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Buprenorphine – the 'new’ drug addiction treatment |
Buprenorphine is classified as a mixed agonist-antagonist. It has partial agonist activity at mu and antagonist at kappa opioid receptors and may also be an agonist at delta receptors. It has been used extensively in many countries for the management of acute pain, and is as effective an analgesic as morphine with a longer duration of action and greater safety in overdose. One potential advantage of buprenorphine over full mu opioid agonists is its reported low physical dependence profile.
US studies show benefits
Seven sizeable clinical trials in the US have used buprenorphine, according to Dr W Ling. These have involved 1,152 patients and trial lengths have varied from 2 to 52 weeks, but were on average six months. The US trials can be broadly classified into three groups: studies comparing buprenorphine and methadone, dose-ranging studies and ongoing studies of the combination product. All of these studies showed that buprenorphine reduces opiate use, retains patients in treatment, and has few side effects. Most studies have used sublingual liquid buprenorphine, but a sublingual tablet has now been prepared for clinical use.
Study 1 (Bickell, 1988)
Results: Buprenorphine (2mg) and methadone (30mg) had similar effects on all measures of treatment outcome: retention in treatment, illicit drug use, withdrawal symptoms, and self-reports of drug effects. Methadone attenuated the effects of hydromorphine to a greater extent than buprenorphine.
Conclusions: this study confirmed the efficacy and acceptability of buprenorphine for detoxification. The 2mg dose of sublingual liquid buprenorphine was found to be equivalent to 30mg methadone.
Study 2 (Johnson, 1992)
Results: Treatment retention of the 8mg buprenorphine group (42%) was slightly higher than the 60mg methadone group (32%) and significantly higher than the 20mg methadone group (20%). The percentage of opiate negative urines showed a similar trend. Patients did not always provide urine samples, and by excluding missed samples, 63% of the buprenorphine group were found to be negative for opiates compared with 51% and 35% in the high and low dose methadone groups, respectively.
Buprenorphine at 8mg/day was found to be significantly better at reducing illicit opiate use than methadone 20mg/day. The trend favoured buprenorphine 8mg/day over methadone 60mg/day. Patients who liked the treatment were also considered. In the 60mg/day methadone group, patients reported liking treatment significantly more often than was the case than with the other two treatments and reported a higher degree of euphoria. However, patients also felt significantly more ‘hooked’ on this dose of methadone. Buprenorphine patients felt less 'hooked’ than the 20mg/day methadone patients, although this was not statistically significant.
Withdrawal scores were similar for all groups, possibly due to illicit ‘topping up’ with street opiates. Adverse events were similar between groups and were consistent with withdrawal.
Conclusions: Buprenorphine 8mg/day was found to be more effective than methadone 20mg/day and was comparable with methadone 60mg/day in the treatment of opiate dependent addicts.
Study 3 (Ling, 1996)
Results: This study compared 8mg/day buprenorphine with 30mg/day and 80mg/day methadone in 225 subjects who were divided equally among the three groups. Retention data were similar for patients treated with buprenorphine and the lower methadone dose. Greater retention was observed in the higher methadone dose group. A similar number of opiate negative urine samples were observed in the buprenorphine and lower dose methadone group. In the higher dose methadone group there were significantly more opiate-negative urine samples.
Conclusion: This study showed that 80mg/day methadone is superior to both 30mg/day methadone and 8 mg/day buprenorphine in the treatment of opiate dependent patients. The latter two were similar in efficacy.
In summary, the forgoing comparison studies, with a combined total of more than 350 opiate-dependent patients, established the efficacy of buprenorphine compared with methadone as a maintenance treatment for opiate dependence. A dose of 8mg/day buprenorphine was found to be equivalent to 30mg/day methadone and perhaps even comparable to 60mg/day methadone. This confirms the usefulness of buprenorphine as an alternative to methadone.
Study 4 (Strain, 1994)
Report – In this 26 week, double-blind, double-dummy comparison study of 164 subjects, randomised patients received either blindly increased doses of buprenorphine (8-16 mg/day) or methadone (0-90mg/day). At week 16 patients were gradually detoxified. Counselling and weekly group therapy were offered and patients were asked to provide thrice weekly urine samples.
Results: No significant differences in retention, compliance (based on number of days patients attended the clinic), amount of counselling contact, or use of illicit opiates, cocaine or benzodiazepines were observed between treatment groups. Both groups had a similar number of opiate-positive urines (40% for each group across maintenance period of study). In addition, 55% of the methadone-treated patients and 50% of the buprenorphine-treated patients abstained from opiate use for two or more weeks. A similar number of requests for dose increases were observed in the two treatment groups and a similar response rate was seen. 56% of both groups remained in treatment until week 16.
Conclusion: The use of flexible dosing reflects clinical practice, and the benefit of increasing the maintenance dose was evident. No differences were observed between the two treatment groups, possibly due to the patients’ ability to self-regulate their dosage. Buprenorphine was equivalent to methadone in helping patients to successfully detox from opiates.
Study 5 (Schottenfeld, 1997)
In a double-blind trial 116 opiate-dependent patients (also using cocaine) were randomised to one of two buprenorphine groups (4&12mg) or one of two methadone groups (20&65mg).
Results: No differences were observed between the two treatment groups in terms of retention. The rate of illicit drug use, as indicated by opiate-positive urine samples, was significantly greater for patients receiving 20 mg/day methadone and 4mg/day buprenorphine, and was similar in patients receiving high dose methadone (45%) and high-dose buprenorphine (58%). Patients in the high-dose methadone and buprenorphine groups were more likely to achieve 3 weeks or more of total abstinence from illicit opiates. Neither treatment reduced the use of cocaine.
Conclusion: Methadone and buprenorphine were both well tolerated, and no adverse effects that necessitated a change in dose or discontinuation of treatment were reported. Higher dose buprenorphine and methadone were found to be more effective.
Study 6 (Ling, 1998)
736 heroin dependent subjects received one of four different buprenorphine doses (1,4,8 & 16mg/day). Patients attended the clinics daily and were offered weekly counselling. Treatment was offered in two phases: 1) a 16 week efficacy phase during which opiate-negative urine samples, retention, opiate craving, and global ratings were assessed; and treatment effectiveness scores were obtained based on the number of opiate-negative urine samples obtained; and 2) a 36 week safety extension with evaluation over the full 52 weeks. During the safety extension phase, patients could receive a dose that was double or half their initial assigned dose.
Results: 51% of patients completed the 16-week trial. Significantly more patients on 8 and 16 mg/day buprenorphine completed treatment compared with those receiving 1mg/day. The percentage of patients achieving 13 consecutive negative urine samples and total number of negative urine samples assessed by Treatment Effectiveness Scores was higher. Illicit use of opiates, as indicated by positive urine samples, was more common among those receiving 1 mg/day buprenorphine. Significantly more patients provided 13 consecutive opiate-negative urine samples in the group treated with 16 mg/day buprenorphine compared with those treated with 1mg/day and 4mg/day buprenorphine and there was more sustained abstinance in this group. Increasing the daily doses enhanced treatment efficacy, except when comparing 8 mg/day and 16mg/day. No increase in adverse effects was seen with increasing doses. Craving was lower in the 8mg/day group compared with the 1mg/day group (this was significant at 4 and 8 weeks after beginning treatment). No dose escalation was seen over the 52-week period.
Conclusion: This study showed that 8mg/day buprenorphine was significantly superior to 1mg/day buprenorphine. Buprenorphine was effective and safe as a maintenance treatment for heroin users, reduced the illicit use of heroin, and alleviated cravings. Buprenorphine showed a good safety profile with no unexpected adverse events, making it useful in maintenance therapy.
First line of treatment
Dr Ling concludes that buprenorphine is a first line treatment for opiate addiction and offers the widest range of options. It is relatively easy to transfer patients from buprenorphine to methadone or LAAM but much more difficult to transfer addicts from a high dose full agonist to buprenorphine. Thirty years of methadone treatment have confirmed that the situation in the US is not the ideal. There are more effective ways of treating opiate addicts and we should learn from our experience.
French study shows high patient retention
In the now famous French study by Auriacombe (1997) where buprenorphine has been used since 1988 results indicate a high level of opioid-clean urines and patient retention in treatment. Quality of life is improved significantly when measured by a variety of methods. The approach adopted by the Substance Abuse Treatment Unit of the Dept. of Psychiatry of the University of Victor Segalen, Bordeaux involves a high degree of control. Patients are provided with consultation, regular urinalysis, and supervision of buprenorphine delivery by the local pharmacist prevents diversion whilst allowing the patients to integrate into society. The success of the program to date is reflected in the instigation of a new trial involving prescribing by GPs outside the academic setting and the first-choice status of buprenorphine, above methadone, for this indication.
The situation in France
Buprenorphine was made available in France in February 1996 as a standard registered medication and can be prescribed by any medical doctor, whether GP or specialist, in private or public practice, with in- or out-patient settings. The treatment can be delivered in any pharmacy and control is minimal. It is essential that the prescription be on a special prescription pad for controlled substances, which is delivered to GPs on request. The other restriction is that one prescription is only valid for a maximum of 28 days and, as such, one pharmacist can only deliver 28 days of treatment at one time.
The population of France is close to 60 million and it is estimated that there are at least 150,000-300,000 heroin-dependent subjects. The number receiving methadone is about 6-7,000 and the estimated number receiving buprenorphine is 40-50,000. There has been a significant decrease in reported overdose cases since 1996 from over 500 deaths/year to less than 250 deaths/year.
The situation in Europe
A meeting in Milan, Italy, in October 1998 discussed the development of European-wide guidelines for the use of high dose buprenorphine in the treatment of opiate addiction. It was generally well accepted that buprenorphine has a wide effect dose range (2-32mg/day), a wide safety margin, is well tolerated, is widely accepted by addicts, has only mild withdrawal and a low dependence liability and offers flexibility in dosing.
Subutex
Two buprenorphine products will ultimately be available for the treatment of opiate dependence. Subutex, the so-called ‘mono’ product, in use in France, is a sublingual tablet containing buprenorphine at doses of 2mg and 8mg, including a less commonly used 0.4mg tablet.
Suboxone
There is a second product in development called Suboxone, or the combination product; that is, a fixed-dose combination of buprenorphine with naloxone in a 4:1 ratio. The inclusion of this low dose of naloxone results in precipitated withdrawal if the product is injected; this is due to the differing bioavailabilities of the two substances with the naloxone reaching the receptors more quickly than buprenorphine. Sublingually, however, the combination product behaves like Subutex as this route poorly absorbs the naloxone. The development of the combination product is of particular interest to the treatment provider, as it is expected that naloxone will deter diversion and thus makes for an appropriate and safer take-home medication.
From methadone to buprenorphine
Studies in various parts of Europe initially by Reisinger (1985, 1988) and then Carpentier (1995) demonstrated the effectiveness of buprenorphine in both maintenance and detoxification programs. Studies by Myles (1997), Rindom (1997), Fischer (1998) confirmed the ease of transfer of addicts from methadone to buprenorphine and the use of buprenorphine as a detoxification agent. Recent studies by Eder (Austria), Gessa (Italy) and Petitjean (Switzerland) report generally a more favourable response with buprenorphine over methadone, though dose levels of buprenorphine may need to be reviewed as present recommended levels appear to be different to experienced positive outcome levels between European and American studies.
Two studies suggest that less than daily dosing maybe an option with buprenorphine (Casas, Spain). In the US, studies have been carried out using the sublingual tablet at doses of up to 32mg, and these have demonstrated a ceiling effect on the efficacy of buprenorphine. With doses higher than 12mg/day, the level of euphoria is not enhanced, but the duration of action is prolonged and cardiorespiratory effects plateau. Side effects including sedation, nausea and itching at the site of injection, if used intravenously, along with irritability, but there were no changes in mental status and subjects remained responsive.
Fischer (1999) found that Methadone and slow-release morphine proved to be safe and efficacious in pregnancy but were found to cause neonatal syndrome (NAS) in infants of treated women. Buprenorphine, however, was associated with no or mild NAS and could provide a useful alternative to methadone in the maintenance treatment of opiate dependent women.
Pilot studies in Australia
Currently pilot studies are being conducted in Queensland, New South Wales and Victoria investigating methadone withdrawal using buprenorphine. They are mostly in the third stage of this investigation, however, preliminary findings from the first two stages showed that there was 94% of subjects that completed the buprenorphine induction, 59% completed stabilisation, 29% did not complete buprenorphine reductions.
The average time to reduce to 0mg of buprenorphine was 10 weeks and the average number of dirty urines was 1 /subject/reduction period. They have so far concluded that it is a quick and easy induction to buprenorphine from 25-30mg of methadone, that the transition from methadone to buprenorphine may be preferable to clients at lower doses of methadone, that there are quick and easy reductions from buprenorphine and that there is low heroin use during buprenorphine reductions. It is anticipated that within the second half of this year buprenorphine will be available for use by GPs, especially those already prescribing methadone.
Rapid induction preferable
A clinical profile of buprenorphine shows that a rapid rather than slow induction phase is preferable, when stabilised on an adequate dose buprenorphine blocks the intravenous misuse of other opiates, withdrawal from buprenorphine is relatively mild, addicts report feeling more normal, buprenorphine has a low dependence liability, a lower level of reinforcement and buprenorphine offers flexibility in dosing in that it can be administered daily, every other day or thrice weekly.
One of the worse fears for any opium addict is not being able to get their drug – if an addict misses their dose of methadone, they will suffer withdrawal but this is not the case with buprenorphine. The fear of withdrawal is the greatest fear for an addict, so buprenorphine has a tremendous advantage.
At this stage buprenorphine is not available in NSW, but hopefully will be in the near future.
Gareth Daniels is the D&A project officer for the Northern Rivers and Tweed Valley divisions of general practice.
This article was first published in GPSpeak, the magazine of the Northern Rivers Division of General Practice.
References:
Auriacombe, M., and Tignol, J., 1997. Buprenorphine Use in France: quality of life and conditions for treatment success. Research & Clinical Forums 19:25-32.
Auriacombe, M., Franques, P., Daulouede, J-P. & Tignol, J. 1999. The French Experience. Research & Clinical Forums 21(3):9-16.
Auriacombe, M., Grabot, D. and Daulouded, J.P., 1994. A Naturalistic Follow-up Study of French Speaking Opiate Maintained Heroin Addicts. Effects on Biopsychosocial Status. Journal of Substance Abuse Treatment 11:565-68.
Bickel, W.K., and Amass, L., 1995. Buprenorphine Treatment of Opioid Dependence: a review. Explorations in Clinical Psychopharmacology 3:477-89.
Chapleo, C. B., 1999. European Studies (Buprenorphine). Research & Clinical Forums 21(3):29-36.
Fischer, G. & Peternell, A., 1999. The Use of Buprenorphine in Pregnancy. Research & Clinical Forums 21(3):17-28.
Fischer, G., 1999. Introduction (Buprenorphine). Research & Clinical Forums 21(3):7-8.
Fischer, G., Gombas, W., Eder, H., Jagsch, R., Peternell, A., Stuhlinger, G., Pezawas, L., Aschauer, H.N. & Kasper, S. 1999. Buprenorphine versus Methadone Maintenance for the treatment of Opioid Dependence. Addiction 94(9):1337-47.
Greenwald, M.K., Johanson, C-E. and Schuster, C.R., 1999. Opioid Reinforcement in Heroin-dependent Volunteers during Outpatient Buprenorphine Maintenance. Drug and Alcohol Dependence 56:191-203.
Johnson, R.E., Jaffe, J.H. & Fudala, 1992. A Controlled Trial of Buprenorphine Treatment for Opioid Dependence. Journal of the American Medical Association 267:2750-2755.
Ling, W., 1999. Clinical Guidelines for Buprenorphine: USA. Research & Clinical Forums 21(3):37-50.
Ling, W., Charuvastra, V.C. and Collins, J.F., 1998. Buprenorphine Maintenance Treatment of Opiate Dependence: a multicenter, randomised clinical trial. Addiction 93:475-86.
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