Elsevier

Drug and Alcohol Dependence

Volume 64, Issue 1, 1 September 2001, Pages 111-116
Drug and Alcohol Dependence

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Limits to buprenorphine dosing: a comparison between quintuple and sextuple the maintenance dose every 5 days

https://doi.org/10.1016/S0376-8716(00)00227-1Get rights and content

Abstract

The relative efficacy of quintuple and sextuple buprenorphine dosing in abating withdrawal symptoms for 120 h was compared in opioid-dependent outpatients. Fourteen subjects received buprenorphine in a double-blind, placebo-controlled, cross-over design. Daily sublingual maintenance doses were 4 mg/70 kg (n=4) and 8 mg/70 kg (n=10). After a stabilization period of daily maintenance administration, subjects received quintuple (5× daily maintenance dose) and sextuple (6× daily maintenance dose) doses every 120 h. Measures of opioid agonist and withdrawal effects were assessed daily. Subjective ratings of withdrawal were significantly greater than baseline ratings beyond 96-h post dosing under both regimens. There was no evidence, however, that those subjective ratings of withdrawal differed between the two regimens. Thus, these data suggest that sextuple buprenorphine dosing, administered every 5 days, does not abate opioid-withdrawal beyond 96 hours.

Introduction

Buprenorphine, a high affinity, partial μ-opioid agonist is a new, promising alternative to methadone and levo-acetyl alpha methadol (LAAM) for opioid agonist maintenance treatment. Numerous clinical trials conducted over the past decade confirmed buprenorphine's utility for opioid dependence treatment. In double-blind, randomized clinical trials the efficacies of various doses of buprenorphine and methadone or LAAM were compared to find the most appropriate dosages of buprenorphine for the treatment of opioid dependence (Bickel et al., 1988, Johnson et al., 1992, Kosten et al., 1993, Strain et al., 1994, Strain et al., 1996, Ling et al., 1996, Schottenfeld et al., 1997). Subsequent research demonstrated that buprenorphine is a safe, effective candidate for long-term maintenance (Johnson et al., 1995, Ling et al., 1998, Johnson et al., 2000) and that it produces significant substantial improvements in psychosocial functioning over time (Strain et al., 1996).

Buprenorphine dissociates relatively slowly from μ-opioid receptors (Rance and Dickens, 1978), resulting in a long duration of action (Jasinski et al., 1978). Because of buprenorphine's long duration of action it can be, unlike methadone and like LAAM, administered on a less than daily basis (Amass et al., 1994, Amass et al., 1998, Fudala et al., 1990, Johnson et al., 1995). Our laboratory has been engaged in a series of investigations to identify how long the interdosing interval can be extended by increasing the buprenorphine dose. We have shown, for example, that opioid-dependent individuals can be safely maintained for 96 h by administering quadruple the daily maintenance dose of buprenorphine (Bickel et al., 1999, Petry et al., 1999). In another study, however, it was found that opioid-dependent individuals could not be maintained for 120 h by administering quintuple doses. Quintuple dosing did not abate subjective withdrawal complaints for 120 h and was not a preferred dosing schedule (Petry et al., submitted).

In light of these findings, this study was designed to determine if the interdosing interval could be safely and effectively extended to 120 h by administering more than a quintuple dose of buprenorphine. Specifically, we examined if administering sextuple doses (6× daily maintenance dose) might abate subjective withdrawal symptoms throughout a time interval of 120 h without producing excessive agonist effects.

Section snippets

Methods

Since several similar studies from this research group are already published, the description of the methods has been abbreviated to avoid redundance. The interested reader is referred to a study by Bickel et al. (1999) for detailed descriptions of the general procedures (including dependent measures), medication administration, and the laboratory safety session.

Results

Fourteen participants completed the study. No significant effect of buprenorphine dose (4 mg/70 kg vs. 8 mg/70 kg) was found for any of the outcome measures. Table 1 displays summary statistics for all outcome measures for each dosing regimen collapsed across participants’ buprenorphine dose.

All measures of subjective agonist effects increased significantly 24 h after quintuple and sextuple dosing. Significant withdrawal-related effects were observed starting 96 h after quintuple and sextuple

Discussion

This study examined whether six times the maintenance dose of sublingual buprenorphine was more efficacious than five times the maintenance dose in preventing withdrawal symptoms for 120 h. The results indicate that subjective complaints of withdrawal increased significantly beyond 96 h post buprenorphine dosing under both schedules, suggesting that the maximum effective interdosing interval may be limited to shorter dosing schedules.

When participants were exposed to both regimens (quintuple

Acknowledgements

We thank Dan Hammond for technical assistance, Marcia Dunham and David McGarry for medication preparation, Marne Moegelin, Tyler Wood and Bruce Brown for counseling services, and John B. Brooklyn and John R. Hughes for medical consultation. We thank Lisa A. Marsch for comments on earlier drafts of this paper. Preparation of this report was supported by Grants R29-DA12056 and R01-DA06969 from the National Institute on Drug Abuse. Anke Gross was supported by an educational grant of the

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      For example, in patients maintained daily on 8 mg sublingual buprenorphine, administration of intramuscular doses up to 16 mg (equivalent to ca. 21 mg, s.l.) was well-tolerated without adverse effects (Strain et al., 1997). Other clinical studies seeking to examine the duration of action for buprenorphine in order to reduce the need for daily dosing (and described in more detail below) have shown that patients stabilized on buprenorphine can readily tolerate double (Amass et al., 1994, 1998; Eissenberg et al., 1997), triple (Bickel et al., 1999), quadruple (Petry et al., 2000) and even sextuple (Gross et al., 2001) their usual daily dose of buprenorphine. Perhaps the most compelling evidence for the superior safety of buprenorphine is the near absence of lethal overdose cases in the literature attributable to respiratory depression produced by buprenorphine alone (but see Kintz, 2002).

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    1

    Present address: Southern Illinois University, Carbondale, IL 62901-6502, USA.

    2

    Present address: Department of Psychiatry, University of Connecticut Health Center, Farmington, CT 06030-1517, USA.

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