Post-marketing surveillance of buprenorphine-naloxone in Australia: Diversion, injection and adherence with supervised dosing

Abstract

Background

These studies compared the diversion and injection of buprenorphine-naloxone (BNX), buprenorphine (BPN) and methadone (MET) in Australia.

Methods

Surveys were conducted with regular injecting drug users (IDUs) (2004–2009, N = 881–943), opioid substitution treatment (OST) clients (2008, N = 440) and authorised OST prescribers (2007, N = 291). Key outcome measures include the unsanctioned removal of supervised doses, diversion, injection, motivations, drug liking and street price. Levels of injection among IDUs were adjusted for background availability of medications. Doses not taken as directed by OST clients were adjusted by total number of daily doses dispensed.

Results

Among regular IDUs, levels of injection were lower for BNX relative to BPN, but comparable to those for MET, adjusting for background availability. Among OST clients, fewer BNX clients (13%) reported recently injecting their medication, than BPN (28%) and MET clients (23%). Fewer MET clients (10%) reported removal of supervised doses, than BPN (35%) and BNX clients (22%). There were no differences in prevalence of recent diversion (28% of all OST clients). Adjusting for the total doses dispensed, more BPN was injected (10%), removed (12%) and diverted (5%), than MET (5%, <1% and 2% respectively) and BNX (5%, 9% and <1% respectively). In 2009, the median street price of BNX was equivalent to that for BPN.

Conclusions

BNX was less commonly and less frequently injected than BPN, but both sublingual medications were diverted more than liquid MET.

Introduction

Opioid substitution treatment (OST) for opioid dependence is effective in reducing mortality, HIV transmission, crime, and other drug use (Mattick et al., 2003, Mattick et al., 2008, Mattick and Degenhardt, 2003, HIV/AIDS, 2004). Two risks associated with OST are the diversion of medication to illicit markets, and injection of drugs designed for oral use. The resultant public health concerns include dependence, injection-related injuries and diseases, overdose, and mortality (Degenhardt et al., 2008). A black market in OST medications contributes to the burden of disease and social costs of opioid dependence.

In this paper, the term diversion describes the unsanctioned supply of regulated pharmaceuticals from legal sources to the illicit drug market, or to a user for whom the drugs were not intended (Inciardi et al., 2007). Adherence describes the taking of medication in accordance with prescription directions and specified treatment conditions (e.g. consumption of specified doses at specified intervals via the intended route of administration and, in most cases in OST, under supervision). Non-adherence is, therefore, any use of a medication by the individual to whom it was prescribed where the medication was not taken exactly as directed. This includes (but is not limited to) the unsanctioned removal of all or part of a supervised dose from the dosing site for personal use or diversion to others, using additional sources of medication, splitting doses, stockpiling doses, taking more or less than the prescribed dose, and alternative routes of administration (including injecting, smoking or snorting prescribed medications) (Larance et al., in press-a).

Several international studies have reported the nature, extent and consequences of injecting buprenorphine (BPN) (e.g. Aboltins et al., 2005, Aitken et al., 2008, Berson et al., 2001, Boyd et al., 2003, Degenhardt et al., 2008, Feeney and Fairweather, 2003, Jenkinson et al., 2005, Pirnay et al., 2004, Winstock et al., 2008b). Buprenorphine-naloxone (BNX), an opioid agonist-antagonist formulation, was specifically developed to deter injection by precipitating withdrawal symptoms if injected by opioid dependent users (Chiang and Hawks, 2003, Mammen and Bell, 2009, Mendelson and Jones, 2003) – a seemingly “simple” and potentially cost-effective deterrence strategy (Fudala and Johnson, 2006, Grudzinskas et al., 2006, Sapienza, 2006, Schuster, 2006). Few studies have evaluated this strategy empirically under usual prescribing conditions, and the studies that have been conducted offer mixed support for the BNX formulation.

Six published studies have documented the diversion and/or injection of BNX (Alho et al., 2007, Bruce et al., 2009, Degenhardt et al., 2009a, Monte et al., 2009, Robinson et al., 1993, Vicknasingam et al., 2010). These studies have been subject to a number of limitations, including: small sample sizes (Alho et al., 2007, Bruce et al., 2009, Monte et al., 2009, Robinson et al., 1993); being in the period immediately after the medication was introduced (Alho et al., 2007, Vicknasingam et al., 2010); failure to quantify levels of diversion and/or injection (Bruce et al., 2009, Monte et al., 2009); and failure to compare BNX with other OST medications (Alho et al., 2007, Bruce et al., 2009, Monte et al., 2009). Three of these studies found BNX to have a lower street value than BPN in the period immediately following the medication's introduction (Alho et al., 2007, Robinson et al., 1993, Vicknasingam et al., 2010), although it is not clear whether this is sustained over time. A Malaysian study found that the introduction of BNX did not reduce injection-related risk behaviours among participants who had previously injected BPN, and although symptoms of withdrawal were reported, they did not result in a decrease in the self-administered BNX dose (Bruce et al., 2009). Larger unpublished studies by Schuster and colleagues in the United States (US) concluded that BNX had a low abuse potential, and that extra-medical use was mainly for “therapeutic” reasons (i.e. self-treatment of withdrawal symptoms) (Schuster, 2005). These population-level studies drew on multiple data sources to minimise bias, but did not collect data from an important ‘at risk’ population – regular IDUs who are not in treatment.

BNX has been available for the treatment of opioid dependence in Australia since April 2006, and by early 2007 sales of BNX exceeded those for BPN.¹ Although methadone (MET) retains the largest share of the OST market, from late 2008 there has been an apparent relative increase in overall market share of BPN (any form) from 26% in August 2008 to 34% in September 2009 (see Supplementary material). Upon commencing OST in Australia, clients usually attend the clinic or pharmacy to take their doses under supervision (i.e. a pharmacist or clinician directly observes the client consuming the dose). In most jurisdictions, the majority of OST doses are administered daily under supervision. Stable OST clients may be eligible for some unsupervised doses of their medication (i.e. they are dispensed their medication to take without being directly observed). In general, there is provision for unsupervised dosing of MET and BNX, but not BPN, based on individualised risk assessments with each patient. There are some jurisdictional policy differences regarding required length of time in treatment and the number of unsupervised doses permitted. Where patients are suspected of removing supervised doses or diverting BPN, some jurisdictional policies encourage transfer to BNX, even if the patient is not eligible for unsupervised doses.

Soon after its introduction, we concluded that BNX was injected by fewer IDUs, less frequently, than the mono-BPN product (Degenhardt et al., 2009a). The current paper builds on this preliminary work by utilising multiple data sources collected over a longer time period. This is the first study directly comparing the diversion and injection of MET, BPN and BNX among two important ‘at risk’ populations – regular, out of treatment IDUs and current OST clients.

Specifically, this study seeks to answer the following questions:

• Is there less injection of BNX, compared to BPN and MET, among regular (out of treatment) IDUs and OST clients, over a sustained period of time (beyond the initial 12 months of BNX availability)?

• What quantities of OST medications are not taken as directed and/or leaked to the illicit market by clients receiving treatment (“non-adherence”)?

• What are the motivations for these (non-adherent) behaviours?

• What is the illicit street price of BNX, compared to BPN, over time?