A randomised controlled trial of sublingual buprenorphine–naloxone film versus tablets in the management of opioid dependence

https://doi.org/10.1016/j.drugalcdep.2012.12.009Get rights and content

Abstract

Background

Buprenorphine–naloxone sublingual film was introduced in 2011 in Australia as an alternative to tablets. This study compared the two formulations on subjective dose effects and equivalence, trough plasma levels, adverse events, patient satisfaction, supervised dosing time, and impact upon treatment outcomes (substance use, psychosocial function).

Methods

92 buprenorphine–naloxone tablet patients were recruited to this outpatient multi-site double-blind double-dummy parallel group trial. Patients were randomised to either tablets or film, without dose changes, over a 31 day period.

Results

No significant group differences were observed for subjective dose effects, trough plasma buprenorphine or norbuprenorphine levels, adverse events and treatment outcomes. Buprenorphine–naloxone film took significantly less time to dissolve than tablets (173 ± 71 versus 242 ± 141 s, p = 0.007, F = 7.67).

Conclusions

The study demonstrated dose equivalence and comparable clinical outcomes between the buprenorphine–naloxone film and tablet preparations, whilst showing improved dispensing times and patient ratings of satisfaction with the film.

Introduction

Opioid dependence is a disorder that can have serious adverse impacts upon opioid users, their families and the community. Around one in four people who use heroin have been estimated to meet criteria for dependence during their use career (Anthony et al., 1994); an Australian study estimated that perhaps 0.4% of adults 15–54 years were regular or dependent heroin users (Degenhardt et al., 2004). Opioid substitution therapy (OST) using sublingual buprenorphine tablets is a cost-effective treatment approach to reducing heroin use (Doran et al., 2003) and has been widely used for this indication since its first license in 1995. Many countries have introduced treatment systems that require supervised dosing of opioid substitution medications (methadone, buprenorphine), particularly for high-risk patients, and supervised dosing is recommended in many clinical guidelines (Lintzeris et al., 2006, World Health Organisation, 2009) in an attempt to reduce buprenorphine diversion, with particular concerns about the injecting of buprenorphine tablets (Jenkinson et al., 2005, Winstock et al., 2008, Winstock et al., 2009).

However, there are practical difficulties in the effective supervision of sublingual buprenorphine tablets. The tablets routinely take between 3 and 8 min to dissolve sublingually, making complete supervision of dosing inconvenient, labour intensive and often stigmatising for patients (particularly in community pharmacy settings), and substantially increases the cost of treatment (Bell et al., 2007). There have also been a number of reports of fungal, systemic and ophthalmic infections following the injection of tablets that have been administered sublingually and later removed (Cassoux et al., 2002, Feeney and Fairweather, 2003, Loo et al., 2005).

Several approaches have been used to minimise the difficulties of supervising sublingual tablets, such as ‘off-label’ crushing of sublingual tablets prior to dosing to lessen dissolution and supervision time (Muhleisen et al., 2010, Simojoki et al., 2010). Another is the introduction of the buprenorphine–naloxone tablets. Whilst the combination tablets appear to reduce injecting compared to the buprenorphine-mono tablets (Comer et al., 2010, Degenhardt et al., 2009, Larance et al., 2011), they do not address other problems of inconvenience and staff time. Further, it is estimated that between 10 and 15% of ‘supervised’ doses are removed from the dispensing pharmacies and clinic dosing sites in Australia (Larance et al., 2011). Concerns regarding diversion and the difficulties of effective supervision of buprenorphine tablets have resulted in this medication not being available in some treatment settings (e.g., prisons) or by some practitioners (e.g., some GP prescribers or community pharmacies).

A recent development has been the introduction of buprenorphine–naloxone soluble sublingual film preparation in the USA (licensed 2010) and Australia (licensed 2011), in the same 2/0.5 mg and 8/2 mg doses as the existing tablets. The rationale for introducing the buprenorphine–naloxone film is that it would (a) adhere to sublingual mucosa quickly, be less easy to remove and hence require less time for supervised dosing, and (b) have more tamper-proof unit packaging (compared to the tablets) to limit accidental consumption by children (Das and Das, 2004). Strain et al. (2011) demonstrated that 5-days of dosing with 16/4 mg buprenorphine–naloxone film was effective in suppressing withdrawal features in opioid dependent individuals. Single dose studies comparing the kinetics of buprenorphine–naloxone film and buprenorphine–naloxone tablets suggest a higher peak plasma concentration (Cmax) and total bioavailability of the buprenorphine in the buprenorphine–naloxone film preparation compared to the buprenorphine–naloxone tablets preparation (Reckitt Benckiser (Australia) Pty and Ltd., 2011), although the clinical significance of this in treatment-maintained populations (e.g., subjective dose effects, ability to ‘hold’ over 24 h dosing interval) remains unclear.

There have been no controlled studies of the transfer of patients currently treated with buprenorphine–naloxone tablets to the buprenorphine–naloxone film preparation. The introduction of any new medication or formulation in the treatment of opioid dependence can be associated with anxiety for many patients, and can be resisted by some patients and service providers. Particular questions include how the new formulation compares to the existing tablets with regards to: (i) dose effects and dose equivalence, (ii) adverse events, (iii) patient satisfaction, (iv) the time required for effective supervised dosing, and ultimately (v) any impact upon treatment outcomes.

In order to address these questions, a multisite double-blind double-dummy randomised controlled trial (RCT) was conducted comparing buprenorphine–naloxone film to tablets in patients already in treatment with the buprenorphine–naloxone tablet preparation.

Section snippets

Materials and methods

The study design was an RCT comparing buprenorphine–naloxone tablets (Control condition) to buprenorphine–naloxone film (Experimental condition) on a range of outcomes over a 31-day treatment period. The study was conducted in four specialist outpatient opioid treatment programmes (Sydney, Adelaide, South Adelaide, Newcastle), approved by local human research ethics committees and registered with the Therapeutics Goods Administration and the Australian New Zealand Clinical Trials Registry (No.

Results

A recruitment flowchart is shown in Fig. 2. One hundred and thirty-two patients were approached to participate in the trial. Of these, 33 were not interested and/or did not attend recruitment research interviews, and 7 were ineligible due to concurrent serious medical or psychiatric conditions. 92 patients were eligible, enrolled, underwent randomisation and were included in the intention-to-treat analysis. Of those, 85 patients completed study treatment in full and all associated research

Discussion

This is the first paper to compare buprenorphine–naloxone sublingual tablets and film preparations over an extended period of time (24 days) in patients already enrolled in buprenorphine–naloxone treatment. The introduction of new medication formulations can be associated with considerable anxiety for some patients, which can impact upon treatment adherence and outcomes. In order to provide objective data on the differences (if any) across the two formulations (which can also go some way

Conclusions

The buprenorphine–naloxone film appears comparable to the existing tablet preparations across measures of dose effect, adverse events, plasma levels and global clinical outcomes. Most patients should be able to freely transfer between preparations with little need to adjust dosages. The real benefit of the film appears to be the reduced time required to effectively supervise dosing (generally within 30 s) compared to the tablets (several minutes), which should make supervised dosing less

Role of funding source

The study was investigator-led and sponsored by the local health services conducting the study. Reckitt Benckiser had no role in the study design, data collection, analysis, interpretation of data or publication of findings for either study. The Company also played no role in the conception of, or decision to submit, this paper for publication.

Contributors

Authors Lintzeris, Ali, Dunlop, Degenhardt and Leung designed the study and wrote the protocol. Author Lintzeris managed the literature searches and summaries of previous related work and co-wrote the first draft of the manuscript. Author Leung coordinated the conduct of the clinical trial across all participating sites, undertook statistical analysis and co-wrote the first draft of the manuscript. Authors Lintzeris, Ali and Dunlop acted as site investigators and supervised clinical services

Conflict of interest

Authors Nicholas Lintzeris, Robert Ali, Adrian Dunlop and Peter Muhleisen have received honoraria and travel support from Reckitt Benckiser for presenting at professional educational forums and conferences. Nicholas Lintzeris has received untied educational grants from Reckitt Benckiser to conduct research examining intranasal buprenorphine preparations (2007–2008), and drug interactions with benzodiazepines (2003–2006). Louisa Degenhardt and Briony Larance received untied educational grants

Acknowledgements

Reckitt Benckiser (RB), the manufacturer of Suboxone preparations, provided the investigators an untied educational grant for the conduct of this study and also provided trial medications (Suboxone active and placebo preparations). Louisa Degenhardt was supported with NHMRC Fellowship. The authors would like to thank all staff and patients at the Langton Centre, Newcastle Pharmacotherapy Service, Warinilla Clinic and Southern Clinic for their valuable time and contribution to the study.

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    Supplementary materials for this article can be found by accessing the online version of this paper at http://dx.doi.org/10.1016/j.drugalcdep.2012.12.009. Please see Appendix A for more information.

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