Sublingual buprenorphine/naloxone precipitated withdrawal in subjects maintained on 100 mg of daily methadone

doi:10.1016/j.drugalcdep.2007.04.006

Drug and Alcohol Dependence

Volume 90, Issues 2–3, 8 October 2007, Pages 261-269

https://doi.org/10.1016/j.drugalcdep.2007.04.006 Get rights and content

Abstract

Rationale

Acute doses of buprenorphine can precipitate withdrawal in opioid dependent persons. The likelihood of this withdrawal increases as a function of the level of physical dependence.

Objectives

To test the acute effects of sublingual buprenorphine/naloxone tablets in volunteers with a higher level of physical dependence. The goal was to identify a dose that would precipitate withdrawal (Phase 1), then determine if withdrawal could be attenuated by splitting this dose (Phase 2).

Methods

Residential laboratory study; subjects (N = 16) maintained on 100 mg per day of methadone. Phase 1: randomized, double blind, triple dummy, within subject study. Conditions were sublingual buprenorphine/naloxone (4/1, 8/2, 16/4, 32 mg/8 mg), intramuscular naloxone (0.2 mg), oral methadone (100 mg), or placebo. Medication conditions were randomized, but buprenorphine/naloxone doses were ascending within the randomization. Phase 2: Conditions were methadone, placebo, naloxone, 100% of the buprenorphine/naloxone dose that precipitated withdrawal in Phase 1 (full dose), and 50% of this dose administered twice in a session (split dose). Analyses covaried by trough methadone serum levels.

Results

Six subjects did not complete the study. Of the 10 who completed, 3 tolerated up to 32 mg/8 mg of buprenorphine/naloxone without evidence of precipitated withdrawal. For the seven completing both phases, split doses generally produced less precipitated withdrawal compared to full doses.

Conclusions

There is considerable between subject variability in sensitivity to buprenorphine's antagonist effects. Low, repeated doses of buprenorphine/naloxone (e.g., 2 mg/0.5 mg) may be an effective mechanism for safely dosing this medication in persons with higher levels of physical dependence.

Introduction

Buprenorphine is available in many countries for use as a sublingual medication that is effective in the treatment of opioid dependence (Ling and Wesson, 2003, Mattick et al., 2004, Strain, 2002). It acts as a partial agonist at the mu opioid receptor and as a kappa opioid antagonist; preclinical and clinical studies have shown that it exhibits a bell-shaped dose response curve and produces less of a maximal effect than full agonist opioids (Doxey et al., 1982, Liguori et al., 1996, Strain, 2006, Walsh et al., 1994). When administered to opioid dependent persons, it can precipitate withdrawal under certain experimental and clinical conditions (Clark et al., 2002, Strain et al., 1995, Walsh et al., 1995). Buprenorphine-related precipitated withdrawal is thought to occur due to its partial mu agonist effects (Strain et al., 1992, Walsh and Eissenberg, 2003).

The risk of buprenorphine-precipitated withdrawal is increased as a function of three parameters: higher doses of buprenorphine, a shorter time interval between the exposure to the full agonist and buprenorphine administration (which may vary as a function of the half life of the full agonist), and higher levels of physical dependence. With respect to the last of these, clinical guidelines have recommended patients with levels of physical dependence greater than 30 mg of daily methadone should not be given acute doses of buprenorphine because of the risk of precipitated withdrawal (McNicholas, 2004). It is quite common for patients to have levels of physical dependence that are higher than that produced by 30 mg per day of methadone, so this recommendation makes it problematic to consider transferring such patients to sublingual buprenorphine. While one strategy to address this problem is to increase the time since the last dose of opioid agonist, this can be difficult in practice. Patients may be unwilling or unable to wait for dosing, and may begin to experience spontaneous opioid withdrawal and use illicit opioids before the first dose of buprenorphine can be administered. These experiences may decrease patient acceptance of initiating buprenorphine therapy.

The risk of precipitated withdrawal from a partial agonist also increases as the dose of the partial agonist increases. However, acute smaller doses of partial agonists do not precipitate withdrawal (Strain et al., 1995). This suggests that it may be possible to administer small, repeated doses of buprenorphine in a person with a higher level of physical dependence and avoid precipitated withdrawal. While smaller doses of buprenorphine may produce minimal or no detectable precipitated withdrawal, the patient may experience sufficient cumulative opioid agonist effect to produce the desired therapeutic outcome with repeated dosing. Such an observation would suggest that partial agonist-induced precipitated withdrawal is related to the immediate delivery of total dose rather than a cumulative effect of dose exposure over time. Conversely, if the same degree of partial agonist-induced precipitated withdrawal were observed after both a single acute larger dose and repeated smaller doses, this would suggest that a specific amount of drug produces precipitated withdrawal without respect to the rate of delivery.

The purpose of this study was to examine the relationship between buprenorphine delivery and occurrence of buprenorphine-induced precipitated withdrawal. In this study, the buprenorphine/naloxone combination product (Suboxone^®) was employed rather than the single buprenorphine formulation (Subutex^®), because the former is the more commonly prescribed medication in the United States. It is important to note that the naloxone in sublingual buprenorphine/naloxone does not increase the risk of precipitated withdrawal compared to buprenorphine alone, because sublingual naloxone has poor bioavailability and bioactivity (Ciraulo et al., 2006, Harris et al., 2000, Harris et al., 2004, Preston et al., 1990, Strain et al., 2004). This study first identified a dose of sublingual buprenorphine that produced precipitated withdrawal in individuals with higher levels of opioid physical dependence, and then examined whether this same dose of buprenorphine could be administered as split doses separated by a relatively short time interval without producing the same severity of precipitated withdrawal.

Section snippets

Subjects

A total of 16 subjects were enrolled in the study. Participants were adult male and female volunteers eligible for methadone maintenance treatment. Pregnancy, significant medical, and severe non-substance use psychiatric illnesses (e.g., schizophrenia) were exclusionary. Prior to study enrollment, applicants to the study were screened by medical staff not directly involved in the study as investigators; assessments included a medical history and physical examination, psychiatric history,

Results

Six of the 16 subjects left without completing both study phases. Three other subjects received all doses of buprenorphine/naloxone (i.e., up to 32 mg/8 mg) without reliably showing evidence of precipitated withdrawal. While one of the three subjects had the lowest trough methadone serum level (0.11 mg/L), the other two participants had levels (0.48 and 0.41 mg/L) that were close or identical to the mean for all subjects (0.41 mg/L). The remaining seven subjects completed both phases of the study.

Discussion

This study tested the acute effects of sublingual buprenorphine/naloxone in subjects maintained on 100 mg of daily methadone. This dose of methadone was selected to represent a relatively high level of physical dependence and is a dose commonly used in clinical practice. Given evidence that buprenorphine can precipitate withdrawal in subjects maintained on daily doses of 30 and 60 mg of methadone (Strain et al., 1995, Walsh et al., 1995), the selection of 100 mg per day for this study was thought

Acknowledgements

Supported by U.S. Public Health Service Scientist Development Award K02 DA00332 and R01 DA08045 from the National Institute on Drug Abuse. Dr. Bigelow has received, or anticipates receiving, research support from Purdue Pharma L.P., Biotek, Inc. and Titan Pharmaceuticals, Inc. for studies of other buprenorphine formulations. Drs. Strain and Walsh have served as speakers for Reckitt Benckiser, and Dr. Strain has provided or anticipates providing consulting services to Titan Pharmaceuticals,

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^☆: A table showing peak change from baseline results for all three full dose administrations of buprenorphine/naloxone can be found as supplementary material by accessing the online version of this paper at http://dx.doi.org by entering doi:10.1016/j.drugalcdep.2007.04.006.

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Sublingual buprenorphine/naloxone precipitated withdrawal in subjects maintained on 100 mg of daily methadone☆

Abstract

Rationale

Objectives

Methods

Results

Conclusions

Introduction

Section snippets

Subjects

Results

Discussion

Acknowledgements

Drug Alcohol Depend.

Drug Alcohol Depend.

Drug Alcohol Depend.

Drug Alcohol Depend.

Drug Alcohol Depend.

Drug Alcohol Depend.

Pharmacokinetics and pharmacodynamics of multiple sublingual buprenorphine tablets in dose-escalation trials

J. Clin. Pharmacol.

Severe opiate withdrawal in a heroin user precipitated by a massive buprenorphine dose

Med. J. Aust.

Effects associated with double-blind omission of buprenorphine/naloxone over a 98-h period

Psychopharmacology (Berl.)

A comparison of the effects of buprenorphine and morphine on the blood gases of conscious rats

Br. J. Pharmacol.

High interindividual variability of methadone enantiomer blood levels to dose ratios

Arch. Gen. Psychiatry

Interindividual variability of the clinical pharmacokinetics of methadone: implications for the treatment of opioid dependence

Clin. Pharmacokinet.

Methods for evaluating addiction liability. (A) “Attitude” of opiate addicts toward opiate-like drugs, (B) a short-term “direct” addiction test

J. Pharmacol. Exp. Ther.

Pharmacokinetics and subjective effects of sublingual buprenorphine, alone or in combination with naloxone: lack of dose proportionality

Clin. Pharmacokinet.

Plasma levels and symptom complaints in patients maintained on daily dosage of methadone hydrochloride

Clin. Pharmacol. Ther.

Assessment of the abuse potentiality of morphine-like drugs (methods used in man)