Maintenance drugs to treat opioid dependenceBMJ 2012; 344 doi: http://dx.doi.org/10.1136/bmj.e2823 (Published 15 May 2012) Cite this as: BMJ 2012;344:e2823
- 1National Drug and Alcohol Research Centre, University of New South Wales, Sydney NSW 2031, Australia
- 2Alcohol and Drug Service, St Vincent’s Hospital, Darlinghurst NSW 2010, Australia
- 3Discipline of Pharmacology, University of Adelaide, SA 5005, Australia
- Correspondence to: M Farrell
A 39 year old woman started injecting heroin when she was 18 but soon found she could not control her drug intake or her life in general. At age 30, she sought help and did well with methadone treatment, taking no illicit drugs for three years. However, she then relapsed to heroin use and spent a year in prison, where she continued to inject heroin. After being released, she went to a residential rehabilitation centre. Subsequently in the community her general practitioner started her on buprenorphine. Her life became more stable. She did well with buprenorphine treatment for a few years but restarted injecting heroin after stopping buprenorphine. She restarted buprenorphine and now takes no non-prescribed medication. She works as a waitress and lives with her non-drug using partner.
What is opioid dependence?
This article is intended for practitioners who occasionally manage patients with opioid dependence. Methadone, a mu opioid agonist, and buprenorphine, a partial agonist, are the main drug treatments for dependence on opioids (which include heroin, morphine, and oxycodone, as well as the other pharmaceutical opioids1 2) for detoxification, maintenance, and ultimately abstinence. Treatment with maintenance goals is referred to as opioid substitution treatment or opioid agonist pharmacotherapy.3 Such treatment is reserved for patients with clearly established opioid dependence and prolonged daily opioid use (by either smoking or injecting). In some countries the combination of buprenorphine and naloxone is preferred (and is now becoming available as a film taken sublingually). Prescription heroin, known in the United Kingdom as heroin assisted treatment or injectable opiate treatment, is used in some countries but is not discussed in this article.4 5 6 Naltrexone blocks the effects of heroin on the mu receptor,2 but oral naltrexone treatment has had low adherence and high discontinuity rates.7 8 Use of naltrexone in the form of implants and extended release injection is currently in the research and development phase9 and is outside the scope of this paper.
How well do methadone and buprenorphine work?
More than 30 randomised controlled trials report moderately strong evidence of efficacy as measured by reduction in non-prescribed opioid use, reduction in mortality, and retention in treatment.3 10 11 12 13 A Cochrane review found that retention in treatment was lower for buprenorphine than for methadone when flexible doses were used (relative risk 0.85; 95% confidence interval 0.73 to 0.98).11 This translates to a number needed to treat of 9.62, indicating that for every nine people treated with methadone one additional person will be retained in treatment than would be the case with buprenorphine. Despite the breadth of published evidence (summarised in the table⇓), opioid substitution treatment remains controversial, with some strongly polarised views on the priority of outcomes ranging from stable maintenance to stable abstinence from all drugs.
Data on mortality from randomised controlled trials is weak because of the small size of the studies, but larger scale cohort studies report a significant reduction in mortality for methadone maintenance compared with no treatment (relative risk 0.17; 0.05 to 0.63).3 A wide range of clinical guidelines including those from the World Health Organization,3 National Institute for Health and Clinical Excellence (NICE)14 and more than 20 multilingual national guidelines,1 15 support the use of methadone and buprenorphine. Although treatment often includes psychosocial assistance (as in the case scenario above), the nature, extent, and benefits of adjuvant psychosocial assistance is uncertain.3 16 Nevertheless, psychosocial assistance is generally demanded as a necessary component of the overall treatment programme and considered an indicator of quality. When cessation of medication is unplanned, most individuals return to heroin use and crime.17
How safe are methadone and buprenorphine?
A recent analysis of data from the UK General Practice Research Database calculated standardised mortality ratios of 5.3 (95% confidence interval 4.0 to 6.8) for patients “on treatment” (taking opiate substitution treatment) and 10.9 (9.0 to 13.1) for patients “off treatment” (not taking it).18 Other studies have also found high rates of deaths from overdose after cessation of opiate substitution treatment, and significantly lower annual death rates for those in continuous opiate substitution treatment (1.6%) compared with death rates in the year after patients stopped treatment (8.2%).17 This substantial difference in mortality risk3 17 18 19 makes both methadone and buprenorphine important agents for reducing mortality in a treatment population.
The first two weeks after methadone is started has been reported as being associated with a greater risk of death (crude mortality rate 1.7 per 100 person years compared with 1.3 per 100 person years for those off treatment),18 but once patients are stabilised on methadone the mortality risk drops significantly (to 1.32 per 100 person years in weeks 3 and 4 of treatment, and to 0.61 per 100 person years for the rest of time on treatment).1 18 20
A dose related prolongation of the QT interval and sleep apnoea is reported with methadone, but cardiac events are infrequently reported.21 Individuals with a history of cardiac disease and those taking very high doses of methadone should have electrocardiography.
Buprenorphine is less of a depressant than methadone and is thought to cause a lower mortality risk from overdose at the start of treatment, and fewer QT interval changes, but insufficient data are available for quantifying the difference.
What are the precautions?
Cautious dose initiation with methadone is essential. Supervision of dispensed medication is needed, together with regular monitoring and review with appropriate adjustment of dosage.1 If the patient has received treatment recently elsewhere, obtain full information about that treatment from the previous prescribing doctor and/or dispensing pharmacist and check that the patient is not currently receiving medication from elsewhere.1 The half life of a single first dose of methadone is 12-18 hours, with a mean of 15 hours. With ongoing dosing, the half life of methadone is extended to 13-47 hours with a mean of 24 hours. This prolonged half life contributes to the fact that blood methadone concentrations continue to rise during the first week of daily dosing and fall relatively slowly between doses. Methadone reaches steady state in the body (where drug elimination equals the rate of drug administration) after a period equivalent to 4-5 half lives or 3-10 days. Clinicians should explain clearly that it takes time to complete induction on to methadone and that patients will experience increasing effects from methadone over the first few days of treatment even if the dose is not increased.
Contraindications and use of other drugs
There are no absolute contraindications to methadone or buprenorphine. However, all patients starting on methadone and buprenorphine must be informed of the risk of toxicity and overdose. The risk is highest in the initial period of treatment as stable blood concentrations of methadone are achieved, particularly if heroin or other sedating drugs are used on top of the prescribed medication.
Use of hypnosedative medication with either buprenorphine or methadone is associated with increased risk of overdose and death.1 When patients are reporting heavy use of alcohol and benzodiazepines and other sedative medication, exercise extreme caution in the early induction and subsequent maintenance phase. In addition, it is essential that the medication is safely stored to avoid children taking it. Supervised dispensing is an important safety strategy, to improve treatment adherence and reduce risk of overdose. Medication supervision will enable monitoring and liaison with the dispensing pharmacist and is strongly encouraged, at least in the early phase of treatment.
Avoid coprescribing of benzodiazepines and tricyclic antidepressants as far as possible. Antiretroviral treatments may interact with methadone, less so with buprenorphine; monitoring is needed, with appropriate dose adjustment.
Severe liver and renal disease
Severe liver and renal disease can result in dose accumulation resulting from slow metabolism and delayed elimination. Consider dose reduction or complete withdrawal when the patient is at risk of hepatic encephalopathy. Monitor liver function enzymes for patients prescribed high doses of buprenorphine. Buprenorphine is contraindicated in the presence of severe liver disease.
Pregnancy and breast feeding
Methadone is safe and effective in terms of consistently better obstetric and perinatal outcomes22 23 compared with pregnancies in opioid dependent women not receiving opioid substitution treatment. Further studies of buprenorphine in pregnancy are needed, but studies to date indicate its potential usefulness.24 Opioid substitution treatment can be associated with neonatal abstinence syndrome, but this can be readily managed with withdrawal mangement and supportive care. If required or indicated, medications such as methadone, tincture of opium, morphine, or diazepam can be titrated to withdrawal symptoms.
The most critical side effect is overdose toxicity (fatal and non-fatal), which seems to be a higher risk with methadone than with buprenorphine.1 2 Other side effects of opiates are constipation, sweating, pruritis, loss of libido, and impotence. Patients also complain of severe difficulty in withdrawing from methadone and argue that it results in longer dependence on opioids for them. Clinicians and users state that it is easier to withdraw from buprenorphine, but no robust evidence exists to support this belief.
How cost effective are methadone and buprenorphine?
The NICE and WHO guidelines both considered the comparative cost effectiveness of methadone and buprenorphine.3 13 Methadone costs less and was more cost effective than buprenorphine,3 but when other factors (such as patient choice, treatment retention, and the comparatively greater need for supervised dispensing with methadone) were taken into account, NICE concluded that there was a good case for clinicians and patients having access to both medications and for individual clinical considerations to determine which drug to prescribe.13 Overall, both methadone and buprenorphine are highly cost effective when compared to no treatment. Treatment confers a £5 saving for every £1 spent—that is, savings in costs of criminal justice and health and social care (box 1).13
Box 1 Cost effectiveness of maintenance treatment versus no treatment*
The incremental cost effectiveness ratio for methadone was £13 700 per QALY (quality adjusted life year) gained; the ratio for buprenorphine was £26 400 per QALY gained.
Methadone was more cost effective than buprenorphine in all scenarios considered because it is cheaper and yields marginally more QALYs (0.067).
*From cost effectiveness analysis conducted by a NICE panel13
How are methadone and buprenorphine taken and monitored?
Methadone is taken orally, buprenorphine sublingually. In most settings the initial period of medication is under the supervision and observation of a pharmacy or clinic, where instalment prescriptions are written to enable daily or regular supervised dispensing of medication. Methadone is taken once daily. Most patients take buprenorphine daily, but some take it every other day or very occasionally three times a week. Methadone requires low dose induction, with a maximum initial dose of 30-40 mg (but note that 30 mg is a potentially fatal dose in a non-tolerant individual); maintenance doses range from 60 mg to 120 mg, built up over time. Buprenorphine doses can be increased at a faster rate but may precipitate opioid withdrawal if heroin has been recently consumed. Box 2 provides practical guidance to doctors for prescribing these agents, and box 3 outlines tips for patients.
Supervised urine collection and analysis can show if the patient is using non-prescribed drugs but this adds to costs. The evidence for cost effectiveness of urine testing is weak.
Box 2 Practical guidance for doctors
Start of treatment (first episode)
Offer oral methadone or buprenorphine
The choice of drug should be made jointly by the healthcare professional and the patient (and carer if the patient agrees) after considering the options and taking into consideration the history of previous treatment and previous dose of methadone or buprenorphine
Clarify that the aim of treatment is to achieve good adherence, stop injecting drug use, and stop use of non-prescribed drugs; where this is not possible, the aim is to reach goals such as reduction in injecting and drug risk behaviour
Before starting an opioid agonist, offer the patient electrocardiography if physical examination identifies a specific cardiovascular risk or if the patient has a history of cardiovascular disease or a family history of long QT syndrome
With methadone, begin treatment at the lower end of the licensed dose range and slowly titrate upwards. Doctors need to be aware that methadone 30 mg can be a fatal dose in a non-tolerant individual. Once the patient has been inducted and stabilised, gradually work up to a maximum dose of 60-120 mg over several weeks or months. Be aware that because of the long half life of methadone the cumulative dosing will result in rising blood concentrations by the third day of treatment. When the patient reports high dependence and high dose illicit heroin or methadone use, a clinician may titrate the dose upwards more quickly, but this is best done by a specialist aware of the risk of dose accumulation and potential toxicity. Blood methadone concentrations continue to rise in the first week of treatment, stabilising at 7-10 days. Evidence of intoxication or sedation in the early phase of treatment should result in a reduction in dosage
With buprenorphine, start with 4 mg and work rapidly up to 8 mg or 16 mg as clinically indicated and in discussion with the patient. Again blood concentrations take 7 to 10 days to stabilise
Throughout treatment, and especially during titration, monitor and record clinical response, adverse effects, physical health (including changes in weight), and adherence. There is a risk of diversion of prescribed medication and there are dangers to individuals who consume non-prescribed medication if they are not dependent. There are complex legal implications, moral responsibilities, and potential harms around diversion. The nature of the doctor’s legal responsibilities differs in different jurisdictions. Doctors need to be aware of the local regulations on prescribing controlled drugs. Treatment monitoring should aim to minimise diversion
Treatment of recurrence
Be non-judgmental, as in any other condition, and encourage a fresh start and offer oral medication again. Base the choice of drug on the criteria above as well as previous treatment response. Changing from buprenorphine to methadone or vice versa is a useful way to have a fresh start and focus on options for treatment adherence, a treatment plan, and treatment goals
Listen clearly to and establish agreed treatment goals, both short and long term, and review progress on a quarterly basis. Review long term goals annually
Advise the patient of the high risk of relapse if he or she discontinues use in the next year
When the response to agonist treatment is inadequate, review use of alcohol and psychostimulants and the adherence to and dose of medication; consider other causes of non-response, such as comorbid mental health problems
Management of adverse effects
If the patient reports unwanted effects such as excessive sweating, breakthrough withdrawal symptoms, abdominal discomfort, or other somatic symptoms, consider either increasing the dose for withdrawal symptoms or switching to the alternative medication (methadone or buprenorphine)
Encourage patients to maintain a healthy diet and to exercise regularly to avoid excessive weight gain
Encourage reduction or cessation of nicotine and cannabis; assess for the risk of blood borne virus and status (and inform the patient about risks) and possible treatment need. Assess mood and risk of self harm when appropriate
Box 3 Tips for patients*
There are two main opioid-type agonist drugs that are effective and available: methadone and buprenorphine. Neither is perfect, but both can help you stay away from heroin. Having a very clear focus on what you expect the drug to do will help. Both these drugs are opioids and you will be dependent on them. Users’ views vary widely on the difficulty involved in coming off methadone, and some users state that they would prefer to come off buprenorphine. It’s possible to work down to a low dose of methadone and switch to buprenorphine, but many prefer to stick to the medication they are familiar with
You need to be aware that, like heroin, these drugs when taken in larger doses can seriously suppress breathing and consciousness and can result in overdose and death. Mixing these tablets with heroin and other opiates can also be dangerous and result in serious consequences
You will do much better if you are on a higher dose (methadone >80 mg/day; buprenorphine 12 mg/day); for a longer period (at least 18 months), think carefully about stopping treatment before doing so; plan your discharge from treatment and decrease the dose very slowly (more than three months)
If you are still using heroin, ask if your dose of your opioid can be increased
This is a good time to try and sort out other problems in your life and engage in education, training, or to get work
If you are provided with doses of methadone or buprenorphine, keep these in a child proof container in a safe place
If you do inject drugs, make sure that you use a sterile needle and syringe every time
Have a test for HIV and hepatitis C virus, and arrange vaccination for hepatitis A and B
Try to stop smoking—if you need help to do this, phone a helpline, visit a website, or see a counsellor (phone Smokefree (0800 022 4 332) or go to http://smokefree.nhs.uk/; in Australia go to www.quitnow.gov.au/)
Take care of your health, including dental health and gum disease, to ensure that dental disease that is caused by drug use is kept to a minimum
The length of treatment is variable. Some people who do very well on methadone and buprenorphine are advised to stay on it indefinitely; others, after a period of stability, want to get off it. Some do so successfully, but many others find they have to restart the medication. It is much better to restart the medication than to return to street heroin use and crime
It is important that your GP or treatment specialist monitors your physical health as well as your mental health while you are receiving treatment
You can take methadone in liquid form usually once a day. Some people prefer to take it twice daily—this is usually more practical once you are able to take medication home from the pharmacy
Buprenorphine (and buprenorphine with naloxone) comes as a small tablet that is inserted under the tongue and dissolves; in some countries it is available as a small film strip, which dissolves under the tongue more quickly than the tablet
Alcohol and illicit drugs can interfere with the effects of the opioid drugs and can make you more likely to lose control of your substance consumption and consume a range of other drugs
It’s important that you make your treatment preference clear to your doctor and also that you make clear what you hope to get out of the treatment and that you have a chance to review whether you are getting to where you want to get to and that other options for change are considered if you feel that you have got stuck and stopped making progress
*Based on advice from the Reading Users Forum (a forum in Reading for drug and alcohol users)
How do methadone and buprenorphine compare with other drugs and each other?
Compared with buprenorphine, methadone is associated with considerable stigma but is less expensive, achieves higher rates of retention, and has been used more extensively and evaluated more frequently.3 10 11 12 19 The increased risk of death when starting methadone can be reduced by adherence to induction guidelines.
Some people find both methadone and buprenorphine unacceptable, and use of dihydrocodeine25 has been tried off licence with reasonable success. Studies of slow release oral morphine have also reported positive outcomes.26 Heroin assisted treatment can also be considered for patients who find methadone and buprenorphine unacceptable but is generally reserved for patients who are severely dependent and have been refractory to all other treatments on many previous occasions.4 27 When heroin is not available, other medications, such as hydromorphone, have been studied for such patients.28 Methadone and buprenorphine are now available in 73 countries, and the evidence for effectiveness and cost effectiveness is far stronger than for all other treatments for severe heroin dependence.
Cite this as: BMJ 2012;344:e2823
This is one of a series of occasional articles on therapeutics for common or serious conditions, covering new drugs and old drugs with important new indications or concerns. The series advisers are Robin Ferner, honorary professor of clinical pharmacology, University of Birmingham and Birmingham City Hospital, and Philip Routledge, professor of clinical pharmacology, Cardiff University. To suggest a topic for this series, please email us at.
We thank John Howard and the Reading Users Forum for their advice for the “Tips” box.
Contributors: All authors wrote the article. MF and LG estimated the numbers needed to treat. MF is the guarantor.
Competing interests: All authors have completed the ICMJE uniform disclosure form at www.icmje.org/coi_disclosure.pdf (available on request from the corresponding author) and declare: no support from any organisation for the submitted work. The National Drug and Alcohol Research Centre, of which MF is the director, has received unrestricted grant income from Reckitt Benckiser for post-marketing surveillance and for other evaluation of buprenorphine and naloxone combined. MF has participated in workshops in the Asia Pacific region on the development of treatment services and of research with opioid users; these workshops were supported by an unrestricted educational grant from Reckitt Benckiser, paid to the University of Adelaide. The authors declare no other relationships or activities that could appear to have influenced the submitted work.
Provenance and peer review: Commissioned; externally peer reviewed.
Patient consent not required (patient anonymised, dead, or hypothetical).