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N&PD Moderators: Skorpio | thegreenhand
Reversal of Benzos Tolerance (??)
- Thread starter Charles Ferdinand
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Hammilton
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OP: No, it shouldn't - it's been discussed before
Benzos are not direct agonists. They are allosteric modulators. The mechanism is just different from that of flumazenil.
Besides, as ebola suggested, it is a ridiculous idea to toy around with a convulsant in hopes of lowering tolerance to benzos.
I don't know what you mean by this. The binding site is completely irrelevant in this discussion, actually. Benzo's bind directly to the GABA-A receptor complex, and by doing so, increase the effect that GABA has when it binds to its own site on the receptor (benzodiazepines bind to a variety of 'receptors' located on the GABA-A receptor complex).
Flumazenil directly binds to relevant allosteric sites but does not induce the conformational change needed to increase GABA's effect when it binds. This keeps agonist benzos and the natural ligand out of the receptor, which is why it can result in seizures in even a non-dependent person.
It is fairly safe, though, especially at lower doses.
It has been shown to reduce tolerance, but even more, low dose flumazenil partially blocks the development of tolerance. Like we've seen with low-dose naltrexone taken with agonist opioids results in diminished or eliminated tolerance and, if I remember correctly, even increases te analgesic activity. There will be a time in the future when just about every oral opiate preparation will contain a tiny bit of naltrexone. It'd be nice if that day was sooner.
Such a thing may also work with Benzo / Flumazenil combinations, too. I wonder how low your dose of flumazenil would need to get benefits and no negatives. Considering a 200ug dose for adults (IV I believe) the dose would have to be miniscule. And probably extended release.
Jamshyd
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My point was that you cannot deduce flumazenil's potential by comparing it to Naloxone.
Naloxone is an atnagonist, and recreational opioids are agonists.
Flumazenil is an antagonist but benzos are not agonists, regardless of where they bind.
I don't really care what flumazenil does to mice because it goes against all reason that a human is to take a convulsant knowingly!!
Naloxone is an atnagonist, and recreational opioids are agonists.
Flumazenil is an antagonist but benzos are not agonists, regardless of where they bind.
I don't really care what flumazenil does to mice because it goes against all reason that a human is to take a convulsant knowingly!!
In Western Australia they use Flumazenil to do a benzo flush via IV to detox people from benzo addiction. I am not sure how they stop the rapid onset of withdrawal symptoms like seizures n shit. I wanted to get this done but Flumazenil is very costly like $200 a day treatment i believe.
I would love to kick benzos its been going on way too long on..years.
I have heard that the benzo flush feels good but i suspect that to stop the seizures they IV barbs or something into you. I can only imagine that a rapid flushing benzos free of my brain would cause so much upset.
Anyone had any experience getting off benzos with it?
I would love to kick benzos its been going on way too long on..years.
Are you saying that substances like bupe with naltrexone reduce tolerance to opiates? hmmm The other day i try to use some Dihydrocodone after taking bupe the night before it didn't do much.
I have heard that the benzo flush feels good but i suspect that to stop the seizures they IV barbs or something into you. I can only imagine that a rapid flushing benzos free of my brain would cause so much upset.
Anyone had any experience getting off benzos with it?
The antagonist must in administered in an "ultra low dose" format...
Charles Ferdinand
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So another question would be, Is there a direct antagonist of benzos
Not sure, you'd have to get an answer from someone who knows their pharmacology a lot better than me. My 2c: I don't think that allosteric modulators can be antagonists (unless there is complete inhibition... ?). The binding of an antagonist to a receptor produces a conformation of the protein such that no signal is transmitted or allowed to be transmitted. Allosteric modulators do not themselves cause signal to be transmitted. They simply increase or decrease the activity of the protein, which, in the case of the GABAa receptor, is stimulated by endogenous ligands.
However with regard to the tolerance question.....
US Pat 4666903
They say that flumazepil is an antagonist... but it's an old patent, and patents aren't exactly known for their pedantic accuracy.
However with regard to the tolerance question.....
US Pat 4666903
They say that flumazepil is an antagonist... but it's an old patent, and patents aren't exactly known for their pedantic accuracy.
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I have noticed taking a high dose of Lyrica which has short half life has had lasting effects on my GABA's. Go figure i have half'ed my dose and handling it well with only a day or so after having 600mg. I have cut it down 90% in last few months adn would lvoe to finish this long pain in the ass taper with a quick flush. 
THe Flush is just the term the doctor and everyone at clinic used. I would love to know what other drugs they put in your to keep you stable and not twitching into seizure. I think a rapid detox of benzos would cause seizure and maybe death. I know that i had many seizures quitting benzos but i think i had strong long term addiction.
THe Flush is just the term the doctor and everyone at clinic used. I would love to know what other drugs they put in your to keep you stable and not twitching into seizure. I think a rapid detox of benzos would cause seizure and maybe death. I know that i had many seizures quitting benzos but i think i had strong long term addiction.
Heuristic
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First, bad idea. Dangerous and nasty. Well said. Brainstorming is fun, but this isn't an idea to pursue via human testing. You might try searching in databases for articles that have run similar tests. There might be one or two on mice. Do not do this on yourself.
Second, you might simply taper and learn to use CBT for the anxiety disorder. Prescription of benzos for 2 years is a little too long, in my opinion. There's some evidence that long-term use can result in permanent cognitive impairment, which, though likely at a level to be not noticeable in your daily life, might still be an adverse effect you had not considered.
Heuristic
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Heh, no not you Tadfish.
Your doctor is right that more research is needed. The studies done are somewhat scattered in nature, involve relatively small numbers of subjects, and often fail to control for various factors.
Because there's often no data on how well the benzo-user group performed prior to using benzos, the studies generally attempt to use either general norms of performance on cognitive tests as a control, or, in some cases, use a group suffering from the same ailments that caused the benzo-group to begin taking the benzos (e.g. anxiety, depression), as a control. Some of the studies control for education levels, type of work, etc., and some don't. All studies involved groups of benzo-users who had checked themselves in for help withdrawing; self-reporting as to other drug-use was relied upon, even though such individuals are more likely to have used, or abused, other drugs which have definitive long-term cognitive effects. Etc. There are numerous problems with the studies.
But, that said, the studies that have been done are suggestive of possible permanent damage, post-withdrawal. I want to stress that even to the extent that permanent damage is suggested, it's unlikely to be of the kind that would be noticeable in day-to-day life, and some of the studies also suggest that impairments resolve themselves after 6 months of non-use. Nonetheless, it's a factor to consider. Here's a link to a full-text meta-analysis of several studies, with a copy of the abstract pasted below the link:
http://www.sciencedirect.com/scienc...serid=10&md5=858edb0c06398c7c3bc9a371aa9e3219
Persistence of cognitive effects after withdrawal from long-term benzodiazepine use: a meta-analysis
Melinda J. Barker , Kenneth M. Greenwood , Martin Jackson and Simon F. Crowe ,
School of Psychological Science, La Trobe University, Vic. 3086, Australia
Accepted 19 May 2003. Available online 13 September 2003.
Abstract
Despite the widespread prescribing of benzodiazepines, uncertainty still surrounds the potential for cognitive impairment following their long-term use. Furthermore, the degree of recovery that may take place after withdrawal or the level of residual impairment, if any, that is maintained in long-term benzodiazepine users is also unclear. The current paper employed meta-analytic techniques to address two questions: (1) Does the cognitive function of long-term benzodiazepine users improve following withdrawal? (2) Are previous long-term benzodiazepine users still impaired at follow-up compared to controls or normative data? Results of the meta-analyses indicated that long-term benzodiazepine users do show recovery of function in many areas after withdrawal. However, there remains a significant impairment in most areas of cognition in comparison to controls or normative data. The findings of this study highlight the problems associated with long-term benzodiazepine therapy and suggest that previous benzodiazepine users would be likely to experience the benefit of improved cognitive functioning after withdrawal. However, the reviewed data did not support full restitution of function, at least in the first 6 months following cessation and suggest that there may be some permanent deficits or deficits that take longer than 6 months to completely recover.
Now, look, that said, it doesn't mean you should stop using benzos if they're needed. I don't know you. BUT, it might be worthwhile to consider alternative approaches. 8+ years is a long time to be using this type of medication.
Of course, the jury is definitely in with a verdict on CURRENT long-term use of benzos: they result in cognitive impairment. The only question is whether an individual fully recovers following withdrawal.
Your doctor is right that more research is needed. The studies done are somewhat scattered in nature, involve relatively small numbers of subjects, and often fail to control for various factors.
Because there's often no data on how well the benzo-user group performed prior to using benzos, the studies generally attempt to use either general norms of performance on cognitive tests as a control, or, in some cases, use a group suffering from the same ailments that caused the benzo-group to begin taking the benzos (e.g. anxiety, depression), as a control. Some of the studies control for education levels, type of work, etc., and some don't. All studies involved groups of benzo-users who had checked themselves in for help withdrawing; self-reporting as to other drug-use was relied upon, even though such individuals are more likely to have used, or abused, other drugs which have definitive long-term cognitive effects. Etc. There are numerous problems with the studies.
But, that said, the studies that have been done are suggestive of possible permanent damage, post-withdrawal. I want to stress that even to the extent that permanent damage is suggested, it's unlikely to be of the kind that would be noticeable in day-to-day life, and some of the studies also suggest that impairments resolve themselves after 6 months of non-use. Nonetheless, it's a factor to consider. Here's a link to a full-text meta-analysis of several studies, with a copy of the abstract pasted below the link:
http://www.sciencedirect.com/scienc...serid=10&md5=858edb0c06398c7c3bc9a371aa9e3219
Persistence of cognitive effects after withdrawal from long-term benzodiazepine use: a meta-analysis
Melinda J. Barker , Kenneth M. Greenwood , Martin Jackson and Simon F. Crowe ,
School of Psychological Science, La Trobe University, Vic. 3086, Australia
Accepted 19 May 2003. Available online 13 September 2003.
Abstract
Despite the widespread prescribing of benzodiazepines, uncertainty still surrounds the potential for cognitive impairment following their long-term use. Furthermore, the degree of recovery that may take place after withdrawal or the level of residual impairment, if any, that is maintained in long-term benzodiazepine users is also unclear. The current paper employed meta-analytic techniques to address two questions: (1) Does the cognitive function of long-term benzodiazepine users improve following withdrawal? (2) Are previous long-term benzodiazepine users still impaired at follow-up compared to controls or normative data? Results of the meta-analyses indicated that long-term benzodiazepine users do show recovery of function in many areas after withdrawal. However, there remains a significant impairment in most areas of cognition in comparison to controls or normative data. The findings of this study highlight the problems associated with long-term benzodiazepine therapy and suggest that previous benzodiazepine users would be likely to experience the benefit of improved cognitive functioning after withdrawal. However, the reviewed data did not support full restitution of function, at least in the first 6 months following cessation and suggest that there may be some permanent deficits or deficits that take longer than 6 months to completely recover.
Now, look, that said, it doesn't mean you should stop using benzos if they're needed. I don't know you. BUT, it might be worthwhile to consider alternative approaches. 8+ years is a long time to be using this type of medication.
Of course, the jury is definitely in with a verdict on CURRENT long-term use of benzos: they result in cognitive impairment. The only question is whether an individual fully recovers following withdrawal.
Charles Ferdinand
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Agreed. I can't use them forever and will have to start to taper off one of this days, hehe
DopaMan
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Direct agonists are probably gold when is use with opioid agonists (oh to be free of dependence again) BUT as Jamshyd and others stated flumazenil is dangerous and rarely used compared to opioid antagonists like naloxone, etc. because they lower the seizure threshold so much and are more trouble than they are worth....usually.
Especially if you have a benzo tolerance, please avoid flumazenil. No offense, but a nice big book can offer what seems to be great info, but without proper training it can just be the key to a casket.
Godspeed.
Especially if you have a benzo tolerance, please avoid flumazenil. No offense, but a nice big book can offer what seems to be great info, but without proper training it can just be the key to a casket.
Godspeed.
Dr FeelBetter
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Wow I can't believe that no one bothers to do a little research before they just discount what is not only a novel idea, but a potentially very useful long term strategy in the very dilemma that they themselves face.
Wikipedia-
Effect of flumazenil
A study into the effects of the benzodiazepine receptor antagonist, flumazenil, on benzodiazepine withdrawal symptoms persisting after withdrawal was carried out by Lader and Morton. Study subjects had been benzodiazepine-free for between one month and five years, but all reported persisting withdrawal effects to varying degrees. Persistent symptoms included clouded thinking, tiredness, muscular symptoms such as neck tension, depersonalisation, cramps and shaking and the characteristic perceptual symptoms of benzodiazepine withdrawal, namely, pins and needles, burning skin, pain and subjective sensations of bodily distortion. Therapy with 0.2–2 mg of flumazenil intravenously was found to decrease these symptoms in a placebo controlled study. This is of interest as benzodiazepine receptor antagonists are neutral and have no clinical effects. The author of the study suggested that the most likely explanation is that past benzodiazepine use and subsequent tolerance had locked the conformation of the GABA-BZD receptor complex into an inverse agonist conformation, and that the antagonist flumazenil resets benzodiazepine receptors to their original sensitivity. Flumazenil was found in this study to be a successful treatment for protracted benzodiazepine withdrawal syndrome, but it was noted that further research is required.[1] A study by Professor Borg in Sweden produced similar results in patients suffering from protracted withdrawal.[2]
[1] Professor Malcolm Lader (1992). "A pilot study of the effects of flumazenil on symptoms persisting after benzodiazepine withdrawal". Journal of Psychopharmacology. http://www.bcnc.org.uk/flumazenil.html.
[2] Saxon L, Hjemdahl P, Hiltunen AJ, Borg S (May 1997). "Effects of flumazenil in the treatment of benzodiazepine withdrawal--a double-blind pilot study" (PDF). Psychopharmacology (Berl.) 131 (2): 153–60. doi:10.1007/s002130050278. PMID 9201803. http://www.springerlink.com/content/2vpf562teffglej5/fulltext.pdf.
In case you are skeptical of wikipedia(as all should be to some extent)
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.
Savic I, Widen L, Stone-Elander S. Feasibility of reversing benzodiazepine tolerance with flumazenil. Lancet 1991; 337: 133-137.
And another, though I can't track down the abstract-
Lader MB, Morton SV. A pilot study of the effects of flumazenil on symptoms persisting after benzodiazepine withdrawal. JPsychopharmacol. 1992; 6: 19-28.
I think its ludicrous to suggest that after 3-6 months of abstinence, in the grips of protracted withdrawal syndrome living in fairly consistent agony that to take flumazenil is 'nasty' and 'dangerous'. Especially considering any decent facility with respectable doctors are going to proceed cautiously with initially small and gently escalating doses, and a bucket full of backup options. That being said, I certainly wouldnt go this route without a LONG period free of all benzos.
Lack of large scale clinical trials likely reflect the stigma placed on anxiety ridden psychiatric patients who are rarely taken seriously as is, and a lack of any sustainable profit in the process secondly.
I for one will be happy to be the next trial, If I could find a doctor who didn't look at me cross-eyed or laugh if I proposed the idea. My last attempt at obtaining this treatment resulted in the doctor writing me a prescription for klonopin lol...
Just my 2 cents.
Wikipedia-
Effect of flumazenil
A study into the effects of the benzodiazepine receptor antagonist, flumazenil, on benzodiazepine withdrawal symptoms persisting after withdrawal was carried out by Lader and Morton. Study subjects had been benzodiazepine-free for between one month and five years, but all reported persisting withdrawal effects to varying degrees. Persistent symptoms included clouded thinking, tiredness, muscular symptoms such as neck tension, depersonalisation, cramps and shaking and the characteristic perceptual symptoms of benzodiazepine withdrawal, namely, pins and needles, burning skin, pain and subjective sensations of bodily distortion. Therapy with 0.2–2 mg of flumazenil intravenously was found to decrease these symptoms in a placebo controlled study. This is of interest as benzodiazepine receptor antagonists are neutral and have no clinical effects. The author of the study suggested that the most likely explanation is that past benzodiazepine use and subsequent tolerance had locked the conformation of the GABA-BZD receptor complex into an inverse agonist conformation, and that the antagonist flumazenil resets benzodiazepine receptors to their original sensitivity. Flumazenil was found in this study to be a successful treatment for protracted benzodiazepine withdrawal syndrome, but it was noted that further research is required.[1] A study by Professor Borg in Sweden produced similar results in patients suffering from protracted withdrawal.[2]
[1] Professor Malcolm Lader (1992). "A pilot study of the effects of flumazenil on symptoms persisting after benzodiazepine withdrawal". Journal of Psychopharmacology. http://www.bcnc.org.uk/flumazenil.html.
[2] Saxon L, Hjemdahl P, Hiltunen AJ, Borg S (May 1997). "Effects of flumazenil in the treatment of benzodiazepine withdrawal--a double-blind pilot study" (PDF). Psychopharmacology (Berl.) 131 (2): 153–60. doi:10.1007/s002130050278. PMID 9201803. http://www.springerlink.com/content/2vpf562teffglej5/fulltext.pdf.
In case you are skeptical of wikipedia(as all should be to some extent)
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.
Savic I, Widen L, Stone-Elander S. Feasibility of reversing benzodiazepine tolerance with flumazenil. Lancet 1991; 337: 133-137.
And another, though I can't track down the abstract-
Lader MB, Morton SV. A pilot study of the effects of flumazenil on symptoms persisting after benzodiazepine withdrawal. JPsychopharmacol. 1992; 6: 19-28.
I think its ludicrous to suggest that after 3-6 months of abstinence, in the grips of protracted withdrawal syndrome living in fairly consistent agony that to take flumazenil is 'nasty' and 'dangerous'. Especially considering any decent facility with respectable doctors are going to proceed cautiously with initially small and gently escalating doses, and a bucket full of backup options. That being said, I certainly wouldnt go this route without a LONG period free of all benzos.
Lack of large scale clinical trials likely reflect the stigma placed on anxiety ridden psychiatric patients who are rarely taken seriously as is, and a lack of any sustainable profit in the process secondly.
I for one will be happy to be the next trial, If I could find a doctor who didn't look at me cross-eyed or laugh if I proposed the idea. My last attempt at obtaining this treatment resulted in the doctor writing me a prescription for klonopin lol...
Just my 2 cents.
Charles Ferdinand
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Unfrikinbelievable...
Can anyone please comment on this?
My second thought was:
If I leave benzos and expect to face the abstinence hell for 2 months to 5 years or possibly more, as no one is really sure, then why leave them? Perhaps I should come clean first and take some flumanezil, maybe that would greatly speed up the recovery process. If not, then I would have no real reason to stop taking them.
Can anyone please comment on this?
My second thought was:
If I leave benzos and expect to face the abstinence hell for 2 months to 5 years or possibly more, as no one is really sure, then why leave them? Perhaps I should come clean first and take some flumanezil, maybe that would greatly speed up the recovery process. If not, then I would have no real reason to stop taking them.
Charles Ferdinand
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yeah, my dad is a surgeon and General Brig. here.
But I get along very well with him. =)
But I get along very well with him. =)