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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
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).
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. 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: 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.
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: 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.
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:
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.”
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,2 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 narcotic hunger and to ensure a narcotic blockade, a range of 80 to 120 mgs/day would, at least at the beginning of treatment, be reasonable for patients entering treatment. Problems in Achieving a Stable Methadone Dose On average a dose range of 80 to 120 mgs/day will relieve narcotic hunger and ensure a high enough level of tolerance for narcotic blockade. However, there is a small group of patients, perhaps 5 percent, who are fast metabolizers (Tennant, 1987). These patients may need doses in excess of 120 mgs/day to achieve a steady plasma level of methadone for 24-hours. Any drug that stimulates the liver’s microsomal enzyme-oxidizing system may accelerate the metabolism of methadone and produce withdrawal symptoms (Kreek, 1987). Again, the proper procedure is to increase the dose to over 100 mg/day to treat patients receiving medications that stimulate the liver’s microsomal enzyme-oxidizing system. Another strategy is to increase the dosage and administer the medication in split doses, half in the morning and half in the evening. Medication known to produce these effects are rifampin for drug-restraint TB and dilantin and carbamazepine for patients with epileptic seizures (Kreek, Garfield, Gutjahr et al, 1976). Excessive use of barbiturates, other sedative hypnotic drugs and alcohol may also produce withdrawal symptoms (Tong, Pond, Kreek et al, 1981). A recent investigation on the effects of cocaine/crack on the endogenous opioid receptor-ligand system has reported that crack/cocaine increases the number of opiate receptors in the brain (Unterwald, Horne-King & Kreek, 1992). While the impact of this effect on methadone dose has not been studied, taken with other evidence that the majority of cocaine/crack using methadone patients request dose increases, it is likely that the use of cocaine/crack can disrupt the ratio of methadone binding to receptors. The increase in the number of opiate receptors may necessitate an increase in methadone in order to maintain an adequate dose. The dose of methadone, as in any other medication, is critical to achieving a therapeutic effect. The most effective method to determine the proper and adequate dose is through measurement of methadone blood levels, which should be between 150 to 600 ng/ml and is equivalent in the average patient to about 80 to 100 mgs/day. Patients not receiving an adequate dose do not obtain the benefits of the medication, including the blocking of drug craving and hunger, the blocking of any euphoric effects should heroin be tried, and a degree of protection from respiratory depression and opioid overdose should illicit heroin be attempted. For the opiate-dependent person methadone when prescribed adequately acts as a stabilizer of a dysfunctional physiology by maintaining adequate opiate receptor occupation over a 24- to 36-hour period. Many states, regions and/or programs limit methadone dose by not prescribing any dose above 50 mg/day despite the evidence to the contrary that doses below 50 mg/day are not effective for most patients (Cooper, 1992; D’Annuno & Vaughn, 1992; GAO, 1990). Medical decisions about dose should be based on sound scientific knowledge and clinical evaluation, rather than on public biases or politics (Ball & Ross, 1991). It cannot be over emphasized that using methadone as a tool to control social behavior is destructive to patients self-esteem and their therapeutic relationship to the program (Dole, 1988), and that decisions regarding methadone dosage not based on sound medical principles in fact, prevent the effective treatment of narcotic addiction (Cooper, 1992; Schuster, 1989). Kreek (1988 & 1986; Borg, Ho & Kreek, 1992) states that whatever method is used to determine methadone dosage, either through blood levels or observation of the patient, “methadone dosage should never be used for social rewards or punishment” as dependence has been medically induced. Since dose is clinically determined, patients take home medication should not be linked to the amount of methadone prescribed, i.e. patients on lower doses allowed take home medication while those on higher doses receive no take home privilege at all. This encourages patients to prematurely lower their methadone dose resulting in the possible return to drug use and risk of HIV infection. In addition, methadone should never be used as a behavioral tool to manipulate the patient to comply with program policy (Brecher, 1972). Methadone medication should not be withheld or delayed, except for medical reasons. Program policies that encourage manipulation of patient behavior and control in order to comply are destructive to the patients trust in the program. Knowledge of dose should never be withheld. Methadone patients have the right to know their dose as do other medical patients (D’Annuno & Vaughn, 1992). The harm of withholding the amount of methadone prescribed is damaging to patients’ feelings of self-worth, trust in the program, their subsequent adjustment and retention in treatment (D’Annuno & Vaughn, 1992). The Medical Safety of Methadone The steady state of blood plasma levels produced by an adequate daily dose of methadone normalizes the deranged physiological functioning of the endocrine and immune systems induced by heroin addiction (Dole, 1988). The following studies validate the medical safety of long term methadone treatment. Studies of socially rehabilitated methadone patients in continuous treatment for over ten years, active heroin addicts and non-drug using healthy controls have shown that natural killer cell activity of the immune system was impaired for the heroin-addicted population. However, killer cell activity of the immune system was normal for the methadone patients and non-drug using healthy controls (Novick, Ochshorn, Ghali et al, 1989). All subjects and controls in this study were HIV negative therefore drug injection during heroin addiction can impair immune functioning independent of HIV infection. Female menses which may have been interrupted while using heroin are restored to normal for the majority of opiate dependent women maintained on methadone (Kreek, 1992; Kreek, 1986). Therefore, women maintained on methadone are able to experience normal pregnancies. Human sexuality and fertility are seriously impaired while persons are dependent on heroin. Libido and fertility can be restored within a normal range of functioning for both male and female patients who are maintained on adequate doses of methadone. However, those who abuse alcohol, cocaine or other drugs may experience reductions in libido and disruptions in the reproductive system (Kreek, 1992). Women of child bearing age should be advised of this upon entering treatment. Major medical problems effecting methadone patients are usually related to unhealthy life styles and unsterile injecting practices of the previous heroin addiction. Common medical problems include HIV infection, AIDS and drug-resistant TB; chronic liver disease resulting from either chronic alcoholism with cirrhosis or hepatitis usually contracted through use of contaminated needles to inject heroin and/or cocaine; and chronic illnesses presented at the time of admission to the program (Kreek, 1992; Kreek, 1986; Novick, Joseph, Croxson et al, 1990; Novick, Khan & Kreek, 1986). Upon entering methadone maintenance treatment these conditions can either be managed or treated, thus improving the patient’s health (Kreek, 1992; Novick, Richman, Friedman et al, 1993). A recent study of 110 methadone patients in treatment for 11 to 18 years showed that for most patients long term methadone treatment has facilitated social rehabilitation (e.g., employment, family stability, cessation of criminal activity, reduction or elimination of heroin addiction and polydrug use) and resulted in an overall improvement of their health (Novick, Richman, Friedman et al, 1993). Medical problems in this advancing age group of methadone patients are similar to those medical problems found in the general middle-aged and older populations (e.g., cardiac problems, cancer, etc.). Heroin addiction has either been completely eliminated or greatly curtailed with a reduced incidence of diseases related to the use of contaminated needles; reduction in the incidence of sexually transmitted diseases; improved endocrine and immune functioning; and less frequent abuse of cocaine and alcohol, although these drugs continue to pose significant problems for some patients. HIV entered the heroin injecting population in New York City in the late 1970s. In the 1980s examination of stored blood collected in the 1970s from addicts and three deceased infants revealed the presence of HIV (Des Jarlais, Friedman, Novick et al, 1989; Novick, Khan & Kreek, 1986). Retrospective estimates indicate that by 1980, prior to the discovery of the HIV virus, about 35 percent of the heroin injectors in New York City were already infected. In the mid 1980s, prevalence of HIV infection among intravenous drug users increased to about 55 percent, and by 1990 the prevalence had leveled off to about 50 percent (Des Jarlais, Friedman, Novick et al, 1989; Marmor, Des Jarlais & Cohen, 1987). Injecting and non injecting drug users, their sexual partners and their offspring are at high risk for contracting HIV. The prevalence of HIV infection among patients entering methadone maintenance treatment in New York City varies from about 21 percent to about 60 percent depending on the program and its geographic location (Joseph & Springer, 1990). When properly administered, methadone maintenance treatment can be a highly effective intervention to reduce transmission of HIV among injecting heroin addicts and provide medical services and referrals. Evidence collected in Europe and the United States validates the findings of laboratory and clinical studies about the effectiveness of adequate methadone treatment in preventing transmission of HIV and in the treatment of infected individuals. Several independent studies have shown that successful methadone maintenance treatment reduces risk behavior to contract and transmit HIV.
Methadone programs are placed in a unique position to monitor HIV and other infectious diseases and provide clinical prevention and intervention. For example, AZT can be administered as well as medications for drug-resistant TB. Most importantly, clinics can offer AIDS prevention, counseling and referrals for services that exist in the community. Special methadone clinics and programs can be developed that serve patients infected with HIV (e.g., St. Claire’s MMTP, Beth Israel AIDS program on 125th Street). Methadone Treatment and Pregnancy The information presented here is collected from the Treatment Improvement Protocol (TIP) on Pregnancy and Substance Abusing Women (Kandall, 1993) sponsored by the Center for Substance Abuse Treatment chaired by Janet Mitchell, M.D., M.P.H. of the Harlem Hospital Medical Center in New York City. It is important for the health of the fetus that pregnant heroin users be placed in treatment during the first trimester of pregnancy (Kaltenbach & Finnegan, 1992). Since heroin is a short-acting drug with a half-life of four to six hours, the pregnant heroin addict will be subjected to periodic daily episodes of withdrawal resulting in fetal stress and risking intrauterine death. Methadone prescribed in adequate doses provides a relatively non-stressful environment in which the fetus can develop throughout pregnancy because of its long-acting duration (Kandall, 1993). Entrance into methadone maintenance treatment during the first trimester of pregnancy is also associated with higher infant birth weights (Kaltenbach & Finnegan, 1992). There is evidence that methadone maintenance treatment, combined with prenatal services, promotes fetal growth, while continued use of heroin during pregnancy may result in infant morbidity (Kandall, 1993). The pregnant methadone-maintained patient may experience withdrawal symptoms and need an increase in the daily dose of the medication because of changes in metabolism and blood plasma levels of methadone, especially in the third trimester (Kaltenbach & Finnegan, 1992; Kandall, 1993). Methadone maintenance with psychosocial counseling and prenatal care is recommended as the treatment of choice for opioid dependent pregnant women. The safety to the fetus of slow withdrawal from opiates has not been documented. Medical withdrawal of opioid dependent women (including methadone maintained women) is not recommended during pregnancy because of increased risk to the fetus of intrauterine death even under the most optimal circumstances such as close medical monitoring. Also, there are no research data that suggest withdrawal in one trimester is worse than in others, although some physicians have serious concerns of withdrawing a pregnant woman prior to 14 weeks and after 32 weeks of the pregnancy (Kandall, 1993). Current research shows that doses below 60 mgs/day are “not effective and hence not appropriate” and “low dose policies for pregnant patients are often associated with increased drug use as well as reduced program retention.” Methadone dose should be “individually determined by absence of subjective and objective abstinence symptoms and the reduction of drug hunger” (Kandall, 1993). Most importantly, methadone dose may have to be increased or split (half in the morning and evening) to produce a beneficial effect during the later stages of pregnancy since greater plasma volume and renal blood flow during pregnancy can contribute to a reduced plasma blood level of methadone. Therefore, the pregnant woman’s initial maintenance dose may be inadequate to prevent narcotic craving, and suppress symptoms of the abstinence syndrome resulting in the subsequent return to heroin use and relapse (Finnegan, 1993; Kaltenbach & Finnegan, 1992; Kandall, 1993). Pregnant methadone maintained patients should be counseled about the effects of pregnancy on their maintenance dose and the possibility of their needing a dose increase during pregnancy. It is most important that pregnant patients understand that the fetus will also feel it if they experience symptoms of the abstinence syndrome, so they will not resist a necessary increase in their dose. In addition to this pregnant patients should also be advised of the safety of methadone to the fetus and assured that dose has no relationship to the newborn being born drug dependent. The comfort of the mother and the fetus should be of paramount concern and understood by the mother. Guidelines for Methadone Maintenance and Pregnancy Methadone maintenance is strongly encouraged for all pregnant opioid-dependent women (Kandall, 1993). It provides the following advantages:
Breast feeding of neonates is recommended if the pregnant woman maintained on methadone is HIV negative. Although minute traces of methadone have been found in mother’s milk, they are of such low density as to be pharmacologically inert and do not cause physical dependency for the neonate. However, if the mother is HIV positive, breast feeding is not recommended since the HIV will be transmitted to the baby (Finnegan, 1993; Kaltenbach & Finnegan, 1992; Kandall, 1993). Talwin, Nubain, Stadol and other agonist/antagonists should not be prescribed during pregnancy because of the dramatic withdrawal this class of drugs can precipitate thereby endangering the fetus. Narcan or any narcotic antagonist should never be given to pregnant substance-using women except as a last resort to reverse severe narcotic overdose. Administration of a narcotic antagonist, such as naltrexone to a pregnant opiate dependent woman could result in spontaneous abortion, premature labor and/or stillbirth. The long term effects and safety of clonidine in pregnancy are not known at the present time. Therefore, the drug should not be prescribed to pregnant opiate dependent women for withdrawal (Kandall, 1993). Paregoric and phenobarbital are recommended for neonatal withdrawal symptoms (Kandall, 1993). However, some physicians may prefer paregoric for treatment of neonatal opiate withdrawal symptoms (Neuspiel, 1993). Kaltenbach and Finnegan (1992) report that neonatal abstinence symptoms are not related to the mother’s methadone dose. Finnegan (1993) indicates that treatment of the opiate withdrawal symptoms in neonates is an easily treatable condition when prescribing paregoric. If the mother is a polysubstance user, however, both paregoric and/or phenobarbital may be necessary to withdraw the neonate (Kandall, 1993). The proper drugs to use in withdrawing a neonate are dependent on the drugs used by the mother. Methadone maintenance treatment, developed by Drs. Vincent Dole and Marie Nyswander in the 1960s at The Rockefeller University has been thoroughly researched and evaluated during the past thirty years. Several variables distinguish methadone as a preferable maintenance medication including, the lack of mood altering effects, the blocking of drug craving or hunger, the blocking of the effects of heroin, protection from overdose, no change in tolerance level, oral administration with a half life of 24 to 36 hours, and medically safe (nontoxic with minimal side effects). A small number of methadone patients are aberrant metabolizers and some medications may speed liver metabolism. These patients may need doses in excess of 120 mg/day.
For the long term heroin addict methadone maintenance treatment is truly a life saving medication. Thousands of once formerly considered intractable heroin addicts have been restored to productive lives. Methadone maintenance stabilizes a physiology deranged by illicit heroin use and normalizes endocrine and immune functioning and is the best prevention of HIV infection. Heroin addiction to be sure is a complex problem involving sociological and psychological factors, however because of the recent discoveries of the endogenous opioid receptor-ligand system the importance of biology can not be ignored. Methadone, therefore, acts as a normalizer for a deranged physiology in maintenance treatment and not a mood altering narcotic. Methadone maintenance is replacement therapy for the neurological deficits caused by heroin addiction. As such it is therapeutic, but not a curative. Communities should welcome methadone programs because they reduce addict-related crime and reduce morbidity and mortality related to the transmission of infection. The quality of life in a community is improved for all residents by the presence of a well administered methadone maintenance program. Notes
Abdul-Quader, A.S.; Tross, S.; Friedman, S.R.; Kouzi, A.C. and Des Jarlais, D.C. Street recruited intravenous drug users and sexual risk reduction in New York City. AIDS 1990 4: 1075-1079. Addiction Treatment Forum. A.T.F. dosage survey. Addiction Treatment Forum 1993 2(3): 1, 3, 5. Ball, J.C.; Lange, W.R.; Myers, C.P.; Friedman, S.R. Reducing the risk of AIDS through methadone maintenance treatment. Journal of Health and Social Behavior 1988 29(3): 214-226. Ball, J.C. and Ross, A. The Effectiveness of Methadone Maintenance Treatment. New York: Springer-Verlag, 1991. Blix, O. Personal communication, 1990. Blix, O. and Grondbladh, L. AIDS and IV heroin addicts: The preventive effect of methadone maintenance in Sweden. IV International Conference On AIDS, No. 8548. Stockholm, Sweden: 1988. Borg, L.; Ho, A. and Kreek, M.J. Correlation of methadone blood levels from three laboratories with dosage and abstinence symptoms: A pilot study. In: Problems of Drug Dependence 1992. Proceedings of the 54th Annual Scientific Meeting of the Committee on the Problems of Drug Dependence (June, 1992). Keystone, CO: Committee on the Problems of Drug Dependence, 1992. Brecher, E.M. Licit and Illicit Drugs. The Consumers Union Report. Boston: Little, Brown and Company, 1972. Caplehorn, J.R.M. and Bell, J Methadone dosage and retention of patients in maintenance treatment. Medical Journal of Australia 1991 (February 4) 154: 195-199. Cooper, J. Ineffective use of psychoactive drugs methadone is no exception (Editorial). Journal of the American Medical Association 1992 (January 8) 267(2): 281-282. Courtwright, D.T., Joseph, H. and Des Jarlais, D.C. Addicts Who Survived: An Oral History of Narcotic Use in America, 1923-1965. Knoxville, TN: University of Tennessee Press, 1989. Cushman, P. The major medical sequelae of opioid addiction. Drug and Alcohol Dependence 1980 5: 239-254. D’Aunno, T. and Vaughn, T.E. Variations in methadone treatment practices. Journal of the American Medical Association 1992 (January 8) 267(2): 253-258. Des Jarlais, D.C.; Friedman, S.R.; Novick, D.M. et al. HIV-1 infection among intravenous drug users in Manhattan. Journal of the American Medical Association 1989 261: 1008-1012. Des Jarlais, D.C.; Joseph, H.; Dole, V.P. and Schmeidler, J. Predicting post-treatment narcotic use among patients terminating from methadone maintenance. Journal of Alcohol and Substance Abuse 1983. Dole, V.P. Implications of methadone maintenance for theories of narcotic addiction. Journal of the American Medical Association 1988 (November 25) 260(20): 3025-3029. Dole, V.P. Addictive behavior. Scientific American 1980 (December) 243(6): 138-154. Dole, V.P. and Joseph, H. Long-term outcome of patients treated with methadone maintenance. Annals of the New York Academy of Sciences 1978 311: 181-189. Dole, V.P. and Nyswander, M.E. Methadone maintenance A ten year perspective. Journal of the American Medical Association 1976 235(19): 2117-2119. Dole, V.P. and Nyswander, M.E. Heroin addiction: Metabolic disease. Archives of Internal Medicine 1967 120: 19-24. Dole, V.P. and Nyswander, M.E. A medical treatment for diacetylmorphine (heroin) addiction. Journal of the American Medical Association 1965 (August 23) 193(8): 646-650. Dole, V.P., Nyswander, M.E. and Kreek, M.J. Narcotic blockade. Archives of Internal Medicine 1966 (October) 118:304-309. Dole, V.P., Nyswander, M.E. and Warner, A. Successful treatment of 750 criminal addicts. Journal of the American Medical Association 1968 (December 16) 206: 2710-2711. Finnegan, L.P. The success of methadone in the treatment of pregnant opiate dependent women. Presented at the Second European Symposium on Drug Addiction and AIDS. Sienna, Italy: October 1993. Food and Drug Administration. FDA Regulations in the Federal Register, 21 CFR Parts 200 to 299. Washington, D.C.: U.S. Government Printing Office, 1993. Gearing, F.R. Success and failures in methadone maintenance treatment of heroin addiction in New York City. In: Proceedings of the Third National Conference on Methadone Treatment, p 2-16. Rockville: US Public Health Service, #2172, 1970. Gearing, F.R. and Schweitzer, M.D. An epidemiologic evaluation of long-term methadone maintenance treatment for heroin addiction. American Journal of Epidemiology 1974 100: 101-112. General Accounting Office. Methadone Maintenance: Some Treatment Programs are Not Effective; Greater Federal Oversight Needed. GAO/HRD-90-104, 1990. Gordon, N. Reaction-times of methadone treated ex-heroin addicts. Psychopharmacologia 1970 16: 337-344. Gunne, L.M.; Gronbladh, L. and Ohlund, L.S. The street life and treatment response of 105 heroin addicted women. Presented at the Second European Symposium on Drug Addiction and AIDS, p 18. Sienna, Italy: 4-6 October 1993. Hargreaves, W.A. Methadone dose and duration for maintenance treatment. In: Research on the Treatment of Narcotic Addiction: State of the Art. NIDA Research Monograph. Washington, D.C.: U.S. Government Printing Office (DHHS No. (ADM)97-1281)), 1983. Hartel, D.; Selwyn, P.A.; Schoenbaum, E.E. et al. Methadone maintenance treatment and reduced risk of AIDS and AID-specific mortality in intravenous drug users. No. 8546. Stockholm, Sweden: IV International Conference on AIDS, 1988. Hentoff, N. A Doctor Among the Addicts: The Story of Marie Nyswander. Chicago: Rand McNally and Company, 1969. 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. Inciardi, J.A. Some considerations in the clinical efficacy of compulsory treatment: Reviewing the New York experience. In: Compulsory Treatment of Drug Abuse and Clinical Practice. NIDA Research Monograph No. 86, p 126-138. Rockville: 1988. Joseph, H. Substance abuse and homelessness within the inner cities. In: Lowenson, J.H.; Ruiz, P.; Millman, R.B. and Langrod, J.G. (eds). Substance Abuse, A Comprehensive Textbook. Baltimore: Williams and Wilkins, 1992. Joseph, H. The criminal justice system and opiate addiction: A historical perspective. In: Leukefeld, C.G.; Times, F.M. (eds), Compulsory Treatment of Drug Abuse: Research and Clinical Practice, NIDA Research Monograph 86 (ADM 88-1578). Rockville: U.S. Department of Health and Human Services, 1988. Joseph, H. and Appel, P. Historical perspectives and public health issues. In: Parrino, M. (Chair/Editor) State Methadone Maintenance Treatment Guidelines. Rockville: U.S. Dept. of Health and Human Services, 1992. Joseph, H. and Appel, P. Alcoholism and methadone treatment: Consequences for the patient and the program. American Journal for Drug and Alcohol Abuse 1985 11(1&2): 37-54. Joseph, H. and Des Jarlais, D.C. Methadone Patients in Conventional Society (unpublished internal report of the Research Bureau). New York: NYS Office of Alcoholism and Substance Abuse Services, 1980. Joseph, H. and Dole, V.P. Methadone patients on probation and parole. Federal Probation 1970 June: 42-48. Joseph, H and Springer, E. Methadone maintenance treatment and the AIDS epidemic. In: The Effectiveness of Drug Abuse Treatment: Dutch and American Perspectives, p 261-274. Malabar, Florida: Robert E. Krieger, 1990. Kaltenbach, K. and Finnegan, L.P. Methadone maintenance during pregnancy: Implications for perinatal and developmental outcome. In: T. Sonderegger (ed), Perinatal Substance Abuse: Research Findings and Clinical Implications. Baltimore: John Hopkins University Press, 1992. Kandall, S. R. (consensus panel chair). Improving Treatment for Drug-Exposed Infants. Treatment Improvement Protocol (TIP) Series 5, # (SMA) 93-2011. Rockville, MD: U.S. Department of Health and Human Services (DHHS), Center for Substance Abuse Treatment (CSAT), 1993. Kreek, M.J. Methadone treatment (Special Presentation). Staten Island, NY: 30th Anniversary of Methadone Maintenance Treatment, 1993. Kreek, M.J. The addict as patient. In: Lowenson, J.H.; Ruiz, P.; Millman, R.B. and Langrod, J.G. (eds), Substance Abuse A Comprehensive Textbook. Baltimore: Williams and Wilkins, 1992. Kreek, M.J. Summary of Presentation at 1988 meeting of the Committee for the Problems of Drug Dependence. NIDA Notes 1988 Fall: 12, 25. Kreek, M.J. Tolerance and dependence: Implications for the pharmacological treatment of addiction. In: Harris, L.S. (ed), Problems of Drug Dependence. Proceedings of the 48th Scientific Meeting of the Committee of the Problems of Drug Dependence, 1986. DHHS No. (ADM)87-1508. Rockville, MD: National Institute on Drug Abuse. Kreek, M.J. Multiple drug abuse patterns and medical consequences. In: Meltzer, H.Y. (ed), Psychopharmacology: The Third Generation of Progress (Chapter 172), p 1597-1604. New York: Raven Press, 1987. 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. Medical complications in methadone patients. Annals of the New York Academy of Sciences 1978 311: 110-134. Kreek, M.J. Medical safety and side effects of methadone in tolerant individuals. Journal of the American Medical Association 1973 (February 5) 223(6): 665-668. Kreek, M.J.; Dodes, L.; Kane, S.; Knobler, J. and Martin, R. Long-term methadone maintenance therapy: Effects on liver function. Annals of Internal Medicine 1972 (October) 77(4): 598-602. Loimer, N.; Schmid, R.; Grunberger, J.; Jagsch, R.; Linzmayer, L. and Presslich, O. Psychophysiological reactions in methadone maintenance patients do not correlate with methadone plasma levels. Psychopharmacology (Berl) 1991 103(4): 538-540. Marmor, M.; Des Jarlais, D.C. and Cohen, H. Risk factors for infection with human immunodeficiency virus among intravenous drug abusers in New York City. AIDS 1987 1: 39-44. Martin, W.R.; Wilker, A.; Eades, C.G. et al. Tolerance and physical dependence on morphine in rats. Psychopharmacology 1963 4: 247-260. McLellan, T.A.; Arndt, T.O.; Metzger, D.S.; Woody, G.E. and O’Brien, C.P. The effects of psychosocial services in substance abuse treatment. Journal of the American Medical Association 1993 (April 21) 269(15): 1953-1959. Newman, R.G. and Cates, M. Methadone Treatment in Narcotic Addiction: Program Management, Findings and Prospects for the Future. New York: Academic Press, 1977. Neuspiel, D. Personal communication, 1993. Novick, D.M.; Joseph, H.; Croxson, T.S. et al. Absence of antibody to human immunodeficiency virus in long-term, socially rehabilitated methadone maintenance patients. Archives of Internal Medicine 1990 (January) 150: 97-99. Novick, D.M.; Ochshorn, M.; Ghali, V. et al. Natural killer activity and lymphocyte subsets in parental heroin abusers and long-term methadone maintenance patients. Journal of Journal of Pharmacology and Experimental Therapeutics 1989 250: 606-610. Novick, D.M.; Khan, I. and Kreek, M.J. Acquired immunodeficiency syndrome and infection with hepatitis viruses in individuals abusing drugs by injection. Bulletin of Narcotics 1986 38: 15-25. Novick, D.M.; Richman, B.L.; Friedman, J.M.; Friedman, J.E.; Fried, C.; Wilson, J.P.; Townley, A. and Kreek, M.J. The medical status of methadone maintenance patients in treatment for 11-18 years. Drug and Alcohol Dependence 1993 33: 235-245. Nyswander, M.E. The Drug Addict As A Patient. New York: Grune & Stratton, 1956. Parrino, M.W. Overview: Current treatment realities and Future Trends. In: Parrino, M.W. (Chair & Editor), State Methadone Maintenance Treatment Guidelines (The Purple Book). Rockville, MD: U.S. Department of Health and Human Services, Center for Substance Abuse Treatment; 1992. Payte, J.T. and Khuri, E. Principles of methadone dose determination. In: Parrino, M.W. (Chair & Editor). State Methadone Maintenance Treatment Guidelines (The Purple Book). Rockville, MD: U.S. Department of Health and Human Services, Center for Substance Abuse Treatment; 1992. Payte, J.T.; Khuri, E.; Joseph, H. and Woods, J. Methadone patients and the treatment of pain. In: Methadone Treatment Is Recovery: A Manual for Methadone Maintenance Treatment, Part 1. New York: Chemical Dependency Research Working Group, NYS Office of Alcoholism and Substance Abuse Services, 1994. Randall, J. Personal communication, 1994. Schuster, C. Methadone maintenance: An adequate dose is vital in checking the spread of AIDS (Director’s Column). NIDA Notes 1989 Spring/Summer: 3. Stimmel, B.; Goldberg, J.; Cohen, M. and Rotkopf, E. Detoxification from methadone maintenance: Risk factors associated with relapse to narcotic use. In: Kissen, B.; Lowenson, J.H. and Millman, R. (eds), Recent Developments in the Chemotherapy of Narcotic Addiction. New York: New York Academy of Sciences, 1978. Simpson, D.D. Treatment for drug abuse follow up outcomes and length of times spent. Archives of General Psychiatry 1981 38: 875-880. 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. Unterwald, E.M.; Horne-King, J. and Kreek, M.J. Chronic cocaine alters brain mu opioid receptors. Brain Research 1992 584: 314-318. Watters, J.A. and Price, R.H. The relationship of treatment policy to client retention. In: Appel, P., Treatment Issue Report #56 (unpublished internal report). New York: New York State Division of Substance Abuse Services, 1985.
Weber, R.; Ledergerber, B.; Opravil, M. and Luthy, R. Cessation of intravenous drug use reduces progression of HIV infection in HIV+ drug users. Presented at the VI International Conference on AIDS. San Francisco: 1990. |