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Rats alive! Alcohol Reductions Possible with Adequate Buprenorphine Doses.

Dr Andrew Byrne & Associates
A Harm-Minimisation Research Perspective

Issue 79: February 2009
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Editor's Note:Dr Byrne (and his associates) advocate for better policies which are proven to reduce risks for drug users and the general community under a framework in parallel with Australia's official policy of harm minimization. The findings of the New South Wales Drug Summit recommend better access to methadone, detoxification and other dependency treatments. It also advised investigating alternative services such as supervised injecting centres, leading to the opening of the Sydney Medically Supervised Injecting Centre in 2001. Dr Andrew Byrne has been involved in opioid treatments from a primary care background for 20 years at the same site in Redfern, an inner suburb of Sydney. He is recognised worldwide as a specialist in the addiction field and was involved in the seminal stages of the Chapter of Addiction Medicine, Royal Australasian College of Physicians. He received the Dole-Nyswander award from the American Association for the Treatment of Opioid Dependence in April 2006. In this edition of i2P, Dr Byrne comments on an article from Biological Psychiatry 2007 61:4-12 titled "Buprenorphine Reduces Alcohol Drinking Through Activation of the Nociceptin/Orphanin FQ-NOP Receptor System."
Ciccocioppo R, Economidou D, Rimondini R, Sommer W, Massi M, Heilig M.

Dear Colleagues,

In spite of the title, this rat experiment showed both significant increases (at low doses) and decreases (at high doses) in alcohol consumption with the use of buprenorphine injected intraperitoneally 1½ hours before access to alcohol. Four dose levels ranged over 3+ orders of magnitude from 0.03 to 6mg/kg. Additional experimental conditions included the use of pre-treatment naltrexone which predictably blocked some of the increased alcohol consumption while using “the selective NOP receptor antagonist UFP-101” in two similar dose ranges abolished the suppression of drinking at the higher range dose level of buprenorphine administration.

While there may be relevant receptor issues here, clinicians will be more interested in the behavioural findings and their relevance to humans. Hence these detailed rodent experiments show two quite separate outcomes: (1) the consumption of alcohol, food and liquids and (2) deductions as to the reasons behind these observations based on changes when certain blockers are used. Cicciocioppo, Heilig and colleagues’ conclusions about why these rats drank more or less alcohol are well beyond my field. Further, they are of limited interest clinically at the present time.

Sinclair reported the addition of morphine reducing alcohol consumption in rats many years ago (Nature 1973) and 14 years later wrote an editorial in BMJ about the feasibility of using drugs for alcoholism. We now use effective anti-craving drugs which are not psychoactive themselves (acamprosate and naltrexone for example). Tennant reported a possible link between increasing methadone levels and reducing alcohol use in a small study (n=18). Unfortunately, this has not yet been replicated, despite its simplicity and apparent significance.

By my raw calculations the experimental dose levels used in these rat studies translated to a 70kg person would equate to 2mg, 20mg, 200mg and 400mg as single doses. These are all well above the normal therapeutic range for analgesic use (0.2-0.8mg) although the lower two doses are well within the range used in dependency treatments (doses vary from about 1mg to 32mg daily). The high doses (200 and 400mg) are supratherapeutic and could be fatal, especially in combination with alcohol as given here. Such doses are not realistic in humans, being cumbersome to administer while the cost may be over $100 daily. Evidently no rat died in this study and the lead author believes that this may be due to the hyposensitivity of Sardinian rats to opioids and other depressants.

The study of drug ‘replacement’ is still in its infancy but already it is clear that some opioid users become stimulant users and vice versa (see Darke 1999). Equally, some alcoholics largely cease alcohol use once they ‘discover’ opioids. Others, probably a certain minority, continue to consume both drugs.

At the same time, this study reminds us that inadequate doses of buprenorphine will limit its usefulness. This is the same as penicillin, cortisone, insulin or any other medication. And the consequences from excessive dosing in a supervised treatment setting are usually limited to minor sedation, causing the patient to seek a dose decrease or simply to miss days.

Comments by Andrew Byrne ..

Sinclair JD, Adkins J, Walker S. Morphine-induced suppression of voluntary alcohol drinking in rats. Nature (1973) 246: 425-427

Sinclair JD. The feasibility of effective psychopharmacological treatments for alcoholism. British Journal of Addiction (1987) 82: 1213-1223

Tennant FS. Inadequate Plasma Concentrations in Some High-Dose Methadone Maintenance Patients. Am J Psychiatry 1987; 144: 1349-1350.

Darke S, Kaye S, Ross J. Transitions between the injection of heroin and amphetamines. Addiction 1999 94:1795-1803

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