BMJ  2005;331:1352-1353 (10 December), doi:10.1136/bmj.331.7529.1352

Editorial

Is methadone too dangerous for opiate addiction?

The case for using a safer alternative, buprenorphine, is strong

Methadone is an effective treatment for heroin addiction, and it remains the mainstay of drug treatment for opiate dependence in the United Kingdom.¹ The lethal dose of methadone is estimated at 50 mg for an opiate-naive adult.² Nevertheless, many authorities recommend that methadone doses should be gradually increased to maintenance doses of 80-120 mg¹—that is, twice the lethal dose for non-users. The greatly increased risk to users from methadone, particularly black market methadone, thus remains a major concern. Buprenorphine is a partial agonist that has a lower potential for causing respiratory depression than many other opioids, including methadone and heroin.³ It is increasingly used in the United Kingdom to treat opiate dependence, with guidelines for clinical management in primary and secondary care summarised by Ford et al⁴ and Taikato et al.⁵ It is time it replaced methadone as the mainstay of drug treatment for opiate dependence.

A long running debate continues between proponents of long term maintenance treatment with methadone and the proponents of detoxification (in which the dose of a substitute drug is reduced over time to achieve abstinence from all agents). An expert US panel concluded, "although the drug free state represents an optimal treatment goal, research has demonstrated that the state cannot be achieved or sustained by the majority of persons dependent on opiates."⁶ Without digressing further into this debate, we point out that that buprenorphine is at least as effective as methadone in both maintenance and detoxification.^7-9

One mechanism to reduce the diversion of methadone on to the black market is to insist that these drugs are taken in the presence of a pharmacist rather than being given "to take away." Repeated advice to this effect is provided by the UK Department of Health and the Home Office.^{1 10} We have recently contacted 120 of the 140 community drug teams in England and Wales to ask what proportion of new patients on methadone undergo supervised consumption. We found that at least 25% of people who start prescriptions for methadone are still prescribed methadone to take away. This proportion is likely to be much higher in people who remain on methadone in the long term. Historical practice, and the reluctance of many pharmacies to provide supervised consumption facilities, make routine supervised consumption of methadone difficult to provide.

In 2003 there were 167 drug related deaths in Britain where methadone was solely or partly involved.² Just over half of these deaths were due to diverted methadone—that is, methadone that had been sold to the victim on the black market. A total of 1 486 800 prescriptions for methadone were issued in 2003 (www.ppa.org.uk). This translates into an annual death rate of 112 deaths per million methadone prescriptions. In contrast, the risk of death from overdose of tricyclic antidepressants is estimated at 30 per million prescriptions.¹¹ Clearly, opiate dependent people are likely to have much higher levels of risk taking behaviour than recipients of antidepressants, but these figures indicate the relative risk of methadone compared with other drugs that are regularly cited in fatal overdose.

In 2003 310 700 prescriptions were issued for buprenorphine (www.ppa.org.uk). Buprenorphine has not been cited in any drug related deaths reported to coroners in England and Wales since it was licensed for the treatment of opiate dependence in 1999. The Medicines Control Agency adverse drug reactions database has received reports of seven deaths involving buprenorphine, (www.mca.gov.uk), although to what extent these cases were related to buprenorphine or to other factors (such as intercurrent cardiac illness or continued illicit drug use) is unknown.

The maximum licensed dose of buprenorphine is 32 mg, with a suggested maintenance dose of 16 mg/day. Trials have shown that even opiate-naive individuals can tolerate doses of 32 mg of buprenorphine while "experiments on rhesus monkeys proved that buprenorphine does not cause any respiratory depression that requires intervention, even at very high doses (10 mg/kg)."³ Pirnay et al reported a series of 34 deaths involving buprenorphine in France,¹² but buprenorphine was "clearly" responsible for only four of these; most deaths involved its intake with other drugs, especially benzodiazepines and antipsychotics.

Buprenorphine is as prone as methadone to diversion to the black market and it may have a higher propensity to be injected than oral methadone.^{5 8} This is probably the main reason for the reluctance to use this drug in preference to methadone in some areas. Cost may be another reason; although buprenorphine has clearly been shown to be cost effective,¹³ it is about four times more expensive than methadone (www.BNF.org). Nevertheless, the safety of buprenorphine in overdose is a significant advantage over methadone, especially considering the continued failure to prevent diversion of these agents on to the black market.

(sl006h3607{at}blueyonder.co.uk)
Cambridge and Peterborough Mental Health NHS Trust, Taylor Centre, Southend on Sea, Essex SS4 1RB

National Addiction Centre, Institute of Psychiatry, London, SE5 8BB

Merton Community Drug Team, Department of Addictive Behaviour, St George's Hospital Medical School, London SW17 0RE

---

Competing interests: None declared. None of the authors have received grants, hospitality, financial support, or any other incentives by the manufacturers of buprenorphine; nor do we write this article in the expectation of such incentives.

References

1. Department of Health. Drug misuse and dependence: guidelines for clinical management. London: Stationery Office, 1999.
2. Ghodse H, Schizfano F, Oyefeso A, Bannister D, Cobain K, Dryden R, et al. Drug-related deaths as reported by participating Procurator Fiscal and Coroners. London: St George's Hospital Medical School, 2004 (International Centre for Drug Policy Report 13).
3. Davids E, Gastpar M. Buprenorphine in the treatment of opioid dependence. Eur Neuropsychopharm 2004;14: 209-16.[Medline]
4. Ford C, Morton S, Lintzeris N, Bury J, Gerada C. Guidance for the use of burprenorphine for the treatment of opioid dependence in primary care. London: Royal College of General Practitioners, 2003.
5. Taikato M, Kidd B, Baldacchino A. What every psychiatrist should know about buprenorphine in substance misuse. Psychiatric Bull 2005;29: 225-7.[CrossRef]
6. National Consensus Development Panel. Effective medical treatment of opiate addiction. JAMA 1998;280: 1936-43.[Abstract/Free Full Text]
7. Ling W, Wesson DR, Charuvastra C, Klett CJ. A controlled trial comparing buprenorphine and methadone maintenance in opioid dependence. Arch Gen Psych 1996;53: 401-7.[Abstract]
8. Gowing L, Ali R, White J. Buprenorphine for the management of opioid withdrawal. Cochrane Database Syst Rev 2004;4: CD004417.
9. Simoens, S, Matheson, C, Bond, C, Inkster K, Ludbrook A. The effectiveness of community maintenance with methadone or buprenorphine for treating opiate dependence. Br J Gen Pract 2005;55: 139-46.[Medline]
10. Advisory Council on the Misuse of Drugs. Home Office Report: Reducing Drug Related Deaths. London: The Stationery Office, 2000.
11. Nutt D. Death by tricyclic. J Psychopharm 2005;19(2): 123-34.[CrossRef][ISI][Medline]
12. Pirnay S, Borron SW, Giudicelli CP, Tourneau J, Baud FJ, Ricordel I. A critical review of the causes of death among post-mortem toxicological investigations: analysis of 34 buprenorphine-associated and 35 methadone-associated deaths. Addiction 2004;99(8): 978-88.[Medline]
13. Doran CM, Shanahan M, Mattick RP, Ali R, White J, Bell J. Buprenorphine versus methadone maintenance: a cost effectiveness analysis. Drug Alcohol Depend 2003;71: 295-302.[CrossRef][Medline]

CiteULike    Complore    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this?

Related Articles

Is methadone too dangerous for opiate addiction?: Issue is one of toxicity v acceptability

Adam Bakker and Vanessa Sibanda
BMJ 2006 332: 53. [Extract] [Full Text]

Is methadone too dangerous for opiate addiction?: Methadone is still needed in addiction treatments

Andrew Byrne and Richard Hallinan
BMJ 2006 332: 53. [Extract] [Full Text]

This article has been cited by other articles:

• Kakko, J., Gronbladh, L., Svanborg, K. D., von Wachenfeldt, J., Ruck, C., Rawlings, B., Nilsson, L.-H., Heilig, M. (2007). A Stepped Care Strategy Using Buprenorphine and Methadone Versus Conventional Methadone Maintenance in Heroin Dependence: A Randomized Controlled Trial. Am. J. Psychiatry 164: 797-803 [Abstract] [Full text]  
• Littlewood, C. (2007). A new buprenorphine prescribing service for opiate detoxification. Psychiatr. Bull. 31: 91-93 [Abstract] [Full text]  
• Bakker, A., Sibanda, V. (2006). Is methadone too dangerous for opiate addiction?: Issue is one of toxicity v acceptability. BMJ 332: 53-53 [Full text]  
• Byrne, A., Hallinan, R. (2006). Is methadone too dangerous for opiate addiction?: Methadone is still needed in addiction treatments. BMJ 332: 53-53 [Full text]  

Rapid Responses:

Read all Rapid Responses

Sedative quality of methadone

Jonathan C Haynes, et al.
bmj.com, 9 Dec 2005 [Full text]

Buprenorphine in opiate addiction

Graham Brack
bmj.com, 9 Dec 2005 [Full text]

Methadone deaths. What about Heroin, Alcohol, Benzodiazepines etc?

Roger L Weeks
bmj.com, 12 Dec 2005 [Full text]

Medical change has always needed overwhelming evidence

Andrew J Ashworth
bmj.com, 14 Dec 2005 [Full text]

There is not a case to replace methadone by buprenorphine

Chris H Ford
bmj.com, 15 Dec 2005 [Full text]

Toxicity versus Acceptability

Adam Bakker, et al.
bmj.com, 15 Dec 2005 [Full text]

Safer alternatives to methadone overdue

Clive L Morrison
bmj.com, 15 Dec 2005 [Full text]

Re: Methadone deaths. What about Heroin, Alcohol, Benzodiazepines etc?

David O Yates
bmj.com, 15 Dec 2005 [Full text]

Methadone still needed in addiction treatments.

Andrew Byrne, et al.
bmj.com, 15 Dec 2005 [Full text]

lack of evidence

Jim L Barnard
bmj.com, 16 Dec 2005 [Full text]

partial agonist effect of buprenorphine

ivor p hodgson
bmj.com, 15 Dec 2005 [Full text]

response to editorial

george ryan
bmj.com, 16 Dec 2005 [Full text]

Choice versus Hobson's Choice

Gordon R. Morse
bmj.com, 16 Dec 2005 [Full text]

shooting ourselves in the foot?

stephen brinksman
bmj.com, 19 Dec 2005 [Full text]

Get the facts right please

Adam Bakker
bmj.com, 18 Dec 2005 [Full text]

Buprenorphine is no wonder drug remember temegesic.

Jeff Fernandez
bmj.com, 19 Dec 2005 [Full text]

Better drug treatment infrastructure needed

Michael P Scully, et al.
bmj.com, 19 Dec 2005 [Full text]

Patient choice cannot be ignored/crushing buprenorphine prevents diversion

Susi R Harris
bmj.com, 20 Dec 2005 [Full text]

Re: Get the facts right please

Clive L Morrison
bmj.com, 21 Dec 2005 [Full text]

Deaths involving methadone and buprenorphine were underreported while the risk of methadone poisoning was overestimated

Oliver WC Morgan, et al.
bmj.com, 22 Dec 2005 [Full text]

Response to the editorial "Is methadone too dangerous for opiate addiction?"

Marina Davoli, et al.
bmj.com, 30 Dec 2005 [Full text]

Buprenorphine: no evidence of benefit at three times the cost

John Robson
bmj.com, 1 Jan 2006 [Full text]

Buprenorphine is safer than methadone for antenatal opioid addiction.

Swapna Patankar, et al.
bmj.com, 4 Jan 2006 [Full text]

The relative safety and efficacy of methadone and buprenorphine

Billy Boland, et al.
bmj.com, 13 Jan 2006 [Full text]

Flaws in the argument 'Is methadone too dangerous for opiate addiction?'

Linda D Harris, et al.
bmj.com, 17 Jan 2006 [Full text]

Re: Methadone deaths. What about Heroin, Alcohol, Benzodiazepines etc?

Kristan E Hilchey
bmj.com, 19 Jan 2006 [Full text]