We have added following document to the archive as it no longer appears to be available on the web. It provides a great deal of useful background information on methadone and methadone treatment. It also includes references to other relevant documents.

METHADONE TREATMENT WORKS:

A Compendium For
Methadone Maintenance Treatment

Monograph Series Number 2

December 1994

Marguerite T. Saunders, Commissioner
NYS Office of Alcoholism and Substance Abuse Services

Addie Corradi, Associate Commissioner
Health and Planning Services

John Perez, Assistant Director
Bureau of Methadone Planning and Policy

Chemical Dependency Research Working Group Project Staff

Herman Joseph, Chair and Executive Editor
NYS OASAS, Bureau of Methadone Planning and Policy

Joycelyn Sue Woods, Managing Editor
Medical and Health Research Association of New York City, Inc.

Literature produced by the Chemical Dependency Research Working Group (CDRWG, formerly the Cocaine/Crack Research Working Group, C/CRWG) is published by the New York State Office of Alcoholism and Substance Abuse Services (OASAS). Resources for literature production and mailing were provided by the Aaron Diamond Foundation, Inc. through a grant to Medical and Health Research Association of New York City, Inc. (MHRA).

For further information about the activities of the Chemical Dependency Research Working Group contact Dr. Herman Joseph at (212) 961-8491.

MONOGRAPH POLICY

Opinions contained in this compendium are those of the author(s) and are not necessarily endorsed by the Aaron Diamond Foundation, Medical and Health Research Association of New York City, Inc. (MHRA), or the New York State Office of Alcoholism and Substance Abuse Services (OASAS).

Contents

• A Word From The Commissioner by Marguerite Saunders
  

• Welcome From The Chair by Herman Joseph
  

• Contributing Authors
  
  

• I. Introduction to Neuroscience and Theories of Addiction

• The Discovery of Endogenous Opiates by Joycelyn Woods
  

• Neuroscience Questions and Answers by Joycelyn Woods
  

• Implications of Methadone Maintenance for Theories of Narcotic Addiction by Vincent P. Dole
  

• Comparison Chart of Illicit Heroin Addiction and Stabilized Methadone Maintenance by Herman Joseph and Joycelyn Woods
  

• Defining An Addiction
  
  

• II. Methadone Maintenance Treatment

• Methadone Maintenance Treatment and Clinical Issues by Herman Joseph
  

• The History of Methadone Maintenance
  

• The Eight Important Findings That Distinguish Methadone as a Preferred Maintenance Drug
  

• Admissions Protocols
  

• Methadone Maintenance Expands: The Gearing Study and Subsequent Evaluations
  

• A Review of Methadone Treatment: Outcome and Follow Up Studies
  

• Achieving An Effective/Adequate Methadone Dose
  

• The Importance of Achieving An Effective Methadone Dose
  

• Pharmacology of Methadone
  

• Determining Dosage Through Blood Levels
  

• Problems in Achieving a Stable Methadone Dose
  

• Methadone Dose and Policy
  

• The Medical Safety of Methadone
  

• Methadone Treatment and AIDS
  

• Methadone Treatment and Pregnancy
  

• Guidelines for Methadone Maintenance and Pregnancy
  

• Neonatal Withdrawal
  

• Conclusion
  
  

• III. Special Topics for Methadone Treatment

• The Methadone Maintained Patient and Pain Medication by J. Thomas Payte, Elizabeth Khuri, Herman Joseph and Joycelyn Woods
  

• The Functional Potential of the Methadone Maintained Person by Norman B. Gordon
  

• Selective Attention in Opiate Dependent Individuals: A Pilot Study Investigating the Effects of Endorphin Levels on Attention by Ann Rosenberg

A Word From The Commissioner
by
Marguerite Saunders

The primary purpose of the Chemical Dependency Research Working Group (CDRWG) is to encourage collaborative research by institutions and to bring together professionals from diverse disciplines including researchers, clinicians, policy makers, community groups, methadone patients and consumers of drug related services. The CDRWG, formerly the Cocaine/Crack Research Working Group was initially conceptualized to address the growing problems associated with the use of cocaine and crack. However, in 1993 the scope of the project was expanded to include all chemical dependency-related issues. An important mission of the CDRWG is to not only enhance treatment, but to find better and more effective strategies and solutions to the drug-related problems that are negatively impacting our communities and reduce the quality of life for all. Presently the CDRWG has undertaken over twenty-five symposia and published timely materials to address the many difficult issues and problems that have become associated with drug use. A final change is the monograph format for publications with articles that focus on a single topic, instead of the previous newsletters.

The recently formed Bureau of Methadone Planning and Policy is dedicated to the many issues and concerns that effect the quality of methadone treatment. It is the purpose of the Bureau to assist programs and thus enhance the recovery of methadone patients and their integration into society. To reduce the stigma and provide effective treatment it has become the responsibility of OASAS to make information regarding methadone treatment available and accurate.

This compendium was developed as a resource for researchers, providers, clinicians, policy makers and patients. It may also serve as an educational tool for communities, and the family and friends of methadone patients. The New York State Office of Alcoholism and Substance Abuse Services (OASAS) has been committed to providing effective methadone treatment and to ensure that former chemically dependent individuals will become contributing citizens of their communities. For this purpose OASAS works to provide accurate information about methadone treatment and in dispelling the many misconceptions and myths about it that hinder quality treatment and the progress of methadone patients. We at OASAS regard methadone maintenance as an important treatment to ensure recovery from heroin addiction.

The information presented in this publication is based on thirty years of scientific research which forms the medical basis of methadone treatment. With the emergence of exceptionally pure heroin it is important that people associated with drug treatment and prevention and AIDS outreach understand the basic scientific principles upon which methadone maintenance has been developed. An anticipated forthcoming compendium (Part II) will focus on social issues that impact on the functioning of programs and the subsequent adjustment of methadone patients.

Welcome From The Chair
by
Herman Joseph, Chair, CDRWG

During the past year, the Cocaine/Crack Research Working Group (C/CRWG) changed its name to the Chemical Dependency Research Working Group (CDRWG) of the New York State Office of Alcoholism and Substance Abuse Services (OASAS). The CDRWG is now part of the OASAS Bureau of Methadone Planning and Policy which has allowed us to enlarge the scope of our interests. The CDRWG is funded by the Aaron Diamond Foundation through a grant to Medical and Health Research Association of New York City, Inc. (MHRA). With such diversified support the CDRWG will continue publishing timely information and organizing symposia around medical and social issues related to chemical dependency.

This compendium is devoted to scientific and selected clinical issues involved in methadone maintenance treatment. Although methadone maintenance was developed thirty years ago at The Rockefeller University, it remains a controversial and misunderstood approach to the treatment of heroin addiction. This compendium presents information to help persons involved with the treatment of addiction and policy decisions to understand some of the complicated, yet important scientific concepts that have evolved over the past thirty years.

Articles in the first section of the compendium focus on recent neuroscience discoveries and their relationship to the biological theory of addiction. The section begins with two articles by Joycelyn Woods that introduce the reader to a variety of difficult scientific topics including pharmacology, neuroscience and the endogenous opiate receptor-ligand system. The introductory material is followed by Dr. Vincent P. Dole's article, Implications of Methadone Maintenance for Theories of Narcotic Addiction which has been reprinted with the permission of the Journal of the American Medical Association (JAMA). This paper presents a summary of research issues involved in addiction theory and methadone maintenance treatment and was written for JAMA by Dr. Dole when he received the Lasker Award for Clinical Medical Research in 1988. Following the article by Dr. Dole is a Comparison Chart of Illicit Heroin Addiction and Stabilized Methadone Maintenance that compares the profound differences between illicit heroin addiction and methadone maintenance. The chart was developed by CDRWG staff as a response to the oft quoted criticism of methadone maintenance as "just substituting one addiction for another." In reality methadone maintenance has been a thoroughly researched and, when implemented correctly, the most effective treatment for heroin addiction. This section ends with Defining an Addiction which is reprinted from the Diagnostic and Statistical Manual of Mental Disorders.

The second section by this writer summarizes the basic information necessary to understand the rationale behind methadone maintenance treatment Topics included are history, methadone dosage, medical safety, adjustment of patients in treatment, review of follow up studies, AIDS and pregnancy. The information in this section is arranged so the compendium can be used as a resource manual and reference guide.

The third section presents special topics written especially for this compendium. The first article, written by Drs. J. Thomas Payte, Elizabeth Khuri and the CDRWG staff discusses the prescribing of pain medication to methadone patients and provides several clinical procedures. The second paper, by Dr. Norman Gordon, Functional Potential of the Methadone Maintained Patient, demonstrates that methadone patients function within the normal range in tests that measure ability, intelligence and coordination. The final paper by Dr. Ann Rosenberg, Selective Attention in Opiate Dependent Individuals: A Pilot Study Investigating the Effects of Endorphin Levels on Attention, shows that there are similar trends on performance tasks of selective attention in methadone patients and persons who do not use opiates.

It is our hope that this compendium will begin to break through many of the stereotypes and mythologies that are directed towards methadone programs and especially patients. In the final analysis it is the patients who are unjustly stigmatized by misinformation and a poor understanding of the complex issues involved in heroin addiction and methadone maintenance treatment. Communities are also adversely impacted by a lack of methadone treatment; properly administered programs have the potential to reduce drug-related crime, lessen the transmission of HIV and drug resistant TB, improve the patient's employment possibilities and assist patients in becoming contributing members of their community. Thus, the presence of well administered methadone programs improves the quality of life for all in the community.

A forthcoming and anticipated second compendium on methadone treatment will address poly drug use and social issues, including articles on cocaine/crack use, alcoholism, counseling, unemployment, vocational rehabilitation, homelessness, stigma and patient advocacy. The CDRWG will continue to publish articles on topics that are timely and of great concern. Through this monograph format, organizing articles around a specific issue, the CDRWG will be able to cover areas from various aspects and disciplines. The CDRWG will continue to present symposia and to facilitate the formation of committees to investigate and consider solutions to issues related to chemical dependency.

Contributing Authors

I. Introduction to Neuroscience and Theories of Addiction

"A modern theory of narcotic addiction is that the compulsive (and quite specific) craving for narcotic drugs is a symptom of deficiency in function of the natural opiate-like substances in the brain. To be sure, sociological and psychological forces enter into the making of an addict, but these factors determine exposure - - - whether or not addictive drugs are available in the environment and whether a person chooses to experiment with them. In any person, with repeated exposure to a narcotic drug, the brain adapts and becomes pharmacologically dependent on a continuing input. In some susceptible persons - fortunately a minority of the population - the adaptation becomes fixed, and with repeated use a regular input of narcotic becomes a necessity. The experimenter has become an addict.

From this perspective methadone maintenance is replacement treatment, compensating for impairment in function of natural opiate-like substances."

Dr. Vincent P. Dole. Methadone maintenance: Optimizing dosage by estimating plasma level (Editorial). Journal of Addictive Diseases 1994 13(1): 1-4.

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The Discovery of Endogenous Opiates
by
Joycelyn Sue Woods

For years it had been suspected that opiates had specific binding sites in the brain. There were several attempts to locate these sites, but the existing technologies were unable to distinguish between the non specific binding to tissue and the specific binding to receptors. It must be mentioned here that the first attempt to actually measure specific opiate binding was in the laboratory of Dr. Vincent Dole (Ingolia & Dole, 1970). Although the technology was not available at that time he laid the foundations for the discovery of opiate receptors.

By the early 1970s scientific technology had evolved to the point where the discovery of opiate binding sites seemed almost inevitable. The first to shake the scientific community was Solomon Snyder and his student, Candice Pert of John Hopkins University (Pert & Snyder, 1973). Using a technique developed by Avram Goldstein of Stanford University, Snyder and Pert located the elusive opiate receptor (Goldstein, Lowney & Pal, 1971). That same year, two other groups headed by Eric J. Simon of New York University (1973) and Lars Terenius in Uppsala, Sweden (1973) demonstrated specific opiate binding in nervous tissue. The treasure hunt had begun! "For why," Goldstein asked, "would God have made opiate receptors unless he had also made an endogenous morphine-like substance?"

In the mid-1960s, Choh Li of the University of California at Berkeley had isolated a pituitary hormone which he named B-Lipotropin (Li, 1964). He noted that one portion of this hormone had analgesic properties. One year after the discovery of the receptor sites, John Hughes at the laboratory of Hans Kosterlitz in Aberdeen, Scotland, reported the existence of an endogenous morphine-like substance which they later purified and named Enkephalin for 'in the head' (Hughes, 1975a; Hughes, 1975b; Kosterlitz, 1976) The Aberdeen group recognized that the peptide sequence of Enkephalin was contained within Li's B-Lipotropin. Li would later name the other endogenous morphine-like peptides, which also come from his pituitary hormone, Endorphin for morphine within.

Today the term opioid is used for all endogenous morphine-like substances, including Dynorphin another brain opioid peptide system found by Avram Goldstein (Goldstein, Tachibana, Lowney, Hunkapiller & Hood, 1979). Other psychoactive peptides have been discovered and isolated using the techniques developed in these laboratories. In 1978, Solomon Snyder, John Hughes and Hans Kosterlitz shared the Lasker Award for their discoveries. Paralleling the discovery of Enkephalins, Endorphins and opiate receptors have been advances in the field of neuroscience. These advances have led to many exciting discoveries and generated a new interest in the functioning of the brain. We have entered a new era in our understanding of human behavior.

References

Goldstein, A.; Lowney, L.I. and Pal, B.K. Stereospecific and non stereospecific interactions of the morphine congener levorphanol in sub cellular fractions of mouse brain. Proceedings of the National Academy of Science USA 1971 68: 1742-1747.

Goldstein, A.; Tachibana, S.; Lowney, L.I.; Hunkapiller M. and Hood, L. Dynorphin-(1-13), an extraordinary potent opioid peptide. Proceedings of the National Academy of Science USA 1979 76: 6666-6670.

Hughes, J. Isolation of an endogenous compound from the brain with properties similar to morphine. Brain Research 1975 (a), 88: 295-308.

Hughes, J. Search for the endogenous ligand of the opiate receptors. Neuroscience Research Program Bulletin 1975 (b), 13: 55-58.

Ingolia, N.A. and Dole, V.P. Localization of d and l-methadone after intraventricular injection into rat brains. Journal of Pharmacology and Experimental Therapeutics 1970, 175: 84-87.

Kosterlitz, H.W. The incorporation of H3 -glycine into enkephalins in the brains of morphine treated rats. In: Kosterlitz, H.W. (ed), Opiates and Endogenous Opioid Peptides. Amsterdam: North Holland Biomedical Press, 1976.

Li, C.H. Lipotropin: A new active peptide from pituitary glands [abstract]. Nature 1964 201: 924.

Pert, C.B. and Snyder, S. Opiate receptor: Demonstration in nervous tissue. Science 1973, 179: 1011-1014.

Pert, C.B. and Snyder, S. Identification of opiate receptor binding in intact animals. Life Science 1975, 16: 1623-1634.

Simon, E.J.; Hiller, J.M. and Edelman, I. Stereospecific binding of the potent narcotic analgesic (3H) etorphine to rat brain homogenate. Proceedings National Academy of Science USA 1973, 70: 1947-1949.

Terenius, L. Stereospecific interaction between narcotic analgesics and a synaptic plasma membrane fraction of rat cerebral cortex. ACTA Pharmacological Toxicology 1973, 32: 317-320.

Neuroscience Questions and Answers
by
Joycelyn Sue Woods

Special Communications
Implications of Methadone Maintenance for Theories of Narcotic Addiction
by
Vincent P. Dole M.D.
On The Occasion of The Presentation of
The Albert Lasker Award for Clinical Medical Research

Vincent P. Dole, M.D. is Professor Emeritus at The Rockefeller University, New York City.

This article is based on a lecture given at the presentation of the Albert Lasker Clinical Medicine Research Award on November 18, 1988, New York, NY. It was first published in the Journal of the American Medical Association, 1988, Volume 260, pages 3025-3029 and is published here with their gracious permission.

This article is dedicated to the memory of Marie Nyswander, M.D. who opened the modern era of treatment with her book The Drug Addict As A Patient (New York: Grune & Stratton, 1956). Her experience and compassion guided the development of methadone maintenance.

Abstract

Clinical success in rehabilitation of heroin addicts with maintenance treatment requires stability of the blood level in a pharmacologically effective range (optimally, 150 to 600 ng/mL) a phenomenon that emphasizes the central importance of narcotic receptor occupation. It is postulated that the high rate of relapse of addicts after detoxification from heroin use is due to persistent derangement of the endogenous ligand-narcotic receptor system and that methadone in an adequate daily dose compensates for this defect. Some patients with long histories of heroin use and subsequent rehabilitation on a maintenance program do well when the treatment is terminated. The majority, unfortunately, experience a return of symptoms after maintenance is stopped. The treatment, therefore, is corrective but not curative for severely addicted persons. A major challenge for future research is to identity the specific defect in receptor function and to repair it. Meanwhile, methadone maintenance provides a safe and effective way to normalize the function of otherwise intractable narcotic addicts. (JAMA 1988 260: 3025-3029)

The achievements of molecular biology in analyzing processes of cell function suggest that all diseases, including disorders of behavior, might ultimately be reduced to biochemical terms. The claim is extreme, but at least for narcotic addiction the optimism seems to be justified. Analysis of the clinical results of methadone maintenance treatment during the past 25 years, coupled with advances in the understanding of narcotic receptors and their ligands, support the view that compulsive use of narcotic stems from receptor dysfunction.

This is a departure from the traditional concept of addiction as misbehavior— a distinction of great practical consequence. As recently as four months ago the Supreme Court affirmed the denial of veteran's benefits to alcoholics on the ground that their condition is due to "willful misconduct" (Trayner v. Turnage, 1988), an opinion that seems to be at odds with the medical tradition of basing services on need rather than on fault. The ruling made explicit the widespread prejudice against addicts, one that if carried to logical limits would deny treatment to a skier with a broken leg or a sunbather with skin cancer. For the immediate future, the harshness of the ruling has stimulated corrective action in the legislature. In the longer term, scientific understanding should displace prejudice, and attitudes toward addictive behavior should become more consistent with medical tradition. At least so one may hope, provided that the scientific community can provide a basis for rational understanding of addictions as diseases.

Methadone Normalizes Function

This article, updating previous analyzes (Dole & Nyswander, 1968; Dole, 1970), is concerned mainly with the theoretical implications of methadone maintenance treatment and the direction of future work. The practical success of maintenance in rehabilitation of tens of thousands of addicts, now especially important as a measure of limiting the spread of acquired immunodeficiency syndrome, has been documented and need not be reviewed further (Dole & Joseph, 1978; Cooper, Altman, Brown et al, 1983; Newman, 1986; Kreek, 1987). The issue to be considered here is the basis of this success. The treatment is corrective, normalizing neurological and endocrinologic processes in patients whose endogenous ligand-receptor function has been deranged by long-term use of powerful narcotic drugs. Why some persons who are exposed to narcotics are more susceptible than others to this derangement and whether long-term addicts can recover normal function without maintenance therapy are questions for the future. At present, the most that can be said is that there seems to be a specific neurological basis for the compulsive use of heroin by addicts and that methadone taken in optimal doses can correct the disorder. When somatic function has been normalized, the ex-addict, supported by counseling and social service, can begin the long process of social rehabilitation.

The social rehabilitation of methadone maintenance patients and the normalization of endocrine function substantially exceed the expectation that Marie Nyswander, M.D., and I brought to the problem 25 years ago. Then, as now, it was clear that narcotic addiction could not be eliminated simply by prohibition, however severe the penalties. For a chronic user, the need for narcotic is inelastic. With tens of thousands of such persons as a market, limiting supply without reducing demand increases the price of illicit drugs to the point that black marketers are willing to take the necessary risks. The net result is a highly profitable business for the drug sellers, corruption of government officials, infiltration of legitimate business with laundered money, increase in crime committed by addicts to support their expensive habits, filling of jails, and deaths from injection of contaminated drugs of uncertain potency. The clear lesson to be learned from repeated failures of past policy is that demand must be reduced by effective treatment. The epidemic of narcotic use has not been extinguished by prohibition, civil commitment, jailing, or other punishments.

On the other hand, it must be conceded that attempts to treat addicts with narcotic maintenance 70 years ago were not successful. Indeed, leaders in the medical profession and the Public Health Service cooperated with enforcement agents in closing the experimental clinics, thus effectively transferring responsibility for control of addiction to the police (Musto, 1973). When Marie Nyswander and I began our work, the position of the Federal Bureau of Narcotics was that maintenance had been tried and had failed. The argument could not be denied, but it seemed self-serving. The failure of clinics that had been organized hastily in response to the panic that followed enactment of the Harrison Narcotic Act constituted the database. Not only were physicians ill prepared to deal with the flood of desperate addicts, they had only two narcotic drugs, morphine and heroin, to prescribe. In retrospect, a major reason for their failure is clear: the physicians were using the wrong drug.

Our objective at the onset was simply to find a medication that would keep addicts content without causing medical harm and that would be safe and effective for use over long periods in relatively stable doses. The goal of social rehabilitation of addicts was not part of the original plan. Merely satisfying addicts, although not an ideal result, seemed better than the existing policy that forced incurable addicts into criminal activity.

Stability Essential

The initial studies, conducted at Rockefeller Hospital (New York) in collaboration with Mary Jeanne Kreek, M.D., examined the clinical effects of different narcotic drugs when given in various doses to long-term users of heroin. All drugs were of the opiate class that is, they were known to exhibit cross tolerance with morphine and all had been approved for human use as analgesics. The reason for failure of previous attempts to maintain addicts on morphine soon became apparent: the patients could not be stabilized on the drug. Despite frequent injections, their condition fluctuated between somnolence and agitation throughout each day, with tolerance increasing over consecutive days to the point that they were almost continuously agitated even when receiving huge doses of morphine. Similar results were obtained with heroin (which is essentially the same drug as morphine since it is rapidly converted to morphine in the body), hydromorphone, codeine, oxycodone, and meperidine. The prospect for maintenance treatment did not look promising at this point.

A remarkably different result was seen when, in the course of the scheduled testing, methadone was administered. The fluctuation in clinical state became less and then disappeared. Doses became stable. The patients seemed normal. Most remarkably, their interests shifted from the usual obsessive preoccupation with timing and dose of narcotic to more ordinary topics (Dole, Nyswander & Kreek, 1966). We had no explanation for this surprising result. Prior to our studies, methadone had been tested at the Public Health Hospital (Lexington, KY) and was found to be a typical opiate, distinguished from morphine only by greater oral effectiveness and a somewhat longer period of action (Eddy, Halbach & Breanden, 1957). However, because of the favorable response, we decided to continue administration of methadone beyond the original schedule and to observe longer-term effects. It was not until several years later that an explanation for the unusual result became apparent: the concentration of methadone in blood is stabilized by reversible absorption into tissues (Dole & Kreek, 1973), mainly the liver (Kreek, Oratz, Rothschild, 1978). The key factor is the reversibility of this absorption. Immediately after ingestion of the daily dose, 99% of the medication is bound to the tissues in equilibrium with the concentration in blood. It is released as the concentration falls, thus buffering the level. With a relatively steady concentration in blood, the narcotic receptors in critical cells remain continuously occupied and the patient becomes functionally normal. The essential feature in the treatment is the stability of receptor occupation, which permits interacting systems to function normally. The physiological and behavioral disturbances in heroin addiction apparently are consequences of the rapid changes in status of the endogenous narcotic receptor-ligand system. When the addict takes short acting narcotics, the system cycles between abstinence and narcosis several times a day. A stable state of adaptation is impossible.

Our work involved a fortunate accident that explains why the unique value of methadone for maintenance had not been discovered previously. The patients had just completed a long series of tests with other opiates and, as a consequence, had developed a high tolerance to narcotics. Therefore, methadone was administered in exceptionally high doses, about ten times greater than is needed for analgesic action in naive patients. Injected in a single, small dose to a nontolerant patient, methadone is a relatively short-acting drug. The bulk of the dose is quickly removed from blood and later is returned to circulation at a pharmacologically insignificant level. Only when large doses of methadone have been administered repeatedly do the nonspecific binding sites come into equilibrium with a pharmacologically effective concentration in circulating blood. When this condition is reached, all that is needed for buffering the concentration at a high enough level to ensure significant occupation of receptors is a single daily dose to replace the amount of drug that has been eliminated by metabolism. Moreover, because of efficient absorption from the gastrointestinal tract, the dose can be given orally, thus eliminating needle use.

Specificity

Studies of the original six patients on our metabolic ward demonstrated the absence of acute narcotic effect in methadone maintenance patients and provided an understanding of the importance of receptor occupation. Switching the daily dose to d-methadone in place of the usual racemic mixture of d- and l- methadone was followed by the gradual appearance of abstinence symptoms, as expected from the fact that the narcotic activity of methadone is limited to the l isomer. The patients, not noticing any difference in the taste or immediate effects of the daily dose, reported on the next day that they seemed to be "getting the flu." Only on the third day did they begin to suspect the medication and asked if "something had happened to the methadone." At this point they were returned to the usual racemic mixture. All symptoms cleared immediately. The patients had responded to the fall in concentration of l-methadone in blood and the resultant dissociation of this active isomer from critical receptors. When returned to medication containing l methadone, they again became functionally normal.

The acute effect of naloxone, an antagonist that displaces narcotic ligands from receptors, shows the extreme sensitivity of physically dependent patients to the degree of occupancy of their narcotic receptors. Within a few seconds after an intravenous injection of a minute dose of naloxone (1/20 the amount that might be used in treating a nontolerant patient with narcotic overdose), a maintenance patient will be put into acute abstinence, with profound dysphoria. The subjective sensation apparently defies description in ordinary terms, being reported as a terrible feeling not like anything else. To an observer the patient appears to have been suddenly plunged into severe depression; he becomes immobile, sagging in posture, apparently grief-stricken.

Nontolerant patients are essentially unreactive to naloxone but are highly sensitive to narcotics. The classic studies of Houde et al (1960), quantitating the analgesia in pain patients following administration of a single dose of narcotic, showed a reproducible time course that depended on the dose and degree of tolerance induced by previous exposure. Subsequent studies by Berkowitz et al (1975) correlated this effect with the blood level of morphine, thus demonstrating a direct, moment-to-moment relation between analgesia and occupation of narcotic receptors. Studies by Inturrisi et al (1987) during the past 15 years have provided quantitative analyses of pain relief as a function of narcotic blood level. Clearly, the subjective experience of pain is inversely related to receptor occupation, given a constant input of sensory signals from injured tissue and dependent on the degree of narcotic tolerance.

Persistent Receptor Disorder

An interpretation of these phenomena is that the narcotic receptor-ligand system acts as a modulator, adjusting the intensity of suffering and the body's hormonal response to stress. In nontolerant patients, the reactions to tissue damage and related stresses are modulated by the natural ligands, the opioid peptides, while pain can be abolished therapeutically for a limited time by a dose of narcotic drug. However, repeated injections of narcotic lead to down-regulation of the modulating system and possibly also to suppression of endogenous ligands, thus contributing to narcotic tolerance and dependence and progressively diminishing the analgesic utility of narcotics.

This oversimplified analysis assumes a balance between activating and modulating processes. Under normal, unstimulated conditions, both processes are quiescent. When sensory stimuli activate neurological and humoral systems, the modulating processes react to protect against excessive response. With long-term administration of narcotics, the modulating system is down-regulated. The receptors become insensitive both to narcotic drugs and to their natural ligands. A new stability is achieved if methadone is given in an adequate daily dose, but at the price of continued dependence on the medication. Thus, a fundamental question in treatment of long-term users of narcotics is whether the modulating systems can return to normal function after termination of narcotic input. Ideally, methadone would be used as a stabilizing medication to provide immediate intervention, stopping the use of illicit narcotics and normalizing general metabolism. Later, after medical and social rehabilitation, the maintenance medicine would be withdrawn slowly and the patient would be totally cured.

Unfortunately, cure of chronic narcotic addiction is not that simple. Some patients do well after rehabilitation and termination of methadone maintenance, but the majority, although equally motivated, experience dysphoria, restlessness, irritability, and recurrent urges to use heroin again. The danger of relapse is great under these conditions. Objectively measurable physiological disturbances persist after detoxification from heroin or any other narcotic that has been used for a long time. These were noted by Himmelsbach (1968) in early studies of the abstinence syndrome at the Public Health Hospital. Observing signs of dependence (sympathetic nervous system hyperactivity) that persisted up to two years in prisoners serving long sentences, he surmised that the almost invariable relapse of prisoners after release was "abetted by what seem to be indelible effects of addiction on the nervous system" (Himmelsbach, 1968).

It had, of course, long been known that most long-term users of narcotics relapse after withdrawal of the drug. The Public Health Hospital was started in 1935 under the reasonable assumption that medically assisted detoxification with counseling, general medical care, and healthy living on a Kentucky farm would provide optimal conditions for cure. Nevertheless, more than 90% relapsed after return to New York City (Hunt & Odoroff, 1962). Although the hospital made major scientific contributions, using volunteers from the population of prisoners to test the addictive potential of new drugs and conducting fundamental studies of narcotic pharmacology, including the work of Wikler (1958) on conditioning, the initial goal "that of curing addicts" was never realized.

Persistent after effects of narcotic exposure also have been found in experimental animals. Physiological disturbances were demonstrated by Martin et al (1963) and Cochin and Kornetsky (1964) months after treatment of rats with morphine. Brase and associates (1976) have used a small priming injection of morphine followed by naloxone as a probe to unmask residual abnormalities in rats long after exposure to narcotic drugs. Surprisingly, little new clinical research has been directed to the phenomenon of protracted abstinence despite the fact that relapse after completion of treatment is the central problem of narcotic addiction. With the present availability of sensitive analytic techniques, including specific ligands for analysis of receptor binding, the problem seems ripe for renewed investigation. What is needed now are methods to assess the kind and degree of receptor derangement in addicts and a better understanding of the function of this modulating system in response to physiological stress. With a more detailed understanding of addiction in molecular terms, a fundamental cure may be possible. Indeed, progress may come from work on other conditions in which chronic exposure to powerful nonnarcotic drugs leads, in susceptible persons, to persistent derangement of neurological (Gunne & Barany, 1976; Gunne & Haggstrom, 1984) or endocrine (Williams, Dluhy & Thorn, 1980) function.

Practical Considerations

None of these theoretical speculations should divert attention from the fact that methadone maintenance is an available treatment for otherwise intractable addicts. It is effective under a wide variety of conditions provided that an adequate, constant daily dose is given. Like digitalis, methadone can be lifesaving. Although it is now possible to provide a theoretical explanation for their beneficial actions, in practical terms, the justification for use of either methadone or digitalis, and the details of how they should be used, stem from experience.

The comparison goes deeper. No one questions the need for efforts to prevent the cardiac damage that ultimately leads to congestive failure or the importance of protecting young people from exposure to narcotic drugs. Prevention is fundamental in limiting the prevalence of these conditions. In principle, there should be no conflict between prevention of a disease and treatment of an established disability, and in the case of heart disease there is none. But with drug addiction, a serious dilemma arises: limiting the supply of a dangerous drug, which is an essential part of prevention, can cause more damage to society than the addiction itself if extremes of enforcement promote criminal behavior. There is no simple answer to this dilemma. Obviously there should be a balance between enforcement and treatment, reducing both supply and demand proportionally. With heroin and related narcotics, methadone maintenance has by far the greatest immediate potential for reducing demand. It is therefore important that the medical profession understand its pharmacology, its indications, and its limitations.

The optimal daily dose of methadone for maintenance is the quantity that will hold the blood level in the 150 to 600 ng/mL range. This concentration range is consistent with binding to narcotic receptors when allowance is made for binding of methadone to plasma proteins and reduction in sensitivity of receptors with narcotic tolerance. As a general rule, 60 to 80 mg of oral d-methadone hydrochloride a day (reached by gradual increase over four to six weeks) is adequate and not excessive, although in exceptional cases substantially higher doses may be needed. If the activity of the hepatic microsomal enzyme oxidizing system has been increased by interaction with other medications being taken concurrently (Kreek, Garfield, Gutjahr et al, 1976; Tong, Pond, Kreek et al, 1981), or for unknown reasons (Tennant, 1987), the elimination of methadone will be accelerated. In extreme cases, even 100 mg/d may fail to hold the blood methadone level within the therapeutic range for the full 24 hours and a higher divided dose will be needed for optimal results. However, these cases are unusual. Usually patients after stabilization for some months on a 60 to 80 mg/d dose can be lowered to the 40 to 60 mg/d range without difficulty. Some can be maintained successfully with even lower doses but, except the rare cases in which full tolerance to the narcotic effects of methadone may not be developed, there is no compelling reason for prescribing doses that are only marginally adequate. As with antibiotics, the prudent policy is give enough medication to ensure success.

This perhaps is too casual an answer to the question of optimal dosage. If the instruments and funding required for repeated measurement of methadone blood levels were generally available (which they are not) it would be apparent that any rigid set of dosing guidelines would be misleading. The levels vary substantially from patient to patient receiving the same daily doses (Kreek, 1973; Holmstead, Anggard & Gunne, 1978). Analytic data, if available, would permit a fine-tuned adjustment of doses to optimal amounts for individual patients. Fortunately, this laboratory support is not needed. An experienced clinician can judge the adequacy of the dose from the effects. Symptoms of abstinence can be distinguished from anxiety, and narcosis from neurasthenia, by carefully listening to the symptoms, considering their timing in relation to the daily dose of methadone, noting the patient's response to a change in dose, and evaluating his or her emotional stability. The patient's clinical state is correlated reliably with the blood level and the degree of tolerance.

Some maintenance programs, committed philosophically to low-dose regimens, expose their patients to a significant degree of abstinence each day, as the blood level falls into the low range (Dole & Nyswander, 1983). Other programs, seeing the medication as psychological rather than pharmacological treatment, give methadone as a reward for good behavior and withhold it for drug abuse and other infractions of rules. The results are generally poor, as might be expected from the fact that limiting or withholding medication that reduces drug hunger increases the need for illicit narcotics.

Alternative Theory

The hypothesis suggested herein- that narcotic-seeking behavior is a symptom of deranged receptor function- is most directly challenged by treatment of addicts with an antagonist such as naltrexone to block all narcotic actions. Use of antagonists stems from traditional views of addiction as a pleasure-seeking escape from reality employed by persons of weak will who are living in a stressful environment. Add to this the postulated influence of conditioned reflexes that generate an irresistible craving for narcotic when the addict is in the company of other drug users, and one has a theory of addiction (Wilker, 1958). The escapist-conditioning explanation is so plausible that it has influenced medical thinking and public health policy for three decades. Although this conception has never led to a treatment with consistent success, the failure has been excused by the practical difficulty of removing stress and bad companions from the environment of an addict and by the inability of counselors to eliminate character defects.

According to the conditioning theory, antagonist treatment, which blocks the narcotic effects of heroin and related drugs, should insulate the addict from temptation, especially after he has found them to be unrewarding. With no reinforcement, the interest in the narcotic should subside and the patient should become responsive to counseling. Again, there is an explanation for the repeated failures of antagonist treatment to stop heroin use during the past ten years: addicts can easily quit treatment and return to the illicit drug. Current research in some laboratories, aimed at development of implantable preparations of antagonist, is intended to close this loophole.

From the perspective of the receptor derangement theory, this approach is pharmacologically wrong. Antagonist drugs block the action of natural ligands as well as that of illicit narcotics. If the basic problem leading to relapse is a failure of the modulating system to return to normal function after withdrawal of narcotic, than antagonist treatment adds to the problem. The issue, therefore, is clearly drawn. If long-lasting, implantable preparations of narcotic antagonists prove to be as successful as methadone maintenance treatment in rehabilitation of addicts, this certainly would be a useful result. Further research is needed to determine whether the result was in fact due to deconditioning or to a positive interaction with endogenous opioid processes. On the other hand, if the treatment with implanted antagonist fails, then proponents of the conditioning theory should reconsider their position. This important experiment, if conducted, should be well documented and independently evaluated.

The Future

Apart from theory, the most striking fact is the physiological normality of maintenance patients. Persons who have taken a constant daily dose over a period of months to years are indistinguishable from normal peers. Despite a daily dose that would induce a coma in a naive patient, the patients are normally alert and functional; they live active lives, hold responsible jobs, succeed in school, care for families, have normal sexual activity and normal children, and have no greater incidence of psychopathology or general medical problems than their drug-free peers. Surprisingly, considering the constant input of narcotic, they have a normal response to painful stimuli, including specifically the warning symptoms of surgical emergencies.

All this does not fit neatly into the pharmacology learned from experiments involving single injections of narcotic drugs. The molecular biology of adaptation to chronic narcotic input must be better defined before we can fully understand the pharmacology of maintenance. Somehow the receptors adapt to a steady level of occupancy. They react to a change in conditions, either in degree of receptor occupation by ligands or in the intensity of sensory stimuli, while being adapted to a constant high level of narcotic in tissue fluids.

Here, then, are basic questions to be answered by molecular biologists: How can this system function normally under such abnormal conditions? Why is stability of narcotic concentration more important than the absolute level? Are chronic adaptive changes completely reversible?

Needless to say, any attempt to relate behavioral disorders to molecular processes must start with an oversimplified model. Much more work is needed to take account of the diversity of narcotic receptors and endogenous ligands, the dynamics of receptor formation and internalization, the release of second messengers, and the interactions of modulating processes with other parts of the nervous system (Snyder, 1979; Ariena, 1984). Nevertheless, the broad outline of a metabolic theory of narcotic addiction is coming into view. Two general conclusions emerge from the experience to date: it is not necessary to await an ultimate reduction of addictive behavior to molecular terms before effective treatment can be provided. On the contrary, effective treatment, empirically found, can lead to a better understanding of molecular processes.

References

Ariena, E.J. Receptors: Perspectives in pathology and clinical medicine. Journal of Receptor Research 1984 4: 1-17.

Berkowitz, B.A.; Ngai, S.H.; Yang, J.C. et al. The disposition of morphine in surgical patients. Clinical Pharmacology 1975 17: 629-635.

Brase, D.A.; Iwamoto, E.T.; Loh, H.H. et al. Reinitiation of sensitivity to naloxone by a single narcotic injection in post addict mice. Journal of Pharmacology and Experimental Therapeutics 1976 197: 317-325.

Cochin, J. and Kornetsky, C. Development and loss of tolerance to morphine in the rat after single and multiple injections. Journal of Pharmacology and Experimental Therapeutics 1964 145: 1-10.

Cooper, J.R.; Altman, F.; Brown, B.S. et al (eds), Research on the Treatment of Narcotic Addiction. State of the Art. National Institute on Drug Abuse, Treatment Monograph Series. Rockville: US Dept. of Health and Human Services, 1983.

Dole, V.P. Biochemistry of addiction. Annual Review of Biochemistry 1970 39: 821-840.

Dole, V.P. and Joseph, H. Long-term outcome of patient treated with methadone maintenance. Annals of the New York Academy of Science 1978 311:181-189.

Dole, V.P. and Kreek, M.J. Methadone plasma level: Sustained by a reservoir of drug in tissue. Proceedings of the National Academy of Science USA 1973: 70-10.

Dole, V.P. and Nyswander, M.E. Behavioral pharmacology and treatment of human drug abuse: Methadone maintenance of narcotic addicts. In: Smith, J.E. and Lane, J.D. (eds), The Neurobiology of Opiate Reward Processes, p 211-232. Amsterdam: Elsevier Biomedical Press, 1983.

Dole, V.P. and Nyswander, M.E. Methadone maintenance and its implications for theories of narcotic addiction. In: Wikler, A (ed), The Addictive State, p 359-366. Baltimore: Williams and Wilkins, 1968.

Dole, V.P.; Nyswander, M.E. and Kreek, M.J. Narcotic blockade. Archives of Internal Medicine 1966 118: 304-309.

Eddy, N.B.; Halbach, H. and Braenden, O.J. Synthetic substances with morphine-like effect: Clinical experience—potency, side effects, addiction liability. Bulletin WH0 1957 17: 569-863.

Gunne, L-M. and Haggstrom, J-E. Studies in experimental tardive dyskinesia. In: Catecholamines: Neuropharmacology and Central Nervous System - Therapeutic Aspects, p 79-84. New York: Alan R. Lisa, Inc., 1984.

Gunne, L-M. and Barany, S. Haloperidol-induced tardive dyskinesia in monkeys. Psychopharmacology 1976 197: 317-325.

Himmelsbach, C. Clinical studies of morphine addictions. Nathan B. Eddy Memorial Award Lecture. In: Harris, L.S. (ed), Proceedings of the 49th Annual Scientific Meeting of the Committee on Problems of Drug Dependence. National Institute on Drug Abuse, Research Monograph Series 81. Rockville: U.S. Dept. of Health and Human Services, 1968.

Holmstrand, J.; Anggard, E. and Gunne, L-M. Methadone maintenance: Plasma levels and therapeutic outcome. Clinical Pharmacology and Therapeutics 1978 23: 175-180.

Houde, R.W.; Wallenstein, S.L. and Rogers, A. The disposition of morphine in surgical patients. Clinical Pharmacology and Therapeutics 1960 1: 163-174.

Hunt, C.H. and Odoroff, M.E. Follow up study of narcotic drug addicts after hospitalization. Public Health Reports 1962 77: 41-54.

Inturrisi, C.E.; Colburn, W.A.; Kaiko, R.F. et el. Pharmacokinetics and pharmacodynamics of methadone in patients with chronic pain. Clinical Pharmacology and Therapeutics 1987 41: 392-401.

Kreek, M.J. Multiple drug abuse patterns and medical consequences. In: Meltzer, H.Y. (ed), Psychopharmacology: Third Generation of Progress, p 1597-1604. New York: Raven Press, 1987.

Kreek, M.J. Plasma and urine levels of methadone. New York State Journal of Medicine 1973 73: 2773-2777.

Kreek, M.J.; Garfield, J.W.; Gutjahr, C.L. et al. Rifampin-induced methadone withdrawal. New England Journal of Medicine 1976 294: 1104-1106.

Kreek, M.J.; Oratz, M. and Rothschild, M.A. Hepatic extraction of long-and short-acting narcotics in the isolated perfused rabbit liver. Gastroenterology 1978 75: 88-94.

Martin, W.R.; Wilker, A.; Eades, C.G. et al. Tolerance and physical dependence on morphine in rats. Psychopharmacology 1963 4: 247-260.

Musto, D.F. The American Disease: Origins of Narcotic Control. New Haven: Yale University Press, 1973.

Newman, R.G. Narcotic addiction and methadone treatment in Hong Kong: Lessons for the United States. Journal of Public Health Policy 1986 6: 526-638.

Snyder, S.H. Receptors, neurotransmitters and drug responses. New England Journal of Medicine 1979 300: 465-472.

Tennant Jr., F.S. Inadequate plasma concentrations in some high-dose methadone maintenance patients. American Journal of Psychiatry 1987 144: 1349-1350.

Tong, T.G.; Pond, D.M.; Kreek, M.J. et al. Phenytoin-induced methadone withdrawal. Annals of Internal Medicine 1981 94: 349-351.

Trayner v Turnage, 108 US 1372 (April 20, 1988).

Wikler, A. Mechanisms of Action of Opiate Antagonist: A Review of their Action in Relation to Clinical Problems. Rockville: Public Health Service, 1958.

Williams, G.H.; Dluhy, R.G. and Thorn, G.W. Disease of the adrenal cortex. In: Isselbacher, K.S.; Adams, R.D.; Braunwald, E. et al (eds), Principles of Internal Medicine (9th edition), p 1711-1736. New York: McGraw-Hill International Book Co., 1980.

Comparison Chart of Illicit Heroin Addiction
and Stabilized Methadone Maintenance

Topic	Illicit Heroin Addiction	Stabilized Methadone Maintenance
Onset of action	Immediate	Thirty minutes
Duration of action	Four to 6 hours	Twenty-four to 36 hours or half life
Route of administration	Injection, snorting, smoking, several times a day	Orally administered once per day
Effective dose	Not applicable	For many patients 60 mg/day is lowest effective dose; doses between 80 and 120 mgs/day are most effective for preventing HIV transmission, retention in treatment, reducing the use of other drugs and increasing social productivity
Overall safety	Potentially lethal	Medically safe, no toxic effects found in patients maintained on methadone for up to 18 years
Overdose	Can die from overdose of narcotics; potentially lethal, even for tolerant individuals death can occur quite fast without proper medical treatment with narcan	A degree of protection from death by overdose is achieved when receiving 100 mg/day or more; methadone is potentially lethal for non tolerant individuals, death can occur but more slowly than heroin overdose however, overdose reaction can be reversed and person's life saved if narcotic antagonist such as narcan is prescribed for 24-36 hours
Narcotic effects of other opiates	Feels narcotic effects of opiates	At 80 mgs/day or more narcotic effects of opiates are blocked (if tried)
Withdrawal syndrome	Can be severe, but can be controlled with methadone	Less severe than heroin but more extended, can be controlled by slow reduction in methadone dose
Mood alteration	Constant swings	None, if patient is not emotionally disturbed or using other drugs
Euphoric effects	Approximately 2 hours duration after administration	None after administration
Tolerance level	Increasing dosage needed	Stable level at same dose
Narcotic craving	Recurring	Relieved and blocked
HIV transmission	Effective transmission	Transmission of HIV by injection reduced or eliminated for patients who remain in treatment
Immune and endocrine functioning in HIV- persons	Impaired	Normalizes during treatment
Immune system HIV+ persons	Rapid progression to AIDS	Preliminary studies indicate that progression to AIDS is slower
Hypothalamus Pituitary Adrenal Axis	Suppressed	Normalizes during treatment
Libido/Sexual functioning	Impaired	Normalizes during treatment
Female menses	Impaired	Normalizes during treatment
Pregnancy	Serious problems difficult to treat	Problems can be brought under control with medical, social and prenatal care
Fetal environment	Stressful for fetal development	Not stressful, helps create stable environment for normal development of the fetus
Emotional affect	Impaired	Normal, if patient is not emotionally disturbed or using other drugs
Pain and emotion	Blunted	Feels normal pain and experiences normal range of emotions if not using other drugs
Intellectual functioning	Impaired	Normal if person is not emotionally disturbed or using other drugs
Physical reaction time	Impaired	Normalizes during treatment
Personal relationships	Disrupted	Restored with counseling
Social functioning	Impaired	Normalizes with counseling
Vocational rehabilitation and education	High proportion of failure	High proportion of success in vocational rehabilitation, education and employability
Employment	Difficult if not impossible to hold a job	Can function in every level and type of profession e.g., bus driver, lawyer, doctor, teacher or pilot
Mental illness	Difficult to treat	Treatable if integrated resources exist, however many psychiatric services discriminate against methadone patients and will not accept them
Poly drug abuse	High level (alcohol, crack, cocaine, nicotine)	High level but potentially treatable
Criminal activity	Constant high level	Reduced level or eliminated
Effect on community	Destructive, high crime and death rates, transmission of disease	A good methadone program contributes to public safety, reduces crime, reduces mortality and improves quality of life for all
Criteria for addiction	Fits criteria for addiction as listed in the "Diagnostic and Statistical Manual of Mental Disorders"	Does not fit criteria for addiction, methadone maintenance is a thoroughly researched and effective medical treatment
Life-style	Heroin addiction is about acquired infection and death	Methadone maintenance treatment is about good health and life (Methadone chemotherapy normalizes a deranged physiology so patients can stabilize their lives.)

Defining An Addiction

The formal diagnosis of "psychoactive substance dependence" is now made if at least three of the following statements are true.

• The substance is taken in larger amounts or over a longer period than the person intended.

• There is a persistent desire or unsuccessful efforts to stop.

• The person spends a great deal of time trying to get the substance (e.g., robberies to raise the money), taking it or recovering from its effects.

• Using the substance disrupts important social obligations or work activities.

• The person continues to use the substance despite knowing that it is causing problems (e.g., drinking even though it makes an ulcer worse).

• There is a marked tolerance: the person needs increased amounts of the substance to become intoxicated or has a marked reduction of the desired effect if using the same amount.

• There are withdrawal symptoms.

• The substance is taken to avoid the withdrawal symptoms.

Source: Diagnostic and Statistical Manual of Mental Disorders III, 1980.

II. Methadone Maintenance Treatment

Methadone Maintenance Treatment and Clinical Issues
by
Herman Joseph

The History of Methadone Maintenance

Methadone maintenance treatment has been thoroughly researched and carefully evaluated for almost three decades. It has received more scientific scrutiny and evaluation than any other medical treatment or human service program (Ball & Ross, 1991; Brecher, 1972; Des Jarlais, Joseph, Dole & Schmeidler, 1983; Dole & Joseph, 1978; Dole & Nyswander, 1976; Dole & Nyswander, 1965; Dole, Nyswander & Warner, 1968; FDA, 1989; Gearing, 1970; Gearing & Schweitzer, 1974; GAO, 1990; Gordon, 1970; Hartel, Selwyn, Schoenbaum et al, 1988; Joseph & Dole, 1970; McLellan, Arndt, Metzger, Woody & O'Brien, 1993; Newman & Cates, 1977; Parrino, 1992; Simpson, 1981; Stimmel, Goldberg, Cohen & Rotkopfe, 1978). Most evaluations have shown that, when correctly implemented, the treatment is capable of producing remarkable improvements in patients who were previously dysfunctional heroin addicts. Methadone maintenance patients throughout the world have been restored to productive lives, relations with families and children have been reestablished, many have furthered their educations, obtained employment and improved their physical and mental health. Nevertheless, contrary to scientific evidence, methadone maintenance treatment remains a controversial issue among substance abuse treatment providers, public officials and policy makers, the public at large and the medical profession itself.

Methadone was synthesized in Germany during World War II as a substitute for morphine when supplies of opium from Turkey were cut off by the United States and their allies. The drug was brought to this country after the war and studied in 1946 at the United States Public Health Hospital in Lexington, Kentucky. It was found to be similar in its effects to morphine but possibly longer acting. Clinical research showed that the drug could be used effectively in the treatment of the opiate abstinence syndrome by substituting it for morphine and slowly tapering down the dose over a period of about one week to ten days (Brecher, 1972). Until the development of methadone as a maintenance medication in 1964, the primary use of methadone in the treatment of addiction was to withdraw addicts from heroin, a procedure that differs from maintenance and exploits only a few of the potentially useful properties of the medication.

By the late 1960s in New York City, heroin related mortality was the leading cause of death for young adults between the ages of 15 and 35 (Joseph & Dole, 1970). Serum hepatitis cases related to injection of narcotics with contaminated needles were increasing. A record number of addicts were being arrested for drug-related crimes, including possession, sales, robbery and burglary, and overcrowded jail facilities with no medical care to ease withdrawal were creating havoc (Brecher, 1972; Inciardi, 1988; Joseph, 1992; Joseph & Dole, 1970). By 1968, the Manhattan County Jail for Men (known as the Tombs) was racked by riots because of the severe overcrowding and lack of medical care for arrested addicts. With the medical and legal professions calling for a reevaluation of American narcotic policies in respect to treating addicts, the climate was more favorable to challenge the Bureau of Narcotics' anti-maintenance position.

In 1962, Dr. Vincent P. Dole, a specialist in metabolism at the Rockefeller University was appointed to look into the situation by Dr. Lewis Thomas, chair of the Narcotics Committee of the Health Research Council of New York City. After studying the scientific, public health and social ramifications of the addiction problem in the city, Dr. Dole received a grant from the Health Research Council to establish a research unit at the Rockefeller University to investigate the feasibility of opiate maintenance.

In preparing for his research he read the book, The Drug Addict As A Patient by Dr. Marie E. Nyswander (1956), a psychiatrist who had extensive experience treating addicts. She had served as a physician at the U.S. Public Health Service Hospital in Lexington, Kentucky, treated addicts in private psychiatric practice, established a store front for treating addicts in East Harlem and was the psychiatrist for the Musicians Clinic, a program which treated addicted musicians (Hentoff, 1969). Dr. Nyswander believed addicts could be treated within the medical profession rather than through incarceration in the criminal justice system. However, she believed that many would have to be maintained on narcotics in order to function, since the majority relapsed despite many hospitalizations, withdrawal and therapy (Brecher, 1972; Courtwright, Joseph & Des Jarlais, 1989). Dr. Nyswander joined Dr. Dole's research staff in 1964. At the same time, a young clinical investigator, Dr. Mary Jeanne Kreek, completing her training in internal medicine and neuroendocrinology at the New York Hospital-Cornell Medical Center, was also recruited to join the research team.

Maintenance with low doses of morphine was administered to the first two patients who had used narcotics for at least eight years and had extensive criminal histories related to their addictions (Brecher, 1972; Dole & Nyswander, 1967). Both had previously attempted therapy and had withdrawn from heroin several times, only to relapse. Since morphine has a half life of four to six hours, the patients required injections at least four times per day. As tolerance developed to the morphine, they required increasing amounts administered at more frequent intervals to remain comfortable. And they remained preoccupied with drugs, apathetic and sedated from the narcotizing effects of the morphine.

The researchers knew that morphine's effects are similar to heroin. It was not a good choice as a maintenance drug. While criminal behavior might be reduced because the drug would be obtained legally, the patient would remain dysfunctional. Impairment would result from morphine's narcotizing qualities and the short half life of the drug requiring several injections per day. With the development of tolerance increasing amounts would be needed to remain comfortable over a short period of time. Similar results were obtained for other short-acting narcotics such as hydromorphone, codeine, oxycodone and meriperidine (Dole, 1988; Dole, 1980; Dole, Nyswander & Kreek, 1966). A distinct disadvantage of most of the short-acting narcotics was that to be maximally effective they had to be injected.

With the failure of short-acting narcotics to properly maintain patients, the research revolved around the choice of a possible maintenance medication that was orally administered and long acting. Methadone appeared to have these qualities and was selected based on the observations of addicts being withdrawn from heroin and research into its use as an analgesic in the experimental treatment of pain (Dole, 1988; Joseph & Dole, 1970; Kreek, 1973). In 1964, the technology was not yet available to measure the blood levels of heroin, morphine and methadone. The results concerning the outcome of methadone as a maintenance medication depended on the observations and insights of the researchers.

The Eight Important Findings That Distinguish
Methadone as a Preferred Maintenance Drug

Once methadone was established as a proper maintenance medication at doses of 80 to 120 mg/day, eight important findings were noted. These findings would constitute the basis of a maintenance program capable of permitting otherwise intractable addicts to function normally within society (Dole, 1988; Dole, 1980; Dole & Nyswander, 1965; Dole, Nyswander & Kreek, 1966; Gordon, 1970; Joseph & Dole, 1970; Kreek, 1978; Kreek, 1973; Newman & Cates, 1977).

1. The narcotic craving described by addicts as a major factor in relapse and the continued illegal use of heroin was relieved. This is perhaps the most important property of methadone, thus allowing addicts to live a stable life.
   
   

2. Tolerance to the narcotic effects of all opiate class drugs is blocked. At doses beginning at 80 mgs/day tolerance is held at a high enough level to block the euphoric and tranquilizing effects of all opiate class drugs. Should the patient administer any opiate, including methadone, either orally, through injection or by smoking the effect will be blocked. Also, beginning at 80- mg/day the patient is protected from overdose and respiratory depression if large amounts of narcotics should be administered. This protection is strengthened at higher doses of 100 mg/day or more.
   
   

3. Stabilized patients do not experience any euphoric, tranquilizing or analgesic effects. Their affect is clear and enables them to socialize and work normally without the incapacitating properties of short-acting narcotics such as morphine or heroin.
   
   

4. There is no change in tolerance levels. Therefore, the same dose of methadone can be prescribed to a patient for an indefinite period of time (e.g. 20 years). This effect contrasts with other opiates such as morphine and heroin whose dose must be increased.
   
   

5. Methadone can be taken orally by patients once per day. This eliminates the use of needles for injection and immediately reduces the risk of HIV infection and other serious conditions caused by using unsterile needles.
   
   

6. Studies undertaken over the past two decades, primarily by Dr. Mary Jeanne Kreek of The Rockefeller University, and corroborated by other scientists throughout the world have established the long-term medical safety of methadone maintenance treatment (Kreek, 1992; Kreek, 1987; Kreek, 1986; Kreek, 1978; Kreek, 1973; Kreek et al, 1972; Novick, Richman, Friedman et al, 1993). There are no toxic effects, somatic damage or functional deficits associated with or attributable to methadone for patients who are stabilized at appropriate doses including those receiving over 100 mgs/day, who are not heavily abusing other drugs (e.g., alcohol and cocaine), and who have remained in continuous treatment for up to 18 years. There are minimal nontoxic side effects, such as constipation, that can be treated; excessive sweating that in most cases subsides over time; and decreased libido and, in some males, delayed orgasm that normalizes within the first few months of treatment or with dose adjustment (Kreek, 1978; Kreek, 1973). Methadone is safe for persons who have been properly stabilized, since methadone can be lethal for nontolerant persons who will require emergency treatment with narcan for about 24 to 36 hours if they should accidently ingest a dose prescribed for a tolerant patient.
   
   

7. Motor coordination, reaction time and intelligence tests to determine if patients can function normally have been administered to patients maintained on high doses of methadone (over 80 mg/day). No significant differences have been found between maintained patients and the non-maintained controls. On some tests the patients even exceeded the performance of the controls. Patients' intelligence scores also improve over time. The conclusion was that patients are able to function within normal parameters when prescribed the high doses of methadone necessary for maintenance (Gordon, 1970).
   
   

8. It should be understood that tolerance to the analgesic effects of methadone are quickly achieved and methadone patients can be treated for severe acute and chronic pain by administration of morphine, as would any other patient (Dole, Nyswander & Kreek, 1966). Morphine, or any other short-acting narcotic, can be given at regular or more frequent time intervals and at higher levels in accordance with the patient's tolerance. Mixed agonist/antagonist drugs such as Talwin, Nubain and Stadol should never be administered to a methadone patient. Methadone will block the euphoric and tranquilizing effects of short-acting narcotics however, the analgesic or pain killing properties of short-acting narcotics will be able to penetrate the blockade phenomenon and the patient will receive the necessary pain relief (Payte, Khuri, Joseph & Woods, 1994).

In conclusion, methadone when prescribed as a maintenance medication functions as a normalizer for a deranged physiology and not as a mood altering narcotic substitute (Dole, Nyswander & Kreek, 1966; Joseph & Dole, 1970). Also, methadone maintenance is a corrective but not a curative regimen.

Admissions Protocols

Initially the criteria for admission to methadone conformed to the needs of a strict research protocol (Brecher, 1972; Gearing & Schweitzer, 1974; Joseph & Dole, 1970). Only addicts between the ages of 21 and 40 were admitted. The upper age limit was based on the theory that addicts begin to mature out of addiction over the age of 40. The applicants had to be addicted to heroin for at least four years and have relapsed after previous attempts at withdrawal from heroin and treatment. Addicts who were polysubstance users, including alcoholics and those afflicted with major psychiatric and medical problems such as tuberculosis, were not considered eligible. Initially women of child bearing age and pregnant addicts were not permitted because the effects of methadone on the reproductive system and developing fetus were not known and the researchers were investigating a new medical procedure (Joseph & Dole, 1970). As methadone treatment proved to be successful and medically safe, the admission criteria were gradually modified.

Today, the regulations of the Food and Drug Administration (FDA) allow heroin addicts to be admitted with a one year addiction history including current use (FDA, 1993). The lower age limit has been reduced to 16, however applicants between the ages of 16 and 18 must have two prior episodes of either withdrawal from heroin or drug free treatment and parental consent or be declared emancipated before being admitted. The upper age limit has been eliminated since it is now known that while a group of addicts do mature out the majority do not. It has subsequently been learned that untreated addicts have high death rates at young ages, may be incarcerated or become seriously alcoholic (Dole & Joseph, 1978; Joseph & Appel, 1985). Women of child bearing age and pregnant women are now accepted and, with special medical justification, a pregnant woman can be admitted with an addiction history of slightly less than one year. Applicants with major medical conditions and polysubstance abuse problems including alcoholism are now eligible for treatment (FDA, 1993).

Methadone Maintenance Expands:
The Gearing Study and Subsequent Evaluations

In 1965, under the guidance of Dr. Ray Trussell, the New York City Commissioner of Hospitals, the initial research project was expanded and transferred to the Manhattan General Hospital in New York City where a heroin withdrawal program had previously been established. An impartial unit to evaluate the expansion and progress of methadone treatment was created at the Columbia University School of Public Health and Administrative Medicine with Dr. Frances Rowe Gearing as the chief of evaluation. The unit's work was reviewed by an independent committee composed of physicians and scientists with Dr. Henry Brill as its chairman. The committee made recommendations for further evaluation, research and expansion of the program (Joseph & Appel, 1992; Joseph & Dole, 1970). Thus, methadone maintenance received rigorous scrutiny and evaluations with follow-up studies that continue to this day.

No matter what country, ethnicity, sex, education or economic background of the patients, studies evaluating methadone have been consistent. The following summarizes the findings from major studies conducted over the past approximate three decades.

1. When placed on an adequate dose of methadone (e.g., 80 to 120 mgs/day), heroin use by patients is significantly reduced within the first two months of treatment and eventually either eliminated or significantly curtailed with time in treatment (Ball & Ross, 1991; Cooper, 1992; Dole & Nyswander, 1965; Dole, Nyswander & Kreek, 1966; GAO, 1990; Schuster, 1989).
   
   

2. Crime related to drug use is reduced significantly within the first year of treatment and the reductions continue with time in treatment. These trends persist irrespective of cities, culture or era. A study of 1,870 methadone patients admitted to treatment in New York City in the 1960s showed that arrest rates decreased 95 percent when compared to arrest rates three years prior to entering and three years after entering treatment (120 vs 5.5 arrests per 100 man years) (Gearing, 1970; Gearing & Schweitzer, 1974). The city of Hong Kong introduced methadone treatment for its addicts in 1976 and subsequently there was an 85 percent reduction in the number of heroin addicts admitted to prisons in the city from 1976 to 1980 (Newman & Cates, 1977). In 1985, a study of methadone programs in Baltimore, Philadelphia and New York City found a 79 percent decrease in the number crimes committed by patients during their first six months of treatment as compared to their last episode of addiction (Ball & Ross, 1991). Criminal behavior declined the longer patients were in treatment.
   
   

3. Productive behavior as measured by employment, school attendance or homemaker status increases with time in treatment. When the program was first implemented in 1964, the patients were able to obtain jobs in manufacturing, trades and construction. Within the first year of treatment, about 60 percent were socially productive (Dole & Joseph, 1978). These trends continued into the 1970s. However, with the change in the employment market from manufacturing to service jobs, the lower levels of education among new admissions, the periodic economic downturns, increased homelessness, cocaine/crack use and HIV infection among the patients, productivity and employment levels for patients declined from a high of about 60 percent in the late 1970s to about 28 percent in 1994 (Gearing & Schweitzer, 1994; Joseph, 1992; Kreek, 1992; Randall, 1994).
   
   

4. Poly drug abuse and alcoholism affect a significant minority of the patients. Generally speaking, those patients that are dually addicted when entering methadone treatment continue poly drug abuse and alcoholism, unless they are treated for these conditions. Prior to the AIDS epidemic, the physical effects of alcoholism were the major causes of death for patients in treatment and the second major cause of death after heroin overdose in the posttreatment period (Joseph & Appel, 1985). However, with the high prevalence of HIV infection among methadone patients in treatment HIV infection has become the major cause of death (Joseph & Springer, 1990)
   
   

5. Studies by Ball and Ross (1991) and McClellan and colleagues (1993) demonstrate the need for psychosocial services in methadone programs to ensure their maximum potential in helping patients. In the 1980s and currently in the 1990s, new admissions present serious social, psychological and medical problems to clinics. Among the problems are homelessness, cocaine/crack addiction, alcoholism, HIV infection, drug resistant TB, mental illness, chronic unemployment, poor education and a host of social problems (Joseph, 1992; Joseph & Appel, 1992).
   
   

6. In an important study, McLellan and colleagues (1993) have shown that while methadone alone is effective for some patients, the addition of services results in better treatment outcomes for a greater number of patients. All patients in the study were maintained at 60 mgs/day or more of methadone and dose was increased as needed if use of opiates persisted. Patients were assigned to one of three service components: (1) Minimal care included an adequate dose of methadone but no other services. (2) Standard care included an adequate dose of methadone plus counselling. (3) Enhanced services included an adequate dose of methadone plus counseling, on-site medical/psychiatric/employment services and family therapy.
   
   The study found that patients involved in enhanced program services showed significant improvements in social adjustment and employment status, with significant decreases in alcohol and cocaine use and illegal activity. McLellan also reported that when dysfunctional patients receiving minimal care were given standard care, the improvements in reduction of illicit opiate and cocaine use were significant and occurred rapidly within a period of four weeks. Patients receiving enhanced care in the McLellan study made significantly greater improvements than those receiving standard or minimal care.
   
   

7. A study of socially productive methadone patients (employed, in school or homemakers) by Joseph and Des Jarlais (1980) shows that patients are able to hold positions across the spectrum of the job market. To qualify for an interview in this study, patients had to be in treatment for at least four years, not involved with illicit drugs or criminality for at least three years, and be employed outside the field of drug treatment, drug-related research or drug-related social services. Furthermore, they had to have addiction histories of four or more years.
   
   It was found that among the 47 who met these criteria and volunteered for taped interviews at three programs the daily methadone doses ranged from 5 to 100 mg/day with patients at the low dose level withdrawing from the program. About 54 percent of the patients interviewed were receiving between 60 and 100 mg/day. There were no particular relationships between dosage and salary levels. The patients were primarily employed in jobs and professions in private industry. Some examples of jobs at different dose levels included an attorney who was withdrawing (5 mgs/day), an architect (30 mgs/day), a rock musician (30 mgs/day), two truck drivers (40 and 100 mgs/day), an auto mechanic (40 mgs/day), a window cleaner on skyscrapers (60 mgs/day), a producer of documentary films (70 mgs/day), two housewives (20 mgs/day and 90 mgs/day), a computer technology worker (90 mgs/day), a chef in a gourmet restaurant (100 mgs/day) and a road construction laborer (100 mgs/day).
   
   At the time of the interviews 72 percent of the patients had one continuous episode of treatment, 21 percent were in their second episode of treatment and 6 percent in their third episode of treatment. Patients with two or more episodes of treatment relapsed to use of heroin during their posttreatment periods in spite of their good adjustments, including gainful employment, and had to re enter treatment.
   
   All of the patients were acutely aware of the stigmatization of being maintained on methadone. For over half of this group, no one at work knew about their addiction history or enrollment in methadone treatment. In cases where somebody did know, it was usually an immediate supervisor, personnel administrator or a trusted colleague. This pattern of concealment was carried over into their family and social lives. Old friends who were aware of the patient's prior addiction history may or may not have known about their current treatment. Patients, however, rarely told new friends about their prior addiction or methadone treatment. The patients also concealed their enrollment in methadone treatment from members of their own immediate families. Parents, siblings and children may not have been told about methadone and were under the impression that the patients were cured and had "kicked their habits." The exceptions were spouses who were aware of the patients' histories and enrollment in treatment.
   
   Only 13 percent socialized with other methadone patients. The great majority socialized with family and "straight people. Since the patients did not use other drugs and took their methadone as directed, concealment of their methadone status was made easier by the absence of narcotic effects, the ability to work and interact socially without impairment.

The work of Drs. Dole and Nyswander has had a great impact on the treatment of heroin addicts in the United States today. First, they brought the treatment and care of addicts into the medical profession, albeit a controlled isolated and highly regulated clinical system. Nevertheless, this was an incredible accomplishment in itself, considering the lack of understanding of opiate addiction as a metabolic condition at that time and the 50 year history of treating heroin addiction as a criminal justice problem. However, it must be emphasized that methadone maintenance did not expand because society wanted to provide treatment for heroin addicts. To the contrary, the main concern was reducing the number of crimes committed by addicts. That included the curtailment of the spread of addiction-related infections, such as HIV and hepatitis.

Their second accomplishment was the launching of the first and most effective harm reduction program. Harm reduction takes a public health approach toward the problem of drug use with pragmatic strategies to reduce the harm that drugs do to the individual and society. The emphasis on drug enforcement and punishment as the primary strategies to control drug use is replaced with education, prevention and treatment. Today the methadone maintenance program has been expanded and is the major public health program for the treatment of heroin addition in the United States. From 1964 through 1994 there have been over approximately 2,000,000 patient-years on methadone maintenance treatment in the United States. Presently, there are about 115,000 persons known to be enrolled in approximately 850 methadone maintenance treatment programs in 40 states. Also, methadone maintenance programs are expanding throughout the world to prevent the transmission of HIV.

A Review of Methadone Treatment:
Outcome and Follow-up Studies

The major findings of follow-up studies of discharged methadone patients in the United States and Europe have found that a large majority are unable to maintain abstinence and eventually relapse to daily heroin use. Despite the fact that many of these studies were conducted prior to the homelessness, AIDS and crack/cocaine epidemics, they are remarkably consistent across ethnic, racial and cultural differences. These studies are important since they show that the majority of discharged patients were unable to make sustained good post-treatment adjustments in a less threatening era. The studies include those by Ball and Ross, 1991; Cushman, 1980; Des Jarlais, Joseph, Dole and Schmeidler, 1983; Dole and Joseph, 1978; Dole and Nyswander, 1976; Gearing & Schweitzer, 1974; Gunne, Gronbladh and Ohlund, 1993; Joseph and Dole, 1970; Simpson, 1981; Stimmel, Goldberg and Cohen et al, 1978.

The overwhelming evidence is that the majority of patients who leave methadone maintenance, irrespective of their type of discharge (favorable vs. unfavorable) and their individual prospects for successful abstinence, eventually relapse to daily use of narcotics. Today, persons who are HIV- and leave methadone treatment are at high risk of contracting HIV after leaving treatment because of the high rate of relapse to drug use.

1. Death rates for patients who leave treatment are more than twice the rate of patients who remain in treatment. Excessive posttreatment deaths are usually associated with factors involving the injection of heroin (e.g., overdose and transmission of infectious diseases) and violence. Death rates are excessive irrespective of the type of discharge, but former patients with favorable terminations have lower death rates than those discharged for other reasons. Within the past six years AIDS has become the major cause of death in many methadone programs. In some areas it is estimated that about 50 percent of new admissions to methadone maintenance treatment are infected with HIV.
   
   

2. In most studies about 80 percent of the former patients relapse to use of heroin and/or other narcotics within approximately two years after leaving treatment. Excessive, life threatening use of alcohol and other drugs (e.g., cocaine) effects a substantial number of former patients who may not relapse to heroin. In one study, only eight percent of the former patients were abstinent from daily use of narcotics, non-opiate drugs and life threatening alcoholism after one episode of methadone treatment.
   
   

3. Gender, ethnicity and level of education did not predict posttreatment daily narcotic use. While these factors may influence decisions to enter treatment, they appear to have little or no influence in preventing relapse to daily heroin use after leaving treatment.
   
   

4. Years of heroin use, time in treatment, abuse of drugs while in treatment, employment status and type of discharge were the factors that contributed most to predicting posttreatment heroin use. Patients who were able to remain abstinent after leaving usually used heroin for shorter periods prior to entering treatment than those who relapsed. They also remained in treatment longer, did not abuse other drugs, were fully employed and received a favorable termination from treatment.
   
   

5. Although social rehabilitation is important for a positive posttreatment adjustment, the duration of a heroin addiction may also be a crucial factor for patients to remain abstinent after terminating treatment. Patients in good standing with longer histories of heroin addiction have higher probabilities for relapse than patients in good standing with shorter periods of addiction. Also, longer durations of methadone treatment contribute to posttreatment abstention, implying that pharmacological and biological factors may also influence post treatment outcomes. These include the type of narcotic (heroin-short acting vs. methadone-long acting), the route of administration (oral vs. injection), and the circumstances under which a narcotic is administered. Even under the most optimistic conditions, patients in good standing still have a high probability of posttreatment relapse. Therefore, there should be no moral judgement on the part of treatment staff, family, friends or employers if patients in good standing relapse after leaving treatment. Patients who relapse after leaving treatment should be allowed to reenter the program without feeling guilty or a failure.
   
   

6. In the Des Jarlais, Joseph, Dole and Schmeidler (1983) study, using the various factors to predict post treatment abstention, it was found that about 70 percent of those who met optimal conditions for discharge, relapsed to daily use of heroin in comparison to the 90 percent who relapsed when conditions were less than optimal.

These studies emphasize the importance of retaining patients in methadone treatment. Even patients whose individual prospects for successful abstinence are optimal are likely to eventually relapse to daily use of heroin. Factors that contribute somewhat to successful outcomes after discharge from treatment are favorable discharge, stable life style and a shorter period of illicit heroin use. Programs which encourage patients to withdraw from methadone are not setting policies based on scientific evidence, nor are they serving their community.

Patients who do decide to withdraw from methadone and leave treatment should be given the facts regarding their prospects for abstinence and encouraged to return to treatment should they relapse to heroin use. Patients who do return to treatment because they have relapsed should never be made to feel guilty and every effort should be made to help them understand that this is the nature of their disease and that their decision to return to treatment was positive.

Achieving An Effective/Adequate Methadone Dose

Numerous studies have indicated that the most effective range for methadone maintenance is between 80 to 120 mg/day at the beginning of treatment (Ball & Ross, 1991; Ball, Lange, Myers & Friedman, 1988; Cooper, 1992; Dole, Nyswander & Kreek, 1966; GAO, 1990; Hartel, Selwyn, Schoenbaum et al, 1988; Kreek, 1992; Kreek, 1986; Payte & Khuri, 1992; Schuster, 1989). Methadone dose should be determined, like the prescribing of any other medication, through consultation between physician and patient. During the later stages of treatment the dosage may be either lowered or raised depending on the requirements of the patient.

The original research upon which methadone maintenance is predicated was based upon a dose range of about 80 mg to 120 mgs/day (Dole, Nyswander & Kreek, 1966). For a dose of methadone to be effective three types of phenomena must be met:

1. Relief of drug craving that begins at about 60 mgs per day for most patients (Dole, Nyswander & Kreek, 1966; Kreek, 1988; Kreek, 1986).
   
   

2. A high enough tolerance level must be reached to block the narcotic effects of all opiate drugs, including methadone itself if it should be administered. This blockade effect begins at about 70 to 80 mgs/day and the effect is strengthened at the higher doses (100 to 120 mgs/day) (Dole, Nyswander & Kreek, 1966; Kreek, 1988; Kreek, 1986).
   
   

3. The patient must be able to function normally without the impairing effects of narcotics namely, euphoria, tranquilization and analgesia. The patient must be able to maintain physical coordination and dexterity (Dole, Nyswander & Kreek, 1966; Kreek, 1988; Kreek, 1986).

At high doses (e.g. 100 mg/day), patients have a degree of protection from heroin overdose. At this level they are less likely to succumb to respiratory depression if they should administer illicit narcotics to challenge the blockade (Dole, Nyswander & Kreek, 1966). This is especially important at the beginning of treatment, when patients may experiment with heroin to test the effectiveness of the medication (Hartel, Selwyn, Schoenbaum et al, 1988). For the patient entering treatment methadone dose is the most critical element to ensure the patient's later adjustment.

The Importance of Achieving An Effective Methadone Dose

All clinical surveys implemented in the United States and world wide validate the importance of prescribing an adequate and effective dose (80 to 120 mg/day) of methadone (Ball, Lange, Myers & Friedman, 1988; Ball & Ross, 1991; Blix & Grondbladh, 1988; Caplehorn & Bell, 1991; Cooper, 1992; D'Aunno & Vaughn, 1992; Dole & Joseph, 1978; GAO, 1990; Kreek, 1992; Payte & Khuri, 1992; Schuster, 1989). The following studies confirm the clinical findings of the original study by Drs. Dole, Nyswander and Kreek (1966) and reported in the article "Narcotic Blockade."

1. In a review of the literature, Hargreaves (1983) indicated that patients appear to do better on the higher doses within the range of 50 to 100 mg/day. This is especially true at the beginning of treatment when patients need full pharmacological support. The review recommended that NIDA encourage state agencies to allow local programs to prescribe methadone up to a dose level of at least 100 mg/day.
   
   

2. Watters and Price (1985) reviewed 44 methadone maintenance programs and determined that dose was the single most important factor related to retention in treatment. The higher the dose, the longer patients remained in treatment.
   
   

3. Hartel and colleagues (1988) undertook what is probably the largest and most sensitively designed study at Montefiore Hospital in the Bronx. Hartel, an epidemiologist, examined the records of approximately 2,400 methadone patients over a 15-year period. She identified a trend line that started at about 70 mgs/day and began to achieve real clinical significance at 80 mgs/day. With the higher doses, from 80 to about 100 mg/day, patients had better retention in treatment, less HIV infection and less polysubstance use, including cocaine and crack.
   
   

4. A comprehensive study by Ball and Ross (1991) of six programs located in Baltimore, New York City and Philadelphia demonstrated that patients reduced their use of IV heroin by 71 percent compared with their pre-admission drug use. The study followed the IV heroin use of 407 patients over a period of one month and found that the higher the methadone dose, the less the frequency of heroin use. About 27.9 percent of the 204 patients receiving 45 mg/day or less used heroin, compared to only 5.4 percent of the 203 patients maintained on doses greater than 45 mg/day. And, for those patients maintained on doses of 75 mg/day or greater, no evidence of heroin use was found.
   
   

5. In Australia, Caplehorn and Bell (1991) showed that retention in treatment increased by a factor of about two across each of three stratified levels of dose: <60 mg/day, 60-79 mg/day, and 80+ mg/day. Patients stabilized at a blockade level of 80+ mg/day or greater have longer periods of treatment than patients maintained on lower doses. Variables usually associated with good treatment outcomes, such as employment, educational level and degree of criminality, appeared to have less of an impact on retention than the patient's dose of methadone.
   
   

6. In a nationwide study of 172 randomly selected methadone maintenance treatment programs, 72 percent responded representing approximately 20 percent of the programs in operation. D'Aunno and Vaughn (1992) found that about half of the programs encouraged patients to withdraw from methadone within six months after admission to treatment. Sixty-eight percent of the programs set an upper limit for methadone doses at 50 mg/day.
   
   In addiction to the above findings, D'Aunno and Vaughn (1992) determined that patients maintained on the higher doses remained in treatment longer. Positive treatment outcomes were more likely in programs with flexible take-home privileges and in programs that included patients in decisions related to dosage. They recommended monitoring and, in certain cases, changing the treatment practices of programs prescribing inadequate doses with minimal patient participation in decision making. Programs treating high percentages of African-American patients, younger populations and the unemployed appeared to have set lower dose limits for patients and on the average administered lower doses of methadone. Many of these programs may have encouraged patients to withdraw from methadone and leave treatment prematurely, and had less patient participation in decision making.
   
   

7. The United States General Accounting Office (GAO) reviewed 24 methadone programs in eight states and concluded that "60 milligrams of methadone is the lowest effective dose to stop heroin use and low dose maintenance (20 to 40 mg) is inappropriate" (GAO, 1990). The GAO report indicated that in an effective program no more than 20 percent of the patients should have positive urine screenings for heroin at any given time.
   
   

8. Results of a recent reader survey undertaken by the Addiction Treatment Forum (1993) reported a mean dose of 56.58 mg/day and a median dose of 60 mg/day for the 203 programs that responded. While this dose is above the average dose reported by D'Annuno and Vaughn (45 mg/day), about 50 percent of the patients included in this survey are below the optimum dose range of 80 to 100 mg/day as recommended by NIDA (Schuster, 1989), the GAO (1990) and the studies reviewed in this article.

Pharmacology of Methadone

After oral ingestion, methadone goes directly to the intestinal tract and about 98 percent of the drug is absorbed and bound mostly in the liver and the remainder is stored in nonspecific tissues throughout the body (Borg, Ho & Kreek, 1992; Dole, 1988; Kreek, 1988; Kreek, 1986). This bound methadone acts as a reservoir and is gradually released back into the blood stream. With an adequate daily dose, the blood level of methadone is steadily maintained and continuously buffered by the reserve in the tissues and liver over a 24- to 36-hour period.

The daily dose of methadone must be adequate and concentrated in the blood between 150 to 600 ng/ml, (1) which is equivalent in the average patient to about 80 to 100 mg/day. A smooth flat curve of circulating methadone is achieved with a peak level occurring between two and six hours after ingestion. Since the patient is tolerant to the narcotic effects of methadone, the peak level of concentration does not produce narcosis. The concentration of methadone in the blood is therefore stabilized by its reversible binding to nonspecific tissues and the liver (Dole, 1988; Kreek, 1988; Kreek, 1986). Most importantly, with an adequate, steady and stable concentration of methadone circulating in the blood, the m receptor sites within the brain and central nervous system are continuously occupied by methadone (Dole, 1988).

Because of differences in metabolism and body weight, methadone dose must be determined individually to maintain appropriate methadone blood levels throughout the 24-hour period. If a patient metabolizes methadone at a fast rate, the dose should be increased until a steady state is achieved. A few patients may need 100 to 120 mg/day or greater. On the other side of the spectrum, those patients with slow metabolic rates may be able to adjust on doses lower than 60 mg/day. Patients who do not receive an adequate dose of methadone will experience drug hunger and symptoms of the abstinence syndrome within a 24-hour period (Kreek, 1988; Kreek, 1986).

Determining Dosage Through Blood Levels

Physicians in Europe and the United States have been determining methadone dose by measuring plasma levels (Blix, 1990; Lorimer, Schmid, Grunberger, Jagsch, Linzmayer & Presslich, 1991; Tennant, 1987). Methadone plasma levels were measured at the peak hours after dosing, two, four and 24 hours, and by then raising the methadone dose until a stable plasma level is achieved throughout the 24-hour period. Methadone plasma levels should never be used to set an upper dosing limit and it is important that dose be determined individually through consultation with the patient who should feel comfortable and be able to function. The refinement of this technology in methadone treatment is important so that dose levels be given a scientific basis.

At present, 150 ng/ml is generally accepted as the lowest plasma level of methadone that will maintain the 24-hour steady-state effect (Borg, Ho & Kreek, 1992). The optimum dose is the level at which there is adequate methadone to provide constant availability to the opiate receptors. The optimum 24-hour mean plasma level may be more in the 400 ng/ml range. Loimer and colleagues (1991) suggest that "methadone plasma concentrations of 400 ng/ml are necessary to suppress any further opiate action and to provide stabilized maintenance. Therefore, to achieve relief of na