METHADONE
MAINTENANCE
VERSUS
BUPRENORPHINE MAINTENANCE
Is Buprenorphine Safer Than Methadone?
This paper is in response to a letter dated 2 July 1999 by Mr Rob Whiddon, Chief of Staff of the office of the Queensland Premier, Mr Peter Beattie, where Mr Whiddon states "as you may be aware, there is overwhelming evidence that the use of Methadone maintenance treatment is currently the most effective treatment for opioid addiction. Although, not all people benefit from methadone maintenance treatment, there is substantial evidence that the treatment assists people to stabilise their lives and that it reduces crime"
Has Queensland moved from an official policy of methadone treatment to methadone maintenance, if so, on whose authority has this policy shift been implemented? It does appear that addicts may have the right to sue the Government Health Authorities if we are to believe the detailed paper by Barrister Goodridge called "The Methadone Conspiracy can Addicts Sue?" nevertheless, let’s look at buprenorphine maintenance for addicts against methadone maintenance.
What does the Australian Health Professional say about Buprenorphine? Wayne Hall and Richard P Mattick’s book Methadone Maintenance Treatment and Other Opioid Replacement Therapies clearly explain Australian Methadone Maintenance Policy.
A major consideration in the development of a viable treatment product for opioid dependence has been the perceived need to avoid injectable formulations. Since buprenorphine has poor oral bioavailability in due to intestinal metabolism, most of the subsequent clinical pharmacology and clinical studies have administered buprenorphine beneath the tongue, via the sublingual route in an ethanol solution. For a time, this offered the most convenient formulation for the range of doses used in the various studies. The successful development of the sublingual analgesic tablet has also proved it to be an acceptable route of administration, albeit with lower bioavailability than the ethanol formulation (Mendelson et al., 1995).
It is a potent analgesic considered to be 25 - 50 times more potent than morphine for pain relief and 30 times more potent than morphine in its ability to produce effects in opioid-dependent subjects (Jasinski & Preston, 1996). Taken orally it is a relatively ineffective drug due to the efficient "first-pass" metabolism by the liver. However, the drug is quite well absorbed sublingually and has been shown to be effective when administered via this route. It is also potent when injected and has the potential for abuse, as the tablet is easily crushed and injected. This property has led to the development of research to evaluate the ability of a combined buprenorphine-naloxone sublingual preparation to prevent injection (Robertson et al., 1993). Various ratios of buprenorphine to naloxone are being trialed (1:1, 4:1, 6:1) to determine the best ratio.
Buprenorphine is well absorbed via the sublingual route (Lewis, 1985), whereas the bioavailability of buprenorphine is decreased if the medication is swallowed, as oral absorption is 15% of sublingual absorption. This poor oral absorption also provides greater safety in the case of overdose, compared to other pure agonists which are well absorbed orally.
Buprenorphine has abuse potential, as do all other psychotrophic medications available to injecting drug users. Early research showed that the medication had the potential to produce opioid-like effects. Both acute and chronic administration of subcutaneous buprenorphine produces euphoria and ratings of "drug liking" (Jasinski et al., 1978). Similar results were also obtained by others (Pickworth et al., 1993). Abuse has been reported in Western Australia, Scotland and New Zealand (Robinson et al., 1993) and the research is currently being pursued further in the U.S.A. The concerns about injection of the mono-therapy buprenorphine may lead to the combination buprenorphine-naloxone preparation being the preferred formulation.
Research cited earlier has used fixed and sometimes low doses of methadone, and this has important implications for understanding the possible efficacy of buprenorphine. If patients in methadone treatment were maintained on a sub-optimal dose, it is possible that they were in a low-grade withdrawal. To the extent that this occurred, it is possible that buprenorphine (as a partial agonist) also leaves patients in a low-grade withdrawal. Increasing doses of methadone to maximise patient comfort will, we believe, reduce withdrawal symptoms and craving, but it is possible that increasing buprenorphine doses will not yield the same result. As such, buprenorphine may never have the ability to suppress withdrawal symptoms and craving that a full agonist possesses.
As well as drugs that enhance or inhibit the metabolism of methadone, opiate antagonists, such as naloxone, and partial agonists, such as buprenorphine and pentazocine, will produce withdrawal signs and symptoms in methadone-maintained individuals. Accordingly, the partial agonists should not be used for pain management in methadone maintenance patients (Kreek, 1983b; Strain et al., 1993; Walsh et al., 1995). The capacity for buprenorphine to precipitate withdrawal appears to be a dose-related phenomenon in methadone-maintained individuals, with the likelihood of withdrawal increasing as methadone dose increases. Initiating buprenorphine maintenance in methadone-maintained patients is best achieved by reducing the methadone dose to approximately 30 mg per day and increasing the dose of buprenorphine gradually from a low to a maintenance dose.
Another approach to increasing treatment efficiency may be to use longer acting opioid maintenance drugs, such as buprenorphine and LAAM. Because these drugs have a longer half-life than methadone, the frequency of dosing could be three times a week rather than daily, reducing the costs of maintaining an opioid-dependent person, and the necessity for irksome and disruptive daily attendance for patients. Buprenorphine is a mixed agonist-antagonist opioid which has the additional advantages of a lower risk of overdose and an easier withdrawal process than methadone. These are substantial advantages. Methadone has a bad (if not always deserved) reputation for greater addictiveness, side-effects and overdose risk than heroin among heroin users in the United States (Beschner & Walters, 1985; Hunt et al., 1986; Rosenblum et al., 1991). There is an anecdotal evidence of similar views among heroin users in Australia but no research has been done on the issue.
Methadone Maintenance Treatment and Other Opioid Replacement Therapies
Funded by the Drug and Alcohol Directorate of the New South Wales Department of Health. Harwood Academic Publishers. Copyright 1998 OPA (Overseas Publishers Association), Amsterdam B.V. Published in the Netherlands by Harwood Academic Publishers.
Ongoing research with a combination of buprenorphine-naloxone tablets appears likely to result in a take-home product with characteristics of low-abuse liability, low-diversion potential and diminished risk of overdose in non-tolerant individuals. The high safety profile, long duration of action and patient acceptance, as evidenced by the ease of patient accrual in this study, make buprenorphine an attractive alternative to methadone or LAAM for the treatment of opioid dependence, and the buprenorphine/naloxone comination product offers the potential first opportunity in three decades to treat opioid addicts in the private physician’s office away from the traditional methadone clinic setting. A sequential pharmacological treatment strategy beginning with buprenorphine might advantageous because it offers patients and clinicians the widest subsequent treatment options. Because of its high safety profile, patients can be treated more vigorously with buprenorphine. Patients who respond well to buprenorphine can opt to continue, at perhaps less than daily dosing, or to work towards abstinence through detoxification, with or without a subsequent period of naltrexone treatment. Patients whose level of physical dependence can not be adequately addressed by buprenorphine, a partial agonist, can be offered the full agonists, LAAM and methadone. One can conclude that, for the maintenance treatment of opioid dependence, buprenorphine will be a useful and welcome addition to methadone, LAAM and naltrexone.
Buprenorphine maintenance treatment of opiate dependence: a multicenter, randomized clinical trial
WALTER LING, CHARLES CHARUVASTRA, JOSEPH F. COLLINS, STEVE BATKI, LAWRENCE S. BROWN JR, PRUDENCIA KINTAUDI, DONALD R. WESSON, LAURA McNICHOLAS, DONALD J. TUSEL, USHA MALKERNEKER, JOHN A. RENNER JR, ERICK SANTOS, PAUL CASADONTE, CAROL FYE, SUSAN STINE, RICHARD I. H. WANG, & DORALIE SEGAL
Design. Full investigation of cause of death was conducted for six drug abusers. Setting. The deaths occurred in two regions of France (Auvergne and Lorraine). Assays were carried out by the Institut de Medecine Legale at Strasbourg, France, one of the few French laboratories equipped to assay buprenorphine. Measurement. First, the blood and urine underwent triple exhaustive screening. Secondly, buprenorphine and norbuprenorphine were analysed in all the autopsy samples by HPLC/MS. Findings. Benzodiazepine-buprenorphine associations were found in every case; no other substances that could account for the death were found. The tissue concentrations were markedly higher than the blood levels. Conclusion. If the number of deaths linked to such drug misuse proves high, it may be necessary to review how buprenorphine is dispensed. Results. Benzodiazepine-buprenorphine associations were found in every case (norbuprenorphine was found less systematically). No other substance that could account for the death was found (e.g. illicit poisons, psychotropics, other drugs).
These cases were drug abusers who were not included in well-organized care programs, and who were deliberately misusing prescriptions (a relatively common occurrence). However, the demonstration of potentially lethal effects of the buprenorphine-benzodiazepine association challenges the purported harmlessness of buprenorphine.
Six deaths linked to concomitant use of buprenorphine and benzodiazepines
MICHEL REYNAUD, GEORGES PETIT, DENIS POTARD & PASCAL COURTY
In countries with a longer experience than France in this field, concerns have already been raised that pressure from large numbers of IDUs in the practice may make some GPs prescribe replacement drugs in an insufficiently controlled way, and risks of buprenorphine intravenous misuse by drug takers have been documented. In the current context, where a shift away from injecting mainly heroin to multiple drug use has been observed in many countries, including France, such concerns are especially disturbing.
French general practitioners’ attitudes toward maintenance drug abuse treatment with buprenorphine
J. P. MOATTI, M. SOUVILLE, N. ESCAFFRE & Y. OBADIA
Demonstration of specific withdrawal symptoms for any drug confirms its potential for physical dependence. In practical terms, withdrawal symptoms provide strong reasons for dependent individuals to continue taking their drugs even in the absence of continued pleasurable effects.
In India buprenorphine is readily available, even without a prescription, from a large number of pharmacists in the urban areas. The cost of an average daily dose of buprenorphine is only a fraction of the cost of heroin to an addict. This has led to a substantial proportion of heroin-dependent individuals shifting to buprenorphine for short or long periods. The present study substantiates the physical dependence potential of buprenorphine and hence the need to enforce the existing laws, so that this drug is available only for valid medical reasons.
The results of the present study have relevance for policy regarding use of buprenorphine in the treatment of heroin dependence as well as in the care of buprenorphine-dependent patients who seek help in abstaining from this drug. The results also strengthen the case for further restricting the availability of buprenorphine, as suggested by the WHO Expert Committee in Drug Dependence (1989).
Naloxone-induced withdrawal in patients with buprenorphine dependence
ANIL K. NIGAM, R. P. SRIVASTAVA, SHEKHAR SAXENA, B. S. CHAVAN & K. R. SUNDARAM
Concern about the abuse liability of buprenorphine/naloxone combination product arise from two sources. One is the possibility of illicit diversion and abuse of buprenorphine products marketed for analgesia. The second is the fact that buprenorphine is being evaluated as a potential treatment medication for drug abuse and drug abuse patients could be expected at least to attempt abuse of any such medication. Buprenorphine is marketed as an analgesic in both parenteral and sublingual formulations, though only the parenteral formulation is currently available in the USA. Sublingual formulations are being evaluated for efficacy as a drug abuse treatment medication.
Buprenorphine alone and in combination with naloxone in non-dependent humans
LINDA L. WEINHOLD, KENZIE L. PRESTON, MAGI FARRE, IRA A. LIEBSON AND GEORGE E. BIGELOW
At very high doses there is evidence from animal studies for developing tolerance to buprenorphine and cross tolerance with morphine.
Animal studies have shown evidence for a potentiation of action between buprenorphine and centrally acting drugs likely to be used concurrently, e.g. halothane, fluothane and thiopentone sodium.
Warnings. Because of the narcotic antagonist activity of buprenorphine, use in individuals dependent on other opioids may result in withdrawal effects.
Use in pregnancy. (Category C). Narcotic analgesics may cause respiratory depression in the newborn infant. Therefore, during the last two to three hours before expected delivery these products should only be used after weighting the needs of the mother against the risk to the fetus.
Buprenorphine readily crosses the placental barrier. The safety of buprenorphine in pregnancy has not been established and therefore it should not be used in women who are pregnant or who are likely to become pregnant unless the potential benefits outweigh the possible risks.
Central nervous system depressants. Buprenorphine may cause some drowsiness, and this could be potentiated by other centrally acting agents such as long acting benzodiazepines, volatile anaesthetics and certain induction agents; hence ambulant patients should be warned no to drive or operate machinery if affected.
Dependence. Buprenorphine is a partial agonist of the morphine type, i.e. it has certain opioid properties which may lead to psychic dependence of the morphine type due to an opioid-like euphoric component of the drug. Direct dependence studies have shown little physical dependence on withdrawal of the drug. However, caution should be used when prescribing to individuals who are known to be drug abusers or ex-narcotic addicts. The drug may not substitute in acutely dependent narcotic addicts due to its antagonist component.
MIMS Annual 1998, Simple analgesics and antipyretics, pp. 4-378.
At this stage in the development of buprenorphine as a maintenance treatment, the research interest is shifting from whether or not buprenorphine is effective to a search for the daily dosage that will be considered optimal for most patients. The tactic of this search to date has been to compare one or more doses of buprenorphine with one or more doses of methadone in an attempt to position buprenorphine on the methadone dosage spectrum. Work in progress continues this tactic, but also makes direct comparisons among several buprenorphine doses. One can conclude that, for the maintenance treatment of opioid dependence buprenorphine will be a useful and welcome addition to methadone, LAAM and naltrexone
A Controlled Trial Comparing Buprenorphine and Methadone Maintenance in Opioid Dependence
WALTER LING, MD., DONALD R. WESSON, MD., CHARLES CHARUVASTRA, MD., C. JAMES KLETT, PhD.
Conclusions
Patients who respond well to buprenorphine can opt to continue, at perhaps less than daily dosing, or to work towards abstinence through detoxification, with or without a subsequent period of naltrexone treatment.
One can conclude that, for the maintenance treatment of opioid dependence buprenorphine will be a useful and welcome addition to methadone, LAAM and naltrexone
Parrino, M. W. (1993) Overview: current treatment realities and future trends, in: Parrino, M. W. (ed.) State Methadone Treatment Guidelines, p1 (Rockville, MD, US Department of Health and Human Services Publication No. (SMA) 93-1991).
APFDFY RECOMMENDATIONS
(1). Naltrexone Detoxification Induction under General Anaesthesia for addicts who pre detox evaluation identify indicators of good prognosis of benefit from Naltrexone treatment.
(2). Recognising that what happens to patients after detoxification is often more important than what happens during it.
(3). The patient has a support network for a drug free recovery.
(4). Naltrexone Maintenance/Rehabilitation Program/Follow-up Urinalysis/Evaluation of clinical outcomes for the most safe and cost effective method for Rapid Opiate Detoxification using Naltrexone under general anaesthesia.
REFERENCES
ACUTE REACTIONS TO DRUGS OF ABUSE (1996) Medical Letter, 38, 43-46.
BICKEL, W. K., AMAS, L., CREAN, J. P. & HIGGINS, S. T. (1994) Triple buprenorphine maintenance doses maintain opioid-dependent outpatients for 72 hours with minimal withdrawal, in: HARRIS, L. S. (Ed.) Problems of Drug Dependence 1994, proceedings of the 56th Annual Scientific Meeting, p. 161 (Washington, DC, US Government Printing Office).
BLOM, Y., BONDESSON, U. & GUNNE, L. M. (1987) Effect of buprenorphine in heroin addicts, Drug and Alcohol Dependence, 20, pp. 1-7.
CHOWDHURI, A. N. & CHOWDHURI, S. (1990) Buprenorphine abuse: a report from India, British Journal of Addiction, 85, pp. 1349-1350.
COWAN, A., LEWIS, J. W. & MACFARLANE, I. R. (1977) Agonist antagonist properties of buprenorphine, a new antinociceptive agent, British Journal of Pharmacology, 60, pp. 537-545.
DUM, J., BLASIG, J. & HERZ, H. (1981) Buprenorphine: demonstration of physical dependence liability, European Journal of Pharmacology, 70, pp. 293-300.
HAMMERSLEY, R., CASSIDY, M. & OLIVER, J. (1995) Drugs associated with drug-related deaths in Edinburgh and Glasgow, November 1990 to October 1992, Addiction, 90, 959-965.
INGOLD, F.R. & TOUSSIRT, M. (1997) Attitudes and behaviors of drug users in the context of AIDS and hepatitis epidemics, Bulletin de l’Académie Nationale de Médecine, 181, 555-568.
JASINSKI, D. R., PEVNICK, J. S., & GRIFFITH, J. D. (1978). Human pharmacology and abuse potential of the analgesic buprenorphine. Archives of General Psychiatry, 35, 501-516.
JASINSKI, D. R., & PRESTON, K. L.(1996). Laboratory studies of buprenorphine in opioid abusers. In A. Cowan & J. W. Lewis (Eds.), Buprenorphine: Combatting drug abuse with a unique opioid (pp. 189-211). New York: Wiley-Liss.
KAA, E. & TEIGE, B. (1993) Drug-related deaths during the 1980s. A comparative study of drug addict deaths examined at the institutes of forensic medicine in Aarhus, Denmark and Oslo, Norway, International Journal of Legal Medicine, 106, 5-9.
KREEK, M. J. (1983B). Health consequences associated with the use of methadone. In J. R. Cooper, F. Altman, B, S. Brown, & D. Czechowicz (Eds.), Research on the treatment of narcotic addiction: State of the art (pp. 456-491). Rockville, MD: National Institute on Drug Abuse.
LEWIS, J. W. (1985). Buprenorphine. Drug and Alcohol Dependence, 14, 363-372.
MARTIN, J. (1996) Utilisation abusive du flunitrazépam (Rohypnol) par les toxicomanes [Abuse of nitrazepam (Rohypnol) by drug addicts], Prescrire, 16, 376-377.
MENDELSON, J., UPTON, R., JONES, R. T., & JACOB, P. (1995). Buprenorphine pharmacokinetics:: Bioequivalence of an 8mg sublingual tablet formulation. Paper presented at the Problems of drug dependence, 1995: Proceedings of the 55th annual scientific meeting of the College on problems of drug dependence, Inc, Phoenix, AZ
PARRINO, M. W. (1993) Overview: current treatment realities and future trends, in: PARRINO, M. W. (Ed) State Methadone Treatment Guidelines, p.1 (Rockville, MD, US Department of Health and Human Services Publications No. (SMA) 93-1991).
PEZOUS, A. M. & SCHMITT, L. (1994) Drogues [Drugs], Revue du Practicien, 44, 689-698.
RICHARD, D. & COLLARD, C. (1991) Toxicomanies: les divers types de dépendances [Drugs addictions: different dependences], Moniteur Internat, 25, 97-106.
PICKWORTH, W. R., JOHNSON, R. E., HOLICKY, B. A., & CONE, E. J. (1993). Subjective and physiologic effects of intravenous buprenorphine in humans. Clinical Pharmacology and Therapeutics, 53, 570-576.
QUIGLEY, A. J., BREDENEYER, D. E. & DEOW, S. S. (1984) A case of buprenorphine abuse, The Medical Journal of Australia, 140, pp. 425-426.
RALSTON, G. E. & KIDD, B. A. (1996) General practitioners and drug users: their current practice and expectations of specialist service, Health Bulletin, 54, 16-21.
ROBINSON, G. M., DUKES, P. D., ROBINSON, B. J., COOKE, R. R., & MAHONEY, G. N. (1993). The misuse of buprenorphine and buprenorphine-naloxone combination in Wellington, New Zealand. Drug and Alcohol Dependence, 33, 81-86.
ROSEN, M. I., WALLACE, E. A. & MCMAHON, T. J. et al. (1994) Buprenorphine: duration of blockade effects of intramuscular hydromorphone, Drug and Alcohol Dependence, 35, 141-149.
SAKOL, M. S., STARK, C. & SYKES, R. (1989) Buprenorphine and temazepam abuse by drug takers in Glasgow: an increase, British Journal of Addiction, 84, 439-441.
SEKAR, M. & MIMPRISS, T. I. (1987) Buprenorphine, benzodiazepines and prolonged respiratory depression, Anaesthesia, 42, 567-568.
SENAY, E. C. & CLARA, J. R. (1985) Impact of Talwin Nx. In: Problems of drug dependence (Harris, L. S. ed.), pp. 170-177. National Institute on Drug Abuse Research Monograph 55, DHHS (ADM), Washington D. C.
SINGH, R. A., MATTOO, S. K., MALHOTRA, A., et al. (1992) Cases of buprenorphine abuse in India, Acta Psychiatrica Scandinavica, 86, pp. 46-48.
SKIDMORE, C. A., ROBERTSON, J. R., ROBERTSON, A. A. & ELTON, R. A. (1990) After the epidemic: follow-up study of HIV seroprevalence and changing patterns of use, British Medical Journal, 300, 219-223.
STRAIN, E. C., PRESTON, K. L. LIEBSON, I. A., & BIGELOW, G. E. (1993a). Precipitated withdrawal by pentazocine in methadone-maintained volunteers. Journal of Pharmacology and Experimental Therapeutics, 267, 624-634.
STRANG, J., SHERIDAN, J. & BARBER, N. (1996) Prescribing injectable and oral methadone to opiate addicts: results from the 1995 national postal survey of community pharmacies in England and Wales, British Medical Journal, 313, 270-272.
THAMMAKUMPEE, G. & SUMPATANUKULE, P. (1994) Noncardiogenic pulmonary edema induced by sublingual buprenorphine, Chest, 106, 306-308.
THORN, S. E., RAWAL, N. & WENHAGER, M. (1988) Prolonged respiratory depression caused by sublingual buprenorphine, Lancet, 179-180.
WALSH, S. L., JUNE, H. L., SCHUH, K. J,, PRESTON, K. L., BIGELOW, G. E. & STITZER, M. L. (1995). Effects of buprenorphine and methadone in methadone-maintained subjects. Psychopharmacology, 119, 268-276.
WALSH, S. L., PRESTON, K. L., STITZER, M. L., CONE, E. J. & BIGELOW, G. E. (1994) Clinical pharmacology of buprenorphine: ceiling effects at high doses, Clinical Pharmacology and Therapeutics, 55, 569-580.
WALSH, S. L., PRESTON, K. L., BIGELOW, G. E. & STITZER, M. L. (1995) Acute administration of buprenorphine in humans: partial agonist and blockade effects, Journal of Pharmacology and Experimental Therapeutics, 274, 361-372.
WHO EXPERT COMMITTEE IN DRUG DEPENDENCE (1989) Twenty-fifth Report, World Health Organisation Technical Report Series, 775, pp. 21-24.
|
|
| Information is supplied by the APFDFY PO Box 73 Maryborough Qld 4650 Australia Phone/Fax 0741 233 810 |