5 June 2003

Flumazenil infusion for benzo addiction - still experimental but promising.

Intravenous flumazenil versus oxazepam tapering in the treatment ofbenzodiazepine withdrawal: a randomized, placebo-controlled study. Gerra G,Zaimovic A, Guisti F, Moi G, Brewer C. Addiction Biology 2002 7:385-395

This small randomized, placebo controlled study lends weight to the use ofintravenous flumazenil in the reversal of tolerance to benzodiazepines. Ina well designed study involving 50 patients addicted to benzodiazepines theauthors infused 2mg of flumazenil over 8 hours each day for 8 days in a daycare hospital setting. Twenty such patients were compared with another 20given oxazepam taper with saline placebo and another 10 given placebos ofboth.

Some of the effects of benzodiazepines were reversed almost immediately (eg.balance test performed each day on the subjects) while the modest dosesgiven for night-time sedation (15mg oxazepam) for 3 days were very effectivein inducing sleep, unlike the patients' previous experience which hadinvolved very much higher doses of flunitrazepam, bromazepam, etc. It appeared that the flumazenil reversed the tolerance to benzodiazepines evenfrom day one. There was no increase in anxiety symptoms and convulsions didnot eventuate, perhaps due to some intrinsic agonist activity of the drug.A previous study had shown re-emergence of panic symptoms in some patientswith a previous history but this involved the drug being infused over 5minutes and not 8 hours.

Most impressive, the patients all appeared to be fully detoxified whilerelapse occurred in only half the patients given the flumazenil whencompared with those on oxazepam taper. The relapse rates at days 15, 23 and30 were 25/55%, 30/60% and 40/70% in flumazenil vs. oxazepam taper groups.These results are impressive but need to be confirmed before being accepted.More research is certainly warranted in this difficult area as there iscurrently no single accepted management strategy for benzodiazepineaddiction.

The authors make much of receptors and GABA allosteric effects in theirdiscussion. However, this is a clinical paper and such speculation probablybelongs elsewhere. However interesting they may find it, the authors reallyhave no idea why the drug did what it did as far as I can read and themechanisms are only of distant relevance to the patients involved.

There is a very comprehensive list of references relating to the use offlumazenil for benzodiazepine addiction, from 1986 with animal studies andto controlled studies, observational work and opinion pieces since.

comments by Andrew Byrne ..

other reference:Mintzer MZ, Stoller KB, Griffiths RR. A controlled study offlumazanil-precipitated withdrawal in chronic low-dose benzodiazepine users.Psychopharmacology (Berlin) (1999) 147:146-50