Buprenorphine-with-naloxone sublingual film can be prescribed on the Pharmaceutical Benefits Scheme (PBS) for opiate dependence from 1 September 2011. Its listing means that there are now three buprenorphine products subsidised for this indication (Table 1).
Sublingual buprenorphine products PBS-listed for opiate dependence*
2 mg / 0.5 mg
2 mg / 0.5 mg
* Listed under Section 100 (Opiate Dependence Treatment Program) with supply only through clinics and
pharmacies approved by State and Territory governments
The Pharmaceutical Benefits Advisory Committee recommended listing buprenorphine-with-naloxone sublingual film on a cost-minimisation basis — that is, similar efficacy and cost — compared with buprenorphine-with-naloxone sublingual tablets.1 Treatment must be in conjunction with medical, psychological and social counselling as part of a comprehensive addiction program, and must be in accordance with State or Territory law. For contact details of State or Territory approval bodies, see Appendix 2 of the National clinical guidelines and procedure for use of buprenorphine . Where State or Territory laws permit, authorised nurse practitioners may prescribe this medicine as part of a formal care plan with a medical practitioner (shared care model). See the PBS website for more information on nurse practitioner PBS prescribing.
Less potential for abuse in supervised dosing settings
The sublingual film formulation of buprenorphine with naloxone is intended to make dosing of buprenorphine easier to supervise and so deter misuse of the drug.2 Effective supervision reduces the opportunity for patients to remove the dose from their mouth, which can be later misused by the patient (e.g. injected, snorted) or diverted to others (e.g. given to friends or sold on the illicit drug market).3 Buprenorphine-containing sublingual tablets take 2–10 minutes to dissolve4, which can make supervision of dosing difficult, particularly in pharmacies.5
Buprenorphine-with-naloxone sublingual films dissolve faster under the tongue than buprenorphine-with-naloxone sublingual tablets (on average 6 minutes faster for the 8 mg / 2mg dose2). More importantly, the film rapidly adheres to the oral mucosa, making it difficult to remove.2 While these characteristics should deter removal of the product, it remains to be seen whether the sublingual film has a lower rate of abuse than the combination sublingual tablet (administered whole, broken or crushed) or than methadone syrup.
History of buprenorphine use for opiate dependence
Buprenorphine is a partial opioid agonist with a high affinity for the µ-receptor. It reduces craving and diminishes the effects of heroin or other full opioid agonists by blocking them from binding to the µ-receptor.3
Buprenorphine is less effective than methadone syrup for retaining people on treatment, but is equally effective — in flexible doses — at suppressing heroin use.6
Its partial agonist activity means it has a lower overdose risk than methadone, although it can cause fatal overdose if combined with other sedatives.3
Given differences between individuals and programs, factors such as individual preference, variation in absorption, response to treatment, adverse effects and logistics of dosing should determine treatment selection.3
Buprenorphine is poorly absorbed if swallowed (10% bioavailability) and so must be administered sublingually (30–55% bioavailability) to be effective.3
Naloxone is used to discourage injection of buprenorphine.3 Naloxone is poorly absorbed sublingually and orally but if injected can reduce the agonist effects of buprenorphine and may precipitate unpleasant withdrawal symptoms in people who are opioid dependent.3
Buprenorphine sublingual tablets (Subutex) were PBS listed in 2001 but have been associated with high rates of diversion and abuse.7,8 Buprenorphine-with-naloxone sublingual tablets (Suboxone) were PBS listed in 20069; postmarketing surveillance indicates that they are less abused than the single-ingredient tablet (see below).10–12
An alternative to buprenorphine-with-naloxone tablets for unsupervised dosing
There are no data to suggest that the sublingual film is less likely to be abused than the combination tablets when dosing is unsupervised.
Naloxone has reduced but not eliminated buprenorphine abuse.10 Australian postmarketing surveillance from 2006 to 2009 found that a minority of people who inject drugs (either on or off treatment with opioid substitution) had recently injected buprenorphine-with-naloxone sublingual tablets.11,12 However, fewer had injected them than had injected buprenorphine single-ingredient tablets or methadone syrup. Overall, levels of injection for the combination tablets were lower than for the single-ingredient tablets but were about the same as for methadone syrup.11,12†
†Adjusted for availability of the opioid substitution therapy.
Be vigilant for intravenous misuse
It is not known whether the risk of post-injection thrombosis differs between buprenorphine-with-naloxone film and buprenophine-containing tablets.
Serious local reactions, such as tissue necrosis, thrombosis, nerve damage and limb ischaemia as well as potentially serious acute hepatitis have been reported with injection of sublingual buprenorphine tablets.10,13
Possible film-specific adverse reactions
Like buprenorphine-with-naloxone tablets, the sublingual film, particularly if not dosed carefully, commonly causes withdrawal symptoms, including insomnia, abdominal pain, diarrhoea, muscle aches, anxiety, and/or sweating.13
Oral mucosal erythema, glossodynia, oral hypo-aesthesia, stomatitis, toothache and a coated tongue were reported in small numbers of people in an uncontrolled safety study of buprenorphine-with-naloxone film, but it is uncertain if they are related to the film formulation specifically.2
Dose adjustment may be required when switching between tablets and film
Monitor closely and assess if dosage adjustment is required when switching between the sublingual film and buprenorphine-containing tablets because some individuals may experience a difference in clinical effect.13 The bioavailability (Cmax or AUC) of buprenorphine is about 20% greater for buprenorphine with naloxone 8 mg / 2 mg sublingual film than for the corresponding tablets; but this may not be clinically important for many patients.2
A starting dose of 6–8 mg of buprenorphine on day 1 is recommended.3 This can be given as a single dose if the patient is in moderate to severe opiate withdrawal. For patients who are in mild to moderate opiate withdrawal or transferring from methadone, the dose should be divided (e.g. 4 mg + 4 mg) with an observation period of at least 1 hour after the first dose.3
Doses should be titrated on subsequent days by increments of 2–8 mg/day until a therapeutic dose is achieved (usually between 12–24 mg/day for most patients).14,15 The maximum daily dose of buprenorphine is 32 mg.13
Starting buprenorphine-with-naloxone sublingual film
To help plan dosing, assess the following before starting buprenorphine3,13:
- opioid dependency (quantity, frequency, duration)
- the time when the person last administered an opioid
- the type of opioid dependence (that is, long- or short-acting opiates)
- the likelihood of concurrent opiate use
- concurrent medical conditions
- use of other drugs, particularly benzodiazepines and alcohol.
To avoid precipitating opioid withdrawal, delay the first buprenorphine dose until early signs of withdrawal appear.3
- at least 6 hours, and preferably 12 hours, after last heroin use.
- at least 24 hours after last methadone dose — reduce methadone dose to lowest tolerable level before transfer (generally aim for methadone doses of < 40 mg).
If the patient has recently used methadone, treat initially with buprenorphine monotherapy rather than the naloxone-containing tablet or film, and switch to buprenorphine-with-naloxone film or tablet on the third day.3
Advice for patients
Provide patients with the following information.13,16
- Place buprenorphine-with-naloxone sublingual film under the tongue and keep it there until completely dissolved (4–8 minutes on average).
- Do not swallow, chew or move the film after it is placed under the tongue, as doing any of these makes the medicine less effective.
- Do not eat or drink anything until the film is completely dissolved.
- Do not inject buprenorphine-with-naloxone sublingual film. People are likely to experience strong opioid withdrawal symptoms from naloxone if they inject the medicine while still receiving other opioids. Also, people have developed blood clots, liver problems, and infections from injecting buprenorphine-with-naloxone tablets.13,17
For people on a dose that requires more than one film:
- place no more than two films at a time under the tongue, taking care not to overlap them.
- wait until the first two films are completely dissolved before placing any additional ones.
- Do not use any benzodiazepines (medicines used to treat anxiety or sleeping problems) unless prescribed. People have died from respiratory failure when using benzodiazepines at the same time as buprenorphine.
- Do not take buprenorphine-with-naloxone sublingual film too close to other opioids, as it can cause withdrawal symptoms. Wait 6 hours or more after short-acting opioids (e.g. heroin, morphine, oxycodone) and wait 24 hours or more after methadone before taking buprenorphine with naloxone.
- Buprenorphine-with-naloxone sublingual film can cause drowsiness, which is made worse by drinking alcohol or taking sedatives or anti-anxiety medicines.
- Tell your doctor about all other medicines you are taking. Several medicines can change the effect of buprenorphine with naloxone, making it either less effective (e.g. some medicines for HIV) or increasing the risk of side effects (e.g. benzodiazepines, sedative antihistamines, antidepressants, antipsychotics).
What does the sublingual film look like?
Buprenorphine-with-naloxone sublingual film is a paper-thin, orange-coloured rectangular strip. The two strengths (buprenorphine with naloxone 2 mg / 0.5mg and 8mg /2 mg) are identical in length and width (approximately 22 × 13 mm) but are distinguishable by a white ink imprint of the product strength on each film: ‘N2’ and ‘N8’, respectively. Each film is enclosed in a sachet, with 28 films per carton.2,13
- Pharmaceutical Benefits Advisory Commitee. March 2011 PBAC meeting outcomes – positive recommendations. Canberra: Department of Health and Ageing, 2011. http://www.health.gov.au/internet/main/publishing.nsf/Content/pbacrec-mar11-positive (accessed 13 May 2011).
- Therapeutic Goods Administration. Australian Public Assessment Report for Buprenorphine/Naloxone (Suboxone Sublingual Film), March 2011. Canberra: Commonwealth of Australia, 2011. http://www.tga.gov.au/pdf/auspar/auspar-suboxone.pdf (accessed 10 May 2011).
- Lintzeris N, Clark N, Winstock A, et al. National clinical guidelines and procedures for the use of buprenorphine in the maintenance treatment of opioid dependence. Canberra: Commonwealth of Australia, 2006. http://www.health.gov.au/internet/drugstrategy/publishing.nsf/Content/buprenorphine-guide (accessed 10 May 2011).
- Reckitt Benckiser Pty Ltd. Suboxone (buprenorphine + naloxone) sublingual tablets product information (last updated 27 July 2005).
- Muhleisen P, Neilsen S, Spence J, et al. Crushing sublingual buprenorphine-naloxone tablets: Impact upon dissolution time for supervised dispensing. Australian Pharmacist 2010;19:158–62. http://www.psa.org.au/site.php?id=5436
- Mattick RP, Kimber J, Breen C, et al. Buprenorphine maintenance versus placebo or methadone maintenance for opioid dependence. Cochrane Database Syst Rev 2008;CD002207. [PubMed]
- Winstock AR, Lea T, Sheridan J. Prevalence of diversion and injection of methadone and buprenorphine among clients receiving opioid treatment at community pharmacies in New South Wales, Australia. Int J Drug Policy 2008;19:450–8. [PubMed]
- Jenkinson RA, Clark NC, Fry CL, et al. Buprenorphine diversion and injection in Melbourne, Australia: an emerging issue? Addiction 2005;100:197–205. [PubMed]
- Therapeutic Goods Administration. Public summary document for buprenorphine hydrochloride with naloxone hydrochloride, sublingual tablets, 2 mg (base) – 500 micrograms and 8 mg (base) – 2 mg, Suboxone, November 2005. Canberra, 2005. http://www.health.gov.au/internet/main/publishing.nsf/Content/pbac-psd-buprenorphine-nov05 (accessed 8 July 2011).
- Degenhardt L, Larance BK, Bell JR, et al. Injection of medications used in opioid substitution treatment in Australia after the introduction of a mixed partial agonist-antagonist formulation. Med J Aust 2009;191:161–5. [PubMed]
- Larance B, Degenhardt L, Lintzeris N, et al. Post-marketing surveillance of buprenorphine-naloxone in Australia: Diversion, injection and adherence with supervised dosing. Drug Alcohol Depend 2011, May 12. [PubMed].
- Larance B. K, Degenhardt L, Mattick R.P, et al. The diversion and injection of the pharmaceutical opioids used in opioid substitution treatment: findings from the Australian post-marketing surveillance studies of buprenorphine–naloxone, 2006–2008. Technical Report No 302. Sydney: National Drug and Alcohol Research Centre, 2009. http://www.med.unsw.edu.au/NDARCWeb.nsf/page/NDARC%20Technical%20Reports (accessed 13 May 2011).
- Reckitt Benckiser Pty Ltd. Suboxone Sublingual Film (buprenorphine + naloxone) product information (last updated 4 February 2011).
- Royal College of General Practice (UK). Guidance for the use of buprenorphine for the treatment of opioid dependence in primary care. 2004. http://www.rcgp.org.uk/PDF/drug_buprenorphine.pdf (accessed 7 July 2011).
- Rossi S, ed. Australian Medicines Handbook. Adelaide: Australian Medicines Handbook Pty Ltd, 2011.
- Reckitt Benckiser Pty Ltd. Suboxone Sublingual Film (buprenorphine + naloxone) consumer medicine information (December 2010).
- Ho RCM, Ho ECL, Mak A. Cutaneous complications among i.v. buprenorphine users. J Dermatol 2009;36:22–9. [PubMed]