintained throughout the patient's illness, up until the moment of death. The terminally ill patient is considered a unique individual whose needs require careful and sophisticated symptom management, constant monitoring and continuous assessment of all procedures. Non-essential procedures which prove distressful to the patient should be discontinued, and all therapy should be directed at enhancing and improving the quality of life. It is equally important that the medical staff not only be able to recognize and accept when a patient has reached the Jying stage, but also to recognize those rare instances when disease progression abates and a remission phase follows. Because palliative care means total care for the patient, the unit of care includes the patient's family. When the patient suffers so does the family, and understandably, the reverse is also true. The attitude of the family towards the illness and impending death must be considered equally as important as the patient's, both during the illness and during bereavement following death. Dr. Cicely Saunders, Medical Director of St. Christopher's Hosr .ce in London, described this delicate period for the patient and his/her family as "the unique time in the patient's illness when the long defeat of livir can be gradually converted into a positive achievement in dying... Paradoxically, this can be a time for reconciliation and fulfillment for the patient and his family, and it may be the most important period that they spend together." 1 Aggressive palliative care requires a multidisciplinary team of health-care specialists who are highly skilled -. trained, and specifically oriented in caring for the terminally ill. Such a team typically consists of nurses, physicians, psychologists and/or psychiatrists, social workers, physiotherapists, clergymen and volunteers. This staff must work together smoothly and efficiently with tne patient and family, maning use of all available resources to enhance the quality of the patient's remaining life. It is important that each member of the team be carefully selected after an assessment has been made regarding their motivation, professional competence and experience, stability, sensitivity, cooperativeness, resourcefulness and tolerance for stress, in regard to their potential for working with terminally ill patients and the supporting health care staff. Medical and professional nursing staff must be particularly well- trained and highly skilled in traditional and modern medical practices as well as in methods of care for the terminally ill. Although the staff is required to use many known medical techniques, one of the major differences between terminal care and cure-oriented care is that® the specific orientation and knowledge necessary for effective terminal care is geared to the special problems. associated with the dying process. These problems require more scrupulous attention, careful monitoring, 1 saunders, Cicely, "The Challenge of Terminal Care," from Scientific Foundation of Oncology, edited by T. Tympton & R.L. Carter, W. Heinemann Medical Books, Ltd., London, 1975. Iv-12 continuous assessment of procedures and the use of creative polypharmacy. It is particularly important that the medical staff be experienced and knowledgeable in the most modern developments of clinical pharmacology so that the patient's symptoms may be treated most effectively. The appropriate choice of drugs, the carefully determined dose and combination of medication, and close and careful monitoring to assess this effect are crucial to control of symptoms in malignant disease and terminal illness. Another important difference in terminal care is the necessity of a high ratio of health care staff to each patient; in particular, profes- sional nursing staff are required to be available for each patient since the professional nurse is the key person involved in the patient's overall care. As the patient's strength wanes in the advanced stages of illness, she/he becomes more dependent and consequently needs more constant care and attention. Well-trained volunteers and other non-professional staff members play a significant role at this time, as they do during all other stages of the patient's illness. This does not imply that volunteers and non-professionals replace the professional staff, but rather that they augment and assist professional staff in caring for the patient. Each member of the team must regard the patient as a unique individual who deserves to die in peace and with dignity. The entire staff has a responsibility to learn to be critically sensitive to the physical and emotional needs of each patient for whom they care. Emotional pain in particular is too often ignored and yet it is the emotional pain that frequently causes or contributes to a significant degree of the total pain and discomfort experienced by the patient. Often a sympathetic listener is more helpful to a patient in alleviating his fear and pain than drug therapy can ever be. A good health care team learns to make appropriate judgments as to when the patient needs drug therapy or some other form of medical treatment and when the patient needs psychological support. Sylvia Lack, Medical Director of Hospice, Inc. in New Haven, Connecticut, described one aspect of a palliative health care team as follows: "Any group concerned with service to the dying should be talking about smoothing sheets, rubbing bottoms, relieving constipation, and sitting up at night. Counseling a dying person who is lying in a wet bed is ineffective. Such concerns loom large in the lives of critically ill patients and must be of importance to the physician if the physician is to treat the whole person. A certain amount of interdisciplinary role blurring may be necessary to ensure patient comfort at all times." 2 Lack, Sylvia, "Philosophy and Organization of a Hospice Program,' First National Training Conference for Physicians on Psychosocial Care of the Dying Patient, Charles Farfield, Ph.D., Editor, University of California School of Medicine, San Francisco, 1976. Iv-13 The effective management and control of symptoms have been achieved with reported success by such programs as St. Christopher's Hospice in London, with over 12 years experience, the Palliative Care Service of the Roval Victoria Hospital in Montreal, Canada, which has been serving the terminally ill for the past 5 years, and Hospice, Inc. of New Haven, Connecticut which has also been in operation for 5 years. The experience of such programs has resulted in the identification of certain symptoms which are commonly recognized and documented as being associated with terminal illness. The following section identifies these symptoms and describes some of the preferred methods for symptom management and control based on known techniques and common experiences. This descriptive section is not intended, however, to be a rigid set of guidelines to be followed in all cases, nor do the preferred methods of treatment outlined below preclude further improvements or changes in the future. It should be understood clearly that flexibility and individualized treatment and care plans are the cornerstones of the medical armamentarium. Again, it should be stressed that all symptom management must be combined with a highly-skilled, well-trained staff of professionals, non-professionals and volunteers who are oriented to the special problems of the terminally ill, a very high ratio of staff to each patient, creative polypharmacy, concentrated attention to detail, constant monitoring and continuous assessment of all procedures. Symptoms can be categorized into five main areas: Gastrointestinal, Respiratory, Genital-Urinary, Neurological, and Skin Problems. The most common symptom which is present in most patients with terminal illness is weakness. Once it is determined that the cause of weakness is not due to any correctable deficiencies, such as anemia, management can be approached in terms of both prevention and treatment. The physician, nurse and physiotherapist must first determine a careful balance between the patient's need for physical exercise to induce strength and his need for rest to prevent fatigue and overexertion. Bedpans, commodes and similar devices are effective means of avoiding fatigue, whereas careful postioning and appropriate exercises as suggested by the physiotherapist are effective in building strength. In some cases of non-specific weakness, the administration of prednisone has been found to be effective. 1. Gastrointestinal symptoms The most common symptoms of gastrointestinal distress include thirst, anorexia, nausea and vomiting, dysphagia, constipation, diarrhea, ascites, hiccoughs, and malignant bowel obstruction. IV-14 Thirst - In the advanced stages of disease, good mouth care will normally counteract the symptoms of thirst and dry mouth. Thirst is one of the most common gastrointestinal symptoms due to the adverse effect of phenothiazines, antihistamines, and tricyclic antidepressants. Reduction in dose or discontinuance of these drugs will help alleviate this symptom. The offering of frequent sips of liquid, gum, sour candies, ice chips and lemon glycerine sticks are some of the effective methods the health care staff can use for good mouth care. Mouth washes which contain astrigents or local anesthetics are particularly effective in alleviating stomatitis. In addition, sometimes a dentist needs to be consulted to alleviate such problems as poor fitting dentures which result from severe cachexia. Anorexia - One of the most common characteristics of terminal disease is anorexia, the condition in which the patient loses his appetite for food. This condition is aggravated by a perversion or loss of the taste and olfactory senses. In order to minimize anorexia and the resulting wasting and malnutrition, the patient, family and health care staff must work together with a dietary consultant to find the most effective methods for stimulating the patient's appetite and maintaining good dietary care. Some of the most effective means of stimulating the patient's appetite include careful preparation of food with special attention to the appearance, aroma, and temperature of food; a varied and creative menu allowing choices and including the option of having special favorite or ethnic foods prepared by staff, family, or friends; avail- ability of facilities for heating and cooling food at all times; frequent but small snacks and meals; particular attention to the psychological and social aspects of eating (such as celebration of any occasion or anniversary of staff or family with food or sharing a cocktail with a friend or family member) and the administration of blucocorticosteroids which stimulate the appetite. Also, nutritionally balanced liquid supplements such as Sustagen, complement the basic diet. Nausea and Vomiting - Drug therapy is successful in treating the nausea and vomiting which accompany advanced terminal disease. Antiemetic drugs need to be regularly administered to combat these symptoms. The three groups of drugs generally available to treat nausea and vomiting include metoclopramide, phenothiazines and antihistamines. Sometimes it is more effective to prescribe a combination of two medications rather than to increase the dose of the initial drug. IV-15 Dysphagia - This symptom causes difficulty in the coordination of the swallowing reflex. Treatment consists of eliminating non-essential drugs and substituting pills for liquid whenever possible. Essential tablets can be crushed and served with soft foods, such as ice cream. Nutrition can be balanced and maintained with small but frequent feedings of soft foods like jello, custards and beverages. Constipation - Constipation is a common side effect of narcotic analgesia. It can be treated by digital disimpaction, enemas, and suppositories. However, it is generally considered more important that treatment be aimed at the prevention of constipation. Patients who receive narcotic analgesics regularly should be simultaneously administered a stool softener and a peristaltic stimulant. Diarrhea - Mild cases of diarrhea have been successfully treated with a variety of chalk-containing compounds. More persistent cases can be effectively treated with anti-diarrhea medications. In severe cases, narcotics or mixtures containing opium may be required. Rectal examination should be performed to check for overflow diarrhea around fecal impaction. If such is the case, digital disimpaction and enemas will be effective in treating this condition. Ascites - If the abdomen is tense, causing the patient discomfort or dyspnea, paracentesis should be considered. Hiccoughs — Inhalation of carbon dioxide, such as that achieved by breathing into a paper bag, is usually helpful in controlling this symptom. Effective drug therapy includes tranquilizers or simple antiflatulents. Bowel Obstruction Due to Malignancy - In the early stages of terminal disease, treatment of bowel obstruction includes nasogastric suction and intravenous hydration with or without colostomy. In the advanced stages, an alternative treatment includes the use of anti-emetics, analgesics, stool softener, and oral hydration. a. Anti-emetics - Often, both an antihistamine and a phenothiazine is administered to eliminate nausea and limit the vomiting to once or twice daily or less. Initial therapy using the intra- muscular route for rapid relief should be changed to oral route as soon as possible. b. Analgesics - Abdominal pain usually requires the use of regular narcotics. Initially, control of pain is established with administration of an intramuscular narcotic (preferably morphine) and then switched to the use of Hospice Mix, consisting of morphine, ethyl alcohol, simple syrup and a flavoring agent. Concern must also be given to the causes of abdominal pain not related to the malignant disease such as acute appendicitis or other possibly treatable situations. IV-16 Anti-diarrhea medications usually control any cramping which may occur because of peristalsis against the obstruction. c. Stool softeners — Stool softeners are effective in cases of partial obstruction because they prevent constipation and future obstruction. d. Oral hydration - The use of intravenous fluid is not necessary once vomiting is limited; instead, sufficient hydration and nutrition can be maintained with a diet of soft foods and liquid. Respiratory Symptoms Dyspnea - This symptom requires much calm and quiet reassurance by both staff and family. Every effort should be made to see that someone is with the patient as much as possible. Proper positioning in bed or in a reclining chair is very helpful. Good mouth care is partic- ularly important because of breathing by mouth. Other preferred methods of treatment which have been found to be effective in the experiences of some hospice programs include: a) oxygen by mask, b) systematic steroids (useful for managing lymphangitic spread), c) anxiolytics (useful when dyspnea is associated with anxiety attacks), d) thoracentesis (performed with or without chemotherapeutic agents when pleural effusion occurs) and e) narcotics (especially mdrphine) help to decrease dyspnea and in severe cases of air hunger may be the only appropriate method to control this symptom. Respiratory Infection - Antibiotics are effective in controlling infection and may be particularly effective in decreasing sputum production. It has been the experience of some hospice programs that patients are resistant to antibiotics during the advanced stage of terminal illness. Broncho-spasm - Bronchodilators are effective in controlling this symptom. Cough - Narcotics are the most effective method of treatment for suppressing cough. Morphine given for pain also acts as a cough suppressant. Physiotherapy and hydration are effective in producing expectoration. Secretions - As the patient nears death, his chest may fill with moist secretions. Hyoscine is very effective in drying these secretions. When the patient is unable to expectorate because of an accumulation of thick sputum, it is occasionally necessary to suction the pharynx. Iv-17 Genital Urinary Symptoms The most common genital-urinary symptoms associated with terminal illness include urinary incontinence, urinary tract infections, and hematuria. Urinary tract infections should be treated with the appropriate antibiotic as determined by the culture and sensitivity of the urine. If this symptom occurs only at night, treatment can be approached by frequent waking, condom drainage or administration of diuretics only in the morning. If incontinence occurs throughout the day and night, an indwelling catheter should be considered. Routine irrigation or prophylactic antibiotics are not recommended. Irrigation with sterile saline is effective if debris becomes a problem. Hematuria - When this condition is present, use of a mushroom-type catheter is effective. In order to prevent the catheter from being blocked by clots, regular irrigation should be performed. Neurological Symptoms The most common neurological symptoms associated with terminal illness are insomnia, depression, paralysis, and organic brain syndrome. Insomnia - In managing and treating insomnia, barbiturates should be avoided if possible. Non-barbiturate sedatives which do not interfere with REM sleep are useful in inducing sleep. Analgesics and anti- emetics may be helpful due to their sedative effect on the patient. Depression — Although it is expected that the dying patient must undergo a certain amount of normal grief, including a stage of depression, the emotional support the patient receives from the staff and the family cannot be overstressed. When the depression is either prolonged or extreme in severity, tricyclic antidepressants should be considered. Drug therapy in elderly or debilitated patients should be initiated at a lower dosage. Elderly patients have greater sensitivity to tricyclic antidepressants; therefore, drug therapy for depression of older people needs to consider this factor, possibly initiating administration of drugs at a lower dosage than would be given to a younger person. Paralysis - Although hemiplegia or paraplegia is usually irreversible in the advanced stages of terminal disease, health care staff can encourage realistic goals through physiotherapy. Contractures can be prevented with passive exercises. IV-18 Organic Brain Syndrome - Once easily correctable causes have been eliminated as the source of the problem, a careful review of drugs and dosages should be initiated to assure that intoxication has not occured. This is especially important in the presence of renal or hepatic disease. Patients who develop an organic brain syndrome should have a stable environment with a consistent and well ordered routine to avoid confusion and disorientation. Staff and family should give frequent reminders and clues to orient the patient. Unusual sounds should be avoided if possible. Night lights also help to prevent confusion and disorientation. In terms of drug therapy, phenothiazines and other major tranquilizers have been found to be most effective. 5. Skin Problems Pruritis and decubitus ulcers are often associated with terminal disease. With careful attention and proper treatment, these problems can frequently be prevented. Moisturizers, skin creams, and bath oils alleviate pruritis when it is caused by dry skin. When caused by systemic disease or sensitivity reactions, antihistamines offer at least partial relief. Prevention of decubitus ulcers can be achieved by keeping the skin clean and dry, frequent position change to avoid constant pressure to any skin area, and use of air mattresses half filled with water for bedridden patients. Psychosocial Issues Relevant to Terminal Illness Over the past decade there has been a substantial upsurge of interest in clinical studies relevant to death and dying. A survey of the world bibliography on the psychosocial aspects of death and dying for the years 1950 to the present reveal a total of about 200 books and over 2500 articles, a majority of which were written within the past decade. Despite the large number of publications (many of which are filled with advice on how to die and how to work with the dying), there appears to be little systematic research to substantiate or contradict most of the statements concerning psychosocial care of the dying (Kalish, Richard A.: A Little Myth is a Dangerous Thing: Research in the Service of the Dying. In Garfield, Charles A. (ED.): Psychosocial Care of the Dying Patient. McGraw Hill Book Company, New York, 1978). There are many justifiable questions about our current knowledge of death, dying, and bereavement; and it is quite apparent that we need good, rigorous, and creative research in this area. A review of the literature points to a need for further study in the following area: 1. Understanding the Needs of the Individual with Terminal Illness The literature to date, as well as the experience at St. Christopher's IV-19 Hospice and other hospices in England and in this country, strongly suggests that psychological and social factors are as important as specific pharmacological regimens in influencing the quality of the subjective experience of the dying patient. The needs of the patient with terminal illness are multiple and complex. First is the need for comfort, both physical and mental. Successful control of severe pain is of paramount importance in the management of patients with painful terminal illness, and failure to do so would deprive the patient of the opportunity to face death, or even to face the family and close friends with self-respect and dignity. The importance of controlling terminal pain has been well discussed by individuals like Saunders ('The Treatment of Intractable Pain in Terminal Cancer." In Proceedings of the Royal Society of Medicine. 56(3): 191-197, 1963), and Twycross (Choice of Strong Analgesic in Terminal Cancer: '"Diamorphine or Morphine?" In Pain. 3(2): April 1977). However, it should be pointed out that the true prevalence of physical pain in patients with terminal illness from cancer and other diseases is still unknown. Good epidemiological data in this area are vitally needed. Mental distress of the patient with terminal illness may be even more intractable than that of physical origin and needs to be better understood. Objective reports on the distress of dying patients have previously been made by Hinton (Quarterly Journal of Medicine 32: 1-21, January 1963), Exton-Smith (Lancet 2: 305-308, 1961), Rees (British Medical Journal 3: 105-107, 1972), and others represent- ing an area requiring further elucidation. A large number of psychological, social, and environmental factors can critically influence the experience of pain and distress of the terminally ill, including belief systems and cultural practices. Concurrent levels of fear, anxiety, and depression can greatly influence the patient's perception, reaction, and experience of pain and distress. For example, different individuals have markedly different capacities to deal with threat in general and the specific threat of death and dying in particular. Recent research has suggested differences (and similarities) in the way men and women cope with pain and distress (Boud and Pilowsky: 1978). Can we predict what personality traits will require more or less of what type of support in dealing with terminal illness? We should not, of course, overlook the fact that "terminal illness" is not a homogeneous entity and that different etiologies of illness may have uniquely different physical, emotional, and social concomitants. A better understanding of the commonalities and differences among different types of terminal illnesses would provide a better base upon which to plan our care of a particular patient. Much more needs to be known about the affect dimensions confronting the dying patient. It has been reported that the terminally ill patient wants to be regarded as a person aswell as a patient IV-20 (Buckingham, R.W., et al: "Living with the Dying: Use of the Technique of Participant Observation." Canadian Medical Association Journal 115: 1211-1218, 1976). This requires others to see the patient as an individual and not just as host to the disease. The need to be treated as a person must take into account the sense of isolation which the terminally ill experiences as his world contracts. Despite the extreme popularity of Kubler-Ross (1969) concerning the universality of the dying process and the stages that the terminally ill patient experiences, clinical research concerning the dying process by other investigators does not clearly support the exis- tence of the five stages or any universal form of staging. The dying process is not the same throughout the life cycle. One's stage in life profoundly influences one's sense of identity, one's sense of self, and one's sense of death. An area of needed research would be to identify the ways individuals cope with dying throughout the life cycle--from childhood, adolescence, adulthood, middle age, and old age. Social Support Systems Research has shown that the dying patient and his or her family constitute an optimal unit of health care. The family is uniquely organized to carry out its stress-mediating responsibility and is in a strategic position to do so. There is an emergent sensitivity toward the dying individual and an appreication of the role of the family in caring for such an individual. However, as a result of technological progress and increased mobility, Western society has moved from the extended family of old to the smaller nuclear family of today. Consequently, the traditional support systems used to care for a terminally ill family member have become less available. Additionally, shifting sociocultural patterns add to the plight of the terminally ill in our Western society. There is a loneliness about dying in Western culture which does not exist in certain other cultures, such as in the American Indians and in the Eastern and Oriental cultures. Additional research is needed to identify the emotional needs of the dying patient and his family and how the role of family support can be enhanced. We need studies to better comprehend the cross cultural variation in value systems and the support that sociocultural factors can provide to the dying patient. The process of dying with a terminal illness is a uniquely stressful experience. More needs to be learned about adaptive and maladaptive coping responses by the family and by the individual, and ways need to be found to mitigate the impact of stress on the individual patient as well as upon individual family members. In this context, we need also to know how best to prepare family members for the process of bereavement. Research in preventive health indicates that the bereaved are much more susceptible to mental and physical illness, including early death, than people not suffering from the loss of a close friend or relative. What alternative modes of social support IV-21 systems could be developed and utilized to mitigate the impact of such stresses? The Health Care System in the Management of Terminal Illness Once it becomes apparent that an illness is terminal, our conven- tional medical system seems ill prepared and the physician and other health professionals are often poorly trained to deal with the issues of death and dying. Our existing health care delivery system is geared principally toward treatment and cure, delivering its services in an episodic fashion (only when sickness occurs), relying often on the highest level of technology as its most appropriate level of care. Faced with a situation like terminal illness, where cure is less important than appropriate use of human resources, and where biochemistry and pharmacology may be less important than psychosocial issues related to dying, death, and bereavement, our existing health care delivery system falls far short of the optimum. Our medical institutions, which are cure- oriented, often have a strong death-denying bias militating against acceptance of death. What is the impact of such institutional attitudes on the patient's ability to cope with impending death? Our ability to offer help to the dying patient is influenced by our views about death. Dying in our culture is viewed as a pathological problem to be treated (Engle, G.: "Is Grief A Disease?" Psychosomatic Medicine 23: 18-22, 1961). Our treatment-oriented health care system, with its intense focus on cure and cure-related activities, may not be well suited to provide care-centered services to dying + people. How could the shift from cure-centered activities to a primary focus on care-centered goals for dying patients best be achieved? The shift to a care-centered orientation will require an understanding of the attitudes and behavior of a given patient. This will require a better understanding of each patient's ''death style," which is as unique as his life style. How can we assist the individual patient to achieve a style of dying that is adaptive to the specific person (what Weisman describes as ''appropriate death"). The criteria for an "appropriate death' need to be better elucidated, keeping in mind that these will be fulfilled in different ways for different people under different circumstances. In the same manner, our physicians are well trained in the physiology of illness and death but poorly educated about the psychosocial aspects of the families and the individuals who experience the emotional intensity of impending death. And yet, as Weisman has pointed out, "We (physicians) are not immune to the process of denial, dissimilation, antipathy, and fears of personal annihilation" (Psychosocial consideration in terminal care. In Schoenber, B., et al, (Eds.): "Psychosocial Aspects of Terminal Patients Care." Columbia, New York, 1972). Thus a physician's effectiveness in coping with the anxiety and other emotions aroused by a patient's IV-22 imminent death become of crucial importance in the relationship between the patient and physician. Relatively few studies to date have focused on the physician's reaction to the dying patient. As has been pointed out, there are virtually no available emotional support systems for physicians (Garfield: Psychosocial Care of the Dying Patient. New York, McGraw-Hill, 1978). Thus the physician treating the terminally ill patient faces isolation as much as the patient. This sense of isolation is further confounded by ambiguous communication on the part of physicians, families, and the patient facing life threatening illness. A ''conspiracy of silence" often develops, in which everyone knows and yet no one is willing to share the fact that they know. This often results in isolating and alienating the patient, family, and the physician. Just as it is essential to understand the emotional realities of dying in the patient's perspective, it is also important to compre- hend its emotional impact on the physician and other health personnel. Further research is vitally needed in this area. Iv-23 RESEARCH NEEDS AND OPPORTUNITIES IN THE CONTROL OF PAIN AND DISCOMFORT I. Introduction Although pain sensations normally serve as a signal for impending or already present tissue damage, there are many instances when pain and discomfort outlast their usefulness to human survival and contribute to a decrement in the quality of life. Such a decrease in human well- being is often a problem for the chronically ill, the terminally ill, and the aged. Unfortunately, health research in this area has not benefited from a high priority in the past. Analysis of the data files related to the current research programs of NIH/ADAMHA substan- tiates scattered support of pain control research with minimum funding levels. In response to such benign neglect, the charge of this Subcommittee has been to develop recommendations that point to urgent research needs that may ultimately contribute to the relief of pain and discomfort and to improvements in human well-being. In our review of the present status of knowledge regarding the control of pain and discomfort, there emerged the overwhelming sense that too little is known about pain mechanisms, alternative modalities of therapy, and the incidence and prevalence of pain. Moreover, there appears to be a similar dearth of knowledge relating to social attitudes towards human pain, even among the deliverers of health care whose responsibility it is to deal with pain in others. Successful utiliza- tion of currently recognized, as well as new modalities developed for pain relief, depends to no small degree on this interpersonal interaction. In essence, the needs and opportunities for research described below are directed at the enhancement of human well-being as a goal fully equal in importance to the achievement of significant gains in the understanding of disease mechanisms. A concerted effort in pain control provides a unique starting point for the implementation of an integrated approach to the improvement of the quality of life for the chronically and terminally ill, and for the elderly. IV-24 SUMMARY OF RECOMMENDATIONS A. There are a number of areas of pain research which require particular emphasis. These include the incidence and prevalence of chronic refrac- tory pain, the neural basis of pain, and psychological aspects of pain. Experimental approaches to pain control need to be expanded. Preclinical research and larger programs in development of new drugs and derivatives of existing drugs for pain control should be instigated. Clinical trials concerned with pain alleviation present special problems and improved guidelines for such trials are needed. Mechanisms to foster interagency coordination and information transfer need to be established. Funding for pre-clinical and clinical research in pain control appears to be inadequate and should be increased. An appropriately constituted study section to serve as a focus for the receipt and review of proposed studies should be created. IV-25 II. Detailed Recommendations A. Areas of Urgent Research Need l.. Incidence and prevalence of refractory pain. We recommend that epidemiological studies be initiated to determine the incidence and prevalence of pain refractory to currently- applied therapies (e.g., chronic intractable pain, pain of long-duration) in the general population. This should include disorders such as intractable low back pain, arthritic pain, etc., as well as pain associated with terminal illness, e.g., cancer. There is little data available on the epidemiology of these disorders and such investigations should be a prerequisite to further evaluation of new therapies for pain and discomfort. In addition, surveys should be conducted on the present patterns of patient care for refractory pain by physicians and other health care practitioners. 2. The neural basis of pain. Any program purporting to have as its goal new modalities for pain control must strongly support further research on the neural mecha- nisms underlying the transmission of signals in the nervous system related to pain sensation and reaction. We recommend basic physiological, pharmacological, anatomical and psychological research on the neural basis of pain. 3. Psychological aspects of pain. Pain is a subjective experience of the total individual. The neural mechanisms described above are part of a larger biobehavioral system which modulates neural activity and determines the perceived meaning, extent and significance of pain sensations. Therefore, there is the need to study the total person, as well as the specific neural mechanisms described above. a. We recommend further studies on quantifiable measures for assessing pain magnitude and pain relief following therapeutic inter- vention. This includes research in the areas of psychometrics, social science and psychopharmacology with the goal of attaining more quanti- fiable methods for assessing the subjective sensations, perceptions and reactions associated with pain disorders. Reliable measures are needed to determine the affective state of the individual; e.g., feelings about the pain, general anxiety, general psychological state. This recommen- dation deals with our concern about total well-being of the individual rather than sole concern with pain relief, per se. b. We recommend research on the influence of personality and the emotional status of the individual on pain perception and reaction. Included are factors such as personality, previous experiences, etc. and their role in pain. There is a general need for research on predisposing IV-26 factors which may lead to increases in pain responsivity in some in- dividuals. Recent research has shown that the brain has its own pain- suppressing systems and further research is needed on those psycho- logical factors and behaviors which result in either activation or suppression of such systems; e.g., manipulation of release of endor- phins. Cc. We recommend further research on the influence of the environment on pain perception and response. Research is needed on the impact of familial, cultural, economic, educational, and other psycho- social factors on pain responsivity in chronically ill patients. The extent to which different support systems influence the experience of pain, as well as the capacity to deal with it, should be studied. Research should be conducted on better training of primary care physicians and professional nurses and improvement of their attitudes towards the problem of refractory pain. Other factors to be considered include the role of the clinical setting, the paramedical professional and the patient's family in the development of a more comprehensive approach to patient needs. 4. Expanded experimental approaches to pain control a. We recommend the further study of integrated, comprehensive long-term approaches to the management of intractable or refractory pain and the relief of discomfort in chronically and terminally ill patients. One example of such an approach is the hospice method and we recommend study of the hospice approach and other comprehensive models of pain management to accurately gauge their long-term impact and to determine their essential elements. b. We recommend additional emphasis on preclinical studies applicable to the relief of pain and discomfort in the chronically and and terminally ill. Preclinical research is needed on the development of new chemotherapeutic agents as well as to determine optimum drug treatment and optimum delivery for existing potentially useful agents. For example, a variety of derivatives of morphine are available and the possible advantages of these derivatives over the parent compound should be assessed before initiation of extensive clinical trials. C. We recommend the development of improved guidelines for the design of clinical trials in the evaluation of new therapies. There should be expanded coordination between research groups during clinical trials so that maximum research benefits can be derived from adequate numbers of patients subjected to controlled clinical trials. There is a need for further research on the use of different combinations of pharmacological agents which not only produce pain relief but also improve "patient well-being". Previous studies usually have been limited to controlled studies of single agents such as narcotic analgesic or sedative-hynotic drugs. The use of combinations of pharmacological agents and nonpharmacological methods which provide analgesia and at the Iv-27 same time allow patients to maintain or increase their routine daily activities is worthy of careful examination in controlled clinical trials. d. We recommend further research on non-pharmacological therapies for pain and discomfort such as electrical stimulation of peripheral tissues or the central nervous system, and other forms of sensory modulation such as hypnosis, biofeedback, etc. These methods may provide patients an opportunity to control. their own pain by facilitating the activation of endogenous brain processes which suppress the transmission of pain signals, thereby reducing pain sensation and reaction. B. Mechanisms for Achieving these Research Goals 1. Interagency Participation and Coordination in Development and Funding of Research into Pain Control It is clear from the deliberations among members of this Subcommittee who represent markedly diverse agencies that there is an unwarranted compartmentalization of historical knowledge, current thinking, and perceived research needs in pain research. A formal interagency working group with access to an appropriate data base (see below) would serve an important role in coordinating pain research, identifying gap areas, and making recommendations for changes in funding and research emphasis. 2. National Conference on Pain and Discomfort and Humanitarian Care of the Chronically Ill. We propose that a national meeting be held on the "state of the art" in pain and pain control, treatment and care of the chronically and terminally ill, and improved training and education of health care professionals in these areas. 3. Information Transfer This Subcommittee has encountered difficulty in drawing up with any degree of confidence a complete and accurate listing of all federally-sponsored pain research. There is a clear need for a computer file of funded pain research projects. This file would list the in- stitution, the investigators, the research goals, and the level of funding of each project and would be critical to the planning activities of the proposed interagency working group. 4, Level of Funding A survey of NCI ($863,650), NIDA ($319,500), NIDR ($601,800), NIGMS ($205,100), NIMH ($309,200), and NINCDS ($231,900) for FY 1977 revealed an apparent total of $2,531,150 committed to pain ccntrol IV-28 research for a given year. We recognize the pitfalls in trying to put forth an exact dollar amount early on as a projection of research needs, but clearly $2.5 million is far from being enough. We would estimate that at least a ten-fold increase in funding over a five year period would be required to underwrite the broad requirements in the control of refractory pain. 5. Study Section There was universal agreement about and concern over the need for a study section, patterned after the NIH/ADAMHA model, composed of laboratory and clinical scientists with expertise in pain research ranging from neurobiological studies to behavioral studies to clinical trials of the comprehensive management of pain problems. In the absence of such a review body, the risk of misunderstanding and inappropriately rejecting innovative studies or clinical projects remains high. Pain is a major problem for the aged, the chronically ill, and the dying patient, and research into their problems has not really had a home in the review process. A study section attuned to these areas would be important to correcting these deficiencies. We recognize the difficulty in maintaininc let alone increasing the number of consulting committees in government agencies, but the urgent need for "quality control" of research in this area, as well as public accountability, outweighs the small increase in consultants this would represent. We are pleased that the Director, DRG, has agreed to the formation of an Ad-Hoc Study Section in this area until a regularly-constituted group can be established. 6. Funding Mechanisms a, Individual Research Grants = Traditionally this mechanism has supported basic research studies and we recommend that research applications in the area of pain be encouraged. b. Contracts - This mechanism can be used to stimulate coordinated clinical trials between different institutes or centers on new modalities for the relief of pain and discomfort. Cc. Program Project Grants - There are virtually no multi- disciplinary, integrated research programs in extramural institutions which are studying the control of pain in a comprehensive fashion. We recommend that program project grant applications be encouraged for the support of such research. d. Regional Pain Centers - We recommend the development and support of regional pain centers with expertise in pain research ranging from fundamental studies to clinical trials of the comprehensive manage- ment of pain. e. Demonstration Projects - Medical personnel do not receive adequate training in the control of refractory pain, especially in the IV-29 use of an holistic approach to patients. Funds should be earmarked for demonstration projects in this area as well as for training and educa- tion of health care practitioners. f. Intramural Research - Collaborative research on pain mechanisms and new modalities for the control of pain and discomfort should be encouraged. g. Collaborative Projects Between Federal Agencies - Research should be coordinated between agencies concerned with the problem of the management of pain and discomfort. h. Research Training - Further advances in this area require personnel trained in multidisciplinary approaches to the study of pain. We recommend training support of opportunities in order to recruit young researchers into this field. IV-30 8:00 9:00 9:30 10:15 10:45 11:00 11:30 12:00 12:45 2:15 2:45 3:15 CONSENSUS DEVELOPMENT CONFERENCE PROGRAM PAIN, DISCOMFORT, AND HUMANITARIAN CARE February 15-16, 1979 Clinical Center, Masur Auditorium National Institutes of Health Registration Opening Remarks Welcome Comments on the Interagency Committee on New Therapies for Pain and Discomfort Overview: Chronic Pain-A Serious National Health Problem Panel: Understanding Pain -- Anatomy and Physiology Pain Pathways Coffee Break Peripheral and Central Mechanisms Descending Control Mechanisms Discussion Lunch Panel: Understanding Pain -- Measurement and Pharmacology Pain Measurement in Man Neuropharmacology of Pain Coffee Break Iv-31 Dr. William E. Bunney, Jr. Dr. Donald S. Fredrickson Dr. Gerald L. Klerman Dr. Seymour Perry Dr. John Bonica Chairperson - Dr. William D. Willis Rapporteur - Dr. Richard E. Coggeshall Dr. Frederick W. L. Kerr Dr. Ronald Dubner Dr. David Mayer Chairperson - Dr. William Pollin Rapporteur - Dr. John D. Griffith Dr. Richard Gracely Dr. Agu Pert 3:30 Clinical Pharmacology (Opiates and Other Compounds) Dr. Raymond Houde Chairperson - Dr. Herbert Pardes Rapporteur - Dr. Glenn C. Davis Dr. Richard Black Dr. Glenn C. Davis Dr. Wilbert E. Fordyce Dr. John Loeser Chairperson - Dr. Diane Fink Rapporteur - Dr. Paul F. Engstrom Dr. Robert Butler Dr. Melvin J. Krant Dr. William Fischer Dr. Thomas West 4:00 Discussion a.m. Friday, February 16 Panel: Treating Pain -- Endogenous and Exogenous Pain Control Methods 8:30 The Clinical Syndrome of Chronic Pain 9:00 Pain and Psychiatric Disorders 9:30 A Behavioral Perspective on Chronic Pain 10:00 Coffee Break 10:15 Non-Pharmacological Approaches to Pain Relief (Hypnosis, Biofeedback, Placebo Effects) Dr. Martin Orne 10:45 Non-Pharmacological Approaches to Pain Relief (Neurosurgical relief of pain, Elec- rical Stimulation, Acupuncture) 11:15 Discussion 12:00 Lunch p.m Consensus Development Panel: Pain, Discomfort and Humanitarian Care -- A Perspective 1:15 Care of the Aged 1:45 Death and Dying 2:15 Hospice Approach to Terminal Illness 2:45 Management of Pain in the Terminally I11 3:15 Coffee Break IV-32 3:30 Pain and Well-Being: A Challenge for Biomedicine 4:00 Discussion and Consensus Development on the Management of Pain and Dis- comfort in the Terminally Ill 5:30 Adjournment PARTICIPANTS Richard G. Black, M.D. Co-Director Pain Treatment Center Associate Professor Anesthesiology Assistant Professor Neurological Surgery Blalock Building, Room 618 Johns Hopkins Hospital 601 North Broadway Baltimore, Maryland 21205 John J. Bonica, M.D., D.Sc. Director of Pain Center University of Washington Seattle, Washington 98195 Dr. William E. Bunney, Jr. Deputy Director of Clinical Research, DCBR National Institute of Mental Health Alcohol, Drub Abuse and Mental Health Administration Building 10, Room 3N212 Bethesda, Maryland 20014 Robert N. Butler, M.D. Director National Institute on Aging National Institutes of Health Building 31, Room 5C-02 Bethesda, Maryland 20014 Dr. Richard E. Coggeshall Department of Anatomy University of Texas Medical Branch Galveston, Texas 77550 Glenn Craig Davis, M.D. Chief Unit on Drug Abuse Biological Psychiatry Branch National Institute of Mental Health Building 10, Room 2N210 Bethesda, Maryland 20014 IV-33 Dr. Lorenze K.Y. Ng Participants (cont'd) Ronald Dubner, M.D. Chief, Neurobiology and Anesthesiology Branch National Institute of Dental Research National Institutes of Health Building 30, Room B-18 Bethesda, Maryland 20014 Paul F. Engstrom, M.D. Director, Department of Medicine American Oncologic Hospital Central and Shelmire Avenues Philadelphia, Pennsylvania 19111 Dr. Diane Fink Division of Cancer Control & Rehabilitation National Cancer Institute Blair Building, Room 732 8300 Colesville Road Silver Spring, Maryland 20910 William Fischer, M.D. Deputy Medical Director Hospice, Inc. 765 Prospect Street New Haven, Connecticut 06511 Dr. Wilbert E. Fordyce Department of Rehabilitation Medicine University of Washington Seattle, Washington 98915 Donald S. Fredrickson, M.D. Director National Institutes of Health Building 1, Room 124 Bethesda, Maryland 20014 Dr. Richard H. Gracely Research Psychologist Neurobiology and Anesthesiology Branch National Institute of Dental Research National Institutes of Health Building 10, Room 2B-07 Bethesda, Maryland 20014 John D. Griffith, M.D. Special Assistant to the Director Division of Research National Institute on Drug Abuse Parklawn Building, Room 9-36 5600 Fishers Lane Rockville, Maryland 20857 IV-34 Participants (cont'd) Raymond W. Houde, M.D. Attending Physician and Chief, Analgesic Studies Section Memorial Sloan Kettering Cancer Center 1275 York Avenue New York, New York 10021 Dr. Frederick Kerr Department of Neurological Surgery Medical Science Building Mayo Clinic 321 Third Avenue, S.E. Rochester, Minnesota 55901 Dr. Gerald L. Klerman Administrator Alcohol, Drug Abuse and Mental Health Administration Parklawn Building, Room 12-105 5600 Fishers Lane Rockville, Maryland 20857 Dr. Melvin J. Krant Professor of Medicine University of Massachusetts Medical Center 55 Lake Street Worcester, Massachusetts 01605 John D. Loeser, M.D. Associate Professor Department of Neurological Surgery University of Washington School of Medicine Seattle, Washington 98195 Dr. David J. Mayer Professor of Physiology Department of Physiology Medical College of Virginia Richmond, Virginia 23298 Dr. Lorenz K.Y. Ng Division of Research National Institute on Drug Abuse Building 10, Room 4N202 Bethesda, Maryland 20014 Martin T. Orne, M.D., Ph.D. Professor of Psychiatry University of Pennsylvania and Director, Unit for Experimental Psychiatry The Institute of Pennsylvania Hospital 111 North 49th Street Philadelphia, Pennsylvania 19139 Iv-35 Participants (cont'd) Dr. Herbert Pardes Director National Institute of Mental Health Parklawn Building, Room 1799 5600 Fishers Lane Rockville, Maryland 20852 Dr. Seymour Perry Associate Director for Medical Applications of Research Office of the Director National Institutes of Health Building 1, Room 216 Bethesda, Maryland 20014 Agu Pert, Ph.D. Psychologist Biological Psychiatry Branch National Institute of Mental Health Building 10, Room 2N315 Bethesda, Maryland 20014 William Pollin, M.D. Director, Division of Research National Institute on Drug Abuse Parklawn Building, Room 9-36 5600 Fishers Lane Rockville, Maryland 20857 Dr. Thomas West St. Christopher's Hospice 51-53 Lawrie Park Road Sydenham, London S.E. 26-6DZ England Dr. William D. Willis, Jr. Professor and Director Marine Biomedical Institute University of Texas Medical Branch Galveston, Texas 77550 IV-36 Organized under the Interagency Committee on New Therapies for Pain and Discomfort Sponsored by: National Institute of Mental Health, ADAMHA National Institute on Aging, NIH National Cancer Institute, NIH National Institute of Neurological and Communicative Disorders and Stroke, NIH National Institute of Dental Research, NIH National Institute on Drug Abuse, ADAMHA Bureau of Drugs, FDA Office for Medical Applications of Research, NIH Fogarty International Center, NIH Iv-37 REPORT OF CONFERENCE PAIN, DISCOMFORT, AND HUMANITARIAN CARE HELD AT THE NATIONAL INSTITUTES OF HEALTH FEBRUARY 15-16, 1979 The Conference on Pain, Discomfort, and Humanitarian Care was convened by the Interagency Committee on New Therapies for Pain and Discomfort, with the assistance of the NIH Office for Medical Applications of Research, the Fogarty International Center, and a number of institutes of the National Institutes of Health and the Alcohol, Drug Abuse, and Mental Health Administration. The Conference brought together scientists, physicians, health pro- fessionals of various disciplines, and the concerned public, to review the status of current knowledge about pain, its mechanism, diagnosis, and treat- ment. Particular focus was placed on developing recommendations for future research and treatment of pain and discomfort in the chronically ill, terminally ill, and the aged. On the first day of the meeting, Dr. John J. Bonica, President of the International Association for the Study of Pain and founder of the first multidisciplinary center for the treatment of chronic pain, opened the dis- cussion with a general overview of "Chronic Pain: A serious National Health Problem". The magnitude of disabling, chronic pain is summarized in the statistics presented by Dr. Bonica: e About 75 million Americans suffer from some kind of chronic pain; e Their disabilities result in the loss of approximately 700 million work days every year; e The cost in terms of lost production, medications (prescription and over-the-counter), doctors and hospitals, totals about 57 billion dollars every year; e Backaches alone afflict about 23 million Americans; e Arthritis claims about 28 million people in this country, costing about 15.1 billion dollars; e Severe headaches attack approximately 24 million Americans at a cost of 8.2 billion dollars; e Almost 400,000 people in the United States will die of cancer this year and most of them will endure intense pain before their deaths; eo Despite the magnitude and seriousness of chronic pain and dis- ability, the National Institutes of Health has allocated only about 0.02 percent of its annual budget to studies of the basic mechanism of pain. IV-38 Understanding Pain: Anatomy, Physiology and Pharmacology Following Dr. Bonica's overview, the Conference focused on important research findings concerning the anatomy and physiology of the neural path- ways responsible for the sensation of pain and its modulation. Also dis- cussed were the neuropharmacology of pain, the clinical pharmacology of analgesic drugs, and the problem of pain measurement in man. The panelists recommended the following areas as deserving of more intense scientific effort: (1) anatomy and physiology of pain transmission path- ways and to better understand the role of chemical transmitters involved in pain transmission and pain modulation; (2) functioning of the naturally occurring "analgesia systems" and the role that these can play in modifying transmission in the pain pathways. Of particular interest in this regard are the naturally occurring morphine-like substances, and the endorphins, which are thought to interact with opiate receptors in the brain. A better understanding of the mechanisms by which the endogenous pain- suppression systems can be activated could possibly lead to novel and more efficacious ways to manage chronic pain; (3) role and function of other non-opioid analgesic polypeptides since such understanding could provide a basis for the development of non-addicting analgesics; (4) non-opiate analgesics and new drug combinations, in the hope that such combinations may provide enhanced pain relief with a diminished addiction liability. Treating Pain: Endogenous and Exogenous Pain Control Methods This panel addressed itself to the treatment of pain, to the current state of knowledge on the efficacy of a variety of treatment modalities, and finally, to future research priorities. The differences between acute and chronic pain were emphasized and it was concluded that a concerted effort to study chronic pain, recognizing its special features, is of particular importance in order to provide more effective treatment. It was recognized that conceptions of pain are too narrow and that there is a need for better understanding of the various facets of pain and its treatment, including the pharmacological, non-pharmalogical, as well as behavioral. The current state of knowledge on the effects of hypnosis, suggestion, and placebo on pain appreciation was reviewed. It was concluded that there has been relatively little work on psychological factors affecting pain and emphasis was given to the need to develop multidisciplinary pain clinics with a programmatic approach to psychological research and scientific evaluation of efficacy. The role of acupuncture, nerve blocks, electrical stimulation, and neurosurgery in the treatment of chronic pain was reviewed. It was concluded that each of these interventions has an appropriate use in carefully selected patients. IV-39 Pain, Discomfort and Humanitarian Care: A Perspective The meeting concluded with a consensus development panel on the management of pain and discomfort in the terminally ill. This section included dis- cussion of care of the aged patient, death and dying, the hospice approach to terminal illness, and an exposition on the concept of wellness (as opposed to illness) and its implications for biomedicine and humanitarian care. The following statements highlight the conclusion of the panel: 1. Biomedical scientists recognize that compassion plus knowledge and technical skills are required to manage the aged person and the terminally ill patient. The physician with this humanitarian approach will be able to shift his emphasis from keeping the patient alive ("curing'") to allowing the patient to die with dignity ("caring"). The pain experienced by many persons afflicted with chronic or terminal illnesses is a multidimensional, hierarchical phenomenon that is influenced by somatosensory, affective, cognitive, social and behavioral factors. The treatment of this suffering requires an integrated approach exemplified by the hospice model which ad- dresses the patient's physical, mental, social, and spiritual needs. Important principles for the management of terminally ill patients including the following: a. Pain should be treated with continuous, long-acting, narcotic analgesics individually titrated to keep the patient in the therapeutic range. Subsequent doses of opiates may be depressed if appropriate adjuctive therapy is used, e.g. radiotherapy for bone metastases or nonsteroidal anti-inflammatory drugs for arthritis. b. Antinauseants, antibiotics, stool softeners, cortico-steroids, and antidepressants should be used as necessary for symptom management. Because many patients are dying at home, a contingency plan should be developed for medical emergencies to prevent in- appropriate hospital diagnostic studies and therapies. c. The patient and the family should be treated as a unit in order to lessen the loneliness, guilt, anger, and conflict that often accompany death. Several disciplines, in addition to the medical profession, contribute to the care of the dying patient; nurses, social workers, rehabilitation specialists, nutritionists, pharmacists, spiritual counselors, volunteer aids, and health administrators are important members of this health team. IV-40 The principles of the care of the aged and terminally ill are compatible with the goals of the existing health care system in the United States. In order to define an effective mechanism for delivering these services, the role of the traditional medical center, of the health care professional, and of society will have to be reassessed in light of the hospice model. Clinical research should be directed to the following problems: the epidemiology of aging and death in the United States, the mechanism, measurement and management of cancer pain; and the efficacy of bereavement counseling. Physicians and nurses need to be educated in chronic pain and cancer pain diagnosis and management. The curricula of medical and nursing schools should include factual material and clinical experience in pain management, the problems of the aged, and the care of the dying. 1Iv-41 IND PROCESS FOR SCHEDULE I DRUGS Introduction This Subcommittee was created in response to concern about poten- tial difficulties which investigators might encounter in obtaining Investigational New Drug licenses (INDs) to perform research with Schedule I drugs. Its immediate focus had been the study of heroin and tetrahydrocannabinol (THC) in cancer patients, but it recog- nized that many other research areas outside of oncology were potentially involved and should be considered. The representation on the Subcommittee of the agencies most imme- diately involved in IND development for these drugs (FDA, NIDA, and NIH) allowed the rapid exchange of information about the require- ments for Schedule I drug IND approval and about anticipating and correcting problems whereby applications might be delayed or disapproved. These deliberations in fact greatly accelerated the development of the Division of Cancer Treatment's INDs for heroin and THC and have resulted in a set of recommendations for other institutes which seek to become involved in research with these drugs: SUMMARY OF RECOMMENDATIONS A. Each institute should serve as a source of information about Schedule I drug research in its areas of scienti- fic responsibility and should relate as directly as possible to the DFA in developing INDs for a given research project. B. Institutions outside the NCI can obtain assistance from the Drug Development Program of the Division of Cancer Treatment, NCI, and from this Subcommittee in managing the details of IND submission. In some cases, it may be possible to cross-file on NCI's INDs. C. Institutes involved in Schedule I drug research should either directly utilize the NCI's drug distribution system or else model their own system after one in use at NCI. IV-42 Requests for clinical use of Schedule I drugs out- side of research protocols should be denied. Efforts should be made to accommodate such requests by refer- ring them to an ongoing study in an institution near the physician making the inquiry. II. Detailed Recommendations A. IND Development - There are many areas potentially relating to research with Schedule I drugs. Some examples include the use of heroin for terminal cancer patients; the use of THC for the control of refractory emesis in cancer chemother- apy patients; the use of THC for glaucoma; the use of THC for multiple sclerosis patients; the use of THC for epilepsy; and the possible use of THC in controlling bronchospasm. Since the background preclinical data, the drug dosage form, the scheduling and route of administration of the drug, and the type of research question being asked will vary signifi- cantly from one research program to the next, it is recommended that each institute relate directly to the Food and Drug Ad- ministration in obtaining IND's for Schedule I drug research in its areas of interest. For example, the National Eye Institute should be the focal point for disseminating infor- mation about ophthalmic research with these drugs to appro- priate researchers as to the state of the art, research oppor- tunities, availability of the drugs, and IND application alter- natives. Similarly, the National Institute of Neurological and Communicative Disorders and Stroke should play a similar role in neurologic research. It may be useful for the categorical institutes to collaborate with the Division of Cancer Treatment, NCI, which has had considerable experience in sponsoring the preclinical develop- ment and clinical testing of cancer chemotherapy drugs. The DCT has filed an IND for research in heroin for advanced can- cer patients, and it is in the process of preparing an IND for research in THC for emesis control during cancer chemo- therapy. To the extent that the research of other nstitutes can fit within this scope, it will be possible for them to cross—-file with the NCI's IND's. These other nstitutes are encouraged to consult directly with the FDA for additional advice and guidance in these matters. IV-43 B. The Subcommittee on the IND Process for Schedule I Drugs can also provide further assistance, and to this end, it is re- commended that in the future, the Subcommittee reconvene on an as-needed basis (as determined by any future problems which arise) and that its membership be broadened to include repre- sentatives from all the institutes involved in the development of INDs for Schedule I drugs. Drug Distribution - Where other institutes of the NIH develop research interests in Schedule I drugs, it is suggested that they consider a drug distribution system similar to the one used by the DCT, NCI, for the handling of experimental anti- cancer drugs (see below). In addition, once the Pharmaceutical Resources Branch, DCT, NCI, has developed a suitable formula- tion of any given drug, it may be possible to extend its drug distribution capability to research areas not directly under DCT's control. For example, the NIDA-sponsored study being conducted by Dr. Houde at Memorial Sloan-Kettering will re- ceive its heroin from the PRB, By the same token, it should be possible in the future for other institutes to work through the PRB in order to distribute these compounds to its inves- tigators (assuming that the volume of additional tasks does not interfere with its primary responsibility to the DCT's drug development program). As appropriate, funds can be trans- ferred to cover the cost of these operations. In brief, under the arrangement used by DCT, Group A drugs are those which are limited to DCT-supported Phase I and Phase IT studies. The DCT takes responsibility for approving, re- viewing, and monitoring these studies and for filing periodic reports with the FDA, Group B drugs are available for late Phase II (and beyond) studies by cancer cooperative group members (DCT grantees), DCT contractors, and, for certain drugs, cancer center affi- liated investigators. Again, the DCT is responsible to the FDA for the execution and the reporting of these studies, except that for certain drugs in later stages of development, cancer center directors are delegated the authority for pro- tocol approval and for the monitoring and reporting of the data from the trials of these agents (these reports go first to the DCT, then on to the FDA), In either case, the Pharma- ceutical Resources Branch of the DCT still handles the actual distribution of the compounds themselves, IV-44 Group C drugs are those with established indications. Had they been developed commercially, they would now be in their pre-NDA phase. They are available to qualified, registered investigators for use under FDA-approved guidelines. The investigators are required only to promptly report adverse drug reactions. Again, the PRB handles Group C drug distri- bution. 1. Heroin and THC - The FDA has concluded that heroin and THC should be placed into Group A and the limited distri- bution part of Group B during the initial phases of test- ing. It is committed to handling INDs for these drugs in a timely manner, and if promising data emerge as the studies progress, it will then consider authorizing their movement into the broader distribution plan under Group B. Individual Drug Requests - It is recommended that requests for use of these drugs outside of research protocols be denied. Physicians who are unwilling or unable to apply for research approval will be referred to institutions conducting studies in their geographic areas and/or they will receive information on alternative methods to deal with the medical conditions of the patient for whom they are seeking relief, It is also suggeste~ that each institute of NTH sponsoring research in Schedule I drugs identify for the full Committee an individual who can provide information and referral for inquiries in their areas of research interest, In this regard, the full Committee is developing ''state of the art' papers on heroin and THC which will be used to give advice and guidance to patients, practitioners, or investigators seeking information about Schedule I drugs, ITI, Additional Comments A. Formulation and Distribution of Heroin and THC for Cancer- Related Studies =~ At the present time, the Pharmaceutical Resources Branch and the Investigational Drug Branch of the DCT have respectively assumed the responsibility for the for- mulation and for the approval of the distribution of heroin for clinical trials of pain relief in cancer patients, The National Institute on Drug Abuse will continue to store and ship at NCI's request this formulation of heroin, and NIDA currently retains the responsibility for the distribution of THC. By common agreement, approval for new anti-emetic studies must come from NCI. The PRB is conducting research to obtain a more suitable formulation of THC, and it antici- pates that this project will require nine to twelve months for full development. At the end of this period, there is a strong possibility that the DCT will take over distribution control of THC from NIDA for research in emesis control. With regard IV-45 to Nabilone, a synthetic compound which is structurally related to THC, Eli Lilly & Company has been responsible for the develop- ment of this drug and is closely controlling its distribution and study. It should be pointed out that presently THC is in limited supply, and any future investigators will have to discuss well in advance with NIDA the prospects for obtaining the drug. IV-46 APPENDIX Commissioned Scientific Papers The Chemistry and Metabolism of the Cannabinoids - M.E. Wall Is There a Place for Heroin in the Symtomatic Support of Cancer Patients? - B.J. Lewis, V.T. DeVita Heroin, A Brief History of Its Control and A Review of Its Pharmacologic Actions - W.R. Martin Use of Cannabis Constituents and Homologs as Therapeutic Agents - L.E. Hollister Current Status of Pain Therapy - J.J. Bonica Supplementary Material to Report of Subcommittee on Terminal Illness: The Effects of Illness and Death of One Family Member and Other Family Members: A Review with Some Recommendations for Research and Medical Practice - S.C. Jacobs, A.M. Ostfeld The Ethics of Terminal Care - H. Y. Vanderpool Bibliography of Publications Related to Hospice Antimetic Research Working Group: Minutes of Meeting of March 22, 1979 INFORMATTONAL MATERIAL: Background and Description of the Interagency Committee Marijuana: Current Status Fact Sheet (Marijuana and Glaucoma) Heroin: Current Status Fact Sheet (heroin and tetrahydrocannibinol research for relief in pain and other discomforts) Nightingale, S.L., Perry, S.: Marijuana and Heroin by Prescrip- tion? Recent Developments at the State and Federal Levels. JAMA 241:373-375, 1979. Letters to state legislatures, medical societies, House and Senate Legislative Committees, and Council of State Govern- ments 75 83 96 110 115 157 159 163 172 175 178 180 182 185 188 The Chemistry and Metabolism of the Cannabinoids Monroe E. Wall Chemistry and Life Sciences Group, Research Triangle Institute Research Triangle Park, North Carolina 27709 INDEX Page I. INTRODUCTION . . . © © © vee eee 1 II. NOMENCLATURE OF CANNABINOIDS . . . . . . . . . . « « « . . . 2 III. NATURALLY OCCURRING CONSTITUENTS OF MARIHUANA . . . . . . . 5 IV. SYNTHESIS OF A’ -TETRAHYDROCANNABINOL Ce ee ee ee ee 8 A. Basic Synthetic Procedure . . . . . . . . . . . . . .. 8 B. Radiolabeled Synthesis of A°-THC PP V. METABOLISM OF 2% -TETRAHYDROCANNABINOL AND RELATED COMPOUNDS . . . © © « « « vv vv 4 et vv wv wo vo... 16 A. In Vitro Metabolism . . . . . . . . . . . . . . . .... 16 B. In Vivo Metabolism . . . . . . . . . . . . ....... 18 1. Comparison of Oral ys Intravenous Administration of A"-THC . . . . . . . . . . . . . . 25 2. Metabolism of A%-THC After Administration by Smoking . . . . . . . . . . . . . . 32 3. Extretion Patterns . . . . . . . . . . . . . . ... 36 (a) Urinary Excretion . . . . . . . . . . . . . . . 36 (b) Fecal Excretion . . . . . . . . . . . . .,. . . 37 4. Summary of A%-THC Metabolism in Man . . . . . . . . . 40 5. Metabolism of Other Cannabinoids in Man . . . . . . . 42 VI. ACTIVITY OF A%-THC METABOLITES AND RELATED CANNABINOIDS . . 43 VII. SYNTHETIC CANNABINOIDS . . . . . . . . . +. « « « « « « « . . 4&5 VIII. REFERENCES . . . . . . . . . . . . . . . +... .... 46 SUPPLEMENT - RTI Inventory of Cannabinoids and Metabolites ii 1 The Chemistry and Metabolism of the Cannabinoids Monroe E. Wall Chemistry and Life Sciences Group Research Triangle Institute Research Triangle Park, North Carolina 27709 I. INTRODUCTION The psychotomimetic activity of the variety of hemp known as Cannabis sativa has been known since antiquity. Various preparations of this plant under the names of marihuana, hashish, charas, dagga, and bhang are smoked or chewed by possibly two to three hundred million people. Accordingly, these materials undoubtedly constitute the most widely used group of illicit drugs. The chemistry of these Cannabis constituents, studied extensively during the 1940's by Todd and his colleagues and the late Roger Adams and his students, has been reviewed. ® However, real progress in the isolation, structural elucidation and synthesis of the various cannabinoids has come only in the last fifteen years, aided by the numerous modern separation methods, analytical techniques, and, most notably, by the development of nuclear magnetic resonance and mass spectrometry. Our knowledge of the metabolism of the cannabinoids is even more recent, ?> and took place only after the synthetic methodology was placed on a firm basis. In turn, as the knowledge of cannabinoid metabolites has increased, new targets have been given to the synthetic chemist, many of which have already been successfully attained. As a result, pharma- cologists, clinicians, and biochemists now have at their disposal a large number of pure cannabinoids, unlabeled, radiolabeled or heavy isotope- labeled, and the number is increasing rapidly. This review will attempt to present the somewhat synergistic manner in which chemistry and metabo- lism have been interwoven to contribute to recent progress. Of necessity, many of the studies cited will be from the author's point of view and are taken from the work of his laboratory. II. NOMENCLATURE OF CANNABINOIDS There are at least four different numbering systems which have been used in publications relating to cannabinoids. Two of the most common are shown in Figure 1. According to these, the major psychotomimetically active constifuent of marihuana would be called A°-mHC or Al-tetrahydro- cannabinol (a°- or Al-tHe). The A°- nomenclature is utilized in the system for numbering dibenzopyrane compounds and will be used throughout this review. This system is utilized by "Chemical Abstracts" and was adopted by the U. S. National Institute of Mental Health (now National Institute on Drug Abuse). The Al- system was introduced by Mechoulam and has certain general advantages when applied to a large variety of cannabinoids, some of which resemble monoterpenoids rather than dibenzo- pyranes. The dual nomenclature for other compounds which will be discussed extensively in this review are 11-hydroxy-A°-THC (7-hydroxy-AL-THC) and 11-nor-A’-THC-9- carboxylic acid (7-nor-Al-THC-1-carboxylic acid). The structure of A%-THC was established by spectroscopic measurements and chemical correlations.®’’ Its detailed conformational analysis. has been reported,’ and indicates that the cyclohexene ring A in the formula shown in Figure 2 exists in the half chair conformation. As a consequence, substituents at positions 7 and 8 can be regarded as axial or equatorial. In this review hydroxylated constituents are named according to the steroid system. Thus, 7a- and 2-tydrosy are axial; 7B- or 8a-hydroxy are equatorial constituents. 3 Figure 1 31 2 3 4 YF "CH, CH,CH,CH2CH3 Monoterpenoid Dibenzopyran III. NATURALLY OCCURRING CONSTITUENTS OF MARIHUANA Figure 3 shows a number of naturally occurring constituents which are found in marihuana. Of these, A%-THC, cannabidiol and cannabinol are the most important. A8-THC is probably not found per se in plant materials but is an artifact which is produced, in part, upon pyrolysis, since it is considerably more stable than the A%-analog. 7 isolated in pure form from a hexane hashish Gaoni and Mechoulam® extract the cannabinoids (with the exception of 28-THC) shown in Figure 3. Mechoulam et a1.’ showed that A%-THC was the only constituent of the mixture responsible for the psychotomimetic activity observed in the entire mixture. In 1969, under a contract with the Center for Studies of Narcotic and Drug Abuse (now NIDA), Wall and his coworkers at RTI prepared the first A%-THC concentrates of known analysis for distribution to research groups. These products were prepared by molecular distilla- tion or chromatography of hexane extracts. 1? The products contained 20- 30% A%-THC plus other cannabinoids. Their use has largely been superseded by pure, synthetic products which will be discussed subsequently. The major cannabinoids occur naturally as the o- or p-carboxylic derivatives on the THC aromatic ring. These carboxylic acid derivatives are quite unstable to heat, and will slowly decarboxylate at room tempera- ture. However, they can be differentiated by gas-liquid chromatography (gle). 1 The methodology is illustrated in Figure 4. As can be seen, glc of the underivatized marihuana plant extracts shows no signs of any carboxylic acid constituent. However, if the total cannabinoids are converted to the corresponding trimethylsilyl (tms) derivatives, the corresponding carboxylic acid tms ethers are now stable and can be readily shown to be present by glc analysis. From a practical view, 6 Figure 3 CsH11 ® L 1 | HO CsHi me” >So Me Me Cannabidiol Cannabinol CsHis Me OH Me 0 CsH11 N HO 0 AN HO CsH; 1 ---Me OH Me Me Me Me Me Me Cannabigerol Cannabichromene Cannabicyclol Solvent | Solvent A —THC A B Internal Standard A°—THC Acid-TMS A°—THC-TMS Cannabidiol Cannabinol u SUM Le oovoao boyy a boa boyy a bag 0 5 10 15 20 25 0 5 10 15 20 TIME (MIN) TIME (MIN) Figure 4 8 however, the underivatized carboxylic THC analogs are so unstable to heat that, when pyrolyzed by smoking marihuana, the acids are quantita- tively converted by decarboxylation to the parent compounds. The develop- ment of accurate glc procedures has permitted the facile assessment of the composition of various types of cannabinoid preparations. There seem to be two major types of Cannabis varieties. One form which is exemplified by the type found in Mexico has A%-THC as the pre- dominant constituent. On the other hand, Cannabis obtained from Turkey and the Near East in general usually has cannabidiol as the major con- stituent. As another point of interest, compounds analogous to A°-THC, cannabinol, and cannabidiol but with a propyl instead of an amyl side- chain have recently been found in samples of Pakistani and Nepalese hashish. 1? In the Nepalese hashish this was a major constituent. Propyl-A’-THC is also biologically active. IV. SYNTHESIS OF A’ -TETRAHYDROCANNABINOL A. Basic Synthetic Procedure Mechoulam™ has made an excellent review of synthetic methods. In this section we will review only methodology of particular importance to the theme of the review. Although various syntheses had been reported previously, the major breakthroughs in this area came in 1967, from the pioneering work of Mechoulam.® This involved the condensation of a pinene derative, (-)-verbenol, with olivetol in the presence of p- toluenesulfonic acid to give an intermediate which could then be further converted to A8-THC as shown in Figure 5. By addition of the elements of hydrochloric acid across the double bond, followed by dehydrochlorina- tion, A°-THC could be produced. Almost simultaneously Petrzilka and 13,14 coworkers published a method which, with modifications, has become OH CsH1n C—O J — “ ) OH H OH cis-Verbenol Cl OH Figure 5 10 the basis for most of the current synthesis of unlabeled A%-THC. This method is shown in Figure 6 in a slightly improved and modified foe %_THC. The procedure suitable for the synthesis of tritium-labeled A utilized the readily available mentha-2,8-diene-1-ol. In the presence of weak acids, cannabidiol can be obtained directly from this reaction, but with strong acids, such as p-toluenesulfonic or trifluoroacetic acid, A8-THC is obtained. These compounds are never obtained pure but usually can be purified by chromatography on adsorbents such as florosil or by high pressure liquid chromatography. Normally the purified A8-THC can be treated in the original Petrzilka method with HCl and then dehydro- chlorinated with potassium tert-amylate. Although Petrzilka claimed that the final reaction proceeds in very high yield, a number of impuri- ties have been shown to be present by glc. These require a careful and laborious chromatography. This procedure with some modifications can be used to synthesize A%-THC on a kilogram scale. A more recent procedure in which olivetol is condensed with mentha- 2,8-diene-1-ol in the presence of boron trifluoride and magnesium sulfate gives a A°-THC directly. l® Although there are other by-products, the crude A°-THC can be readily purified on a small scale. If the procedure is applicable to a large scale, it could replace the previously published methodology. B. Radiolabeled Synthesis of A%-THC The above procedures are not applicable to the preparation of tritium-labeled cannabinoids of high specific activity. For certain purposes, particularly studies involving possible receptor sites, it is absolutely required that the radiolabeled compound be carrier free. Under these circumstances, methods of a different nature are required, Me OH OH he HO CsH1q Me Me OH OH OH HCI R3COK —————— — LiCl ! me” >No CsH1q me >No CsH1q ve” >No CsH1q Me Me Me A8_THC A°—THC Tritium-labeled Tritium-labeled Figure 6 Ll 12 in which the label is in the sidechain. Gill and Jones published one of the earliest of these procedures in which the tritium label was located in the 1',2'-position of the sidechain of olivetol, followed by standard condensation of this compound with p-menthadienone to give radiolabeled A8-mHc of rather high specific activity.l’ The method is shown in Figure 7. There are some drawbacks to the procedure. The location of the tritium in the 1'-position places the radiolabel on a benzylic carbon which means that it may be readily exchangeable. Moreover, the highly radioactive intermediate must go through more steps ,prior to conversion to A8- or A°-THC. Pitt and coworkers have described a method by which a 4',5'-unsaturated analog of olivetol is preparedl® (see Figure 8). The unsaturated olivetol analog is converted in the usual manner to the corresponding 28- or A’-4',5" -unsaturated analog. Radio- activity is introduced by tritiation over a homogenous rhodium catalyst. The procedure produces carrier free A8- or A°-THC. The latter compound is unstable and must be used soon after preparation. In some cases it may be desirable or necessary to use 140 1abeled THC for certain studies, particularly if a metabolic site is involved. Pitt et a1.1® developed a procedure, outlined in Figure 9, for the synthesis of Yao a9 The, labeled at carbon -11. Other methods utilize the synthesis of 140 labeled olivetol, followed by the conversion of this compound to 28 or A2-14¢ labeled THC via condensation with the menthadienol in the standard manner. Pitt's procedure involves conversion 9(11) of A8-mHc to the corresponding A -THC benzyl ether, which is oxidized to give the 9-ketone, and converted to the 140 1abeled INAS -THC benzyl ether or acetate by reaction with the labeled Wittig reagent. Halogena- tion followed by dehydrohalogenation in the standard manner gives Lao. labeled-A’-THC. Oo OH NaBH4 _NaHS04 COC4Hy —m— CsHy C3H7 MeO MeO H HQ ~ __BBrs TCH.Chb CzH CH HO T HO + OH OR | . ch ro HZ / ~N HO A8—THC MeO To, _T2,CeFs 10% Pd/C Pd/C Figure 7 14 Figure 8 OMe OMe 61% + @3P = CH{CH}0Ph —2 2°, MeO CHO MeO CH = CH{CH,)»0Ph 100% | H,Pd OH BBs “100% HO (CH2)5—Br 36% (CH2)50Ph 100% T2/(Ph3P)3RhCI io Me *CH, OCH2Ph CsH1 >90% * CH, = PPh; OCH,Ph 70% CsH11 156 Figure 9 PhCH2Br eee DMF 100% a. HCI b. R3COK CH» OCH2Ph KMnOg4 A — NalO4 ' Me —80% A%1 THC benzyl ether *Me OH HCI/ZnCl; —— R3CO® O | Me A? —THC 16 V. METABOLISM OF A’ -TETRAHYDROCANNABINOL AND RELATED COMPOUNDS A. In Vitro Metabolism The availability of pure, unlabeled and radiolabeled cannabinoid substrates permitted, for the first time, valid metabolic and pharmaco- logical studies. Almost simultaneously, Israeli,’ Swedish?’ and American groupe) studied the in vitro metabolism of A8- and A%-THC. Mechoulam et a1.1? found that 11-hydroxy-AS-THe was the major product of the metabolism of 28-THe by a rabbit liver microsomal preparation. Agurell, et a. and Wall, et a1.%! found that similarly, 11-hydroxy-A°-THC was the major product of metabolism of A’-THC by a rat liver microsomal preparation. wa11%! also found that 8a-,ll-dihydroxy- and 8B,11-dihy- droxy-A°-THC were metabolic products; From similar metabolic studies with A8-Hc, Wa1122 reported isolation of ll-hydroxy-, 7a,ll-dihydroxy- and 7B,11-dihydroxy-A -THC. Wa1122 also reported isolation of 8fB- hydroxy-A’-THC from in vitro metabolism of A’-THC by a rabbit liver microsomal preparation. The above studies were the basis of the con- clusion by Wall that microsomal hydroxylation of A8- or A%-THC proceeds largely by a route involving allylic hydroxylation? with respect to the double bond. Working with cannabinol, Wa1122 reported for the first time hydroxylation at the 2'-position in the sidechain. The study involved the utilization of combined gas-liquid chromatography-mass spectrometry (glc-ms). Subsequently Agurell, et a1.23 and Wall and Brine? have shown that under in vitro conditions, hydroxylation at all the other sites on the sidechain occur. Usually such compounds are minor products, but under some special conditions, e.g., in vitro dog 23 lung perfusion, 3'- and 4" -hydroxy-A2-THC become major metabolites. The various sites of hydroxylation are shown in Figure 10 and the 17 Figure 10 Hydroxylation Sites of Cannabinoids Observed /n Vitro or In Vivo 1" 2 3 4 % CH2CH2CH2CHLCH3 IN J vv A — Hydroxylation at 11 position observed /n vitro and in vivo singly or in combination with hydroxylation in other positions. Oxidation to carboxyl also frequently observed. —— Hydroxylation at 8 position found only in A—THC series, 8a or 843 both found as minor metabolites, 8,11-dihydroxy metabolites frequently observed. —— 7a, 73 or 7,11-Dihydroxy found only in A8— series. Hydroxylation at 1",2",3" ,4’ occasionally found, also as 1,11; 2’ ,11—etc. dihydroxy metabolites. 18 structures of major metabolites in Figure 10A. There is little doubt that the products of microsomal hydroxylation can vary with the canna- binoid substrate. The species, the organ (usually liver or lung), experimental conditions (use of organ homogenates, microsomal prepa- rations, or organ perfusion), are all important factors. For further details of this interesting subject the reader is referred to the reviews by Agure1123 and wa1l.2 The cannabinoid ll-nor acids (cf., Figures 10 and 10A) are observed at times under in vitro metabolic conditions and always (especially in urine) under in vivo conditions. Further discussion of these acids will be found in the following section. B. In Vivo Metabolism Since this review is being prepared as part of a study to assess the potentialities of A%-THC as a possible therapeutic agent in man, we will restrict this section largely to human metabolism of A%-THC and re- lated compounds. The monograph edited by Braude and Szara®d covers the area thoroughly up to 1974. Initial studies in man were conducted by Lemberger and coworkers during 1970-1971.292"C They found that A°-THC was rapidly metabolized and converted to more polar substances. The methodology and standards were not available at this time to permit accurate quantitative studies. Subsequently extensive studies on the metabolism of A’-THC and related compounds in man have been conducted utilizing more rigid chemical techniques by Wall and his clinical col- league, Perez-Reyes. After administration of A%-THC orally to human volunteers, Wall et a1.?’ identified in plasma, using glc-ms techniques, in addition to the parent compound, the following metabolites: 8a- and 19 Figure 10A C OH 0 CsH11 11 —Hydroxy —A°—THC (a) 8a —Hydroxy—A®—THC R=0H; Ry =H (b) 83—Hydroxy—A%—THC R =H; Ri = OH CsH11 CH,OH COOH “TC OH ® OH 0 CsHy4 Oo CsH11 (a) 8a,11—Dihydroxy—A°—THC 11 —nor—A%3—THC —9— carboxylic acid R=0H; Ri =H (b) 883,11 —Dihydroxy —A°—THC R =H; Ry = OH 20 8B-hydroxy-A°-THC, 11-hydroxy-A°-THC, and 8a,11- and 8B-11-dihydroxy-A°- 24,28 showed that the acidic metabolite THC. Subsequently Wall and Brine 11-nor-A-THC-9-carboxylic acid could be found after in vitro metabolism and in urine, feces, and plasma after in vivo metabolism in man. Between 1972-1973 pure non-labeled and labeled A%-THC and metabolites prepared synthetically were made increasingly generally available under contract programs sponsored by NIDA. As a consequence, Wall, Perez-Reyes and coworkers were able to study in detail the metabolism of A°-THC and related compounds in man, 2830 by oral, intravenous and smoking routes. Charts 1, 2 and 3 outline the methods employed by Wall and coworkers for extraction and analysis of A°-THC in plasma, urine, and feces, respec- tively. The basic feature of the procedure involves the administration of tritium labeled A%-THC, ether extraction and separation of ether soluble cannabinoids into neutral and acidic fractions, and separation by thin layer chromatography (tlc) of A%-THC and its metabolites, cf. Figure 11A and B. Subsequently, the tlc plate is cut into appropriate zones with the assistance of reference compounds (cf. Fig. 11), and the radiolabeled cannabinoid in the zones determined by scintillation count- ing. Conjugated material (present only in urine in significant quantity) is determined by enzymatic hydrolysis followed by extraction and standard analysis. The procedure has been validated by comparing the radiolabeled techniques with the more rigorous quantitative glc-ms techniques for A°- THC, 11-hydroxy-A°-THC and 11-nor-A’-THC-9- carboxylic acid. 31-33 More- over, cannabinol, which would have the same retention time as A%-THC 21 Chart 1 Standard Analysis of Plasma Sample Example of 3 ml Plasma Plasma (3 ml) of acetone. Sonicate 30 min. protein pellet. Rinse pellet with 30 described above. to leave water. Add slowly while sonicating 30 ml Centrifuge. Decant acetone from ml acetone as Combine acetone. Evaporate in vacuo Acetone-Water Fraction Protein Pellet Adjust volume to 3 ml H20 and pH to 3. Add 12 ml diethyl ether containing 1.5% isoamyl alcohol. Vortex 1 hour. Centrifuge. Remove ether. Repeat extraction as above and combine ether extracts. Ether Extract H20 Fraction Very few counts Extract 1 x with an equal volume of 0.1N NaOH. Very few counts Ether extract, Neutral Compounds NaOH extract Concentrate. Run on tlc plates in t-BuOH/CHClj3 (5:95). Scrape plates; count samples in liquid scintillation counter. Data in 2 Dose/Liter plasma for each tlc zone. , acids Adjust pH to 3. Extract 2x with an equal volume of ether. Ether extract, acids Concentrate. Run on tlc plate in acetone/CHCl3 (7:3) Scrape plate and count samples in liquid scintillation counter. Data in X Dose/Liter plasma for each acid zone Aqueous fraction Very few counts 22 Chart 2 Standard Analysis of Urine Samples Urine Chromatograph on Amberlite XAD-2 column. 1. Wash with water. 2. Rinse off cannabinoids with MeOH. MeOH Fraction Evaporate MeOH to leave H20. Adjust pH to 3. Extract with equal volume of ether. Repeat extraction. Ether extract - Free compounds Water Fraction - Conjugates Apply aliquot to tlc plate Incubate with Helix Run in acetone/CHC13 (7:3) pomatia enzyme. Scrape plate in zones and Chromatograph on count in liquid scintillation Amberlite XAD-2 counter. column as above. Data in % dose/total sample in each acid zone. MeOH Fraction Evaporate MeOH to leave H20. Adjust pH to 3. Extract with an equal volume of ether. Repeat. Ether extract Water Fraction Extract 2x with an equal volume of 0.1N NaOH. Ether extract, Neutral Compounds NaOH Fraction Use aliquot to run tlc in Adjust pH to 3. t-BuOH/CHC13 (5:95). Extract with an Scrape plate; count equal volume of samples ether. Repeat. Data in X Dose in urine sample/tlc zone. Ether extract, acids Water Fraction Use aliquot to run tlc in acetone/CHC1l3 (8:2). Scrape plate; count samples. Data in X Dose in urine sample in each acid zone. 23 Chart 3 Standard Analysis of Feces Samples Thawed Feces S le 1. Heat on steam bath for 30 min with 150 ml methanol. 2. Shake for 5 minutes, centrifuge, and filter the supernatant. Repeat twice. Co] Methanol extract Residue 1. Evaporate methanol to leave water. Make up to 400 ml with distilled water. Adjust pH to 3. 2. Shake for 30 minutes with 400 ml ether. Repeat. Ether extract, Free Compounds Aqueous Fraction, Conjugates Few Counts Evaporate to 100 ml. Extract 2x with an equal volume of 0.1N NaOH. Ether extract, Neutral Compounds NaOH Fraction Run on tlc plate in t-BuOH/CHC13 (5:95) Adjust pH to 3. Scrape plate and count samples. Extract 2x with an equal volume of Data in 2 dose in feces sample ether. in each tlc zone Cl Ether Bheract Acids Aqueous Fraction Run on tlc plate in acetone/CHCl3 (8:2). Scrape plate and count samples. Data in % dose in feces sample in each acid zone. 24 Figure 11 Sovent i Soweto 7 Front A Front B @ 1°—-THC 11— COOH — A°—THC 11— COOH, © 83—OH— ’ £_ OH— A9—THC A°—THC 8a—OH— ®e A°—THC ®11—0OH— A®—THC 83, 11-diOH— § “Coo BN / A? —THC THC 8a 11-diOH— . 8.~ THC - Polar acids Origin Origin Acidic Cannabinoids Neutral cannabinoids ; Solvent: tBuOH—CHCI3 (5:95) Solvent: Acetone/CHCIs3 (8:2) 25 on tlc plates, has been shown by glc-ms to be absent in human plasma Lo . 9 32 after administration of A”-THC. Because of the current interest in the potential therapeutic uses of A%-THC and analogs, we will present in considerable detail our data (some of which is unpublished) on the effects of oral, intravenous, and smoking administration of A°-THC and related cannabinoids on plasma levels and urinary and fecal excretion in human volunteers. 1. Comparison of Oral vs Intravenous Administration of A°-THC For the oral studies, the protocol adopted involved administration of 20 mg of A%-THC in sesame oil. Each subject was administered 2 gelatin capsules containing a total of 20 mg of A%-THC which included 150 microcuries of tritium labeled A%-THC. Blood, urine and feces samples were collected at appropriate time intervals. Subjects rated their degree of psychological "high" on a graphic form. Blood pressure and heart rate were monitored. Six subjects were studied and individual data obtained. The data presented in this report will be the average values found. The method utilized for intravenous administration has been reported in detail by Perez-Reyes, Wall et a1.3% Using a commercially available human serum albumin preparation, 4-5 mg of A%-THC can be administered as a microsuspension by an infusion pump. In most cases infusion was completed in 20-25 minutes. This procedure was adopted for the protection of human volunteers so that the IV administration could be interrupted and/or terminated at any time if adverse effects were noted. Biological samples were collected and physiological measurements conducted as described under the oral studies. A total of 7 subjects were used in these studies and average values will be reported. 26 Figure 12 presents the results for the subjective effects and total, free, and conjugated cannabinoids after oral administration of 20 mg of A%-THC. Figure 13 presents comparable data for the intravenous studies. After oral adminstration, as is noted in Figure 12, there is a remarkable agreement between the plot of subjective psychological effects vs. time and the similar plot for the total cannabinoids. The subjective "high" of volunteers receiving A%-THC by the oral route slowly increased from 30 minutes after administration through 120 minutes. The degree of subjective "high' reached maximal values at about 150-180, minutes after administration. Although the total cannabinoids began to decrease 6 hours after administration, subjects still reported feeling quite "high at this time. The subjects had normal responses 24 hours after admin- istration. It will also be noted from Figure 12 that almost all the cannabinoid in the plasma is found in the free form, conjugates consti- tuting less than 10% of the total. Turning next to inspection of Figure 13 which gives similar data for intravenous administration, results quite similar to the oral data are shown, although the time frame is different. Maximal subjective effects were noted within 30-50 minutes after IV infusion. Total canna- binoids peaked at 30 minutes, and then decreased slowly through a 90 minute period. Values for total cannabinoids decreased at 6 hours and then fell sharply during the 24, 48, and 72 hours periods. It will be noted that the volunteers still indicated some degree of "high" at 6 hours, although by this time the level of cannabinoid in the blood would scarcely have been responsible. As in the case of the oral administration, free cannabinoids constitute by far the major fraction, conjugates being relatively minor. 27 Figure 12 Subjective Effects and Total Free and Conjugated Cannabinoids After Oral Administration of 20 mg of A°>—THC A o—0 Subjective Psychological — Effects wl << 3 ~ S oO n O—0 Total OE O0—oO Free Q o GQ 2} v—=¥ Conjugated D0Ww oT LL ow n> 1 wn a { 20 1.0 < i = i wn << | — oa o | Lu = = 01} TT | wn oO | a | © _ 0.01 L 1 1 Lp l la 30 60 90 120 150 180 3620 MINUTES SUBJECTIVE PSYCHOLOGICAL % DOSE/LITER PLASMA EFFECTS 28 Figure 13 Subjective Effects and Total Free and Conjugated Cannabinoids Found in Plasma After Intravenous Administration of A°—THC +4 +3 +2 +1 0 -1 2.0 1.0 .01 A 0——0 Subjective Psychological — Effects Y O0—O Free ' v+—= Conjugated — O—qa Total i v v 1 rFrrrirg I v doo be bo by se a1 7 / = 20 40 60 80 360 2880 TIME IN MINUTES 29 The individual metabolites found after oral administration of 2- THC are shown in Table 1. Approximately equal quantities of A%-THC and its 1ll-hydroxy metabolite were found at virtually all time periods. Maximal levels (6-8 ng/ml) of both the parent drug and its active metabolite were found 2-3 hours after administration and remained at the same levels up to 6 hours after administration. The ll-nor acid and the polar acids were the major constitutents of the plasma. Levels of the order of 65-70 nanograms/ml were found for each of these groups for considerable time periods. The continuous production of 11-hydroxy-A°- THC under oral administration and the finding of comparable levels of the parent drug indicate that A%-THC was being well absorbed under our experimental conditions over a long time period. As we will show subse- quently, intestinal absorption was excellent. Relatively small amounts of A%-THC were found in the feces, although major quantities of the other metabolites were noted. Comparable data for the individual metabolites found after intravenous administration are shown in Table 2. Comparison of these two tables show some major differences as well as certain similarities. Peak values after intravenous administration reached levels of the order of 60 nanograms/ml of A%-THC in 30 minutes. The active metabolite, 11- hydroxy-A°-THC, was only about 1/20th of this level at this time period and remained low at all time periods in marked contrast to the results found for oral administration. Following cessation of infusion, the levels of A%-THC fell rapidly. However, as noted earlier the subjects indicated positive subjective effects at 90 minutes after administration at which time the level of IN was only around 9 ng/ml. The major Table 1 a2-tHC and Its Metabolites Found in Human Plasma Following Oral Administration of 20 mg 2%-Te ng/ml plasma + S.E. found as Intermediate Time Polar Polarity 11-GOOH- Polar DIZOH- 1]1-OH- 9 (min) Acids Acids A” -THC Neutrals A” -THC A” -THC A” -THC 45 7.7 + 5.1 1.1 + 0.3 5.7 + 4.4 0.35 + 0.07 0.53 + 0.21 0.99 + 0.48 0.81 + 0.45 60 17 + 10 2.5 + 1.4 14+ 9 2.3 + 1.2 2.0 + 0.9 3.4 + 1.6 3.8 + 2.9 75 24 + 8 2.2 + 1.1 22 + 11 3.4 + 1.9 2.4 + 1.2 3.7 + 1.7 4.7 + 3.4 90 37+ 11 3.7 + 1.5 30+ 10 5.1 + 2.1 3.8 + 1.0 4.7 + 1.5 5.7 + 3.5 105 46 + 10 7.9 + 2.7 41 + 14 5.5 + 1.6 5.3 + 0.6 5.8 + 1.7 4.9 + 2.6 120 64 + 16 8.5 + 3.6 54 + 18 7.3 + 3.1 6.0 + .5 7.2 + 1.8 4.3 + .6 135 66 + 13 8.6 + 1.4 49 + 6 9.1 + 1.8 6.6 + 1.1 8.3 + 1.3 7.9 + 3.6 150 69 + 10 9.4 + 2.4 64 + 13 8.0 + 1.0 6.8 + 1.4 8.4 + 2.1 6.6 + 3.5 165 70 + 14 10+ 2 65 + 16 7.4 + 2.1 7.3 + 1.2 8.3 + 2.0 6.4 + 3.8 180 62 + 7 9.6 + 1.6 62 + 17 5.4 + 0.7 6.7 + 1.4 8.5 + 2.0 7.1 + 4.9 360 50 + 18 10+ 3 46 + 11 13 + 2 8.9 + 2.0 8.8 + 1.7 9.3 + 3.5 1440 12+ 3 3.2 + 1.9 21+ 8 3.7 + 0.8 1.8 + 1.0 1.1 + .5 1.3 + .4 0€ Table 2 31 4 o ON TTON |S] . eo eo oo oo oo & OCMANNMITNHMe~OOOO~O os +o HHH HHH HHH HH HH << ~N Cuno s eM MM rd N rd \O MN TON oo oo o OCMITNWOOMMmMHO®IT NNN 1 Dally TOOWN® & Cram MNNNOH~OO . « oo eo eo 28 Coco 0cCO0O0O000CO0000 SE HoH HHH HH HHH HHH HHH Zon ™ OO MN 1 HNO AORNMNSNINONMDO ONT QQ eo © eo © © @ © © © © eo © eo oo oo @© COmMmmMNmrmee~e~O00O -THC 8a-hydroxy- A9 Aas ~S nO CWVWOVOVOVWOITNTM cecoocaNmaNoOcoOCcO~OoOooOOo Ccoocococococococococooooo +H HHH HH HHH HHH HH 4H ~N OTTO AMANO WVNDOM™~MN~NN OCANMAONOMMNS OND OOM er ee coccoocMoocococoooGooo pstatronzi mi wn \O Wn TN EHANINOMMANNN-OOOCO coocococococococooooo00O +o FH HHH HH HF HF H+ ~ © ~N ON KN m“RANMMOVIOIONOIOMNNN COMNNMANNMMMRROOOO nanograms * S.E./ml plasma, Free Fraction A2-THC and Metabolites Found in the Plasma, Free Fraction A9-THC nv 3 0 SEmNo®NANNINNT NN Ccococo~NOO0O0O0O0OO0O0 HoH HHH HHH FD HH HH H+ ydroxy [11-carboxy- 11-dih A9-THC 8, MAO TO oo NF oN cCcocoHwHNNNNMAHOOCO coocococococococoocoo0o0OoO +H HHH HH HH HH HHH HH @ Mw I~ © nO Ov 8M8h%oo~ao0~0BS]R CSS CCN HOHHHO000 Neutral Polar Fraction em COCO mMANNMHMMHANGOGO +H HH HHH HHH HH HH + I) . Wn TNO oe eo oo oo wd . HONITIITIITIO oo Ori NTO rd rd rd rd ed rd vd ef Time (min) ocwnounong ~ = ON ON 32 constituents which reached peak levels at 30-50 minutes after adminis- tration were the two acid fractions, the ll-nor- acid and the so-called polar acids. It will be noted that the production of ll-nor acids and polar acids occurred almost immediately after the administration. There is little doubt that both ll-nor and the polar acids are derived from 11-hydroxy-A°-THC, but as we will show later, the polar acids are probably are not derived from the ll-nor (ll-carboxy) acids. 2. Metabolism of A°-THC After Administration by Smoking In the smoking studies standard Mexican marihuana was extracted with a solvent so as to remove all the cannabinoids. The placebo marihuana was then mixed with a suitable quantity of cold and tritium labeled A%-HC so that the final preparation contained between 10-20 mg of 2% -THe containing 150-200 microcuries of tritium label. Studies in the writer's laboratory have shown that experienced smokers will receive by inhalation approximately 40% of the A%-THC in the original marihuana. In the smoking studies, A%-THC was administered in two ways; one by means of smoking labeled marihuana with a water pipe, the other by preparing ''reefers" from the radiolabeled marihuana described above and then smoking the labeled product. Figure 14 contains a great deal of information. It compares the metabolism of A%-THC administered intra- venously (14A) with that of the A°-THC metabolite, 11-hydroxy-A°-THC, also administered intravenously (14B). Figure also 14 presents data obtained after smoking the radiolabeled A%-THC in a water pipe (14C). The data in Figure 14A and C, which are presented in terms of the per- cent dose/liter plasma found at various time intervals, are quite similar. It will be noted that after smoking, A’-HC levels dropped rapidly after an early increase. As stated previously, after IV administration of % DOSE/LITER PLASMA 2.0 1.0 0.10 0.01 0.10 | 1.0 0.10 33 Figure 14 Metabolism of A—THC and 11—OH—A°—THC by Human Subjects ™ I £3 TT TTT 77 ts, Lider gy 10 3050 70 90 8 24 48 72 MINUTES HOURS A.—Metabolism of A°—THC, i.v. O-—=—-0 A°—THC Bevin 4 11—COOH—A°—THC &——@ Polar Acids &—-4A 11—0OH—-A°—-THC B. —Metabolism of 11—OH—A°—THC, i.v. O-——=0 11—0OH—A°—THC 11—COOH—A°—~THC &——@ Polar Acids C. — Metabolism of A®—THC, smoking O-——-0 A°—THC Le 11—COOH—AS—THC ———@ Polar Acids 34 A%-THe, 11-hydroxy-A°-THC was a minor component (14A). Although not shown in 14C, the data for 11-hydroxy-A°-THC was obtained in the smoking study and follows the same pattern as the intravenous studies, i.e., 11- hydroxy is definitely a very minor component after smoking. The major metabolites found after smoking A%-THC were the ll-nor and and the polar acids whose precise chemical constitution is as yet unknown. Interest- ingly enough, when 11-hydroxy-A’-THC was administered intravenously (Fig. 14B) we see a similar pattern. The ll-nor acid and the polar acid fraction are the major metabolites produced from the parent compound which in turn is undoubtedly a primary metabolite of A°-THC The metabolism of A%-THC was also studied by the more common pro- cedure of inhaling smoke from reefers. The reefers were prepared from extracted marihuana mixed with A%-THC in such proportions that each reefer contained 17 mg of A%-THC and 160 pC of tritium label. About 40% or 6.8 mg was actually inhaled in the smoke, the remainder being lost mainly by pyrolysis. Figure 15 presents the results. The findings here are most interesting. As can be noted, A%-THC levels dropped rapidly after smoking. As found in the oral, intravenous, and water pipe smoking studies, the polar acids and 11-nor-A’-THC-9- carboxylic acid were the major metabolites found in the plasma. 11-Hydroxy-A’-THC is formed in low quantities. The interesting feature is that the volunteers show a subjective "high" with a maximum from about 30 to at least 90 minutes after smoking. It is evident that there is a time lag between the occurrence of the maximum subjective "high" and maximum A%-THC levels. The time of maximum high correlates better with the levels of the metabolites. However, the ll-nor acid is known to be inactive. Pre- sumably the polar acids are also inactive, although this is an assump- tion because reference quantities of the polar acids are not available. 35 Figure 15 A°—THC and Metabolites Found in Human Plasma Following Administration of 6.8 mg A°>—THC via Smoking Reefers % DOSE/LITER PLASMA 2.0 1.0 1.0 0.8 0.6 0.4 0.3 0.2 0.1 0.08 0.06 0.04 0.03 0.02 - 0—o0 AS—THC O-——0 11—0H—A°—THC &-—--A 11—Nor—A?—THC—9— COOH — @—-—@ Polar Acids A——4A Subjective Psychological Effects L N LL ey 10 20 30 40 50 60 70 80 90 1440 MINUTES 36 From the data thus presented, it is evident that the method of administration profoundly affects the ratio of A%-HC and its highly active metabolite, 11-hydroxy-A’-THC. These compounds are produced in approximately equal quantities for considerable period of time after oral administration. In contrast, intravenous administration or smoking produces very little 11-hydroxy-A°-THC. However, the subjective highs produced are certainly of an equal magnitude. These factors will have to be taken into consideration when studies are made for the therapeutic efficacy of A°-THC in various disease states. The metabolism of A%-THC evidently proceeds through its 1ll-hydroxy primary metabolite. The latter compound is converted to the ll-nor and polar acids, probably by alcohol dehydrogenase enzymes. We know little about the chemistry of the polar acids except that they are acidic and so polar that they cannot be moved from the origin on silica gel tlc plates with solvents which readily move the ll-nor acids. Hence, we are dealing either with a highly hydroxylated acid or possibly a polymeric form. Unpublished studies from our group have shown interestingly enough that when the 11- nor acid is administered intravenously, virtually no metabolism occurs. Hence we can say with considerable confidence that the polar acids are not derived from the ll-nor acids but are produced from 11-hydroxy-A°- THC by a different mechanism. 3. Excretion Patterns (a) Urinary Excretion Over a 72 hour period approximately 10-15% of the total dose is excreted by the various administration routes studied. The urine is the only biological material we have analyzed which contains significant quantities of conjugates, most of which are hydrolyzed by glucuronidase 37 enzymes. In some cases we find more cannabinoid in the free form and in others more in the conjugated form, but in any case appreciable quantities of free and conjugated cannabinoids are always found. A typical example is shown in Figure 16 which shows the total free and conjugated cannabinoids found in urine after intravenous infusion of 4.6 mg of A%-THC. The individual metabolites found after all routes of administration both in the free and in the hydrolyzed conjugated forms, all show the same patterns. The composition of the metabolites in the urine is overwhelmingly acidic. The polar acids are usually the major fraction. 11-Nor-A’-THC-9-carboxlic acid (ll-carboxy) acid is usually the next largest component. In both the urinary free and conjugated fraction the quantities of neutral cannabinoids are negligible. (b) Fecal Excretion The feces are the major excretion route in all the administration routes studied (IV, oral, and smoking). In contrast to the urine, the conjugated fraction is insignificant. Moreover, major quantities of 11-hydroxy-A’-THC as well as acids are found. Over a 72 hour period as much as 35% of the total cannabinoids are excreted in the feces after oral administration. About two-thirds of the total dose are found in the first 24 hours. The composition of 24 hour feces after IV, oral, and smoking (reefer) administration of A°-THC is shown in Table 5. It is apparent from inspection of the table that 11-hydroxy-A° -THC is a major com- ponent in each administration route. Other major metabolites include 11-nor-A’-THC-9-carboxylic acid, and the less well defined polar acid fraction. Particlarly significant are the low A%-THC levels found in feces after administration of the drug. This is particularly signifi- cant for oral administration. The data indicate excellent absorption of % DOSE IN THE URINE 5.0 38 Figure 16 Total, Free, and Conjugated Cannabinoids Found in the Urine after IV Administration O—0 Free O—{] Total V7 Conjugated Ll l 36 24 48 TIME (hours) Table 3 Composition of Cannabinoids Excreted in 24 Hour Feces Composition of Cannabinoids (Percent) Administration Intermediate 1ll-nor- 8,11-diOH- 11-0H- 8a-0H- Route Polar Acids Acids A? -THC-9-COOH A -THC A2-THC A2-THC Oral 29 8 23 10 25 - IV 26 28 8 20 6 Smoking 21 10 31 6 26 - (cigarette) 6€ 40 the drug. This statement is based on the assumption that the major metabolites noted could be produced only after intestinal absorption and first pass metabolism by the liver microsomal enzyme system. It is also based on the correlative assumption that enzymes in the small and large intestine would not produce the various cannabinoid metabolites noted. We have some proof of the latter statement. We administered 2%-THC rectally to several volunteers. After 24 hours, the material was flushed out and analyzed. Only unchanged A%-THC was found. The cannabinoid metabolites which were found using our radiolabeled tlc procedure were validated by glc-mass spectrometry, with the exception of the polar acid fraction which cannot be analyzed by this method. A particular search by glc-ms techniques was made for the presence of metabolites hydroxylated in the sidechain. However, these could not be found. Since the feces is the richest source of A%-THC metabolites, we must conclude that sidechain hydroxylation is not a significant factor in the in vivo metabolism of A%-THC in man. 4. Summary of A°-HC Metabolism in Man We are now in a position to summarize and discuss our findings on the metabolism of A’-THC in man. After oral administration the plasma concentration of A%-THC and its active metabolite, 11-hydroxy-A’-THC, increased steadily. Both compounds are found at the same levels, 6-8 ng/ml between 2-6 hours after administration. It is conceivable that the quantity of 11-hydroxy-A°-THC which passes the blood brain barrier is much higher than A%-THC. After tail vein administration in mice, 11- hydroxy-A’-THC passes from blood to brain at approximately 5-fold levels 35 over A2-THC administered at the same concentration. If this holds true for man, the strong psychomimetic effects of the rather low 41 concentration of active cannabinoids noted after oral dosage may be better rationalized. After intravenous and smoking administration, the high levels of A’-THC initially found in the plasma decrease rapidly with time (a phase) and then persist at low levels for long time periods (B phase). The active metabolite, 11-hydroxy-A°-THC, is found at all times as a minor component (1/10-1/5 the level of A2-THC) In all routes of administration studied the major plasma metabolites are the acids, 11-nor-A°-THC-9-carboxylic acid and the less well defined polar acids (these acids are immobile in a tlc system which moves the ll-nor acids almost to the origin). Conjugated cannabinoids are found only to a minor extent in the plasma of man. Urinary excretion accounts for 12-15% of the total dose in 72 hours. Conjugation is significant although not necessarily major by all routes of administration. The composition of the urinary cannabinoids is overwhelmingly acidic (ll-nor and polar acids). Since the non- conjugate urinary fraction frequently exceeds 50% of the total excreted, it is evident that these acidic compounds have sufficient water solubility and/or ionization to pass out of the kidney tubles and be excreted in the urine. After 72 hours as much as 35% of the total cannabinoid dose is excreted in the feces. The cannabinoids in the feces after all forms of administration are always found non-conjugated in our studies with man. This finding is rahter surprising. Frequently the biliary excretion of compounds occurs via their conjugates. Widman, Agurell, et a1.36 found that the major proportion of A’-THC and metabolites excreted in the bile of the rat was in the conjugated form. They also found that various segments of rat intestine can hydrolyze cannabinoid conjugates. Conceiv- ably then, in man A%-THC and metabolites may be excreted largely in 42 conjugate form in the bile. The conjugates may be hydrolyzed in the small and large intestine and excreted in the free form in the feces. In any event, the small proportion of A%-THC excreted in the feces points to excellent absorption of this compound in the sesame oil vehicle used in our studies. 5. Metabolism of Other Cannabinoids in Man Studies similar to those described under A%-THC in the previous sections have been conducted primarily by IV infusion with a number of cannabinoid metabolites, including 8B-hydroxy-A°-THC,>’ 11-hydroxy-A2- THC, 28 11-nor-A’-THC-9-carboxylic acid, 2? cannabinol (caD),%8 and canna- binol (CBN). 2° These studies will not be reported in detail. In brief, as we stated earlier, the metabolism of 11-hydroxy-A°-THC resembles that of A°-THC. Urinary and fecal patterns were also similar. 8B-Hydroxy- A%-THC, a compound showing 1/4 activity of A%-THC, was also metabolized by hydroxylation at the ll-position followed by further oxidation to acids, all the metabolites, of course, having the 8B-hydroxyl. Intravenous administration of 20 mg 11-nor-A-THC-9-COOH revealed that this compound was inactive. Surprisingly, the compound was not metabolized to any extent and was found to be by far the major metabo- lite in plasma, urine, and feces.2? Hence, it cannot be the precursor of polar acids. Cannablinol,28 although generally believed inactive,! was found to be active at high dose levels (18 mg IV infusion) producing a subjective high of relatively short duration. In general it resembled other canna- binoids in its metabolic and excretion patterns; the cannabinol polar acids were major metabolites in plasma. Cannabidiol?® was completely inactive after IV administration of 20 mg. Its metabolism resembled 43 9 A’-THC and CBN as did urinary excretion patterns. Fecal excretion showed a major difference; free CBD was by far the major component. VI. ACTIVITY OF A%-THC METABOLITES AND RELATED CANNABINOIDS In this section the psychotomimetic activity in man of some A%-THC metabolites or analogs will be discussed briefly. Although there have been numerous studies of the effects of A’ -THC and its analogs in animals, the only thorough study in man has been made by Perez-Reyes, et a1.38,39 These workers administered A°-THC and its 1ll-hydroxy-, 8B-hydroxy-, and 8a-hydroxy metabolites by intravenous infusion. They compared the effects of these cannabinoids on the subjective evaluation of marihuana "high" and the objective heart rate acceleration measurements. The application of subjective or objective measurements to the estimate of potency of each cannabinoid gave roughly similar results. The 11- hydroxy- metabolite was somewhat more active than A%-THC, but the dif- ferences were not statistically significant. The 8B-hydroxy analog was 1/3 as active as A%-THC, whereas the 8a- epimer was inactive. A similar study, 3? compared A%-THC with cannabinol and cannabidiol. Although cannabinol is usually considered to be inactive,! at high doses Perez- Reyes found it had psychological and heart rate effects; its potency was estimated to be about 1/10 that of A%-THC. Cannabidiol, a major con- stituent of hashish was inactive. In another study which compared both the effects on intraocular pressure with the subjective psychological and objective heart rate measurement, Perez-Reyes compared all of the cannabinoids discussed in this section and also included the double bond isomer, A8-Tnc 40 He concluded, cf. Table 4, that the best results in regard to IC pressure drop were obtained with A8-, Ao-, and ll-hydroxy- A%-THC. Rather surprisingly, A8-mHC had significantly less effects on Table 4 Comparison of the Clinical Effects to the Intravenous Infusion of Cannabinoids 22-THC 11-0H-22-THC 28-THC 88-0H-A-THC Cannabinol Cannabidiol Total Dose mg/kg 51.39+7.11 42.32+10.20 84.63%£20.40 126.95+30.60 342.59+447.41 342.59+47.41 Maximum Level of "High" 36.17+5.01 35.33+14.16 27.33+18.98 19.83+15.81 20.50+9.95 0 Maximum Heart Acceleration 41.12+12.00 42.15+20.63 19.32+3.16 12.63+7.14 18.42+13.01 12.80+5.48 Initial Intraocular Pressure (mm Hg) 17.17+£1.99 16.75+2.62 17.08+1.93 17.25+3.79 15.50+3.57 17.08+3.48 Intraocular Pressure Decrease (mm Hg) 5.75%2.17 5.58+2.29 6.33+2.53 4.17+2.03 4.00+1.68 1.83+1.34 Percentage Change -32.98+10.50 -34.01+13.51 -37.13+13.62 -22.12+8.06 -26.87+14.90 -10.73+7.42 vy Figures represent the mean of the groups * the standard deviation. Intraocular pressure values represent the average of both eyes. 45 the heart acceleration and psychological behavior (although it was far from inactive). Relatively little work has been done with this canna- binoid metabolically or otherwise. The data in Table 4 suggest that this isomer of A%-THC should have more study. VII. SYNTHETIC CANNABINOIDS At the beginning of this review, the writer stated that there was a somewhat synergistic relationship between the development of the synthetic chemistry of the cannabinoids and metabolic studies with these compounds. The first metabolic studies were only possible as a result’ of the avail- ability of pure synthetic A’-THC or radiolabeled A’-THC. Subsequently synthetic efforts have been stimulated by the discovery of many new metabolites, thus providing synthetic goals so that the new compound could be pharmacologically and/or therapeutically evaluated. A detailed review of synthetic procedures will not be presented. However, the writer would like to acknowledge the synthetic efforts of Dr. Colin Pitt and his associates at RTI, Jhose synthetic efforts have permitted initia- tion of many metabolic and pharmacological investigations. The synthesis of radiolabed and deuterium labeled A8-and A’ -THC has been described by Pitt, et a1.1® These workers also are responsible for syntheses making available 8a-, 8B-, and 11-hydroxy-A°-THC, 8a,11-, and 8B,ll1-dihydroxy- A%-THC; and 11-nor-A’-THC-9-carboxylic acid?! In some cases, radiolabeled analogs are available. Recently, Pitt, et al. have published the synthe- sis of all of the sidechain hydroxy analogs of A%-The. 4? All of the aforementioned synthetic work has been conducted under NIDA contracts. Radiolabeled, deuterium labeled, and "cold" cannabinoids are made avail- able to qualified investigators who apply and receive NIDA approval. Attached as a supplement is a list of compounds available for distribution at RTI. 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The Metabolism of Cannabinoids in Man. In "Pharmacology of Marihuana" (M. C. Braude & S. Szara, Eds.), pp. 93-113, Raven Press, New York, N. Y. Wall, M. E. and D. R. Brine. 1976. Methodological and Clinical Approaches to Quantitative Determination of Cannabinoids and Metabolites in Body Fluids. Ann. Rept. 1975-1976, NIDA Contract HSM-42-71-95. Wall, M. E., D. R. Brine & M. Perez-Reyes. 1979. Metabolism of A°-THC in Man after Oral and Intravenous Administration. Submitted to Drug Metabol. and Disp. Wall, M. E., T. M. Harvey, J. T. Bursey, D. R. Brine & D. Rosenthal. 1975. Proc. 2nd Int. Conf. Stable Isotopes, p. 105. 1976. Analytical Methods for the Determination of Cannabinoids in Biological Materials. In '"Cannabinoid Assays in Humans", NIDA Research Monograph Series #7, p. 107. Wall, M. E., D. R. Brine, J. T. Bursey & D. Rosenthal. 1979. Detection and Quantitation of Tetrahydrocannabinol and Its Metabolites" (J. A. Vinson, Ed.), ACS Publications, In Press. Perez-Reyes, M., M. C. Timmons, M. A. Lipton, K. H. Davis & M. E. Wall. 1972. Science, 177: 633. Wall, M. E. & D. R. Brine. 1978. Abstracts, 7th Int. Cong., Pharmacol., Paris, p. 2585. Widman, M., S. Agurell, N. Nordqvist, J. E. Lindgren & F. Sandberg. 1974. Biochem. Pharmacol., 23: 1163. 37. 38. 39. 40. 41. 42. 49 Wall, M. E. & D. R. Brine. 1974. Methodological and Clinical Approaches to Quantitative Determination of Cannabinoids and Metabolites. Ann. Rept. 1974-1975, NIDA Contract HSM-42-71-95. Perez-Reyes, M., M. C. Timmons, M. A. Lipton, H. D. Christensen, K. H. Davis & M. E. Wall. 1973. Experient., 29: 1009. Perez-Reyes, M., M. C. Timmons, K. H. Davis & M. E. Wall. 1973. Experient., 29: 1368. Perez-Reyes, M., D. Wagner, M. E. Wall & K. H. Davis. 1976. Intravenous Administration of Cannabinoids and Intraocular Pressure. In "Pharmacology of Marihuana" (M. C. Braude and S. Szara, Eds.) p. 829. C. G. Pitt, M. S. Fowler, S. C. Srivastava & D. L. Williams. 1975. J. Am. Chem. Soc., 97: 3798. Pitt, C. G., H. Seltzman, Y. Sayed, C. E. Twine, Jr. & D. L. Williams 1979. J. Org. Chem. In press. 50 SUPPLEMENT RTI Inventory of Cannabinoids and Metabolites Contract No. 271-76-3326, NIDA Contract No. 271-76-3326 Inventory of Cannabinoids A%-ie and Metabolites December 31, 1978 Compounds Lot # Purity Activity Amount Prepared Amount Shipped Amount on Hand Comments A%-THC 1',2'-n, DW-V-147 >952 100 pC/mg 220 mg mg, gm, mg, mg, mg, mg, .5 mg, 9 mg, 20 mg, 20 mg, 10 mg, 40 mg, 1 mg, 9 mg, 6 mg, 30 mg, 25 mg, 10 mg, — Ok O WWM ON Bhargava Dalcason Harmon Olmsted Valentine Harris Harris Wall Nir Siemens Borden Wall Nahas Blevins Wall Karler Eichler Fischer 2.5 mg Prepared 4/25/75 CT-1V-43 >957 165 puC/mg 130 mg 28 mg, 3 mg, 15 mg, 12 mg, 20 mg, mg, mg, mg, mg, mg, mg, 0. AE NWN Davis Davis Karler Wall Jones Wall Garey Ahluwalia Nahas Vinson Craigmill 28 mg Prepared 6/77 HHS-I-114 >95% 152 uC/mg 218 mg 12 mg, 42 mg, Wall Wall 164 mg Prepared 3/10/78 IS A 9 -THC (cont'd) Compounds Lot # Purity Activity Amount Prepared Amount Shipped Amount on Hand Comments A°-THC-11- 14, DW-VII-153 >967 107 pC/mg 110 mg 12 4 mg, 11 mg, 3.6 oN w own mg, mg, mg, mg, mg, mg, Siemens Siemens Purification Agurell Jones Siemens Siemens Burstein 59 mg Prepared 8/76 DW-VI-58 >957% 101 uC/mg 160 mg 2 mg, 11 mg, 5 mg, 2 mg, 41 mg, 1 mg, 10 mg, 10 mg, 2 mg, 33 mg, 0.1 16 mg, 5 mg, 10 mg, 2 mg, mg, Nahas Harclerode Burstein Harmon Borden Jones Vardaris Graham Salemink Borden Taunton-R. Siemens Garrett Jones Harclerode 1.3 mg Prepared 11/12/75 7 mg consumed in purifi- cation, 7/21/76. 1.7 mg consumed in purifi- cation, 2/25/77. zs A’-THC (cont'd) Amount Amount on Compounds Lot # Purity Activity Prepared Amount Shipped Hand Comments A%-THC-5'- DW-VI-66 >90% 1.1% 4, 200 mg 10 mg, Gorman 169 mg | Prepared 11/26/75 2 1 mg, Chesher Hy 93.5% dy 20 mg, Graham 4.47 d 2 0.6% d; 0.47 dg meena a%-ic-11-"H, | DH-1-578 >957 96.0% d, | 97 mg 9 ug, Potts 92 mg | Prepared 2/22/78 2.6% d 5 mg, Wall 1.47 d, £S A 9 -THC (cont'd) Amount Amount on Compounds Lot # Purity Activity Prepared Amount Shipped Hand Comments a8-tHe- MF-I11-74 >95% 90 uC/mg 200 mg 1 mg, Bhargava 167 mg | Prepared 7/8/75 1',2'- 5 mg, Rawitch 27 mg consumed by 3 repurification, 1/12/78. H 2 DW-1X-43 >95% 50 C/mmol 637 mg 2 mC, Nahas 554 mC | Prepared 5/78 20 mC, Gross’ 51 mC used in repurif. a8-Tnc- NM-VI-59A 907% 17.1 uC/mg 112 mg 10 mg, Axelrod 59 mg 2 4-1 25 mg, Fenimore 2 2 4 mg, Rubin 5 mg, Schou 5 mg, Vestergaard 4 mg, Green 8_tuc- NM-VI-31B 967% 17.5 uC/mg 324 mg 259 mg used to pre- | 24.5 mg | Rechromatographed to 2 4-14c pare A -THC increase purity 8/27/71. ’ 2 5.7 mg, Kopin 5 mg, consumed by this 1.0 mg, Van Zanukis processing 10 mg, Harbison 5 mg, Paris 2.85 mg, Snyder 10 mg, Harbison 1 mg, M.R.C. A8-THc- DW-VI-14 >95% 121 uC/mg 55 mg 0.1 mg, Taunton-R. [54.7 mg Prepared 6/11/75 11-Y4c 0.2 mg, Jones 7S 11-Hydroxy-A°~THC Amount Amount on Compounds Lot # Purity Activity Prepared Amount Shipped Hand Comments 11-Hydroxy- DW-1IV-27 >957% 320 uC/mg 1.010 g 0.1 mg, Jones 325 mg | Prepared 5/24/74. A°-THC-4",5'- 10 mg, Foltz 90 mg consumed by re- 3 10 mg, Foltz purification, 6/2/75. H, 1 mg, Leute ’ 10 mg, MRC 10 mg consumed by re- 3.3 mg, Davis purification 11/11/76. 1 mg, Siemens 0.4 mg, Harbison 198 mg consumed by 1 mg, Davis purification 10/27/77. 1 mg, Foltz 5 mg, Harris 270 mg consumed by 2 mg, Borden purification 2/14/78 20 mg, Nir 5 mg, Garrett . 2 mg, Harmon 0.1 mg, Jones 4 mg, Holloway 10 mg, Stein 1 mg, Siemens 10 mg, Leighty 20 mg, Leighty Unlabeled 11- | CT-1IV-181 >98% 0 10.110 g 0 10.110 g | Prepared 4/24/78 Hydroxy-A~-TH SG 11-Hydroxy-A°~THC (cont'd) Compounds Lot # Purity Activity Amount Prepared Amount Shipped Amount on Hand Comments Unlabeled 11-Hydroxy- a%-tuc MF-II11-57 >952% Unlabeled 6.4 g 3 g, Hardman 1 g, Leighty 27 mg, Carney 150 mg, Weissman 100 mg, McMillan 1 g, Leighty 100 mg, Garey 3 mg, Cook 5 mg, Moss 200 mg, Forney 10 mg, Craigmill 10 mg, Burstein 10 mg, Foltz 300 mg, Rawitch 100 mg, Karler 0.5 mg, McBay 384.5 mg Prepared 6/27/75. 200 mg consumed at RTI. 11-Hydroxy- a? 2 - -— |. THC-5 Hy CT-1-41-A >95% 95.5% d, 2.45 d, 1.8% d, 12 mg mg, Foltz mg, Chesher mg, Graham pp 6 mg Prepared 7/28/78 96 88-Hydroxy-A’-THC mg, Siemens Amount Amount on Compounds Lot # Purity Activity Prepared Amount Shipped Hand Comments Unlabeled- DW-VII-125 987% Unlabeled 900 mg 100 mg, Harris 240 mg| Prepared 6/30/76 88-Hydroxy- 200 mg, Aliapoulis 9_ 150 mg, Aliapoulis 4"-THC 100 mg, McMillan 100 mg, McMillan 10 mg, Burstein 8B8-Hydroxy- RLH-ITII-103B >98% 19.8 uC/mg 115 mg 2.4 mg, Paris 32.2 mg| Prepared 4/7/72 9 67.4 mg, Davis A THE=2,4, 2.0 mg, Harris 8,10- H, 4.0 mg, Wall 2.0 5.0 mg, Leighty LS 8a-Hydroxy-A’~THC Compounds Lot # Purity Activity Amount Prepared Amount Shipped Amount on Hand Comments Unlabeled 8a-Hydroxy- A%-HC DW-VII-141 >957% Unlabeled 132 mg mg, Harris mg, Schmidt mg, Burstein mg, Snyder mg, Siemens mg, Burstein mg, Green mg, NIDA mg, Moffat 20 mg Prepared 8/6/76 DW-VIII-129 >957 Unlabeled 520 mg 100 20 10 mg, McMillan mg, Leighty mg, Burstein 390 mg Prepared 9/77 86 8a, 11-Dihydroxy-A~THC Amount Amount on Compounds Lot # Purity Activity Prepared Amount Shipped Hand Comments 8a,11-Di- DW-11-27 >957% 98 uC/mg 75 mg 1 mg, Wall 27 mg | Prepared 7/16/73. hydroxy- 1 mg, Pirch A2-THC 2 mg, Harris 27 mg consumed by 3 2 mg, MRC purification by 2/14/78 1',2'- H, 1 mg, Harbison 6 mg, Harbison 6 mg, Wall 1 mg, Siemens 1 mg, Leighty Unlabeled CT-III-5 957% Unlabeled 45 mg 10 mg, Nahas 2 mg Prepared 6/16/76 8a,11-Di-~ 2 mg, NIDA hydroxy- 20 mg, Moffat 9 5 mg, Burstein A"-THC 5 mg, Karler 1 mg, Pert CT-IV-101A | >95% Unlabeled 90 mg 15 mg, McMillan | >° M8 Prepared 9/77 20 mg, Leighty 10 mg, Burstein 10 mg, Karler 6G 88, 11-Dihydroxy-A ~THC (cont'd) Compounds Lot # Purity Activity Amount Prepared Amount Shipped Amount on Hand Comments 88,11-Dihy- droxy-A9-THC CT-1Iv-1018 >95% Unlabeled 370 mg 50 mg, McMillan 20 mg, Leighty 100 mg, McMillan 200 mg Prepared 9/77 DH-11I-42 >957 Unlabeled 90 mg mg, mg, mg, mg, mg, mg, mg, mg, mg, Ww =O oN LULL nnn No Harris Taunton-R. Schmidt Hollister Burstein Siemens Green NIDA Moffat 12 mg Prepared 3/11/75 09 A%-carboxylic Acids Amount Amount on Compounds Lot # Purity Activity Prepared Amount Shipped Hand Comments 11-Nor-a3- DW-VI-21 >95% 0.47 d, 60 mg 5 mg, Foltz 20 mg| Prepared 6/30/75 THC-9-Car- 0.6% d 5 mg, Wall boxylic Acid- CTL 10 mg, Holloway 51-2 4.47 d, 10 mg, Foltz 3 93.57 d 5 mg, Wall I 5 mg, Jones 1.17% d, DW-VI-30 >95% 0.47 d_ 75 mg 0 mg 75 mg| Prepared 7/20/75 0.6% d, 4.4% d, 93.5% d, 1.17% d, A8-mc-s'- DW-1IV-101 >95% | 1.94 uC/mg 250 mg 50 mg, Cook 72.5 mg Prepared. 8/74 coon-5'-L4c 51 mg, Gross 51.5 mg, Purific. 25 mg, McBay 19 28_carboxylic Acids (cont'd) Amount Amount on Compounds Lot # Purity Activity Prepared Amount Shipped Hand Comments 11-Nor-a8- CT-1V-77 >95% Unlabeled 500 mg 100 mg, Graham 130 mg Prepared 8/2/77 THC-9-Car- 100 mg, Rubenstein boxylic Acid 150 mg, Finkle 20 mg, Kaul 29 a%-carboxylic Acids } Amount Amount on Compounds Lot # Purity Activity Prepared Amount Shipped Hand Comments 11-Nor-a’- DW-V-93 >957% 103 uC/mg 65 mg 0.5 mg, Wall 38.5 mg| Prepared 2/14/75 THC-9-Car- 1.0 mg, Gross boxylic Acid 1.0 mg, Wall v gr 3 3.0 mg, Wall 47,5", 6.0 mg, Wall 1.0 mg, Rowley 4.0 mg, Burstein 5.0 mg, Foltz 5.0 mg, Fenimore 11-Nor-a’- DW-VII-107 >957 Unlabeled 38 mg 5 mg, Burstein Prepared 6/11/76 THC-9-Car- 5 mg, Wall 3.8 mg boxylic Acid 3 mg, Dubowski 5 mg, Forney 10 mg, Foltz 1 mg, Cook 2 mg, NIDA 2 mg, Moffat 1.2 mg, Cook DW-IX-11 >957 Unlabeled 20 mg 0.5 mg, McBay 19.5 mg | Prepared 3/15/78 11-Nor-A’- DW-VIII-85 >957% 1.17% d, 42 mg 5 mg, Wall 27 mg | Prepared 6/15/77 THC-9-Car- 2.4% 4 10 mg, Foltz boxylic Acid I] 51-2, 95.8% dy £9 Miscellaneous Cannabinoids Amount Amount on Compounds Lot # Purity Activity Prepared Amount Shipped Hand Comments 11-Hydroxy- DW-III-43 >95% Unlabeled 500 mg 1 mg, Pert 44 mg Prepare 1/9/74 8 15 mg, Davis AZ-THC 50 mg, Friedman 100 mg, Sobol 10 mg, Turner 200 mg, Harris 10 mg, Kaistha 5 mg, Green 11-Hydroxy- DH-1-77 >957% 114 uC/mg 170 mg 2 mg, Graham 168 mg Prepared 9/74 a8_tc-4', 3 '_ 5 H, Cannabigerol MF-11-83 >95% Unlabeled 3.0 g 100 mg, Burstein 633 mg Prepared 1/75 300 mg, Turner 100 mg, Domino 300 mg, Dainis 300 mg, Gasdia 300 mg, Graham 15 mg, Mahilberg 25 mg, Baggil 500 mg, Ramachandran 2 mg, NIDA 5 mg, Moffat 100 mg, Ramachandran 200 mg, Graham 10 mg, Cohn 100 mg, McKinley 10 mg, Asaad 79 Miscellaneous Cannabinoids (cont'd) Amount Amount on Compounds Lot # Purity Activity Prepared Amount Shipped Hand Comments Cannabichro- |MF-II-137 >95% 85 uC/mg 135 mg 0 mg 135 mg | Prepared 3/75 mene-1',2"'- } 3 Hy 11-0xo-A8-THC CT-11-29 >95% Unlabeled 400 mg 0 mg 400 mg { Prepared 12/19/75 S9 Miscellaneous Cannabinoids (cont'd) Amount Amount on Compounds Lot # Purity Activity Prepared Amount Shipped Hand Comments Hexahydro- DW-VII-41 >95% Unlabeled 2.0g 10 mg, Forrest 1.385 g Prepared 3/23/76 cannabinol 200 mg, Garrett 10 mg, Valentine 10 mg, Cook 5 mg, Moffat 80 mg, Consroe 300 mg, Graham 99 Cannabinol, Cannabidiol Amount Amount on Compounds Lot # Purity Activity Prepared Amount Shipped Hand Comments Cannabidiol- CT-11I-3 >98% 89 uCi/mg 106 mg 20 mg, Dewey 20.4 mg | Prepared 7/7/76 1'.2'-3y 30 mg, Karler ’ 2 3 mg, Burstein 4 mg, Siemens 1 mg, Bhargava 12.6 mg, Siemens 15 mg, Karler CT-1V-129 >987% 147 uC/mg 151 mg 1 mg, Leighty 140 mg | Prepared 12/12/77 2.3 mg, Graham 7.6 mg, Siemens L9 Cannabinol, Cannabidiol (cont'd) Compounds Lot # Purity Activity Amount Prepared Amount Shipped Amount on Hand Comments Cannabinol- 3 1',2'- H, 1530-55-1 >99% 121 uC/mg 192 mg mg, mg, mg, mg, mg, mg, mg, mg, mg, mg, 20 mg, 9.3 mg, 15 mg, 2 mg, w =e Oo = . NOUFEWNO®O®N w . Ww Burstein Davis Salemink Friedhof f Davis Leute Siemens Siemens Burstein Siemens Stein Siemens Dewey Graham 76 mg Prepared 2/3/73 19 consumed by repurification on 1/15/75 MF-I1I-75 >99% 76 uC/mg 250 mg 15 mg, Bhargava Siemens 205 mg Prepared 7/17/75 29 mg consumed by repuri fication 3/12/77 = Cannabinol- 2 LI. 5 Hy MF-11-95 >957% 4.0% 85.27% 10.2% 0.6% a A A A wn & WN 160 mg 5 mg, 10 mg, 10 mg, 2 mg, 10 mg, Rosenthal Wall Valentine Forrest Siemens Wall 122 mg Prepared 1/17/75 89 Cannabinol, Cannabidiol (cont'd) ] Amount Amount on Compounds Lot # Purity Activity Prepared Amount Shipped Hand Comments Cannabinol- CT-1I-22 >95% 101 uC/mg 8.5 mg 2 mg, Burstein 0.7 mg | Prepared 10/31/75 11-14¢ 0.2 mg, McCullum 0.1 mg, Taunton-R. 2 mg, consumed by puri- 0.5 mg, Leighty fication on 9/21/76 3.0 mg, Burstein DW-IX-113 >95% 101 uC/mg 4.0 mg 0 4.0 mg | Prepared 8/25/78 Cannabinol DW-V-59 >95% Unlabeled 500 mg 5 mg, Green 395 mg | Prepared 12/27/74 Acetate 100 mg, May 11-Hydroxy- DH-III-3 >95% Unlabeled 115 mg 100 mg, Wilson 1.6 mg {| Prepared 5/22/75 Cannabinol 2 mg, Wall 0.4 mg, Wall 1.0 mg, Taunton 10 mg, Burstein DW-VII-147 >96% Unlabeled 120 mg 5 mg, Siemens Prepared 8/25/76 5 mg, Moffat 15 mg 10 mg, Burstein 5 mg, Wall 80 mg, Consroe 69 Cannabinol, Cannabidiol (cont'd) Amount Amount on Compounds Lot # Purity Activity Prepared Amount Shipped Hand Comments 11-Hydroxy- DW-VIII-127 >95% Unlabeled 145 mg 100 mg, Leighty 45 mg| Prepared 9/77 Cannbinol 11-Norcanna- CT-11I-38 >95% Unlabeled 96 mg 1.6 mg, Wall 12.5 mg| Prepared 1/14/76 binol-9-Car- 45 mg, Fenselau boxylic Acid 5 mg, Burstein 5 mg, Malberg 20 mg, Fenselau 5 mg, Moffat 2 mg, Hollister CT-1IV-183 >95% Unlabeled 55 mg 0 55 mg| Prepared 5/78 10-Hydroxy DW-VII-53 >95% Unlabeled 220 mg 5 mg, Siemens 214 mg Prepared 3/3/77 Cannabidiol* 1 mg, Hollister * Terpene Numbering 0¢ Side Chain Derivatives Compounds Lot # Purity Activity Amount Prepared Amount Shipped Amount on Hand Comments 5'-Hydroxy- a%-THC DW-VI-71 >957% Unlabeled 580 mg mg, mg, mg, mg, mg, mg, mg, mg, mg, mg, mg, mg, mg, pe = =} HFUuWwuUuNhNULOoOWHEUL LOE [— Taunton-R. Snyder Schmidt Burstein Gross Siemens Cook Wall NIDA Moffat Wall Carney Hollister 424 mg Prepared 12/15/75 4'-Hydroxy- a°-THC CT-III-95-1 927% Unlabeled 12 mg 3 mg, 5 mg, Siemens Wall Prepared 11/76 TL Side Chain Derivative (cont'd) . Amount Amount on Compounds Lot # Purity Activity Prepared Amount Shipped Hand Comments 4'-Hydroxy- DW-VIII-91 >95% Unlabeled 95 mg 15 mg, Carney 77 mg | Prepared 6/29/77 a%-uc 5 mg, Jones 3'-Hydroxy- DW-VIII-41 >95% Unlabeled 35 mg 2 mg, NIDA 13 mg | Prepared 3/2/77 9 5 mg, Burstein A” -THC 3 mg, Wall 6 mg, Wall 1 mg, Hollister 5 mg, Jones DW-VIII-183 >957 Unlabeled 186 mg 30 mg, Carney 155 mg { Prepared 12/21/77 1 mg, Wall 2'-Hydroxy-A’-| HHS-1-72 5977 | unlabeled 86 mg 3 mg, Wall 63 mg | Prepared 7/1/77 THC 15 mg, Carney 5 mg, Jones 1'-Hydroxy-A’- DW-IX-69A >85% Unlabeled 33 mg 0 mg 33 mg | Prepared 8/78 THC (Isomer A) 1'-Hydroxy-A’- DW-IX-69B >90% Unlabeled 33 mg 0 mg 33 mg | Prepared 8/78 THC (Isomer B) iL Side Chain Derivatives (cont'd) Amount Amount on Compounds Lot # Purity Activity Prepared Amount Shipped Hand Comments 1'-Hydroxy- CT-I1I-39 >987% Unlabeled 210 mg 3 mg, Siemens 191 mg | Prepared 8/4/76 cannabinol 5 mg, Moffat 10 mg, Burstein 1 mg, Hollister | 1'-0Oxo- CT-1I1-21 >987% Unlabeled 84 mg 3 mg, Siemens 65 mg | Prepared 7/19/76 | cannabinol 5 mg, Moffat 10 mg, Burstein 1 mg, Hollister crete a pn sneered eL wt Noms Side Chain Derivatives (cont'd) trinor-A%-THC Amount Amount on Compounds Lot # Purity Activity Prepared Amount Shipped Hand Comments 1',2',3',4',5'4 HHS-1I-72-27 >95% Unlabeled 15 mg 0 mg 15 mg Prepared 7/77 Pentanorcanna- binol-3-car- boxylic Acid DW-IX-79 >89% Unlabeled 32 mg 0 mg 32 mg Prepared 8/78 1'-Carboxy- DW-IX-89 >967% Unlabeled 8 mg 0 mg 8 mg Preparad 8/78 2',3',4',5'- : tetranor- A’-THC 2'-Carboxy- DW-IX-83 >85% Unlabeled 20 mg 0 mg 20 mg Prepared 8/78 3',4',5'- wL 75 Is There a Place for Heroin in the Symptomatic Support of Cancer Patients? Cancer therapy usually implies drugs, irradiation, or surgery. However, it properly also includes supportive care such as effective pain relief. Just as we work to identify and test new cytotoxic drugs and move those proven effective into clinical usage, we also need to be alert for any new and better ways to provide analgesia, especially for the cancer patient with refractory disease. In the latter instance, the question has recently arisen (1) whether heroin has a role in the symptomatic support of cancer patients. To address this issue, we have asked if there are data which would indicate whether or not we have failed to exploit or at least to properly test the use of heroin in treating pain in patients with malignant illness. Heroin, also known as either diacetylmorphine or diamorphine, was synthesized in England in the late 19th century and received widespread application for a host of indications until recognition of its addiction potential finally halted its use in the United States in the 1920's (2). England did not impose a ban on it, however, and it continues to be prescribed there, albeit with less frequency in recent years (2), possibly because its ethical use lies in the shadow of the enormous problems associated with heroin addiction. An indication for prescribing heroin in Britain has been the treatment of pain in cancer patients (2,3). R. G. Twycross has summarized the reasons he perceives that physicians working in oncology would want to administer the drug (2). Heroin is said to produce less nausea and vomiting than morphine; it supposedly increases the appetite of anorectic patients; it may be less constipating then morphine; it allegedly raises the mood of depressed patients back towards normal (as distinct from the more common notion that it actually causes euphoria); it is said to leave patients more alert, active, and cooperative than does morphine; it is said to be a better antitussive; and it is alleged to be better at relieving "malignant dyspnea." Twycross qualifies these observations as unsupported claims based upon strong clinical impressions. He has also published a review of the use of heroin in treating terminal illness in 500 cancer patients from St. Christopher's Hospice at London (4,5). Eighty-five percent of patients in the study were said to have received adequate pain relief with an orally administered elixir of heroin up until their final 12 to 24 hours of life when they required parenteral medication. The initial dose of heroin ranged from 2.5 to 10 milligrams every four hours and was increased over time to meet each patient's needs. Each 20cc dose of the elixir also contained 10 milligrams of cocaine and 12% ethyl alcohol. 76 The author gave case reports of prolonged success in achieving marked subjective improvement (5) and noted that there was also the unrestricted use of other psychotropic drugs such as tranquilizers and antidepressants. The study did not attempt to control variables such as patient age, disease type or stage, concomitant use of other drugs, placebo effect, or the presence or absence of other, non-oncologic pathologic states. The conclusions of the report were that there was no evidence that heroin led to psychological dependence; that there may have been physical dependence, but it did not appear to interfere with the effective use of the elixir; that there was no fixed, single, optimal dose of heroin; that drug tolerance was not a ''practical' problem (see also (6)); and that there appeared to be, according to the author's clinical impressions, no mental dysfunction attributable to the heroin. These British reports appeared in the last seven years. From the United States, there was a 1936 report which also drew positive conclusions about heroin (7). It has received severe criticism, both because of flaws in its inherent design and because it was said to have been often cited as evidence that heroin is a valuable addition to the task of producing effective analgesia (8). The 1936 study involved 8 normal male volunteers who received fixed subcutaneous doses of heroin, morphine, Dilaudid, or codeine, and who then had their pain thresholds measured over time. The authors summarized by noting that heroin had the most rapid onset of action and that all the subjects 'preferred it" and found it "superior" to the other drugs from the "subjective standpoint." They stated that morphine had the longest duration of action, heroin the shortest; that morphine had the greatest intensity and duration of "subjective depression," heroin next to least; that heroin produced the most "euphoria" followed by morphine, Dilaudid, and codeine in descending order; and that for "side actions," morphine produced the most, heroin the least. In 1964, Louis Lasagna reviewed the clinical data on morphine and its congeners as analgesics (8). He discussed the problems one encounters in the sifting of literature on analgesia, and if one takes the presence of several of these problems in a given study as a reason to doubt or reject the conclusions or implications of the study, then the work of Twycross (4,5) and Seever and Pfeiffer (7) above must remain open to serious question. The difficulties (8) include (a) failing to construct a dose- response curve for the test drug and to vary the dose schedule and routes of administration; (b) the '"semantics' of pain relief, the problem of quantifying and qualifying pain to make interstudy data comparable; (c) not addressing the differences between acute and chronic drug administration, since most studies are short term and by definition 77 cannot examine cumulative effects or drug tolerance; (d) the difficulty in controlling population differences such as patient age, underlying health, source of pain, and the difficulty in appropriately extrapolating the results of the study of one type of subject (normal volunteer, postaddict, or the chronically ill) or disease (inflammatory disease such as arthritis vs. post-operative pain) to another; (e) not allowing for differences between individuals; and (f) measuring the side effect potential or addiction potential of a drug usually in non-patients and then applying conclusions to very different, very ill patients (i.e., those with advanced cancer). Those portions of Twycross' work (4,5) which are essentially a series of anecdotal experiences suffer, thereby, in a comparison with these criteria and conform to them only in point (e) above where his studies recount the practice of constantly varying the drug dosage to meet the patients' individual and changing requirements. His reports do, however, look at the population of concern to oncologists, and, therefore, their conclusions may yet turn out to be generally applicable to oncologic practice. The study of Seevers and Pfeiffer (7) also fails to meet Lasagna's criteria. It is impossible to extend to cancer patients the findings of a 1936 study of fixed, single-dose, single-route heroin administration in an acute study of eight normal volunteers' reactions to pain induced by pricks with a standardized set of bristles. In a later section of Lasagna's review (8), he analyzes the literature specifically relating to the testing of heroin in human subjects. Twycross' reports (4,5), of course, were not published then, but Lasagna emphatically pointed out how little justification there was for those who advocated the therapeutic use of heroin on the basis of Seevers and Pfeiffer's study. In further support of his downgrading of the therapeutic value of heroin, Lasagna cited recent past work by Beecher, himself, and others (9,10,11,12,13). The first reference was a 1955 comparative study of placebo, amphetamine, pentobarbital, heroin, and morphine (9). The subjects were healthy volunteers, chronically ill patients, or post- addicts. The drugs were given at one of two fixed doses, and the patients were queried about the effects of the therapy. Table 1 shows the results in a small heterogeneous group of 30 hospitalized chronically ill patients and indicates little difference between the effects of heroin and morphine. The authors noted that in the 20 normal subjects, there was no difference in the incidence of side effects with morphine vs. heroin, although in their overall conclusion to the study, they surmised that morphine was most frequently associated with a dysphoric state and that "in the normal subjects and to a lesser degree in the chronically ill patients, amphetamine surpassed morphine, heroin, pentobarbital, and a placebo in its ability to produce a pleasurable state." 78 The other references involved no chronically ill patients at all. One concluded that in postaddicts (10), the data did not support the assertion that tolerance developed more rapidly to heroin than to morphine. The second paper (11) established the comparative analgesic potency of heroin and morphine on post-operative patients and showed that 2.3 to 5.2 milligrams of heroin were equipotent with 10 milligrams of morphine. The third report (12) studied the subjective effects of heroin and morphine in 24 male college studies and found that the drugs produced "similar subjective effects" although those of heroin appeared earlier and were more intense. The final reference (13) showed that both opiates produced mental clouding in normal volunteers. With this background, can one then take definitive stand for or against using heroin to treat cancer patients? Those saying use the drug would likely refer to certain of Twycross' studies (2,4,5), but they would not be resting upon a rigorously, tightly constructed edifice of reproducible, objective data. Those saying heroin has no role, in addition to drawing upon the general condemnation by our society of the drug, and sharing in everyone's concern about its addictive potential (the latter point in fact being moot with respect to terminal cancer patients), would also marshall Lasagna's review (8) and the unspectacular conclusions it drew from the available data on the clinical pharmacology of heroin. However, the data supporting these conclusions clearly have limited applicability to cancer patients, and even by Lasagna's own criteria, the studies he referenced (9,10,11,12,13) are also subject to serious criticism of the methodologies they used. Also on the negative side, Twycross has recently published an article comparing heroin to morphine in terminal cancer patients (14). Both drugs were given orally in the cocaine-containing elixir described earlier. The patients also received other psychotropic drugs during the time of study. In addition, a subset of the patients crossed over from one drug to the other. The female patients noted no difference between the agents, while the male cross-over patients reported more pain and were more depressed when they were taking heroin. The author concluded that there was no demonstrable advantage of heroin over morphine within the limitations of his study design. What one can conclude at this point is that we have no firmly established basis on which to make a final judgment about the role of heroin in cancer therapy. There are, however, some additional clues which might stimulate further interest and study. A 1975 paper (15) reviewed the metabolism of morphine and heroin in man. Heroin appears to be less polar than morphine and has a shorter half-life after intravenous administration. Thirty-eight percent of a given dose appears in the urine as conjugated morphine, 47% as free morphine. 79 In addition, 6-monoacetylmorphine is probably the major metabolite which leaves the bloodstream after heroin administration. In vitro assays with homogenates of adult human tissues (Table 2) indicate that liver has the highest level of hydrolytic activity, brain the least (16). Does this mean that higher levels of the less polar heroin and monoacetylmorphine appear in the brain after heroin administration and consistently produce central effects different from those seen after morphine administration? If this phenomenon does occur, would it persist or change in patients on chronic heroin use? What would be the influence of the route of administration or the concomitant use of other drugs? These questions remain unresolved. Finally, there are other investigative leads or caveats in research on the pharmacology of heroin as summarized by Twycross (2). He points out that (a) heroin is less stable than morphine in solution, and failure to use freshly dissolved drug may lead to false conclusions; (b) there seem to be wide variations in drug requirements in terminal patients, and the potency ratio of heroin to other drugs, therefore, may not be so exact; thus, future studies should involve "within patient' crossover of drugs and schedules; (c) the pharmacology of orally administered heroin requires extensive study (also see (8)), and the drug appears to be absorbed sublingually (however, Way's study (16) of drug hydrolysis suggests that any drug absorbed into the portal circulation will be converted primarily into morphine); (d) until recently, biochemical assays for heroin have had a low and limiting sensitivity suggesting that our knowledge about its drug disposition is incomplete; (e) there may be a sex difference in the response to heroin, and future drug studies should control for this possibility (see also (6)); and (f) the mobility of patients during drug testing may have a major influence on drug side effects. In regard to this last point, Twycross cited earlier obser- vations that morphine produced a low incidence (15%) of vomiting in bedridden subjects but caused 90% of ambulatory patients to vomit. In short, there are no definitive conclusions to be drawn about the general use of heroin for the terminally ill cancer patient. The data which support using heroin are less rigorous than one would prefer, the data which oppose its prescription are in part incomplete and in part not applicable to the cancer patient. Many of us who have worked with oncology patients in the United States have heard by word of mouth that we are missing an opportunity in supportive oncology care, in contrast to our British colleagues, because we do not take advantage of heroin's special, albeit ill-defined, psychotropic properties. Part of the appeal of the idea may be the novelty of applying something illicit to a good end. However, if we are missing a chance to provide our patients with adequate analgesia, it is probably closer to the truth to say that it is because we do not know how to optimally use the approved agents already in hand (15,16). Further research will have to resolve these issues. 80 Since this review was assembled in late 1977, the proponents of heroin use in cancer patients have shifted their emphasis. Because of the types of observations made in Twycross' 1977 article (14), they no longer claim that heroin is superior to morphine as an analgesic per se. Instead, they argue that its greater solubility permits the administration of smaller volumes of drug to patients who require parenteral medication but who have little muscle mass or subcutaneous tissue remaining because of advanced disease. The practical significance of this attribute has yet to be established. 10. 11. 12. 81 REFERENCES Upton AC: Interview on "Meet the Press,’ National Broadcasting Company, August 28, 1977 Twycross RG: Stumbling blocks in the study of diamorphine. Post Grad Med J 49:309-313, 1973 Editorial Review: Narcotic Analgesics in Terminal Cancer. Lancet 2(7937):694-695, 1975 Twycross RG: Clinical experience with diamorphine in advanced malignant disease. Int J Clin Pharm 9:184-198, 1974 Twycross RG: The use of narcotic analgesics in terminal illhess. J Med Ethics 1:10-17, 1975 Twycross RG, Wald SJ: Long-term use of diamorphine in advanced cancer. In Advances in Pain Research and Therapy, Volume 1. Edited by JJ Bonica and D. Albe-Fessard. Raven Press, New York, 1976, pp 653-661 Seevers ME, Pfeiffer CC: A study of the analgesia, subjective depression, and euphoria produced by morphine, heroin, Dilaudid, and codeine in the normal human subject. J Pharmacol 56:166-187, 1936 Lasagna L: The clinical evaluation of morphine and its substitutes as analgesics. Pharmacol Rev 16:47-83, 1964 Lasagna L, von Felsinger JM, Beecher HK: Drug-induced mood changes in man. Observations on health subjects, chronically ill patients, and post-addicts. JAMA 157:1006+1020, 1955 Martin WR, Fraser HF: A comparative study of physiological and subjective effects of heroin and morphine administered intravenously in postaddicts. J Pharmacol 133:388-399, 1961 Reichle CW, Smith GM, Gravenstein JS, et al: Comparative analgesic potency of heroin and morphine in post-operative patients. J Pharmacol 136:43-46, 1962 Smith GM, Beecher HK: Subjective effects of heroin and morphine in normal subjects. J. Pharmacol 136:47-52, 1962 13. 14. 15. 16. 17. 18. 82 Smith GM, Semke CW, Beecher HK: Objective evidence of mental effects of heroin, morphine, and placebo in normal subjects, J Pharmacol 136:53-58, 1962 Twycross RG: Choice of strong analgesic in terminal cancer: dia- morphine or morphine? Pain 3:93-104, 1977 Boerner U, Abbott S, Roe RL: The metabolism of morphine and heroin in man. Drug Metab Rev 4:39-73, 1975 Way EL, Young JM, Kemp JW: Metabolism of heroin and its pharmaco- logic implications. Bull Narcotics 17:25-33, 1965 Catalano RB: The medical approach to management of pain caused by cancer. Semin Oncol 2:379-392, 1975 Marks RM, Sachar EJ: Undertreatment of medical in-patients with narcotic analgesics. Ann Int Med 78:173-181, 1973 83 HEROIN, A BRIEF HISTORY OF ITS CONTROL AND A REVIEW OF ITS PHARMACOLOGIC ACTIONS W. R. Martin Professor and Chairman Department of Pharmacology University of Kentucky Lexington, Kentucky 40506 84 HEROIN, A BRIEF HISTORY OF ITS CONTROL AND A REVIEW OF ITS PHARMACOLOGIC ACTIONS Heroin, diacetylmorphine, was first reported to be synthesized in 1874 by C.R.A. Wright. It was subsequently prepared in 1890 by W. Dankwortt. In the 1890's, the pharmacology of diacetylmorphine was studied and the compound was marketed in 1898 by the Bayer Company. It was found to be a potent analgesic and was used in the treatment of tuberculosis for relieving cough and producing sleep as well as in other respiratory conditions, such as bronchitis and asthma, where codeine was thought to be ineffective. Earlier reports indicated that heroin was more potent than codeine in treating respiratory diseases, and less toxic, with a rough estimate of therapeutic ratio of approximately 100. By the turn of the century, heroin's ability to produce tolerance with chronic administration was becoming recognized, as was its habit-forming properties. Nevertheless, it was thought to have especially desirable therapeutic properties. It was actually proposed as a treatment of morphinism. Several physicians and authorities recognized that the use of heroin for the treatment of morphinism produced heroinism. The history of control of heroin cannot be viewed without some discussion of the emergence of attitudes toward narcotics and other drugs of abuse. Discussions of these issues can be found in a variety of sources [Terry & Pellens, (1928), Anslinger and Tompkins (1953), Isbell (1963), Livingston, (1958), Musto, (1973), Martin (1977), Platt and Labate, (1976)]. Probably at least five major influences can be identified: (1) Prohibitionist ethic which relates to the assault of drugs on the dignity, sanctity and health of man; (2) economic factors, some of which were probably related to our desire to cultivate our relationship with China by assisting them in limiting opium use, probably in the hopes of obtaining favorable trade concessions; (3) domestic concern of the relationship of drug abuse to crime and its related cost; (4) narcotic abuse (@ddiction) had political implications as they related to our trusteeship over the Phillipines following the Spanish- American War and (5) concern based on public health considerations. A variety of efforts to restrict narcotic use and abuse emanated from the Food and Drug Administration, the American Pharmaceutical Association, the American Medical Association and the U.S. Public Health Service. The reasons for passing the 1924 law that prohibited the importation of opium for the manufacturing of heroin appeared to be several in number. First it was recognized and probably correctly, that heroin had no definite advantages as a respiratory sedative in the treatment of tuberculosis. Certainly, in this day and age, with the presence of highly effective anti- biotics for the treatment of tuberculosis, this evaluation would be even more correct. However, the uses of heroin which are currently being advocated are quite different and refer more to its use as an analgesic particularly for the treatment of incurably ill patients and for narcotic maintenance therapy. These issues will be dealt with subsequently in this paper. Other 85 reasons for controlling heroin were that it was much more toxic than morphine; heroin addiction was thought to give rise to violent crimes as well as other types of criminalities; it was thought to be especially habit forming or addictive and extremely pernicious in that it decreased moral sense, the herd instinct and enhanced muscular reactions, thus increasing the effectiveness of the criminal. Finally, the incidence of criminal activity by heroin abusers appeared to be increasing rapidly. Heroin was also alleged to make criminals more reckless and inflate their personality and cause them to lose their sense of right and wrong (Bull. on Narcotics, 1953). Undoubtedly it was felt that the banning of pro- duction of heroin would decrease the magnitude of the problem. The most recent legislative actions regarding heroin were the Boggs Act of 1951, which made it a copital offense to sell heroin to a minor and the Comprehensive Drug Abuse Law. The one inconvertible fact that now stands is that after over fifty years of attempting to curtail heroin use and abuse, it still remains the narcotic of choice of most addicts, followed in order by methadone, propoxyphene, codeine, morphine, oxycodone, pentazocine and dihydromorphone. The question of why heroin should remain one of our primary drug abuse problems remains a perplexing question. It is quite apparent that prohibition of the manufacturing of heroin and its use by the medical profession has not eradicated the problem of its abuse. The question as to why heroin remains such a popular drug with narcotic addicts cannot readily be explained on a scientific or pharmacologic basis. Heroin is a much more lipid-soluble drug than morphine and crosses mucosal membranes with ease. Thus, it can be administered by sniffing as it was at one time and this was thought to be one of the reasons for its high abuse. However, for many years, the primary route of administration of heroin has been intraveneously, so its ability to cross mucous membranes can hardly be the reason for its continued illicit popularity. Its lipid-solubility allows it to cross the blood brain barrier with ease and it is thought to have a more rapid onset of action than morphine. Heroin is rapidly absorbed when administered subcutaneously to mice and its subcutaneous and intra-venous potencies are nearly equal (Smith et al., 1976). There are some who believe that this is an important consideration in its abuse and popularity. Heroin is approximately two and one-half to three times more potent than morphine both as an analgesic and euphoriant in man. Since heroin is readily convertible to morphine through a relatively simple chemical reaction, it becomes, at least from the stand- point of the buyer, a more economic drug in that it is easier to smuggle equally effective doses and the cost of producing an equieffective agent is probably less than for morphine. The role of fadism and established traditions cannot be discounted. From a pharmacologic point of view, however, it is difficult to see why heroin retains its popularity. 86 Actions of Heroin The older literature has been reviewed by Kruger, Eddy and Sumwalt, (1943) and by Eddy (1953). It will suffice to say, at this time, that it is well documented that heroin is an effective analgesic in man and animals (Brands et al., 1976). It is a respiratory and cough depressant, produces con- stipation and is capable of inducing tolerance and physical dependence of the morphine type. Estimates of its potency as an analgesic vary greatly, not only from animal to animal, but also from study to study. Furthermore, heroin is toxic and can produce convulsions. In this regard, it is approximately twice as potent as morphine (Eddy and Howes, 1935). Some data indicates that heroin had a more rapid onset and a shorter duration of action than does morphine. CARDIOVASCULAR EFFECTS The predominant effect of heroin in anesthetized dogs, rabbits and cats is to decrease systemic blood pressure, cardiac output, cardiac contractibility (Grundy, 1971; Brashear et al., 1971). The depressor effect may be preceeded by a short-lived modest pressor response which has been attributed to catecholamine release. These cardiovascular effects are also produced by morphine and other narcotic analgesics. Therapeutic’ and even moderately large doses have little effect on blood pressure and pulse in the absence of other drugs in man. EEG EFFECTS Heroin produces convulsions and EEG seizure activity in man (Zaks et al., 1969; Volavka et al., 1970), baboons (Reichman et al., 1973) and other animals and this effect can be antagonized by naloxone (Gilbert and Martin, 1975). In lower doses, heroin increased and then decreased alpha wave amplitude and decreased alpha frequency in addicts. Spindling and delta activity were increased. Heroin (7.5 mg) like morphine, decreases REMS (Lewis et al., 1970) in man. TOLERANCE AND PHYSICAL DEPENDENCE IN MAN Himmelsbach (See Eddy, 1953) studied the ability of heroin to produce physical dependence in dependent addicts admitted to the U.S. Public Health Service Hospital at Lexington who had been stabilized on varying doses of morphine. Heroin was substituted for morphine in doses sufficient to prevent the emergence of an abstinence syndrome, In a dose ratio of 1 mg of heroin for 3 mg of morphine. Upon abrupt withdrawal, a typical morphine-like abstinence syndrome emerged which had an onset somewhat earlier (approximately five hours) than morphine and persisted for a shorter period of time. Statistics were not employed to determine whether these differences were significant. In a second experiment, two non-tolerant and non-dependent addicts were addicted to 180 mg heroin per day for 59 days and then abruptly withdrawn. A typical 87 abstinence syndrome emerged which peaked between the 19th and 28th hour. Fraser et al., (1961), compared heroin with a variety of other narcotic analgesics including morphine. In a cross-over study, patients were made dependent on these drugs using a rapidly accelerating dose schedule for 18 to 20 days and were then abruptly withdrawn for 10 days before administering another drug. For morphine, the starting dose level was 30.6 mg/day and was increased to 207 mg/day over the next 18 to 20 days. For heroin, the starting dose level was 13 mg/day which was increased to 86.8 mg/day. During the course of the addiction, there were no significant differences between the patients' ability to identify either morphine or heroin as a narcotic, their estimation of strength of the medications or their desire to take the drug daily. In this study, the intensity of abstinence in morphine dependent subjects was 198 + 16 as compared to 150 + 15.6 for heroin dependent subjects (mean + standard error) Himmelsbach scores (Himmelsbach 1937; Kolb and Himmelsbach, 1938 and Himmelsbach, 1939). .The morphine absti- nence syndrome came on as rapidly as did that of heroin and there was essen- tially no difference in persistence of abstinence signs. Martin and Fraser (1961) iperod single doses of heroin with single doses of morphine and found, depending on the measure, that heroin was 1.8 to 2.7 times more potent than morphine when both drugs were administered intravenously. Martin and Fraser (1961) also studied dependence produced by the intravenous administra- tion of heroin and morphine. Again using the short addiction model, the subjects were given heroin in doses of 7.2 to 76 mg/day or morphine in doses of 18 to 180 mg/day over a period of 19 days, followed by abrupt withdrawal. A ten day interval of saline injections was interposed between these two addiction cycles. In brief, subjects became as tolerant, if not more tolerant, to morphine than they did to heroin. The degree of acceptance of the two drugs by the patients was approximately equal; the type of subjective changes reported by the patient was approximately the same for the two drugs and finally, the abstinence syndrome came on at approximately the same time for the two drugs. There was a tendency for the morphine abstinence syndrome to persist somewhat longer than the heroin abstinence syndrome. Thus, the dependence capacity of the two drugs appeared to be, for all intents and purposes, the same. Subjective Effects in Man Martin & Fraser (1961) compared single intravenously administered doses of morphine and heroin on pupillary diameter and subjective state in abstinent prisoner narcotic addicts. Both drugs constructed pupils, produced feelings of itchy skin, relaxation, coasting, soap boxing (talkativeness), drive (energy) but little sleepiness. Heroin and morphine produced similar changes with heroin being approximately twice as potent as morphine. Jasinski and Nutt (1972) and Nutt and Jasinski (1973) compared intravenously administered heroin (2 %, 5 and 10 mg) with intravenously administered morphine (5, 10, and 20 mg) and methadone (5,10 and 20 mg) and found that the effects of heroin, morphine, and methadone were indistinguishable by the addicts, that heroin was approximately twice as potent as morphine and methadone on all measures, and that the time effect curves for heroin and morphine both on pupils and subjective effects were indistinguishable, The predominant effect of heroin, morphine and methadone was to produce euphoria as indicated by dose related elevations of score on the morphine-benzedrine group scale. 88 Smith et al., 1962 and Smith and Beecher (1962) compared the subjective effects of heroin and morphine in college students and found that both drugs produced mental clouding, decreases in feelings of friendliness and euphoria as well as a variety of somatic changes including dizziness, itchiness, and nausea. Although equianalgesic doses were employed in these studies, the effects of heroin were greater than those of morphine. Further, both drugs impaired mental function with heroin's effects having a more rapid onset than morphine's and its effects were more profound. Metabolism in Man and Animals It has been known that heroin is degraded to morphine in man since the work of Oberst (1943). This raised the question of whether heroin has activity in its own right or whether it is pro-drug with its metabolites being the active drug. Animal studies have demonstrated the metabolism of heroin to 6-monoacetylmorphine (6MAM) and to morphine (Wright, 1941, 1942; Ellis, 1948; and Cohn et al., 1973). Eddy and Howes, (1935) and Wright and Barbour (1935) suggest that heroin was converted to 6-MAM and that 6-MAM was responsible for heroin's pharmacologic activity. The most compelling reason for this suggestion was that morphine and 6-MAM were equipotent analgesics in the mouse. Way et al. (1960) conducted a definitive study of heroin metabolism in the mouse and confirmed the observations that heroin was metabolized to 6-MAM and morphine. In this regard, the homogenates of liver and kidney produced a more complete degradation of heroin to morphine than did brain homogenate and blood. They found brain levels of heroin following intravenous administration fell to undetectable levels in less than 10 minutes, 6-MAM had a half life of approximately 10 minutes, while morphine did not reach peak levels until 15 minutes after injection. Way et al. (1960) confirmed earlier observations that heroin and 6-MAM were equipotent and several times more potent than morphine when the drugs were administered subcutaneously. Important were the observations that morphine was 6 times more potent and heroin twice as potent as 6-MAM when administered intracerebrally. Yeh and McQuinn (1975) and Yeh et al. (1977) identified morphine, 6-MAM, normorphine, morphine 3-glucuronide, morphine 6-glucuronide, 6-acetylmorphine 3-glucuronide and normorphine glucuronide in the urine of subjects who had received 10 mg/70Kg of heroin intravenously. Only small quanitities of heroin were found in the urine of patients receiving heroin and then only in urine specimens collected within two hours after the administered dose. Morphine and its glucuronides are heroin's major metabolites and can be detected in urine for over 96 hours (Gorodetzky et al., 1974; Yeh et al., 1976). The half life morphine and 6-MAM are just over 1 hour. Mo et al., (1966) studied the metabolism of heroin inhaled using "ack-ack" (dipping the lighted end of a cigarette into heroin and then inhaling the cigarette smoke) or "chasing the dragon' where heroin is mixed with barbital, heated in tin foil and the vapor inhaled. ' Chasing the dragon" 89 was about 40% as efficient as intravenous injection and "ack-ack" less than 20% as efficient. Barbital appeared to decrease the pyrolysis of heroin and increase its volitization. SELF ADMINISTRATION AND SELF STIMULATION The rhesus monkey, trained to self administer other drugs, will self administer heroin as well as morphine, methadone and LAAM (Harrigan and Downs, 1978). Methadone and LAAM appeared to be more depressant and toxic to the rhesus monkey than heroin and morphine. Heroin dependent baboons will also self administer heroin and the amount self administered can be reduced by passively administering morphine or by making food availability contingent on dose reduction (Wurster et al., 1977). VanRee and DeWeed (1977) have shown the polypeptides will, alter self administration of heroin by rats. Desglycinamide”?, arginine vasopressin and pressinamide reduce self administration, while oxytocin and prolyl-leucyl-glycinamide enhance it. Heroin (5 mg/kg) enhances the bar pressing rate for intracranial self stimulation, but not bar pressing for food and water (Koob et al., 1975), an effect previously observed for morphine. Heroin dependent baboons will increase bar pressing for heroin in a dose related manner following the injection of naloxone (Griffith et al. 1976). Methadone decreased bar pressing for heroin. BEHAVIORAL EFFECTS Morphine (5, 10 and 30 mg/kg) and heroin (2.5, 5 and 10 mg/kg) disrupted performance on maze learning and impaired the consolidation of the learning of this task in rats (Castellano, 1975). These effects were antagonizable by naloxone and performance recovered when the drugs were withheld. Heroin, like morphine, enhances bar pressing for food at low doses and decreases it at higher doses (Thornhill et al., 1975; Rhodus et al., 1974). Conclusion Heroin is metabolized to monoacetylmorphine and then to morphine in both the brain and body. Most evidence would indicate that its actions are not only indistinguishable from morphine, but attributable for the most part to. its metabolic conversion to morphine. It may have a somewhat more rapid onset of action due to the transient presence of the two labile acetyl groups. Thus it is unlikely thatheroin, on the basis of existing data, is either substantively more pernicious or therapeutically more efficacious than many other closely related analgesics. Two special theraputic indications for heroin have been advocated, (1) for maintenance therapy and (2) for the treatment of the suffering and terminally ill. Advocates of heroin maintenance for the treatment of narcotic addicts hope that it will bring more addicts into maintenance therapy and hold them longer. Although existing evidence does not indicate that this hope is realistic, a well designed and executed study could vigorously test it. 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The pharmacologic effects of heroin in relationship to its rate of biotransformation. J. Pharmacol. Exp. Ther. 129:144-154 (1960). Wright, C. I. The enzymatic deacetylation of heroin and related morphine derivatives by blood serum. J. Pharmacol. Exp. Ther. 71:164-177 (1941). Wright, C. I. The deacetylation of heroin and related compounds by mammalian tissues. J. Pharmacol. Exp. Ther. 75:328-337 (1942). Wright, C. I., Barbour, F. A. The respiratory effects of morphine, codeine and related substances. IV. The effect of a monoacetyl- morphine, monoacetyl dihydromorphine, diacetylmorphine (heroin) and diacetyldihydromorphine on the respiratory activity of the rabbit. J. Pharmacol. Exp. Ther. 54:25-33 (1935). Wurster, Richard M., Griffiths, Roland R., Findley, Jack D., and Brady, Joseph V. Reduction of heroin self-administration in baboons by manipulation of behavioral and pharmacological conditions. Pharmacology Biochemistry & Behavior 7:519-528 (1977). Yeh, S. Y., McQuinn, R. L. GLC determination of heroin and its metabolites in human urine. J. of Pharmaceutical Sciences 64(7):1237-1239 (1975). 49. 50. 51. 95 Yeh, S. Y., Gorodetzky, C. W., McQuinn, R. L. Urinary excretion of heroin and its metabolites in man. J. Pharmacol. Exp. Ther. 196(2): 249-256 (1976). Yeh, S. Y., McQuinn, R. L., Gorodetzky, C. W. Identification of diacetylmorphine metabolites in humans. J. Pharmaceutical Sciences 66(2):201-204 (1977). Zaks, A. M., Bruner, A., Fink, M. and Freedman, A. M. Intravenous diacetylmorphine (heroin) in studies of opiate dependence. Dis. Nerv. Syst. Suppl. 30:89-92 (1969). 96 State-of-the-Art Paper Use of Cannabis Constituents and Homologs as Therapeutic Agents Prepared by Leo E. Hollister, M.D. Professor of Medicine, Psychiatry and Pharmacology Stanford University School of Medicine Palo Alto, California 97 Use of Cannabis Constituents or Homologs as Therapeutic Agents Cannabis has been used as a remedy for many centuries. The era of its therapeutic use in Western medicine began in 1839, with the publication of a long article which reviewed many aspects of the drug as a medication, includ- ing such therapeutic uses as an analgesic and anticonvulsant agent (1). During the remainder of the 19th century, a lively interest in exploiting the therapeutic potential of cannabis continued. Among the conditions for which cannabis was reported to be effective were tetanus, convulsive disorders, neuralgia, migraine, dysmenorrhea, obstetrical labor, uterine hemorrhage, rheumatism, asthma, chronic bronchitis, postpartum psychoses, senile insomnia, depression, gonorrhea and opium or chloral hydrate addiction, as well as its use to stimulate appetite and to allay the pain and anxiety of patients ter- minally ill with cancer (2,3). The introduction of many new synthetic drugs from 1900 on decreased the enthusiasm for cannabis as a treatment. The strict control of the material imposed by its inclusion in the Tax Act of 1937 further discouraged its therapeutic use. By 1941, it had been deleted from the U.S. Pharmacopoeia and the National Formulary. About the same time, however, advances were being made in the chemistry of cannabis that defined the major active component as tetrahydrocannabinol (THC). It also was possible to make semisynthetic compounds such as synhexyl, that had THC-like activity. These developments spurred a renewed interest in the therapeutic potential of cannabis constituents. The euphoriant effects of cannabis suggested its possible use in depressed patients, ‘simplistic as this notion may appear. A number of clinical trials, usually employing the synthetic homolog, synhexyl, were undertaken in the late 1940s and early 1950s. Despite some early enthusiasm for its efficacy in depressed patients, subsequent studies indicated that synhexyl had no better effect than a placebo and actually seemed to be less effective than ampheta- mine (4-6). A similar course was followed in regard to its use as a substi- tute for patients being withdrawn from alcohol and opiates, an initially favorable report being followed by one indicating little amelioration of the natural withdrawal syndromes (7,8). These discouraging results once again diminished enthusiasm for using cannabinoids as therapeutic agents. The determination in 1964 of the actual structure of THC in cannabis as delta-9-trans-tetrahydrocannabinol and its subsequent synthesis made available to scientists a large supply of this and other constituents of cannabis. From 1968 to the present time, cannabis has been one of the most diligently studied of all drugs. These modern studies have once again included potential therapeutic uses, some of which were hinted at early on, others of which have been discovered somewhat empirically (9). Use of cannabis-like compounds has enough potential financial reward that a number of pharmaceutical houses have active programs in operation to develop homologs of cannabinoids as therapeutic agents. Several hundred such homologs 98 have already been synthesized, but therapeutic trials in man have been meager. The major goal of such efforts has been to separate, by various chemical modifications, specific desired pharmacologic effects of THC from what is now construed to be an undesired effect, that is, the pronounced mental effects. The quickening pace of research interest in the therapeutic potential of cannabis has been reviewed elsewhere (10). The goal of this review will be to try to assess the present state of these developments, indicating areas that look relatively promising as well as those which do not. Control of Nausea and Vomiting from Cancer Chemotherapeutic Agents Nausea and vomiting which accompanies the use of cancer chemotherapeutic agents is extremely difficult to treat with ordinary antiemetic drugs, such as prochlorperazine. This drug, as well as many other phenothiazines, acts specifically at chemoreceptor trigger zones in the medulla sensitive to chemical stimuli that induce vomiting, such as apomorphine. For reasons still not clear, the vomiting induced by anticancer drugs does not respond well to such antiemetics, even though it is chemically induced. A young patient with leukemia was said to have first noted that he did not vomit if he smoked marihuana prior to and during treatment with chemo- therapy. Whether or not the story is true cannot be ascertained, but the observation had become part of the lore as early as 1972 (11). The first serious trial of THC as an antiemetic was a controlled comparison of this drug with placebo in 20 patients undergoing cancer chemotherapy. Doses of THC were given orally as gelatin capsules in which THC was dissolved in sesame oil, The dose was 15 mg every four hours for three doses in 19 patients with 20 mg doses in 3 patients. Doses were started two hours before chemotherapy and repeated two and six hours after. Results were outstanding. Fourteen of 20 patients in whom an evaluation could be made had an antiemetic effect from THC while none was observed from placebo during 22 courses (12). Further experimental verification of this effect of THC has not yet been published, but many patients are now treating themselves with apparent satis- faction. A homolog of cannabinol known as nabiline was developed in 1972. Initially, it was thought that the drug might be highly useful as an anti- anxiety drug, a class of drugs that has apotentially huge market. Early trials of nabilone in man indicated that it had a very narrow therapeutic margin. Single doses of 1 and 2.5 mg produced only sedative effects, while a dose of 5 mg produced marked euphoria, dry mouth and postural hypotension. Tolerance developed to these effects with repeated doses (13). Using a model of experimentally-induced anxiety, a single dose of 2 mg of nabilone was compared with 5 mg of diazepam in subjects with high levels of anxiety. In this experimental model the drug did not look so promising, being less effective than diazepam (14). 99 Nabilone looked far better when it was tested as an antiemetic agent. It significantly reduced the nausea and vomiting induced by cancer chemo- therapy in 10 of 13 patients refractory to usual antiemetics. Each patient received two doses of nabilone (1 or 2 mg orally) before chemotherapy was started and this dose was repeated every 8 hours for 5 days. Side effects of somnolence, dizziness, decreased coordination and postural hypotension were experienced by some patients but were not considered to be major problems. Euphoria was minimal at the dose levels used (15). Other unpublished studies of nabilone, as well as an extension of the reported study, confirmed this antiemetic action of nabilone. As yet, the drug has not been compared in a controlled trial with a conventional antiemetic, such as prochlorperazine, or with THC. It is unfortunate that a comparison with THC was not made earlier, for recently clinical trials of nabilone have been suspended due to reports of marked mental effects, including hallucinations, associated with its repeated use. My group was enthusiastic about entering a phase 3 protocol for compar- ing nabilone with prochlorperazine in such patients. When the protocol was submitted to the FDA, it was changed to make the comparison against a placebo, on the basis that the use of prochlorperazine for this indication had never been approved. It may not have been, but its use for this purpose was common clinical practice. We did not feel that we could ethically treat our patients without the use of some drug likely to have effect and demurred from further participation. One would hope that if these studies are resumed they will take into account the responsibility of the physician to his patient. Despite the uncertain fate of nabilone, it seems reasonable to believe that either it or some other homolog of cannabinoids or THC itself should be useful for this unsolved problem. Other possible beneficial effects of these drugs in patients with cancer could be relief of depression, stimulation of appetite or relief of pain. Early on, I treated one cancer patient with THC and found that the drug did not agree with the patient, who asked that it be discontinued. Still, other patients might find it to be helpful and the mental side effects may be tolerable in this situation. Treatment of Glaucoma The discovery that smoking cannabis reduced intraocular pressure was unpredicted and fortuitous. A survey of possible ocular effects of cannabis was added to a multifaceted study of the effects of chronic smoking of large amounts of the drug. Decreases of intraocular pressure up to 45 percent were found in 9 of 11 subjects after 30 minutes of smoking (16). This effect lasted for 4 to 5 hours after smoking a single cigarette. Its magnitude was unrelated to the total number of cigarettes smoked. Thus, it appeared that a maximal effect was produced by the amount of THC absorbed from a single cigarette containing 19 mg of THC. In patients with ocular hypertension or glaucoma, 7 of 11 patients showed a fall in intraocular pressure of 30 percent. 100 The clinical importance of this observation has been questioned. One group found that tolerance developed to this effect of THC when it was given orally. They felt that the lowering of pressure occurred only in conjunction with a general state of sedation and relaxation produced by cannabis, suggest- ing that it was a nonspecific effect (17). Further evidence indicates that the effect is real, for it has been confirmed in man. Intravenous injection of THC in doses of 22 ug/kg and 44 ug/kg produced an average fall in intra- ocular pressure of 37 percent, with some decreases as much as 51 percent (18). Similar experiments in rabbits, using several routes of administration has also confirmed the reduction in pressure. ; Obviously, smoking marihuana or taking it intravenously are hardly reasonable recommendations to make for patients with glaucoma, many of whom are elderly. If the drug could be administered topically, however, many impediments to its use would be overcome. Thus far, all experiments have been done only in rabbits, a traditional animal model for studying topical eye medications. The group at the Medical College of Georgia has made considerable progress. The problem of high lipid solubility of THC has been overcome by developing a well tolerated oily vehicle for instillation in the eye. The degree of lowering of pressure is at least as great as with conven- tional eye drops, such as pilocarpine, and the duration of effect is often longer. A minimal systemic absorption of the drug occurs when it is applied to the conjunctivae, but it is of no consequence in producing mental effects. Besides THC, other cannabinoids, such as cannabinol or THC metabolites, such as 8-alpha- and 8-beta-1l-dihydroxy-delta-9-THC have shown this effect in rabbits (19). As these agents have no mental effects, they are of considerable interest for this purpose. The mechanism of action of THC in lowering ocular pressure has been extensively investigated by the Georgia group. Blood flow through the iris, ciliary processes and choroid was increased by THC. The increased blood flow is due to dilation of vessels leading away from the anterior uvea consequently reducing the ultrafiltration pressure for aqueous humor formation. Removal of aqueous humor is also facilitated (20). Thus, this class of agents for treat- ing glaucoma is novel not only for their chemistry but also for their mode of action. The outlook for this exploitation of cannabinoids in treatment is quite promising. It will take a considerable amount of further developmental work to be sure that whichever cannabinoid is selected for clinical use will be lastingly effective and well tolerated. Nonetheless, the potential benefit will be great, for glaucoma treatment has not changed significantly in years and it still does not prevent blindness as often as it might. Further, the effects of cannabinoids may be additive with those of other drugs, so that the overall benefit to patients may be greater than is currently possible from treatment. 101 Treatment of Insomnia The sedative-hypnotic effects of marihuana and THC are well known. They usually follow an initial stage of stimulation associated with the "high", but some subjects merely show sedative effects. Cannabis resembles alcohol in this respect. The social use of cannabis is probably based to a great extent upon obtaining sedating and relaxing effects, again similar to the social use of alcohol. Although early speculation had suggested that THC might differ from conventional hypnotics in not reducing rapid eye movement (REM) sleep, study of the drug in the sleep laboratory showed that it did (21). Doses of THC ranging from 61 to 258 ug/kg in normal subjects produced increments in stage 4 sleep and decrements in REM sleep. The REM rebound so characteristically produced after successive doses of hypnotics did not follow chronic treatment with THC. A subsequent clinical study of THC administered orally as a hydroalcoholic solution in doses of 10, 20 and 30 mg showed a shortening of the time that it took for subjects to fall asleep. Prior to falling asleep, however, mood alterations were noted consistent with a "high". Some degree of hangover the day following was noted from the larger doses (22). Another sleep laboratory study showed that a dose of 20 mg of THC given orally decreased REM sleep. Abrupt discontinuation of THC after 4 to 5 nights of use produced a mild insomnia but no marked REM rebound (23). The lack of effect on REM rebound seen with low doses of THC was not apparent when very high doses (70 to 210 mg) were given orally. REM was reduced during treatment and marked REM rebound was observed after withdrawal (24). These studies indicate that the sleep produced by THC does not differ much from that of most currently used hypnotics. The side effects of the drug before sleep induction as well as the hangover effects make the drug less acceptable than the currently popular benzodiazepines, such as flurazepam. As many other effective hypnotics are currently being developed, it seems unlikely that THC will find a place in treatment of insomnia. Anticonvulsant Effects Anticonvulsant activity was one of the first therapeutic uses suggested for cannabis and was documented experimentally many years ago (25). Subse- quently, a great many studies in various animal species have validated this action. Treatment of cats with THC temporarily reduced the clinical and electrographic seizure activity induced by electrical stimulation of subcortical structures (26). Cannabidiol protected mice against maximal electroshock seizures but not against those caused by pentylenetetrazole. Its profile of activity more resembled that of phenytoin than of THC (27). Both THC and cannabidiol caused potentiation of the anticonvulsant effects of phenytoin against electrically induced seizures in mice. Combining the two cannabinoids 102 produced the most effect (28). The technique of kindling involves the once- daily application of initially subconvulsive electrical stimulation to culminate in generalized convulsive seizures. Chronic administration of THC in rats prevented the kindling effect (29). Despite all these various lines of evidence supporting an anticonvulsant action of various cannabinoids, clinical testing of this activity has not yet been undertaken. A single case report of better control of seizures following regular marihuana smoking is not very convincing (30). On the other hand, neither is a single report of convulsions induced by marihuana. If clinical trials were to be done in man, cannabidiol would seem to be the most likely candidate for testing. It is devoid of mental effects and could possibly decrease the metabolism of phenytoin. It is possible also that the convulsant action of cannabis may reside in the THC component and not be a property of cannabidiol. Analgesia Evaluation of new analgesics is-a specialized field that might be called analgesiology. To date, few experienced analgesiologists have studied cannabis. Normal subjects tested for sensitivity to an electric shock applied to the skin showed an increased sensitivity to pain following smoking of material estimated to deliver 12 mg of THC (31). On the other hand, THC in single oral doses of 10 and 20 mg was compared with codeine (60 and 120 mg) in patients with cancer pain. The larger THC dose was comparable to both doses of codeine, but the smaller dose, which was better tolerated, was less effective than either dose of codeine (32). When THC was given intravenously in doses of 44 ug/kg to patients undergoing dental extraction, an analgesic effect was demonstrated. It was not as good as that achieved by doses of 157 ug/kg of diazepam intravenously. Anxiety and dysphoria were produced in these patients, several of whom actually preferred the placebo to the dose of 22 ug/kg of THC (33). One is faced with an apparent paradox. THC both increases and decreases pain. Actually, it could do both. Pain derived from the integument is usually treated with drugs such as aspirin, which work peripherally by opposing the action of bradykinin and possibly also by inhibiting the synthesis of prostag- landins. THC may inhibit prostaglandin synthesis, but its initial stimulation might increase sensitivity to this kind of pain. Pain from viscera, such as that of cancer patients, is usually treated by opiates. The site of action here is not peripheral but central. Some recent evidence suggests that opiates may act directly on pain pathways, even in the spinal cord, but they also reduce the processing component of pain, that is, the affect that accompanies it. This latter action could conceivably be attributed to cannabis. Thus, when the two types of pain are distinguished from each other the apparent paradox is solved. 103 In view of the relatively weak effect of THC as an opiatelike analgesic, as well as its prominent mental effects at high doses, it would not seem worth pursuing its potential use as an analgesic, even though THC is not addicting as the opiates are. Despite this small advantage, it seems unlikely that cannabis has much future as an analgesic. Opiates are reliable and addiction to them in a medical setting is a negligible problem. Bronchial Asthma Bronchodilation from marihuana smoke was discovered during a general study of the effects of the drug on respiration. Normal volunteer subjects were exposed to marihuana smoke calculated to deliver 84 ug/kg or 32 ug/kg. The high-dose group showed a fall of 38 percent in airway resistance and an increase of 44 percent in airway conductance. Changes were less in the low- dose group, but still significant as compared with baseline. Neither dose altered the sensitivity of the respiratory center to carbon dioxide (34). Thus, the drug produced no central respiratory depression. To test the bronchodilating action further, asthma was deliberately induced by either inhalation of methacholine or exercise. The asthmatic patients were then tested with either inhalation of placebo marihuana, of saline, of isoproterenol or of smoke derived from marihuana containing 1 g of THC. Both marihuana smoke and isoproterenol aerosol effectively reversed both methacholine- and exercise-induced asthma. Saline and placebo marihuana had no effect (35). Ten stable asthmatic patients were treated in another study with aerosols of placebo-ethanol, of THC 200 ug in ethanol, or of salbutamol 100 ug. Forced expiratory volume in 1 second, forced vital capa- city and peak flow rate were measured on each occasion. Salbutamol and THC significantly improved ventilatory function. Improvement was more rapid with salbutamol but the two treatments were equally effective at the end of one hour (36). These encouraging studies were somewhat clouded by another indicating that some patients might experience bronchoconstriction following THC. The drug was given orally in a dose of 10 mg. A mild and inconstant bronchodilator effect was associated with significant central nervous system effects. Worst of all, one patient of the six studied developed severe bronchoconstriction (37). It is difficult to know how to interpret this single instance of broncho- constriction following oral THC. As THC is eminently suitable for aerosol administration, the side effects of mental symptoms might be avoided. The doses were small, but as this route is commonly used for social use of the drug, some abuse would be possible. Whether this route of administration would be less likely to be associated with bronchoconstriction is difficult to predict. The fact that THC increases airway conductance by a mechanism of action that may be different from the usual beta adrenergic stimulants 104 makes further inquiry necessary. Asthmatic patients sometimes become resist- ant to repeated applications of beta adrenergic stimulants and the possibility of being able to use another type of bronchodilator might help some patients. On the other hand, the recent introduction of highly effective steroid aerosols, such as beclomethasone, meets that need to a considerable extent. Hypertension THC itself occasionally produces orthostatic hypotension (38). However, most interest has centered around a dimethylheptyl side-chain derivative that has more profound and constant effects on blood pressure. Studies of this compound in man have consistently shown a marked orthostatic hypotensive effect, as well as production of tachycardia and some symptoms resembling those of THC. Although the latter are less in proportion to the blood pres- sure lowering effect than is the case with THC, a definite separation of pharmacological effects has not really been attained (39). Many of the acute effects of THC on the heart resemble those of beta adrenergic stimulation. This action might be one to be avoided in hyper- tensive patients. On the contrary, chronic effects tend to be the opposite, leading to the possibility of a biphasic effect on the sympathetic nervous system with inhibition after chronic exposure (40). The development of effective antihypertensive drugs has been one of the outstanding achievements of pharmacology over the past 25 years. The prospect of a new antihypertensive based on orthostatic hypotension, perhaps the least desirable mode of lowering blood pressure, is hardly very enticing (40). Further, it is by no means certain that the mental effects of any homolog of THC can be completely eliminated without losing many of the desired pharma- cological actions as well. The issue seems hardly worth pursuing further. Miscellaneous Potential Uses Abstinence Syndromes due to Central Nervous System Depressants. As mentioned earlier, synhexyl, the first THC homolog to be synthesized, had been tested as a treatment for withdrawal reactions from opiates and alcohol with little evidence for its efficacy. THC reduced some of the withdrawal symptoms experienced by rats following morphine pellet implantation and precipitation of abstinence by subsequent injection of naloxone. Cannabidiol, without any direct effect itself, augmented the action of THC (42). It seems unlikely that this relatively weak effect of cannabinoids in opiate dependence could be useful clinically. Existing detoxification programs using methadone have been highly successful and acceptable. 105 Antineoplastic Activity. Both isomers of THC, the delta-9 and the delta-8, as well as cannabinol, have some antineoplastic effect on transplanted lung tumors in animals, as well as on tumors in vitro (43). THC may have a general ability to reduce synthesis of nucleic acids, which may account for the reported immunosuppressant effects as well. In view of the fact that many agents are available that can strongly inhibit nucleic acid synthesis, the possibility that THC or other cannabinoids might be advantageous seems rather unlikely. Antimicrobial Action. Both THC and cannabidiol inhibit and kill staphylococci and streptococci in vitro at concentrations of 1 to 5 ug/ml (44). Such con- centrations are well above those reported from use of THC in man , even at the highest tolerated doses. Thus, this effect seems to have little practical application. Migraine. This indication is an old one, but one that curiously has not been studied systematically in recent years. I tried the drug in one patient, but the side effects, that is the mental effects sought socially, caused the patient to abandon treatment. The number of successful treatments for migraine that have been reported at one time or another would virtually fill this page. Appetite Stimulant. Very few drugs stimulate appetite, although most of the antipsychotic agents will. Appetite stimulation could be of some help in treating anorexia nervosa. In an experimental study of this effect of THC, as compared with that of ethanol and that of dextroamphetamine, we found that both in fasted and fed subjects, the response was variable with the majority showing an increase in appetite and food consumption as compared with placebo (45). A controlled clinical trial in anorexics has been sponsored by the National Institute of Mental Health. THC is being compared against cypro- heptadine, a known appetite stimulant, and placebo. The final report has not yet been published. The list of potential clinical uses of cannabinoids or their homologs could be extended further, but I have tried to cover those that would be most likely to work and which would represent greatest clinical innovation. Cannabis should be treated like any other investigational new drug as the search for a clinical use in medicine goes on. We should éxpect neither less nor more in regard to safety and efficacy than we would from other new agents. Those who argue for its acceptance as a social drug are most enthusiastic about its potential medical use; in their view, the latter would somehow or other sanction the former, although it is difficult to follow such logic. Paradoxically, the greatest deterrent to the use of these agents in medicine may very well turn out to be the mental effects so sought by the social user. 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Munson, A.E., Harris, L.S., Friedman, M.A., Dewey, W.L. and Carchman, R.A.: Antineoplastic activity of cannabinoids. J. Natl. Cancer Inst. 55:597-602, 1975. Van Klingeren, B. and Ten Ham, M.: Antibacterial activity of delta-9-tetrahydrocannabinol and cannabidiol. Antonie van Leeuwenhoek 42:9-12, 1976. Hollister, L.E.: Hunger and appetite after single doses of marihuana, alcohol and dextroamphetamine. Clin. Pharmacol. Ther. 12:44-49, 1971. 110 CURRENT STATUS OF PAIN THERAPY BY JOHN J. BONICA, M.D., D.Sc., F.F.A.R.C.S. DIRECTOR MULTIDISCIPLINARY PAIN CENTER UNIVERSITY OF WASHINGTON SEATTLE, WASHINGTON 98195 PRESIDENT INTERNATIONAL ASSOCIATION FOR THE STUDY OF PAIN 111 CURRENT STATUS OF PAIN THERAPY Proper control of pain is one of the most important and pressing issues of American medicine. Acute and chronic pain afflict over a quarter of Americans annually and in many patients with chronic pain, and in some with acute pain, it is not adequately relieved. Consequently, it is the most frequent cause of disability and suffering in the United States. Although accurate statistics from national epidemiologic studies are not available, there are data which suggest that over 40 million Americans are either partially or totally disabled, either temporarily or, more frequently, permanently, by chronic pain. In most patients with arthritis, back disorders, coronary disease, and other chronic conditions, it is not the underlying pathology but the pain that prevents the patient from carrying out a productive life. It is estimated that as a result nearly 700 million workdays are lost, which together with health care costs and payments for compensation, litigation, and quackery, total between $40 and $50 billion annually. This equals nearly 107 of our national budget and 25-307 of total health care cost. These figures do not include the economic impact of acute pain due to dental disorders or acute disease or injury. Even more important is the cost in terms of human suffering. In considering the magnitude of this aspect of pain, it is important to recognize the differences between acute pain and chronic pain, especially in regard to cause, function, diagnosis, and therapy. Acute pain is invariably due to disease or injury, its diagnosis is usually not difficult and with some exceptions therapy is effectively carried out. In the initial phase, acute pain usually has the important biologic function of warning the individual that something is wrong and usually prompts him or her to seek medical counsel and is used by the physician as a diagnostic aid. On the other hand, severe acute pain that develops following certain operations, burns, or accidental injury has no useful function and if not adequately relieved produces serious psychologic and physiologic responses which often cause complications. Similar effects result if, after it has served its biologic function, severe pain of myocardial infarction, pancreatitis, and other acute bodily process is not effectively relieved. Chronic pain, defined as pain which persists or recurs at intervals for months and years, is caused not only by chronic pathologic processes in the body or nervous system, but also by psychopathology and environmental influences. Chronic pain never has a biologic function but is a malefic force which imposes severe physicial, psycho- logic, social and economic stresses on the patient and the family. Many patients with chronic pain undergo a progressive physical deterioration, develop anxiety, depression, and other emotional disturbances and have additional behavioral changes often as the result of improper therapy. The social effects of chronic pain are equally devastating: many patients become estranged from their families, are unable to work or lose their jobs, and some become so discouraged and so desperate as to contemplate or even commit suicide. These effects are especially severe in patients with cancer pain. The many reasons for the serious deficiencies of current pain therapy may be grouped into two major categories: (a) voids in our knowledge about pain and its mechanisms; and (b) inadequate or improper application of the knowledge currently available. Despite its overwhelming clinical importance, until very recently, pain research was virtually neglected by scientists and research agencies - a fact which has been duly emphasized by the INTERAGENCY COMMITTEE ON NEW THERAPIES FOR PAIN AND DISCOMFORT. Equally, or more important to the thesis of this report, is that know- ledge, agents, and technics currently available generally have been improperly applied. 112 CURRENT STATUS OF PAIN THERAPY This in turn has been due to lack of organized teaching of medical students, physi- cians and other health professionals about pain as a major clinical problem. Students have been taught to consider pain as a symptom of disease, to use it as a diagnostic aid and the various modalities for treatment of acute pain, but very few, if any health professional schools, include in their curriculum formal courses on chronic pain. Consequently, many patients with chronic pain do not respond to the usual medical management currently provided and the pain, suffering and disability remain. Indeed an impressive number of patients with chronic pain are exposed to the risk of iatrogenic (treatment produced) complications including drug toxicity and narcotic addiction and multiple, and often useless, surgical operations. Although several very recent developments hold the promise of helping to rectify these deficiencies, much much more needs to be done. The critical need to expand research and research training as defined by the INTERAGENCY COMMITTEE requires no elaboration. It is hoped that all of the recommendations made by the Committee will be implemented soon because the potential payoff of research in this heretofore neg- lected field is great especially in elucidating basic mechanisms. Once we acquire this information, we possess the scientific knowledge and technology to produce agents with exquisitely specific effects to promptly relieve some kinds of pain without unwanted side effects. However, until new information is acquired currently available knowledge and therapeutic modalities should be used more effectively to treat patients with acute and chronic pain. To achieve this goal it is necessary to greatly expand educational programs in pain therapy for students, physicians and other health professionals. Current therapy. Obivously the best method to treat pain is to eliminate its cause and mechanisms, but unfortunately, in many patients these are unknown, or if known, cannot be eliminated and the pain must be relieved by the use of one or more of the following methods: (a) pharmacologic agents; (b) psychologic techniques; (c) nerve blocks; (d) physical methods; and (e) neurosurgical procedures. To determine the best therapeutic modality or combination of therapies, it is essential to consider the causes, mechanisms and characteristics of the pain; the age and social responsi- bilities of the patient; the chronology of the disease, its prognosis and previous therapy; and various other aspects which can only be ascertained by a detailed history, a comprehensive generation examinations and complete psychologic evaluation. Finally, it is essential to know the analgesic efficacy, advantages, limitations and disadvantages of each of the aforementioned therapeutic methods. Pharmacologic agents. These include aspirin and other non-narcotic analgesics, corticosteroids, psychotropic, anticonvulsant and vaSoconstrictive drugs and narcotics. All of these drugs are readily available, relatively cheap and simple to administer and if properly used are reasonably effective in relieving pain. Unfortunately, in many instances they are not administered in the most effective way, and consequently the patients do not derive optimal benefit and indeed may incur serious side effects. In patients with mild to moderate pain non-narcotic analgesics such as aspirin and other non-steroidal anti-inflammatory drugs in doses 2 to 3 times of those generally prescribed are effective and should be used before considering narcotics. Cortico- steroids enhance analgesia by preventing the release of prostoglandins and in other ways reduce the inflammatory process and stimulate appetite and elevate mood. Many patients with chronic pain also require antidepressant tricyclic drugs, or anxiolytic agents, or both. Anti-convulsant drugs such as carbamazetine are effective in control- ing moderate tic douloureux and certain other pains due to central nervous system disease. Ergotamine and other vasoconstrictive drugs are effective in preventing or relieving migraine headache. 113 CURRENT STATUS OF PAIN THERAPY Narcotics are effective in providing adequate relief for severe pain caused by an acute (transient) process or by inoperable cancer. Unfortunately many physicians prescribe insufficient amounts of narcotics and these are given only when the pain returns because of concern about addiction. Addiction does not occur with the short term use of the drugs and the problem should be ignored in patients with inoperable cancer. These patients should be given sufficient amounts of the drug at fixed inter- vals to produce continuous pain relief. If the narcotic is carefully titrated to the needs of the patient, good pain relief is achieved with minimal depression and other side effects. Even in patients with severe disabling pain caused by a non-malignant process such as arthritis, the controlled use of narcotics often permits the patient to carry on a productive life. On the other hand, narcotics should be avoided in patients in whom psychologic or environmental factors contribute to chronic pain. ] Psychologic techniques. Psychotherapy, operant conditioning, biofeedback, hyp- nosis and suggestions are the principal psychologic techniques that may be used to relieve acute and chronic pain in certain patients. Individual or group psychotherapy is effective in patients with pain due primarily to emotional disorders. Operant conditioning techniques are effective if the patient's chronic pain behavior has been produced primarily by environmental reinforcements such as the attention and concern of others or the avoidance of unpleasant activities. Treatment is aimed at changing pain behavior by systematically increasing activity with graded exercise and physical therapy, progressive reduction in pain medication and encouraging "well behavior' by positively reinforcing it by staff and family. Biofeedback of muscle tension, skin temperature and other body functions is a relatively new technique that has been used to treat tension and migraine headaches, low back pain and other painful disorders with fair success. Hypnosis is an effective means of reducing or eliminating pain and its affective components as well as encouraging more positive attitudes of health and wellbeing. It has the advantage of minimal or no side effects, but it only works in a small percent of patients and pain relief may not be complete or long term. Less intense forms of suggestion by the therapist, such as giving a placebo, is also effec- tive in relieving mild to moderate pain in about a quarter of patients. Recent evi- dence suggests these agents produce relief by increasing the liberation of endorphins (opiate-like substances produced in the nervous system) and stimulating other neural systems that inhibit transmission of pain messages. These modulating systems are probably activated by psychologic factors and other mental activities. Similar mechanisms have been proposed to explain the pain relief achieved by patients with high motivation and coping skills and the total absence of pain that is experienced by war-wounded soldiers, injured athletes, and women in childbirth. Typically, these cases of self-induced analgesia take place in a dramatic setting which generate strong emotions in the individual. With future research findings it should be possible to exploit these and other mechanisms responsible for such analgesia to a much greater degree in relieving patients with acute and chronic pain. Local anesthetics and nerve blocks. Local anesthetics injected into tissues or near nerves produce complete relief for several hours and by injecting them through very small catheters left in place provide continuous pain relief for days and even weeks. Because these techniques produce complete block of pain pathways, they are “more effective than narcotics in relieving very severe pain following surgery, injury, myocardial infarction, pancreatitis, colic and other acute and chronic pathologic processes in body tissues. Moreover, a series of nerve blocks initiated promptly after the onset of the condition produce permanent relief of pain of causalgia, reflex sympathetic dystrophy, myofascial syndromes and certain other musculoskeletal problems. Nerve blocks with alcohol or phenol, both of which destroy nerves, are useful in relieving severe cancer pain for weeks and months in about 60-70% of patients. The risk of serious complication from neurolytic blocks which include bladder dysfunction and weakness of the limbs can be minimized by skillful administration in selected patients. 114 CURRENT STATUS OF PAIN THERAPY Physical methods. Heat and cold, exercise, postural instruction, massage, traction, manipulation and bracing has long been used to relieve pain. Until recently, most of these non-harmacologic and non-surgical therapies have received little research attention and were considered empirical therapy. However, recent studies have provi- ded plausable scientific explanation for their efficacy. Properly used in selected patients, these techniques are an effective adjunction therapy to help relieve acute and chronic pain and rehabilitate the patient to a more active and productive life. Neurosurgical and neurologic techniques. Modern techniques of nuerosurgery have made destructive and stimulating technics of relieving chronic pain safer and more effective. Surgical interruption of pain pathways in the spinal cord and higher levels of the nervous system can provide complete relief of severe pain in terminal cancer patients and in carefully selected patients with severe non-malignant chronic pain. Vascular surgery or electrocoagulation of the trigeminal nerve are highly effective in relieving severe tic douloureux, an excruciating chronic pain syndrome. The des- truction of the pituitary gland is effective in relieving severe widespread pain in patients with inoperable cancer. Since all of these techniques have the potential of producing serious side effects they must be done by experienced surgeons. Recent theoretical consideratons have prompted the reintroduction of electrical stimulation to relieve pain. Stimulation of the skin is simple, relatively inexpensive and effective in producing short term pain relief in about 50-60% of patients with acute and chronic pain, and lasting relief in about 20% of patients with chronic pain. Acupuncture, achieved by electrical stimulation of the needles, produces short term relief of chronic pain in about 40-60% of patients but only about 15% derive long term relief. Although this procedure, like skin stimulation and placebo, has been shown to probably activate nervous system mechanisms which modulate pain, its role in pain therapy is still uncertain and requies well controlled clinical trials. Stimulators implanted on major nerves or on spinal cord, are also effective in reliev- ing chronic pain primarily due to nervous disease or injury. Stimulation of the brain, achieved by surgically inserting tiny microelectrodes into certain structures in the middle of the brain, is one of the newest and most promising non-destructive technique of pain control. Preliminary data suggest that it is particularly valuable in reliev- ing severe pain from inoperable cancer and severe pain originating within the central nervous system itself which is notoriously resistant to other forms of therapy. Multidisciplinary pain therapy. The multidisciplinary team approach to pain diag- nosis and therapy is based on the thesis that complex chronic pain problems require the coordinated efforts of a team of health professionals who contribute their indi- vidualized knowledge and expertise to the common goal of making a correct diagnosis and developing the appropriate therapeutic strategy. Although this concept was pro- posed and put into practice by Bonica over three decades ago, it did not achieve wider application until recent years. The collective experience of about 60 such facilities, which have been developed in this and other countries, suggests that many patients with chronic pain, including patients with certain types of cancer pain, are best managed by the team approach. In addition to providing service to patients, such a prog- ram is conducive to more effective teaching and to collaborative pain research. JIB/rw 1/12/79 115 THE EFFECTS OF ILLNESS AND DEATH OF ONE FAMILY MEMBER \ ON OTHER FAMILY MEMBERS: A REVIEW WITH SOME RECOMMENDATIONS FOR RESEARCH AND MEDICAL PRACTICE by Selby C. Jacobs, M.D. Adrian M. Ostfeld, M.D. Edited September 1978 From the Departments of Psychiatry and Epidemiology and Public Health, Yale University School of Medicine, New Haven, Connecticut. 116 INTRODUCTION Severe or life threatening illness resulting in the hospitalization of a spouse and the death of a spouse are two major health crises in the older family. This paper will review the literature pertaining to such health crises. The relevant literature comes from diverse psychological, sociological, and clinical (mainly psychiatric) sources. First, this review will summarize studies which &xamine the effect of a spouse's illness on the health status of the conjugal partner. Next, it will review the effect of the death of a spouse on the health of the survivor. In this case the empirical literature is more ample and the studies will be subcategorized into those that report on the mortality experience of the survivors and those that report on morbidity. Next, the review will turn to studies that report on the stress response of a spouse to illness or death of a marital partner. Though little has been done to characterize the response to illness, a sizable literature exists on the response to loss (or grief) which may serve as a model for the response to illness. The part of the review that focuses on mediating processes will supplement the studies on morbidity and mortality and will create a background for the consideration of mechanisms of pathogenesis. A final section is devoted to recommenda- tion for practicing health professionals and for additional research. THE EFFECT OF A SPOUSE'S ILLNESS ON THE HEALTH STATUS OF THE CONJUGAL PARTNER Numerous articles from the sociological literature report on the general issue of the impact of illness on family structure and function. This literature which is largely theoretical will not be reviewed. Aside from a few studies that note the presence of psychosomatic symptoms, there are only a few studies which examine the effect of one spouse's illness on the other person's state of physical health. On the other hand, the specific effect of one spouse's illness on the mental health and the role performance of the partner is better documented. None of these studies has investigated large numbers of subjects; and, in general, the studies are notable for an absence of controls. The literature appears to be far from the point at which firm conclusions may be drawn. The relevant studies are summarized below. Holcomb and MacDonald (1973) have studied the social and family functioning of 23 kidney patients who had home maintenance hemodialysis for an average of 2 years. According to the self-report of spouses, 65% were extremely depressed at times, 57% were frustrated because the patient's illness prevented them from doing things properly, 53% felt vaguely insecure, and 357% could not relax. Problems in sexual relations were also common in another study of 37 arthritic women and their husbands; all the men expressed concern about their wives condition and many were anxious (Wright and Owen, 1976). Anxiety levels were highest among men who were married for the longest time, who had the most children, and who had wives who were the least ill. 117 Various aspects of coronary heart disease and its influence on the spouses of patients have also been explored. In a study of 142 male heart patients and their spouses, Ruskin et al. (1970) have found that the men had elevated MMPI scores but that the wives were, for the most part, within normal limits. Some of the women, however, reported depression and psychosomatic symptoms, especially low back pain. On the other hand, in Shelton and Dominian's (1973) study of 65 wives of men hospitalized for myocardial infarction, feelings of distress were universal —-- guilt, loss, and depression were common. Some psychosomatic symptoms, particularly sleep and eating disturbances, were also noted. Similarly, Croog and Fitzgerald (in press) have interviewed 263 wives of men who have suffered a first myocardial infarction. Patterns of subjective stress remained relatively stable over a one-year period, but at the end of the study year, women whose husbands were rehospitalized for heart-related reasons reported significantly higher levels of stress than did the wives of non- rehospitalized men. Croog and Levine (1977) have recently published a longitudinal study of 345 men and their families after the men suffered a first myocardial infarction. Men age 30 to 60 from several Boston area hospitals were included if they had an uncomplicated, immediate course of recovery and were followed for one year. The investigators observed minimal impact on the family life or marital integration of the family except for changes in role performance in which wives took more leadership and protected the husband. Among families in which there was no serious illness previous to the man's myocardial infarction, 27.5% report serious illness in another family member in the year following the heart attack. In the year before the occurrence of the index illness, 15% of families report serious illness. This difference between the periods before and after the illness event is not statistically significant. Among the latter group, 36% report a recurrence of serious illness after the myocardial infarction. Klein et al. (1967) have observed 121 outpatients who had one or more chronic illnesses and 73 of their spouses. They measured levels of symptomatology using materials from Srole's Midtown Manhattan Study and assessed interpersonal tension from Farber's Index of Marital Inte- gration. Their results showed that 677% of the spouses reported an increase in symptoms when current rates were compared with retrospective pre-illness rates. Fifty-six percent also noted an increase in role tension. The authors interpreted their data according to the belief that illness in the family leads to role failure and, consequently, to the experience of interpersonal tension and psychosomatic symptoms. 118 THE EFFECT OF A SPOUSE'S DEATH ON THE HEALTH STATUS OF THE CONJUGAL PARTNER The Mortality of Surviving Spouses A basic pattern of excess mortality in the widowed, especially in males, is discernable in the studies to be summarized (see tables 1 and 2 for literature citations). The duration of the elevated risk varies by sex and is no more than two years for both men and women. The peak risk for men is in the first six months of widowerhood; for women it is in the second year. Prospective studies have failed to confirm an elevated risk for women in the second year that is apparent in work based on death certificates. The period of excess risk for suicide in the widowed may be several years. For all causes of death other than suicide, there may be a slight dip in observed mortality by comparison with that expected in the fourth and fifth years. Cohort studies of young widowed are notably absent from the liter- ature; therefore, this part of the picture is incomplete. In studies using secondary sources of data, the elevated risk for the young of both sexes, and particularly for men compared to women, is consistent. While the prospective studies do not have sufficient sample sizes to address specific cause of death, the studies using secondary sources have documented manifold specific causes. There appears to be a broad effect which includes conditions that are manifest in middle and late life. Cause specificity varies by sex. For men there is excess mortality from tuberculosis, influenza and pneumonia, cirrhosis and alcoholism, suicides and accidents, and heart disease. For women, there is elevated mortality from tuberculosis, cirrhosis and alcoholism, heart disease, and cancer. For women over 60 years of age, there is a suggestion of elevated risk of mortality from suicide and accidents, and diabetes. The infectious causes of death, observed in the first half of this century before antibiotics, are apparently no longer important. Clinical studies of the occurrence of various morbid conditions tend to confirm the epidemiological findings about heart disease (myocardial infarction) and some neoplastic diseases. Judging from this clinical literature, bereavement is also a potential cause of asthma, ulcerative colitis, and depressive symptoms. The above conclusions are based on studies summarized in the following review. Using data from the Office of Vital Statistics for the period 1949- 1951 in the United States, Kraus and Lilienfeld compared death rates of several nonmarried groups to those of a married group (Kraus and Lilienfeld, 1959). They found high ratios of mortality for non- married as opposed to married which held true especially for the widowed. Compared with single and divorced (or separated) persons, the widowed had the highest ratios. These observations were particularly notable in the age range 20-34. The ratios decreased as age advanced. Ratios for men exceeded those for women. Sources of potential bias in these observations include different average ages for subjects and controls in specific age groups (higher in the widowed). selective remarrying of the healthy widowed, and misstatement of 119 marital status on death certificates. Accepting the association as valid, there remain problems of interpretation. One cannot conclude from these data that death is a consequence of bereavement. Alternate explanations of the association are unfavorable marital environment, homogamy (the unfit marry the unfit), and common disease processes. Of course, none of these alternate hypotheses is exclusive of a direct effect of bereavement itself. There is little or no chance, however, of controlling for and testing these variables in a study using secondary sources of data. The problems with the Kraus and Lilienfeld data that have been discussed are inherent in many of the retrospective studies to be reviewed subsequently. Still, there is value in this type of work for the prelim- inary generation of hypotheses and the identification of variables that may be important to consider in cohort studies designed to test hypotheses with a prospective research strategy. Durkeim first emphasized the association between widowhood and suicide. He characterized the vulnerability of the widowed as domestic anomie resulting from the loss of a spouse (Durkheim, 1951). Subsequent studies have replicated Durkheim's findings which state the widowed have higher rates of suicide. In addition, it is noted that rate of successful suicide is higher for widowers. MacMahon and Pugh investigated vital records in Massachusetts from 1948 through 1952 searching for death by suicide among spouses who had survived the death of their conjugal partners (MacMahon and Pugh, 1965). They found that the relative risk of suicide in the first year after death of a spouse was 2.5; in the second, third, and fourth years it was 1.5. The period of time beyond four years was used arbitrarily as the basis for computation of the relative risk. Men consistently are at higher risk than women for this outcome and manifest sustained high rates through later life (range 60-80/100,000). Women's rates are lower and peak at age 50, declining thereafter (range 5-20/100,000). This is a study using secondary sources of data and is limited in the ways mentioned earlier. In a sample of widowers over 55 years of age who were registered in the National Health Service, Young and associates investigated mortality subsequent to bereavement by using death certificates (Young et al., 1963). When they compared the mortality in this group with that of married men of the same age, they found a high ratio of widowed to controls in the first six months of bereavement. There was little differential thereafter up to four years. Subsequent analyses of this group of widowers by Parkes and associates revealed no "duration" effect; in other words, no later rise in mortality (Parkes et al., 1969). The same methodological problems that were discussed with respect to Kraus and Lilienfeld's study arise and are not felt by the authors to undermine the accuracy of the association. In the follow- up study by Parkes, there is a trend of increasing ratios as one goes up the social class scale. Moreover, there is evidence of widowers dying more frequently than expected from cariovascular disease. 120 Townsend made a cross-sectional study of the social adjustment of older people in an East London community in the mid 1950's and generated hypotheses that influence the two studies of widowers just reviewed (Townsend, 1957). Although he had no mortality data to verify his suggestions, he was impressed with the effect of retirement, social isolation, and social desolation (loss) on the life expectancy of his cohort of 203 elderly. Based on a review, he concluded that little data from secondary sources is available which bear on the effects of retirement and social isolation. On the other hand, the vital statistics of Great Britain for the years 1950-1952 document a greater mortality in widowed people by comparison with those of the same age who are single or married. These observations tended to confirm his impressions about the consequences of bereavement for the elderly. Additionally, he emphasized the fact that the effects of these stresses for elderly men were more severe. Since the adjustment to retirement is more difficult for men than for women, the retired man is more vulnerable to other stresses. Cox and Ford reported on the mortality rates of 60,000 British widows under age 70 who were awarded widow's pensions in the year 1927 (Cox and Ford, 1964). They compared rates for each year of the five-year period following bereavement to the overall mortality rates for the same group. This technique revealed ratios greater than one of actual to expected deaths in the second and third years of bereavement. The findings were most significant for the second year. Illness or mortality in the first year of ‘bereavement may have impeded the appli- cation for widow's benefits and explain the absence of higher risk for this period in this sample. By comparison with the data of Young and associates on mortality in widowers, Cox and Ford's data on women may point to a difference between men and women. This conclusion is, in fact, borne out in a study by McNeill of 9,247 individuals widowed in the year 1965 in Connecticut (McNeill, 1973). These people were followed through 1968 in order to document their mortality experience. Other differences in the pattern of mortality by sex were documented. For widowers under 60 years of age, the first six months after the death of a spouse is the period of greatest risk, whereas for widows of the same age, the second year after death is the period of highest risk. The cause specific patterns of mortality were also different. For widowers, there was a significant excess of deaths during the first six months from "suicide and accidents" and "diseases of the heart'. For widows, there was a higher risk of "diseases of the heart" in the first six months and "malignant neoplasms'" in the second six months. Both men and women were subject to higher risk of "cirrhosis and alcoholism" in the second and third years. The differing patterns of cause specific death may explain the different peaks in overall risk for men and women. 121 The recent study by McNeill replicates observations of previous studies and gives them cohesiveness in pointing out the important sex differences in patterns of mortality, thereby apparently exhausting the potential in pursuing findings based on secondary sources of data. A r:search strategy that is prospectively based on the follow-up of a cohort over time provides an opportunity to overcome the limitations of studies relying on vital statistics. The largest and most definitive cohort study is the six-year survey of Rees and Lutkins who followed 585 survivors of 371 deceased residents in a semirural area of Wales with a population of 5,184 (Rees and Lutkins, 1967). The survivors were matched with 878 close relatives of 371 persons on age, sex and marital status with the deceased. The survey found a highly significant, sevenfold increase in risk within one year between the bereaved and control group. The risk was greatest for widowed persons who had a tenfold increase com- pared with parents, siblings, and children. Bereaved male relatives had the highest rates of mortality. Widowers were subject to the greatest risk of all, especially in the first six months. A histogram of the age distribution of relatives who died in the first year of bereavement demonstrated a biphasic curve. One peak at age 80 was expected based on the age distribution of all the people who died in the area. The second peak between 60 and 70 was unexpected and suggested that deaths in this age group contribute substantially to the excess number of deaths observed. The site of death was an important determinant of risk for bereaved relatives. If death occurred in a public place such as in a shop, on a road, or in a field, as opposed to at home or in the hospital, there was a higher risk. This last observation raises questions about an additional factor: the expectedness of death, which is probably an important element underlying the influence of site. In both Clayton's and Parkes' prospective studies of widowed subjects that will be reviewed in discussing the process of grief, there was no evidence of excess mortality for the 13 months that the subjects were followed (Clayton, 1975b; Parkes, 1970). Both study samples were small in number. In Sheffield, England, Ward recently reported on the mortality experience of 366 widowed persons where death of the spouse occurred during 1971 or 1972 from cancer (Ward, 1976). She covered all deaths from cancer in Sheffield during this period and achieved 100% follow- up for two years. Using expected rates calculated from life tables for England and Wales, 1970-72, Ward found that the .expected and observed mortality rates for the two-year period did not differ significantly. For widows the expected and observed rates were identical. On the other hand, Ward observed a greater number of deaths than expected in widowers, an observation that clustered heavily in the first six months of bereavement (seven of nine). If the index death of a spouse occurred in the hospital, there was greater risk (not significant) of death for the survivor. In these circumstances, 16.3% of the sur- viving spouses were assessed to be in "poor health, unable to cope 122 adequately (or unable to care for their spouse)". If the index death of the spouse occurred at home, only 6.47% of survivors were so rated. There was no difference in mortality rates in survivors whether the illness of the deceased spouse was chronic or acute. The prospective studies of bereavement do not bear out some of the consistent findings of studies based on secondary sources. For example, Rees and Lutkins do not find significantly elevated rates of death for women in the second year of bereavement nor are the ob- servations of high mortality rates in young men and women elucidated by virtue of their absence from study. Yet other findings based on vital statistics are confirmed. Specifically, the evidence of elevated mortality rates for elderly men is strongly reinforced. In addition to age and sex, several factors are identified as important in determining the risk of death associated with bereavement. Many of the factors to be considered have already been mentioned in the review of individual studies in which they were identified. The aim now is to summarize them systematically. The following specific factors to be considered are kinship, sex, age, race, socioeconomic status, duration of illness in the deceased spouse, pre-existing illness in the survivor, and site of death of the deceased spouse. A consideration of kinship to the deceased and its influence on the pattern of mortality helps to set conjugal bereavement in a spectrum of severity. Only one of the studies addresses this question and documents that conjugal and parental bereavement are more severe than sibling and childhood losses (Rees and Lutkins, 1967). None of the studies using secondary sources of data offer comparative rates by kinship. It is assumed that the severity of bereavement will be a function of the type of attachment that has been severed. The complicated qualities of attachment that have been conceptualized (Bowlby, 1971) have not been addressed by epidemiologic studies. Men are consistently at greater risk at all ages than women. This is a finding in studies using secondary sources (Kraus and Lilienfeld, 1959; McNeill, 1973) as well as in prospective studies (Rees and Lutkins, 1967; Ward, 1976). Worth emphasizing is the persistently high risk of elderly widowers noted in prospective studies. Moreover, there is a different interaction by sex with specific cause of death and with the duration of risk. Younger widowed have a greater relative risk than older (Kraus and Lilienfeld, 1959; McNeill, 1973). In the studies that employ death certificates, young widowed are either omitted or apparently represented in very small numbers. Similarly, they are represented in small numbers 123 in all the prospective studies, a lack which makes it impossible to bring confirmation (or not) of the previous work. One small, controlled, pro- spective study of bereavement over four years in a sample of widows and widowers age 45 or under failed to elucidate further this risk factor (Parkes and Brown, 1972). Of all the studies reviewed only one comments on race as a factor. Kraus and Lilienfeld found greater relative risks in white widowed than in blacks before the age of 35. Then, due to a more rapid decline of rates for whites, the relationship is reversed (Kraus and Lilienfeld, 1959). The prospective studies are socially homogeneous thereby preventing analysis of this factor. Socioeconomic status, and perhaps more important, change in socio- economic status as a result of the death are generally ignored in this entire literature. One study suggests that there may be an inverse relationship between risk of mortality and social status in men over 55 (Parkes et al., 1969). Additional factors that influence the basic pattern are the duration of illness in the deceased spouse and preexisting illness in the survivor. A common assumption is that a prolonged terminal illness in the deceased may permit the survivor to prepare himself through anticipatory grief. In the one study that compares the widowed on this factor, there was no salutory effect from a long terminal illness (Ward, 1976). Two other studies of the physical and psychological morbidity of bereavement support this finding (Gerber et al., 1975; Clayton et al., 1973). Young widowed are not well represented in the samples involved here, and this conclusion should not be generalized to them because the opposite may be true (Glick et al., 1974). Preexisting illness in the survivor may carry an elevated risk of mortality in the survivor (Ward, 1976). This may be particularly true of survivors who ultimately die, themselves, by suicide (Shepherd and Barraclough, 1974). Site of death of the deceased spouse is another factor identified to be important (Rees and Lutkins, 1967). This factor is in part a function of preexisting illness in the survivor (Ward, 1976) and probably does not operate independently. It may also be a function of the expectedness of death, especially for younger widowed. The Morbidity of Surviving Spouses The research evidence to be reviewed indicates that persons who experience bereavement are exposed to a higher risk of morbidity manifested by specific diseases, which are those already identified in the review of mortality by psychiatric disorders and by a decrease in general well- being. In addition, the bereaved will seek health care with greater 124 frequency during the bereavement period. Similar conclusions have been reached by other investigators who have recently reviewed the literature (Klerman and Izen, 1977). The findings on the mortality of bereavement together with studies of the morbidity of bereavement establish that there exists a significant threat to the health of one marital partner when death occurs to the other. The studies that form the basis for these conclusions will be summarized after discussion of several methodological problems in the following paragraphs. Reviewing the morbidity of bereavement is a most difficult task. The number of studies is not large. On the other hand, there is a lack of cohesiveness and comparability among the studies that prevents simple integration and conclusions. Multiple end points are reported: medical care and psychiatric care; general health and illness severity; and multiple somatic, psychiatric, and psychosomatic syndromes or symptoms. Participation rates are frequently problematic because of geographic mobility in the postbereavement period and because of the sensitiveness of gaining cooperation for research in this period. Variations in partic- ipation undermines the generalizability of the studies. An explicit, logical framework for drawing inferences is sometimes absent. Occasionally, simple tautologies involving independent and dependent variables occur. Clinical studies that do not employ sampling techniques or controls will be excluded from consideration even though they may be well known. For the sake of this review, no overriding effort will be made to organize the studies according to traditional categories of somatic, psychiatric, or psychosomatic illness. Rather, attention will be focused on major outcomes (defined as major on the basis of their threat to life, by the frequency of their occurrence, or by an established association of important theoretical significance). No serious review of morbidity as an outcome may be done without acknowledging the distinction between illness behavior and actual disease. Perhaps the most influential factor in this regard that has been identified by studies in the field of bereavement is the type of health service for which the subjects are eligible. Most of the studies have been completed in countries where there is a national health service. Maddison and Viola indicate differences in health status as measured by a combination of the occurrence of symptoms and medical consultation between Boston and Sydney widows that may be partially based on the type of health service (Maddison and Viola, 1968). Availability of social supports and other alternatives to professional, clinical care will also affect help-seeking behavior and are implicated by some authors (Parkes and Brown, 1974). These factors that are encompassed under the rubric of illness behavior and its determinants must be kept in mind when considering the validity of case identification. Contacts with clinical services for the purposes of obtaining care are an indirect, nonspecific measure of morbidity. While hospitalizations probably reflect serious morbidity in the private or the public health service setting, this assumption is more doubtful in the private arena. 125 Here, hospitalizations may simply be a means of utilizing insurance benefits for minor work-ups. Consultations with a medical practitioner are even more doubtful as an index of physical morbidity. Yet, there are more data on them by comparison with hospitalizations, and they will be cited accordingly. Hospitalization and Visits to a Physician Parkes studied the case records of 44 widows with an average age of 60.2 years (range 38-81) whose husbands had died in one of eight representative London-based general practices to determine the effect of bereavement on their physical and mental health (Parkes, 1964). The sampling frame for the study is vague and, hence, its generalizability uncertain. Comparing consultation rates for the 24 months before death with the first 18 months after, Parkes found a statistically significant increase in the number of consultations. This is true of the total group and particularly true of widows 65 years and older for whom rates went from 2.7 per patient per six months during the control period to 4.4 in the first six months after bereavement and 4.3 thereafter. Muscle and joint disorders were the only one of several subcategories of illness that showed a significant increase after bereavement. Three of the entire sample, or 6.8%, were hospitalized in the 18-month post- bereavement period under circumstances that are not clarified. The subjects served as their own controls in this study. There were no hospitalizations in the 24 months before the death of the husband. The problems of interpretation of the increased rates of consultation and hospitalization are complex. One explanation is that medical care was simply deferred because of the illness of the partner. Clayton argues this position and cites reduced consultation rates in the immediate six months before bereavement and the fact of increasing consultation rates with increasing age as support (Clayton, 1973). Parkes presents an age breakdown of the consultation rates which refute the age factor. The reduction in frequency of prebereavement consultation does not appear quantitatively sufficient to explain the excess after bereavement. Maddison and Viola used a case control strategy in making a self report survey of widows' health 13 months after bereavement (Maddison and Viola, 1968). Theirs was a two-part study including a Boston sample of 132 and a Sydney sample of 243 subjects, with 98 and 101 controls from those cities respectively. The average age of both groups was approximately 50 years. Nonresponse rates were high with an average of approximately 507% on the whole -- higher in Boston and lower in Sydney. No characterization of non- responders was reported. Health deterioration was measured using a weighted system in which "major diseases such as asthma" received a heavy score; first occurrence of symptoms and medical consultation were also weighted heavier than symptoms without these associated factors. Using this scoring system, 21.27 of Boston widows and 32.17% of Sydney widows reported a marked deterioration in health which was significantly different from their respec- tive control groups. There is no independent mention of hospitaliztion rates. When their questionnaires were rescored to eliminate the weighting based on medical consultation, the observed differences persisted, sug- gesting it was an actual deterioration in health rather than a manifestation 126 of doctor dependence for nonmedical support. Still, in the absence of objective clinical criteria, the question of nonmedical supportive use of doctors remains as an alternate explanation of their results. Hypo- chondriasis or the chronic adoption of the sick role is another interpre- tation of the results which is discounted by Maddison and Viola. Their conclusion here is based on overall impressions derived from the question- naires of substantial health problems in subjects with "marked deterioration" in health. Brief case reports are appended to support their conclusion. Parkes followed a small cohort of 22 London widows under the age of 65 (average 48.8 years) on a prospective basis over 13 months (Parkes, 1970a). These subjects who were willing to be interviewed by an investigator were referred by general practitioners who had an interest in the study. The patients were referred frequently on the basis of their having visited their G.P.'s in the first month of bereavement. Nine of 12 referring G.P.'s characterized 16 potential referrals who were not included as subject to typical grief reactions as follows: 4 were not referred through oversight; 6 through fear of the G.P. that participation would be detrimental; 4 through the subjects' refusal; and 2 through unavailability. In this "fairly" representative sample of widows, Parkes found six subjects (22.2%) whose health was definitely worse in the first.13 months of bereavement. None was clearly healthier and no hospitalizations are reported. The type of illness was elaborated other than to mention the "common complaints" of headaches, digestive disturbances, and aching limbs. Of interest in this study, in view of Maddison and Viola's work, is the close correlation between measure of irritation and anger according to self-assessments made by widows of their own general health. Objective measures of ill health employed in the study were not as closely correlated. Parkes and Brown employing a case control in a study of 49 widows and widowers, under age 45 who were identified in Boston during a period of two and one-half years. This is certainly a low participation rate and inhibits generalization of the findings. Seventy-five of the 309 eligible subjects could not be located, 116 declined to participate and 40 dropped out in the prospective follow-up for a two to four years postbereavement period. Through a telephone follow-up 13 "refusers" who cooperated on the phone (out of 41 for whom telephone contact was tried) were found to be basically similar to the subjects in the study. Twelve subjects (18%) were admitted to the hospital in the first year of bereavement. This percentage was signi- ficantly different from controls who, even when they went to the hospital, were admitted for minor conditions. Of interest is the similarity between bereaved and controls in consultation with doctors. The apparent reluc-— tance of bereaved subjects to consult a doctor in contrast to the occur- rence of increased hospitalizations (covered by insurance in most cases) and significantly more frequent disturbances of sleep, appetite, weight, autonomic function, and symptoms (especially in men) may be determined by a documented drop in income in the postbereavement period. They found that 10 of 68 bereaved subjects had consulted with psychiatrists, 9 with clergy- men, and 3 with social workers. Approximately half (12) had had four or more consultations indicating the occurrence of brief treatment. Ten had never previously sought this type of help. No hospitalizations are 127 mentioned. The difficulties with the sample in this study have already been mentioned. Possibly those who agreed to participate were atypical compared with general population in terms of their attitude towards professional help. Borstein and associates have followed 92 (88%) of an original sample of 109 randomly selected subjects through the first year of bereavement on a prospective basis (Bornstein et al., 1973). The sample and methodological features of this investigation have been summarized pre- viously. Young widowed manifested a significant increase in medical hospital- izations in the first year (Clayton, 1975). The total group was no different from married controls in medical consultation rates and rates of hospitalizations. As part of a prospective investigation of the Center for the Study of Aging and Human Development at Duke University, Heyman and Gianturco reported on 41 bereaved survivors out of a total of 256 elderly volunteers who have been followed since 1955 (Heyman and Gianturco, 1973). There are serious limitations in the sample which is representative of the Piedmont, though not randomly selected, and which excludes subjects for whom comparable data before and after bereavement were not available. Further- more, 25 of the bereaved sample of 41 were not seen until 18 months after bereavement. This period of time is ample for dropouts from the sample based on illness. These issues are not explained. A Physical Function Rating, in which a high rating indicates limitation of function over 807% based on medical history, physical examination, and lab tests, is employed along with a psychiatric evaluation as an estimate of health. The subjects served as their own controls. They manifested no change in ratings after bereavement by comparison with before. In his study of the elderly in East London with good participation rates (78%), Townsend documents a high hospitalization rate in geriatric facilities for bereaved subjects (Townsend, 1957). These observations are based on a random sample of 203 elderly drawn from seven general practices. Mental hospitalizations and consultation rates are generally considered separately in the literature. Studies using secondary sources of data have documented increased mental hospitalization rates for the widowed. Pugh and MacMahon's study is one of the most thorough in this regard (Pugh and MacMahon, 1962). It demonstrates high rates of first admission among widows and widowers for a variety of conditions. There are implications that psychotic disorders, in particular, are important. The disparity between the widowed and the married occurs at younger ages (20-29) and is more pronounced for widowers. Lower probability of remarriage in previous- ly ill persons who become widowed and loss of social support and care may explain the results, as well as the existence of a pathogenic effect of bereavement. The inability to determine the duration of widowhood in this type of study is a major limitation for interpretations about bereavement itself as a causative influence. 128 Parkes conducted a review of the case summaries of 3,245 admissions to Bethlem Royal and Maudsley hospitals during 1949-51 to study the relationships of bereavement to mental illness (Parkes, 1946b). Ninety- four cases, or 2.9% of the total admissions were identified whose present- ing illness came on within six months following the death of a parent, spouse, sibling, or child. The frequency of patients who suffered conjugal bereavement was six times greater than expected. Compared with men, women were subject to additional excess risk. This finding contrasts with MacMahon and Pugh's analysis of hospital data indicating that widowers are at higher risk. No relationship between loss of other kin and mental illness was documented. Affective disorders, particularly neurotic depressive reactions, were significantly greater among the bereaved though only accounting for 287% of diagnoses. No other specificity of effect was documented. The expected rates of bereavement were derived from vital statistics data for the general population of Great Britain. Though a question exists about the comparability of the general population to the bereaved sample, Parkes contends that the differences are relatively small. Utilizing a case register in Salford, England, Stein and Susser have studied inceptions of psychiatric illness, as reflected in help seeking contact with a clinical facility, and the timing of this contact after bereavement (Stein and Susser, 1969). Inceptions, defined as first episode of psychiatric care in a person's life, were greater for young widowed women than for men. Inception rates for all age groups were con- sistently higher for widowed than for the married. Depressive psychosis in women, alcoholic psychosis in men, and organic dementias in both sexes were the diagnoses contributing most to the excess over a married comparison group adjusted for age. Inceptions for both inpatient and outpatient care clustered in the first year after bereavement. This observation provides strong support for an etiologic relationship of the transition into widow- hood to the inception of severe mental illness. Based on their knowledge of the Salford Register, the authors conclude that first entry to care as documented by the register is relatively complete for severe illness and, hence, presumptive evidence of the incidence of severe mental illness. Self-medication is a less convincing but nonetheless interesting reflection of an individual's wish for help and of underlying illness, Several studies that have been reviewed document a high utilization of tobacco, alcohol, and tranquilizers. Maddison characterized these changes in habits as alterations in oral personality traits (Maddison and Viola, 1968). He discovers an interesting contrast between Boston widows who are more likely to increase their consumption of alcohol and Sydney widows who are more likely to increase their use of tranquilizers. Rahe and associates have used recent life event scores in both case control, clinical samples, and prospective studies of large naval populations to demonstrate a relationship between high scores and medical consultation rates (Rahe, 1972). It is not determinable what the specific contribution of bereavement is in these findings. Presumably all types of bereavements, which are ranked among the most severely stressful events, play a role. Non-specific social stress which has been quantified into life-change units (LCU's) based on weightings of severity is, nonetheless, a factor ’ 129 predicting the utilization of medical services in large military populations. Some cause specific investigatory leads that may be drawn from this literature have already been alluded to in describing the studies from the perspective of illness behavior. In the following paragraphs, the relation- ship between bereavement and specific morbid outcomes will be system-— atically reviewed. A number of studies have investigated the relationship between bereavement and morbidity by defining specific clinical syndromes, problems, or anatomical systems. Cause Specific Morbidity Etiologic hypotheses are often implicit in this work. The network of conceivable etiologic relationships is complex. Bereavement may be related to a specific morbid outcome in numerous ways. As a factor, it may be characterized in terms of abstract qualities such as predisposing, pre- cipitating, necessary, sufficient or not sufficient, contributing, and causal. The available studies usually do not permit an explanation of the complexity and the specific nature of the etiologic relationship. Authors seldom address these questions (Parkes et al., 1969; McNeill, 1973). Heart Disease Heart disease has been implicated by two large studies of cause specific mortality using secondary sources of data. Parkes and associates, in a study that extended the follow-up period from five to nine years on the male subjects over fifty-five years of age (originally reported by Young, Benjamin, and Wallis), found the greatest contribution to the excess mortality observed in the first six months was from "coronary thrombosis and other arteriosclerotic and degenerative heart disease" (Young et al., 1963; Parkes et al., 1969). No other categories of disease reached statistical significance, though there was evidence of greater than expected mortality in all. When coronary thrombosis and other arteriosclerotic and degenerative heart disease were combined with "other heart and circulatory disease," they accounted for two-thirds of the overall excess mortality. McNeill found highly significant risk of death from ''diseases of the heart" (ICDA 410-433) in men under 60 years of age in the first six months bereavement (McNeill, 1973). Women under 60 were at higher risk in the first six months, though not as high as men. In contrast to men, the high risk for women persisted throughout the remainder of the study period of three and one-half years. Men and women over age 60 were not at higher risk than the general population. Approximately a third of subjects under age 60 in this sample were in the 55-59 age category. To what extent they contribute to.the cause specific mortality risks for the whole subsample under 60 is not clear. Parkes' sample of men were all 55 years of age or older. Another study of the medical records of widows carried out by Parkes and reviewed in the previous section classified consultations into anatomical categories depending on the principal symptoms and the treat- ment given (Parkes, 1964a). Cardiovascular problems did not apparently 130 represent a substantial group of disorders with the exception of hyper- tensive conditions in which blood pressures had to exceed 180 systolic and/or 100 diastolic or where there was attendance for antihypertensive therapy. The numbers of consultations for categories of disorder were small. Only one -- muscular and articular afflictions, particularly osteoarthritis -- was associated with a significant increase in consulta- tions. Connolly recently studied a systematic sample of 120 consecutive admissions to a coronary unit with an acute myocardial infarction (Connolly, 1976). None of them reported the death of a spouse in the six-month period for which a structured history of life events was elicited. Cirrhosis and Alcoholism Cirrhosis and alcoholism have been identified by McNeill as a specific cause of excess deaths in the bereaved (McNeill, 1973). Women under 40 years of age appeared to have a significantly high risk of death from cirrhosis and alcoholism for the study's entire period of three and one- half years. The risk peaks in the second half of the first year and the second year. Men under 60 have a high risk during the second year only. Over 60 years of age, neither group is subject to increased risk. In a follow-up article to his original report on the Bethlem Royal and Maudsley Hospital previously summarized, Parkes directly interviewed 21 psychiatric patients whose illness started in close relationship to bereavement (Parkes, 1965b). Adding these 21 to the patients already identified and for whom careful chart reviews were completed, he reported that 13 of the total 115 (11.3%) had "alcoholic episodes!'. Five of these developed Korsakoff's psychosis. He proposed a nonspecific stress hypothesis of relapse in what, he implies, were cases of chronic alcoholism. As reviewed earlier, Stein and Susser analyzed the annual rates of first psychiatric consultation by selected diagnoses utilizing a case register In Salford (Stein and Susser, 1969). Men with problems of addic- tion were presented in high numbers compared with single and married control groups. This pattern was not apparent for women. Based on other tables that Stein and Susser provide in their article, one may suppose that the majority of these first consultations came from young age groups; however, there is no certain way of knowing from the study as it is published. There is no breakdown of addfctions into drug or alcohol abuse. Diabetes Diabetes is another disease implicated in McNeill's study (McNeill, 1973). Women over 60 are significantly more likely to die in the first year of bereavement from this cause. Men over 60 have excess rates of death in the second year, though the difference is not statistically significant. These findings do not hold for men and women under 60 years of age. ‘ 131 Malignant Neoplasms McNeill also finds more observed deaths from malignant neoplasms than expected in women under 60 for the three and one-half year duration of his study (McNeill, 1973). The difference reaches statistical significance only in the second half of the first year. Respiratory Disease In the pre-antibiotic era, Ciocco reported an elevated risk of mortality among the bereaved from tuberculosis, pneumonia, and influenza (Ciocco, 1940). This finding is lost in later studies based on death certificates (Parkes et al., 1969; McNeill, 1973). The idea is picked up indirectly by observations on the consequences of depressive tendencies on the MMPI and the duration of convalescence from influenza (Imboden, et al., 1961). The finding of an association between depressive symptoms and a delayed recovery from influenza -- a respiratory disease least affected by antibiotic treatment —— has not been repeated specifically for bereavement; yet it is an intriguing echo of the original finding by Ciocco. "Psychosomatic" Conditions "Psychosomatic" conditions were not specifically identified and studied by McNeill. A number of clinical studies that are well know have addressed the effect of loss on numerous conditions including asthma, ulcerative colitis, and hyperthyroidism (Parkes, 1970b). All these studies are intensive clinical investigations flawed, however, by inadequate sampling, absence of controls, and a retrospective perspective. In regard to "psychosomatic" conditions, it is interesting that Maddison found no cases of traditional psychosomatic disorders in his survey study of Boston and Sydney widows (Maddison and Viola, 1968). Parkes did note an elevated rate of consultations in his study of the case records of London general practitioners who treated widows (Parkes, 1964a). The differential in consultation compared with a 24-month period before bereavement was not significant. Given the theoretical mediation .of psychophysiologic symptoms via the autonomic nervous system, it is interesting that Parkes and Brown find a nonspecific increase in the report of "autonomic symptoms" in bereaved subjects compared with controls (Parkes and Brown, 1972). This difference diminishes in the second year of bereavement and disappears in the third and fourth. Depression Depression is a morbid outcome of major proportions according to several studies that have searched for its occurrence. An early inves- tigation was by Parkes in his review of the case notes of patients admitted to Bethlem Royal and Maudsley Hospital (Parkes, 1964b). He found a greater 132 than expected occurrence of affective disorders in bereaved by contrast with nonbereaved patients. Reactive and neurotic depressions accounted for this differential of affective conditions. To put these observations into perspective, it is important to know that the diagnoses accounted for only 287 of bereaved patients. Hence, it would appear that there is no great specificity of the reaction of bereavement, Socioeconomic status and physical health were not taken into account by Parkes, Such variables may be important if Bellin and Hardt's community survey of the mental health of the elderly in upstate New York has specific implications for depression (Bellin and Hardt, 1958), They found no significant relationship between a mental status rating and marital status if age, SES, and physical health were taken into account. Nevertheless, non-significant trends in the data suggested an association between widow- hood and mental disorder. Their findings are flowed by their failure to control for duration of widowhood and by a tautology involving the social history and mental status rating. The latter were based in part on the former and may explain the relationship observed between SES and mental status. Maddison estimated that one in eight of his overall sample of widows (12.8%) had consulted her physician to seek treatment for depression (Maddison and Viola, 1968). One and one-third percent of the widowed group (or approximately 107% of the depressed persons) needed hospitalization for treatment of this condition, Morrison and associates in a nonrandom sample of 102 patients with mental disorders who were matched with medical patients on age, sex, marital status, race, and cost of hospitalization, found no difference between the two groups in the occurrence of recent life events and losses (Morrison et al., 1968). In fact, there were no deaths of spouses reported at all. Forty of the subjects in this investigation had a primary affective dis- order (Hudgens et al., 1967), This case control strategy, which had good participation from those approached, did not incorporate a healthy control group from the general population, Thus, it is impossible to conclude that interpersonal losses have no relationship to the onset of affective dis- order. What may be observed is a nonspecific relationship of loss to both medical and psychiatric patients, Extracting from their data the number of subjects with acute losses in the year prior to illness, seven out of 40 affective patients had positive histories as opposed to two controls. The acute losses did not include, as indicated above, the death of a spouse. In another case controlled study of the relationship of recent life events to depression in 185 depressed women, Paykel and associates found a significant relationship between events characterized as "social exits" and the occurrence of depression (Paykel et al., 1969). There was actually only one death of a spouse in this group of events. The control group was drawn from the general population and matched on age, sex, SES, race, and marital status. Matching on the last variable may 133 tend to reduce the chances of finding a relationship between widowhood in the patient and the control. Its effect on the study in question is unclear, though it would not alter the fact that only one death of a spouse occurred in the year previous to onset of depressive illness in the patient group. Parkes and Brown extracted "depression' scores for their bereaved sample and controls based on 18 items identified by factor analysis (Parkes and Brown, 1972). It is not certain what this score represents, though it apparently is not based on well established clinical criteria of a depressive syndrome. With this qualification in mind, it is still interesting that the average score on these items was significantly higher for the whole group of men and women 14 months after bereavement than in controls. The scores for bereaved women were higher than bereaved men. Scores for control women approximated the scores for bereaved men -- falling slightly short. When the average score on these items for the entire group was charted over time, it was found that the score diminished in the second year and then approximated the score of controls at three and four years after bereavement. Clayton and associates have done the most to elucidate the relationship of bereavement to depression in their cohort study of 109 randomly selected subjects (Clayton et al., 1972; Bornstein et al., 1973). Follow-up proved difficult for them as they lost 12% (13) of the survivors (4 had died) at 13 months after the death of their spouse. The original participation rate for the study was 58%. A strength of this study is the use of well established criteria for the occurrence of primary affective disorder. These findings will be discussed with respect to the natural history of the bereavement process. Thirty-five percent of the sample were definitely or probably depressed at one month after bereave- ment and 17% at 13 months. Thirty-nine percent had a depressive syn- drome at sometime during the period. Practically all of these conditions were manifest by four months. In terms of poor outcome, the depressed at 13 months, who were 17% of the sample, correspond to Maddison's bad outcome group of 21% in Boston widows and 32% in Sydney widows, and to Parkes' group of widows (14% of 22) who were poorly adjusted, depressed, and still grieving. The occurrence of symptoms in bereavement that correspond to primary affective disorder has been called by Clayton a normal depressive reaction of bereavement (Clayton et al., 1972). The main determinant of this terminology is the absence of illness behavior in the bereaved group who have depressive symptoms. A close reading of Clayton's work distinguishes the normal depression of bereavement from primary affective illness by additional criteria: the absence of disturbance or self-esteem, the absence of suicidal behavior, the absence of motor retardation, and the 134 absence of a feeling of losing control in the bereaved. The following are also important features of the clinical history of the normal depression of bereavement: (1) it is not more common in women than men, (2) it is not more often associated with a positive family history of psychiatric illness or of affective disorder in first degree relatives, and (3) it is not more common in those previously treated for a depression. Knowledge of Feighner's criteria for primary affective disorder leads one to wonder how accurately the occurrence of depression in the elderly will be identified. In Clayton's research pseudodemented de- pression may possibly have been excluded and hypochondriacal depressions may not have met all the criteria. Apropos of somatic symptoms, 20% of the sample reported three or more symptoms at one month after bereavement. Later frequencies are not reported, and there is no control group for comparison. It is recognized that somatic symptoms may be a function of complex identification mechanisms involving the deceased, resulting in a hypochondriacal or even a conversion symptom. Such symptoms are not related only to depression. Suicide Consideration of the relationship between bereavement and depression cannot be concluded without reference to epidemiological studies on suicide. Data regarding this aspect of bereavement have been summarized (Durkheim, 1951; MacMahon and Pugh, 1965). It was found that there is a higher risk of suicide in bereaved subjects based on two large studies of vital statistics data. It was not possible to comment on the specific context and etiology of the suicide. In addition, it should be noted that the risk of suicide in those suffering from a mental illness is many times higher (25-35) than the risk in the general population. Among those with mental illness, de- pressive disorders make the greatest contribution to suicide rates. Anxiety Disorders Anxiety syndromes are another major form of morbidity that is implicated as an outcome of bereavement. Phobic anxiety syndromes, which have been considered to be an atypical variant of depressive illness in young persons, may be the most incapacitating of these syndromes. Neither phobic anxiety syndromes nor anxiety syndromes, in general, have been closely studied. In Roth's original description of 135 phobic-anxiety depersonalization cases, he notes that 347% followed the death or serious illness of a close friend or relative (Roth, 1959). Klein also emphasizes the close relation- ship between sudden separation from valued family members, bereavement being one of the most important examples, and the occurrence of panic attacks or phobic anxiety syndromes (Klein, 1964; Klein, 1969). Parkes does not substantiate the occurrence of phobic-anxiety syndrome in the 115 bereaved psychiatric patients on whom he reported (Parkes, 1965b). Panic attacks occurred in the patient sample of a type that was similar 135 to the panic attacks of phobic patients in general. Depersonalization also occurred and was viewed as an exaggeration of the numbness that occurs as an early phase of grief. There was no evidence of phobic anxiety until after the depersonalization had passed, in contrast to Roth's patients who often experienced depersonalization concomitantly with panic attacks. Anxiety attacks and panic as isolated symptoms occur in all major studies on bereavement, with 10%-20% of patients reporting such symp- toms. No study has directly addressed the occurrence of phobic anxiety syndromes using carefully derived clinical criteria. Dementias A final category of mental illness is organic brain syndrome and senile changes. The evidence on this category as an outcome is meager. In part, it is based on Parkes' observation of a nonsignificant tendency of bereaved subjects to be diagnosed as organic disorders more fre- quently than nonbereaved patients in Bethlem Royal and Maudsley Hospitals (Parkes, 1964b). In addition, Stein and Susser document high inception rates for organic and senile disorders in the widowed based on data from the Salford Case Register (Stein and Susser, 1969). ‘The Stress Response of a Spouse to Illness or Death of a Marital Partner Given a greater or lesser threat to the health of a spouse when death or severe illness occurs to a marital partner, the next question to be asked concerns those processes that mediate between the event and the health status of the nonhospitalized spouse. It is reasonable to assume that the stress response of the nonhospitalized spouse to the illness or death of a conjugal partner will help to provide clues to the mechanisms of pathogenesis of illness. In the following review of the stress response of a threatened spouse, the literature will be divided into studies on the stress response to illness and studies on the stress response to death. The Stress Response to Illness The literature on the stress response to illness is characterized by a meager number of studies of a systematic, controlled, and prospective nature. A number of studies that have already been reviewed in the section on "The effect of a spouse's illness on the health status of the conjugal partner" contain suggestive ideas. Together they document the occurrence of depression, anxiety, tension, a variety of psychosomatic symptoms, role tension, role failure, and interpersonal tension. A limitation of many of these studies is the failure to differ- entiate between the occurrence of a normal adaptive response to a stressor and the occurrence of a process which is considered pathological itself in respect to a person's physical or mental health. One ‘study, the exception among this group of studies, gives specific attention to the occurrence and evolution of the stress response (Shelton and Dominian, 1973). 136 Shelton and Dominian report on the psychological stress in 65 wives of husbands who had a first myocardial infarction and were admitted to a coronary care unit. Their reaction to illness in their husbands was described at three different points: at the time of hospitalization, three months after the myocardial infarct, and one year after the infarct. At the time of hospitalization, the wives reported feelings of numbness and panic, feelings of unreality, a sense of loss, guilt and self-blame, anxiety, depression, sleep disturbance, appetite disturbance, and psychosomatic symptoms to a lesser extent. Twenty-eight of the 65 demonstrated marked severity of these symptoms. Three months after the myocardial infarct -theugh there was. some relief on discharge from the hospital -- anxiety, depression, sleep disturbance, appetite disturbance, and psychosomatic symptoms continued for 25 of the 65 wives, 22 of whom were among those with a severe initial reaction. A sense of loss of a "strong husband" persisted. Tension and hostility arose, secondary to irritability, when the husband's dependency caused the wife to feel it necessary to keep her anger in for fear of causing another heart attack. At one year, 16 of 65 wives continued to manifest a severe emotional disturbance. Of these 65, only eight were faced with death or in- capacitating illness in the husband during the previous year. What is particularly notable in this study is the similarity of the process just described to the clinical descriptions of anticipatory grief among the spouses of cancer patients and to existing knowledge of the process of actual grief. The latter two processes are summarized subsequently. Anticipatory grief is a concept that appeared originally in Lindeman's work to describe the reaction of women to the departure of a husband to war (Lindeman, 1944). Subsequently it has been the object of much attention in describing the family response to patients with cancer. Anticipatory grief is considered to be a type of separation reaction distinct from actual grief in its reversibility, the presence of a final end point, acceleration of the process up to the end point, the existence of hope, and other features (Lindeman, 1944; Aldrich, 1974). The concept includes three elements: the impending death of a person who is part of a nexus of primary role relationships, an awareness of the impending death by the others in the nexus of relationships, and a subjective state paralleling the subjective state associated with bereavement (Budner, 1974). The literature which describes the process of anticipatory grief is almost entirely clinical and currently lacks systematic, quantified observation (Shoenberg et al., 1974). Several studies of anticipatory grief as a risk factor for physical and mental morbidity have been published in addition to the clinical descriptions. These other studies will be briefly summarized. No direct studies of anticipatory grief have actually appeared. Yet if one will accept the occurrence of a prolonged final illness as a rough index of the presence or absence of anticipatory grief (at least the opportunity for it), then there are several applicable studies. For a young widowed person, evidence indicates that the sudden death of a spouse is associated with a higher risk of intense and prolonged grief, which is also more symptomatic 137 (Lindeman, 1944; Parkes, 1972; Parkes and Brown, 1974; Glick et al., 1974; Vachon, 1976). For older persons, no apparent difference in effect is observed when outcome is measured by physical or psychological morbidity (Gerber et al., 1975; Clayton et al., 1973) or by mortality (Ward, 1976). The literature on the stress response to illness of a marital partner is limited in scope and lacks conclusive evidence. Multiple meanings inher- ent > in the idea of stress: threat, uncertainty and unpredictability, conflict, excessive demands, failure of aspirations, frustration of needs, and loss are included. Yet if Parkes' conclusions about the centrality of loss in psychosocial transitions (loss of possessions, loss of health when illness occurs, loss of position and status) is true, then our knowledge of the process of grief may elucidate the stress response to illness. In the latter situation, loss through death has not occurred; but, rather, there are losses such as the "loss of a strong partner," loss of a certain future, and loss of a self-image through the need to take new roles. The Stress Response to Death: Grief A general picture of grief in adult life resulting from conjugal loss emerges from the studies reviewed. Present knowledge of adult grief is the most convincing for women of age 65 and under. Men, the elderly, and social minorities are poorly represented in the groups that have been studied. On the other hand, there is no suggestion in the available literature that the pattern of grief is fundamentally different for these underrepresented persons although variation in specific elements of their grief may exist (Stern and Williams, 1951; Gramlich, 1968; Gerber et al., 1975; Glick et al. 1974). The studies that have been reviewed focus in large measure on grief that results from untimely death and do not adequately take into con- sideration the phenomenon of anticipatory grief and its effect on grief. In general, grief is recognized as a basic human response which is uni- versal and inevitable. Several authors agree that the most important, distinctive feature of grieving is the widowed person's preoccupation with the deceased and the pining associated with it (Parkes, 1972; Lindeman, 1944; Freud, 1917, Glick et al., 1974). A central component of grief is the searching activity of the bereaved for the lost person, which is associated with separation anxiety (Parkes, 1972). As such, it is identified as an active, evolving process and not a steady state which simply diminishes, though for some it is over for the most part after four months (Parkes, 1970; Lindeman, 1944). No clear end point is established, though some point after one year and not exceeding two years is most likely. The peak intensity is usually past by the fifth to sixth month (Parkes, 1970; (Clayton, 1973). About one-third 138 of a group of widows manifest grief of mild to moderate intensity after six months and two-thirds are still actively grieving one year after a loss (Parkes, 1970). Grief has various manifestations including anxiety, dejection, anger, hallucinations or illusions, and nonspecific somatic symptoms. Variation in the manifestations of grief among individuals is considerable in normal grieving. The extremes of variation are defined as patterns of a typical grief characterized by delay, inhibition, prolongation, intense separation anxiety, intense avoidance, and other features. A typical grief carries a high risk of prolonged suffering secondary to un- resolved grief and other nonspecific psychological complications. The variation in grieving is determined by multiple factors which have been summarized by Parkes (Parkes, 1972). Variation among those subjects who are poorly represented in the studies that have been reviewed is unrecorded. Current understanding of biological processes underlying the psychological picture is limited. Yet, promising leads from the neuro- endocrine literature exist. These include the investigation of adrenal cortical hormones, epinephrine and norepinephrine ratios, testosterone and multihormonal profiles to elucidate the physiological relections or con- comitants of various psychological processes that have been discussed. Grief evolves in a social context which has an important influence on the process. The mourning ritual of society shapes the response (Krupp and Kligfeld, 1962; Mathison, 1970; Yamamoto, 1969). In addition, the grieving person must adjust to new roles and changed status. The changed social environment may result in loneliness and cause a sense of insecurity. Furthermore, the sociological literature on sexually deter- mined social expectations and rules holds important clues to how the threat of a conjugal loss might be perceived differently by men and women. These different perceptions may explain the differential and particularly negative consequences of bereavement for men. The studies upon which these conclusions are based are briefly summarized in the following paragraphs. Parkes, who owes a debt to Bowlby for his conceptualization of normal grieving (Bowlby, 1973), has played a central role in the modern study of adult grief in which experimental methods and statistical analyses have been applied (Parkes, 1972). His conclusions are based on extensive clinical work with bereaved patients and the systematic study of two London samples. One sample was a group of twenty-two widows with an average age of 49, referred through general practitioners (Parkes, 1970); the other was a group of twenty-one bereaved patients at the Bethlem Royal and Maudsley Hospitals, four of whom were men with a mean age of 49 (Parkes, 1965). Direct observations on this small sample were supplemented by chart reviews on an additional 94 patients. The first sample was a group followed prospectively using a standardized interview who were selected first after having consulted with a general practitioner and also by their willingness to participate in Parkes' study. The second sample was a group of psychiatric 139 patients who were studied retrospectively after having been hospitalized for mental disorder. Neither sample was random; hence the number of normals studied was small and neither sample was representative of the general population. Based on his work, Parkes proposed that bereavement be viewed as a process characterized by a progression of changes or phases. The first phase was a period of numbness that lasted from a few hours up to a few days. Widows reported the state of feeling stunned, dazed, shocked, blunted or numb which was sometimes experienced as a relief from the feeling evoked by the loss. The second phase began after a relatively clear-cut transition from the initial brief period of numbness. The second phase was characterized by separation anxiety, the hallmark of which was preoccupation with thoughts of the deceased. It was this preoccupation along with its affective component of pining that Parkes considered pathognomonic for the grief reaction. Active, mostly unconscious searching for the deceased was linked to separation anxiety that was presumably generated from a basic motivating need to recover the lost person. Feelings of anger (protest) and guilt were an additional part of this phase. In recognition of the promi- nence of angry feelings, Bowlby had characterized this stage of grieving as one of yearning and protest. The angry feelings diminished in intensity, alternated with, and finally gave way to feelings of sadness and apathy. The searching phase peaked in two to four weeks following the death. Further progression of the grieving process into feelings of apathy and despair associated with aimlessness and disorganization of behavior patterns was the next change. Here the change was subtle, and it was difficult to recognize the end of one phase or the beginning of another. Intense, yet less frequent and briefer episodes of yearning for the de- ceased person occurred for several months. At the same time that the separation anxiety slowly subsided, the expression of anger became variable and finally diminished. This seemed to occur concomitantly with growing feelings of depression. The period of depression which had been denoted as a period of disorganization by Bowlby because of apathy and aimlessness did not establish itself as a well demarcated phase of grief. Rather, it - occurred repetitively in one context or another. When the depression be- came minimal or when circumstances forced it (and partially through the process of identification with the deceased '), the bereaved person relin- quished the old bond and ventured out into new roles and a new life. A year after the death of a spouse, the majority of subjects in the sample from general practice were still actively grieving, and for 8 (of 22) subjects the severity of the emotional disturbance remained moderate or severe. 140 This review has emphasized the chronological unfolding of the human response to loss with an eye to elucidating questions of pathogenesis. It warrants additional emphasis that the phasic development presented in this review is not in actuality as clear as a summary might suggest. Moreover, the various features of grief and progression of changes that Parkes described were not universal; most occurred in the range of 50 to 75% of subjects in varying intensities. Yet Parkes’ conceptualization is convincing because of its clarity, its consistency with observations made by Bowlby and his associates, and its basic consistency with other observations of grieving reported in the clinical and the sociological literature. Other Clinical Observations Freud's Mourning and Melancholia is the origin for several current concepts that are central to our understanding of grief (Freud, 1917). He identified four distinguishing features of the condition as part of an idealized account of "normal" mourning. They were a profoundly painful dejection, a loss of capacity to adopt new love objects, an inhibition of activity or turning away from activity not connected with thoughts of the loved person, and a loss of interest in the outside world insofar as it does not recall the deceased (Siggens, 1966). Subsequently, Cobb and Linderman reported observations on 101 sur- vivors of the Coconut Grove fire (Cobb and Lindeman, 1943; Lindeman, 1944). He defined five characteristics of the condition which he considered pathognomonic. Included were somatic distress, preoccupation with the image of the deceased, guilt, hostile reactions, and loss of patterns of conduct. It seems he preferred to characterize the anxiety in terms of somatic distress. In addition, he suggested that normal grieving was a process of four months average duration. No description of his sample was provided other than the information that the loss resulted from a sudden, violent death. Lindeman's characterization of the main features of grief, although lacking a quantified basis in his clinical writing, corre- sponded to parts of Freud's description and was borne out in the studies of grief by Parkes. Clayton and associates have reported on a random sample of 109 adult survivors of spouses who died either at Barnes Hospital or in the St. Louis area (Clayton et al., 1971; Clayton et al., 1972; Bornstein et al., 1973). This study is limited in its contribution to understanding the natural history of grief by virtue of its focus on psychopathological symptoms. The occurrence of depressive symptoms is given thorough attention. These findings have been summarized in the part of the review that deals with cause specific morbidity. The high frequency of depressive symptoms, not to mention primary depressive syndromes in Clayton's cohort, is con- vincing support for Parkes' concept of a phase of bereavement character- ized by depressed emotion and despair. There is less convincing affir- mation of a phase of anxious searching, in part, because Clayton did not directly address the question. It is perplexing that only 10% of subjects 141 in her study report anxiety as a symptom. Of course, anxiety may be experienced in many ways and, in fact, Lindeman preferred to charac- terize it as somatic distress. The absence of a greater proportion of subjects who report anxiety is nevertheless troublesome. The grief of the elderly has features which distinguish it from that in younger persons (Stern and Williams, 1951; Gramlich, 1968; Tunstall, 1966; Gerber et al., 1975; Heyman and Gianturco, 1973). Specifically, a loss is faced with more acceptance, is associated with more psychosomatic symptoms, and is characterized by less numbness, denial, and guilt. Hallucinations and illusions occur with greater frequency (Rees, 1971). It is logical that some of these features -- acceptance, reduced numbness, denial, and guilt -- are related to the anticipation of death before the actual death. If so, and if the same assumption may be made about younger persons, anticipatory grief may play an important role as a determinant of the content and pattern of actual grieving. Sociological Studies Sociological studies of grieving have introduced into consideration the widow's social status, social roles, and social adjustment. In one study the deprivation, as a result of change in status, and the loneli- ness, as a result of social isolation, were important elements of be- reavement that caused suffering and problems in their own right (Glick et al., 1974). Whereas these investigators noted a reduction in the in- tense emotional response associated with a loss in most widows after two months, impairment in social functioning was prolonged and lasted several months. Other sociological studies reporting on cross-sectional data support the conclusions mentioned previously that there are changes in status and disruption of social roles resulting from conjugal loss (Tunstall, 1966; Lopata, 1973; Berardo, 1968; Berardo, 1970). In general, the social environment of the bereaved is changed and appears insecure or threatening. Faced with the loss and a changed social environment, the bereaved person turns for support to his established social network (Walker et al., 1977). No empirical literature on social supports of the bereaved currently exists, with the exception of how the social network is perceived by the bereaved (Maddison and. Walker, 1967; Raphael and Maddison, 1976). Perceived nonsupportiveness of the social network has proven to be a powerful variable in predicting poor outcome of the grieving process. Clinical observations from these studies affirm that the perceptions of the bereaved are probably accurate. Nevertheless, the actual social support network was not described; and based on this work alone, it is impossible to choose between the possibilities that perceived nonsupportiveness may reflect either a quality of personal social functioning or an actual deficiency in the social network of the individual. 142 The studies described above provide a basis for the importance of studying social expectations, roles, and relationships in the process and consequences of grief. Further, certain dimensions of sex roles such as the expectation for men to appear strong and independent, the need of the average man to maintain emotional control, and the deficiencies of certain social role proficiencies in many men may distinguish the process of grief for men as opposed to women and serve as explanatory factors for sex differences found in the outcome of bereavement. In fact, minor support for the discriminating power of such factors already exists (Glick, Weiss, and Parkes, 1974). As a specific example, loss of occupational role through retirement (or other means) aggravates the risk of social iso- lation among widowers without supplemental social role effectiveness which may elevate, in turn, the risk of illness (Berardo, 1970). Such differences in sex roles may help explain the higher risk of negative experiences of bereavement for men. Biological Studies In general, there has been little systematic work reported on biological aspects of grieving in adults. One exception is the work by Hofer et al., in which urinary corticosteroid levels in parents were compared before the death of a child from leukemia and during the bereavement period, at intervals of 6 months and 2 years following the child's death. This study indicated that an individual's characteristic adrenal cortical excretion level during a period of impending object loss can be significantly different from that during the bereavement period. Hofer's study also indicated that the direction of the difference is an important characteristic of the individual subject, particularly with regard to the style and effectiveness of psychological defenses and the intensity of grief experienced (Hofer et al., 1972a; 1972b). This study, however, was not primarily concerned with the postloss period and was limited with regard to sampling intervals and the scope of the endocrine, psychological, and social variables which could be assessed. Another exception is the recent- ly reported finding of depressed T-cell function in a prospective clinical study of 26 bereaved spouses six weeks after the loss. This finding indicates an abnormality in immune function which possibly might be secondarily related to psychoendocrine reactions (Bartrop et al., 1977). To our knowledge, there are no other reports of research dealing directly with neuroendocrine mechanisms in relation to grieving. Since the autonomic nervous system is heavily implicated by clinical studies in the appearance of psychophysiological symptoms which occur frequently in grief, studies of autonomic nervous system functioning hold potential interest for the elucidation of the grieving process. Apropos of this, the concept of a conservation-withdrawal response has been postulated and presumed to be related to a parasympathetic activity (Schmale, 1973). The cognitive and affective features of the conservation-withdrawal 143 response include the experience of helplessness and hopelessness which may lead to periods of giving up. Schmale indicates this is part of the normal grieving process. During periods of giving up and before new patterns of coping are acquired, both Schmale and Engel suggest there is an increased general susceptibility to illness (Schmale, 1958; 1973; Engel, 1968). The clinical syndrome of depression represents for Schmale only one possible psychic consequence of the effects of depression described above. Attention to systematic, reliable collection of data and to the use of controls has been absent in these studies. Concomitant objective observations of the neurophysiology to substantiate the autonomic hypotheses are difficult to make (if not impossible with current technology) and have not appeared. A study of young widows provided a measure of autonomic symptoms that has no convincing validation (Parkes and Brown, 1972). In this study, Parkes and Brown demonstrate a high frequency of autonomic symptoms during the first year, especially in women, that diminish to normal levels by the third year. No distinction between sympathetic and parasympathetic functioning is made. Whereas studies of autonomic nervous system functioning have not been fruitful yet, it is evident that a number of findings and concepts which have emerged from the field of psychoendocrine research appear to have rather direct relevance and potentially important implicationg for the study of the grieving or mourning process. Measurement of corticosteroid levels, for example, has been demonstrated repeatedly to be a sensitive index of the general level of emotional arousal, distress, or involvement in subjects exposed to stressful life situations (Mason, 1968). The study by Hofer et al., furthermore, indicates that it may provide a useful index for the assessment of the intensity of grief reaction during bereavement, in conjunction with psychological measures (Hofer et al., 1972a; 1972b). A fascinating observation is one in which, among multiple determinants of corticosteroid levels, men who had lost a mother during childhood tended to fall in the lowest quartile and those who had lost a father in the highest (Poe et al., 1970). It has also been discovered that chronic mean adrenal cortical hormone excretion correlates highly with the level of effectiveness of psychological defenses, as assessed in such diverse populations as the parents of leukemic children (Wolff et al., 1964a; 1964b), army recruits during basic combat training (Rose et al., 1968, Poe at al., 1970), and women awaiting breast tumor biopsy (Katz et al., 1970). A particularly interesting finding was that subjects prone to rely heavily upon the defensive mechanism of denial not only tended to run low chronic mean corticosteroid levels, but also tended to suppress corticosteroid levels even lower on acutely distressing occasions. The latter suggests that overcompensatory use of denial may lead to marked disturbances in endocrine balance but in the opposite direction from that observed in other subjects whose defenses are less effective in minimizing distress or emotional arousal in stressful situations (Mason, 1975). 144 There are other areas of psychoendocrine literature which appear to have considerable relevance for the study of bereaved subjects, including a rather extensive body of research on hormonal levels in patients with depressive syndromes. This work has been reviewed in depth, especially by Sachar (Sachar, 1975) and Carroll (Carroll, 1972, 1976) and has established the usefulness of studying adrenal cortical activity in depressed patients. Pathogenesis of Complications: Considerations Based on an understanding of the process of grief and a knowledge of the pattern of mortality associated with conjugal bereavement, three conceptual levels of pathogenetic mechanisms appear relevant: physiological behavioral, and social. Assuming Ciocco's observation that death is rare before four months have elapsed after a conjugal loss is true and not a methodological artifact, it appears most promising to look for pathogenetic forces in the phase of despair (Ciocco, 1940). On the other hand, given a limited state of knowledge, consideration of all elements and phases of grief should not be excluded. On a physiological level, the postulated parasympathetic activation of the conservation-withdrawal reaction, a state thought to be associated with increased vulnerability to illness, may have cardiovascular and other consequences. Depression and the accompanying physiological changes, both in endocrine functioning and in monoamine neurotransmitters, may provide to be a mediating mechanism leading to illness and death through suicide, cardiovascular disease, infectious disease, or general suscepti- bility to disease (Lebovits et al., 1967; Kasl et al., 1977; Markush et al., 1977; Imboden et al., 1961). Apropos of depression as a patho- genetic mechanism, it is recognized that the occurrence of "clinical depression" in bereavement is controversial (Clayton et al., 1972; Bornstein et al., 1973). Alterations in immune mechanisms may lower vulnerability to infectious diseases that increases the risk of morbidity and mortality from these diseases (Bartrop et al., 1977; Ciocco, 1940; Amkrant and Solomon, 1975). Finally, the neuroendocrine system, as an effector system with far-reaching biochemical regulatory actions on virtually every tissue in the body including the brain, provides a par- ticularly promising view of a major mediating linkage through which psychological processes can exert pathogenetic influences upon bodily processes (Mason et al., 1967; Bulbrook and Hayward, 1967). Cohort Studies. MORTALITY OF . JUGAL BEREAVEMENT, Study Year Published Place’ Bereaved Subjects Year of Bereavement Causes of death Number Average age Sex (% men) Refusals Mortality of Bereaved (%) LT 6 months 7-12 13-24 Type of Comparison Group Mortality of Controls LT 12 months 13-24 months Rees and Lutkin 1967 Llanidloes, Wales 1960-1966 all causes 156 69.7% (Women 70, Men 67) 32.7 None Widows Widowers 13.7 8.5 5.9 6.7 4.9 15.2 24.5 Matched on age and sex 1.2 3.0 *Average age of those in the cohort who died Clayton et al 1974 St. Louis, Mo. 1968 all causes 109 62 30 427% Widows Widowers 3 2.6 3 5.2 3 7.8 ° 9.0 Matched on age and sex 5 not reported yet Gerbel et al 1975 New York, N.Y. early 1970s all causes 169 (only 53 did not receive intervention) 67 28 6-25%, no difference from participants "no increase", 2.47% in the first 15 month period Group matched on age, sex, religion, and ethnicity rates for controls not reported Ward 1976 Sheffield, England 1971-1972 Cancer 366 64 23.8 None Widows Widowers 0.4 8 1.8 0 1.8 2.2 4.0 10.2 No controls; expected rates from England and Wales life tables, 1971-72 Women (Expected) Men (Ex pected) 6.9 AN MORTALITY OF CONJUGAL BEREAVEMENT, STUDIES USING VITAL STATISTICS. Study Kraus and Lilienfeld Young et al- Cox & Ford McNeill Year Published 1959 1963 1964 1973 Place United States Great Britain Great Britain Connecticut Type of Data Mortality Data Death Certificates Death Certificates Death Certificates Bereaved Subjects: Year of bereavement Number Average Age Sex (% men) Mortality of Bereaved (%) LT 6 months 7-12 months 13-24 months LT 24 months Type of Comparison Group Mortality of controls LT 6 months 7-12 months 13-24 months 1949-1951 All deaths, U.S.A. Not specified Not specified Annual rates; no control for dura- tion of bereavement Mortality ratios range from 1.14 to 4.32, higher in men and younger ages Married; bereaved also had higher rates than single and divorces 1957 4,486 GT 55 100 5 3.7 7 15.5 British total pop- ulation, expected rates Ratios of bereaved to expected rates = 1.4 for 1st 6 mo, otherwise = 1 1927 60,000 LT 70 0 1.4 1.5 2.9 Their own con-~ trols; annual periods compared to average of 5 years ratios 0.99 1.08 1965-1968 9,247 range = 20 - 74 31.8 Widows Widowers 0.6 2.0 0.6 1.7 1.3 3.2 2.5% 6.9% Expected mortality rates de- rived from Connecticut tables, by age and sex Women (Expected) Men(Expected) .6 1.7 .6 1.8 1.4 3.7 2.6 7.2 *Although these figures do nctdemonstrate an elevated risk in the widowed, when age, and specific cause of death were controlled, the characteristic pattern of elevated risk among the bereaved emerged. IT 147 On a behavioral level of conceptualization, changes in health practices of the surviving spouse may lead to illness and death. This idea is consistent with the observation that most of the causes of mortality among the bereaved are conditions of middle and late life. Such changes in health practices such as the neglect of early signs of disease, the neglect of the proper management of disease or the excessive use of alcohol may be related to several aspects of grief. These aspects include the disorganization and the aimlessness of the despair phase of grief, the exhaustion of searching unsuccessfully in a sustained state of high arousal, the challenge to adapt to new roles in a threatening social environment, or a change in socioeconomic status in a society in which the highest quality of health care is usually purchased privately at high cost. The potential importance of health practices is compatible with the idea that bereavement increases the risk of premature illness or death in bereaved persons who were already vulnerable by virtue of a diathesis or preexisting disease. This is consistent with the obser- vation of a "compensatory dip" in mortality among the bereaved in the third, fourth, and fifth years after their conjugal loss. On a social level of conceptualization, the loss of care suffered by a bereaved spouse in circumstances where the conjugal partner who has died was the medically responsible member of the family may be another pathogenetic mechanism. The social isolation of widowhood and the widowed person's loss of power to purchase care may be related to this mechanism. The clinical literature on the morbidity of bereavement gives some attention to these issues (Parkes, 1972; Clayton, 1973; Shepherd and Barraclough, 1974). Recommendations for Additional Research Several major areas of research are suggested by the content and the deficiencies of the literature. They include: 1. Studies of the process of grief in its psychological, social, and biological dimensions and interactions. 2. The studies of the biology of grief may appropriately be con- cerned with the neuroendocrinology and immunology of grief, the understanding of biological correlates and determinants of the psychological and social dimensions of the process, and the causes of the increased susceptibility to illness that accompanies grief. 3. Longitudinal studies of the social, psychological and biological features of grief are essential to an understanding of the causes of the morbid and mortal consequences of the process. Such studies should delineate the characteristics of those at high and low risk for these consequences. 148 Studies of both young and elderly grieving men to elucidate the particularly high risk of morbidity and mortality in them. Studies of parents whose children die before full maturity to elucidate for the survivor the risk of illness and death. Evaluation of programs designed to provide services to the bereaved that employ new techniques such as volunteer caregivers. Similar evaluation of programs that may be helpful for grieving older persons is advisable. Such programs may include Foster Grandparents, RSVP, Senior Centers, tenant association in elderly housing projects, hot meals programs, and associations of retired persons. Studies that elucidate the relationship of loss to the depressive symptoms of bereavement, as well as both of these to clinical depression. Clinical trials of various treatments such as brief psychotherapy and antidepressant drugs for grieving persons at high risk of morbidity and mortality. Studies that compare the human response to loss with the general response to stress -— with the aim of understanding the human response to various environmental stressors. Implications for Medical Practice from the Literature on Loss and Bereavement I. All physicians engaged in the practice of medicine ought to be aware of these issues. a) When one spouse dies, the survivor has an increased risk of illness and death. b) The kinds of morbidity and mortality for which the survivor is at risk are multiple, various in etiology and organ site. They include ischemic heart disease, several cancers, tuberculosis, influenza, suicide, alcoholism, accidents, and possibly diabetes. c) The effects of bereavement may cause new illness, make latent illness manifest, or worsen overt disease. d) The effect of bereavement on health may be mediated through the following mechanism: 1) the survivor neglects medical care; i.e., stops taking insulin or antihypertensive drugs, II. e) £) 149 2) the survivor discovers new symptoms or illness but neglects to see a physician, 3) the survivor deferred to the deceased spouse in health matters and, after the loss, cannot cope with responsi- bility for personal medical care, 4) the survivor may neglect an adequate diet, 5) the survivor may take to alcohol or other drugs or may increase consumption of these substances, 6) the survivor, while depressed and/or intoxicated may have an accident or commit suicide, 7) the survivor may be at increased risk of communicable disease because of the effect of bereavement on immune function. The period of increased morbidity and mortality is limited to about one year after death of spouse for surviving men and two years after loss of spouse for surviving women. The expenses connected with grave illness or death of a spouse are always large and may be overwhelming. There has been no systematic study of the effect of this financial loss on the health of the survivor. The econaqmic loss may induce or worsen depression and substance abuse, lead to self-neglect for medications or medical care, or induce lapses of medical or hospital insurance. Physicians caring for a terminally ill spouse should be alert to changes in the health status in the other spouse. a) b) c) d) Signs of depression such as depressive affect, sleeplessness, anorexia and weight loss, psychomotor retardation and talk of self-injury or death. Signs of behavior change that may be induced by alcohol. or drug abuse. Neglect of medical regimens. Other evidence of disease such as worsening of diabetes or hyper- tension, acute or chronic infection, symptoms or signs of cardiovascular or neoplastic disease. III. IV. 150 Evidence of change in the health status of the surviving spouse should lead to appropriate medical care. If the same physician cares for both spouses the responsibility belongs to that physician. If not, the physician caring for the dying spouse who notices health changes in the survivor ought to make prompt referral of the survivor to his/her own physician. There may be an advantage to the surviving spouse if the same physician has been responsible for the care of both marital partners. In such cases, the physician has unique knowledge of the health of both spouses, their special susceptibilities to illness and their medical care. The physician is enabled to detect lapses in care, or changes in health or behavior in the survivor and to plan for their management early. Physicians should know the community social and psychiatric resources available to patients with severe grief and bereavement and how to use these resources. 151 BIBLIOGRAPHY Aldrich, C.K.: Some dynamics of anticipatory grief. In Anticipa- tory Grief, Shoenberg, B. et al., (Eds.). New York: Columbia University Press, 1974. Bartrop, R.W., Luckhurst, E., Lazarus, L., Kiloh, L.G., and Penny, R.: Depressed lymphocyte function after bereavement. Lancet 1: 834 36, 1977. Bellin, S.S. and Hardt, R.H.: Marital status and mental disorders. Amer. Soc. Rev. 23:155, 1958. Berardo, F.M.: Widowhood status in the United States: perspective on a neglected aspect of the family life cycle. Family Coordinator 17:191-203, 1968. , Berardo, F.M.: Survivorship and social isolation: the case of the aged widower. Family Coordinator 19:11-25, 1970. Bornstein, P.E., Clayton, P.J., Halikas, J.A., Maurice, W.L., and Robins, E.: The depression of widowhood after thirteen months. Brit. J. 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Rose, R.M., Poe, R.0., Mason J.W.: Psychological state and body size as determinants of 17-OHCS excretion. Arch. Int. Med. 121: 406-13, 1968. Ruskin, H., Stein, L.L., Slelsky, J.M., and Baily, M.A.: MMPI: Comparison between patients with coronary heart disease and their spouses together with other demographic data. Scandinavian Journal of Rehabilitative Medicine 2:99-104, 1970. Sachar, E.J.: Neuroendocrine abnormalities in depressive illness. In Topics in Psychoendocrinology, Sachar, E.J., (Ed.). Grune and Stratton, New York, 1975. Schmale, A.H.: Relationship of separation and depression to disease. Psychosom. Med. 20:259-77, 1958. 156 Schmale, A.H.: Adaptive role of depression in health and disease, in Separation and Depression: Clinical and Research Aspects. Edited by Scott, J.P. and Senay, E. Washington, D.C.: AAAS, 1973. Shelton, M. and Dominian, J.: Psychological stress in wives of patients with mycardial infarction. Brit. Med. J. 2:101-103, 1973. Shepherd, D. and Barraclough, B.M.: The aftermath of suicide. Brit. Med. J. 2:600-603, 1974. Shoenberg, B., Carr, A.C., Kutscher, A.H., Peretz, D. and Goldberg, ~I.K.: Anticpatory Grief. New York: Columbia U. Press, 1974. Siggens, L.D.: Mournings: a critical survey of the literature. Int. J. Psychoanal. 47:14-25, 1966. Stein, Z. and Susser, M.: Widowhood and mental illness. Brit. J. Prev. Soc. Med. 23:106-110, 1969. Stern, K. and Williams, G.M.: Grief reactions in later life. Am. J. Psychiat. 108:289-94, 1951. Townsend, P.: The Family Life of Old People: An Inquiry in East London. Glencoe, Ill.: The Free Press, 1957. Tunstall, J.: Old and Alone. London: Routledge and Kegan Paul, London, 1966. Vachon, M.L.S.: Grief and bereavement following the death of a spouse. Com. Psychiat. J. 21:35-44, 1976. Walker, K. N., MacBridge, A., and Vachon, M.L.S.: Social support networks and the crisis of bereavement. Soc. Sci. and Med. 11: 35-41, 1977. Ward, A.W.M.: Mortality of bereavement. Brit. Med. J. 1:700- 702, 1976. Wolff, C.T., Friedman, S.B., Hofer, M.A., Mason, J.W.: Relationship between psychological defenses and mean urinary 17-OHCS excretion rates: Part I. A predictive study of parents of fatally ill children. Psychosom. Med. 26:576-91, 1964a. Wolff, C.T., Friedman, S.B., Hofer, M.A., Mason, J.W.: Relationship between psychological defenses and mean urinary 17-OHCS excretion rates: Part II. Methodological and theoretical considerations. Psychosom. Med. 26:592-609, 1964b. Young, M., Benjamin, B. and Wallis, C.: The mortality of widows. Lancet 2:454, 1963. 157 Special Communication The Ethics of Terminal Care Harold Y. Vanderpool, PhD ® The widely used notion of dignity is questioned as an adequate ideal for care of terminally ill persons. Instead of dying with dignity, the essential ethical components of dying with a sense of worth are proposed as comprising truly humane and personal cara. (JAMA 239:850-852, 1978) THE PHRASE “dying with dignity” has come to symbolize ethical care for terminally ill persons. However, the meaning of this phrase is not at all clear. What ideals does this phrase invoke, and are these ideals adequate for our care of the dying? Dying With Dignity One of the problems with using the . phrase “dying with dignity” involves its having not one but at least four current meanings. The first has to do with prolonging the life of those who are irreversibly comatose. By removing the mechanical equipment, which alone supports life, physicians are said to enable patients to die with dignity. The classic case here is that of Karen Quin- lan. Any association of human dignity with the final cessation of bodily func- tions is, however, unclear. Dying with dignity has at least three possible meanings in such cases. It may mean that the physical body of the patient should not lose its last vestiges of dignity by being further distorted or disfigured. Or it may mean that some kind of generic human dignity is main- From the Institute for the Medical Humanities, University of Texas Medical Branch, Galveston. Reprint requests to Institute for the Medical Humanities, University of Texas Medical Branch, Galveston, TX 77550 (Dr Vanderpool). 850 tained if vegetating human bodies are allowed to die rather than to use up great amounts of energy and medical resources needed by others.! Or, prob- ably most meaningfully, it indicates how dignity is lost when a person's conscious and social life is unnaturally separated from mere physiological ex- istence. In this sense Karen Quinlan’s indignity lay in the long-term, mechan- ical attachment of her body to life- support machinery after her psycho- logical and social awareness was gone. Second, death with dignity is some- times used as a symbol for voluntary euthanasia or suicide. To die with dignity is to control one’s fate rather than passively to endure the indignities of “an incurable disease or injury in its terminal stages.”” Dignity thus in- volves a heroic resistance against the loss of autonomy, beauty, and vitality. Whether this form of euthanasia truly constitutes dying with dignity is dis- puted. Some argue that the individual freedom and dignity gained here is counterbalanced by a general cheap- ening of life, which will adversely affect public policy.>® Many physicians believe that the dignity of their profes- sion lies’ much more with prolonging life than with assisting patients to die by request. Third, dying with dignity is asso- JAMA, Feb-27, 1978—Vol 239, No. 9 ciated with mature psychological and philosophical coping. Persons who are able to accept death, not deny or rage against it, are those who are said to die “with peace and dignity.” It is thus undignified for persons not to face death frankly and courageously and for health professionals not to assist patients psychologically.*® Fourth, dying with dignity is equated with maintaining as much self-esteem as possible. This self- esteem is inextricably related to what are most highly valued in our culture— independence, success, good looks, and so on. To die with dignity is thus to die with as much self-control, privacy, individual attention, and support as achievable.’ Therefore, patients should be assisted, hot dominated: they should, participate in the decisions affecting them, not merely be expected to follow orders. Ideal of Dignity The delineation of these meanings of “death with dignity” indicates how important the phrase now is. Dignity is used as an ethical ideal that assists us in making critical decisions about prolonging the life of irreversibly comatcse individuals, about euthana- sia, about coping psychologically with death, and about managing terminally ill persons so that they will lose as little self-esteem as possible. There are at least three reasons, however, why the term “dignity” is extremely prob- lematic as an ideal for terminal care. First, due to its many uses the meaning of the term is unclear, even Terminal Care— Vanderpool confusing. As we have seen, dignity is used in a variety of contexts with respect to terminally ill persons. It means everything from letting nature take its course by letting comatose persons die to a willful resistance of natural processes by the taking of one’s life before pain and unconsciousness set in. “Dying with dignity” has become a catchall phrase. Too often it is a cliché with many possible mean- ings. Second, when the term is carefully defined, “dignity” is of limited validity as a norm that defines what it means to care for the dying. What is the precise meaning of the term? Drawn from the Latin word digni- tas, the essential root meaning of “dig- nity” denotes honorableness, grandeur, esteem, or high rank. The term is appropriately used both in generic and restrictive senses. In its generic sense, human dignity refers to those attributes that consti- tute the characteristic excellence or grandeur of man. The loss of conscious- ness and rationality thus entails a loss of human dignity, a loss that is rightly described as dehumanizing. In this sense dignity is largely lost when irre- versibly ill persons are reduced to plant-like dependence on life-support equipment. This unadorned, generic meaning of dignity represents the most appropriate use of the term with respect to human dying. With this understanding of dignity as a guide- line, one could “pull the plug” on bodies that are irreversibly comatose not for these bodies to die with dignity, but for then: to die because by and large, they are devoid of human dignity. In its restrictive sense, however, “dignity” can hardly be used for every human being. “Dignity” commonly serves as a term of distinction reserved for individuals manifesting nobility and excellence. In this sense notable humans or martyrs may die with dignity, but death with fame or gran- deur (death with dignity in the restric- tive sense) makes little sense for humans generally. The difficulty of democratizing the term is reflected in the quip that, “It was good that Sam wanted to die with dignity; he lived with so little of it.” Third, given this restrictive but also commonly used meaning, dignity can- not serve as an appropriate moral norm for the care of most terminally ill JAMA, Feb 27, 1978—Vol 239, No. 9 158 persons. As a term of distinction, the term is associated throughout history with that which is esteemed or honored in each culture. In those eras and cultures where death was viewed as a dramatic, center-stage performance for each person, it was indeed possible for many persons to face death with digni- tatis in its restrictive sense. But for the majority of terminally ill persons, these cuitural resources appear to be lost at the present time. Indeed, prob- ably the main reason why death is so widely denied, so characteristically shunned in our culture is owing to its radical contrast with many deeply rooted Western social values. Our society esteems individualism, autono- my, activism, physical vitality, and sexuality. Conversely, it views de- pendency, burdensomeness, passivity, and the loss of beauty and vitality through sickness or aging as degrad- ing. It is manifestly undignified to be passive, burdensome, and unattractive in our society; yet, these are precisely the conditions that characterize termi- nal illness. No wonder the great majority of adult Americans, when polled, would prefer to die “suddenly and unexpectedly.”*® + Given the degrees to which terminal illness is generally regarded as undig- nifying and debasing, the use of dignity as an ideal for terminal care is absurd. Although certain ethnic and religious traditions represent occasional excep- tions, modern society places few pre- miums on suffering and death. It places decreasing value on faithful witnessing at the time of death and eternal blessings thereafter. To put it mildly, dying is not dignified in secular America. Therefore, dignity can hardly serve as a moral basis for the care of most terminally ill persons. Its only meaningful application involves its appropriateness as a concept that justi- fies disconnecting the irreversibly co- matose person from life-support ma- chinery. If we abandon dignity as an adequate ideal for the general care of terminally ill persons, how can we speak appropriately about meaningful dying and the care of persons who are dying? Can we develop an ethical model of terminal care that draws on shared values that attribute worth and meaning to every stage of human life, including terminal illness? Perhaps no single, encompassing phrase can serve as a shorthand symbol for these values, but if candidates are nominated, dying with humanity or dying with a sense of worth is far more satisfactory than dying with dignity. More Adequate Ideals In seeking to set forth ethical guide- lines for terminal care, I propose to sketch out a fundamental set of features that are present when life has meaning and worth. These features will be used to indicate how meaning and value are preserved even when life is in its terminal stages. The practical implications of these ideals for the management of terminally ill persons will be constantly borne in mind. First, human worth is founded on the principle of respect for the person. One’s personal uniqueness of individu- ality is based on one’s rational consciousness and personality. This individuality is protected when humans are respected -as persons who can define their own ends rather than be treated as means for the goals of others. Human value is thus sustained when persons make their own choices and when they have rights that are protected and honored. With regard to the terminally ill, respect for each person requires at least three concerns about individual choices and rights: (1) In accord with their desires, each patient must be given truthful information about all decisions and procedures affecting his or her well-being and must consent to these procedures before they are per- formed. (2) The current belief that dying with peace and dignity neces- sarily includes passing through certain psychological stages needs to be condi- tioned on patient desires. Helping the terminally ill to pass through stages such as anger and denial to acceptance may be an attractive therapeutic goal, but this form of coping and introspec- tion is not justified unless persons want it. Those who care for the dying must be careful, however, not to misin- terpret patient desires by their own inabilities to cope with death and dying. (3) The autonomy and self- control that characterize Western indi- viduality need to be preserved as much as possible. The sense of lost dignity resulting from excessive dependency and loss of control (even over bowel and bladder) are major problems for the terminally ill person. Terminal Care— Vanderpool 851 Many adult Americans find it hard even to receive help from others without a tinge of regret or guilt. Total dependency is thus characteristically viewed as deeply embarrassing and undignified. This helps explain why many terminally ill persons prefer institutional rather than home care. They believe that they preserve a measure of pride and control when they pay for their care, and they are less embarrassed when they receive aid from professionals. Whether in home or hospital, those who tend to the needs of the dying should think of ways to enhance the choices and self-control of the terminally ill person. Totally man- aging or doing everything for patients ennobles the image of the professional more than it enhances the sense of worth of the dying. Second, human worth is based on the .individual’s inclusion in a community. ‘Being part of a community is essential for the development of consciousness and individuality and is characterized by communication, mutuality, and the ethical ideals of fidelity, gratitude, reciprocity, justice, and love. Persons have worth not just because they are independent, work, reach goals, and have power, but also because they love and are loved and interact with others in numerous ways. Persons who are terminally ill lose a sense of worth if they are left alone, if they are avoided and not touched, if they receive only bland pleasantness, of if they are greeted with silence instead of words. The strength and attractiveness of the hospice movement is associated with this communal framework for human meaning. The hospice makes it possible for terminally ill persons to interact more frequently and freely with kin, friends, children, health 1. Engelhardt HT Jr, Erde EL: A my-t-fine way to die. Hosp Physician 8:37-39, 1976. 2. Kohl M (ed): Beneficent Euthanasia. Buffa- lo, Prometheus Books, 1975, pp 233-236. 3. Dyck A, Fletcher J: To Live and To Die: When, Why, and How, Williams RH (ed). New York, Springer-Verlag, 1973, pp 98-122. 852 JAMA, Feb 27, professionals, social workers, and cler- gy. It allows for and encourages communal experiences such as parties and worship, and understands that a community includes not only people but personal possessions such as cloth- ing, furniture, and pets. These aspects of community need to be taken much more seriously in the hospital. Third, human value is rooted in concern for the body. A person’s sense of worth or well-being is reflected by his bodily carriage and is affected by personal grooming, by the presence or absence of pain, and by disfigurement or mutilation. These observations show that self-worth has extremely impor- tant physiological and aesthetic dimen- sions, and help explain why “do no harm” is a crucial moral norm in past and present codes of medical ethics. In this light heroic medical procedures that disfigure the body must not be automatic, but must be based on serious moral reflection. In this light, also, great attention needs to be given to pain therapy. The personal groom- ing of the terminally ill person should not be regarded simply as one of the little things that can be done for him. Fourth, human worth is often main- tained by considerations of a broader purpose. The human desire to ground personal meaning in some cosmic or purposeful frame of reference is widely shared throughout recorded history. This understanding of individual life as fitting into some ennobling destiny or some ultimate purpose can be framed in naturalistic or theistic terms, and it often, although not inevitably and necessarily, is the way that persons attribute meaning and worth to their lives." As William Osler pointed out at the turn of the century, however most persons seek to terminate life as they References 4. Kiibler-Ross E: On Death and Dying. New York, Macmillan Co Publishers, 1969, pp 7, 9, 113- 115. 5. Morrison RS, Kass LR, Engelhardt HT Jr: Death Inside Out, Steinfels P, Veatch RM (eds). New York, Harper & Row Publishers Inc, 1974, pp 81-225. 1978—Vol 239, No. 9 lived it, many with metaphysical and religious concerns, but others with the everyday preoccupations that they al- ways had.® They should not be denied the rights and possibilities of these alternatives. These four fundamental features of human worth—respect for the individ- ual, inclusion in a community, concern for the body, and considerations of a broader purpose—are offered as ethi- cal guidelines for terminal care. They comprise a set of ideals that move us well beyond the problematic phrase “dying with dignity.” It is impossible, of course, to bestow a sense of worth on the dying; for this sense is inextricably related to the character and will of each person. Yet we can and should seek to preserve, not unwittingly erode, those fundamental aspects of human life on which personal meaning is pred- icated. Whatever else death is, it is not an unnatural aspect of the biologic life process or a unique feature of the human condition. It thus becomes necessary to seek to deal appropriately with the dying even as we relate to persons in every aspect of life. Only a broader ethical framework, not the limited one supplied by the term “dig- nity,” will enable us to tend to the personal needs of the terminally ill person. The four fundamental features of human worth set forth here serve as key ethical considerations that ought to be taken seriously in caring for the dying. Indeed, on the basis of these principles, terminally ill persons may be able to experience a loss of much honorableness or dignity without los- ing the conviction that life has mean- ing even in its final days and hours. 6. Krant MJ: Dying and Dignity. Springfield, Ill, Charles C Thomas Publisher, 1974, pp 33-44. 7. Edwards P: Meaning and value of life. The Encyclopedia of Philosophy. New York, Macmil- lan Co Publishers, 1967, vol 3, pp 467-477. 8. Osler W: Science and Immortality. London, Constable & Co Ltd, 1906, pp 18-20. Terminal Care— Vanderpool 159 Bibliography of Publications Related to Hospice Aries, Phillippe. Western Attitudes Toward Death From the Middle Ages to The Present. Baltimore: Johns Hopkins Press, 1974. Ashley, Beth. "Death Without Pain: A Dying Man Tells How Hospice Helps" (reprint), Independent-Journal, San Rafael, California, November 15, 1976. Barber, Bernard. "Compassion in Medicine: Toward New Definitions and New Institutions," New England Journal of Medicine, 295:7 (October 21, 1976), pp. 939-43. Barnard, C.N., "Good Death at St. Christopher's Hospice," Family Health, 5:40ff. April, 1973. Buckingham, R., Joan Koon and Henry Wald, The Hospice Concept. New York Health Sciences Pub. Corp., 1977. Buckingham, R.W., S.A. Lack, et al.. "Living with the Dying: Use of the Techniques of Participant Observation,'" Canadian Medical Association Journal, Vol. 115 (December 18, 1976), 1211-1215, Chan, Lo-Yi. "Hospice: A New Building Type to Comfort the Dying," (reprint) AIA Journal, December, 1976. Carey, R.J. "Living Until Death," Hospital Progress, Vol 55, No. 2, February, 1974, pp. 82-87. Crase, Dixie and Darrell Crase. "Live Issues Surrounding Death Education," Journal of School of Health, (February, 1974), pp. 70-73. Craven, Joan and Florence S. Wald. "Hospice Care for Dying Patients," American Journal of Nursing, 75:10 (October, 1975), pp. 1816-22. Crowther, Bishop C. Edward. '"Care vs. Cure in the Treatment of the Terminally I11," Report Center for the Study of Democratic Institutions, April, 1976, pp. 20-23. Dunphy, J. Englebest. '"On Caring for the Patient With Cancer," New England Journal of Medicine, 295:6 (August 5, 1976), pp. 313-19. Eissler, Kurt Robert. The Psychiatrist and The Dying Patient. New York International Universities Press, 1955. Feifel, H. "Perception of Death, '" Annals of the New York Academy of Science, Vol. 164 (1969) p.669. 160 Feifel, H., ed. The Meaning of Death. New York: McGraw-Hill, 1969. Garner, J. '"Palliative Care. It's the Quality of Life Remaining That Matters." CMA Journal, 115:179-80 (July 17, 1976). Glick, I.0., R.S. Weiss, and C. M. Parkes, The First Year of Bereavement, New York, J. Wiley and Sons, 1974. : Gorer, Geoffrey. Death, Grief and Mourning. New York: Doubleday, 1965. Hinton, John. '"The Physical and Mental Distress of the Dying." Quarterly Journal of Medicine, Vol. 32, 1963. Hinton, John. Dying. Baltimore, Penguin Books, 1974. Hinton, John. '"Talking With People About To Die," British Medical Journal, Vol. 3, 1974, pp. 25-27. Holden, Constance. 'Hospices for the Dying: Relief from Pain and Fear," Science, July 30, 1976, pp. 389-91. Holford, R.M. "Terminal Care," Nursing Times, January, 1973, pp. 113-115. "Hospice: Pilot Project," (pamphlet). New York: St. Luke's Hospital Center. "Hospice," Thanatos, March, 1977, pp. 6-11. Ingles, Thelma. "St. Christopher's Hospice,' Nursing Outlook, 22:12, December, 1974, pp. 759-63. Jordan, Lynette. "Hospice in America," The Coevolution Quarterly (Summer, 1977), pp. 112-15. Kahn, Sigmund B. and Vincent Zarro. ''The Management of the Dying Patient," Seminars in Drug Treatment, Vol. 3, No. 1, 1973, pp. 37-45. Kastenbaum, R. "Toward Standards of Care for the Terminally Ill: That a Need Exists," Omega, 6:2 (1975), p. 77. Kerstein, M.D. "Care for the Terminally Ill: A Hospice," American Journal of Psychiatry 129:237-38, August, 1972. Kubler-Ross, Elizabeth. On Death and Dying. New York: Macmillan, 1969. Lack, Sylvia A. "Philosophy and Organization of a Hospice Program - Psychological Care of the Dying Patient," University of California School of Medicine, San Francisco, Charles A. Garfield (ed.), 1977. 161 Lack, S.A. '"Management of Pain in Terminal Cancer," Medical News-Tribune. Vol. 4, No. 38, September 18, 1972, 2, England. Lamerton, R. "The Need for Hospices," Nursing Times, 71:155-57, January 23, 1975. Liegner, Leonard M. "St. Christopher's Hospice, 1974," JAMA 234:10, December 8, 1975, pp. 1047-48. McNulty, Barbara. 'St. Christopher's Out Patients," American Journal of Nursing, December, 1971, pp. 2328-30. Mount, Balfour M., Allan Jones and Andrew Patterson. ''Death and Dying: Attitudes in a General Hospital," Urology IV:6, December, 1974, pp. 741-47. Mount, B. 'The Problems of Caring for the Dying in a General Hospital," CMA Journal, July, 1976, pp. 119-24. Mount, B.M. "Use of the Brompton Mixture in Treating the Chronic Pain of Malignant Disease." Canadian Medical Association Journal 115, July, 1976:122-124. "Optimum Care for Hopelessly Ill Patients," New England Journal of Medicine, 295:7, August 12, 1976, pp. 362-4. "Palliative Care Service: Pilot Project." Montreal: Royal Victoria Hospital, McGill University, 1976. Parkes, Colin Murray. Bereavement: Studies of Grief in Adult Life. Middlesex: Penguin 1975. Parkes, Colin Murray, "Effects of Bereavement on Physical and Mental Health - A Study of the Medical Records of Widows,'" British Medical Journal, August 1, 1964. Saunders, Cicely. ed. The Management of Terminal Malignant Disease. London: Edward Arnold, 1978. Saunders, C. "Training for the Practice of Clinical Gerontology: The Role of Social Medicine," Interdisciplinary Topics of Gerontology, 5:72-78, 1975. Saunders, C. ''Care of the Dying," A Nursing Times Publication (second edition). London, 1976. Saunders, C. Care of the Dying. London: Macmillan, 1959. Saunders, C. "Terminal Care," in Medical Oncology, ed. K.D. Bagshawe. Oxford: Blackwell Scientific Publication, 1973. Saunders, C. "Hospice Care," in the American Journal of Medicine, Volume 65, Sydenham, England, 1978. 162 Saunders, C. "The Challenge of Terminal Care," in Scientific Foundations of Oncology, ed. T. Symington and R.L. Carter. London: Heinemann, 1975. Saunders, C. "The Last Stages of Life," American Journal of Nursing (March, 1965), pp. 70-75. Saunders, C. '"The Management of Fatal Illness in Childhood," Proceedings of the Royal Society of Medicine, 62:6 (June, 1969), pp. 550-53. Saunders, C. ''The Management of Terminal Illness," (reprint) Hospital Publications, Ltd. London, 1967. Shephard, David, A.E. "Principles and Practice of Palliative Care," CMA Journal, March 6, 1977, pp. 522-26. Shephard, David, A.E. "Terminal Care: Towards an Ideal," CMA Journal, July 17, 1976, pp. 97-8. Stoddard, Sandol, The Hospice Movement: A Better Way of Caring for the Dying Stein and Day, New York, 1978. "The Hospice: An Alternative," JAMA, 236:18, November 1, 1976, p. 2047. Twycross, R.G., "Choice of Strong Analgesic in Terminal Cancer: Diamorphine or Morphine?" Pain (The Journal of the International Association for the Study of Pain) 3:2 (April, 1977), pp. 93-104. Wald, Florence S. "For Everything There is a Season and A Time to Every Purpose." The New Physician (April, 1969), pp. 278-85. Wentzel, K.B. "Dying are the Living: St. Christopher's Hospice, London," American Journal of Nursing, 76:956-7, January, 1976. West, Thomas S. "Hospice Care for a Dying Person and His Family." Paper presented at the First International Conference on Patient Counseling, Amsterdam, April, 1976. 163 ANTIEMETIC RESEARCH WORKING GROUP - MINUTES OF MEETING, March 22, 1979 The meeting was opened at 8:30 a.m. in Building 31-C of the NIH campus by Dr. Jane Henney, who welcomed the invited speakers and guests present. Reference was made to the preceding meeting on anti-emetic research, held May 9, 1978, inasmuch as the current meeting was being held to update information on clinical research with THC and to explore other compounds with anti-emetic properties. Although Nabilone appeared to be a drug of considerable promise at last year's meeting, it was removed from further clinical trials during the year pending further animal studies. The DCT filed an IND for THC with the FDA last summer. Investigators interested in conducting anti-emetic research in cancer are encouraged to cross-file on the DCT's IND for THC rather than file individually. The Division hopes to facilitate anti-emetic research by utilizing this method of drug procurement. Dr. Henney introduced Dr. Michael Jensen- Akula, DCT drug monitor for THC, who subsequently presided as moderator of the meeting. Dr. Fred Chang of the Surgery Branch at NCI presented the results of its THC vs placebo study. The objectives of the protocol were two- fold: 1) to determine in a prospective, randomized, double-blind study the relative effectiveness of Delta-9-THC vs placebo in patients receiv- ing high-dose chemotherapy and 2) to determine the absorption and effective serum concentration of Delta-9-THC necessary to prevent vomit- ing in patients receiving intensive chemotherapy. The patients eligible for the initial study were receiving high-dose methetrexate and those in the second study, Adriamycin plus Cytoxan. The protocol study design consisted of two parts, Phase I and Phase II. In Phase I, patients were initially randomized to receive THC followed by placebo with a subsequent re-randomization to placebo followed by THC (or vice versa). Patients served as their own controls and after three paired trials (six drug trials), they were classified as excellent responders, fair responders, or non-responders. Patients who were fair responders and non-responders had an elevation of THC dose and re-entered the original randomization 164 scheme. This step was designed to determine if an increase in THC dosage gave any additional benefit in these patients. The dose of THC was 10 mg/m? given orally at 7 a.m. on the day of chemotherapy and at 3-hour intervals for a total of five doses. If the patient vomited during the course of the study, the patient was given a comparable dose of THC in cigarette form. Placebo medications were handled in an identical fashion. In the Phase I study with MTX-treated patients, a reduction of nausea and vomiting was observed in 14 of 15 patients (93%) on THC. Eight of the fifteen patients (53%) experienced an "excellent" response in their reduction of nausea and vomiting on THC. Six of the fifteen patients (40%) experienced a "fair" response in their reduction of nausea and vomiting on THC. One patient experienced no response to THC in reduc- ing nausea and vomiting. In these patients, THC was significantly more effective than placebo with regard to the number of vomiting and retch- ing episodes, degree of nausea, duration of nausea, and volume of emesis. In these patients, there was a 72% incidence of nausea and vomiting on placebo when the THC plasma concentrations measured less than 5, 5 to 10, and greater than 10 ng/ml, the incidence of nausea and vomiting was 44%, 21%, and 6% respectively. All patients who experienced an anti-emetic effect from THC rated themselves as more comfortable and less distressed about their nausea and vomiting than with placebo. In Phase II of the study, patients classified as excel- lent responders went on to receive enriched THC trials specifically receiving eight THC trials and two placebo trials per ten chemotherapy sessions. The rationale for this arm of the study was to determine if excellent responders would maintain their excellent response with repeated trials. Five excellent responders entered Phase II of the study. Four of the five patients became fair responders to THC. One patient is still being evaluated. Of the two fair responders who entered Phase II of the study, both became non-responders to THC. In these six patients, repeated exposure to THC has resulted in a dimin- ished reduction of nausea and vomiting when compared to earlier trials. In the second study for Adriamycin plus Cytoxan~-treated patients, six patients have completed a total of 26 trials: 13 THC trials and 13 placebo trials. To date, three patients were fair responders and three were non-responders. Although this group of patients is too small for these results to be statistically significant, there appears to be a question of THC having a specific drug effect in terms of its anti- emetic properties when one compares different chemotherapy regimens. Dr. Jane Henney reported for Dr. Stephen Frytak on a study conducted at the Mayo Clinic. This study involved a comparison of oral THC vs Compa- zine vs placebo in GI cancer patients receiving 5-Fu and methyl CCNU at a minimum * other chemotherapeutic agents. The median age of patients 165 was 52 years. Analysis of data from this study shows that both THC and Compazine had a significant anti-emetic effect in this patient popula- tion; however, the CNS toxicity associated with THC in these patients was remarkable. CNS toxicity associated with THC has ranged from mild sedation to dysphoria, impaired thinking and incoordination. The final analysis of this study concludes that the two agents appear to be equivalent in regard to anti-emetic effect; however, Compazine is favored over THC due to the high level of toxicity associated with this latter compound. The next speaker was Dr. Stephen Sallan of the Sidney Farber Cancer Institute. Dr. Sallan reviewed the results of an ongoing study compar- ing THC vs prochlorperazine, in which all patients were previously refractory to the latter drug. The study design of this clinical trial followed that of a previous study, published in 1975, which was a randomized, placebo-controlled cross-over study where patients were randomized to receive either THC, placebo, or THC, THC and placebo. The conclusion of the first study was that THC had anti-emetic properties and that it was better in preventing vomiting than in treating existing vomiting. At the present time, 84 patients have been entered on-study and 20 are unevaluable. Of the 64 evaluable patients, 38 completed 3 courses and an additional 8 patients completed just 2 courses. Of the 38 patients who completed 3 courses, 19 patients had no preference between the THC and Compazine, while the other 19 patients had a clear preference. In this group of patients, 13 had a clear preference for THC, while 6 had a clear preference for Compazine. Of the eight patients who completed two courses, seven had a clear preference for THC. There seemed to be a correlation between the high and the anti-emetic response. Of 46 patients who received THC, 27 had a high. Twenty-three of twenty-seven who got high had complete responses. Of the 19 patients who received THC and had no high, only 2 had a complete response. The overall con- clusion to this study is that THC given by the oral route compares favorably with Compazine. The age range in this study is from 12 to 60 with a median of 32 years. Dr. Sallan discussed the issue of toler- ance and noted that this problem was occurring in the Sidney Farber Study in a similar fashion as that presented by Dr. Chang. Patients who are initially complete responders with THC sometimes fail to have an anti-emetic effect with subsequent courses. Dr. Deborah Goldberg of the Georgetown Cancer Center reviewed a study which is only in its initial phase. The study is a prospective randomized trial comparing THC to Compazine. Participants in this study are out- patients. To date, ten patients have been entered on-study. Five of the ten completed three or more cycles. Dr. Goldberg cited some of the diffi- culties encountered with conducting a study on a strictly outpatient basis. 166 Dr. Martin Levitt of the University of Manitoba reviewed an ongoing study sponsored by the Medical Research Council of Canada. The study compares the anti-emetic effectiveness of three different doses of THC (5, 10, 15 mg), with placebo, Compazine 10 mg or no treatment. To date, 70 patients have been entered on-study. The results are still blinded; however, completion and final analysis of this study are planned for 1979. Dr. Levitt reported some observations regarding THC blood levels. In patients receiving 5 or 10 mg, there is very little dif- ference in blood levels, but there is an apparent sixfold rise in serum concentration obtained in patients receiving 15 mg. This is based upon observations in only four patients, and further observations will be reported in the future. Dr. Solomon Garb of the American Cancer Research Center next reported on a study comparing THC plus Compazine to placebo plus Compazine in a double-blind, cross-over, fixed-dosage regimen. The anti-emetic dosages were THC - 40 mg/day and Compazine ~ 40 mg/day. Of 21 patients entered on-study, 14 were not evaluable. Seven patients completed both courses. Of 6/7 patients THC and Compazine was superior to Compazine plus pla- cebo. A second study is being conducted which is a non-blinded, dose- seeking study, the results of which are not yet statistically evaluable. Dr. J. T. Ungerleider of UCLA next discussed an ongoing study compar- ing THC to Compazine in a cross-over, double-blind design. THC is given in a dose of 7.5 to 12.5 mg, and Compazine is given in a fixed 10 mg oral dose. A total of 250 patients have been entered on-study, of which 112 patients completed both cycles of the regimen. Prelimi- nary analysis of data from the first 68 patients showed that 25 patients experienced less nausea and vomiting with THC, 20 patients reported less nausea and vomiting with Compazine, and the remaining 23 patients experienced no difference. In regard to preference, 27 patients pre- ferred THC, 24 preferred Compazine, while 15 patients had no preference. There were no data on two patients. Dr. Ungerleider announced that a group from the University of Washington in Seattle has compiled a manual entitled "Using Marijuana in the Re- duction of Nausea Associated with Chemotherapy." This manual can be obtained from Dr. Roger A. Roffman, Assistant Professor, School of Social Work, University of Washington, Seattle, Washington 98105. Professor Roffman is most interested in obtaining comments regarding the propriety of this publication from responsible clinical investigators. Partici- pants of this meeting were encouraged to contact Professor Roffman. Ms. Theresa Andrysiak, R.N., of UCLA, discussed dysphoric reactions of patients receiving THC in relation to staff attitudes. Of the 250 patients entered on the UCLA protocol, 12 patients experienced dysphoria 167 characterized by dizziness, anxiety, fright, or depersonalized feelings. Patients experiencing dysphoria should receive firm reassurance that the response is transient and drug-induced. The point was made that patients should be asked to describe the feelings they experience rather than be asked directly if they are feeling high. Most of our population is marijuana naive; therefore, in order to qualify cases of dysphoria, patients should be permitted to define their drug-induced reactions. The next speaker was Dr. John Laszlo of Duke University. He reported on a study designed to examine the effect of THC in patients refractory to aggressive standard anti-emetic therapy. Inpatients were initially selected for participation in this study; however, eligibility has been. extended to outpatients as well. Initially, the dosage of THC was 15 mg/m? given orally every 6 hours beginning an hour before chemo- therapy and continuing for four doses. Due to some patients experienc- ing excessive somnolence and becoming frightened of the drug, the dosage was decreased to a range of 5 to 7.5 mg/m“ given every 4 hours. The schedule has been modified to permit administration of THC beginning 12 hours prior to completion of chemotherapy or for eight doses in the case of a patient getting a single course. Fifty-nine patients have been entered of which 38 are evaluable in this study. Of these 38 patients, 9 had complete remission of nausea and vomiting, while 20 patients had a partial remission (77%). Eighty-two percent of the courses given thus far have been associated with a better than 50% improvement in nausea and vomiting compared to prior experience with conventional anti-emetic therapy. Again, there appears to be a question of THC having a specific drug effect dependent upon the chemotherapy regimen. In this study, THC was relatively ineffective in patients receiving high-dose cyclophosphamide; however, THC seemed to be extra- ordinarily effective in a group of patients receiving high-dose BCNU and also in patients receiving total body radiation prior to marrow transplant. . Dr. Laszlo commented on the many requests for THC he has received from patients and doctors throughout the entire Southeastern United States region. He urged the group to recognize that THC is a useful anti-emetic drug with limitations and that a sensible application of it should be pursued. Dr. Wendall Goodwin of Wilford Hall United States Air Force Medical Center reported on an outpatient study being conducted at both Wilford Hall USAF Medical Center and the University of Kansas. Patients are randomized to one of three treatment arms consisting of two courses of THC and two courses of Compazine or vice versa. The third arm consists of four courses of both drugs. THC is administered on a fixed-dose basis of 15 mg and Compazine at 10 mg. To date, 28 patients have been entered on-study of which 8 patients are evaluable. It is too early in the study 168 to draw any conclusions; however, neither drug appears to be remarkable in preventing nausea and vomiting based upon the number of patients who have discontinued participation in the study due to a lack of drug effectiveness. Dr. Ronald Hart of Mt. Sinai Medical Center presented information on a double-blind comparison of the efficacy of THC with Compazine in con=- trolling nausea, anorexia and vomiting in hospitalized patients receiving anti-neoplastic agents. In this study, patients are studied only during their first dose of chemotherapy to minimize the influence of psychogenic vomiting. Patients are randomized to A) three doses of THC on the day before chemotherapy; B) THC on a fixed Q3H schedule on the day of chemo- therapy only; or C) a Compazine control arm in which Compazine is given Q6H schedule on the treatment day. Placebo capsules are administered to make the treatment arms appear identical in a number of medications. Twenty patients have now been entered on-study. Although additional patients are needed to provide a definitive answer, there appear to be trends to suggest that arm B is inferior to the other arms, especially arm C. Following these presentations, Dr. Robert Willett of the National Institute on Drug Abuse (NIDA) addressed the group in regard to supply and distribution problems within the agency. He noted that the current preparation of THC was developed for pharmacological and physiological studies and not for therapeutic use, hence its lack of optimum bio- availability. Investigators were urged to anticipate their drug needs early and to allow ample time for delivery because of staffing shortages coupled with a potential, tremendous demand for drug. The NCI is cur- rently working on an improved formulation of THC. At the present time, NIDA is testing a direct blood radioimmunoassay specific for THC which could be used in hospitals and clinical labora- tories with standard equipment. This RIA kit has been tentatively approved by the FDA and is being field-tested by NIDA. Availability of this kit is projected to be after 1 year. Dr. Jensen-Akula initiated the subsequent discussion session. Highlights of that session were as follows: ° A regular schedule for patients receiving either Compazine or THC is probably more important than which anti-emetic drug is being administered. ° There is a substantial difference between euphoria and dysphoria. Some patients receiving THC experience a "good feeling” from the drug, and this reaction should not be negatively branded as dysphoria. 169 ® Some investigators felt strongly that a consensus on the usefulness of THC in the control of chemotherapy=-induced vomiting should be reached. Other clinical investigators and officials from FDA and NIDA felt that such a step would be premature in the technology transfer process. Dr. Robert A. Archer of Eli Lilly and Company led off the afternoon session by discussing results of clinical studies on Nabilone. Dr. Lawrence Einhorn, Indiana University, and Dr. Terence Herman, University of Arizona, conducted separate studies comparing the anti-emetic effec- tiveness of Nabilone to that of Compazine in double-blind, cross-over studies. In the Arizona study, 30/31 patients (91%) benefited from Nabilone therapy while only 11 (33%) responded to Compazine. Of the 80 evaluable patients in Dr. Einhorn's study, 60 patients (75%) chose Nabi- lone as the preferred anti-emetic, while 17 patients (21%) indicated preference for Compazine. In summary, the results of these two indepen- dent studies arrived at the same conclusion; namely that Nabilone is superior to Compazine in anti-emetic therapy. In.both studies, side effects were qualitatively similar for both drugs with somnolence, dry mouth, and dizziness as the most common side effects reported; however, these effects occurred twice as frequently in patients receiving Nabilone as in those receiving Compazine. In early 1979, clinical trials with Nabilone were suspended by the Eli Lilly Company as a result of data obtained from dog toxicity studies. These studies indicated an accumulation of carbinol metabolites upon chronic dosing with Nabilone. Other measurements indicated that such an accumulation of carbinol metabolites would reach a steady state with chronic dosing. The question then arose whether dog toxicity was a parameter for the human situation. Would humans dosed intermittently for 5 days monthly experience the same adverse effects? As a result, clinical trials were suspended pending further toxicological studies in dogs. After these ongoing animal studies are completed and evaluated, a final decision will be made as to the reinstatement of clinical trials with Nabilone. Dr. John Howes of Cisa, Inc., presented information on a drug, SP-106, now known as Nabutan Hydrochloride. The initial therapeutic goal of this drug was to study it as an analgesic and it is still being studied in this area. The interest in this drug as an anti-emetic arose as a result of the similarity of its molecular structure to that of Delta-9- THC. A clinical study is being instituted at Sidney Farber with Dr. Sallan. The current plan is to study 10 patients in a double-blind cross-over study with Compazine. SP-106 will be given orally at 10 mg/m“ at a maximum dose of 15 mg. Cisa, Inc., would like to study this drug in parenteral form; however, to date, no anti-emetic studies have been done in animals. 170 The next speaker was Dr. George Milne, Pfizer Central Research, who presented developmental therapeutic information on Compound CP-44001. This compound was initially developed for its analagesic properties but is now being studied in animals for its potential as an anti- emetic, as it is structurally similar to Delta-9-THC. Dr. Herbert Borison of Dartmouth then described the physiological mechanisms of vomiting and preliminary results obtained with the testing of Pfizer Compound CP-44001 in decerebrated cats. Dr. Anthony Guarino of the NCI Toxicology Laboratory briefly described an available model for testing anti-emetic compounds in dogs which was initially developed for the study of platinate-analogues. It was Dr. Guarino's belief that Platinum should be used as a model emetic- producing agent in further toxicological work that is done. Dr. Guarino also suggested that compounds other than cannabinoids be explored for anti-emetic properties. The meeting was concluded by Dr. Jane Henney who summarized the pursuable options for advancing THC through the drug development process. It was felt that considerable progress had been achieved in less than a year's time. The maturation of several of the THC studies presented has added to the assignment of an appropriate role to THC as an anti-emetic. If evidence is forthcoming at the conclusion of several of the ongoing studies, one of two options would be pursued by the NCI for broader dis- tribution of the compound. One option would be to move the drug into Class C drugs. There would still be distinct stipulations for receiving the drug; however, the restrictions on distributin would be looser than at present. The second option would be for a pharmaceutical company to take interest in THC and subsequently file for its own NDA. The final conclusion of the meeting was that the field of compounds possessing anti-emetic properties was viewed to be much broader in scope than one specific drug area. Dr. Henney's office will serve as an, interface point between pharmaceutical companies and clinical investigators interested in conducting anti-emetic research. sq / Addendum: A more detailed account of the studies being conducted by Drs. Chang, Sallan, Garb, Goodwin, and Hart or the Eli Lilly Company: can be obtained from: Jane E. Henney, M.D. Assistant to the Director Division of Cancer Treatment National Cancer Institute Building 31, Room 3A49 Bethesda, Maryland 20205 Dre. Ms. Dre. Dre. Dre. Dr. Ms. Dr. Dre. Dr. Dre. Dr. Dre. Dr. Dr. Dre. Dre. Dre. Dre. Dre. Dre. Dre. Dr. Dre. Dre. 171 ATTENDEES ANTI-EMETIC RESEARCH CONFERENCE NATIONAL CANCER INSTITUTE BETHESDA, MARYLAND March 22, 1979 David Abraham Dr. John S. MacDonald Therese Andrysiak Ms. Deborah Mayer-Scogna Robert A. Archer Dr. George M. Milne Agop Y. Bedikian Dr. Michael Moses Herbert Borison Dr. Stuart Nightingale Alfred Chang Dr. Harry Pars Carol Cronin Dr. Ray A. Razdan Paul Davignon Dr. Stephen Sallan Karl Flora Dr. Michael Samon Robert Earhart Dr. Alberta Schumacher Roberto Fraile Dr. J. A. Scigliano Solomon Garb Dr. George W. Shaffer Deborah Goldberg Dr. Milan Slavik Wendell Goodwin Dr. David K. Smith Howard Gross Ms. Nancy Steele Anthony Guarino Ms. Virginia J. Suppers Ronald D. Hart Dr. Edward C. Tocus Lou Harris Dr. J. Thomas Ungerleider Jane E. Henney Dr. Richard S. Ungerleider John Howes Dr. Robert E. Willette Robert B. Ing Dr. Harry B. Wood Michael Jenson-Akula Dr. H. Ko Wright John Laszlo Dr. Charles Young Martin Levitt Dr. John Zimmerson M. Ross Johnson 172 August 1, 1978 INTERAGENCY COMMITTEE ON NEW THERAPIES FOR PAIN AND DISCOMFORT A committee of Federal physicians and scientists has been formed to develop recommendations on the treatment of intractable pain and the humane care of the dying patient. A major goal of the group, the Committee on New Therapies for Pain and Discomfort, will be to encourage research on the mechanisms and appropriate treatment of severe pain, particularly the pain as well as other complications experienced by patients with terminal cancer. The group will assess the current state of knowledge about heroin, marijuana and other agents in the so-called "dangerous drug" category and develop recommendations designed to encourage and facilitate research studies on the use of such drugs for treatment. The Committee held its first meeting January 9, 1978, and has met monthly since that time. It was convened in response to concerns expressed by President Carter that insufficient attention was being paid to supportive care for the dying and to the possible therapeutic usefulness of substances for the relief of pain, which due to their potential for abuse, are not available in this country. Indications that certain of these drugs may be effective as analgesics, as anti-nausea drugs for cancer patients undergoing therapy or for the treatment of glaucoma provided a stimulus for the formation of the Committee. The panel's mandate includes ensuring that responsible research is encouraged and not inhibited by duplicative or unnecessary administrative controls. The Committee's Chairman is Dr. Seymour Perry, Associate Director for Medical Applications of Research, National Institutes of Health. Its membership includes representatives from the National Institute of Mental Health (NIMH), the National Institute on Drug Abuse (NIDA), and Food and Drug Administration (FDA), several components of the National Institutes of Health (NIH), the Office of the Assistant Secretary for Health, the Drug Enforcement Agency (DEA) of the Department of Justice and the White House. Recent collaborative efforts among DEA, FDA, and NIDA have led to the launching of a study to compare the effects of heroin and morphine on patients with severe pain. Such joint efforts have also achieved a reduction in processing time required for approving research on Schedule I Drugs (designated as highly abusable and not approved for marketing). The Interagency Committee will seek and recommend means for further streamlining the approval process so that these agents may be more readily available for research studies. 173 Other activities of the Committee include: e consideration of research guidelines for pain studies and funding recommendations for such research by organizations of the Public Health Service; e study and assessment of hospice concepts and development of recommendations concerning their implementation; e development of plans for a national conference on pain to focus attention on current knowledge and the most pressing needs for research on the treatment of pain; and e planning for a conference to be jointly sponsored with the Institute of Medicine, National Academy of Sciences on the humane care of the terminally ill. The Committee has developed fact sheets on heroin and marijuana- related substances. The latter drugs, specifically tetrahydrocannabinol (THC) and Nabilone, were the subjects of a recent conference held by the National Cancer Institute to assess the status of research on their use in alleviating nausea for cancer patients. Technical papers are being prepared on THC and heroin for the use of physicians and research scientists. In its communications with the medical community the Committee is calling attention to the absence of firm evidence of the superiority of heroin, marijuana, and related drugs and is urging that currently available narcotic drugs be utilized more effectively for the relief of pain and other discomforts, particularly those associated with terminal illness. The Committee will make a special effort to provide more information to State officials, legislators, and community leaders as well as practicing physicians and researchers about the complex issues of drug scheduling, research, and medical practice issues as they relate to State and Federal laws. The possible impact of hasty endorsement of marijuana and heroin by Medical Societies, and of 'band-wagon'' legalization of these drugs by State legislatures is of particular concern to the Committee. They see these actions as potentially complicating rather than facilitating essential research on the substances, thus impeding the development of real improvements in therapies for pain and discomfort. 174 Informational materials dealing with investigational drug applications, guidelines for drug research and sources of funding are in preparation and will be available shortly. Inquiries should be directed to Dr. Seymour Perry, Room 216, Building One, National Institutes of Health, Bethesda, Maryland 20205. 175 March 2, 1979 MARIJUANA Current Status Interagency Committee on New Therapies for Pain and Discomfort Marijuana (cannabis) has been used for centuries as a remedy as well as a stimulant or intoxicant. Its introduction into Western medicine as a therapeutic agent took place in the late 1830's. During the remainder of the 19th century, a lively interest continued in exploiting the presumed medical potential of marijuana. Among the conditions for which marijuana was reported to be effective were tetanus, convulsive disorders, neuralgia, migraine, dysmenorrhea, obstetrical labor, uterine hemorrhage, rheumatism, asthma, chronic bronchitis, postpartum psychoses, senile insomnia, depression, gonorrhea and opium or chloral hydrate addiction. It was also reported to stimulate appetite and to allay the pain and anxiety of patients terminally ill with cancer. In about 1900 when many synthetic drugs were becoming available there was a decrease in enthusiasm for medical use of marijuana. Such use was further discouraged in the United States by the strict controls on the substance embodied in the Marijuana Tax Act of 1937. By 1941 it was deleted from the U.S. Pharmacopeia and the National Formulary on the ground that the drug was ineffective. Subsequently, however, advances were made in understanding the chemistry of marijuana and more recently the major active component (tetrahydro- cannabinol or THC) was identified. It also had become possible to synthesize the THC-like compound synhexyl. These developments spurred a renewed interest in the medical potential of marijuana constituents. The ability of marijuana to produce euphoria suggested its possible use in treating depression, and a number of clinical trials, usually employing synhexyl, were undertaken in the late 1940's and early 1950's. Despite some initial enthusiasm for its efficacy in depressed patients, later studies indicated that synhexyl was no better than a placebo. Studies were also made of its possible use for patients being withdrawn from alcohol and opiates, but after limited trials it was concluded that synhexyl was of little value in easing withdrawal. These discouraging results once again diminished enthusiasm for using marijuana or related substances as therapeutic agents. In 1964, the chemical structure of THC was determined, thus making it possible to synthesize this and other constituents of marijuana. Large and uniform supplies of oral form of THC and other cannabinoids can now be made available for scientific studies and their potential therapeutic value can be scientifically assayed. 176 One important area of investigation concerns the possible use of THC for the nausea and vomiting caused by the chemical agents and radio- therapy used in cancer treatment. These side effects are extremely difficult to treat with available antiemetic drugs. An initial study appeared to demonstrate a beneficial effect of THC as compared to a placebo in controlling the nausea and vomiting experienced by patients undergoing cancer chemotherapy. Similar studies are now being conducted but confirmation has not yet been reported in the scientific literature. These trials appear to indicate some beneficial effects. Another marijuana-related substance known as Nabilone was synthesized in 1972. In preliminary studies, Nabilone was found to reduce significantly the nausea and vomiting induced by cancer chemotherapy in the majority of patients not helped by usual antiemetics. Recently, however, because of long-term toxicity observed in animal models the sponsor has stopped further clinical trials. It seems reasonable to believe that either THC itself or some other marijuana-related drug will turn out to be useful as an antiemetic. The Interagency Committee has discussed clinical evaluation of additional analogues of the major marijuana chemical components. Widespread public media attention has been given to the unanticipated and fortuitous observation that smoking marijuana reduces the pressure within normal eyes and eyes with glaucoma. A survey of the magnitude of this effect was added to an ongoing study of the effects of continued heavy smoking of marijuana. Pressure decreases of up to 45 percent after smoking marijuana were found in patients with glaucoma. For several reasons, however, it is not clear at this time whether smoking marijuana is a potentially beneficial treatment. First, smoking to acquire a medication dose is a less acceptable route of administration for treating the eye than, for example, the direct application of eye drops. Second, researchers have found that patients given the active component of marijuana, THC, by mouth, developed tolerance to the drug and required continuously increased dosages in order for the THC to be effective. Some investigators feel that the lowering of intraocular pressure resulted from the general state of sedation and relaxation induced by marijuana and not as a direct effect of the drug. Finally, there is no proof that the patient with glaucoma whose intraocular pressure is lowered by marijuana, or THC, is safeguarded against loss of visual function. In contrast, medications and surgery conventionally used to treat glaucoma have been proven to be effective in preserving vision. 177 Extensive animal experiments have been conducted at the Medical College of Georgia on the mechanisms of action of THC in lowering intraocular pressure. The studies have indicated that THC dilates some of the blood vessels leading away from the eye, consequently reducing the pressure for formation of the aqueous humor which fills the eyeball. Additionally, studies have indicated marijuana may also cause increased aqueous humor outflow from the eye. A considerable amount of additional research will be required to determine the appropriate role of marijuana- related substances in the treatment of glaucoma. 178 August 16, 1978 FACT SHEET MARLJUANA AND GLAUCOMA A Statement from the National Eye Institute and The Interagency Committee on New Therapies for Pain and Discomfort Glaucoma is an eye disease characterized by increased pressure within the eye (intraocular pressure) and progressive damage to the optic nerve with accompanying impaired visual function. Treatment for glaucoma, either with drugs or surgery, is primarily aimed at lowering the pressure in an attempt to preserve vision. Marijuana is one of many drugs known to reduce intraocular pressure. Research is underway to determine whether marijuana and its derivatives and other promising new drugs now under development have potential as safe and effective alternatives to glaucoma medications in current use. As yet, the possible advantages of marijuana over proven glaucoma medications and other experimental drugs--including whether marijuana may be effective in some individuals who do not respond to those other agents-~have not been established. Because the medical use of marijuana is still under investigation, the drug’s legal use in the treatment of glaucoma is limited to clinical investigations that have been approved by the Food and Drug Administration. In addition, the investigator must be registered with the Drug Enforcement Administration. HEW’s National Institute on Drug Abuse (NIDA), which is the primary supporter of Government sponsored marijuana research, supplies the drug to the qualified scientific investigators who carry out these studies. Current studies of marijuana’s effect on the eye are aimed at determining whether the drug’s intraocular pressure-lowering effects last long enough in most patients for it to be considered for further investi- gation as a possible treatment for glaucoma. Scientists working under grants from both the National Eye Institute and the NIDA are evaluating the use of marijuana derivatives in lowering intraocular pressure in laboratory animals. The NIDA has supported the testing of the drug’s pressure-lowering effects in humans. Because it is difficult to evaluate the potential medical value of marijuana administered in the form of cigarettes, scientists are trying to develop a safe and effective active derivative of the drug which could be 179 applied directly to the eye in drop form. In this form, drug delivery to the eye could be more precisely controlled than is possible with marijuana that is smoked, and controlled studies would be easier to carry out. It is also hoped that such a derivative would eliminate or at least greatly reduce marijuana’s intoxicating effects, an undesirable characteristic of the drug for most patients with glaucoma. It is important to emphasize that studies are also needed to show whether visual function is preserved when marijuana is used to reduce the intraocular pressure in glaucoma patients. No such studies of marijuana are underway as yet. Past experience with other purported glaucoma treatments has shown that although a drug may lower intra- ocular pressure, it does not necessarily follow that visual function will be maintained. Because one of the National Eye Institute’s program priorities is to support the scientific evaluation of new methods of treating glaucoma, the NEI welcomes the submission by qualified investigators of appli- cations for research on the therapeutic potential of marijuana as a glaucoma drug. Any such applications received will undergo the same dual level review for scientific merit and program relevance as do all research grant proposals submitted to the National Institutes of Health and will be given full consideration by the National Eye Institute staff. Any investigator contemplating the submission of such an appli- cation to NIH may therefore wish to contact the National Eye Institute before developing his/her proposal. Inquiries may be directed to Anita Suran, Ph.D., Director, Glaucoma Program, National Eye Institute, Building 31, Room 6A51, National Institutes of Health, Bethesda, Maryland 20014. 180 March 8, 1979 HEROIN Current Status Interagency Committee on New Therapies for Pain and Discomfort Heroin was introduced as a substitute for morphine to minimize the danger of addiction, but by the early part of this century experience suggested that it was even more dangerous. Consequently, in 1924 heroin was banned in the United States. Since heroin is not available to physicians in this country, morphine and other narcotics are employed for the relief of moderate to severe pain. Often the use or misuse of these drugs has not provided adequate pain relief for terminally ill patients. In many instances, the dosage and scheduling used has been insufficient to adequately control the patient's pain. Whatever the reason for the inadequacy, physicians, families of patients, and others sensitive to the suffering of the patients have proposed that heroin be made available for the terminally ill. Anecdotal reports from abroad concerning the use of heroin for such patients have received nationwide publicity, and a number of civic, professional and medical groups in this country have urged that similar use of heroin be permitted here. Few scientific studies have been conducted on the relative safety and efficacy of heroin and morphine. In at least one reported study from England, involving 699 patients, heroin was not found to be superior. England has generally abandoned its use as an orally administered drug. However, concern for the suffering of the terminally ill dictates that additional heroin research be undertaken. The Interagency Committee on Pain and Discomfort was charged early in 1978 with the responsibility of facilitating therapeutic research studies to investigate the mechanisms of pain and its relief. One such investiga- tion includes the scientific evaluation of heroin. Such studies could serve as a basis for decision regarding the status of heroin. The lack of an available commercial product of heroin required a government research effort to develop a suitable human use product. Further, since by law heroin cannot be manufactured in the United States, it had been necessary to use confiscated street heroin as a source of material for research. The adulterants commonly used in street heroin as well as the chemical problems of the drug also posed difficulties in preparing a chemically pure substance for formulation. After some months, these difficulties have been resolved and heroin is now available from the National Cancer Institute for the use of clinical investigators in studies of its effects in terminally ill cancer patients. Two such studies 181 are now underway, one at Memorial Sloan-Kettering Institute in New York and the other at Georgetown University Hospital in Washington. Other studies are anticipated. Studies comparing heroin with morphine and other analgesics are expected to answer the following questions: 1. Does heroin have any advantages over morphine? 2. Does heroin provide pain relief of longer duration? 3. Is heroin more effective in relieving pain? 4. In dosages providing equivalent pain relief, does heroin produce greater sensations of euphoria; and 5. In dosages providing equivalent pain relief, does heroin have more or fewer side effects (e.g., nausea, vomiting, respiratory depression, constipation, etc.)? It should be apparent if there is a useful role for heroin for the relief of severe, chronic pain in the terminally ill patiént once these studies are completed and the data analyzed. II. 182 March 1, 1979 FACT SHEET HEROIN AND TETRAHYDROCANNABINOL RESEARCH FOR RELIEF IN PAIN AND OTHER DISCOMFORTS Statement from the Interagency Committee on New Therapies for Pain and Discomfort Heroin The Division of Cancer Treatment (DCT) has obtained an IND for heroin in order to sponsor studies, within its existing drug testing network, of the efficacy of heroin in treating pain and discomfort in patients with advanced cancer. Dr. Raymond Houde at Memorial-Sloan Kettering Institute in New York City has already obtained a grant from the National Institute of Drug Abuse to study the pharmacology of opitate analgesics, including heroin. His IND for heroin was recently approved by the FDA, and he has given the DCT permission to cross-file. The Pharmaceutical Resources Branch (PRB) of the DCT is overseeing the formulation of a new dosage form of heroin, and through a resource contractor, it will be responsible for the distribution of heroin to approved investigators (for further information in this area, contact Mr. Paul Davignon, Chief, PRB, (301) L27-73L6). The Investigational Drug Branch (IDB) of the DCT is the focal point for the evaluation and review of clinical trials of heroin sponsored by DCT. A phase I-II trial to be carried out by Dr. William Beaver at Georgetown University. The IDB has been responsible for the actual filing of DCT's IND for heroin research which may be submitted by other DCT grantees and contractord (for further information on these matters, contact Dr. Michael Jensen-Akula, Special Assistant to the Chief, IDB, (301)496-1197). Tetrahydrocannabinol (THC) and Nabilone At a symposium (May 9, 1978) on research on the control of cancer chemotherapy-induced vomiting, it was evident that both THC and a structurally similar synthetic compound, Nabilone (Eli Lilly & Company), have potential for controlling the nausea and vomiting produced by cancer chemotherapy. Clinical studies with Nabilone have recently been terminated due to adverse chronic toxicity observed in animal models. The IDB has cross-file on the IND of the Surgery Branch, NCI, for 183 THC in order to sponsor further studies of this drug. Again, these studies will take place through the existing clinical trials network of DCT. The PRB will work to improve the current formulation of THC, and the Cancer Therapy Evaluation Program has assigned Dr. Michael Jensen-Akula to oversee DCT's involvement in emesis control research and to establish a working group to help coordinate and review proposals and research in this area. The following investigators are actively conducting research on THC in cancer chemotherapy patients: 1. Tetrahydrocannabinol A. Dr. Alfred Chang, NCI, Building 10, Room 10N102, 9000 Rockville Pike, Bethesda, Maryland 2001L (301) 496-1437. B. Dr. Stephen Frytak, Mayo Clinic, Rochester, Minnesota 55901, (507) 282-2511. C. Dr. Solomon Garb, American Cancer Research Center, 6401 Colfax Avenue, Lakewood, Colorado 8021Lk, (303) 233-6501. D. Dr. John Laszlo, P.O. Box 3835, Duke University Medical Center, Durham, North Carolina 27710, (919) 684-6450. E. Dr. Stephen Sallan, Sidney Farber Cancer Institute, LL Binney Street, Boston, Massachusetts 02115, (617) 732-3315. F. Dr. Ronald Stephens, Department of Oncology, University of Kansas, 39th and Rainbow Boulevard, Kansas City, Kansas 66103, (913) 588-6029 (now in the process of initiating studies). Ge. Dr. J. Thomas Ungerleider, Department of Psychiatry, UCLA School of Medicine, Los Angeles, California 90024, (213) 825-0293. H. Dr. Edwin H. Cassem, Department of Psychiatry, Massachu- setts General Hospital, 32 Fruit Street, Boston, Massa- chusetts 02114, (617) 523-7900. I. Dr. Richard M. Gottlieb, Department of Psychiatry, Montefiore Hospital & Medical Center, 111 East 210th Street, Bronx, New York 10467, (213) 430-2000. J. Dr. James F. Holland, Mt. Sinai School of Medicine, 100th Street & 5th Avenue, New York, New York 10029, (215) 650-636k. 184 K. Dr. John S. Macdonald & Dr. Deborah Goldberg, Division of Medical Oncology, Georgetown University Hospital, 3800 Reservoir Road, Washington, D.C. 20007, (202) 625-0100. Finally, Dr. Jane Henney, National Cancer Institute, Division of Cancer Treatment, Building 31, Room 3AL9, 9000 Rockville Pike, Bethesda, Maryland 20014, (301) 496-6711, has the overall res- ponsibility within the Division of Cancer Treatment for coordina- ting its research in Schedule I drugs. Additional inquiries not resolved by the above information should be referred directly to her office. 185 Reprinted from the Journal of the American Medical Association January 26, 1979, Volume 241 Copyright 1979, American Medical Association Commentary Marijuana and Heroin by Prescription? Recent Developments at the State and Federal Levels RECENTLY there has been an increased interest in research with two highly abused psychoactive drugs— marijuana and heroin. Neither drug is approved for marketing in this country, but both have been touted as medically useful or effective by the lay press. BACKGROUND Early research with marijuana and its components (particularly tetrahydrocannabinol) has been promising. This development, combined with effective lobbying efforts, has persuaded some states to pass laws whose avowed purpose is the facilitation of research and treat- ment with those substances. These laws contain termi- nology that is an amalgam of research and treatment and permit prescription use under various conditions. Four states (New Mexico, Florida, Illinois, and Louisiana) have enacted such legislation. Press articles concerning these laws present a miscon- ception that marijuana is now available as a prescription drug in those states and should be in others. Further, the stamp of legitimacy placed on marijuana by the passage of such legislation has created the impression in the public’s mind that marijuana is effective to control nausea and vomiting secondary to cancer chemotherapy and radio- therapy and for glaucoma. Physicians are being asked by patients in these states how they can get marijuana. The result is a good deal of confusion among patients, physi- cians, the research community, state and federal govern- ment personnel, and the lay press. Further complicating this already confusing picture are the resolutions passed by certain county, state, and national professional organi- zations. } From the Bureau of Drugs, Food and Drug Administration, Rockville, Md (Dr Nightingale), and National Institutes of Health, Bethesda, Md (Dr Perry). The views expressed herein are-those of the authors and not necessarily those of the Public Health Service or its components. Reprint requests to Bureau of Drugs, HFD-4, Food and Drug Administra- tion, 5600 Fishers Lane, Rockville, MD 20857 (Dr Nightingale). JAMA, Jan 26, 1979—Vol 241, No. 4 The following outlines the current legal and research status of marijuana, tetrahydrocannabinol, and heroin and highlights some problems with state substance- specific legislation for the medical profession as well as state and federal government officials. CURRENT STATUS Marijuana, tetrahydrocannabinol, and heroin are all Schedule I drugs under Title II of the federal Comprehen- sive Drug Abuse Prevention and Control Act of 1970— Controlled Substances Act (CSA). The CSA has provisions for controlling substances in one of five schedules. These vary from Schedule I for unmarketed drugs and substances with the highest abuse potential, through Schedule V for those drugs and substances with the lowest abuse potential. Controlled drugs that are approved for marketing in this country must be in Schedule II to V, since Schedule I drugs, by law, are not approved for marketing. While research can be carried out with a drug in any schedule, when a Schedule I drug is approved for marketing, it must be transferred to another schedule or be decontrolled. Currently, the Department of Health, Education, and Welfare (DHEW) is considering a proposal for reschedul- ing marijuana and tetrahydrocannabinol from Schedule I of the CSA. Clinical research has been carried out with marijuana and tetrahydrocannabinol. The preliminary results, particularly with tetrahydrocannabinol, are prom- ising. Tetrahydrocannabinol appears capable of reducing intraocular pressure in glaucoma patients and relieving nausea and vomiting in patients receiving cancer thera- py.” The National Cancer Institute has taken a major role in sponsoring and guiding further clinical research for the antiemetic indications under the federal Food, Drug, and Cosmetic Act. As for heroin, an investigational new drug exemption for analgesic use has been issued, and clinical research has begun. This is the first investigational new drug exemp- Marijuana and Heroin—Nightingale & Perry 373 tion ever issued for heroin for that indication. A recent article in THE JOURNAL summarized research and treat- ment issues.’ Research with marijuana, tetrahydrocannabinol, and heroin has been facilitated by several federal actions during the past years. Funding of projects by the DHEW has been substantial. The National Institute on Drug Abuse, the Drug Enforcement Administration, and the Food and Drug Administration have collaborated to reduce the paperwork and coordinate activities necessary to supply Schedule I drugs to the research community. The FDA has eliminated a previously mandatory advisory committee review and has published research guidelines for marijuana and tetrahydrocannabinol. A committee of federal scientists and physicians (Interagency Committee on New Therapies for Pain and Discomfort) has been formed, which, among other things, is in the process of developing recommendations for the progress of research with promising drugs, especially those that have been investigated less fully than they might have been because they bear the stigma of abuse. This committee meets frequently and is commissioning state-of-the-art papers on research with marijuana, tetrahydrocannabinol, and heroin. ISSUES AND PROBLEMS State Laws Federal and State Inconsistencies.—The marijuana laws seemingly purport to legalize the use of an unapproved drug for treatment rather than for or in addition to research. Provisions in these state laws impose addition- al requirements on researchers that may or may not be consistent with federal law and regulations, depending on how the former are interpreted and implemented. For example, in the first state to pass such a law (New Mexico), a certification procedure is established whereby a Patient Qualification Review Board administers the Controlled Substances Therapeutic Research Program. While a certification process implemented by a specially created state board—an additional bureaucratic layer—is an unusual mechanism for selecting patients for admis- sion to a clinical research project, there are ways to accommodate this process to the research requirements under the Food, Drug, and Cosmetic Act. The fact remains, however, that there is a blurring of the distinc- tion between research and treatment in this kind of legislation. While these laws could be consistent with the Food, Drug, and Cosmetic Act and the regulations promulgated under that Act, the possibilities are that procedures estab- lished by the state laws to accommodate treatment may not be consistent with federal research requirements. However, the potential for future patient, physician, and federal-state dissatisfaction under the programs estab- lished by these acts is great. A likely outcome of this kind of legislation may be the mistaken belief that these substances are freely available and proved effective. Rescheduling. —Some state legislation would reschedule marijuana and tetrahydrocannabinol from the current Schedule I status to Schedule IT under the state version of the CSA only when used under the terms of these thera- peutic-research acts. Moving an unapproved substance 374 JAMA, Jan 26, 1979—Vol 241, No. 4 186 from Schedule I to II, however, does not amount to approval of that substance for general medical use. A physician cannot prescribe or administer a drug that is not approved under the federal Food, Drug, and Cosmetic Act for marketing unless that physician has an approved investigational new drug exemption. A state statute could technically permit the medical use of a federally unap- proved noncontrolled substance if its use, distribution, and manufacturing are totally within the state. However, regardless of the wording of state laws, no state law may authorize growth or manufacture of marijuana or tetrahy- drocannabinol * without the eRXpress approval of the Department of Justice because of the supremacy of the federal CSA and international treaty obligations. One purpose for rescheduling marijuana or tetrahydro- cannabinol is the belief that such a transfer will in some way destigmatize marijuana or tetrahydrocannabinol and actually facilitate research. It is true that under federal regulations, a special registration from the Drug Enforce- ment Administration and protocol approval by the FDA must be obtained for clinical research with Schedule I substances. The former is not a substantive impediment, and the latter obtains with all substances intended for investigational use regardless of schedule status. Thus, it is questionable whether there is a real benefit in such rescheduling at the state level. Regardless, the mere rescheduling of an unapproved substance, at either the federal or state level, does not per se make that substance available by prescription or in any way legalize it for general use. State and National Resolutions While resolutions do not have the impact of legislation or regulation, they are important statements of policy and are widely reported in the lay press, where they may influence public opinion. Resolutions that call for the use of heroin in the terminally ill, for example, suggest a use that is illegal (if not investigational) and that has not been shown to be more or less safe and effective than morphine. On the other hand, resolutions that encourage further research or more appropriate prescribing of marketed addictive narcotic drugs appear reasonable and have the potential for encouraging new funding for research initia- tives; breaking down barriers to research with unap- proved, abusable drugs at the state and local levels; and discouraging underuse of legitimately available drugs for patients with severe pain. Much of the impetus for prescribing heroin has come from the supporters of the hospice movement. More appropriate prescribing of marketed, potent analgesics would help to counteract the public’s view that physicians often abandon the terminally ill. The humane concern for appropriate treatment for the dying patient is, of course, a major public and professional one today. Resolutions seem a reasonable way to focus public attention on issues such as these but have the potential for causing confusion and being counterproduc- tive. CONCLUSION The concept of state-by-state substance-specific legisla- tion popularized with laetrile’ is beginning to spread to Marijuana and Heroin—Nightingale & Perry other unapproved products, for example, Gerovital and chymopapain. The marijuana bills and acts represent one variant of this approach. We believe that state-by-state drug-specific legislation makes no sense from a practical or even theoretical point of view. Where an attempt is made to approve a drug by state law, circumventing the usual scientific require- ments, protection afforded the public by federal and state health regulatory bodies may be lost. These kinds of decisions should be made by public health officials on the basis of safety and efficacy considerations and not made by legislators. Such legislation represents to the public that these substances are safe and effective and, by imparting an official governmental stamp of approval, undoubtedly increases the demand for these substances. We believe that legitimate research should not be in- hibited and that the federal agencies concerned with funding and regulations governing research with Schedule I substances such as marijuana should stimulate and encourage such research. Practicing physicians are being placed in a difficult position, as state laws, federal laws, and patient concerns intersect in the area of medical research as opposed to treatment with drugs that are not approved for marketing at this time. We believe that research with Schedule I drugs should proceed smoothly and that the demarcation between clinical research and treatment with approved drugs should remain distinct. Information on the status of clinical research with marijuana, tetrahydrocannabinol, and heroin or informa- 187 tion on the requirements for performing research with these substances and guidelines for research can be obtained by writing to the authors. Federal agencies and staff are endeavoring to work closely with state personnel to see that research is not impeded. Specific questions or information on meeting research requirements that have been interposed at the state level must be addressed to the relevant state officials. STUART L. NIGHTINGALE, MD Food and Drug Administration Rockville, Md SEYMOUR PERRY, MD National Institutes of Health Bethesda, Md Nonproprietary Name and Trademark of Drug Chymopapain— Discase. 1. Hepler RS, Petrus RJ: Experiences with the administration of mari- huana to glaucoma patients, in Cohen S, Stillman RC (eds): The Therapeu- tic Potential of Marihuana. New York, Plenum Medical Book Co, 1976, pp 63-75. 2. Peterson RC (ed): Marijuana Research Findings: 1976, National Insti- tute on Drug Abuse research monograph 14. Rockville, Md, US Dept of Health, Education, and Welfare, US Government Printing Office, Alcohol Drug Abuse and Mental Health Administration, 1977. 3. Sallan SE, Zinberg NE, Frei E III: Antiemetic effect of delta- 9-tetrahydrocannabinol in patients receiving cancer chemotherapy. N Engl J Med 293:795-797, 1975. 4. Lewis JE: Should heroin be available to treat severe pain? JAMA 240:1601-1602, 1978. 5. Nightingale SL, Arnold FD: How laetrile laws affect MDs. Leg Aspects Med Prac 6:31-33, 1978. DEPARTMENT OF HEALTH. EDUCATION, AND WELFARE PUBLIC HEALTH SERVICE NATIONAL INSTITUTES OF HEALTH BETHESDA. MARYLAND 20014 188 October 23, 1978 (Sample of letter sent to State Legislatures) (See attached list of addressees) Dear During the past two years, there has been a marked increase in the public's interest in the possible therapeutic uses of some drugs in the so-called "dangerous drug category," particularly heroin and marijuana, for palliation of the pain and discomfort experienced by the terminally ill and others. This concern about humane care of the dying patient is shared by the health care and research communities. However, there has been little research done on the relative merits of the drugs in question as compared with other drugs currently employed by American physicians in the treatment of a variety of illnesses. In January of this year following a meeting at The White House, the Interagency Committee on New Therapies for Pain and Discomfort was established. The Committee, with the National Institutes of Health as the lead agency, is composed of scientists and physicians, nurses and other health professionals from various Federal agencies* concerned with health research or health care. One of its principal tasks is to A number of studies have been mounted in the U.S. in which heroin marijuana, and tetrahydrocannabinol are being evaluated in various Protocols. (See enclosures.) At the same time, several states have enacted legislation dealing with research and therapeutic uses of heroin and marijuana. In some in- stances, it appears that such laws may be in conflict with Federal Statutes and may inhibit rather than facilitate researgh needed to answer the basic questions as to the comparative value of ummarketed drugs with high abuse potential. *Health Resources Administration; Health Care Financing Adminis-— tration; Alcohol, Drug Abuse, and Mental Health Administration; Food and Drug Administration; Drug Enforcement Administration; Veterans Administration; Department of Defense, and The White House. 189 - Lt. Governor Thomas R. DiLuglio If you are considering introducing legislation in your state concerning research and treatment with agents in this category, or if it should be introduced, we would greatly appreciate an opportunity to offer our assistance in explaining current FDA research requirements and the new drug approval process. We suggest that you write to the Division of Neuropharmacological Drug Products (HFD 120), Office of New Drug Evalu- ation, Bureau of Drugs, Food and Drug Administration, 5600 Fishers Lane, Rockville, Maryland 20857. A representative of the Interagency Committee will then contact you. - The goal of the Committee 73 to assure that appropriate research is facilitated and supported, a goal with which I am sure you will agree. Such research is aimed at identifying the most effective means for the relief of pain and other discomforts, particularly those experienced by the terminally ill. Enclosed is a statement more fully descriptive of the Committee and its activities as well as copies of fact sheets dealing with the current research status of heroin and marijuana. Sincerely yours, Au Perry, M. Chairman, InterageWwcy Committee on New Therapies for Pain and Discomfort Associate Difector for Medical Applicatic of Research, NIH Enclosures 190 DEPARTMENT OF HEALTH, EDUCATION, AND WELFARE PUBLIC HEALTH SERVICE NATIONAL INSTITUTES OF HEALTH BETHESDA, MARYLAND 20014 November 9, 1978 SEE ATTACHED LIST OF ADDRESSEES: (Sent to Medical Societies) Dear During the past two years, there has been a marked increase in the public's interest in the possible therapeutic uses of some drugs in the so-called "dangerous drug category," particularly heroin and marijuana, for palliation of the pain and discomfort experienced by the terminally ill and others. This concern about humane care of the dying patient is shared by the health care and research communities. However, there has been little research done on the relative merits of the drugs in question as compared with other drugs currently employed by American physicians in the treatment of a variety of illnesses. In January of this year following a meeting at The White House, the Interagency Committee on New Therapies for Pain and Discomfort was established. The Committee, with the National Institutes of Health as the lead agency, is composed of scientists and physicians, nurses and other health professionals from various Federal agencies* concerned with health research or health care. One of its principal tasks is to encourage and facilitate research with these drugs so that the data base becomes sufficient to permit their further evaluation for possible intro- duction into the practice of medicine. A number of studies have been mounted in the U.S. in which heroin marijuana, and tetrahydrocannabinol are being evaluated in various protocols. (See enclosures.) At the same time, several states have enacted legislation dealing with research and therapeutic uses of heroin and marijuana. In some in- stances, it appears that such laws may be in conflict with Federal statutes and may inhibit rather than facilitate research needed to answer the basic questions as to the comparative value of unmarketed drugs with high abuse potential. *Health Resources Administration; Health Care Financing Adminis- tration; Alcohol, Drug Abuse, and Mental Health Administration; Food and Drug Administration; Drug Enforcement Administration; Veterans Administration; Department of Defense, and The White House. 191 1f your organization should consider the possibility of taking an official position on research and treatment with agents in this category, or is called upon by your State legislative body for advice on the subject, we would greatly appreciate an opportunity to offer our assistance in exploring current FDA research requirements and the new drug approval process. We suggest that you write to the Division of Neuropharmacological Drug Products (HFD 120), Office of New Drug Evaluation, Bureau of Drugs, Food and Drug Administration, 5600 Fishers Lane, Rockville, Maryland 20857. A representative of the Interagency Committee will then contact you. The goal of the Committee is to assure that appropriate research is facilitated and supported, a goal with which I am sure you will agree. Such research is aimed at identifying the most effective means for the relief of pain and other discomforts, particularly those experienced by the terminally ill. Enclosed is a statement more fully descriptive of the Committee and its activities as well as copies of fact sheets dealing with the current research status of heroin and marijuana. Sincerely yours, Seymour Perry, M.D. Chairman, Interagency Committee on New Therapies for Pain and Discomfort Associate Director for Medical Applications of Research, NIH Enclosures NIH:0D:ADC/ADMAR:SWhaley:SPerry:ww 192 DEPARTMEN ° OF HEALTH, EDUCATION, AND WELFARE PUBLIC HEALTH SERVICE NATIONAL INSTITUTES OF HEALTH BETHESDA, MARYLAND 20014 November 22, 1978 Sample of letter sent to The Honorable Warren G. Magnuson House and Senate Legislative Chairman, Subcommittee on Committees concerned with NIH Departments of Labor and HEW Senate Committee on Appropriations U.S. Senate Washington, D.C. 20510 Dear Senator Magnuson: Recently, there has been a considerable amount of interest in the potential therapeutic uses of drugs in the "dangerous drug" category (e.g., marijuana and heroin). Many articles on the subject have appeared in the public media, and a number of individuals and groups have urged that these drugs be made available for use generally in the practice of medicine. Unfortunately, because little prior research has been devoted to therapeutic uses of these drugs, it is not now possible to make a valid comparison between them and agents now legally available. Such research is needed. Late last year an Interagency Committee was established having as two of its primary purposes the stimulation of research on the therapeutic uses of these drugs and the development of recommendations to facilitate access by investigators to supplies of these drugs for research purposes. The group is called The Interagency Committee on New Therapies for Pain and Discomfort, and its composition and purposes are outlined in the enclosed description (Enclosure 1). In the course of its activities, the Committee has developed fact sheets on the status of research with heroin and on the use of marijuana in treating glaucoma (Enclosures 2 and 3). You may find this material useful in responding to inquiries. If you have questions, or if we can be of further help, please do not hesitate to. call on me (301/496-1143). Sincerely yours, Seymour Perry, M.D. Associate Director for Medical Applications of Research (Chairman, Interagency Committee on New Therapies for Pain and Discomfort) Enclosures 193 April 4, 1979 Miss Monica Grobman Information Associate State Information Centelr Council of State Government Lexington, Kentucky Dear Miss Grobman: I enjoyed our recent phone conversation, and your detailed facts about the Council of State Government will be very useful for certain activities of the Federal Intcragency Committee on New Therapies for Pain and Discomfort. As .I mentioned to you, thirty (30) states are presently involved in drug specific legislation (cannabis) and there are at least 9 states whose legislative language conflicts with Federal regulation (e.g., Connecticuz). Six months ago, Dr. Seymour Perry, Chairman of the Interagency Committee on New Therapies for Pain and Discomfort, sent letters to all the State Legislatures and State Medical Societies explaining the activities of this Committee. He also offered assistance in explaining FDA research requirements and the new drug approval process The impact that this correspondence had in slowing new legislation was minimal. I have enclosed a copy of each of those letters. In addition, you will find the following enclosures: a) Fact Sheet on Marihuana and Glaucoma b) Fact Sheet on lleroin and Tetrahydrocannabinol Research... r) Fact Sheet on Interagency Committee on New Therapies for Pain and Discomfort I also want to thank you for offering to send information on the State Legislative Reference Buseau. Sincerely, George W. Shaffer, M.D. Assistant to Associate Director for Medical Applications of Research Enclosures *U.S. GOVERNMENT PRINTING OFFICE : 1979 0-295-520/6278 uc. 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