Intravenous flumazenil versus oxazepam tapering in the treatment of benzodiazepine withdrawal: a randomized, placebo‐controlled study

Abstract

Flumazenil (FLU), a benzodiazepine (BZD) partial agonist with a weak intrinsic activity, was previously found unable to precipitate withdrawal in tolerant subjects submitted to long-lasting BZD treatment. The potential use of FLU to treat BZD withdrawal symptoms has also been evaluated tentatively in clinical studies. In the present experiment, FLU (treatment A) was compared with oxazepam tapering (treatment B) and placebo (treatment C) in the control of BZD withdrawal symptoms in three groups of BZD dependent patients. Group A patients (20) received FLU 1 mg twice a day for 8 days, and oxazepam 30 mg in two divided doses (15 mg + 15 mg) during the first night, oxazepam 15 mg during the second night and oxazepam 7.5 mg during the third night. FLU was injected i.v. in saline for 4 hours in the morning and 4 hours in the afternoon, in association with placebo tablets. Group B patients (20) were treated by tapering of oxazepam dosage (from 120 mg) and with saline solution (as placebo) instead of FLU for 8 days. Group C patients (10) received saline instead of FLU and placebo tablets instead of oxazepam for 8 days. FLU immediately reversed BZD effects on balance task and significantly reduced withdrawal symptoms in comparison with oxazepam and placebo on both self-reported and observer-rated withdrawal scales. The partial agonist also reduced craving scores during the detoxification procedure. In addition, during oxazepam tapering, group B patients experienced paradoxical symptoms that were not apparent in FLU patients. Patients treated with FLU showed a significantly lower relapse rates on days 15, 23 and 30 after the detoxification week. Our data provide further evidence of FLUs ability to counteract BZD effects, control BZD withdrawal and normalize BZD receptor function. The effectiveness of FLU may reflect its capacity to upregulate BZD receptors and to reverse the uncoupling between the recognition sites of BZD and GABA, on the GABA(A) macromolecular complex, that has been reported in tolerant subjects.

Anticonvulsant Agents for the Management of Benzodiazepine Dependence

“…Pregabalin has demonstrated to be effective in the treatment of BD and BWS, exerting its beneficial action by reducing the severity of withdrawal and anxiety symptoms. [19,20]; β-blocker propranolol [21,22]; α2-agonist clonidine [23]; 5-HT 1A partial agonist buspirone [19,20,24]; anxiolytic alpidem [25]; neuroactive steroid progesterone [26]; 5-HT 3 antagonist odansetrone [27]; and BZD partial agonist flumazenil [28,29].…”

Mechanisms of Action and Persistent Neuroplasticity by Drugs of Abuse

“…Although this phenomenon has been tested in BZ-dependent patients with inconsistent efficacy for counteracting tolerance in acute settings (Cittadini and Lader, 1991;Savic et al, 1991;Lader and Morton, 1992), a small clinical study has reported preliminary results on prolonged subcutaneous flumazenil administration in withdrawing BZ-dependent patients (Hulse et al, 2013), suggesting that perhaps longer treatments are needed in human populations. Another study using twice daily intravenous injections of flumazenil showed that flumazenil significantly blocked withdrawal symptoms and kept the patients better in abstinence (Gerra et al, 2002). Because flumazenil increases membrane targeting of GABA A receptors (Flaishon et al, 2003;Pericic et al, 2004), its efficacy in reversing BZ tolerance and in alleviating withdrawal in dependent subjects may at least partly be based on increased number of functional GABA A receptors.…”

“I’m Not Waving, I’m Drowning”

“…In the United States and elsewhere, rapid detoxification in specialist clinics is fashionable, but for benzodiazepine users is potentially harrowing and dangerous (Gerra et al, 2002). Part of the ethos of Internet and face-to-face support groups is to offer continuous and extended support during what might be a year or more of tapering off benzodiazepines (Ashton, 2002;Kellagher, 2006;Samet, 2013).…”

“…"Cold turkey" or rapid withdrawal can lead to fevers, acute psychotic states, seizures and even death (Ashton, 2005;Hu, 2011). Rapid detoxification in medical settings is rarely recommended and often requires the use of adjunct medication (Gerra et al, 2002). Most users are encouraged to undertake a steady taper in their own homes (Ashton, 2005) over a period of weeks, months or years, depending on dose and length of use (Ashton, 2002;Bristol and District Tranquilliser Project, 2013).…”