Ira A. Liebson

A clinical trial of buprenorphine: Comparison with methadone in the detoxification of heroin addicts

The efficacy of buprenorphine and methadone was compared in the outpatient detoxification of heroin addicts. Forty‐five patients were randomized to receive either sublingual buprenorphine or oral methadone under double‐dummy and double‐blind conditions to study the pharmacology of buprenorphine in a 90‐day detoxification protocol. The patients were administered either 2 mg buprenorphine or 30 mg methadone for 3 weeks followed by 4 weeks of dose reductions and 6 weeks of placebo medication. No significant between‐group differences were seen on measures of treatment retention, drug use, or symptom report. During the hydromorphone challenge, methadone attenuated opioid effects to a greater extent than did buprenorphine on both physiologic (pupil constriction) and self‐report measures. However, this did not result in greater abuse of illicit opioid drugs by subjects taking buprenorphine. The results of this clinical trial indicated that buprenorphine was acceptable to patients and as effective as methadone in the detoxification treatment of heroin addicts.

Dose-Response Effects of Methadone in the Treatment of Opioid Dependence

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 methadones 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 patients last treatment at the clinic. Applicants who failed to fulfill the studys 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. Figure 1. Dosing schedule. 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. Table 1. Demographic Characteristics for Patients (n = 247) Assigned to Different Methadone Doses* 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). Figure 2. Retention in treatment. n The number of days retained in treatment was also dose related (P < 0.01); patient

A placebo controlled clinical trial of buprenorphine as a treatment for opioid dependence

Large-scale placebo controlled clinical trials assessing the efficacy of medications for the treatment of drug dependence have generally been limited to alcohol, cocaine and nicotine dependent populations. The purpose of the present study was to assess the early (1-2 week) clinical effectiveness of buprenorphine versus placebo in an opioid dependent population. The study used a parallel-group design with a behavioral choice component to compare buprenorphine (a mu-opioid partial agonist) to placebo for the treatment of opioid dependence. Opioid dependent volunteer patients participated in a 14-day study to assess the effectiveness and patient acceptance of this new pharmacotherapy for the treatment of opioid dependence. Patients were randomly assigned to placebo (n = 60) or 2 mg (n = 60) or 8 mg (n = 30) daily sublingual buprenorphine. All doses were administered double-blind. On days 6-13 all patients could request a dose change, knowing that their new dose would be randomly chosen from the remaining 2 alternatives. Compared to placebo, patients given buprenorphine (independent of dose) showed greater time on initial dose, requested fewer dose changes, used less illicit opioids (assessed by urinalysis), and rated dose adequacy higher. These results demonstrate that a placebo controlled study with a behavioral choice component is an effective means of assessing the potential efficacy and acceptability of new pharmacotherapies for opioid dependence.

Buprenorphine versus methadone in the treatment of opioid dependence : self-reports, urinalysis, and addiction severity index

This article reports results for patients who completed the 16-week maintenance phase of a double-blind clinical trial comparing buprenorphine (N = 43; average dose = 9.0 mg/day sublingually) with methadone (N = 43; average dose = 54 mg/day orally) in the outpatient treatment of opioid dependence. In addition to pharmacotherapy, treatment during the clinical trial included individual counseling, weekly group therapy, and on-site medical services. Patients in both medication groups showed significant and substantial improvements over time in areas of psychosocial functioning, as assessed by the Addiction Severity Index, rates of urinalysis tests positive for opioids, and self-reports of opioid withdrawal symptoms, illicit opioid use, and cocaine use. Buprenorphine and methadone produced very similar outcomes on the wide array of outcome measures assessed, and improvements for both groups were large and occurred rapidly after treatment entry. A trend toward continued improvement in opioid-positive urines over time was noted for the buprenorphine but not the methadone group. These results provide further evidence of the efficacy of buprenorphine in the treatment of opioid dependence and provide a characterization of the time course of effects for buprenorphine and methadone. In addition, these results demonstrate the benefits of drug abuse treatment, both for drug and alcohol use and in other areas of psychosocial functioning.

Buprenorphine versus methadone in the treatment of opioid-dependent cocaine users

This study compared the efficacy of buprenorphine to methadone for decreasing cocaine use in patients with combined opioid and cocaine use. Participants (n=51) were enrolled in a 26-week treatment program and randomly assigned to either buprenorphine or methadone. Dosing was double-blind and double-dummy. Patients were stabilized on either 8 mg sublingual buprenorphine or 50 mg oral methadone, with dose increases given in response to continued illicit cocaine use or opioid use through week 16 of treatment. Maximum doses possible were 16 mg buprenorphine and 90 mg methadone. Average doses achieved were 11.2 mg buprenorphine and 66.6 mg methadone; 49% of the patients received the maximum doses possible. Urine samples were collected three times per week, and there was no significant difference in the rate of cocaine positive urines for the intent-to-treat sample (69% for buprenorphine versus 63% for methadone). For patients who remained in treatment through the flexible dosing period (n=28), there were significant decreases in cocaine positive urines over time (P<0.01), but no significant differences between groups or group × time effects. Buprenorphine and methadone were equally effective on measures of treatment retention, urine results for opioids, and compliance with attendance and counseling. These results demonstrate no selective efficacy of either buprenorphine or methadone in attenuating cocaine use in this population, but do provide further support for the equivalent efficacy of buprenorphine and methadone in the treatment of opioid dependence.

Contingency management in methadone maintenance: Effects of reinforcing and aversive consequences on illicit polydrug use.

Treatment outcomes were compared for an intervention emphasizing reinforcement for abstinence from illicit drug use and an alternative intervention which combined the same reinforcement contingencies with aversive consequences for unauthorized drug use. Sixteen polydrug abusing methadone maintenance patients were randomly assigned to one of two treatment groups. Both groups received the opportunity to take methadone doses away from the clinic (take-home dose) as reinforcement for submitting urines testing negative for illicit substances. A regular weekly take-home dose of methadone could be earned for every 2 weeks of verified abstinence from unauthorized drugs, up to a maximum of three take-home doses per week. The combined intervention group had an additional contingency which involved a reduction in methadone dose as an aversive consequence for submitting urine samples testing positive for illicit substances. Specifically, 10% of the patients daily methadone dose was lost for each week in which two of three urines tested positive for illicit drugs. An examination of the urinalysis results indicated no between group differences. Overall, 8% of the 12-week baseline urinalysis results tested negative for illicit substances while 42% tested negative for unauthorized substances during the 20 weeks of treatment intervention. At the end of the intervention period, nine subjects remained in treatment with three patients in each group receiving at least once weekly take-home privileges. Of the seven subjects no longer in treatment, five were in the combined intervention group.(ABSTRACT TRUNCATED AT 250 WORDS)

Effect of methadone dose contingencies on urinalysis test results of polydrug-abusing methadone-maintenance patients

Drug abuse outcomes were examined during 2 contingency management procedures in which the size of the methadone dose was determined by recent urinalysis test results. Twenty polydrug-abusing methadone-maintenance patients were exposed to one of two specific altered dose consequences: a positive incentive procedure in which dose could only increase above baseline levels as a result of drug-free urines and a negative incentive procedure in which dose could only decrease below original baseline levels as a result of drug-positive urines. About 13% of urinalysis test results were drug-free during a 10-week pre-study baseline period while about 40-50% of urines were drug-free for both treatment groups during an 18-week intervention period. About half of the subjects in each study condition showed marked improvement during the intervention, while the other half failed to improve their urine test results. Treatment failures in the dose decrease as compared with the dose increase condition were more likely to drop out of the study. The study showed that size of the methadone dose can be effectively used as a consequence to influence illicit drug use during treatment. The study suggests that positive reinforcement as compared with aversive control procedures can produce an equivalent number of successful cases while avoiding dropout among patients who fail to respond to treatment.

Cost Factors Controlling Alcoholic Drinking

Alcoholic Ss were given access to alcohol under experimental conditions. Varying the cost of drinking was effective in modifying Ss’ drinking behavior. In Eperiment I, Ss operated a switch on a fixed-ratio schedule to earn alcohol. At higher ratio values, drinking was reduced, occasionally to zero. In Experiment II the number of tokens required to purchase drinks increased if Ss drank more than 2 drinks per hour. This resulted in greater temporal spacing of drinks. In these experiments both the amount consumed and the temporal pattern of consumption were modified. Control was exerted both by immediately prevailing conditions and future consequences. Alcoholic drinking is not an uncontrollable process, but is modifiable by environmental contingencies.

Methadone dose and treatment outcome

Consensus on the optimal dosing of methadone in the treatment of opioid dependence has not yet been achieved, with some programs committed to low dose regimens. This paper presents outcome results for 95 opioid abusers who remained in treatment through a stable dosing period in a double-blind fixed dose clinical trial comparing the relative efficacies of 50 (n = 44) and 20 mg (n = 34) of methadone to methadone-free treatment (n = 17). All patients showed improvements over time on measures of psychosocial functioning and psychological symptoms, emphasizing the important role of non-pharmacologic factors in methadone treatment. Furthermore, orderly dose effect relationships were seen, with patients receiving 50 mg of methadone having significantly lower rates of opioid positive urines (36% vs. 60-73%), and self-reporting a lower frequency of heroin use (3 days vs. 11-12 days per month). These results illustrate the dose-related efficacy of methadone in decreasing illicit opioid use and improving drug-related behavior.

Buprenorphine and naloxone alone and in combination in opioid-dependent humans

Subjective, physiological and behavioral effects of subcutaneously administered hydromorphone (6 mg), naloxone (0.2 mg), buprenorphine (0.2 and 0.3 mg), and two buprenorphine-naloxone combinations (buprenorphine 0.2 mg plus naloxone 0.2 mg and buprenorphine 0.3 mg plus naloxone 0.2 mg) were assessed under double-blind conditions in six opioid-dependent volunteers. Physiologic measures and subject- and observer-rated behavioral responses were measured before dosing and for 120 min after drug administration. Hydromorphone decreased pupil diameter and respiration, increased blood pressure and increased scores on subjective measures indicating opioid-like effects. Buprenorphine given alone had no significant effect on any variable measured. Naloxone given alone produced opioid abstinence-like effects which were measurable on subject- and observer-rated behavioral measures and physiological measures. Buprenorphine in combination with naloxone somewhat attenuated the naloxone-precipitated withdrawal response. Overall, the naloxone-buprenorphine combinations produced effects which were qualitatively similar to the effects of naloxone alone, suggesting a low potential for abuse of the combination product by opioid-dependent individuals.