![[dr. bob]](/dr-bob-sm.gif)
Dr. Bob is Robert Hsiung, MD,
bob@dr-bob.orgShown: posts 1 to 4 of 4. This is the beginning of the thread.
Posted by ed_uk on March 20, 2005, at 19:40:31
Hello everyone!
Flumazenil is widely used as a benzodiazepine antagonist, a benzo 'antidote' or whatever you want to call it. It blocks benzodiazepine receptors and reverses the acute effects of benzodiazepines. It is used in the ICU to wake people up after they have been sedated with a benzo. It is also used to wake people up after surgery when benzos have been used during the operation. It is occasionally used to treat benzo overdose. The manufacturer warns that the administration of flumazenil to patients on long-term benzo treatment may abruptly precipitate withdrawal symptoms, this is because it acts as a competitive antagonist ie. it can displace benzodiazepines from their receptors. Strangely, flumazenil is not always capable of precipitating withdrawal symptoms.
The administration of flumazenil to patients with anxiety disorders has been reported to provoke panic.
Under some conditions, flumazenil may act as a benzodiazepine partial agonist, with weak intrinsic activity. Under other circumstances, it might actually function as a partial inverse agonist with weak intrinsic activity. When administered to a patient who has been given a benzo, it effectively functions as an antagonist.
In rats, flumazenil can reduce anxiety due to ethanol withdrawal. It has been suggested than flumazenil may be antagonising the effects of an endogenous benzodiazepine inverse agonist.
Below is a very interesting study. It has been hypothesised that flumazenil treatment may help to 'normalise' GABAergic function in patients undergoing benzodiazepine withdrawal - as a result, flumazenil may have a role in the treatment of benzodiazepine physical dependence.
Intravenous flumazenil versus oxazepam tapering in the treatment of benzodiazepine withdrawal: a randomized, placebo-controlled study.
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.
I would love to hear your comments. Flumazenil has also been proposed as a treatment for protracted benzodiazepine withdrawal, where neurological symptoms persist long after the drug is discontinued. It is thought that flumazenil might be able 'reset' benzodiazepine receptor function.
/Ed
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
Posted by SLS on March 20, 2005, at 20:59:52
In reply to Re: Some interesting info........, posted by ed_uk on March 20, 2005, at 20:14:09
Interesting stuff, Ed.
Silly allosteric receptors. I wish they'd make up their minds...
:-)
- Scott
Posted by ed_uk on March 21, 2005, at 18:50:01
In reply to Re: Some interesting info........, posted by SLS on March 20, 2005, at 20:59:52
This is the end of the thread.
Psycho-Babble Withdrawal | Extras | FAQ
Dr. Bob is Robert Hsiung, MD,
bob@dr-bob.org
Script revised: February 4, 2008
URL: http://www.dr-bob.org/cgi-bin/pb/mget.pl
Copyright 2006-17 Robert Hsiung.
Owned and operated by Dr. Bob LLC and not the University of Chicago.