This study found sublingual buprenorphine solution, in combination with weekly individual drug abuse counseling, to be effective and well tolerated at higher doses for the maintenance treatment of outpatients with concurrent dependence on opiates and cocaine. Daily doses of 8 and 16 mg showed reductions in opiate and cocaine use individually, and a daily dose of 16 mg showed concomitant reductions in both opiate and cocaine use. This is the first study to demonstrate the efficacy of buprenorphine in reducing cocaine use among opiate-dependent subjects also meeting criteria for cocaine dependence in which a double-blind, controlled clinical trial design and strict eligibility criteria were used. The highest dose tested (16 mg daily) showed significant reductions in cocaine use after adjustment for concurrent opiate use. These reductions were maintained through the withdrawal phase of the study. Our results support the findings of several prior clinical trials suggesting that buprenorphine might be effective in reducing cocaine use among opiate-dependent outpatients who used or abused cocaine.20,21,38
Previous studies testing the use of buprenorphine for treatment of cocaine dependence have shown contrasting results. These contrasting results may result from differences in subject characteristics that may affect treatment outcome (eg, differences in cocaine use or in comorbid psychiatric disorders) or differences in study methods. The reported clinical trials that found buprenorphine treatment to be associated with reductions in cocaine use19-21,39
used higher buprenorphine doses (8−12 mg daily) than the trials that found no evidence of efficacy.18,22,40
The apparent persistence of the reduction in cocaine use during the withdrawal phase raises the possibility that high-dose buprenorphine engendered some change relevant to cocaine addiction that may persist even after medication intake is decreased or stopped. However, the relatively small number of urine toxicology tests obtained during the withdrawal phase precludes any strong conclusions regarding the persistent effects of the maintenance dose. Further studies are needed to determine the optimal doses of buprenorphine and schedule of buprenorphine withdrawal, with evaluation of withdrawal periods longer than 3 weeks.
The lowest dose of buprenorphine (2 mg daily) was not associated with reductions in opiate use, which fails to confirm an earlier suggestion that this low dose might be effective for the treatment of opiate dependence.5
The lack of significant effect from 16 mg every other day is consistent with a recent controlled trial comparing daily (8 mg) versus 3-times-weekly buprenorphine41
but fails to confirm earlier studies of smaller samples that indicated every-other-day dosing could reduce opiate use.6,42
In this study every-other-day dosing was not coupled with reduced clinic attendance requirements, which ensured comparable clinic contact by all groups. Reduced clinic attendance requirements in prior studies could have improved treatment compliance and outcome.
The beneficial effect of 8 mg daily buprenorphine on opiate use observed during maintenance treatment (days 5−70) faded as the buprenorphine dose was reduced (withdrawal phase, days 71−91), although opiate use for the group receiving 16 mg daily and cocaine use for all medication groups (as measured by urine toxicology studies) remained stable during medication withdrawal. These findings indicate that 9 weeks of lower-dose agonist maintenance treatment is not sufficient to substantially alter the course of opiate dependence, a pattern similar to that observed in studies of methadone maintenance treatment.43
As noted for cocaine use, the small number of urine toxicology tests performed during the withdrawal phase precludes any strong conclusions about the persistent effects of the maintenance dose.
Buprenorphine was well tolerated at all doses. Although almost half (40.2%) of the subjects reported adverse events, only 2 were clinically serious and these were not medication-related. Most adverse events appeared to be related to concurrent illnesses common in this population or to opiate withdrawal or other discomforts related to drug use rather than to direct side effects of the medication.
HIV infection, which is common among injecting drug users, was less common in our population, most likely representing a sampling bias among subjects interested in research participation. HIV infection did not appear to be associated with the occurrence of adverse events. This study did not address the interaction of buprenorphine with HAART (highly active antiretroviral therapy) because, at the time the study was conducted, this therapy was not available. The lack of immunologic or virologic analysis in our study precludes drawing firm conclusions about the effects of buprenorphine treatment on the health of this special population. Nonetheless, these findings are consistent with a previous report from a small study sample.44
The safety of buprenorphine in this population was confirmed in a recent study that showed no significant influence of buprenorphine maintenance treatment on CD4 counts or HIV viral load in 20 HIV-infected subjects receiving highly active antiretroviral treatment.45
The buprenorphine in this study, as in almost all previously published US studies, was administered as a sublingual alcoholic solution. The buprenorphine formulations approved by the Food and Drug Administration for opiate dependence treatment are 2-mg and 8-mg tablets to be placed under the tongue for dissolution. They are available as buprenorphine alone and as a combination product with naloxone in a 4:1 ratio to discourage intravenous misuse. The tablet may have up to 50% less bioavailability than the solution, resulting in significantly lower mean and peak plasma buprenorphine concentrations.46-49
This raises the possibility that doses of the buprenorphine tablet may have to be higher than the 8 or 16 mg daily of buprenorphine solution used in this study to achieve comparable effects on cocaine use.
One limitation of this study is the high dropout rate, with fewer than half of the subjects remaining by the end of the maintenance phase (week 10) (). Comparably high dropout rates have been reported in other published clinical trials of buprenorphine treatment.18,21,22,50-52
Early dropout may have been a consequence of the intensive and lengthy nature of treatment monitoring during this study, which may have discouraged some subjects from remaining in treatment. However, this level of monitoring was necessary to ensure the validity of the study results and to adequately assess subject safety. The similar dropout rates in all 4 medication groups support valid between-group comparisons, although the high overall dropout rate may limit the external validity (generalizability) of the findings. Another potential limitation is the use of drug metabolite levels that were not adjusted for urine creatinine concentration; the amount of metabolite in urine depends not only on recent drug intake but also on recent fluid intake. A further limitation of this study is that it was conducted in a treatment research environment that may differ from “real-life” drug abuse treatment settings.53
However, subjects did not receive any special inducements or compensation for treatment compliance or improvement.
The strengths of this study include its large sample size, the use of prospective stratification by age and gender, and the use of quantitative urine results for cocaine and opiates as outcome measures. In addition, data analytic methods that used all data points from all subjects were used, thus reducing the potential for bias from missing data.
In summary, this study demonstrated for the first time in a well-controlled, prospectively stratified clinical trial that high-dose (16 mg daily sublingually) buprenorphine maintenance treatment is well tolerated and can significantly reduce cocaine use among dually (cocaine and opiate) dependent outpatients, while confirming its previously demonstrated efficacy in reducing opiate use. The good tolerability of buprenorphine, even in HIV-infected subjects, suggests that it would be a very useful therapy with which to address the dual epidemic of cocaine and opiate addiction. The recent approval of buprenorphine in the United States for maintenance treatment of opiate dependence, along with its availability for prescribing by office-based physicians rather than in tightly regulated clinics, offers promise that it will be increasingly available to a large number of patients who could benefit. Further studies are needed to clarify the optimal dose of buprenorphine for treatment of dual dependency, as well as to identify prognostic variables that will allow optimal patient-treatment matching.