Moderate- vs high-dose methadone in the treatment of opioid dependence: a randomized trial.

CONTEXT: Methadone hydrochloride treatment is the most common pharmacological intervention for opioid dependence, and recent interest has focused on expanding methadone treatment availability beyond traditional specially licensed clinics. However, despite recommendations regarding effective dosing of methadone, controlled clinical trials of higher-dose methadone have not been conducted. OBJECTIVE: To compare the relative clinical efficacy of moderate- vs high-dose methadone in the treatment of opioid dependence. DESIGN: A 40-week randomized, double-blind clinical trial starting in June 1992 and ending in October 1995. SETTING: Outpatient substance abuse treatment research clinic at the Johns Hopkins University Bayview Campus, Baltimore, Md. PARTICIPANTS: One hundred ninety-two eligible clinic patients. INTERVENTION: Daily oral methadone hydrochloride in the dose range of 40 to 50 mg (n = 97) or 80 to 100 mg (n = 95), with concurrent substance abuse counseling. MAIN OUTCOME MEASURES: Opioid-positive urinalysis results and retention in treatment. RESULTS: By intent-to-treat analysis through week 30 patients in the high-dose group had significantly lower rates of opioid-positive urine samples compared with patients in the moderate-dose group (53.0% [95% confidence interval [CI], 46.9%-59.2%] vs 61.9% [95% CI, 55.9%-68.0%]; P = .047. These differences persisted during withdrawal from methadone. Through day 210 no significant difference was evident between dose groups in treatment retention (high-dose group mean retention, 159 days; moderate-dose group mean retention, 157 days). Nineteen (33%) of 57 patients in the high-dose group and 11 (20%) of 54 patients in the moderate-dose group completed detoxification. CONCLUSIONS: Both moderate- and high-dose methadone treatment resulted in decreased illicit opioid use during methadone maintenance and detoxification. The high-dose group had significantly greater decreases in illicit opioid use.

Controlled opioid withdrawal evaluation during 72 h dose omission in buprenorphine-maintained patients.

Buprenorphine's clinical utility as an opioid dependence pharmacotherapy may be enhanced with less-than-daily dosing. This study assessed opioid withdrawal after an acute 72 h dose omission in buprenorphine-maintained patients (8 mg/day s.l.). Eight outpatients required to remain free of opioids, cocaine and benzodiazepines completed four double-blind, double-dummy, Latin-square ordered conditions. Test conditions of 8 or 16 mg s.l. buprenorphine were followed by 2 days of placebo dosing. Control conditions were buprenorphine maintenance (8 mg/day), to provide a reference for evaluation of placebo test days and naloxone administration (10 mg 70 kg i.m.) during 8 mg buprenorphine maintenance to assess withdrawal measure sensitivity. Subjective measures and pupil diameter were significantly influenced only by naloxone. The lack of subjective symptoms and physiological signs of opioid withdrawal during 72 h of acute dose omission supports the feasibility of less-than-daily dosing at buprenorphine doses of 8 mg/day in patients who have demonstrated an ability to remain drug-free for an extended period.

The effects of buprenorphine in buprenorphine-maintained volunteers.

Buprenorphine is a mu opioid partial agonist currently used as an analgesic, and being developed for the treatment of opioid dependence. The purpose of this study was to determine the abuse liability of parenteral buprenorphine in volunteers maintained on daily sublingual (SL) buprenorphine (8 mg). In a residential laboratory, eight volunteers underwent pharmacologic challenges two times per week. Medication challenges were 16 h after the daily dose of buprenorphine, and consisted of double-blind IM injections of buprenorphine (4, 8, 16 mg), the prototypic mu opioid agonist hydromorphone (9 and 18 mg), or saline. Assessments consisted of physiologic monitoring, subjects' self-reports, and a trained observer's ratings of drug effects, and were collected for 0.5 h before and 2.0 h following injection. Supplemental doses of IM buprenorphine produced opioid agonist-like effects, indicating some abuse potential of parenteral buprenorphine in buprenorphine-maintained patients. There was incomplete cross-tolerance to the effects of hydromorphone, suggesting that higher maintenance doses of buprenorphine may be needed to maximize clinical efficacy. However, there was a lack of graded dose-effects for hydromorphone, suggesting that buprenorphine's combination of partial agonist effects and high affinity for opioid receptors may limit the magnitude of effects of supplemental full agonists. Finally, participants tolerated cumulative doses of maintenance buprenorphine plus challenge buprenorphine without adverse effects, suggesting higher doses of buprenorphine can be safely administered to opioid dependent patients.

Opioid antagonist effects of dezocine in opioid-dependent humans.

Dezocine is an opioid mu-partial agonist recently approved for use as an analgesic in the United States. This study characterized the relative agonist versus antagonist effects of dezocine in comparison to naloxone (an opioid antagonist), hydromorphone (an opioid mu-agonist), and placebo (saline solution) in opioid-dependent volunteers. In a residential laboratory, six volunteer male opioid abusers maintained on 30 mg/day oral methadone underwent pharmacologic challenges two to three times per week, 20 hours after the last dose of methadone. Challenges consisted of a double-blind intramuscular injection of dezocine (dose range, 7.5 to 60 mg), hydromorphone (5 and 10 mg), naloxone (0.1 and 0.2 mg), or saline solution. Measures included physiologic indexes, self-reports of drug effects, and observer ratings of drug effects. Naloxone and hydromorphone produced characteristic antagonist-like and agonist-like effects, respectively. Dezocine acted as an opioid antagonist, precipitating a withdrawal syndrome only slightly different from that produced by naloxone. Dezocine's antagonist effects were not directly dose related, but peaked at intermediate doses and declined at higher doses.

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's physical dependence potential: antagonist-precipitated withdrawal in humans.

Buprenorphine is a partial mu opioid agonist with demonstrated efficacy in the treatment of opioid dependence. One potential advantage of buprenorphine over full mu opioid agonists is its reported low physical dependence profile. This study systematically examined physical dependence produced by maintenance with a clinically relevant dose of buprenorphine using antagonist challenge procedures. In this residential laboratory study, eight opioid-dependent volunteers maintained on 8 mg/day of sublingual buprenorphine were each challenged on independent occasions with placebo, i.m. naloxone (0.3, 1.0, 3.0 and 10.0 mg/70 kg) and p.o. naltrexone (0.3, 1.0 and 3.0 mg/70 kg) 14 hr after their daily buprenorphine dose using a repeated measures, cross-over design. Both naloxone and naltrexone precipitated time- and dose-dependent withdrawal, as evidenced by changes in subject-rated, observer-rated and physiological measures. Significant precipitated withdrawal occurred at 3.0 and 10 mg/70 kg i.m. of naloxone and 3.0 mg/70 kg p.o. of naltrexone. These results indicate that buprenorphine maintenance produces physical dependence and that i.m. naloxone and p.o. naltrexone produce equivalent effects in withdrawal precipitation under these conditions. Findings have implications for selection of antagonist doses for use in formulating combination agonist/antagonist medications and for use in transition of drug abusers from buprenorphine to antagonist maintenance therapies.

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 treatment of opioid dependence: clinical trial of daily versus alternate-day dosing.

Buprenorphine, a mu-opioid partial agonist, has demonstrated efficacy for the treatment of opioid dependence comparable to that of methadone. The clinical utility of buprenorphine would be enhanced if it could be dosed on a less than daily basis. The current study is a parallel-group outpatient clinical trial of daily versus alternate-day dosing with 8 mg sublingual (s.l.) buprenorphine. Participants were randomly assigned to daily (n = 51) or alternate-day (n = 48) schedules of active medication administration for an 11-week double-blind trial. Patients assigned to alternate-day buprenorphine received placebo every other day. Primary outcome measures were retention in treatment and urine specimens positive for opiates. Clinic attendance, dose adequacy ratings, withdrawal symptomatology, and urine specimens positive for cocaine were secondary outcome measures. Neither endpoint analysis with the intent-to-treat sample nor time course analysis with treatment completers revealed any statistically significant differences between the dosing schedules on any outcome measure. Examination of 95% confidence intervals suggested a non-significant trend for the daily dosing schedule to have superior clinical efficacy at the dose tested. Nevertheless, these results are generally consistent with previous studies of less than daily dosing with buprenorphine and support the conclusion that an alternate-day dosing schedule can be effective in and acceptable to a substantial portion of patients.

Buprenorphine effects in methadone-maintained volunteers: effects at two hours after methadone.

Buprenorphine is an opioid partial agonist being developed for possible use in the treatment of opioid dependence. In a previous study up to 8 mg of buprenorphine administered 20 hr after a daily dose of methadone in methadone-maintained volunteers produced neither agonist-like nor antagonist-like effects. The purpose of this study was to examine the effects of buprenorphine challenges given 2 hr after a daily methadone dose in maintained volunteers. Seven male volunteers maintained on 30 mg of methadone daily underwent pharmacologic challenges two to three times per week. Medication challenges consisted of double-blind i.m. injections of buprenorphine (0.5-8.0 mg), the opioid antagonist naloxone (0.1 and 0.2 mg), the prototypic opioid mu agonist hydromorphone (5 and 10 mg) or saline. Assessments of physiologic measures, volunteers' self-reports and observer ratings of drug effects were collected in a laboratory session for 2 hr after drug administration, and then for 8 additional hr postsession. Results from the laboratory session showed that on subject and observer ratings naloxone produced typical antagonist-like effects, hydromorphone produced mild agonist-like effects and buprenorphine produced antagonist-like effects. Interestingly, buprenorphine's antagonist activity was not directly dose-related; its most prominent antagonist effects occurred at the 1- and 2-mg doses. These results are consistent with buprenorphine's action as a partial mu opioid agonist and demonstrate that antagonist-like effects can occur under some conditions suggesting buprenorphine should have a low abuse liability in methadone-maintained patients.

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 x 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.

Comparison of buprenorphine and methadone in the treatment of opioid dependence.

OBJECTIVE: This study compared the efficacy of buprenorphine and methadone in the treatment of opioid dependence. METHOD: Participants (N = 164) were relatively treatment-naive, opioid-dependent applicants to a 26-week treatment program who were randomly assigned to either methadone or buprenorphine treatment. Dosing was double-blind and double-dummy. Patients were stabilized on a regimen of either methadone, 50 mg, or buprenorphine, 8 mg, with dose changes possible through week 16 of treatment. Urine samples were collected three times a week, and weekly counseling was provided. RESULTS: Buprenorphine (mean dose = 8.9 mg/day) and methadone (mean dose = 54 mg/day) were equally effective in sustaining retention in treatment, compliance with medication, and counseling regimens. In both groups, 56% of patients remained in treatment through the 16-week flexible dosing period. Overall opioid-positive urine sample rates were 55% and 47% for buprenorphine and methadone groups, respectively; cocaine-positive urine sample rates were 70% and 58%. Evidence was obtained for the effectiveness of dose increases in suppressing opioid, but not cocaine, use among those who received dose increases. CONCLUSIONS: The results of this study provide further support for the utility of buprenorphine as a new medication in the treatment of opioid dependence and demonstrate efficacy equivalent to that of methadone when used during a clinically guided flexible dosing procedure.

Outcome after methadone treatment: influence of prior treatment factors and current treatment status.

Post-treatment follow-up assessments were conducted on patients from a clinical trial examining the efficacy of different doses of methadone. The Addiction Severity Index (ASI) was administered at treatment entry and ten weeks after the six-month program. Patients were improved in drug and alcohol use, and in areas of pro-social behaviors, at the time of follow-up. Improvements were not related to in-treatment variables, but were related to resumption of treatment during the follow-up interval. These results demonstrate improvement persists after methadone treatment, and further improvement can be achieved by resumption of further treatment.

Precipitated withdrawal by pentazocine in methadone-maintained volunteers.

Pentazocine is a partial mu agonist opioid with one-half to one-sixth the parenteral analgesic potency of morphine. The purpose of this study was to characterize the effects of pentazocine in comparison to naloxone (an opioid antagonist), hydromorphone (an opioid mu agonist) and saline in methadone-dependent volunteers by using the same experimental methods used previously in the study of the opioid analgesics buprenorphine, butorphanol and nalbuphine. In a residential laboratory, five volunteer male opioid abusers, maintained on 30 mg p.o. of methadone daily, underwent pharmacological challenges 2 to 3 times per week. Pharmacological challenges consisted of a double-blind i.m. injection of: pentazocine (dose range 7.5-120 mg), hydromorphone (5 and 10 mg), naloxone (0.1 and 0.2 mg) or saline. Injections were given 20 hr after the last dose of methadone. Measures included physiological indices and self-reports and observer ratings of drug effects. Naloxone and hydromorphone produced characteristic antagonist-like and agonist-like effects, respectively, on subjective, observer and physiological indices. Pentazocine produced primarily antagonist-like effects, with higher doses (> = 60 mg) producing significant elevations of visual analog scale ratings of Drug Effects, Bad Effects and Sick; of observer ratings of piloerection, restlessness and adjective scores of opioid withdrawal; as well as increases in blood pressure, heart rate and pupil diameter and decreases in skin temperature. Similar to the previous study of butorphanol, the specific profile of effects produced by pentazocine differed from that produced by naloxone, suggesting non-mu effects may modulate the mu effects of pentazocine.

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.

Dose-response effects of methadone in the treatment of opioid dependence.

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.

Buprenorphine alone and in combination with naloxone in non-dependent humans.

This study evaluated the effects of concurrent naloxone on the opioid agonist effects of buprenorphine, a mixed agonist-antagonist marketed as an analgesic and under development as a treatment for drug abuse. In a residential laboratory seven non-physically-dependent opioid abuser volunteers received intramuscular buprenorphine (0.4 mg or 0.8 mg/70 kg) alone and in combination with naloxone (0.4 mg or 0.8 mg/70 kg) versus placebo. Buprenorphine produced dose-related opioid agonist effects on physiological and subjective measures. Concurrent naloxone attenuated the opioid agonist effects of buprenorphine. Thus, a combination product of buprenorphine and naloxone may have lower abuse liability than buprenorphine alone.

Acute effects of buprenorphine, hydromorphone and naloxone in methadone-maintained volunteers.

Buprenorphine is an opioid agonist-antagonist being evaluated for treatment of opioid dependence. This study characterized the effects of buprenorphine in comparison to naloxone, hydromorphone and saline, in methadone-dependent volunteers. In a residential laboratory, 6 volunteer male opioid abusers maintained on 30 mg of methadone daily underwent pharmacological challenges 2 to 3 times per week. Pharmacological challenges consisted of a double-blind i.m. injection of: buprenorphine (dose range 0.5-8.0 mg), hydromorphone (5 and 10 mg), naloxone (0.1 and 0.2 mg) or saline. Injections were given 20 hr after the last dose of methadone. Measures included physiologic indices, and self-report and observer ratings of drug effects. Naloxone and hydromorphone produced characteristic antagonist-like and agonist-like effects, respectively, on subjective, observer and physiologic indices. None of the doses of buprenorphine were consistently or systematically identified as an opioid agonist or antagonist on any of the measures. Thus buprenorphine produced minimal effects in methadone-dependent patients. The lack of agonist effects suggests buprenorphine has a low abuse potential in methadone-dependent patients. The lack of antagonist effects suggests buprenorphine can be administered safely to subjects dependent on a low dose of methadone. This lack of effect of buprenorphine distinguishes it from other mixed agonist antagonists previously tested, which produced antagonist effects in this procedure.

Discrimination of agonist-antagonist opioids in humans trained on a two-choice saline-hydromorphone discrimination.

The stimulus properties of four opioid agonist-antagonists were assessed in postaddict volunteers trained in a two-choice drug discrimination procedure to discriminate between the effects of i.m. saline and hydromorphone (3 mg/70 kg). Behavioral, subjective and physiological measures were concurrently collected. After training, generalization curves were determined for hydromorphone, pentazocine, butorphanol, nalbuphine and buprenorphine. In generalization testing, hydromorphone produced dose-related increases in hydromorphone-appropriate responses and in characteristic opioid agonist-like subjective effects measures. In general, each of the study drugs produced a profile of subjective and physiological effects similar to that reported in other human studies. These subjective indices showed the study drugs to be heterogeneous. However, in this two-choice drug discrimination procedure, they were discriminated as homogeneous (i.e., all were discriminated as hydromorphone-like). The present study also found that all test drugs were subjectively identified as being opiates, and all were subjectively rated as similar to the hydromorphone training condition. A previous three-choice discrimination was sensitive to the heterogeneity among these drugs on both the discrimination measures and subjective ratings of similarity to the hydromorphone training condition. Thus, the specific procedures of drug discrimination studies may have an effect on some subjective indices, although this interaction is not apparent for the majority of subjective effect measures. Also, the characterization of opioids in drug discrimination testing appears to depend upon the specific training subjects receive; this is most clear with discrimination measures, and to a more limited extent, with subjective measures.

Acute physical dependence in humans: repeated naloxone-precipitated withdrawal after a single dose of methadone.

This paper reports the intensity and duration of acute physical dependence precipitated by naloxone administration following a single pre-treatment with the opioid against methadone (30 mg/70 kg, i.m.) in six non-dependent human volunteers with histories of prior opioid abuse. In a within-subject cross-over design, challenges of the antagonist naloxone (0.5-1.0 mg, i.m.) were administered at 6, 30 and 54 h, or at only 54 h after methadone pre-treatment. Acute physical dependence, as indicated by physiologic, subjective, and observer rated withdrawal, was seen in all subjects following active naloxone administration, was of nearly uniform intensity for a period of 6-54 h after acute methadone administration, and was not attenuated by prior naloxone administration.

Evaluation of the abuse potential of the novel analgesic flupirtine maleate.

To evaluate the psychopharmacological effects and potential abuse liability of the novel analgesic flupirtine maleate the subjective and behavioral effects of orally administered flupirtine, lorazepam and placebo were studied in polydrug abusers. Effects were measured before and for 6 h after drug administration under double-blind conditions. At therapeutic doses flupirtine was not differentiated from placebo. Lorazepam and higher doses of flupirtine produced increases in subject-rated liking, ARCI MBG scale scores, and sedative-like effects including impaired psychomotor performance. Flupirtine, but not lorazepam, increased ratings on measures indicating dysphoric effects. The results indicate that flupirtine has some sedative-like effects but that its abuse potential is probably modest.