George E. Bigelow

Clinical pharmacology of buprenorphine: ceiling effects at high doses.

The purpose of this study was to characterize the acute effects of buprenorphine, an opioid partial (μ‐agonist, across a wide range of doses in comparison to methadone.

A comparison of levomethadyl acetate, buprenorphine, and methadone for opioid dependence.

BACKGROUND Opioid dependence is a chronic, relapsing disorder with important public health implications. METHODS In a 17-week randomized study of 220 patients, we compared levomethadyl acetate (75 to 115 mg), buprenorphine (16 to 32 mg), and high-dose (60 to 100 mg) and low-dose (20 mg) methadone as treatments for opioid dependence. Levomethadyl acetate and buprenorphine were administered three times a week. Methadone was administered daily. Doses were individualized except in the group assigned to low-dose methadone. Patients with poor responses to treatment were switched to methadone. RESULTS There were 55 patients in each group; 51 percent completed the trial. The mean (+/-SE) number of days that a patient remained in the study was significantly higher for those receiving levomethadyl acetate (89+/-6), buprenorphine (96+/-4), and high-dose methadone (105+/-4) than for those receiving low-dose methadone (70+/-4, P<0.001). Continued participation was also significantly more frequent among patients receiving high-dose methadone than among those receiving levomethadyl acetate (P=0.02). The percentage of patients with 12 or more consecutive opioid-negative urine specimens was 36 percent in the levomethadyl acetate group, 26 percent in the buprenorphine group, 28 percent in the high-dose methadone group, and 8 percent in the low-dose methadone group (P=0.005). At the time of their last report, patients reported on a scale of 0 to 100 that their drug problem had a mean severity of 35 with levomethadyl acetate, 34 with buprenorphine, 38 with high-dose methadone, and 53 with low-dose methadone (P=0.002). CONCLUSIONS As compared with low-dose methadone, levomethadyl acetate, buprenorphine, and high-dose methadone substantially reduce the use of illicit opioids.

College on Problems of Drug Dependence taskforce on prescription opioid non-medical use and abuse: position statement

This position paper from the College on Problems of Drug Dependence addresses the issues related to non-medical use and abuse of prescription opioids. A central theme throughout is the need to strike a balance between risk management strategies to prevent and deter prescription opioid abuse and the need for physicians and patients to have appropriate access to opioid pharmaceuticals for the treatment of pain. The epidemiology of prescription opioid use and abuse is reviewed. Non-medical use and abuse of prescription opioids are on the rise in the United States, illicit use of several widely prescribed opioids has increased disproportionately more than illicit use, and the prevalence of prescription opioid abuse appears to be similar to that of heroin and cocaine abuse. There is a paucity of abuse liability testing of prescription opioids, and methods should be developed to fill critical gaps in our knowledge in this area. The role of regulatory agencies in preventing diversion of prescription opioids and identifying potential sources of diversion are discussed. More research is needed to identify those populations most at risk for abusing prescription opioids, and then to develop appropriately targeted prevention programs. Treatment options are discussed; these depend on whether or not an abuser is in pain. Prescription opioid abuse has harmful ramifications for the legitimate and appropriate use of opioids, including stigmatization, opiophobia, and undertreatment of pain. Recommended steps to take include further epidemiological research, laboratory testing of prescription opioids to determine abuse liability, and clinical trials to determine the efficacy of different approaches to the prevention and treatment of prescription opioid abuse.

An automated version of the digit symbol substitution test (DSST)

An automated version of the Digit Symbol Substitution Test is described that employs a relatively inexpensive, commercially available microcomputer to present and score the task. Advantages of the automated DSST include: (1) objective scoring of both speed and accuracy of test performance, (2) printed copies of test scores, (3) convenient administration under standardized test conditions, and (4) the capacity for repeated assessment of an individual’s performance over time. Task performance data for individual subjects following doses of pentobarbital are presented; these data illustrate both the stability of task performance under constant conditions and the within-subjects sensitivity of task performance to experimental manipulations.

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 reinforcement-based therapeutic workplace for the treatment of drug abuse: three-year abstinence outcomes.

Long-term Therapeutic Workplace effects were evaluated in heroin- and cocaine-dependent, unemployed, treatment-resistant young mothers. Participants were paid to work or to train in the Therapeutic Workplace but had to provide drug-free urine samples to gain daily access. Participants (N = 40) were randomly assigned to a Therapeutic Workplace or usual care control group. Therapeutic Workplace participants could work for 3 years. Relative to controls, Therapeutic Workplace participants increased cocaine (28% vs. 54% negative; p = .04) and opiate (37% vs. 60% negative; p = .05) abstinence on the basis of monthly urine samples collected until 3 years after intake. The Therapeutic Workplace can be an effective long-term treatment of cocaine and heroin addiction in poor and chronically unemployed young mothers.

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.

Voucher-based reinforcement of cocaine abstinence in treatment-resistant methadone patients: Effects of reinforcement magnitude

Abstract Voucher-based reinforcement of cocaine abstinence has been one of the most effective means of treating cocaine abuse in methadone patients, but it has not been effective in all patients. This study was designed to determine if we could promote cocaine abstinence in a population of treatment-resistant cocaine abusing methadone patients by increasing the magnitude of voucher-based abstinence reinforcement. Participants were 29 methadone patients who previously failed to achieve sustained cocaine abstinence when exposed to an intervention in which they could earn up to

Guidelines and methodological reviews concerning drug abuse liability assessment

1155 in vouchers (exchangeable for goods/services) for providing cocaine-free urines. Each patient was exposed in counterbalanced order to three 9-week voucher conditions that varied in magnitude of voucher reinforcement. Patients were exposed to a zero, low and high magnitude condition in which they could earn up to