Title: International review and UK guidance weigh merits of buprenorphine versus methadone maintenance
Author: M3z2ans M3z2xns A4z4x M50z3x S6z5x M2z7x S6z7x D5z1x D5z10x D5z7x R2z1x N9823b
Last saved by: Mike Ashton
Keywords: meta-analysis dose completion crime buprenorphine methadone cost effectiveness guidelines cost benefit illegal drugs treatment pharmacotherapy agonist attendance requirement heroin non-residential
Document comments: Analysis which informed new UK guidelines on the maintenance treatment of opiate dependence concludes that buprenorphine has slightly less 蘇olding power' than methadone but equivalent suppression of opiate use.

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Bulletin November 2008
International review and UK guidance pronounce on the merits of buprenorphine versus methadone maintenance
An analysis of the most clinically relevant studies of buprenorphine versus methadone maintenance treatment of opiate dependence has confirmed that buprenorphine has slightly less ‘holding power’, but that among patients who are retained, there are equivalent reductions in the illegal use of opiate-type drugs. The findings informed new UK guidelines on the treatments.
FINDINGS The comparison between flexible-dose sublingual (absorbed under the tongue) buprenorphine and oral methadone was one of several made in the updated review for the Cochrane Collaboration, one of the world’s most trusted sources. Where possible, results of relevant studies were statistically pooled. The analysis is important because studies which allow clinicians to adjust the dose depending on how the patient reacts more closely reflect actual and recommended clinical practice than fixed-dose studies.

Mattick R.P. et al. Buprenorphine maintenance versus placebo or methadone maintenance for opioid dependence. Cochrane Database of Systematic Reviews: 2008, 2. http://dx.doi.org/10.1002/14651858.CD002207.pub3

Department of Health (England) and the devolved administrations. Drug misuse and dependence: UK guidelines on clinical management. London: Department of Health [etc], 2007. http://www.nta.nhs.uk/areas/clinical_guidance/clinical_guidelines/docs/clinical_guidelines_2007.pdf

Across the eight studies, 18% more methadone than buprenorphine patients remained in treatment for time periods varying from six weeks to a year. This means, for example, that if 60 out of 100 patients were retained on buprenorphine, had they instead been prescribed methadone, typically another 11 would have stayed in treatment. Retention over at least these periods is key because when patients leave, relapse to dependent illicit opiate use is the norm.

The periods assessed by the studies and included in the Cochrane analysis were: 24 weeks; 17 weeks; 6 months; 13 weeks; 12 months; 6 weeks; 16 weeks; 16 weeks.

Among the studies which provided this data, numbers of positive urine tests (indicative of continuing illegal opiate use) only slightly and non-significantly favoured buprenorphine. The same was true for the patients’ own accounts of their heroin use. There were also no significant differences in use of cocaine or benzodiazepines or in crime. 
IN CONTEXT The analysts’ verdict was that given adequate doses, methadone was the more effective treatment, but not by an overwhelming margin. However, limitations in their analysis and in the source studies it relied on introduce considerable uncertainty.
Some of these may have meant that methadone’s advantage would be greater in everyday practice. Even when they could have got methadone elsewhere, patients were prepared to accept the requirements of the research, including possible allocation to an unfamiliar medication. Possibly they were keen on trying a new medication with less strong opiate-type effects. In all but one of the studies they were (compared to UK caseloads) either early in their addiction or treatment careers, relatively young, or relatively socially included. One of the questions marks over buprenorphine is its suitability for more dependent, high-dose heroin users.
Also perhaps disdavantaging methadone was the way the urine test comparison was calculated. This appears to have ignored missed tests (shorter retention means buprenorphine patients probably missed more) and to have credited to buprenorphine results from some patients who avoided positive tests by switching to methadone.
On the other hand, buprenorphine patients too might have been disadvantaged. The drug permits non-daily dosing and perhaps an earlier shift to unsupervised consumption, for many, more attractive than daily supervised methadone. However, most studies sacrificed these advantages to ‘blind’ patients and staff to which drug was being taken. Blinding also (the patient might have been on methadone) caused unnecessary delays in reaching optimal doses of buprenorphine. Both considerations may have diminished retention on buprenorphine.
These considerations also apply to a recent assessment for the UK’s National Institute for Health and Clinical Excellence (NICE). Combining data from the Cochrane review with (largely health-related) quality of life assessments, it found that methadone’s retention advantage in flexible-dose studies translated in to slightly greater improvements. Combined with lower health service costs (not just in addiction treatment), this meant methadone was preferable. However, the analysis did not explore all the ways in which buprenorphine’s costs might be (and are being) reduced such as unsupervised dosing, nor all the ways in which it might enhance quality of life, and did not fully account for the benefits of greater retention on methadone, adding further layers of uncertainty.

Connock M. et al. Methadone and buprenorphine for the management of opioid dependence: a systematic review and economic evaluation. Health Technology Assessment: 2007, 11(9). http://www.hta.ac.uk/execsumm/summ1109.htm

Though one of the eight studies was omitted (Neri 2005).

Best D. et al. National prescribing audit: an assessment of prescribing practices for opioid substitution treatment in England, 2004–2005. National Treatment Agency for Substance Misuse, 2007. http://www.nta.nhs.uk/publications/documents/nta_npa1_prescribing_audit.pdf

PRACTICE IMPLICATIONS For clinical guidance on how to use buprenorphine see UK prescribing guidelines and a review from three leading US researchers.

Department of Health (England) and the devolved administrations. Drug misuse and dependence: UK guidelines on clinical management. London: Department of Health [etc], 2007. http://www.nta.nhs.uk/areas/clinical_guidance/clinical_guidelines/docs/clinical_guidelines_2007.pdf

Johnson R.E. et al. “Buprenorphine: how to use it right.” Drug and Alcohol Dependence: 2003, 70(2, suppl.), p. S59–S77. http://dx.doi.org/10.1016/S0376‑8716(03)00060‑7

For the Cochrane team their findings meant methadone should be the default maintenance medication, with buprenorphine reserved for environments or patients where high dose methadone is not possible. Their reasoning was that at high or flexible doses, methadone is “associated with better suppression of heroin use”, yet their review concluded this was not the case for flexible dose programmes. They added that in some settings, buprenorphine may be advantaged by its relative safety and alternate-day dosing option, a rider which opens the door for the drug where daily supervised consumption would otherwise be required, take-home doses are desirable, and perhaps in some primary care practices.
Experts and advisers convened by the UK’s National Institute for Health and Clinical Excellence (NICE) put a different spin on largely the same evidence. Their advice was that the choice between the medications should be made “case by case”, based on issues like whether buprenorphine’s safety was a priority in that individual case, whether the patient was aiming to withdraw from opiate-type drugs altogether (easier with buprenorphine), and patient preference. When for an individual the medications were equally appropriate, methadone might be preferred because it cost less and on average extended the benefits of being in treatment. UK prescribing guidelines take a similar line.

National Institute for Health and Clinical Excellence. Methadone and buprenorphine for the management of opioid dependence. NICE technology appraisal guidance 114. National Institute for Health and Clinical Excellence, January 2007. http://www.nice.org.uk/guidance/index.jsp?action=byID&o=11606

Department of Health (England) and the devolved administrations. Drug misuse and dependence: UK guidelines on clinical management. London: Department of Health [etc], 2007. http://www.nta.nhs.uk/areas/clinical_guidance/clinical_guidelines/docs/clinical_guidelines_2007.pdf

Neither assessment fully accounted for the cost-savings and convenience possible due to buprenorphine’s extended effects and relative safety, the latter (as Scottish guidelines point out) particularly applying to tablets which combine buprenorphine and naloxone. This formulation reduces the chances of their being crushed and injected, possibly reducing the need to control diversion to the illicit market by insisting on supervised consumption, and could also underpin an expansion in primary care-based treatment.

Scottish Medicines Consortium. Buprenorphine/naloxone 2mg/0.5mg, 8/2mg sublingual tablet (Suboxone). Scottish Medicines Consortium, 2007. http://www.scottishmedicines.org.uk/smc/files/buprenorphine%20naloxone%20sublingual%20tablet%20_Suboxone_(355‑07).pdf

Uncertainty about overall advantage, allied with differences in the safety and effects of the drugs and possible dispensing arrangements, suggest that the most defensible conclusion is that some patients will be most suited to methadone, others to buprenorphine. Unfortunately, there is little in the research to indicate who will be in which camp. Buprenorphine possibly helps depressed patients more than those not suffering depression and given its pharmacology, patients dependent on large doses of opiates may find it inadequate because there is a ceiling beyond which higher doses do not augment opiate-type effects. Patients who value the ‘wrapped in cotton wool’ feeling typical of heroin may prefer methadone, those who value a clearer mind might prefer buprenorphine. 
In England around the years 2005 and 2006 buprenorphine accounted for over a quarter of patients prescribed opiate substitutes, having rapidly gained ground over the previous years.   Though dispensed more often as take-home doses, patients were less likely to use other opiate-type drugs ‘on top’ than with methadone and were also more likely to be satisfied with their treatments. Methadone is likely to remain the mainstay of maintenance prescribing due its wider appeal to patients and lower cost, but the case for considering buprenorphine is strong and may get stronger if potential cost savings are realised and if methadone’s major advantage – greater retention – comes to be seen as an impediment to successful treatment exit.

National Treatment Agency for Substance Misuse (NTA). The NTA’s 2006 survey of user satisfaction in England. NTA, August 2007. http://www.nta.nhs.uk/publications/documents/nta_2006_survey_of_user_satisfaction_in_england.pdf

National Treatment Agency for Substance Misuse (NTA). Harm reduction findings from the NTA’s 2006 survey of user satisfaction in England. NTA, August 2007. http://www.nta.nhs.uk/publications/documents/nta_2006_harm_reduction_survey.pdf

Best D. et al. National prescribing audit: an assessment of prescribing practices for opioid substitution treatment in England, 2004–2005. National Treatment Agency for Substance Misuse, 2007. http://www.nta.nhs.uk/publications/documents/nta_npa1_prescribing_audit.pdf

Gordon D. et al. The 2007 user satisfaction survey of Tier 2 and 3 service users in England. National Treatment Agency for Substance Misuse, May 2008. http://www.nta.nhs.uk/publications/documents/nta_2007_user_satis_survey_tier2and3_service_users_england.pdf

Appendix: Flexible dose comparisons of methadone and buprenorphine
These notes supplement the descriptions and data relating to the eight flexible dose methadone v. buprenorphine comparison studies analysed in the Cochrane review.
General considerations
As a basis for pooling urine test results, the review asked source study authors to “calculate the number of positive urines in each treatment group and derive a mean number of positive urines with a standard deviation”. It seems that effectively this ignored missed tests. Having on average dropped out sooner, buprenorphine patients probably also missed more tests. Usually it’s assumed that missed tests would have indicated a return to opiate use. Had this been the assumption made in the review, it is likely that buprenorphine would have accrued more (assumed or actual) positive tests relative to methadone, making it seem less effective in suppressing opiate use than in the original analysis. For example, assume in a study half the tests taken by buprenorphine patients were positive and 70% of those taken by methadone patients, and that due to greater retention each methadone patient underwent 15 tests compared to 10 among the methadone patients. Then the ratio of positive buprenorphine/methadone tests is 0.48, suggesting that buprenorphine is over twice as effective in suppressing opiate use. However, if missed tests are treated as positive, the ratio becomes 0.97, practically even.
In environments where patients are required to take their medication under supervision at the clinic or pharmacy, buprenorphine’s long-lasting effects enable dosing to be spaced out every two or three days, making life more convenient for patients and staff with only minor detriment to its ability to suppress withdrawal symptoms and some loss in opiate type effects, neither of which unduly distress patients or affect its ability to suppress illegal opiate use.     This gives patients the option of attending three (sometimes fewer) times a week with only weekend take-home doses or triple doses at weekends. Also buprenorphine’s greater safety (in terms of the potential for fatal overdose) makes take-home doses more acceptable. Both these options are generally prized by patients and together offer a much more attractive regimen than daily supervised methadone consumption with no or few take-home doses, potentially counterbalancing the weaker opiate-type effects of buprenorphine. Patients prefer not having to attend daily, especially if they can maintain daily dosing through intervening take-home doses. These extra options of non-daily supervised consumption and/or some take-home doses are respectively unavailable and often less available with methadone.

Ling W. et al. “There is an alternative: buprenorphine maintenance.” Drug and Alcohol Findings: 2002, 7, p. 27–31. https://findings.org.uk/count/downloads/download.php?file=Ling_W_5.pdf

Amass L. et al. “Alternate‑day buprenorphine dosing is preferred to daily dosing by opioid‑dependent humans.” Psychopharmacology: 1998, 136(3), p. 1432‑2072. http://dx.doi.org/10.1007/s002130050559

Amass L. et al. “Thrice‑weekly supervised dosing with the combination buprenorphine‑naloxone tablet is preferred to daily supervised dosing by opioid‑dependent humans.” Drug and Alcohol Dependence: 2001, 61(2), p. 173–181. http://dx.doi.org/10.1016/S0376‑8716(00)00141‑1

Marsch L.A. et al. “Buprenorphine treatment for opioid dependence: the relative efficacy of daily, twice and thrice weekly dosing.” Drug and Alcohol Dependence: 2005, 77(2), p. 195–204. http://dx.doi.org/10.1016/j.drugalcdep.2004.08.011

Lintzeris N. et al. “Implementing buprenorphine treatment in community settings in Australia: experiences from the buprenorphine implementation trial.” American Journal on Addictions: 2004, 13, p. S29–S41. http://dx.doi.org/10.1080/10550490490440799

In order to blind patients to the dosing schedule and/or to equalise everything except the medication taken, in six of the eight studies attendance requirements for methadone and buprenorphine were equalised, eliminating the extra options which in normal practice could be made available to buprenorphine-prescribed patients. Only two of the eight studies  compared less than daily buprenorphine with daily supervised methadone, and neither routinely offered buprenorphine take-home doses. In circumstances where supervised consumption of methadone is required, the comparison becomes one between a normal methadone programme, and a buprenorphine programme encumbered by requirements appropriate to methadone but unnecessary for buprenorphine. In turn this might affect retention on buprenorphine and, if missed urine samples are treated as positive, consequently also affect imputed urine test results.

Lintzeris N. et al. “Implementing buprenorphine treatment in community settings in Australia: experiences from the buprenorphine implementation trial.” American Journal on Addictions: 2004, 13, p. S29–S41. http://dx.doi.org/10.1080/10550490490440799

Neri S. et al. “Randomized clinical trial to compare the effects of methadone and buprenorphine on the immune system in drug abusers.” Psychopharmacology: 2005, 179, p. 700–704. http://dx.doi.org/10.1007/s00213‑005‑2239‑x

Blinded studies also force doctors to assume that the medication the patient is taking might be methadone and to raise doses with the caution appropriate to that drug, making buprenorphine patients wait an unnecessarily long time to reach adequate dose levels. Rapidity of induction is important because when this is unduly drawn studies have found high initial drop-out. 

Pani P.P., et al. “Buprenorphine: a controlled clinical trial in the treatment of opioid dependence.” Drug and Alcohol Dependence: 2000, 60, p. 39–50.

Petitjean S., et al. “Double‑blind randomized trial of buprenorphine and methadone in opiate dependence.” Drug and Alcohol Dependence: 2001, 62, p. 97–104.

These considerations, if they had any impact at all, seem most likely to have disadvantaged buprenorphine patients relative to methadone patients.
Another consideration is the reasons why patients would volunteer for a study which determined their treatment by a virtual throw of the dice. Where acceptable substitute prescribing programmes were easily accessible, it seems likely that these patients were atypical of the treatment seeking population; they were prepared to accept the requirements of the research process and the possibility of allocation to what for most will have been an unfamiliar medication (buprenorphine), and to forgo choice of medication if this was available, yet had no need to in order to receive treatment. Possibly their motivation in some cases is to try the new buprenorphine option, indicative perhaps of a lesser degree of attachment to opiate-type effects and a desire for a more normal psychological state (buprenorphine is less sedating and opiate-like in its effects then methadone). In all but one of the studies patients were (compared to some UK caseloads) either early in their addiction or treatment careers, relatively young, or relatively socially included.
Patients who cannot easily receive methadone from elsewhere will probably be less willing to drop out of a study if an alternative medication is unsatisfactory. This has probably been influential in raising buprenorphine retention rates in the USA, Iran  and Sweden.

Mattick R.P., et al. “The effectiveness of other opioid replacement therapies: LAAM, heroin, buprenorphine, naltrexone and injectable maintenance.” In: Ward J., et al, eds. Methadone maintenance treatment and other opioid replacement therapies. Harwood Academic Publishers, 1998. See p. 133–145.

Ahmadi J. et al. “Twelve‑month maintenance treatment of heroin‑dependent outpatients with buprenorphine.” Journal of Substance Use: 2003, 8(1), p. 39–41.

Ahmadi J. “A controlled trial of buprenorphine treatment for opium dependence: the first experience from Iran.” Drug and Alcohol Dependence: 2002,66, p. 111–114.

Kakko J. et al. “1‑year retention and social function after buprenorphine‑associated relapse prevention treatment for heroin dependence in Sweden: a randomised, placebo‑controlled trial.” Lancet: 2003, 361, p. 662–668.

In one of the studies the low 8mg daily cap on buprenorphine doses probably disadvantaged the buprenorphine patients. But in three others a 100mg cap on methadone in one and a 90mg cap in the other two may had the reverse effect.  

Fischer G. et al. Buprenorphine versus methadone maintenance for the treatment of opioid dependence. Addiction: 1999, 94(9), p. 1337–1347. http://www3.interscience.wiley.com/journal/120836199/abstract

Johnson R.E. et al. “A comparison of levomethadyl acetate, buprenorphine, and methadone for opioid dependence.” New England Journal of Medicine: 2000, 343(18), p. 1290–1297. http://content.nejm.org/cgi/content/abstract/343/18/1290

Strain E.C. et al. “Buprenorphine versus methadone in the treatment of opioid‑dependent cocaine users.” Psychopharmacology: 1994, 116(4), p. 401–406. http://dx.doi.org/10.1007/BF02247469

Strain E.C. et al. “Comparison of buprenorphine and methadone in the treatment of opioid dependence.” American Journal of Psychiatry: 1994, 151, p. 1025‑1030. http://ajp.psychiatryonline.org/cgi/content/abstract/151/7/1025

Three of the studies   (and another not included in the review) allowed buprenorphine patients to switch to methadone if they were not doing well. Understandably, the Cochrane review’s calculations treated these as drop-outs. But in one of the studies, in the process it also eliminated patients who were presumably retained on methadone, reducing methadone’s retention advantage. 

Lintzeris N. et al. “Implementing buprenorphine treatment in community settings in Australia: experiences from the buprenorphine implementation trial.” American Journal on Addictions: 2004, 13, p. S29–S41. http://dx.doi.org/10.1080/10550490490440799

Johnson R.E. et al. “A comparison of levomethadyl acetate, buprenorphine, and methadone for opioid dependence.” New England Journal of Medicine: 2000, 343(18), p. 1290–1297. http://content.nejm.org/cgi/content/abstract/343/18/1290

Petitjean S. et al. “Double‑blind randomized trial of buprenorphine and methadone in opiate dependence.” Drug and Alcohol Dependence: 2001, 62, p. 97–104. http://dx.doi.org/10.1016/S0376‑8716(00)00163‑0

Kakko J. et al. “A stepped care strategy using buprenorphine and methadone versus conventional methadone maintenance in heroin dependence: a randomized controlled trial.” American Journal of Psychiatry: 2007, 164(5), p. 797–803. http://dx.doi.org/10.1176/appi.ajp.164.5.797

Johnson R.E. et al. “A comparison of levomethadyl acetate, buprenorphine, and methadone for opioid dependence.” New England Journal of Medicine: 2000, 343(18), p. 1290–1297. http://content.nejm.org/cgi/content/abstract/343/18/1290

These studies give some indication of what proportion of the caseload might prove unsuitable for buprenorphine. In one, after the study ended 11 of 27 patients had been switched to methadone, probably so high because of a drawn out buprenorphine induction. In another, despite maximum buprenorphine/naloxone doses of 32mg a day, 20 of the 37 remaining (and of the 48 starting) buprenorphine/naloxone patients had been switched to methadone after missing clinic visits, complaining of craving or withdrawal, or testing positive for opiates. In the other two studies just a handful transferred. It is possible that had this been allowed, in some studies methadone patients might have preferred to switch in the other direction to buprenorphine. 

Petitjean S. et al. “Double‑blind randomized trial of buprenorphine and methadone in opiate dependence.” Drug and Alcohol Dependence: 2001, 62, p. 97–104. http://dx.doi.org/10.1016/S0376‑8716(00)00163‑0

Kakko J. et al. “A stepped care strategy using buprenorphine and methadone versus conventional methadone maintenance in heroin dependence: a randomized controlled trial.” American Journal of Psychiatry: 2007, 164(5), p. 797–803. http://dx.doi.org/10.1176/appi.ajp.164.5.797

Urine test results from two of these studies  incorporated in the most important of the Cochrane review’s analysis of opiate use suppression may have credited to buprenorphine the results from patients who avoided positive or missed tests by switching to methadone.

Johnson R.E. et al. “A comparison of levomethadyl acetate, buprenorphine, and methadone for opioid dependence.” New England Journal of Medicine: 2000, 343(18), p. 1290–1297. http://content.nejm.org/cgi/content/abstract/343/18/1290

Petitjean S. et al. “Double‑blind randomized trial of buprenorphine and methadone in opiate dependence.” Drug and Alcohol Dependence: 2001, 62, p. 97–104. http://dx.doi.org/10.1016/S0376‑8716(00)00163‑0

Fischer 1999

Fischer G. et al. Buprenorphine versus methadone maintenance for the treatment of opioid dependence. Addiction: 1999, 94(9), p. 1337–1347. http://www3.interscience.wiley.com/journal/120836199/abstract

Non-blinded Austrian study hampered by low buprenorphine doses which patients had little incentive to stick with, possibly leading to the highest excess drop-out rate among the eight studies..
Recruitment Set in a specialist clinic. The report does not specify how many patients approached to participate in the study turned it down. It is unclear why patients in a country where methadone maintenance was widely available would opt to enter a study with relatively onerous therapeutic requirements and which risked allocation to an unfamiliar medication. The recruited patients were quite young (average about 25) and had been using heroin for on average 4 years. 
Dose Buprenorphine patients may have been disadvantaged because doses were capped to 8mg per day while methadone doses could rise to 80mg per day. According to UK guidelines the former dose was below that normally considered adequate (12 to 16mg) while the latter was within that range (60 to 120mg). Dose equivalence guidance referred to from the manufacturer’s web site suggests that at least 10mg buprenorphine daily is required to match a methadone dose of 60mg. Where this has been systematically assessed, over 80% of patients require at least 12mg of liquid buprenorphine daily (perhaps more in tablet form) to reach stability. That the 8mg limit was constraining is suggested by the fact that doses averaged 7.5mg and were clustered very close to the maximum, while in respect of methadone there was greater variability and the average (63mg) was well below the maximum.

Department of Health (England) and the devolved administrations. Drug misuse and dependence: UK guidelines on clinical management. London: Department of Health [etc], 2007. http://www.nta.nhs.uk/areas/clinical_guidance/clinical_guidelines/docs/clinical_guidelines_2007.pdf

Suboxone. http://www.suboxone.com/hcp/opioiddependence/maintenance_therapy.aspx

Compton P.A. et al. “Buprenorphine as a pharmacotherapy for opiate addiction. What dose provides a therapeutic response?” American Journal on Addictions: 1996, 5(3), p. 220‑230. http://dx.doi.org/10.3109/10550499609041176

Attendance schedule All patients attended the clinic according to the same schedule (daily first three weeks then alternate days with take-home doses in between) and were expected to take their medication daily. This means buprenorphine gained no advantage from alternate day dosing because methadone patients too were not required to attend daily. 
Retention 71% of methadone and 38% of buprenorphine patients were retained in the study for 24 weeks, the largest discrepancy among the eight studies.
Illegal opiate use By the end of the 24-week study the relatively few buprenorphine patients who remained were more likely to submit opiate-negative urine samples (35% v. 24%) but when missed samples were considered positive there was no significant difference between the two groups of patients. 
Other During the buprenorphine induction period all the patients complained about undifferentiated dysphoria and reported a feeling of “clarity” which they described as more “reality‑oriented” compared with previous feelings of “intoxication” on methadone. Austria has good access to adequately dosed methadone treatment so patients might have had little fear of dropping out of the buprenorphine arm of the trial. 
Johnson 2000

Johnson R.E. et al. “A comparison of levomethadyl acetate, buprenorphine, and methadone for opioid dependence.” New England Journal of Medicine: 2000, 343(18), p. 1290–1297. http://content.nejm.org/cgi/content/abstract/343/18/1290

Results from this blinded US trial suggested that individually adjusted high doses of sublingual buprenorphine (up to the equivalent of 16mg daily) given three times a week can substitute for high dose methadone (60–100mg) with some non-significant loss of retention but equal ability to suppress illicit opioid use. In an environment in which methadone treatment may not have been easy to access, the results suggest buprenorphine may be able to stretch higher than the equivalent of 60mg of methadone which previous studies have suggested. 
Recruitment Set in a specialist clinic. Patients were typically unemployed, single men in their mid 30s who had been in treatment two times before and were using heroin three times a day. Nearly half were also dependent on cocaine. In the US context the study’s offer of (presumably) free substitute prescribing for 17 weeks and perhaps follow up care is likely to have been a considerable recruitment and retention incentive except that there was a risk of allocation to a suboptimal methadone dose (20mg) in one of the study’s groups. Even then rescue procedures were in place for patients who were not doing well. Of the 322 patients screened for the study just 24 failed to turn up for admission to treatment. 

There was a “disposition” period from weeks 18 to 28.

Dose Doses of buprenorphine were capped at 32mg on Monday and Wednesday and 48mg on Friday, generally considered maximum practical doses. Methadone was capped at 100mg daily, possibly too low for some patients. The rescue procedure (transfer to methadone) for patients not doing well was applied to 11% of the methadone patients (when presumably it entailed a dose increase outside the study’s limits) and 6% of the buprenorphine patients. To blind patients and staff to the medications they were receiving, all the patients ingested or were given the same number and type of doses varying only in which was the active medication and which the placebos. Individualisation of dose was relatively crude and mechanical. Dose increases were made when patients had attended well but continued to use illegal opiates (as revealed in urine tests), taking no account of patient comfort or the possibility that poor attendance might be a response to under-dosing. 

Johnson R.E. et al. “Buprenorphine: how to use it right.” Drug and Alcohol Dependence: 2003, 70(2, suppl.), p. S59–S77. http://dx.doi.org/10.1016/S0376‑8716(03)00060‑7

Attendance schedule Beyond the induction period all patients attended three times week and were given take-home doses for the remaining days. For the buprenorphine patients these were placebos. This meant the buprenorphine patients were encumbered with an unnecessary daily attendance requirement but still faced the minor detriments to withdrawal suppression and opiate type effects associated with alternate day dosing. 
Retention Retention on the original treatment over 17 weeks (ie, treating ‘rescued’ patients as drop-outs) was non-significantly worse with buprenorphine (32 patients, 58%) than methadone (40 patients, 73%); these were the figures incorporated in the Cochrane review’s calculations. When rescue procedure patients were counted as having been retained in their original treatments, the figures were 64% v. 84%. If it is assumed that the rescued methadone patients actually remained on methadone, so could be counted as retained on their original medication, the gap on this measure would rise to 58% v. 84% in favour of methadone.
Illegal opiate use Average self reports of opiate use frequency (four per week) and positive urine test results (missed tests treated as positive) were practically identical. However, these figures (and in particular the urine test results incorporated in the most important of the Cochrane review’s analysis of opiate use) may have included buprenorphine patients who avoided positive or missed tests by switching to methadone.
Other An attempt was made to identify which types of patient benefited differentially from each of the medications, including the LAAM (long-acting derivative of methadone) arm of the study ignored in the account above. In the buprenorphine group more depressed patients submitted fewer opiate-positive urine tests, an association not seen the methadone group but also apparent in the LAAM group. There was a tendency for this effect to be more pronounced on buprenorphine than LAAM.

Marsch L.A. et al. “Predictors of outcome in LAAM, buprenorphine, and methadone treatment for opioid dependence.” Experimental and Clinical Psychopharmacology: 2005, 13(4), p. 293‑302. http://dx.doi.org/10.1037/1064‑1297.

Lintzeris 2004

Lintzeris N. et al. “Implementing buprenorphine treatment in community settings in Australia: experiences from the buprenorphine implementation trial.” American Journal on Addictions: 2004, 13, p. S29–S41. http://dx.doi.org/10.1080/10550490490440799

In this non-blinded Australian study buprenorphine maintenance patients could transfer to methadone at any stage. Attempts were made to follow-up patients no longer in the study’s treatments. Relative to methadone, buprenorphine patients were allowed the advantage of less than daily dispensing, but not intervening take-home doses. They also received relatively high doses of buprenorphine.
Recruitment Recruitment and treatment occurred across 19 sites, all but one (a specialist clinic) of which were primary care practices which arranged dispensing and supervised consumption at pharmacies. 57 patients were already in methadone treatment and had been able to reduce to 60 mg methadone or less. These patients self-selected in to the study for reasons which may not make them representative of all methadone patients. Given the accessibility of methadone treatment in Australia, a similar concern applies to the other 82 patients, who were heroin users newly starting treatment. How many patients refused to join the study is not reported, but 19 effectively withdrew after agreeing to join. The pattern of withdrawals does not suggest a particular aversion to being allocated to either medication. However, the researchers say “some people had entered the study specifically to gain access to buprenorphine”. Patients were typically unemployed and around 30 years of age, had been using heroin for around a decade, and had an extensive treatment history (8 prior treatment episodes).

Harris A.M. et al. “A randomised trial of the cost effectiveness of buprenorphine as an alternative to methadone maintenance treatment for heroin dependence in a primary care setting.” PharmacoEconomics: 2006, 23(1), p. 77–91. http://www.ingentaconnect.com/content/adis/pec/2005/00000023/00000001/art00007

Dose There were no study limits on the doctor’s discretion to determine methadone dosing and schedules beyond applicable local guidelines. The study provided similar guidelines (including flexible dosing) regarding buprenorphine. On average methadone doses were moderate or low (around 50mg a day or less) but buprenorphine doses were quite high (averaging the equivalent of 13–16mg daily). 
Attendance schedule Patients allocated to methadone attended daily for supervised consumption at pharmacies except for one take-home dose a week. Buprenorphine patients were inducted on daily supervised consumption but once stabilised could opt for this to be spaced every two or three days; no take‑home doses were routinely provided. Of those who remained on buprenorphine, two-thirds or more opted for non-daily schedules. 
Retention Perhaps indicative of their desire to try buprenorphine as an alternative to the methadone they were already receiving, patients recruited from methadone treatment were retained equally well by the two medications. Though not significantly so, the heroin dependent patients starting treatment were retained less well on buprenorphine (average 184 days v. 230 days; 46% in treatment at six months v. 58%). Among the buprenorphine patients were at three months seven of the 51 still in treatment, and at six months three of 41, who had switched to methadone. The Cochrane review used the six-month figures excluding the three patient transfers, ie, the switched patients were treated as drop-outs.
Illegal opiate use At six and 12 months among the roughly three-quarters of patients who could be reassessed, self-reported opiate use was non-significantly less frequent among the buprenorphine patients. Among those starting treatment, differences were greater and described as a “trend”. Only half the patients could be re-assessed at 12 months. No urine test data could be included in the Cochrane review meta-analysis.
Other A cost-effectiveness analysis found nothing decisive to distinguish the two treatments. Here we focus on the results for partient starting treatment rather than those transferring from methadone. Over the year of the trial the number of heroin-free days and health-related quality of life scores were practically the same on both medications. Over the year the buprenorphine patients cost health services more (not just in their addiction treatment but also in other medical services), but only slightly more, partly because of non-daily dispensing. Including crime costs, the overall social costs imposed by the methadone patients was much greater but still not significantly so, and the difference was due to a handful of high-rate offenders. Uncertainties and small differences meant no treatment could be said to be definitely more cost-effective than the other in terms of heroin free days or quality of life per $ in social or health service costs. Nor could one be said to definitely result in lower overall social costs including crime. 

Harris A.M. et al. “A randomised trial of the cost effectiveness of buprenorphine as an alternative to methadone maintenance treatment for heroin dependence in a primary care setting.” PharmacoEconomics: 2006, 23(1), p. 77–91. http://www.ingentaconnect.com/content/adis/pec/2005/00000023/00000001/art00007

Mattick 2003

Mattick R.P. et al. “Buprenorphine versus methadone maintenance therapy: a randomized double‑blind trial with 405 opioid‑dependent patients.” Addiction: 2003, 98, p. 441–452. http://dx.doi.org/10.1046/j.1360‑0443.2003.00335.x

Large (405 patients) blinded Australian study. 13-week trial.
Recruitment Set in specialist clinics. The proportion of eligible patients who agreed to enter the study or how typical they were of all patients at the clinics were not reported. It is unclear why patients approaching a methadone clinic would opt to enter a study which seemingly gave them no advantages over normal care and some disadvantages including the possibility of being allocated to an unfamiliar medication. The fact that methadone doses ranged down to 20mg, and to 10mg from week 6 on, and buprenorphine down to 2mg, suggests some patients were satisfied with (in addiction treatment terms) very low doses. Though averaging 30 years old and using heroin for 8 years, patients had on average experienced only one prior episode of methadone treatment. Typically they were unemployed single men.
Dose To blind patients and staff to the medications they were receiving, all the patients were given the same number and type of doses varying only in which was the active medication and which the placebos. During weeks 1–6, all patients received their active medication daily. For weeks 7–13, patients randomised to buprenorphine received double their week 6 dose every second day. Maximum doses were 150mg daily for methadone and for buprenorphine, 32mg daily during daily dosing and 32mg every two days thereafter. If the latter was inadequate, patients could return to daily dosing. Doctors set dose levels in methadone units based on patient requests and withdrawal signs or toxicity/sedation. Buprenorphine tablet doses were converted from methadone units according to a table. At week 6 the average buprenorphine dose was 10.9 mg/day, and the equivalent of 11.2 mg/day during weeks 12 and 13. The average dose of methadone in week 6 was 52.6 mg/day, increasing slowly to 57.3 mg/day in week 13.
Attendance schedule To maintain blinding all medication/placebos were ingested daily under supervision at the clinic. This meant that buprenorphine patients had to attend daily and take dummy doses even when they were on alternate-day dosing, exposing them to potential slight loss of opiate-type effects due to the extended interval. However, if this proved a problem they could be reverted to daily dosing. 
Retention By the end of the 13 weeks slightly fewer (50% versus 59%) buprenorphine patients were still in treatment (nearly reaching conventional levels of significance) and over the 13 weeks methadone patients stayed slightly (66.8 v 59.2 days) but significantly longer due to excess drop out in the first two weeks, perhaps a consequence of a drawn out induction period, itself possibly because doctors had to prescribe on the assumption that methadone was being taken. 
Not until week 5 did average buprenorphine doses top 10mg. Not until after this time did average scores of withdrawal severity equalise, up to then being slightly more severe for the buprenorphine patients. The switch to alternate-day dosing did not affect retention, perhaps partly because patients who experienced discomfort could return to daily dosing; 11% did so (another 4% were never transferred due to erratic attendance). There has been criticism of the exclusion from the analysis of patients who did not receive a single dose. Had these been included the retention advantage for methadone would have been more clear cut. On the other hand, it is hard to see how drop-out before patients had even experienced the medications could be relevant to the comparison between them. 

Caplehorn J. “Comments on Mattick et al.: the need for independent data re‑analyses.” Addiction: 2003, 98, p. 1633–1634.

Illegal opiate use Fortnightly urine tests and self-reports from patients retained in treatment showed only a slight and non-significant tendency towards a greater reduction of heroin use on buprenorphine (missing tests effectively treated as positive). By the end of treatment patients were injecting heroin about two to three times a week as opposed to two to three times a day before treatment.
Other Methadone patients expressed significantly more liking for their medication, felt a greater ‘buzz’, and experienced slightly fewer withdrawal symptoms. Physical and psychological health, infection risk behaviour, and social functioning, all improved equally in the two groups. 
Based on another three months in the same treatments, but assuming that the buprenorphine patients need attend only on alternate days, another study estimated that the costs of buprenorphine treatment were higher but not significantly so. Assumptions about future price reductions and efficiency improvements rendered costs comparable. In all the scenarios comparable costs and outcomes (heroin-free days) meant that cost-effectiveness also was comparable. Over the six months patients in the methadone group were retained in treatment for an average of 113 days compared with an average of 93 days for patients in the buprenorphine group and it was estimated that methadone patients achieved an additional 6.84 days free of heroin each month compared with 5.27 days for the buprenorphine patients.

Doran C.M. et al. “Buprenorphine versus methadone maintenance: a cost‑effectiveness analysis.” Drug and Alcohol Dependence: 2003, 71(3), p. 295–302. http://dx.doi.org/10.1016/S0376‑8716(03)00169‑8

Though one of these was that average dosing time for buprenorphine could be reduced to that for methadone if pharmacists supervised the consumption of several patients at once, neither necessarily practical nor desirable, and in any event the same could be done for methadone.

Neri 2005

Neri S. et al. “Randomized clinical trial to compare the effects of methadone and buprenorphine on the immune system in drug abusers.” Psychopharmacology: 2005, 179, p. 700–704. http://dx.doi.org/10.1007/s00213‑005‑2239‑x

Small (62 subjects) non-blinded Italian study over 12 months with patients seemingly early in their addiction careers and highly compliant with treatment. How flexible the prescribing was is open to question; patients were prescribed almost uniformly high doses of methadone and medium doses of buprenorphine. 
Recruitment Set in a specialist clinic. The proportion of eligible patients who agreed to enter the study or how typical they were of all patients at the clinics were not reported. In an environment with good access to methadone treatment, these patients who were approaching a methadone clinic opted to enter a study which gave them no advantages over normal care and the possibility of being allocated to an unfamiliar medication. Patients were relatively young (mainly in their twenties) with short (average two years) heroin addiction careers. Possibly they opted for this study for a chance to obtain buprenorphine, suggesting in turn a group with a high level of desire to normalise their functioning with a drug with less noticeable opiate-type effects.
Dose It is unclear for both drugs whether there truly was flexible prescribing and if so how the dose was determined. Methadone was capped at 100mg a day. It is unclear whether this was also the standard dose or whether there was flexibility. Buprenorphine averaged about 10mg daily in the first three weeks, then the dose reached during this period was roughly doubled every other day then two weeks later tripled every third day. From this point on to the end of treatment doses averaged just over 30mg/day with little variation. Possibly the decision to move everyone to dosing every three days necessitated the use of almost uniformly high doses to sustain the effect, though other studies have used up to 48mg to cover the same period. 
Attendance schedule No take-home doses. All doses were supervised by the hospital pharmacist. After the initial three weeks buprenorphine patients presumably attended only every other day and then after another two weeks every three days. 
Retention Retention was remarkably high – just two buprenorphine patients and three on methadone did not remain in treatment over the 12 months, despite the fact that patients were removed from the study if they missed three consecutive methadone doses or one buprenorphine dose. 
Illegal opiate use Weekly urine test data had to be omitted from the Cochrane review meta-analysis. Of (presumably) 52x31=1612 possible tests, on 669 occasions methadone patients tested negative (opiate free) and buprenorphine patients on 760 occasions. The difference expressed as a proportion of tests undergone which were positive was statistically significant. 
Other Buprenorphine patients experienced a lower incidence of side effects and (despite every three days dosing) less craving for heroin and reduced depression relative to methadone patients. 
Petitjean 2001

Petitjean S. et al. “Double‑blind randomized trial of buprenorphine and methadone in opiate dependence.” Drug and Alcohol Dependence: 2001, 62, p. 97–104. http://dx.doi.org/10.1016/S0376‑8716(00)00163‑0

Small scale (58 patients) blinded Swiss study over six weeks of which the first three were the induction and dose adjustment period and the last three weeks the stable dose maintenance period. Unusually (in UK terms) socially included group of patients.
Recruitment Set in specialist clinics. The authors note that recruitment was slow probably because adequate methadone treatment was easily accessible. The proportion of eligible patients who agreed to enter the study or how typical they were of all patients at the clinics were not reported. After the study patients could continue with their respective maintenance treatment or switch to the other medication. Possibly they opted for this study for a chance to try buprenorphine (which none had previously been prescribed), suggesting in turn a group with a high level of desire to achieve therapeutic progress and/or less commitment to continuing to experience opiate-type effects. Three quarters were employed and nearly all stably housed. Most smoked heroin and had used it regularly for on average four to five years. 
Dose Buprenorphine was capped to 16mg a day and methadone to 120mg. To blind patients and staff to the medications, all the patients ingested the same number and type of doses varying only in which was the active medication and which the placebo. Dose was set in first three weeks in accordance with patient request and medical assessments. At the end of the study buprenorphine doses averaged nearly 11mg and methadone 70mg. 
Attendance schedule No take-home doses. All doses supervised daily at the clinics. 
Retention 15 of the 27 (56%) buprenorphine patients completed six weeks on the drug compared to 28 of the 31 (90%) methadone patients, a significant difference, the figures incorporated in the Cochrane review. Almost all the buprenorphine patients who dropped out did so within the first ten days, possibly due to a drawn out induction process. Eight complained of withdrawal symptoms and were switched to methadone. Including these, 23 of the 27 (85%) buprenorphine patients were retained in maintenance treatment. An elevated rate of opiate positive urine samples (over 80%) among buprenorphine patients in weeks two and three also seem indicative of sub-optimal induction. At the end of the study 3 of the 15 patients remaining on buprenorphine were switched to methadone making 11 of 27 in all. 
Illegal opiate use Of the urine tests taken by patients who remained in their treatments, in both groups roughly 60% were positive. For the buprenorphine patients this means if all tests had been taken 3.72 (0.62 x 6) of the possible 6 would have been positive. Yet there were 12 early drop-outs so many tests must have been missed or taken while the patient was in fact receiving methadone. Had these been treated as positive tests then the average number of positive tests among the buprenorphine patients would have been higher. The Cochrane review gives a figure of on average 2.81 positive tests across the 27 buprenorphine patients and 3.41 across the 31 methadone patients. However, these figures may have included buprenorphine patients who avoided positive or missed tests by switching to methadone.
Other There was little difference in heroin craving scores among retained patients. Significantly more patients in the methadone group reported sedation (58 vs. 26%).
Strain 1994a

Strain E.C. et al. “Comparison of buprenorphine and methadone in the treatment of opioid dependence.” American Journal of Psychiatry: 1994, 151, p. 1025‑1030. http://ajp.psychiatryonline.org/cgi/content/abstract/151/7/1025

Blinded US study of 164 relatively treatment naive patients early in their opiate use careers treated over six months in a maintenance to detoxification programme. 
Recruitment Set in a research clinic. Consecutively admitted patients who met the study’s criteria (including no prior methadone treatment lasting over three weeks and no buprenorphine treatment). Patients knew they were entering a maintenance to detoxification programme lasting only six months. They averaged only two and half years use of opioid drugs and had on average been treated less than once before. Such patients are unlikely to be typical of patients seeking and entering long-term maintenance programmes. 
Dose Buprenorphine was capped to 16mg a day and methadone to 90mg. To blind patients and staff to the medications, all the patients ingested the same number and type of doses varying only in which was the active medication and which the placebo. Doses were rapidly increased over four days to 50mg methadone and 8mg buprenorphine and maintained to the end of the third week. Up to week 16 increases or decreases were permitted until doses were tapered of to the end of the six-month study period. Patients and staff knew that detoxification would occur but not the schedule. Dose increases were based on the written request of the patient and continued illicit opioid use, as evidenced by at least two of the last three urine samples testing positive for opiates. Decreases were based on opiate-free urines and no patient complaints about dose. These criteria were hidden from patients and staff. Average daily doses were 9mg for buprenorphine and 54mg for methadone. 
Attendance schedule Daily supervised consumption. No take-home medication.
Retention 56% of the patients in each group stayed to the end of the flexible dosing period (16 weeks, the time period chosen in the Cochrane review), then retention declined to roughly the same degree in each group. Perhaps because of rapid induction there was no excess drop-out among the buprenorphine patients in the first weeks of treatment. 
Illegal opiate use A slightly but not significantly higher (55% v 47%) proportion of submitted urine tests were positive among the buprenorphine patients. In both groups dose increases reduced the number of opiate positive tests. That this was not a time effect was established by comparison with a separate cohort of patients not permitted dose increases. 
Strain 1994b

Strain E.C. et al. “Buprenorphine versus methadone in the treatment of opioid‑dependent cocaine users.” Psychopharmacology: 1994, 116(4), p. 401–406. http://dx.doi.org/10.1007/BF02247469

Blinded US study of 51 relatively treatment naive patients dependent on opiates and also using cocaine, treated over six months in a maintenance to detoxification programme. 
Recruitment Set in a research clinic. Consecutively admitted patients who met the study’s criteria (including recent cocaine use, no prior methadone treatment lasting over three weeks, and no buprenorphine treatment). Patients knew they were entering a maintenance to detoxification programme lasting only six months. They averaged one prior treatment experience. Such patients are unlikely to be typical of patients seeking or entering long-term maintenance programmes. 
Dose Buprenorphine was capped to 16mg a day and methadone to 90mg. To blind patients and staff to the medications they were receiving, all the patients ingested the same number and type of doses varying only in which was the active medication and which the placebo. Doses were rapidly increased over 4 days to 50mg methadone and 8mg buprenorphine and maintained to the end of the third week after which up to week 16 increases or decreases were permitted until doses were tapered of to the end of the six-month study period. Patients and staff knew that detoxification would occur but not the procedure. Dose increases were based on continued illicit opioid or cocaine use, as evidenced by at least two of the last three urine samples testing positive for either drug. Dose decreases to correct over-medication were given if the patient requested or if staff observed evidence of over‑medication. Decreases might also be given if two consecutive weeks of opioid‑negative urine samples plus weekly self‑reports gave no indication that the dose was inadequate. Average doses were 11.2mg buprenorphine and 66.6 mg methadone; nearly half the patients assigned to buprenorphine reached the maximum dose possible, and slightly over half the patients assigned to methadone. 
Attendance schedule Daily supervised consumption. No take‑home medication.
Retention Retention to the end of the maintenance period (16 weeks, the time period used in the Cochrane review) was virtually identical at just over 50%. Perhaps because of rapid induction there was no excess drop-out among the buprenorphine patients in the first weeks of treatment. 

As reported in the Cochrane review.

Illegal opiate use A slightly but not significantly higher (60% v 55%) proportion of submitted urine tests were positive among the methadone patients.
Kakko 2007

Kakko J. et al. “A stepped care strategy using buprenorphine and methadone versus conventional methadone maintenance in heroin dependence: a randomized controlled trial.” American Journal of Psychiatry: 2007, 164(5), p. 797–803. http://dx.doi.org/10.1176/appi.ajp.164.5.797

Published too late to be included in the Cochrane review but seems to meet the criteria. Swedish randomised and blinded study during which patients prescribed buprenorphine/naloxone tablets were transferred to methadone if progress remained unsatisfactory after reaching the maximum buprenorphine dose of 32mg daily. At baseline and 3 and 6 months later, the ASI drug problem assessment survey was administered to patients still in treatment. 
Recruitment 96 heroin dependent patients responding to publicity at specialist drug treatment clinics. Few eligible patients screened for the study refused to join it. Patients who entered the study were typically men in their 30s who had been using heroin for on average ten years. Limited access to methadone maintenance in Sweden may have been an incentive to enter and remain in the trial. 
Dose A fixed induction to 70mg methadone over 10 days and 16mg buprenorphine/naloxone over 2 days with placebos to blind patients to the medication they were taking. During the 24-day stabilisation period staff were also blinded but thereafter doses could be raised every two weeks to 120mg methadone or 32mg day buprenorphine/naloxone if patients had missed at least two visits, complained of craving or withdrawal, or tested positive for opiates. If one or more of these symptoms persisted buprenorphine/naloxone patients were switched to methadone 50mg daily rising to 90mg then adjusted as above. The final methadone dose averaged 110mg a day, buprenorphine/naloxone, about 30mg.
Attendance schedule Daily supervised consumption at the clinic throughout the study. 
Retention After six months 78% of patients remained with little difference between those allocated initially to buprenorphine/naloxone or methadone, but drop-out during the first two weeks of induction was greater on the former. However, 20 of the 37 remaining (and of the 48 starting) buprenorphine/naloxone patients had been switched to methadone. Retention on the starting medication was 17 out of 48 (35%) for buprenorphine/naloxone and 38 of 48 (79%) for methadone. Neither age, gender, duration of heroin use, nor baseline ASI severity ratings significantly predicted whether patients switched to methadone.
Illegal opiate use For the purposes of statistical testing missing urine test samples were treated as positive. There was no difference between the groups. By the end of the study around 80% of samples were negative. ASI improvements were driven largely by a reduction over time of drug‑related problems were also equivalent. 
Other Weekly counselling could be intensified to several times a week if opiate use continued. This was supplemented by 12 weekly group relapse prevention therapy.
Fixed dose studies
For comparison, the Cochrane review found that when patients had been randomly allocated to comparable fixed doses, methadone was preferable because it retained patients longer with equivalent or better suppression of illegal use of opiate-type drugs. 
The economic analysis conducted for the UK’s National Institute for Health and Clinical Excellence

Connock M. et al. Methadone and buprenorphine for the management of opioid dependence: a systematic review and economic evaluation. Health Technology Assessment: 2007, 11(9). http://www.hta.ac.uk/execsumm/summ1109.htm

The limitations of the flexible doses studies used in the Cochrane analysis also apply to a recent assessment for the UK’s National Institute for Health and Clinical Excellence. Based on the Cochrane review, the analysts calculated that for every 10 methadone patients who left treatment, 14 on buprenorphine left, a different way of expressing the same findings. Despite equivalent in-treatment suppression of heroin use, this greater retention meant that improvements in (largely health-related) quality of life were slightly greater on methadone. Methadone resulted in lower costs to the health services in the year after treatment started. The figures (£1971 per patient for methadone and £2491 for buprenorphine) included not just addiction treatment but also other medical care costs. Lower cost plus greater quality of life gains meant methadone was on average preferable, but not so decisively as to override other considerations. The authors argued that the balance might be tipped once medical staff had gained more experience with buprenorphine, by the possible lower risk of death, and by patient preference. For both medications the analysis assumed daily (except for one day) supervised consumption for the first three months, the same schedule of unsupervised dispensing for the next three, reducing to three times a week over the rest of the year.

Though one of the eight studies was omitted (Neri 2005).

Several uncertainties and caveats attach to these calculations. In the studies on which this was based, retention on buprenorphine may have been adversely affected (see above) by patients being required to follow regimens appropriate to methadone. The analysts tried recalculating the figures assuming that in the first six months buprenorphine was dispensed only three days a week (for the first three months supervised and then unsupervised), halving the number of pharmacy visits over the first six months compared to methadone. This made little difference to the costs to the health service associated with buprenorphine treatment (reducing these to £2363 per patient). However, the questions put to the panel whose ratings were used to assess quality of life took no account of the possibility that non-daily dispensing could enhance a patient’s quality of life and/or satisfaction with their treatment. The possibilities that for patients on buprenorphine, unsupervised consumption might be introduced sooner than for methadone or that more treatment might take place in primary care were not explored. It was unrealistic to assume that all the buprenorphine would be supplied in the more expensive 2mg tablet form, raising these costs by up to a third. On the other hand, quality of life gains from extra retention on methadone were probably underestimated because, for example, freedom from high-rate criminality, reduced risk of arrest and imprisonment, improved finances, and normalisation of family and social life, were not accounted for in the questions used to weight quality of life under conditions of treatment versus no treatment.

9807 National Institute for Health and Clinical Excellence. Methadone and buprenorphine for the management of opioid dependence. NICE technology appraisal guidance 114. National Institute for Health and Clinical Excellence, January 2007. http://www.nice.org.uk/guidance/index.jsp?action=byID&o=11606

Who benefits most from buprenorphine?
Though much more work is needed in this area, some studies have found that certain types of patients respond better to buprenorphine than others. Patients with the most severe dependence and other problems are the ones most likely to react to induction discomfort by terminating treatment  or, if allowed, transferring to methadone. High-dose heroin users are unlikely to be satisfied by buprenorphine. Depending on the individual and the effect being measured, doses beyond 8–32mg in liquid form not only have little further impact but can reduce subjective opiate effects.   As a result, further increases do not improve treatment retention or effectiveness.     On average, patients report maximal effects from about 16mg of buprenorphine solution, equivalent in bioabsorption terms to perhaps 24mg (though one study found these forms equivalent) in tablet form and in terms of subjective effects to 60mg of methadone. However, results from a recent US trial suggested that individually adjusted high doses of sublingual buprenorphine (up to the equivalent of 16mg daily) given three times a week can substitute for relatively high dose methadone (60–100mg) with some non-significant loss of retention but equal ability to suppress illicit opioid use. In this study the patients were mainly unemployed, single men using heroin three times a day and nearly half were dependent also on cocaine.

Pani P.P. et al. “Buprenorphine: a controlled clinical trial in the treatment of opioid dependence.” Drug and Alcohol Dependence: 2000, 60, p. 39–50.

Amass L. et al. “Efficacy of daily and alternate-day dosing regimens with the combination buprenorphine-naloxone tablet.” Drug and Alcohol Dependence: 2000, p. 143–152.

Petitjean S., et al. “Double‑blind randomized trial of buprenorphine and methadone in opiate dependence.” Drug and Alcohol Dependence: 2001, 62, p. 97–104.

Mattick R.P., et al. “The effectiveness of other opioid replacement therapies: LAAM, heroin, buprenorphine, naltrexone and injectable maintenance.” In: Ward J., et al, eds. Methadone maintenance treatment and other opioid replacement therapies. Harwood Academic Publishers, 1998. See p. 133–145. 3.2 shelf

Chiang C.N. et al. “Pharmacokinetics of the combination tablet of buprenorphine and naloxone.” Drug and Alcohol Dependence: 2003, 70(2 suppl.), p. S39–S47.

Johnson R.E. et al. “Buprenorphine: how to use it right.” Drug and Alcohol Dependence: 2003, 70(2, suppl.), p. S59–S77.

Pani P.P. et al. “Buprenorphine: a controlled clinical trial in the treatment of opioid dependence.” Drug and Alcohol Dependence: 2000, 60, p. 39–50.

Galanter M., Kleber H.D. Textbook of substance abuse treatment. 2nd edition. American Psychiatric Press, 1999, p. 291.

Mattick R.P., et al. “The effectiveness of other opioid replacement therapies: LAAM, heroin, buprenorphine, naltrexone and injectable maintenance.” In: Ward J., et al, eds. Methadone maintenance treatment and other opioid replacement therapies. Harwood Academic Publishers, 1998. See p. 133–145.

Kastelic A., Scott R. “Introduction.” European Addiction Research: 1998, 4(suppl 1), p. 1–2. Document in F3.2 unnumbered

Oliveto A., Kosten T.R. “Buprenorphine.” In: Stine S.M., Kosten T.R. New treatments for opiate dependence. The Guilford Press, 1997.

Walsh S.L. et al. “The clinical pharmacology of buprenorphine: extrapolating from the laboratory to the clinic.” Drug and Alcohol Dependence: 2003, 70(2 suppl.), p. S13–S27.

Johnson R.E. et al. “Buprenorphine: how to use it right.” Drug and Alcohol Dependence: 2003, 70(2, suppl.), p. S59–S77.

Chiang C.N. et al. “Pharmacokinetics of the combination tablet of buprenorphine and naloxone.” Drug and Alcohol Dependence: 2003, 70(2 suppl.), p. S39–S47.

Johnson R.E., et al. “A comparison of levomethadyl acetate, buprenorphine, and methadone for opioid dependence.” New England Journal of Medicine: 2000, 343(18), p. 1290–1297.

Buprenorphine possibly retains depressed patients and prevents opiate use among them more effectively than among patients not suffering depression.   It also mitigates both mental health and opiate dependence problems in some patients suffering from both. However, it is not clear that it does this any more effectively than methadone.   One randomised study found that depressed patients responded better than non-depressed patients to buprenorphine but not to methadone, and another that symptoms of depression were reduced more by buprenorphine than methadone. A non-randomised study found that depressed patients who were allocated according to normal clinical procedures to buprenorphine were retained better and more often tested opiate free than depressed patients allocated to methadone.

Connock M. et al. Methadone and buprenorphine for the management of opioid dependence: a systematic review and economic evaluation. Health Technology Assessment: 2007, 11(9). http://www.hta.ac.uk/execsumm/summ1109.htm

Marsch L.A. et al. “Predictors of outcome in LAAM, buprenorphine, and methadone treatment for opioid dependence.” Experimental and Clinical Psychopharmacology: 2005, 13(4), p. 293‑302. http://dx.doi.org/10.1037/1064‑1297.

Gerra G. et al. “Buprenorphine versus methadone for opioid dependence: predictor variables for treatment outcome.” Drug and Alcohol Dependence: 2004 , 75(1), p. 37–45. http://dx.doi.org/10.1016/j.drugalcdep.2003.11.017

Maremmani I. et al. “Effectiveness of buprenorphine in double diagnosed patients. Buprenorphine as psychothropic drug.” Heroin Addiction and Related Clinical Problems: 2006, 8(1), p. 31–48. http://www.europad.org/journal/2006/Maremmani%208(1)2006.pdf

Maremmani I. et al. “Substance use and quality of life over 12 months among buprenorphine maintenance‑treated and methadone maintenance‑treated heroin‑addicted patients.” Journal of Substance Abuse Treatment: 2007, 3, p. 91‑98. http://dx.doi.org/10.1016/j.jsat.2006.11.009

Maremmani I. et al. “Improvement in the quality of live in heroin addicts: differences between methadone and buprenorphine treatment.” Heroin Addiction and Related Clinical Problems: 2008, 10(1), p. 41‑48. http://www.europad.org/journal/2008/Maremmani%2010(1)2008.pdf

Marsch L.A. et al. “Predictors of outcome in LAAM, buprenorphine, and methadone treatment for opioid dependence.” Experimental and Clinical Psychopharmacology: 2005, 13(4), p. 293‑302. http://dx.doi.org/10.1037/1064‑1297.

Neri S. et al. “Randomized clinical trial to compare the effects of methadone and buprenorphine on the immune system in drug abusers.” Psychopharmacology: 2005, 179, p. 700–704. http://dx.doi.org/10.1007/s00213‑005‑2239‑x

Gerra G. et al. “Buprenorphine versus methadone for opioid dependence: predictor variables for treatment outcome.” Drug and Alcohol Dependence: 2004 , 75(1), p. 37–45. http://dx.doi.org/10.1016/j.drugalcdep.2003.11.017

In Sweden neither age, gender, duration of heroin use, nor baseline ASI severity ratings significantly predicted which patients would switch to methadone after starting treatment on buprenorphine/naloxone tablets increased up to 32mg a day.

Kakko J. et al. “A stepped care strategy using buprenorphine and methadone versus conventional methadone maintenance in heroin dependence: a randomized controlled trial.” American Journal of Psychiatry: 2007, 164(5), p. 797–803. http://dx.doi.org/10.1176/appi.ajp.164.5.797

In Cornwall in England community addiction treatment patients, most of whom had previously been prescribed both buprenorphine and methadone, had a realistic appreciation of the relative merits of the two. Buprenorphine was rated as better at reducing/blocking the effects of illicit use of heroin, keeping the mind clear and enabling work and daily activities, and easier to withdraw from, while methadone had greater opiate-type effects, was easier to consume and to sell on the illicit market, but less easy to inject. Overall, more preferred methadone than buprenorphine maintenance but the gap was not great – 50% v. 37%.

White R. et al. “Patients’ views of treatment: methadone vs. buprenorphine.” Journal of Substance Use: 2007, 12(5), p. 365–373. http://dx.doi.org/10.1080/14659890701289463

Safety and diversion in take-home regimens
Though buprenorphine is far safer in overdose than either methadone or heroin, there have been cases of fatal overdose, particularly when the drug has been both injected and used with benzodiazepines.   But overall the introduction of buprenorphine as a widespread maintenance treatment in France probably resulted in a substantial reduction the opiate-related death rate.  

Walsh S.L. et al. “The clinical pharmacology of buprenorphine: extrapolating from the laboratory to the clinic.” Drug and Alcohol Dependence: 2003, 70(2 suppl.), p. S13–S27.

Bridge T.P. et al. “Safety and health policy considerations related to the use of buprenorphine/naloxone as an office‑based treatment for opiate dependence.” Drug and Alcohol Dependence: 2003, 70(2 suppl.), p. S79–S85.

Kintz P. “Buprenorphine-related deaths.” In: Kintz P. et al, eds. Buprenorphine therapy of opiate addiction. Totowa, New Jersey: Humana Press, 2002, p. 109–117.

Gueye P.N. et al. “Trends in opiate and opioid poisonings in addicts in north-east Paris and suburbs, 1995–99.” Addiction: 2002, 97(10), p. 1295–1304.

Auriacombe M. et al. “Deaths attributable to methadone vs buprenorphine in France.” Journal of the American Medical Association: 2001, 285(1).

Buprenorphine tablets are easily misused by injection and (where both are available) are injected more widely than methadone linctus or syrup. Such misuse can be widespread among patients  and among drug users in general     with resultant risk of injection-related damage, a disadvantage compared to liquid methadone. Combining buprenorphine with naloxone in the same tablet reduces its attractiveness to dependent opiate users when injected because the naloxone often precipitates withdrawal.     When taken as intended under the tongue, naloxone is very poorly absorbed and the combination tablets act similarly to buprenorphine alone.

Guichard A. et al. “Illicit drug use and injection practices among drug users on methadone and buprenorphine maintenance treatment in France.” Addiction: 2003, 98, p. 1585–1597.

Duburcq A., et al. “Two-years follow-up of heroin users treated by GPs with high dosage buprenorphine: the SPESUB study.” Rev. Epidém. et Santé Publ.: 2000, 48, p. 363–373.

Vidal‑Trecan G. et al. “Intravenous use of prescribed sublingual buprenorphine tablets by drug users receiving maintenance therapy in France.” Drug and Alcohol Dependence: 2003, 69, p. 175–181.

Valenciano M., et al. “Unsafe injecting practices among attendees of syringe exchange programmes in France.” Addiction: 2001, 96, p. 597–606.

Gray R., et al. “Emergence of buprenorphine dependence.” British Journal of Addiction: 1989, 84, p. 1373–1374.

Obadia Y., et al. “Injecting misuse of buprenorphine among French drug users.” Addiction: 2001, 96, p. 267–272.

Ling W., et al. “New trends in opiate pharmacology.” Drug and Alcohol Review: 2001, 20, p. 79–94.

Bell J. The role of supervision of dosing in opioid maintenance treatment. Background document prepared for third meeting of Technical Development Group (TDG) for the WHO Guidelines for psychosocially assisted pharmacotherapy of opioid dependence, 17‑21 September 2007 Geneva, Switzerland. http://www.who.int/substance_abuse/activities/supervision_dosing.pdf

Ling W., et al. “New trends in opiate pharmacology.” Drug and Alcohol Review: 2001, 20, p. 79–94.

Harris D.S., et al. “Buprenorphine and naloxone co‑administration in opiate‑dependent patients stabilized on sublingual buprenorphine.” Drug and Alcohol Dependence: 2000, 61, p. 85–94. 1425 3.2a

Mendelson J. et al. “Clinical and pharmacological evaluation of buprenorphine and naloxone combinations: why the 4:1 ratio for treatment?” Drug and Alcohol Dependence: 2003, 70(2 suppl.), p. S29–S37.

Walsh S.L. et al. “The clinical pharmacology of buprenorphine: extrapolating from the laboratory to the clinic.” Drug and Alcohol Dependence: 2003, 70(2 suppl.), p. S13–S27.

Bell J. et al. "A randomized trial of effectiveness and cost‑effectiveness of observed versus unobserved administration of buprenorphine–naloxone for heroin dependence." Addiction: 2007, 102, p. 1899–1907. http://dx.doi.org/10.1111/j.1360‑0443.2007.01979.x

Chiang C.N. et al. “Pharmacokinetics of the combination tablet of buprenorphine and naloxone.” Drug and Alcohol Dependence: 2003, 70(2 suppl.), p. S39–S47.

The result should be to reduce the temptation for dependent opiate users to crush and inject the tablets and also to reduce the tablets’ street value, making diversion on to the illicit market less of a concern. In non-dependent users precipitated withdrawal is not an issue but there is some lessening in the immediate opiate-type effects experienced after injecting compared to buprenorphine alone. Drug users dependent on buprenorphine itself will also not experience withdrawal if they inject the combination tablet. As a result those most likely to do so should be patients already in treatment with buprenorphine or who have become dependent on illicit sources of the medication.

Bell J. The role of supervision of dosing in opioid maintenance treatment. Background document prepared for third meeting of Technical Development Group (TDG) for the WHO Guidelines for psychosocially assisted pharmacotherapy of opioid dependence, 17‑21 September 2007 Geneva, Switzerland. http://www.who.int/substance_abuse/activities/supervision_dosing.pdf

Walsh S.L. et al. “The clinical pharmacology of buprenorphine: extrapolating from the laboratory to the clinic.” Drug and Alcohol Dependence: 2003, 70(2 suppl.), p. S13–S27.

Bell J. et al. "A randomized trial of effectiveness and cost‑effectiveness of observed versus unobserved administration of buprenorphine–naloxone for heroin dependence." Addiction: 2007, 102, p. 1899–1907. http://dx.doi.org/10.1111/j.1360‑0443.2007.01979.x

Whether these potential safeguards materialise in practice has yet to be adequately determined, but there are some pointers.

Bell J. The role of supervision of dosing in opioid maintenance treatment. Background document prepared for third meeting of Technical Development Group (TDG) for the WHO Guidelines for psychosocially assisted pharmacotherapy of opioid dependence, 17‑21 September 2007 Geneva, Switzerland. http://www.who.int/substance_abuse/activities/supervision_dosing.pdf

In Finland among out-of-treatment needle exchange attenders, over 90% injected the buprenorphine-only product at least several times a week, but just 8% regularly injected the combination tablet, though about two-thirds had tried it. 80% who answered this question had found injecting the combination product a “bad” experience. They were willing to pay on average over twice as much for the buprenorphine-only formulation. 

Alho H. et al. “Abuse liability of buprenorphine–naloxone tablets in untreated IV drug users.” Drug and Alcohol Dependence: 2007, 88, p. 75–78. http://dx.doi.org/10.1016/j.drugalcdep.2006.09.012

In another trial in Australia (confined to patients with stable housing not shared with other opiate users), patients entering maintenance treatment were randomly allocated for 13 weeks to weekly take-home doses of buprenorphine/naloxone tablets, or to supervised consumption which in stable patients could be once every two or three days. Treatment costs were 22% lower when dosing was unsupervised resulting in each heroin-free day costing significantly less to achieve. Five of the 58 patients on take-home doses admitted to injecting the medication of whom three reported precipitated withdrawal. Inspection of injecting sites allied with urine test data indicated that nearly all fresh sites could be accounted for by heroin injections. There was evidence of at least a moderate degree of diversion to the illicit market (which may or may not have been to injecting use). Just one of the 58 patients on take-home doses reported a serious complication due to injecting the medication. 

Bell J. et al. "A randomized trial of effectiveness and cost‑effectiveness of observed versus unobserved administration of buprenorphine–naloxone for heroin dependence." Addiction: 2007, 102, p. 1899–1907. http://dx.doi.org/10.1111/j.1360‑0443.2007.01979.x

This study does not indicate that close clinical monitoring is unnecessary because all patients received this whether or not consumption was supervised. Nor does it indicate that all patients can safely be offered unsupervised dosing because less socially stable patients and those more integrated in drugtaking circles were excluded from the trial, and some who were included did inject or divert the medication. But for relatively socially stable patients entering a programme which in any event offers regular clinical contact and monitoring, it does raise questions over whether the extra safeguard of supervised consumption is worth the extra cost. A review for WHO concluded that there is some limited support for higher supervision of people who are less stable – specifically, unemployed, lack stable housing, using multiple drugs, or continuing to inject – and by implication that the opposite kinds of patients can more safely be allowed take-homes. 

Bell J. The role of supervision of dosing in opioid maintenance treatment. Background document prepared for third meeting of Technical Development Group (TDG) for the WHO Guidelines for psychosocially assisted pharmacotherapy of opioid dependence, 17‑21 September 2007 Geneva, Switzerland. http://www.who.int/substance_abuse/activities/supervision_dosing.pdf

Also in Australia pharmacists reported that attempted or actual diversion of buprenorphine was a major problem because dosing was harder to supervise and took longer than for methadone. The consequence was to make supervision less attractive for the staff.

Nielsen S. et al. “Buprenorphine supply by community pharmacists in Victoria, Australia: perceptions, experiences and key issues identified.” Drug and Alcohol Review: 2007, 26(2), p. 143–152. http://dx.doi.org/10.1080/09595230601146645

In the USA, compared to other opiate-type drugs and in relation to the volume of prescriptions, abuse of both Suboxone (buprenorphine/naloxone) and Subutex (buprenorphine) is relatively rarely reported to regional poison control centres. The slightly higher rate of abuse for Suboxone may be due to its being used more often without supervised consumption.

Smith M.Y. et al. “Abuse of buprenorphine in the United States: 2003‑2005.” Journal of Addictive Diseases: 2007, 26(3), p. 107–111. http://dx.doi.org/10.1300/J069v26n03_12

In Cornwall in England community addiction treatment patients, most of whom had been prescribed both buprenorphine and methadone, were emphatic that under conditions of supervised consumption, buprenorphine was easier to pretend to take and that more people actually did pretend than with methadone.

White R. et al. “Patients’ views of treatment: methadone vs. buprenorphine.” Journal of Substance Use: 2007, 12(5), p. 365–373. http://dx.doi.org/10.1080/14659890701289463

How does non-daily dosing or take-homes affect retention?
In two US studies there was a retention advantage for non-daily attendance schedules which was non-significant possibly due in the first to very low numbers of patients remaining in treatment by the time non-daily dispensing was initiated, and in the second to low numbers in the trial as a whole. In the first there was also no difference in levels of illicit drug use and a greater preference for three days a week dosing with take-homes in between. In the second, opiate-positive urine tests led to discharge from the study which occurred most often under daily supervised consumption (of either active medication or this interspersed with placebo); no take-homes were permitted. 

Amass L. et al. “Thrice-weekly supervised dosing with the combination buprenorphine‑naloxone tablet is preferred to daily supervised dosing by opioid‑dependent humans.” Drug and Alcohol Dependence: 2001, 61(2), p. 173–181. http://dx.doi.org/10.1016/S0376‑8716(00)00141‑1

Amass L. et al. “Alternate-day buprenorphine dosing is preferred to daily dosing by opioid‑dependent humans.” Psychopharmacology: 1998, 136(3), p. 1432‑2072. http://dx.doi.org/10.1007/s002130050559

A trial in Australia confined to applicants with stable housing not shared with other opiate users randomly allocated patients entering maintenance treatment 13 weeks of weekly take-home doses of buprenorphine/naloxone tablets, or to supervised consumption which in stable patients could be once every two or three days. Of the 487 patients seeking maintenance treatment, 131 were eligible for the trial and agreed to participate. About 60% of both groups remained in treatment to the end of the 13 weeks with equivalent reductions in self-reported heroin use and (when missed tests were considered positive) opiate-positive urine tests. All the patients who had achieved stability during the initial 13 weeks could switch to or remain on to take-home doses after the 13 weeks, possibly an incentive for those on supervised consumption to stick with it for three months, and the attendance burden on 28% of the supervised consumption patients was relieved by non-daily dosing. All patients had regular frequent clinical contact and monitoring. After the initial 13 weeks just over a third of both groups were still in treatment and considered stable enough (in their drug use, home circumstances and physical/psychological health) to continue with or switch to take-home doses. After another three months patients who had continued with or switched to supervised consumption were twice as likely to have left treatment; just 7 of 25 remained, suggesting that in the circumstances of the trial, requiring supervised consumption was not the best way to respond to the patients’ instability. However, there was no indication that requiring patients to start the trial on supervised consumption diminished retention.

Bell J. et al. “A randomized trial of effectiveness and cost‑effectiveness of observed versus unobserved administration of buprenorphine–naloxone for heroin dependence.” Addiction: 2007, 102, p. 1899–1907. http://dx.doi.org/10.1111/j.1360‑0443.2007.01979.x

Bell J. et al. “Optimising the benefits of unobserved dose administration for stable opioid maintenance patients: follow‑up of a randomised trial.” Drug and Alcohol Dependence: 2008, 96(1‑2), p. 183–186. http://dx.doi.org/10.1016/j.drugalcdep.2008.02.012

In the USA patients were randomly allocated to supervised consumption of buprenorphine on two, three, or seven days a week, with appropriate multiplication of dose in liquid form to achieve per-day equivalent dose levels. There was no requirement to attend in between dosing and no take-home doses. For the first fortnight all participants attended the clinic daily and their buprenorphine dose was titrated to their maintenance dose (according among other things to patient response) and kept at an equivalent level for the next 24 weeks after which they were gradually withdrawn. Maintenance doses averaged the equivalent of just over 7mg daily, suggestive of a cohort not highly dependent on opiates. Nearly half were employed full time, unusually high for US opiate addiction treatment populations. Retention and opiate-free urines each at about 70% were similar across the three attendance schedules as were improvements in ASI scores and HIV risk behaviour.

Marsch L.A. et al. “Buprenorphine treatment for opioid dependence: the relative efficacy of daily, twice and thrice weekly dosing.” Drug and Alcohol Dependence: 2005, 77(2), p. 195–204. http://dx.doi.org/10.1016/j.drugalcdep.2004.08.011

Also in the USA patients seeking treatment at a hospital primary care centre which provided addiction treatment only in the form of buprenorphine/naloxone were allocated (after a two-week induction and stabilisation period) to be dispensed three times a week or once a week.  There was no supervised consumption. Take-home were provided for intervening doses. There was no difference in retention or illicit opiate use as indicated by urine tests but patients who had to attend just once a week were the ones most satisfied with their treatment. Unusually for a publicly funded programmes, half the participants were in full time employment and only a third injected. Less than half completed the 24-week study, retention averaging about 17 weeks or four months.

Fiellin D.A. et al. “Counseling plus buprenorphine–naloxone maintenance therapy for opioid dependence.” New England Journal of Medicine: 2006, 355(4), p. 365–374. http://content.nejm.org/cgi/content/abstract/355/4/365

Fiellin D.A. et al. “Counseling plus buprenorphine–naloxone maintenance therapy for opioid dependence.” New England Journal of Medicine: 2006, 355(4), p. 365–374. http://content.nejm.org/cgi/content/abstract/355/4/365

The sole study to indicate that prolonged supervised consumption improves retention comes from France. Primary care patients were “quasi‑randomly” allocated to daily supervised buprenorphine for either two weeks, three months, or six months, after which dosing was on a weekly schedule.  Retention in treatment at the six‑month follow‑up was highest for patients in the six‑month daily supervised dosing group (80%) and lowest for those in the two‑week daily supervised dosing group (46%). Unfortunately, it seems this study has never been fully reported and among other things question marks remain over the method of allocation, the comparability of the patients, and the statistical significance of the results.

Auriacombe M. “Buprenorphine prescribed by general practitioners.” In: Waal H. et al, eds. Maintenance treatment of heroin addiction: evidence at the crossroads. Oslo: Cappelans, 2003. p. 190‑204.

Auriacombe M. “Substitution therapy in drug addictions.” Rev Prat.: 2003, 53(12), p. 1327–1334. http://www.ncbi.nlm.nih.gov/pubmed/12920942

Bell J. The role of supervision of dosing in opioid maintenance treatment. Background document prepared for third meeting of Technical Development Group (TDG) for the WHO Guidelines for psychosocially assisted pharmacotherapy of opioid dependence, 17‑21 September 2007 Geneva, Switzerland. http://www.who.int/substance_abuse/activities/supervision_dosing.pdf

Based on these and other studies, a recent review for WHO concluded that the overall impact of supervision on retention and illicit drug use is unclear, but that some stable patients can safely be unsupervised, and that probably this number is greater if these is close clinical supervision and monitoring. To the degree that it can be implemented safely, take-home doses reduce costs, potentially allowing more people to receive treatment. While in relation to methadone the review supported initial and in some cases continued supervised consumption, in relation to buprenorphine the case for both was unproven: “The data do not allow a firm conclusion as to whether it is on balance more beneficial to initiate buprenorphine treatment with supervision of dosing. The benefits of making treatment more accessible, affordable and possibly more attractive to consumers need to be balanced against risk of less effective treatment, creation of a black market, and community antagonism.”

Bell J. The role of supervision of dosing in opioid maintenance treatment. Background document prepared for third meeting of Technical Development Group (TDG) for the WHO Guidelines for psychosocially assisted pharmacotherapy of opioid dependence, 17‑21 September 2007 Geneva, Switzerland. http://www.who.int/substance_abuse/activities/supervision_dosing.pdf

Practice implications
For clinical guidance on how to use buprenorphine see UK prescribing guidelines and a review from three leading US researchers.

Department of Health (England) and the devolved administrations. Drug misuse and dependence: UK guidelines on clinical management. London: Department of Health [etc], 2007. http://www.nta.nhs.uk/areas/clinical_guidance/clinical_guidelines/docs/clinical_guidelines_2007.pdf

Johnson R.E. et al. “Buprenorphine: how to use it right.” Drug and Alcohol Dependence: 2003, 70(2, suppl.), p. S59–S77. http://dx.doi.org/10.1016/S0376‑8716(03)00060‑7

For the Cochrane team the implications of their findings were clear: methadone should be the default maintenance medication, with buprenorphine reserved for environments or patients where high dose methadone is not possible. They added that in some policy or practice settings buprenorphine may be advantaged by its relative safety and alternate-day dosing possibility, a rider which opens the door for the drug to be preferred where daily supervised consumption would otherwise be required or in primary care settings. Their reasoning was that “methadone maintenance treatment at high dose or flexible doses is associated with better suppression of heroin use”, yet their review concluded this was not the case for flexible dose regimens, the kind they considered most relevant to normal practice. 
Experts and advisers convened by the UK’s National Institute for Health and Clinical Excellence (NICE) also thought the flexible dose studies were most clinically relevant. But after considering the Cochrane review and their own analysis (see In Context section), their advice was that the choice between the medications should be made “case by case”, based on issues like whether buprenorphine’s safety was important in that individual case, whether it was preferable because the patient was aiming to move towards abstinence (buprenorphine is easier to withdraw from), and patient preference. They did however say that when for a given individual the medications were equally appropriate, methadone might be preferred because it cost less and on average the money spent on it ‘bought’ a slightly greater quality of life because of its greater retention. 

National Institute for Health and Clinical Excellence. Methadone and buprenorphine for the management of opioid dependence. NICE technology appraisal guidance 114. National Institute for Health and Clinical Excellence, January 2007. http://www.nice.org.uk/guidance/index.jsp?action=byID&o=11606

Connock M. et al. Methadone and buprenorphine for the management of opioid dependence: a systematic review and economic evaluation. Health Technology Assessment: 2007, 11(9). http://www.hta.ac.uk/execsumm/summ1109.htm

UK prescribing guidelines take a similar line on the choice between the medications. They also make no distinction between them in the need for supervised consumption, advocating this for a flexible period (normally about three months) depending on the stability and home circumstances of the patient and the risk of diversion.

Department of Health (England) and the devolved administrations. Drug misuse and dependence: UK guidelines on clinical management. London: Department of Health [etc], 2007. http://www.nta.nhs.uk/areas/clinical_guidance/clinical_guidelines/docs/clinical_guidelines_2007.pdf

Official advice to the NHS in Scotland has dealt specifically with the buprenorphine/allophone tablet. This should it says be “restricted to those patients in whom methadone is not suitable and for whom the use of buprenorphine is considered appropriate”. It notes that “The low abuse potential of buprenorphine/naloxone and a possible reduction in the need for supervised dosing are relevant factors to consider”.

Scottish Medicines Consortium. Buprenorphine/naloxone 2mg/0.5mg, 8/2mg sublingual tablet (Suboxone). Scottish Medicines Consortium, 2007. http://www.scottishmedicines.org.uk/smc/files/buprenorphine%20naloxone%20sublingual%20tablet%20_Suboxone_(355‑07).pdf

Cost and cost-effectiveness could tip the balance between methadone and buprenorphine but which has the advantage is not entirely clear. Per dose buprenorphine costs more than methadone and supervising consumption takes longer. If prescribed in the same sort of maintenance programmes it will prove less cost-effective, especially if current methadone patients divert to buprenorphine. However, buprenorphine permits less than daily supervised dosing and its relative safety (particularly when combined with naloxone) may also be considered to permit take-home doses sooner and more often and to make it suitable for use in a wider range of primary care settings. This formulation could underpin an expansion of primary care-based treatment to opiate addicts of the type currently treated in hospital clinics, decreasing costs. Partly due to non-daily dispensing, in an Australian primary care study, buprenorphine maintenance was not significantly more costly to society and the health services than methadone, even when no take-homes were provided. The economic analysis conducted for the UK’s National Institute for Health and Clinical Excellence only partly accounted for these possible savings but still concluded that the lower costs to the health services associated with methadone (not just in respect of addiction treatment but also other health care costs) were not an overriding consideration.

Connock M. et al. Methadone and buprenorphine for the management of opioid dependence: a systematic review and economic evaluation. Health Technology Assessment: 2007, 11(9). http://www.hta.ac.uk/execsumm/summ1109.htm

Barnett P.G., et al “The cost-effectiveness of buprenorphine maintenance therapy for opiate addiction in the United States.” Addiction: 2001, 96, p. 1267–1278.

Bridge T.P. et al. “Safety and health policy considerations related to the use of buprenorphine/naloxone as an office‑based treatment for opiate dependence.” Drug and Alcohol Dependence: 2003, 70(2 suppl.), p. S79–S85.

Rosenheck R., et al. “Buprenorphine for opiate addiction: potential economic impact.” Drug and Alcohol Dependence: 2001, 63, p. 253–262.

Harris A.M. et al. “A randomised trial of the cost effectiveness of buprenorphine as an alternative to methadone maintenance treatment for heroin dependence in a primary care setting.” PharmacoEconomics: 2006, 23(1), p. 77–91. http://www.ingentaconnect.com/content/adis/pec/2005/00000023/00000001/art00007

Connock M. et al. Methadone and buprenorphine for the management of opioid dependence: a systematic review and economic evaluation. Health Technology Assessment: 2007, 11(9). http://www.hta.ac.uk/execsumm/summ1109.htm

In 2006 63% of the drug treatment clients in England who answered questions about opiate substitute prescribing for an NTA survey were being prescribed methadone and 30% buprenorphine. In the first 12 weeks 69% of the buprenorphine patients were supervised daily compared to 78% on methadone. After this daily supervision continued for 50% and 63% respectively. In the same survey respondents were significantly more likely to never use on top of prescriptions if they received a buprenorphine prescription rather than one for methadone (47.4% of buprenorphine clients and 26.2% of methadone clients never used on top of prescriptions). Also methadone clients were significantly more likely than buprenorphine clients to use on top of prescriptions often or always. The following year a similar survey found that patients prescribed buprenorphine were significantly more likely to be satisfied with their treatment than those who received methadone.

National Treatment Agency for Substance Misuse (NTA). The NTA’s 2006 survey of user satisfaction in England. NTA, August 2007. http://www.nta.nhs.uk/publications/documents/nta_2006_survey_of_user_satisfaction_in_england.pdf

National Treatment Agency for Substance Misuse (NTA). Harm reduction findings from the NTA’s 2006 survey of user satisfaction in England. NTA, August 2007. http://www.nta.nhs.uk/publications/documents/nta_2006_harm_reduction_survey.pdf

Gordon D. et al. The 2007 user satisfaction survey of Tier 2 and 3 service users in England. National Treatment Agency for Substance Misuse, May 2008. http://www.nta.nhs.uk/publications/documents/nta_2007_user_satis_survey_tier2and3_service_users_england.pdf

A survey of specialist community drug prescribing services in England in 2004–2005 found that 88% prescribed buprenorphine to some of their clients compared to 96% for methadone. However, far fewer patients were prescribed buprenorphine – on average 31 versus 133 on methadone. On average, 26% of all clients prescribed opioid substitutes were being prescribed buprenorphine. Within the first 12 weeks during which guidelines operative at the time recommended daily supervised consumption of methadone, half the services which responded said that over 80% of their buprenorphine patients were supervised daily. Three-quarters of services met this criterion in respect of methadone. After the first 12 weeks, 32% of buprenorphine patients remained on daily supervised consumption, while 54% were not supervised at all compared to 54% and 37% respectively for methadone. All these and other such figures were indicative of much less frequent supervised consumption of buprenorphine than methadone. Two-thirds of methadone patients were dispensed daily or nearly daily; no corresponding figure was given for buprenorphine. Though over the years from 2002 to 2004 the number of prescriptions issued for both methadone and buprenorphine increased, in every Government Office region in England, the increase was much greater for buprenorphine, until by 2004 27% of the total was accounted for by buprenorphine. 

Best D. et al. National prescribing audit: an assessment of prescribing practices for opioid substitution treatment in England, 2004–2005. National Treatment Agency for Substance Misuse, 2007. http://www.nta.nhs.uk/publications/documents/nta_npa1_prescribing_audit.pdf

One important question mark is over buprenorphine’s suitability for the prolific offenders from whom treatment reaps its cost-savings.  These also tend to be the most dependent on heroin and the heaviest users, yet there are inherent limits on the extent to which buprenorphine can substitute for high doses of heroin. 

Stewart D., et al. “Drug misuse and acquisitive crime among clients recruited to the National Treatment Outcome Research Study (NTORS).” Criminal Behaviour and Mental Health: 2000, 10, p. 10–20

Ashton M. “NTORS.” Drug and Alcohol Findings: 1999, 2, p. 16–22.

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