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Dose-Response Effects of Methadone in the Treatment of Opioid Dependence
- Eric C. Strain, MD;
- Maxine L. Stitzer, PhD;
- Ira A. Liebson, MD; and
- George E. Bigelow, PhD
- From Johns Hopkins University School of Medicine, Baltimore, Maryland. Requests for Reprints: Eric C. Strain, MD, The Department of Psychiatry, Johns Hopkins University School of Medicine, Francis Scott Key Medical Center, 4940 Eastern Avenue, Baltimore, MD 21224. Acknowledgments: The authors thank the clinic and research staff for their assistance in the execution of this study. Grant Support: By USPHS grant R01-DA05792.
Abstract
Objective: To compare the dose effectiveness of low to moderate doses of methadone in a sample of a contemporary population of opioid abusers, because the optimal dosing of methadone in the treatment of opioid dependence remains an issue.
Design: A randomized, double-blind, placebo-controlled study.
Setting: A methadone treatment research clinic.
Patients: Participants (n = 247) were opioid-dependent patients with a high rate of cocaine use.
Intervention: All participants were initially treated with active methadone for a minimum of 5 weeks and then received 15 weeks of stable dosing at 50, 20, or 0 mg per day. Individual counseling and group therapy were included.
Measurements: Treatment retention and illicit drug use as determined by intensive urine monitoring.
Results: Retention was better for patients who remained on active medication. By treatment week 20, retention was 52.4% for the 50-mg, 41.5% for the 20-mg, and 21.0% for the 0-mg group (50 versus 0 and 20 versus 0, P < 0.05; 50 versus 20, P > 0.05). Only the 50-mg treatment group had a reduced rate of opioid-positive urine samples (56.4% versus 67.6% and 73.6% for the 20-mg and 0-mg groups, respectively; P < 0.05) and cocaine-positive urine samples (52.6% versus 62.4% and 67.1% for the 20- and 0-mg groups, respectively; P < 0.05).
Conclusions: There is a dose-response effect for methadone treatment. Doses as low as 20 mg may improve retention but are inadequate for suppressing illicit drug use.
It is estimated that more than 500 000 people in the United States are dependent on opioids [1, 2]. Methadone, a synthetic opioid first reported as a treatment agent for opioid dependence by Dole and Nyswander in 1965 [3], is the most widely used pharmacologic treatment for opioid dependence. The National Drug and Alcoholism Treatment Unit Survey (NDATUS) determined a point prevalence of 92 715 opioid abusers treated in 758 methadone treatment programs on 30 September 1989 [4]. When used in conjunction with counseling services, methadone treatment has been associated with reduced rates of criminal activity, illicit drug use, and needle sharing and with improved rates of employment [5-9]. With the recognition of intravenous drug use as a primary risk factor for infection with human immunodeficiency virus (HIV), improved access to methadone treatment has been identified as an important means for reducing the risk of HIV infection [10, 11].
Although methadone treatment is effective in decreasing opioid use, recent studies have reported considerable variability across clinics in rates of continued intravenous drug use during treatment [12]. One aspect of this problem is that intravenous use of cocaine has become a serious problem among methadone treatment patients [13-16]. Few systematic studies have addressed the efficacy of methadone treatment since the onset of the cocaine epidemic [17]. Such research could re-evaluate in a contemporary population sample methadone's specific pharmacologic efficacy in decreasing opioid use [18-20] while providing new information about any potential effect of methadone treatment on concurrent cocaine use.
The issue of appropriate methadone dosing levels is highly pertinent because low-dose treatment has been strongly associated with poor drug use outcomes in descriptive clinical studies [12, 21] and because a substantial number of clinics continue to use low doses of methadone [22]. For example, a report prepared by the General Accounting Office (GAO) that summarized the dosing practices of 24 methadone programs in eight states found that doses ranged widely (from 21 to 68 mg) and 29% had a mean dose of less than 40 mg [23]. Thus, despite more than 25 years of clinical experience, optimal dosing levels of methadone remain controversial [24, 25].
Previous studies of methadone dosing have either surveyed clinics for their dosing practice and related doses to clinic-wide outcomes or have randomly assigned patients to a specific predetermined dose of methadone using clinical trial methods. Naturalistic survey studies [5, 6, 12, 21, 26], although valuable for identifying associations between dose and outcome, are methodologically compromised by confounding factors that differ across the clinics surveyed. Previous early clinical trials of methadone dosing [27-29] are also methodologically compromised (for example, being single-blinded) or only tested higher doses of methadone [30]. Thus there is a need for well-controlled research on methadone dosing reflecting doses in common use and incorporating the changing patient population. In this controlled clinical trial we compared moderate and low methadone dosing to methadone-free treatment, providing data in a contemporary population sample of opioid addicts and examining the effect of methadone dose on cocaine as well as opioid use.
Methods
Participants were 247 persons who had consecutive admissions to a methadone research clinic from September 1988 through July 1990. The mean age was 34 years, 70% were male, and 50% were black. Most were unmarried (84%) and unemployed (62%). They had an average of 11 years of education, were generally legally free (72%), and had a mean of two previous admissions for drug abuse treatment. Their primary drug of choice was intravenous heroin, and 47% reported using cocaine in the 30 days before their application to treatment.
Eligibility criteria for study participation were age between 18 and 50 years, history of intravenous opioid dependence (including documentation of previous treatment for opioid dependence or legal involvement secondary to opioid use, a urine sample positive for opioids, and physical examination consistent with acute and chronic needle use), no chronic medical illnesses, absence of a major mental illness, a negative pregnancy test for women, and at least 3 months since the patient's last treatment at the clinic. Applicants who failed to fulfill the study's eligibility criteria were assisted in seeking an alternate treatment program. The study was approved by the institutional review board, and informed consent was obtained from each patient at the time of admission to the study.
Study Procedures
Applicants who fulfilled the eligibility criteria were admitted to a 6-month short-term methadone treatment program. Participants were stratified as to race and sex and were assigned to one of three fixed-dose methadone schedules (Figure 1). Treatment group assignment, stabilization doses, and dosing schedules were double-blind for all patients and the clinic staff who had patient contact. All patients received a minimum of 35 days of active methadone during the first 5 weeks of treatment; this was followed by a 15-week stabilization period at either 50, 20, or 0 mg of methadone. Thus, patients assigned to the 0-mg treatment group received 35-day methadone detoxification. During weeks 21 through 26, the methadone dose was gradually tapered for those patients still receiving active medication because this was a short-term (182-day) treatment episode. A subsample of patients (n = 44) assigned to the 0-mg treatment group received a more prolonged (8-week) induction period, reaching 0 mg at the start of week 9 to compare the effects of a faster to a slower detoxification protocol. In this report data for patients in the alternate 0-mg treatment groups are collapsed.
Treatment Procedures
Patients were assigned an individual counselor who set treatment goals and developed an individualized treatment plan. Patients were given weekly group therapy focusing on relapse prevention. On-site medical services were provided by a full-time internist and a part-time nurse practitioner. Take-home medication was provided only on legal holidays and for documented extenuating circumstances (for example, funeral out of town for a death in the family). Patients who failed to attend the clinic for 3 consecutive days were discharged from treatment.
Outcome Measures
Treatment Retention and Compliance
Treatment retention was calculated as the total number of days between the day of admission and the day of discharge, or the last day of the stable dosing period (day 140) if the patient remained in treatment beyond the stable dosing period. Compliance with treatment was assessed through treatment attendance, the number of days medicated divided by days in treatment, and counseling contacts, which were based on the length (minutes) and number of contacts the patient had with either individual or group treatments.
Urine Testing
Patients provided a supervised urine sample for toxicology screening three times per week. Samples were tested on-site using EMIT (Syva Corporation, Palo Alto, California) for the presence of opioids, cocaine, and benzodiazepines; and cut-off calibration concentrations were set at 300 g/mL for each test (morphine, benzoylecgonine, oxazepam). The specificity of the EMIT system ranges from 96% to 100%. One sample each week was randomly selected to be sent to an outside laboratory for thin-layer chromatography analysis, which detects these same compounds and a wide variety of other less commonly abused substances.
Data Analysis
Retention to week 20, days in treatment, percentage of days attended, and amount of counseling contact time were analyzed with a one-way analysis of variance with methadone dose as the grouping factor and the Tukey Honestly Significant Difference (HSD) test was used for post hoc analyses. Comparisons for which the critical difference value corresponding to P < 0.05 are reported as significant for this and all subsequently described analyses. Treatment survival curves were compared using the Lee-Desu statistic, with pairwise comparisons between each of the three treatment groups.
The percentages of urine positive for opioids, cocaine, benzodiazepines, and any other drugs were calculated for each patient through the end of the stable dosing period. A one-factor analysis of variance with methadone dose as the grouping factor was used for each of these analyses.
Results
Table 1 shows the demographic features of the 247 patients enrolled in the study. The only difference across the three treatment groups on any variable was marital status; 8% of the patients in the 50-mg treatment group were married compared to 17% in the 20-mg and 25% in the 0-mg groups.
Treatment Retention and Compliance
Orderly dose effects were seen for survival in treatment (Figure 2). Although the three treatment groups had similar rates of retention during the first 4 weeks of treatment, when all participants were receiving active methadone, retention rates diverged between weeks 4 and 8 and dose effects were seen from weeks 8 through 20. In the survival analysis, there was an overall difference between the three curves (P < 0.01), and pairwise comparison between the 50-mg and 0-mg treatment groups differed significantly (P < 0.01); the differences between the 50-mg and 20-mg, and 20-mg and 0-mg treatment groups approached significance (P = 0.1 and P = 0.08, respectively). At week 20, the end of the stable dosing period, retention was 52.4% for the 50-mg, 41.5% for the 20-mg, and 21.0% for the 0-mg groups (50 versus 0 and 20 versus 0, P < 0.05; 50 versus 20, P > 0.05).
The number of days retained in treatment was also dose related (P < 0.01); patients who received 50 mg of methadone remained in treatment an average of 100 days compared to 87 days for patients who received the 20-mg dose and 72 days for patients in the 0-mg treatment group. Only the 50-mg and 0-mg treatment groups differed significantly (P < 0.05).
Dose effects were also seen for attendance. Treatment groups differed (P < 0.05); the 50-mg group attended more days (87%) than the 0-mg group (81%; P < 0.05), whereas the 20-mg group (84%) did not differ from either the 50-mg or 0-mg treatment groups on the percentage of days attended. The groups did not differ significantly in the amount of counseling contact (P > 0.2).
Urine Results
Results of urine testing through week 20 showed a dose effect for opioid results, with patients in the 50-mg group having a significantly lower rate of opioid-positive urine samples (56.4%) when compared to the 20-mg and 0-mg groups (67.6 and 73.6%, respectively; Table 2. Patients receiving 50 mg of methadone also had a significantly lower rate of cocaine-positive urine samples [52.6%], whereas rates for the 20-mg and 0-mg groups were virtually identical (62.4% and 67.1%, respectively; Table 2). Treatment groups did not differ in the rates of benzodiazepine [P > 0.2] or other drug-positive urine samples (P = 0.2; Table 2).
Discussion
It is well known that methadone treatment can suppress opioid use through the mechanisms of satiation and cross-tolerance [31], but controversy continues about the dosages that are adequate for this purpose [25]. Despite more than 25 years of methadone use in the treatment of opioid dependence, a substantial proportion of treatment programs continue to use low doses of methadone [23]. Our rigorously conducted clinical trial showed that the effects of methadone on both treatment retention and opioid drug use were dose related between 0 mg and 50 mg. The differences between the 20-mg and 0-mg groups show that methadone is more effective than placebo in keeping patients in treatment (see Figure 2), but urine results show that higher methadone doses are more effective than lower doses in decreasing illicit opioid use (see Table 2). Patients assigned to 0 mg of methadone actually received over 1 month of medication, and their response to treatment may partially reflect this time of active dosing. Nevertheless, the inclusion of a group given an early detoxification and maintained in methadone-free treatment adds a methodologic sophistication not found in previous methadone dosing studies.
One half of the patients entering this study reported cocaine use in the 30 days before their admission to treatment, and high rates of cocaine-positive urine samples were found during treatment (see Table 2). Other studies have shown high rates of cocaine use in methadone treatment [13-16] and at least one study has shown that a portion of opioid abusers begin to use cocaine or have an escalation in their cocaine use after beginning methadone treatment [14]. In our study, patients receiving 50 mg of methadone had a significantly lower rate of cocaine-positive urine samples during treatment. Because a specific pharmacologic action between methadone and cocaine is not known, this finding might be linked to the reduction of opioid use because opioid abusers tend to combine opioids and cocaine as a speedball.
We noted that the rate of opioid- and cocaine-positive urine samples ranged from 53% to 74% across the three treatment groups. Caution should be used in interpreting these rates in relation to actual drug use. The intensive urine testing schedule (three times per week) was designed to maximize the detection of any drug use, and even sporadic drug use could result in high rates of detection. Furthermore, large decreases in weekly drug use could produce minimal changes in the rate of positive urine results because urine testing is relatively insensitive to quantitative changes in drug use. Other studies have documented the observation that substantial reductions in reported drug use occur after treatment entry [8, 32, 33].
Our results have important clinical and policy implications. The study supports the use of higher rather than lower doses of methadone by showing a dose effect on primary outcome measures of treatmentretention and illicit opioid useand suggests that 50 mg of methadone may be a minimal effective dose for the contemporary population of opioid abusers. Doses as low as 20 mg are clearly inadequate for suppressing opioid use, although they can be partially effective in retaining patients in treatment. Because opioid drug use still continued even at a dose of 50 mg in this study, further research exploring the effects of even higher doses of methadone is needed to determine whether suppression of illicit opioid use is greater at higher doses. Such studies could also evaluate the effects of higher doses of methadone on cocaine use. Overall, however, data from the 50-mg group suggest that methadone remains the treatment of choice and is effective in the treatment for opioid dependence for mixed opioid and cocaine abusers.
The results of this study were initially presented at the 53rd Annual Scientific Meeting of the Committee on Problems of Drug Dependence, Palm Beach, Florida, 20 June 1991.
- Copyright 2004 by the American College of Physicians
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