Injection of medications used in opioid substitution treatment in Australia after the introduction of a mixed partial agonist–antagonist formulation

Opioid substitution treatment — administering a substitute opioid to help manage withdrawal or maintain a patient on a controlled dose — aims to reduce illicit opioid use and its attendant harms.1-4 Non-adherence with directions for taking opioid substitution treatment medication includes injection when it is not prescribed as injectable, and diversion for injection by a person for whom it is not prescribed.5,6 Both injection and diversion of pharmaceutical opioids (including those prescribed for pain management) cause significant public health problems in many countries.7-10 However, few strategies to deter injection or reduce diversion have been empirically evaluated.

In Australia, methadone is the most widely used opioid substitution treatment, but since November 2000, higher-dose formulations of buprenorphine (BPN; Subutex, Reckitt Benckiser) have been registered for this purpose. Implementation of BPN is largely based on that used for methadone (Box 1), but with very restricted availability of takeaway (unsupervised) doses, because of the problems of injection and diversion. Injection of BPN sublingual tablets has been associated with limb ischaemia and tissue necrosis, abscesses, cellulitis, endocarditis, nerve damage, thrombosis, pulmonary granuloma, and candida endophthalmitis.9,12-14

Diversion and injection of opioid substitution treatment medications vary according to prescribing, client supervision and dispensing practices; cost of treatment; the availability of other drugs; and cultural factors.10,15 There is suggestive evidence that supervised dosing, and both dilution of methadone takeaways and restricted access to syringes facilitating injection of large volumes, may reduce diversion and injection, respectively.16 To deter injection, a new formulation of opioid substitution treatment has been developed — buprenorphine (a partial opioid agonist) combined with naloxone (an opioid antagonist) in a 4 : 1 ratio (BNX; Suboxone, Reckitt Benckiser).17,18 When taken sublingually, BNX’s actions are indistinguishable from BPN alone. However, when injected by a person dependent on a full agonist, such as heroin or methadone (but who is not in withdrawal), BNX can precipitate a more aversive withdrawal syndrome than injecting BPN alone.17,19 There is also limited laboratory evidence that it can be injected by those already taking BPN without causing withdrawal features.20

BNX was released on the Pharmaceutical Benefits Scheme in April 2006. Policies regarding takeaway doses have varied, but most Australian states have allowed a more liberal takeaway policy for BNX. Despite this, few clients receive more than 1 week’s takeaway supply at a time. There is limited documented experience of the impact of the introduction of BNX on diversion and injection.

We aimed to monitor the levels and predictors of injection of BNX, compared with injection of methadone and BPN, adjusting for availability.

Injecting was studied in two populations: regular injecting drug users (“IDUs”) not in opioid substitution treatment, and current opioid substitution treatment clients (“clients”).

The proportion of opioid substitution treatment medication sales in Australia accounted for by BPN and BNX is shown in Box 2. There was a steady increase in sales of BNX from April 2006; by August 2007, it accounted for more of the total Australian opioid substitution treatment medication sales than BPN. The total buprenorphine (BPN plus BNX) market share did not change: it consistently accounted for just over 25% of all doses (with methadone accounting for the remainder).

We were able to assess changes in the levels of injection of opioid substitution treatment medications among at-risk IDUs in all Australian capital cities, adjusting for availability as indicated by sales data, and allowing for direct comparisons of three opioid substitution treatment medications. These data suggest that BNX is less likely to be regularly injected than either methadone or BPN, consistent with laboratory studies.24

Given that BNX has not only overtaken market sales of BPN, but is also generally available as takeaway medication (unlike BPN), the deterrent effect of the combination product may be even greater than the comparisons in our study suggest. This finding has important implications for public health, given the potential for severe consequences of BPN injection. We acknowledge that particular local factors (eg, treatment access and the illicit drug market) will also exert a strong influence on non-adherence and injection. Nevertheless, our findings, together with those showing that weekly dispensed BNX treatment has comparable efficacy to and greater cost-effectiveness than daily supervised BPN,25 suggest that BNX may be expanded as a safe and effective treatment, with perhaps less requirement for supervised dispensing.

Despite the lower levels of injection, we documented that BNX was injected by IDUs and clients. Thus, even with a formulation designed to deter injection, there continues to be some level of non-adherence and injection. Many factors independent of medication formulation are likely to influence the extent of diversion and injecting, including availability of heroin and policies allowing multiple takeaway doses, as well as client characteristics. Client selection to ensure takeaway doses are restricted to those who have largely ceased injecting and have social stability is the basis of the current Australasian Chapter of Addiction Medicine’s Clinical Guidelines.26 This recommendation is consistent with studies suggesting that the people most likely to inject BPN are more chaotic and socially marginalised.27,28

There was clear evidence in our study that IDUs and clients who were injecting other pharmaceutical opioids were also more likely to inject opioid substitution treatment medication, suggesting a preference for injection, even if the medications are not designed to be injected. The role of injectable opioids as a form of opioid substitution treatment has been hotly debated. There is now evidence showing the feasibility and effectiveness of injectable opioid treatment in reducing unsanctioned drug use and related crime, and in enhancing general health and psychosocial functioning.29 The propensity for this group to inject existing pharmaceutical opioids (eg, methadone, BPN, morphine) suggests that these medications may be more feasible alternatives to establishing a heroin treatment program, with all its complex medicolegal hurdles. A randomised controlled trial comparing injectable methadone, injectable heroin and oral methadone is currently underway in the United Kingdom.30

A limitation of our study was that BNX’s introduction was accompanied by an information campaign suggesting that injecting it would cause “bad effects”, and emphasising the importance of patient selection; namely, that takeaway doses should only be provided to clients who were “stable”. Doctors may have selected such patients for BNX, while those most at risk of injecting continued to receive BPN, and this might account in part for the higher levels of BPN injection. Further and ongoing studies are needed to investigate this and to examine possible changes across time in the levels and correlates of injection. The IDUs and clients recruited for our study were selected from capital cities and areas where levels of injection of opioid substitution treatment medications may be higher; the levels of injection should not be taken to be representative of all clients in opioid substitution treatment in Australia.

In the 18 months after its introduction in Australia, BNX was injected by fewer IDUs and less frequently, compared with BPN, particularly given emerging differences in the availability of these different opioid substitution treatment medications. Some individuals did nonetheless regularly inject BNX. Post-marketing studies must continue for sufficient time to evaluate longer-term trends in use and harms, because it cannot be assumed that more IDUs will not develop practices to minimise the adverse consequences associated with injection of BNX. Although adaptations of drug formulations have an important role in minimising misuse of opioid medications and enhancing adherence with treatment, they must not replace good clinical care and ongoing patient assessment and monitoring. Furthermore, the trends reported here might change if BPN is no longer used as an opioid substitution treatment medication (as some people currently injecting BPN might begin BNX injection), or if other treatment conditions change. Research is underway to examine ongoing patterns of injecting of this medication.

2 Estimated proportion of opioid substitution treatment (OST) medication sales accounted for by buprenorphine and buprenorphine–naloxone, January 2005 – August 2007

3 Ratio of injection of opioid substitution treatment (OST) medications by regular injecting drug users to volume of sales of OST medications, 2003–2007

Bars are 95% CIs. * Data on days of injection were only available for 2005 onwards, and could not be aggregated for buprenorphine forms.