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Although the efficacy of methadone maintenance treatment (MMT) in opioid dependence disorder has been well established, the influence of methadone pharmacokinetics in dose requirement and clinical outcome remains controversial. The aim of this study is to analyze methadone dosage in responder and nonresponder patients considering pharmacogenetic and pharmacokinetic factors that may contribute to dosage adequacy. Opioid dependence patients (meeting Diagnostic and Statistical Manual of Mental Disorders, [4th Edition] criteria) from a MMT community program were recruited. Patients were clinically assessed and blood samples were obtained to determine plasma concentrations of (R,S)-, (R) and (S)- methadone and to study allelic variants of genes encoding CYP3A5, CYP2D6, CYP2B6, CYP2C9, CYP2C19, and P-glycoprotein. Responders and nonresponders were defined by illicit opioid consumption detected in random urinalysis. The final sample consisted in 105 opioid dependent patients of Caucasian origin. Responder patients received higher doses of methadone and have been included into treatment for a longer period. No differences were found in terms of genotype frequencies between groups. Only CYP2D6 metabolizing phenotype differences were found in outcome status, methadone dose requirements, and plasma concentrations, being higher in the ultrarapid metabolizers. No other differences were found between phenotype and responder status, methadone dose requirements, neither in methadone plasma concentrations. Pharmacokinetic factors could explain some but not all differences in MMT outcome and methadone dose requirements. Financial support was received from the TV3 Marató (01/810), Fondo de Investigaciones Sanitarias de la Seguridad Social, FIS (PI040632, PI040619), and the Instituto Carlos III (RTA 06/0001/1009). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript

• A 25-year-old man received methadone hydrochloride maintenance therapy for heroin addiction. Choreic movements involving the upper limbs, torso, and speech mechanisms developed. Discontinuation of methadone resulted in complete alleviation of the abnormal movements with no recurrence during the subsequent eight months. To our knowledge, this is the first recorded instance of a movement disorder induced by an opiate. The mechanisms by which drugs may alter neurotransmitter relationships in the brain and produce symptoms of this type are discussed.

In light of the recent growth in public financial support for the rapid expansion of drug abuse treatment capacity, the unique effectiveness of methadone hydrochloride treatment in reducing intravenous opioid abuse and the associated sharing of injection equipment is reviewed and discussed, and its potential effect on preventing the spread of acquired immunodeficiency syndrome is examined. In addition to methadone, treatment variables that clinical research suggests are integral to effective treatment are identified. Methadone treatment is one of the most helpful means of reducing the risk of acquired immunodeficiency syndrome available, provided that programs of quality are expanded. The medical profession and universities are urged to take steps to ensure quality effort in prevention and treatment.

Narcotics addiction, until a few years ago, was not regarded by most physicians as a serious medical problem. Little was said on the subject when most of us were in medical school and in residency training except for warnings that addicts must be watched carefully whenever we might be obliged to treat them for complications. Addiction was seen as a bizarre symptom of mental disease that might be of some interest to psychiatrists, but for the most part best left to prison hospitals and law enforcement agencies. Since the advent of methadone hydrochloride maintenance treatment (and especially with the rapid expansion of programs in the past two years), medical participation has increased substantially. Approximately 73,000 patients, of whom one half are in the area of New York City, are now being maintained with methadone under medical supervision. At the Fifth National Conference on Methadone Treatment, held this past spring in

• A six- to seven-year follow-up of 1971-1973 admissions to three methadone hydrochloride maintenance programs was conducted. Ninety percent of those alive were interviewed. Two of the programs used a high-dose, long-retention policy, while the third used low doses and a relatively strict policy with respect to involuntary termination for program violations. Retention was much longer for the two high-dose programs, and during the sixto seven-year period from program entry to interview, the clients had significantly less arrests, incarceration, narcotic addiction, and self-reported criminal behavior than did the patients in the low-dose program. These advantages persisted until the time of interview and existed for periods with as well as without methadone. In addition, the overall social costs in the high-dose programs were substantially less than in the low-dose program.

Heroin addicts were recruited for a 14-week open clinical comparison of methadone hydrochloride and methadyl acetate. Patients were randomly assigned to a methadyl acetate clinic in which methadyl acetate was dispensed to patients three times per week or to a methadone clinic in which methadone was dispensed six days per week. No statistically significant differences were observed between groups in retention rates, illicit drug use, employment rates, or arrest rates. The group treated with methadyl acetate had more dropouts in the first seven weeks than the second seven weeks: this pattern was reversed for the methadone-treated group. The differences were significant (P=.01). Spontaneously reported symptoms suggest that induction with methadyl acetate may be a more clinically variable phenomenon than induction with methadone. The reduction of number of clinic visits in the group treated with methadyl acetate was not a source of variance in treatment effectiveness. (JAMA237:138-142, 1977)

We used a method of detoxifying heroin addicts involving a self-regulated schedule of methadone hydrochloride detoxification in an inpatient setting. This method allows the addict to receive methadone on an "as needed" basis within specified guidelines, thus permitting him to regulate his own detoxification. For this study, 30 chronic heroin addicts were detoxified using this self-regulated detoxification procedure. Measures of length of stay, amount of methadone required, and degree of patient satisfaction indicate that this is a practical means of withdrawing chronic heroin addicts that may have advantages over fixed withdrawal schedules.

TEN YEARS ago inThe Journal, we reported on the use of methadone hydrochloride to treat a small group of intractable heroin addicts. The encouraging results of this pilot experiment suggested that larger-scale maintenance programs might provide a treatment alternative for a significant number of heroin addicts. To some extent this expectation has been supported by the experience of clinicians using methadone in treatment programs throughout the United States and abroad. Many thousands of former heroin addicts have been rehabilitated, but on balance today, it must be recognized that the projections of ten years ago were overly optimistic. The great majority of heroin addicts in our cities remain on the streets, and the programs have lost their ability to attract them to treatment. An unfortunate consequence of the early enthusiasm for methadone treatment is today's general disenchantment with chemotherapy for addicts. What was not anticipated at the onset was the

Three hundred thirty-five persons successfully detoxified from methadone hydrochloride maintenance were followed up for as long as six years to determine their ability to remain abstinent from narcotic use. At the end of the observation period, of the 269 persons located, 35% were narcotic-free, 58% had returned to narcotic use, and 8% were either jailed or deceased. The ability of a person to refrain from narcotic use was found to be highly associated with staff's assessment of progress and duration of methadone maintenance treatment. Relapse to narcotic use occurred regardless of length of abstinence, with 35% of relapses occurring after three or more years. While abstinence after narcotic dependency is possible, it is not a realistic goal for all. Premature detoxification from methadone maintenance is associated with a high recidivism rate to narcotics. ( JAMA 237:1216-1220, 1977)

• Sixty-eight heroin addicts maintained for 40 weeks on a regimen of methadyl acetate or methadone hydrochloride in a double-blind study were transferred to a uniform dose of 60 mg of methadone daily at the end of their tenure in the study. They were observed for the ensuing six weeks, during which their daily methadone doses were adjusted according to their clinical needs. Patients were observed for symptoms and signs of discomfort and for the amount of illicit drug use during this period of transition. The results indicate that patients maintained on a regimen of methadyl acetate can be readily restabilized with methadone and that sudden decrease of the methadone dose tends to result in the patient's supplementing with illicit heroin. Conversely, increasing methadone doses resulted in a corresponding reduction in illicit drug use. It is suggested that a chronic covert abstinence syndrome may exist in some patients receiving long-term methadone maintenance therapy, and that while it may contribute to their continued illicit drug use, it may have a different pathophysiologic basis and require different therapeutic considerations.

• Memory tests were administered to 30 patients taking methadone hydrochloride and 31 taking levomethadyl acetate (levo-alpha-acetylmethadol, LAAM) both prior to treatment and after one and three months of continuous treatment. A group of nonopiate using matched control subjects was administered the tests at similar intervals. No statistically significant difference in test performance was found among these groups at any of the three sessions. The methadone and control groups also did not differ significantly in the frequency of subjective reports of decreased memory function. Previous reports of memory deficits during long-term methadone administration may be a result of comparing methadone and control groups at a single point in time and assuming that prior to methadone maintenance the groups were equivalent.

Thirty-eight patients were successfully detoxified from maintenance with methadone hydrochloride. Contrary to results of most previous studies, a substantial number of individuals were found to have remained drug-free, employed, and uninvolved with the criminal justice system since detoxification. Almost half of those who returned to drug use have become reinvolved in treatment. Escalated alcohol use occurred during and following methadone maintenance. ( JAMA 235:2604-2607, 1976)

Propoxyphene napsylate and methadone hydrochloride were each administered under double-blind conditions to 36 outpatients for 21-day heroin detoxification. The initial dosage was 24 mg/day for methadone hydrochloride and 800 mg/day for propoxyphene napsylate. At these dosages, methadone more effectively suppressed the opiate-withdrawal syndrome, and patients remained in treatment longer in the methadone group ( P ( JAMA 232:1019-1022, 1975)

In the current issue of the Archives of General Psychiatry (32:909, 1975), Razani et al describe a method for detoxification of heroin addicts in which patients have active, though limited, control of the frequency of methadone hydrochloride administration during their detoxification. On demand, in any 12-hour period, patients are able to receive up to four oral doses of 5 mg of methadone at intervals of at least one hour. If a patient requests more than the four doses allowed in any 12-hour period, a physician is called and the need for additional methadone is evaluated.In 30 patients studied on a ward for acute psychiatric problems, Razani et al achieved impressive results with this technique: 26 of 30 patients were "satisfied" or "very satisfied," 4 were "neutral," and 4 were "dissatisfied." Average length of stay in a hospital was nine days, including a three-day observation period after detoxification. No patient

During the past two years, the Brooklyn office of the Office of the Chief Medical Examiner of New York City has encountered four deaths in children due to methadone poisoning. In all cases, prepared methadone drinks or methadone hydrochloride tablets were carelessly left around the house within the reach of children by either parents or friends of the family who were on a methadone maintenance program. The increasing use of this oral methadone maintenance technique in the management of heroin addicts has made this drug more accessible, thereby increasing the danger of accidental ingestion by children. It is to be expected that with even wider adoption of this program, that accidental methadone poisoning in children will become more common. Four deaths in children due to methadone poisoning are presented in this communication.

A cytogenic study of 16 opiate addicts receiving methadone hydrochloride compared with a control population revealed an unusual number of chromosome aberrations including dicentric chromosomes and an exchange figure at 72 hours in the addicted group, but no significant increase in chromosome anomalies over the controls at 48 hours. To determine whether methadone was the drug responsible for these chromosome abnormalities an in vitro study was initiated to evaluate the effects of methadone, morphine, and quinine on peripheral blood leukocytes from nonaddicts. Chromosome studies at three times normal, normal, and one third, one sixth, and one twelfth the normal therapeutic concentrations of quinine, morphine, and methadone introduced at 24, 48, and 68 hours into 72-hour leukocyte cultures did not reveal an increased frequency of chromosome damage.

Thirty-four long-term heroin addicts were treated with either methadone hydrochloride or methadyl acetate (dl-methadyl acetate, acetylmethadol) under double-blind conditions over 15 weeks. These drugs were not found to be significantly different with regard to acceptability to patients, reduction of illicit drug use, increase in legitimate employment, reduction of criminal activity, frequency of clinic attendance, and medical safety. These results suggest that the advantages of methadyl acetate, namely reduction in the frequency of clinic visits and the possibility of more effective control over administration and illegal redistribution, are not outweighed by any problems detectable under the conditions of the present study. However, in spite of these potential advantages, the unusual pharmacological actions of methadyl acetate could represent potential hazards.

A 19-year-old former heroin addict developed pulmonary edema within six hours after the oral ingestion of 80 mg of methadone hydrochloride and recovered rapidly and without sequalae, with vigorous ventilatory support. This complication has been observed following intravenous overdosage with morphine and heroin, but has not previously been recorded after methadone ingestion.

Sudden withdrawal from high levels of methadone hydrochloride can be anticipated when patients in methadone maintenance programs are arrested, hospitalized, or stopped in their treatment by other extraneous reasons. While there is general concern that such abrupt withdrawal can be dangerous, the four cases which are presented indicate that the principal responses are subjective, with little in the way of objective physical reactions.

In the treatment of heroin addiction by methadone hydrochloride maintenance, it is customary to test urine specimens regularly, in order to monitor each patient's illicit use of drugs and to assess the general success of the program. Principles and graphs are presented here to aid the physician in choosing an economical testing frequency, and in interpreting the results quantitatively on a correct statistical basis. For most purposes, a random testing schedule at an average frequency of once in five days will suffice.

To the Editor.— I would like to respond to the letter "Oral Methadone Maintenance" by Dr. G. James Berry, which appeared in a recent issue ofThe Journal(220:1617, 1972). Over the past 2 1/2 years we have been involved in observing patients maintained with methadone hydrochloride in a clinic for this purpose. Although it is certainly true that a certain percentage of patients can and will be maintained with dosages as low as 30 mg/day (we have one who is taking 10 mg/day), we do not feel that the implication that most can be maintained with anything like this low dosage should gain credence. Many factors influence dosage, such as psychological situations, habits of previous abuse, fears concerning proper maintenance dosage, variations in perspiration rates, kinds of work, and intercurrent emotional states. In our observation, most of these patients require between 60 and 90 mg of methadone hydrochloride, with

To the Editor.— With one exception, I concur with the position taken by the AMA Council on Mental Health in their explication, "Oral Methadone Maintenance Techniques in the Management of Morphine—Type Dependence." That position perpetuates the impression that, in general, addicts must be maintained at a daily dose level of between 80 and 120 mg. And, occasionally, a daily dose as high as 160 mg and above is required to attain the intended effect. Double-blind studies done in our clinic, and a similar study by Goldstein, demonstrate that most addicts can be successfully maintained with much smaller doses—as low as 30 mg/day. We were unable to demonstrate a significant difference in the behavior of groups of patients maintained continuously with 30, 50, and 100 mg of methadone hydrochloride daily when compared with retention in the program, attendance, employment, illegal activities, and involvement with their families. The one exception was a

To the Editor:— TheSPECIAL COMMUNICATION, "Progress Report of Evaluation of Methadone Maintenance..." ( 206 :2712, 1968) might better have been entitled "Progress Report for Endorsement of Methadone." The aspect of methadone hydrochloride treatment programs most in need of evaluation, ie, the goals, receives no evaluation at all. The assumption that a job, a high school diploma, and a technical skill are approriate goals in the treatment of narcotic addicts is open to question. Drug addiction is a symptom of severe emotional maladjustment. The only tenable approach to helping an addict grow up emotionally is in interpersonal approach. There are many successful examples of this, such as Gaudenzia House, Synanon, Concepts West, and Daytop Inc. To control a person with chemicals to achieve the above goals poses a serious ethical question. The authors of theSPECIAL COMMUNICATIONsound as if they are content to drug hundreds of human beings purely for

Naloxone hydrochloride is safe, effective, rapid, and inexpensive for the diagnosis of physical dependence on opiates. It may be used in an outpatient setting with a minimum of personnel. Unlike urinalysis, it will distinguish a person who is physically dependent from one who is an occasional user, and in 10 to 35 minutes. A significant hazard exists in creating addicts to methadone hydrochloride, since a third of those applying to a methadone clinic without prior documentation of withdrawal in an institution showed no evidence of physical dependence.

We have had the singular opportunity of treating the effects of overdosages of dihydromorphinone (dilaudid®) hydrochloride and methorphinan (dromoran®) hydrobromide in the same patient by injection of N-allylnormorphine ("nalline") hydrochloride. Clinical reports of treatment of poisoning by morphine and meperidine hydrochloride 1 and methadone hydrochloride 2 in man and reports of antagonism of respiratory depression caused by dihydromorphinone and other narcotics in laboratory animals have appeared in the literature. 3 We believe this to be the first instance in which N-allylnormorphine has been used to antagonize the depressant effects of methorphinan and the first clinical instance of its use in dihydromorphinone overdosage, and we feel, therefore, that this case should be of general interest. REPORT OF CASE The patient, a thin, chronically ill 60-year-old man, weight 107 lb. (48.5 kg.), was admitted for drainage of an empyema and bronchopleural fistula that followed pneumonectomy and thoracoplasty for long-standing suppurative disease of

To the Editor.— The report by Jaffe et al (222:437, 1972) is a careful study of methadyl acetate and methadone hydrochloride. Despite the apparent safety of methadyl acetate and its therapeutic equivalence three times a week for methadone daily, the authors choose to caution the reader with the warning, "however, in spite of these potential advantages, the unusual pharmacological actions of methadyl acetate could represent potential hazards." In our studies of a related compound, levomethadyl acetate (220:811, 1972), we were encouraged by our findings that levomethadyl administered three times a week was equivalent to methadone daily in safety, efficacy, and in our physiologic measures. We encouraged further trial of this compound, noting the early reports of some difficulties with methadyl acetate. We have since repeated our study of levomethadyl and affirmed its duration of action and safety. We believe that this compound deserves more extensive clinical trials. The public effort

Ten volunteer patients participating in a methadone hydrochloride maintenance program were assigned randomly to experimental (five patients) or control (five patients) groups. These patients had been in treatment for several months and had been stabilized (had no change of dose for at least three weeks) with methadone prior to inclusion in the study. Patients in the experimental group were given l-methadyl acetate (l-α acetylmethadol) on weekends and methadone on weekdays. Patients in the control group were given methadone each day. Clinic attendance, requests for change in medication, and scores on an opiate-withdrawal test instrument did not reveal differences between groups. Clinical observers blind to the experiment were unable to discriminate experimental and control patients. No untoward reactions were observed in either group. These preliminary observations suggest that l-methadyl acetate can be interchanged repeatedly with methadone without difficulty.

To the Editor.— The AMA Council Report "Treatment of Morphine-Type Dependence by Withdrawal Methods" (219:1611, 1972) is an excellent treatment of the subject. No references are given, which leads to the impression that the report is intended to stand as a definitive position by the AMA at this time. Clinical experience with large numbers of heroin addicts in the Illinois Drug Abuse Program provides the basis for the following suggested alterations in the Council's report. Deep aches, described as "being in my bones," are a common symptom of the methadone withdrawal syndrome. In addition, insomnia, often of the depressive type with early morning awakening, may persist for months following withdrawal from methadone hydrochloride. Decreasing the daily dose of methadone by 50% when the level of 20 mg is reached is too drastic a reduction. Subjective distress may be severe and lead to a discharge against medical advice.

To the Editor:— A recent paper inThe Journal( 208 :2297, 1969) by Kramer and Bass expressed the increasing disillusionment with present approaches to the narcotics problem. At present the emphasis is on education to prevent and on treatment to rehabilitate. Unfortunately there is little cause for satisfaction with the results of either. How much will increased education accomplish as a deterrent? It can have the paradoxical effect of stimulating a morbid curiosity and daring in an immature group that tends to be rebellious and defiant. As to treatment of heroin addiction, the high rate of relapse after the patient's long and costly confinement is discouraging. Yet, another more serious problem arises in connection with both residential care and methadone hydrochloride programs. This therapy may help some individuals, but for the overall problem little is accomplished. For every addict who no longer uses heroin, two novices are introduced to the

To the Editor:— Since March 1968, I have been operating a research clinic on methadone hydrochloride substitution for control of narcotic addiction. The patients studied are unique in that the treatment is totally on an outpatient basis at a private clinic rather than at a governmental institution or bureau. We have followed the daily dosage, with witnessed ingestion of the methadone, as recommended by Dole and Nyswander, and have a Research 6 Narcotics License. This program is funded solely by $7 to $10 weekly payments for treatment, medication, and control urinalysis for heroin. Naturally our program has operated at a financial loss. Our results, to date, on ambulatory patients handled in private practice, without governmental funding, are in complete accord with the successful results of research of the pioneering team of Dole and Nyswander. Any credit for our program goes to the persons whose work we followed and to the

To the Editor.— Kjeldgaard et al (218:882, 1971) reported a case of acute pulmonary edema in a former heroin addict following oral ingestion of 80 mg of methadone hydrochloride. They found no other reports of similar nature. Since then, we have discovered a report by Gardner 1 who noted occurrence of death in 12 patients due to overdose with methadone. All these patients were reported to have had acute pulmonary edema terminally, and a majority had taken the drug orally. We have recently treated a patient of similar nature and would like to add this case report to the literature. Report of a Case.— A 17-year-old youth was brought by his family to the Ben Taub General Hospital unconscious. According to the mother, the patient complained of flu-like symptoms early that morning and took two pills from a bottle of "aspirin," later identified as 10-mg tablets of methadone hydrochloride. Three

In 1950, after a discussion of some of the anesthetic problems in relation to pelvic surgery, the possibility of the use of Hyatrobal (a combination of pentobarbital sodium, atropine sulfate, and scopolamine hydrobromide) and methadone hydrochloride as a substitute for pentobarbital (Nembutal) sodium, morphine, and atropine, the usual preoperative medicaments, was suggested. Since much of the pelvic surgery is done with the vaginal approach on older women we felt that reducing the lasting effects of pentobarbital sodium and morphine, as well as avoiding the respiratory depressant activity of morphine, would be beneficial. We were also interested in any reduction that could be obtained in the postoperative nausea and vomiting that follow all general anesthesias. Hyatrobal and methadone hydrochloride seemed to offer these possibilities. In a few cases in 1950, but the majority in 1951, Hyatrobal and methadone hydrochloride were used as far as possible in all the patients of one