Elsevier

Drug and Alcohol Dependence

Volume 162, 1 May 2016, Pages 190-198
Drug and Alcohol Dependence

Full length article
Intranasal buprenorphine alone and in combination with naloxone: Abuse liability and reinforcing efficacy in physically dependent opioid abusers

https://doi.org/10.1016/j.drugalcdep.2016.03.005Get rights and content

Highlights

  • Inpatient study examined persons dependent on short-acting opioids.

  • Intranasal (IN) buprenorphine/naloxone (BUP/NX) precipitated opioid withdrawal.

  • IN naloxone slowed the onset of buprenorphine’s opioid agonist effects.

  • Buprenorphine was self-administered more than BUP/NX.

  • IN BUP/NX has lower abuse potential and reinforcing efficacy than buprenorphine.

Abstract

Background

Buprenorphine can be abused by the intranasal route. This study sought to examine the relative abuse liability and reinforcing efficacy of intranasal buprenorphine compared to intranasal buprenorphine/naloxone in opioid-dependent individuals.

Methods

Eleven healthy male and female volunteers physically dependent on short-acting opioids resided as inpatients during participation in this double blind, within subject, placebo-controlled study. Participants were maintained on oxycodone (30 mg/q.i.d., p.o.) throughout the 6-week study. Eight pairs of experimental sessions were conducted at ≥48 h intervals to examine the pharmacodynamic profile (Sample) and reinforcing efficacy (Self-administration the following day) of intranasal placebo, oxycodone (60 mg), buprenorphine (2, 8 & 16 mg) and buprenorphine/naloxone (2/0.5, 8/2 & 16/4 mg). Subjective, observer-rated and physiological measures were collected to assess the magnitude of opioid agonist and antagonist effects. A progressive ratio self-administration procedure assessed choices for drug versus money.

Results

All active doses produced opioid agonist-like effects (e.g., increased ratings of “liking,” and miosis) compared to placebo. The effects of buprenorphine and buprenorphine/naloxone were not reliably dose-dependent. Intranasal buprenorphine/naloxone elicited modest and transient opioid withdrawal-like effects in the first hour post-drug administration, while simultaneously blunting or blocking the early onset of agonist effects seen with buprenorphine alone. All active doses of buprenorphine were self-administered more than placebo, but buprenorphine/naloxone doses were not.

Conclusions

These data confirm that intranasal buprenorphine/naloxone has deterrent properties related to transient withdrawal effects that likely decrease its desirability for misuse compared to buprenorphine in opioid-dependent individuals maintained on short-acting opioids.

Introduction

Buprenorphine (BUP), a partial mu opioid agonist, has been successfully used for the treatment of opioid dependence since the 1990’s (see recent reviews Fullerton et al., 2014, Mattick et al., 2014). Following the passage of the U.S. Drug Addiction Treatment Act of 2000 and FDA approval of Suboxone® and Subutex® in 2002, BUP implementation in the U.S. became widespread. While the majority of BUP sold in the U.S. is buprenorphine/naloxone (BUP/NX), many countries outside the U.S. primarily use BUP alone (e.g., France). In part, this was because BUP was introduced in these countries before BUP/NX was available; however, now that BUP/NX is available, reasons for continued preference for BUP alone may not be empirically justified given growing concerns about diversion, misuse, and adult and pediatric overdose (Hayes et al., 2008, Kintz, 2002, Lai and Teo, 2006, Lavonas et al., 2013, Lovegrove et al., 2014, Reynaud et al., 1998, Simonsen et al., 2011, Tracqui et al., 1998). The preferential use of BUP/NX in the U.S. occurred because the FDA approved both formulations simultaneously and the manufacturer, Reckitt-Benckiser Pharmaceuticals, priced BUP/NX lower than BUP to discourage widespread prescribing of BUP. Also, physician trainings and published treatment guidelines (e.g., CSAT, 2004) preferentially recommended BUP/NX (except for induction and supervised dosing and treatment of pregnant women).

The rationale for the combination BUP/NX development was based upon the assumption that adding naloxone would reduce potential misuse and diversion compared to BUP alone, as has been observed with pentacozine/naloxone and tilidine/naloxone (Johnson and McCagh, 2000). Naloxone has poor sublingual bioavailability (Preston et al., 1990) and is functionally inactive when sublingual BUP/NX is taken as directed. However, if misused parenterally, naloxone becomes 100% bioavailable and can precipitate opioid withdrawal in opioid-dependent individuals (e.g., Fudala et al., 1998, Stoller et al., 2001). However, studies and clinical experience have demonstrated that whether BUP and BUP/NX administration is or is not associated with abuse liability and does or does not precipitate opioid withdrawal in opioid-dependent individuals is complicated and determined by numerous factors, including opioid maintenance drug, maintenance dose, time since last dose, BUP or BUP/NX dose, and route of BUP or BUP/NX administration (Clark et al., 2002, Harris et al., 2000, Larance et al., 2014, Mendelson et al., 1996, Preston et al., 1988, Rosado et al., 2007, Schuh et al., 1996, Stoller et al., 2001, Walsh et al., 1995).

Reports indicate that BUP tablets with and without naloxone are being crushed (and sublingual films dissolved) and subsequently injected or insufflated intranasally (Alho et al., 2007, Bruce et al., 2009, Horyniak et al., 2011, Jenkinson et al., 2005, Lofwall and Walsh, 2014, Nordmann et al., 2012, Young et al., 2010). For instance, two studies report that up to 30% of patients enrolled in BUP therapy were snorting their medication (Barrau et al., 2001, Roux et al., 2008). Case reports describe adverse consequences from intranasal BUP, including acute hepatitis and renal failure (Eiden et al., 2013) and fatal overdose (Ferrant et al., 2011, Megarbane et al., 2011). Few controlled human studies have characterized the response to intranasal BUP, BUP/NX or naloxone. We previously examined the pharmacodynamic and pharmacokinetic profiles of intranasal BUP and BUP/NX in opioid abusers who were not physically dependent on opioids (Middleton et al., 2011). That study demonstrated significant intranasal absorption of buprenorphine (∼38–44%) and naloxone (∼24–30%) from BUP/NX yielding naloxone plasma concentrations comparable to those produced by doses that precipitate withdrawal in opioid-dependent individuals; however, this did not translate into meaningful pharmacodynamic differences between BUP and BUP/NX in non-dependent abusers. Jones and colleagues recently reported that intranasal BUP and BUP/NX do have reinforcing efficacy in BUP-maintained individuals (mimicking those receiving treatment with BUP), and this declines as a function of maintenance dose (Jones et al., 2015). Further, they reported that BUP/NX produced decreased positive subjective effects compared to BUP and was associated with increased ratings of aversive effects in BUP-maintained individuals. However, as BUP is known to have very high affinity for the mu receptor and a long duration of action, the effects of intranasal BUP/NX in individuals dependent on BUP may differ substantially from its effects in those dependent on short-acting opioids with lower affinity (e.g., see Schuh et al., 1996, Walsh et al., 1995). Thus, the present study sought to examine the effects of intranasal BUP compared to BUP/NX among opioid-dependent individuals maintained on a short-acting full mu opioid agonist, mimicking the typical out-of-treatment scenario for those dependent on heroin or short-acting prescription opioids who may misuse buprenorphine products.

Section snippets

Participants

Eleven adult volunteers completed this study. All were physically dependent on short-acting opioids, recruited through advertisements, and determined to be in good health by history, physical examination, electrocardiogram and laboratory tests. Inclusion criteria included ages 18–50 years, within 25% of ideal body weight or BMI <30, prior intranasal opioid use, ≥21 of last 30 days short-acting illicit opioid use. Exclusion criteria included: seizure or respiratory disorders, head injury,

Participant characteristics

Sixty-two individuals were screened in-person, twenty were admitted as inpatients, and eleven completed the protocol. Early discharge reasons were: couldn’t tolerate spontaneous withdrawal during first week (n = 1), no naloxone response (n = 1), personal reasons (n = 2), provided poor/inconsistent data (n = 3), and contraband activities (n = 2). Completers were 7/4 males/females, mean age = 28.4 years; all Caucasian, 11.7 mean years of education, 5/2/4 were single/married/divorced. Based upon TLFB, the

Discussion

This inpatient study examined a range of intranasal BUP and BUP/NX doses in opioid-dependent individuals maintained on the short-acting opioid, oxycodone, to assess opioid agonist and antagonist effects, reinforcing efficacy and safety. It was hypothesized that higher doses (e.g., 16/4) of BUP/NX would potentially precipitate robust and frank withdrawal (Stoller et al., 2001, Walsh et al., 1995) and, thus, a priori safety criteria were set to preclude dose escalation to ensure the safety and

Funding

This study was supported by a grant from the National Institute on Drug Abuse, R01 DA016718-04 (SLW) and the National Center for Research Resources and the National Center for Advancing Translational Sciences, National Institutes of Health, UL1TR000117. Reckitt Benckiser and the National Institute on Drug Abuse provided the drug supply at no cost. None of these agencies had any role in the study design; in the collection, analysis and interpretation of the data; in writing of the report; and in

Contributors

SLW, SB and MRL conceived and designed the study. SLW, SB, VAC and PN provided oversight for the conduct of the study and enrollment of volunteers. MRL provided medical evaluations and medical oversight. VAC and PN managed data collection and conducted data analyses. All authors participated in the preparation and review of the final manuscript.

Conflicts of interest

Conflicts of interest for SB, VV and PN: none. SLW and MRL have received honoraria and travel reimbursement for developing and delivering educational talks through an arms-length unrestricted educational grant from Reckitt Benckiser Pharmaceuticals to PCM Scientific, UK; SLW has also received honoraria from the same grant for organizing and serving as a conference chairperson. SLW and MRL are also serving as consultants to Braeburn Pharmaceuticals and Camurus in the development of novel

Acknowledgements

The authors would like to thank the nursing staff at the Center for Clinical and Translational Research, the research staff at the Center on Drug and Alcohol Research, the pharmacy staff at the Investigational Drug Services Pharmacy at the University of Kentucky for support of this project, and Lisa Middleton, Ph.D. for work on an early draft of the protocol. The authors also thank Reckitt Benckiser Pharmaceuticals, especially Dr. Neil Hyde and Dr. Chris Chapleo, for assistance in obtaining the

References (53)

  • B. Megarbane et al.

    Fatalities in relation to buprenorphine snorting and ethanol co-ingestion: mechanisms of toxicity

    Forensic Sci. Int.

    (2011)
  • K.L. Preston et al.

    Effects of sublingually given naloxone in opioid-dependent volunteers

    Drug Alcohol Depend.

    (1990)
  • J. Rosado et al.

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

    Drug Alcohol Depend.

    (2007)
  • P. Roux et al.

    Buprenorphine sniffing as a response to inadequate care in substituted patients: results from the Subazur survey in south-eastern France

    Addict. Behav.

    (2008)
  • K.W. Simonsen et al.

    Fatal poisoning in drug addicts in the Nordic countries in 2007

    Forensic Sci. Int.

    (2011)
  • M.E. Abreu et al.

    Effect of intravenous injection speed on responses to cocaine and hydromorphone in humans

    Psychopharmacology (Berl.)

    (2001)
  • K. Barrau et al.

    Comparison of methadone and high dosage buprenorphine users in French care centres

    Addiction

    (2001)
  • B.A. Berkowitz

    The relationship of pharmacokinetics to pharmacological activity: morphine, methadone and naloxone

    Clin. Pharmacokinet.

    (1976)
  • R.D. Bruce et al.

    Lack of reduction in buprenorphine injection after introduction of co-formulated buprenorphine/naloxone to the Malaysian market

    Am. J. Drug Alcohol Abuse

    (2009)
  • N.C. Clark et al.

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

    Med. J. Aust.

    (2002)
  • A. Cowan et al.

    Agonist and antagonist properties of buprenorphine: a new antinociceptive agent

    Br. J. Pharmacol.

    (1977)
  • CSAT

    Clinical Guidelines for Buprenorphine in the Treatment of Opioid Addiction

    (2004)
  • H. de Wit et al.

    Rate of increase of plasma drug level influences subjective response in humans

    Psychopharmacology (Berl.)

    (1992)
  • H. de Wit et al.

    Subjective and behavioral effects of diazepam depend on its rate of onset

    Psychopharmacology (Berl.)

    (1993)
  • C. Eiden et al.

    Acute hepatitis and renal failure related to intranasal buprenorphine misuse: case report and analysis of cases reported to the French network for drug monitoring

    Ann. Pharmacother

    (2013)
  • T. Eissenberg et al.

    Buprenorphine’s physical dependence potential: antagonist-precipitated withdrawal in humans

    J. Pharmacol. Exp. Ther.

    (1996)
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