Drug and Alcohol Findings home page in a new window Background notes

A comparison of methadone, buprenorphine and alpha2 adrenergic agonists for opioid detoxification: a mixed treatment comparison meta-analysis

Consistent findings from review using conventional methodology

Another analysis conducted under the rigorous Cochrane procedures took in studies published up to 2008 (rather than 2006 in the featured review) and included five (compared to three) head-to-head comparisons between buprenorphine and methadone. Combining these studies, it was estimated while typically 51 people out of a 100 would complete a methadone-based detoxification, 61 would on buprenorphine – not a statistically significant difference, but one which corroborates the findings from the featured review using a different methodology. The contrasts with clonidine and lofexidine were more decisive; on buprenorphine patients stayed in treatment significantly longer and were significantly more likely to complete their withdrawal programmes. As the review commented, buprenorphine's advantage makes sense because its pharmacological profile (binding tightly to opiate receptors in the brain, but without fully activating them – so-called 'partial agonist' properties) limits the severity The cited review observers that "Autonomic signs of opioid withdrawal (e.g. chills, gooseflesh, tremors, rhinorrhea, lacrimation) are generally less pronounced with buprenorphine than with full mu-opioid agonists, although these signs may be present (typically in the first 5 days after abrupt discontinuation)". of withdrawal compared to drugs like heroin and methadone which fully activate opiate receptors but bind to them less tightly. Buprenorphine's reluctance to depart the receptors creates a self-tapering effect, meaning that abruptly stopping the drug causes less distress than stopping methadone or heroin.

Because it was based on direct comparisons between detoxification medications within the same study, this analysis avoided the major risk in the featured review – that, for example, trials comparing clonidine respectively with methadone and with buprenorphine might differ in such a way (patients, settings, procedures, etc) that deducing the relative value of buprenorphine and methadone from those trials would be misleading. On the other hand, the featured review could draw on indirect comparisons from trials the Cochrane review had to exclude in reaching its conclusions on the relative value of each pair of medications. The broad similarity of the conclusion reached by these different types of synthesis gives extra confidence in its validity.

British studies

Published in 2005, the first British study to compare lofexidine with buprenorphine recruited 481 opiate-dependent patients for outpatient detoxification. Of these, 210 agreed to be randomly allocated to one of the medications; the remainder chose between the two. Patients who chose did about as well whichever medication they opted for; about 60% completed the procedure, and a month later a third told researchers they were no longer using illicit opiate-type drugs. But among the randomly allocated patients, buprenorphine proved preferable; on this medication, 65% completed detoxification compared to just 46% on lofexidine, a statistically significant advantage which fed through to a higher proportion (40% v. 32% of those followed up) reporting opiate abstinence a month later. During detoxification buprenorphine patients were also consistently more comfortable, despite not routinely being offered medication for withdrawal symptoms which buprenorphine fails to adequately control. Presumably as word spread, by the end of the study all the patients who exercised choice opted for buprenorphine.

A study published in 2007 of inpatient detoxification appeared to confirm that in this setting too, patients who choose lofexidine do at least as well (in this study, actually better in terms of completion and sustaining opiate abstinence after leaving) as those who choose an opiate type medication (in this case, methadone), possibly because those who opted to do without methadone had less severe problems. Hastening detoxification by pairing lofexidine with the opiate-blocking drug naloxone did not improve completion rates, but did mean patients spent more days at the unit after completing the detoxification phase of the treatment. Presumably because of the extra support and stability they achieved, in turn this meant more (48% v. 38%) avoided relapse to daily opiate use after they left. What seems to have been an earlier report on the same study found that with naloxone the lofexidine patients generally experienced less severe withdrawal symptoms and craving for opiates. Taking the two reports together, it appears The average number of days after completion of detoxification spent on the unit and in receipt of ongoing psychosocial intervention was 10.2 days for lofexidine plus naloxone, 6.7 days for lofexidine alone. The average length of stay overall was 17.5 and 15.3 days respectively. that greater post-detoxification retention was partly due to naloxone shortening the detoxification period and partly to patients staying slightly longer on the unit. In this study, just 41% of the patients approached by the researchers were prepared to detoxify on lofexidine (with or without naloxone) rather than the unit's usual methadone-based programme.

Practice guidance

British guidance for clinicians on how to detoxify opiate-dependent patients is largely based on an appraisal of evidence and expert opinion published in 2007 by Britain's National Institute for Health and Clinical Excellence. These documents found tapering doses of buprenorphine and methadone equally effective in achieving good outcomes from detoxification and more effective than the non-opiate medications clonidine and lofexidine. However, these medications were not dismissed. Lofexidine (the safer of the two) might, the guidance said, help relieve withdrawal in patients using small amounts of opiate-type drugs, may be preferable when it is unclear whether patients are dependent on opiate-type drugs, and may be preferred by patients wishing to rapidly and completely stop taking any opiate-type drug or medication. When it came to choosing between buprenorphine and methadone – seen as "first-line treatment[s] in opioid detoxification" – the recommendation was that patients should normally be detoxified on whichever medication they had already been stabilised on, though the patient's preferences should also be taken in to account. Similar guidance has been issued in respect of children under 16 years of age. At these ages non-opiate medications are likely to be applicable to more patients due to uncertain or low severity dependence. All this guidance predates the featured review and the latest edition of the Cochrane review, new data which might have led the experts to prioritise buprenorphine.

Though in the featured review medications are posed as alternatives, patients' comfort can be improved by using clonidine or lofexidine (and/or other medications) to ameliorate withdrawal symptoms not well controlled by buprenorphine (1 2 3 4).

Some studies (1 2) have found tapering doses of buprenorphine to be a useful bridge from methadone maintenance to abstinence from opiate-type drugs, but others have found withdrawal severity is intensified. Much is likely to depend on doses and timing. Advice is to reduce methadone doses to 40mg a day or less and then (as with buprenorphine-based detoxification in general) to initiate buprenorphine only when withdrawal symptoms have started to became apparent.

Post completion deaths

Completion of detoxification was the criterion used by the featured review, and of course this is an appropriate aim for such a procedure. However, completion is a mixed blessing. British guidance (1 2) warns that the loss of tolerance (the ability to tolerate higher doses after becoming used to regularly taking a drug) to opiate-type drugs following detoxification heightens the risk of overdose and death if patients return to using opiate-type drugs, especially if at the same time they use alcohol or benzodiazepines.

In the British study of inpatient detoxification mentioned above, all three overdose deaths in the four months after patients left the unit were among the 37 who had 'successfully' detoxified and completed the programme. There were none among non-completers. The annualised death rate among completers was 24 in every 100. The longer patients had stayed on the unit, the more likely they were to die after leaving. Among others, recent findings from Italy and Australia have highlighted the need to carefully select and prepare detoxification candidates and to invest in aftercare if patients are to survive loss of protective tolerance to opiate-type drugs after completing withdrawal.

UK national guidelines caution careful selection of patients fully committed to the process and who will enjoy supportive and stable social environments after discharge, among which may be seamless entry in to residential rehabilitation. The general message graphically stressed by a US expert is that detoxification without preceding stabilisation and preparation and succeeding aftercare, including the construction of a resilient post detoxification life, too often risks more harm than good.

Cost considerations

The fact that buprenorphine costs more than methadone is probably the main blockage to its becoming the first-choice detoxification agent. Set against this, buprenorphine programmes can be completed in a shorter time and in some cases after a single dose, potentially reducing or eliminating the difference in the cost of an equally effective course of treatment. Some outpatient studies which have found buprenorphine preferable to clonidine have reduced the programme to four or five days. In one study a single dose of buprenorphine (along with clonidine and other symptom-relief medications) during an inpatient stay prepared patients for initiation of abstinence sustained by the opiate-blocking drug naltrexone the following day. As a prelude to continuing treatment, the study found this combination as effective as rapid detoxification under anaesthesia. A small inpatient study found a single high (24mg) dose of buprenorphine as effective in suppressing withdrawal symptoms and craving as a previous regimen based on a five-day buprenorphine taper.

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