2
Pharmacology and Medical Aspects of Methadone Treatment

Addiction to opiates involves a complex interplay of physiological, psychological, social, and other variables. The primary purpose of methadone treatment is to intervene directly in the physiological processes that underlie addiction. Ideally, such treatment is supported by additional psychological and behavioral therapies. To understand why methadone treatment works, it is important to understand the physiological basis of heroin addiction.

This chapter provides an overview of the development of pharmacotherapeutic approaches to the treatment of opiate addiction and summarizes the key basic scientific investigations of the physiological underpinnings of opiate effects, including the discovery of the endogenous opioid system. In addition, the chapter describes the pharmacological and medical characteristics of methadone as a medication for the treatment of opiate addiction.

The Rationale for Pharmacotherapy

History and Practice

Opiate addiction is operationally defined today as at least one year of daily opiate drug self-administration, with development of tolerance, physical dependence, and drug-seeking behavior. The concepts of tolerance and dependence are thus fundamental to understanding the physiological aspects of opiate addiction. When a person repeatedly uses an opiate drug-like heroin, over time, that person becomes tolerant to heroin; that is, he or she requires greater and greater doses of heroin to achieve the same physiological and psychological effects. The same is true for the opiate drug morphine. Tolerance



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--> 2 Pharmacology and Medical Aspects of Methadone Treatment Addiction to opiates involves a complex interplay of physiological, psychological, social, and other variables. The primary purpose of methadone treatment is to intervene directly in the physiological processes that underlie addiction. Ideally, such treatment is supported by additional psychological and behavioral therapies. To understand why methadone treatment works, it is important to understand the physiological basis of heroin addiction. This chapter provides an overview of the development of pharmacotherapeutic approaches to the treatment of opiate addiction and summarizes the key basic scientific investigations of the physiological underpinnings of opiate effects, including the discovery of the endogenous opioid system. In addition, the chapter describes the pharmacological and medical characteristics of methadone as a medication for the treatment of opiate addiction. The Rationale for Pharmacotherapy History and Practice Opiate addiction is operationally defined today as at least one year of daily opiate drug self-administration, with development of tolerance, physical dependence, and drug-seeking behavior. The concepts of tolerance and dependence are thus fundamental to understanding the physiological aspects of opiate addiction. When a person repeatedly uses an opiate drug-like heroin, over time, that person becomes tolerant to heroin; that is, he or she requires greater and greater doses of heroin to achieve the same physiological and psychological effects. The same is true for the opiate drug morphine. Tolerance

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--> can be thought of as an adaptation of the functional (physiological) systems of the body to opiates. During chronic use of an opiate, physical dependence also develops when the physiological systems have adapted to the point that they actually require the opiate just to maintain physiological equilibrium. Virtually all physiological systems are affected in opiate addiction. A reproducible syndrome occurs when an opiate addict goes through withdrawal. This syndrome includes yawning, lacrimation, piloerection, perspiration, mydriasis, tremor, gooseflesh, restlessness, myalgia, anorexia, nausea, vomiting, abdominal cramps, diarrhea, fever, hyperpnea, and hypertension. When prolonged, the syndrome includes weight loss and, even after acute withdrawal, symptoms subside, persistent symptoms such as sleep disturbances, irritability, restlessness, and poor concentration which can be present for months or years. Both acute and chronic tolerance are physiological phenomena subserved by the central nervous system. However, both acute and chronic tolerance may also be influenced by environmental variables, such as setting, conditioning, and learning. The pharmacological approach to long-term treatment of heroin addiction, first undertaken in early 1964, was rooted in what was then a hypothesis that opiate addiction is a metabolic disease, caused by either intrinsic or drug-induced alterations in physiology. The original researchers in the field, Drs. Vincent Dole, the late Marie Nyswander and Mary Jeanne Kreek, hypothesized that in some or most cases of heroin addiction the addicted individuals had a intrinsic metabolic disorder, possibly with an underlying genetic predisposition, which expressed itself clinically after initial exposure to specific types of drugs or other chemical agents of abuse; and that in other cases, individuals who developed addiction were experiencing drug-induced metabolic disruptions in otherwise normal physiology. They speculated that in the latter cases, heroin-induced changes in specific neurobiological systems persist over long periods and possibly become permanent. The researchers observed that gradual removal of physical dependence upon morphine or heroin (detoxification) followed solely by psychiatric or other behavioral treatment frequently failed to help addicts sustain abstinence. Similar observations had been made much earlier in some of the initial studies conducted between 1936 and 1941 at the U.S. Public Health Service (USPHS) Hospital in Lexington, Kentucky, which showed that less than ten percent of "hard-core" addicts were able to stay free from opiates after discharge from long stays in drug-free treatment programs that only offered counseling and psychiatric care. Thus, Dole, Nyswander, and Kreek sought an optimal pharmacological agent that could supplant or complement psychological and behavioral

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--> treatment approaches. Their first study in 1964 was to repeat earlier studies that attempted unsuccessfully to use short-acting opiates, such as heroin and morphine, in a controlled fashion, in the management of opiate dependence. Morphine was again shown to be an unsuitable pharmacotherapeutic agent for several reasons: short duration of action, requiring four to six administrations per day; necessity for parenteral administration, because of lack of substantial bioavailability after oral administration; and the rapid development of increasing tolerance. Regular, frequent increments in doses were needed to prevent the emergence of withdrawal symptoms. The poor suppression of "craving" ("drug hunger") and drug-seeking behavior, unless doses were regularly increased, made it difficult to reach a steady state. In view of the anticipated limitations of morphine as a maintenance agent, a search was made for a medication that would block withdrawal symptoms of heroin addicts and that would be orally effective, long-acting, nonsedating, and devoid of adverse side effects. Methadone, a synthetic opiate compound originally synthesized in Germany for use as an analgesic in World War II, was selected for study in 1964. Methadone had been introduced between 1958 and 1962 at the USPHS hospital in Lexington, at the Bellevue Medical Center in New York City, and at a limited number of other sites for "detoxification" treatment of heroin addiction. In the early detoxification programs it was given in three or four small daily doses, usually 5 to 10 mg each, because the prolonged duration of action was not yet appreciated and no analytical techniques existed for objective measurements of pharmacokinetics. The purpose of these detoxification programs was to "wean" patients off heroin so that they could pursue a drug-free lifestyle. However, these efforts largely failed. Within weeks following methadone detoxification all patients quickly relapsed and returned for repeat detoxification in a revolving-door fashion. Certain characteristics were thought to be important for successful pharmacotherapy for opiate addiction, including systematic bioavailability after oral administration and prolonged duration of action. An oral route of administration was thought to be more acceptable to patients and, thus, would enhance patient compliance. Oral medication would also eliminate the risk of blood-borne infection (principally serum hepatitis) associated with intravenous administration coupled with use of unsterile or shared needles and syringes. Lastly, oral administration would disrupt the symbolic linkage to an illicit lifestyle and, practically, diminish the behavior of congregating to share needles and other drug paraphernalia. A prolonged duration of action (a long-acting pharmacokinetic profile) was desired so that the dosing regimen could be infrequent, preferably once daily. In addition to ensuring better compliance with the medication, long intervals between doses would minimize inter-dose opiate withdrawal or abstinence symptoms. It was hypothesized that such a long-acting pharmacokinetic profile

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--> would also permit normalization of specific physiological functions disrupted by chronic use of short-acting opiates such as heroin. It was further hypothesized, and later proven, that long-acting agents would be effective at a stable dose for a much longer period of time owing to slower development and sustained level of tolerance. In fact, subsequent studies have shown that once the daily dose of methadone has been stabilized, tolerance does not develop to the essential effects of methadone (prevention of opiate abstinence symptoms and prevention of drug hunger or craving) as used in maintenance treatment. Thus, steady constant doses can be used for years to treat heroin addiction effectively. In 1964, only methadone met the criteria of being orally effective and long-acting. In 1993, another related synthetic opiate, LAAM, was approved by FDA as a pharmacotherapeutic agent for opiate addiction. LAAM has an even slower onset of action than methadone and more prolonged duration of action.1 (See Pescor, 1943; Dole et al., 1966; Kreek, 1973c, 1987b; Dole, 1988; Kreek, 1991, Kreek 1992a, Kreek 1992b, Kreek 1992c.) Basic Science While clinicians treating heroin addicts were developing new pharmacotherapeutic approaches, important discoveries from basic science regarding opiate physiology began to emerge. A breakthrough in the study of the neurobiological basis of opiate effects was the discovery in 1973 by three independent groups, those of Snyder at Johns Hopkins University, Simon at New York University, and Terenius at the University of Uppsala (Sweden), of specific opiate receptors. These studies revolutionized the field of neuropharmacology and neurochemistry and were based, in part, on the earlier work of Dole and Goldstein. Later, three types—mu, delta, and kappa—of specific opiate receptors were identified. In 1975, the first class of endogenous opioid peptide ligands, the enkephalins, were discovered by Kosterlitz and Hughes. Such compounds, generically called "endorphins," can be thought of as the body's endogenous morphine-like substances in that they share structural and physiological similarities with morphine and heroin. Soon thereafter, attention focused on three separate classes of endogenous opioid ligands that bind to the specific opioid receptors. In animals, many of the well-known opiate effects have been reproduced by administering large amounts of these endogenous opioids. 1   This pharmacologic effect depends primarily on the metabolism of the parent LAAM compound to two active metabolites, noracetylmethadol and dinoracetyl-methadol. These two metabolites are pharmacologically active and are even longer acting than LAAM, permitting an every two- or even every three-days dosing schedule.

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--> Tolerance develops to some of these natural opioid peptide effects. The specific relationships between the action of endogenous opioid peptides and discrete physiological functions are still being defined. Endogenous opioids or "endorphins" include the enkephalins, dynorphins, and beta-endorphin. The three opioid peptide genes have been cloned, and each encodes a single large peptide, which is then processed to yield all of the opioid peptides within a class: proenkephalin, prodynorphin, and proopiomelanocortin, the latter of which contains both beta-endorphin and other important nonopioid peptide hormones including adrenocorticotropin hormone (ACTH). As mentioned above, there are at least three types of specific opiate receptors, mu, delta, and kappa, each of which may have several subtypes. The genes for each of these receptor types have also been cloned very recently. Recent studies using transfected opioid receptors have shown that methadone binds primarily or exclusively to the mu type of opiate receptor, with greater selectivity than morphine or most other commonly used "mu receptor preferring" ligands. Currently, studies are in progress to localize and characterize gene expression of the endogenous opioid system peptide and receptor genes, to assess the effects of drugs of abuse and treatment agents on gene expression, and to understand the complex molecular biological interactions of this system. Both basic and clinical studies have focused on the possible role of the endogenous opioid system in the biological basis of addiction. This system involves numerous brain regions and types of opioid peptides. Although the complex interactions of this system within the brain are not fully understood, data suggest that cycles of heroin addiction severely disrupt this system and that chronic, steady-state methadone maintenance attenuates this disruption. A "metabolic disease" concept has been suggested, in addition, which holds that some individuals may be predisposed to heroin addiction because variations in their genes result in abnormal levels of endogenous opioid peptides, levels that can be "corrected" by taking heroin (Goldstein, 1994). The effect of heroin addiction on the genetic regulation of the endogenous opioid system is currently an active area of research that is beginning to reveal intriguing clues about the biological underpinnings of addiction. Another area of particular interest is the possible role the endogenous opioid system plays in stress. It has been hypothesized that an atypical responsivity to stress, including the common stresses in our daily environment, may contribute to the acquisition of drug-seeking behavior, and both laboratory and basic clinical research studies have been conducted to define the stress responsive axis in humans with addictive diseases and in animal models. One of the most important modulators of stress responsivity is the hormones of the hypothalamic-pituitary-adrenal axis. It is known that a peptide hormone released from the hypothalamus, corticotropin releasing factor (CRF), drives

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--> the anterior pituitary in humans to release peptides from one important gene product, proopiomelanocortin (POMC), which yields both the long known peptide hormone ACTH and as one of the endorphins, beta-endorphin. ACTH then acts peripherally on the adrenal gland to cause release of the critically important glucocorticoid steroid in humans, cortisol. In addition to many peripheral actions, cortisol acts in a negative feedback control manner to control both CRF release from the hypothalamus and the release of POMC peptides, ACTH, and beta-endorphin, from the anterior pituitary in humans. Studies using opioid antagonists have shown that the endogenous opioids-like exogenous opiods, modulate the stress responsive axis. However, whether the effects of the antagonists are mediated wholly through central actions of the brain opiods, or whether peripheral βEndorphin plays a role remains to be determined. (See Dole, 1970; Ingoglia and Dole, 1970; Goldstein et al., 1971; Kreek, 1973a, Kreek, 1973c; Pert and Snyder, 1973; Simon et al., 1973; Terenius, 1973; Hughes et al., 1975; Kreek, 1978b; Kreek and Hartmen, 1982; Kreek, Schaefer, et al., 1983; Kreek, Wardlaw, et al., 1983; Kreek, Raghunath, et al., 1984; Kreek, Schneider, et al., 1984; Kreek, 1987a; Branch et al., 1992; Evans et al., 1992; Hurd et al., 1992; Kiefer et al., 1992; Kreek, 1992c; Chen et al., 1993a, 1993b; McGinty et al., 1993; Spangler et al., 1993a, 1993b, 1994; Wang et al., 1993; Yasuda et al., 1993; Unterwald et al., 1993; Kreek, Simon, et al., 1994; Spangler et al., (in press.) Pharmacokinetics of Methadone When methadone maintenance was in its early stages of research and development as a possible treatment for opiate addiction, there were no adequately sensitive and specific analytic methods (e.g., gas-liquid chromatography, mass spectrometry, high-performance liquid chromatography or radioimmunoassay techniques) with which to assess the pharmacokinetics of methadone (or any other opiate such as morphine and heroin); that is, the time course of distribution, metabolism, and clearance in the body. Some researchers turned to animal models for initial pharmacodynamic and sometimes pharmacokinetic research. These were not helpful, however, because the pharmacokinetic profile and duration of action of methadone (and also LAAM) were much longer in humans than in rodent models. Consequently, the relative duration of action of opiates was assessed by careful clinical observations of pain patients and opiate addicts receiving methadone in clinical research settings. Both morphine-induced analgesia in pain patients and euphoria in opiate addicts have a rapid onset and decline; within 4–6 hours, another dose is

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--> required. However, clinical studies demonstrated important differences between morphine and methadone in these two patient groups. Although in early studies methadone seemed to provide full analgesia for only 4–6 hours in pain patients, similar to morphine, when repeated doses of methadone were given over 24 hours, opiate-like side effects were observed. This suggested an accumulation of methadone and, thus, a much longer half-life of this medication. When methadone was given to heroin addicts, it seemed to prevent signs and symptoms of withdrawal for 24 hours. During oral administration of methadone to opiate addicts on doses selected to be less than those to which tolerance had been developed, the "high" or euphoria, and all other perceived opiate effects, are minimal or even absent. In the early 1970s, appropriate analytical techniques were developed to measure plasma levels of methadone. These techniques substantiated the early clinical observations and showed that there was a gradual onset of action of orally administered methadone and that low peaks of methadone were reached. Peak plasma levels were usually less than twice the trough levels, and relatively steady-state sustained plasma levels of methadone were maintained during the remainder of the 24-hour dosing interval. The mechanisms that maintain the steady-state plasma levels were shown to include binding of methadone in body tissues (primarily the liver), with subsequent release into the circulation, and extensive plasma protein binding, which limits plasma total and unbound concentrations of methadone and prolongs the pharmacological actions of methadone in patients receiving a daily maintenance dose. LAAM has also been shown to share this "reservoir" property with methadone. Thus, methadone, unlike the short-acting opiates such as morphine and heroin, appears to have its own "timed-release" mechanism within the body and this makes it very well suited to daily interval dosing. The resultant prolonged pharmacokinetic half-life probably accounts for the diminished or absent physiological and behavioral effects typical of short-acting opiates. (See Inturrisi, and Verebely, 1972; Sullivan et al., 1972; Dole and Kreek, 1973; Kreek, 1973d; Anggard et al., 1974; Hachey et al., 1977; Kreek et al., 1978; Kreek, Hachey, et al., 1979; Nakamura et al., 1982; Kreek, 1991c) Methadone Maintenance Treatment Regimen In maintenance treatment of opiate addicts, methadone is administered as a single constant daily dose after the induction period is over. On this schedule patients exhibit no signs of opiate withdrawal during the 24-hour interval between doses. If a daily dose is missed or omitted, however, a patient on

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--> methadone maintenance will exhibit signs and symptoms of opiate withdrawal, usually within 24 to 36 hours after the last dose of methadone. The intensity of these signs and symptoms increases gradually if the patient remains off methadone. A daily dose of methadone stabilizes a maintenance patient pharmacologically by the creation of a drug reservoir in the tissues of the body that holds the plasma level within narrow limits. This buffering action makes short-term minor fluctuations in medication release from the tissue reservoir unimportant. Although opiate withdrawal symptoms can be prevented with low doses, it is important to provide adequate treatment doses (60–120 mg/day in most patients) to assure plasma levels that "blockade" the effects of any superimposed short-acting opiates. The well-documented importance of constant, steady blood levels argues strongly against the sometimes-used practice of using methadone dose level as a reward or punishment variable in so-called "contingency contracting" or other behavioral interventions. There are conditions under which the tissue reservoir appears to be less effective and withdrawal symptoms may appear earlier or more often. One of these is severe, chronic liver disease, such as postviral or alcoholic cirrhosis, which probably results in a reduction in the amount of hepatic storage capacity for methadone. Less severe liver disease does not seem to have this effect. Also, drug interactions of specific types may accelerate the metabolism of methadone and decrease its effectiveness (see below). (See Dole et al., 1966; Kreek, 1973c; Kreek, 1978b; Kreek, Oratz, and Rothschild, 1978; Novick, Fanizza, et al., 1981; Kreek, 1983a; Novick, Kreek, Arns, et al., 1985; Ball and Ross, 1991, Kreek, 1991c.) Effects, Side Effects, and Special Pharmacological Issues In the original maintenance research in 1964, divided methadone doses were used very briefly, but, as already mentioned, soon it was found that a single daily dose of methadone could suppress withdrawal symptoms for 24 hours. Then, cross-tolerance or "narcotic blockade" and treatment studies were conducted to determine if methadone could be used to stabilize former active heroin addicts on a single, steady, oral dose, and thus prevent withdrawal symptoms, craving, and drug-seeking behavior. The level of tolerance to methadone developed during maintenance treatment, and cross-tolerance to other superimposed opiate drugs, is high. In the 1964 research, the phenomenon of narcotic blockade was described in which cross-tolerance blocks the effect of any superimposed short-acting opiate drug. In double-blind studies conducted on former heroin addicts stabilized on full treatment doses of methadone, doses of heroin far exceeding those that

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--> might be used illicitly had no effects in the research subjects. Occasional medication errors have also been reported in which a stabilized, long-term, methadone-maintained patient has been given up to 10 times the usual dose of medication and, in most cases, there were no untoward effects except for somnolence. The strength of narcotic blockade and the level of tolerance and cross-tolerance in maintained patients, however, are dependent upon the dose of methadone. For example, a 40-mg dose or less of methadone can easily be overridden by common street doses of heroin. Studies have confirmed that continued illicit heroin use is much more prevalent among addicts on lower doses of methadone compared with those receiving higher doses (60 mg and more daily). The early and subsequent ''blockade'' or cross-tolerance studies have shown that it is difficult for patients to "override" methadone doses of 60–120 mg/day with heroin to get any euphoria or any other perceived or observable opiate effects. This lack of any override effect has been established in the clinical research laboratory and subsequently on the street. Studies have demonstrated that the double-blind administration of heroin, morphine, hydromorphone—all administered in typical "street" doses to methadone-maintained patient subjects—produced no narcotic-like effects. In addition, single-blind administration of heroin in increasing doses to methadone-maintained research volunteers had no effects until the doses of heroin administered (up to 200 mg) exceeded street amounts commonly used at that time. Such studies have demonstrated that the margin of safety with respect to respiratory depression is very high. Consequently, if an individual maintained on methadone sought to get "high" on heroin (which frequently is attempted during the first few weeks in treatment), he or she is not likely to experience any desired or adverse effects. Although some methadone is diverted to the street, the instances of primary addiction to methadone are extremely rare. Illicit methadone is used primarily by addicts to self-medicate for a short time for "detoxification" purposes or for extended periods in a "maintenance" mode. (See chapter 4 for an extended discussion of diversion.) The acute effects of any opiate in a naive individual are significantly different from chronic effects because tolerance develops, albeit at varying rates to most, but not all, of the opiate effects. Diverse acute effects of opiates involving multiple organ systems have been recognized for years and more carefully defined and studied in recent years. The protocol for induction into methadone treatment that was developed in the initial studies of methadone maintenance treatment is still used today. During the first few weeks of maintenance treatment, the daily dose gradually is increased at a rate slow enough to prevent any appearance of narcotic-like effects.

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--> From around two months onward, doses are held constant at an adequate "blockading" level, usually of 60 to 120 mg, to provide cross-tolerance and thus prevent any appearance of euphoria if the patient should attempt to superimpose the use of illicit heroin. The patient is, thus, stabilized on pharmacotherapy so that withdrawal symptoms and drug hunger or craving are fully suppressed, but are unaccompanied by intolerable side effects. The side effects, which may occur if methadone is used in doses exceeding the degree of tolerance developed, are somnolence, drowsiness, nausea, vomiting, insomnia, difficulty in urination, edema of the lower extremities, and constipation (to be discussed later). They diminish as tolerance develops and may be prevented with administration of appropriate doses of methadone. Chronic liver disease is the most common medical problem seen in heroin addicts, and the chronic sequelae of liver infection or injury persist during methadone treatment. The majority of heroin addicts entering methadone maintenance treatment have biochemical evidence of chronic liver disease, and, until very recently, 80 to 90 percent have serological evidence of exposure to hepatitis B and/or hepatitis C. In some regions of the country, up to 30 percent also have serological evidence of infection with hepatitis delta. Of patients maintained on methadone for months to years, over one-half have persistent biochemical liver abnormalities. In these patients, the abnormalities result from the complications of previous heroin addiction and include viral hepatitis of one or more type, comorbidity with alcoholism, or both. Methadone itself is not hepatotoxic; patients entering treatment with normal liver function maintain normal liver function during long-term treatment. Chronic renal disease is a medical problem in some heroin addicts entering methadone maintenance, but the presence of chronic renal disease does not result in the systemic accumulation of methadone or its metabolites. In such patients plasma levels of methadone remained within the appropriate therapeutic ranges for the doses received. This is because methadone metabolites are inactive; also, unlike morphine and heroin, methadone and its metabolites are normally excreted in part in feces as well as in urine and may be exclusively excreted by the hepatobiliary fecal route in the presence of renal disease. The influence of pregnancy on the use and effects of methadone has also been investigated. Plasma concentrations of methadone are significantly lower and systemic elimination of methadone more rapid as pregnancy progresses through the third trimester. Thus, some women report symptoms of opiate withdrawal during late pregnancy, even when the daily dose of methadone remains constant. Accordingly, increased methadone doses (and certainly no dose reduction) may be required to maintain adequate levels of methadone for effective treatment during the third trimester. In addition to minimizing risk of

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--> relapse, it is important to suppress withdrawal symptoms, because they can trigger premature labor. To date, the only adverse effects of methadone maintenance treatment on the fetus have been the production of physical dependence, which causes mild to modest opiate withdrawal signs and symptoms in the early postnatal period in many, but not all, babies. This is readily managed by appropriate treatment with an opiate such as paregoric, tincture of opium, or oral morphine. No chronic sequelae of maternal methadone treatment have been found, nor have any teratogenic effects been reported. (See Dole et al., 1966; Cherubin et al., 1972; Gordon and Appel, 1972; Kreek, Dodesn, et al., 1972; Kreek, 1973a; Stimmel et al., 1973; Kreek, Schecter, Gutjahr, Bowen, et al., 1974; Kreek, 1978b; Kreek, 1979; Beverly et al., 1980; Kleber et al., 1980; Kreek, Gutjahr, and Hecht, 1980; Hartman et al., 1983; Kreek, 1983b; Novick, Farci, Karayiannis, 1985; Pond et al., 1985; Kreek, Khuri, et al., 1986; Novick, Khan, and Kreek, 1986; Novick, Stenger, et al., 1986; Kreek, Des Jarlais, et al., 1990; Kreek, 1991c; Kreek, 1992b; Novick, Richman, et al., 1993; Novick, Reagan, et al., in press.) Physiological Functions Disrupted During Heroin Addiction Addicts inject (or self-administer by another route) themselves repeatedly with increasingly larger doses of heroin, usually sufficient to achieve the desired euphoria or "high" effect during chronic use of opiates, and modified responses, or tolerance, to the drug develop. The first self-administrations of heroin by a curious adolescent are likely to cause nausea with or without an accompanying pleasurable feeling. Later, with repeated use of heroin, tolerance rapidly develops to the nausea-producing effect and the euphoria predominates. The euphoric experience becomes central to the addict's life; but with additional heroin use, the addict finds it progressively more difficult to achieve euphoria, unless an increasing dose of heroin is used. Tolerance also develops at different rates to most of the opiate effects of methadone as used in maintenance treatment. Most of the initial opiate effects, predominantly somnolence, can be avoided by starting treatment at relatively low doses and increasing the dose gradually to appropriate treatment levels. Other important physiological functions that are deranged during cycles of heroin addiction include (1) central nervous system stress responses that are mediated by the hypothalamic-pituitary-adrenal axis; (2) reproductive biology hormones of the hypothalamic-pituitary gonadal axis with resultant abnormal function; (3) various indices of immune function that are linked to or modulated by neuroendocrine function. These altered functions, which may contribute to or be part of the mechanism underlying drug-seeking behavior,

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--> this effect could include a disulfiram-induced inhibition of the liver microsomal enzymes that are responsible for the metabolism of methadone, but such an interaction was not found in one study in which average doses of disulfiram were administered to methadone-maintained subjects. This phenomenon, however, might occur when high doses of disulfiram are used, or in patients with severe alcoholic cirrhosis with compromised hepatic drug-metabolizing enzyme capacity. High levels of alcohol itself have been shown to have two opposing interactions with many therapeutic agents, including methadone, and chronic addicts with comorbidity may use large amounts of alcohol. Alcohol is metabolized by the hepatic microsomal enzymes. When present in large amounts, alcohol may retard the biotransformation of medications that are metabolized by the hepatic P450 enzyme related systems; yet when alcohol levels fall, drug metabolism may be accelerated due to the chronic effects of alcohol on hepatic microsomal enzyme activity. (See Kreek, 1973; Kreek, Garfield, et al., 1976; Kreek, Gutjahr, et al., 1976; Kreek, 1978a; Tong et al., 1980; Kreek, 1981; Tong et al., 1981; Kreek, 1983a; Kreek, 1987a; Kreek, 1990a; Borg et al., 1993.) Impact of Methadone Maintenance on Infectious Diseases By the late 1960s, infectious serum hepatitis could be defined more precisely owing to the development of serological tests for hepatitis B disease. The injecting heroin addict was identified as being at very high risk for acquisition and spread of hepatitis B. In multiple studies, over 80 percent of the injecting heroin addicts entering methadone treatment had markers of prior infection and 5 to 15 percent had hepatitis B antigenemia.2 However, studies have also shown that after 10 years or more in maintenance treatment, the percentage of patients with hepatitis B antigenemia drops to less than 5 percent. By the late 1970s a second and lethal form of hepatitis, caused by a viroid-like circular RNA agent (delta agent) that requires hepatitis B for its own infectiousness, was discovered and its biology defined. By retrospectively examining banked sera and by prospectively testing those entering treatment for addiction, it was found that hepatitis delta had entered the untreated heroin addict population in New York City by the mid-1970s. By 1984, approximately 90 percent of the untreated heroin addicts on the streets of New York City 2   A positive marker for hepatitis B virus antigen, indicating the presence of live hepatitis B virus and thus potential viral replication.

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--> continued to show evidence of having been infected with hepatitis B, as evidenced by the presence of some marker for that disease; and approximately 30 percent by that time had evidence of hepatitis delta infection. Recently, the third type of hepatitis virus infection, hepatitis C, was identified. Studies have shown hepatitis C virus infection in 80 to 90 percent of heroin addicts and former heroin addicts in methadone treatment. In 1981, shortly after the clinical symptoms of AIDS were characterized, the etiological viral agent HIV-1 was identified. By examining blood samples that had been banked prospectively from 1969 onward, it was found that HIV-1 infection had reached the drug-injecting population in New York City in 1978 and infection had progressed rapidly until 1983–1984, when the prevalence of HIV-1 infection reached a level of over 50 percent of intravenous users in the inner city area. Of public health importance, investigators further found that heroin addicts in New York City who had entered effective methadone maintenance treatment programs before the 1978 advent of the AIDS epidemic and who remained in treatment displayed a much lower incidence of HIV-1 infection in 1984 than did untreated heroin addicts: less than 10 percent of such methadone patients were infected in 1984, compared to over 50 percent of untreated heroin addicts. Studies of HIV-1 infection in long-term, methadone-maintained patients have been reported in Sweden and other countries worldwide with similar findings of efficacy of methadone treatment in the prevention of HIV-1 infection. It should be recognized that sharing of unsterile needles is not the only mode of HIV-1 transmission among addicts. Cocaine use by methadone patients is also a risk factor for HIV-1 infection, owing to promiscuous sexual behavior commonly associated with cocaine, including sex as payment for the drug. Concurrent use of cocaine by heroin addicts is estimated to be between 50 and 90 percent and, thus, is an added risk factor in the heroin-using population. Once in treatment, the prevalence of cocaine use among heroin addicts generally drops to between 20 and 40 percent. Finally, and of potentially great importance, studies have shown that multiple indices of immune function are deranged during cycles of heroin addiction, probably because of many factors, including lifestyle, multiple infectious diseases, and possible direct or indirect effects of the drug use. Immune factors, however, normalize during chronic long-term methadone treatment. Natural killer cell activity is not altered by methadone in vitro. Long-term methadone maintenance permits return to normal levels of natural killer cell activity, as well as to normal absolute numbers of B cells and T cell subsets, which may have important implications for immune system function and, possibly, for retarding the progress of HIV-1 infection to AIDS. (See Kreek, Dodesn, et al., 1972; Kreek, 1978b; Kreek, 1983b; Des Jarlais, Marmor, et al., 1984; Novick, Farci, Karayiannis, et al., 1985; Kreek, Khuri,

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