Posted by ed_uk on March 20, 2005, at 20:14:09
In reply to Benzodiazepine Withdrawal: A Role for Flumazenil?, posted by ed_uk on March 20, 2005, at 19:40:31
Since the standard diazepam taper is not always effective, innovative strategies for the treatment of benzodiazepine physical dependence are needed, flumazenil could have an important role.
Here are some interesting studies.........
Int Clin Psychopharmacol. 1996 Jun;11(2):81-8.
Intravenous flumazenil following prolonged exposure to lormetazepam in humans: lack of precipitated withdrawal.
The capacity of flumazenil to reverse benzodiazepine agonist effects has been widely demonstrated. In contrast, the role of flumazenil in precipitating withdrawal symptoms is unclear in humans: the inability of RO 15-1788 to induce benzodiazepine withdrawal seems to be related to the duration of exposure to the GABAergic drugs. In the present experiment we evaluated the effects of intravenous flumazenil or placebo in 36 healthy volunteers pretreated with lormetazepam for 30 days (2 mg/day) and 18 lormetazepam-dependent subjects (6-8 mg/day). Measurements of a balance task, subject- and observer-rated symptoms showed a reversal of lormetazepam effects induced by flumazenil without any significant withdrawal symptoms. Slight anxiety, increase in heart rate and perspiration were observed in a few subjects. Independent of benzodiazepine doses, long-term treatment seems to be responsible for tolerance development with consistent changes in GABA-benzodiazepine receptor sensitivity. Flumazenil could be able to normalize benzodiazepine receptor sensitivity and exert its weak agonist activity.
Intermittent flumazenil therapy *may* restore the efficacy of a 'pooped out' benzodiazepine.....
From the Lancet:
Feasibility of reversing benzodiazepine tolerance with flumazenil.
To examine whether the benzodiazepine antagonist flumazenil can reverse tolerance to benzodiazepines but without precipitating withdrawal seizures, the antiepileptic effect of flumazenil itself and its ability to reverse tolerance at a dose that would leave sufficient receptors free for the binding of benzodiazepines were investigated. Electroencephalographic studies in 6 patients with partial and 6 with generalised seizures showed that flumazenil had a short (20 min) non-dose-dependent suppressant effect on epileptic discharges in those with partial seizures. Receptor occupancy studies in 12 patients showed that 1.5 mg flumazenil given intravenously occupied 55% receptors, whereas 15 mg occupied nearly all receptors. When 3 patients with partial seizures who had become tolerant to clonazepam were given 1.5 mg flumazenil, they were seizure-free for 6-21 days after the injection. The value of intermittent therapy with a benzodiazepine antagonist for preventing or reversing tolerance to benzodiazepine agonists ought to be investigated further.
Here is my theory:
In patients who are receiving effective benzo treatment for epilepsy, administration of flumazenil might be expected to cause seizures.
In patients who have developed profound tolerance to the antiepileptic effects of their benzo, flumazenil may restore antiepileptic efficacy. Flumazenil might also exert brief intrinsic antiepileptic effect in these patients.The flumazenil data sheet states that flumazenil exerts a slight intrinsic anticonvulsant effect (in those not exposed to benzodiazepines).
The flumazenil data sheet warns that the administration of flumazenil to chronic benzo users might precipitate withdrawal symptoms. As I have said, it in unclear to what extent this actually occurs, especially as flumazenil can actually relieve withdrawal symptoms in some patients. Roche also warns that the administration of flumazenil to epileptics taking long-term benzos may induce seizures.
Since flumazenil is not approved for the treatment of benzodiazepine dependence, Roche (the manufacturer) advises that that....
'Flumazenil is not recommended either as a treatment for benzodiazepine dependence or for the management of protracted benzodiazepine abstinence syndromes'.
/Ed
poster:ed_uk
thread:473333
URL: http://www.dr-bob.org/babble/wdrawl/20050228/msgs/473345.html