FLUMAZENIL AND BENZO WITHDRAWAL

Flumazenil is an antagonist of the GABAA receptor.  Flumazenil accelerates the onset of the withdrawal process by blocking the benzo binding site on the GABAA receptor.(1)  So, for example, if a person is on a benzo with a long half-life any remaining benzo in their system would no longer be able to bind to the GABAA receptors.  Whether it blocks natural endozepines, a peptide that binds to the same site on the GABAA receptor as benzos do, remains to be determined.

 

Flumazenil reverses sedation from all three Z drugs by blocking their action at the GABAA receptor. (4)

 

Because Flumazenil induces withdrawal scientists like to use it when conducting research on benzo dependence. (2) Medical doctors use it as an antidote for benzodiazepine and Z drug overdose because it stops the action of these drugs. (4, 5)

 

Rapid administration of Flumazenil elicits symptoms of benzodiazepine withdrawal, including seizures, both in animals pretreated with high doses of benzodiazepines over several weeks and adult human subjects. (8, 3)

 

Long term benzo usage can cause what is known as ‘uncoupling’ of the GABAA receptor.  Uncoupling results in a decrease in the ability of Benzos to potentiate the action of GABA on GABAA receptors and in a decrease in the ability of GABA to potentiate BZ binding. This may be due to changes in GABAA receptor gene expression- where the neurons swap out GABAA receptors that contain subunits benzos bind to with ones that don’t to combat the action of the drug. (3)

 

When benzos are stopped changes to GABAA receptor gene expression begin to reverse as the neurons begin swapping the original GABAA receptors back.  Because Flumazenil blocks benzos from binding to the GABAA receptor, treatment may initiate these same reversals.  Reversals happen with benzo discontinuation alone, without Flumazenil treatment.  However, Flumazenil may cause reversals to start a day or so sooner because any benzo left in the system due to half-life won’t be able to bind to the receptor.  If possible, Flumazenil might also block endozepines which could potentially have some involvement as well.

 

There have only been a handful studies with mixed results investigating withdrawal symptom improvement from Flumazenil treatment. (10, 11)  A clinic in Italy claims success administering slow infusion Flumazenil with Benzodiazepine High Dose Dependent (HDD) patients, but acknowledges there is a lack of supporting research. (6, 7)

 

The success or failure of Flumazenil treatment may depend on many variables- such as genetics, benzo type, dose, and duration of use.  Benzo administration can induce a wide variety of changes in neuronal gene expression which may participate in the development of tolerance and dependence.  This may add to the uncertainty of Flumazenil treatment outcome. (3, 9)

 

 

A microarray study showed that even a single dose of diazepam significantly changed the expression of 54 transcripts. Changes in the expression of six transcripts, CaMKIIα, BDNF, MKP-1, GIF, c-fos, and NGFI-A, were mediated via action of diazepam on α1 subunit-containing GABAA receptors. (3)  This might provide insight into potential Flumazenil efficacy.  One study found similarities between Flumazenil and a preferential α1-subunit selective antagonist βCCt on withdrawal symptoms which may imply that the mechanism of Flumazenil antagonism at GABAA receptors involves the α1 subunit. (11)

 

 

There may be other benzo induced changes to neurons that might prevent successful Flumazenil treatment outcomes such as changes to NMDA and AMPA receptors, up regulation of L-type high voltage-gated calcium channels in the cerebral cortex, and potentiation of high voltage-gated calcium channel currents in the hippocampal CA1 neurons. (3)  Therefore Flumazenil treatment outcomes may vary and more studies are needed.

 

References

 

1) Spontaneous and RO 15-1788-induced reversal of subsensitivity to GABA following chronic benzodiazepines.

Gonsalves SF, Gallager DW.

Eur J Pharmacol. 1985 Apr 2;110(2):163-70.

http://www.ncbi.nlm.nih.gov/pubmed/2859214?dopt=Abstract

 

2) Reduction of group II metabotropic glutamate receptors during development of benzodiazepine dependence.

Okamoto R, Itoh Y, Murata Y, Kobayashi D, Hosoi M, Mine K.

Pharmacology. 2013;91(3-4):145-52. doi: 10.1159/000346440. Epub 2013 Jan 31.

https://www.ncbi.nlm.nih.gov/pubmed/23392308

 

3) Regulation of GABAA Receptor Subunit Expression by Pharmacological Agents

Mikko Uusi-Oukari, Esa R. Korpi

Published online before print February 1, 2010, doi: 10.1124/pr.109.002063 Pharmacological Reviews March 2010 vol. 62 no. 1 97-135

http://pharmrev.aspetjournals.org/content/62/1/97.long#title27

 

4) The Clinical and Forensic Toxicology of Z-drugs

Naren Gunja

J. Med. Toxicol. (2013) 9:155–162 DOI 10.1007/s13181-013-0292-0

http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3657020/pdf/13181_2013_Article_292.pdf

 

5) Flumazenil use in benzodiazepine overdose in the UK: a retrospective survey of NPIS data.

Veiraiah A, Dyas J, Cooper G, Routledge PA, Thompson JP.

Emerg Med J. 2012 Jul;29(7):565-9. doi: 10.1136/emj.2010.095075. Epub 2011 Jul 23.

https://www.ncbi.nlm.nih.gov/pubmed/21785147

 

6) What Is Stopping Us From Using Flumazenil?

Fabio Lugoboni, Roberto Leone

Addiction Volume 107, Issue 7, Article first published online: 17 APR 2012

http://onlinelibrary.wiley.com/doi/10.1111/j.1360-0443.2012.03851.x/pdf

 

7) Agonist Substitution For High-Dose Benzodiazepine Dependent Patients: Let Us Not Forget The Importance Of Flumazenil

Fabio Lugoboni, Marco Faccini, Gianluca Quaglio, Rebecca Casari, Anna Albiero, Benedetta Pajusco

Addiction Volume 106, Issue 4, Article first published online: 14 FEB 2011

http://onlinelibrary.wiley.com/doi/10.1111/j.1360-0443.2010.03327.x/pdf

 

8] Flumazenil

Clinical Pharmacology

Wikipedia, the free encyclopedia

https://en.wikipedia.org/wiki/Flumazenil#Clinical_pharmacology

 

9) Antagonist-Induced Reversal of Functional and Structural Measures of Hippocampal Benzodiazepine Tolerance1

Elizabeth I. Tietz, Xu J. Zeng, Shanyi Chen, Scott M. Lilly, Howard C. Rosenberg, Peter Kometiani

JPET December 1, 1999 vol. 291 no. 3 932-942

http://jpet.aspetjournals.org/content/291/3/932.long#sec-28

 

10) Protracted Withdrawal Symptoms From Benzodiazepines

Published in Comprehensive Handbook of Drug & Alcohol Addiction 2004

Professor C Heather Ashton, DM, FRCP

http://www.benzo.org.uk/pws04.htm

 

11) βCCT, AN ANTAGONIST SELECTIVE FOR α1 GABAA RECEPTORS, REVERSES DIAZEPAM WITHDRAWAL-INDUCED ANXIETY IN RATS

Jovana Divljaković, Marija Milić, Ojas A. Namjoshi, Veera V. Tiruveedhula, Tamara, Timić, James M. Cook, Miroslav M. Savić

Brain Res Bull. 2013 February ; 91: 1–7. doi:10.1016/j.brainresbull.2012.10.011.

http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3578024/pdf/nihms422052.pdf

Another great well balanced summary, Pers.

 

:smitten:

Hello Perseverance.  Thank you for an interesting post.  You may be interested in the following article.

 

"Benzodiazepine dependence and its treatment with low dose flumazenil"

Hood et al (2012)

http://www.ncbi.nlm.nih.gov/pubmed/23126253

 

Full text of that article has been posted to Scribd.

http://www.scribd.com/doc/220046125/Hood-Hulse-2014-Flumazenil

 

 

 

 

Unfortunately I think it´s not that easy, although I¨m pretty sure that one day they will develop something from this starting point. The first important problem is that its life in the body is VERY short, of about 1 hour, so even supposing that it magically calms down most of WD sxs, the effect would only last that short period of time.

 

Secondly, if it would help REVERSE the modullation of receptors, you would need to take many constant doses for some while, which is still to be determined by further studies. And you can´t inject IV substances every hour for weeks or months. The subcutaneal suggestion of Braban´s article can certainly give hope, cause that´s more doable and by oneself. They can´t make it in pills, as far as I know, because stomach would destroy the substance.

 

Third, the cost is high and availability low.

 

This said, I wouldn´t mind at all trying it, but that doesn´t seem feasible by now.

 

In the future, I believe they will develop a new GABAA antagonist in pill form, with longer life and better effects. You´ll go to the doctor and he´ll say: "well, you have severe benzo WD syndrome (they´ll know by then and feel ashamed of their long neglect). Take this pill twice a day and you´ll be completely healed in one week or less". 

 

But now, only time, I guess.

Thanks for the articles Braben.

 

Good points Laudante. I think the solution may end up being in some sort of calcium channel blocker that works on neurons- but that would depend on scientists focusing on the Glutamate Hypothesis of BW more than what is happening today.

 

Secondly, if it would help REVERSE the modullation of receptors, you would need to take many constant doses for some while, which is still to be determined by further studies. And you can´t inject IV substances every hour for weeks or months.

 

Sure you can --  Heroin/Meth addicts do it for years. 

 

 

It might help to accelerate the proccess of widthdrawal, but the treatment itself is costly (7500$) and only available in a select few privately owned addiction treatment facility. All in all it needs to be researched further and the prevalence of Flumazenil needs to increase (or a similar drug).

 

Hi Arnie. Over time I have seen several try this treatment with no results for the better.. There was even one guy from over there who came to Australia way down here to recive treatment. He Was given an implant of the stuff for slow release over a period of some months and to my knowledge it did not work for him.. I have just this momenr sent him a message Via Skype to see how he is and asked hiom for a reply and to advisw me if it actually worked at all. I think our mutual friend knows him not sure tho. ( this gut is in auckland where it uses ,but they implant a pump to have it going into your blood.,so it does not appear feasible to me at this time.

Perseverance hasn´t appeared in a long while, I¨m worried for her. Does anybody know something?

 

And regarding Flumazenil, I would certainly try it if I could afford it. I read the story about the guy who went to Australia to try it, and he said the the test wasn´t properly done because de dosage was lower due to his limited possibility to stay there or something like that. But for some days he felt good even with that reduced dosage. Who knows. I would try it, no doubt.

So what did you do to deal with the withdrawal, did anything help you feel better

Unfortunately, flumazenil is only available via I.V. and as an in-patient. It's basically considered an 'antidote,' or reversal agent for benzos much like Narcan is for opioids. When attending an endoscopy in a gastrointestinal unit, I always saw it next to the Narcan and a few other meds to wake the patient when the procedure was finished.

 

Narcan was just approved by the FDA for intranasal administration by first responders:

 

http://www.theguardian.com/society/2015/nov/19/heroin-antidote-narcan-as-a-nasal-spray-gets-clearance-from-us-regulators

 

So, if and when it (Narcan) becomes available for patients, I don't see how flumazenil wouldn't follow the same course?!?!

 

Granted, benzo overdose is much less a problem, although concomitantly with other meds it can easily cause OD...

 

I agree that flumazenil needs more research.  Half-life extension and acute out-patient therapy needs to be a goal for this reason.

 

I'm afraid the problem lies with the FDA and medical community's failure to acknowledge benzo poisoning as a real problem.

There seems to be this widespread, inured denial  that exists within this consortium where a  refusal to believe a pathophysiology can be associated with benzo use.

 

 

 

 

Dear All,

 

I just posted on protrcated before stumbling across this excelent post.  Great job pers, as always.

 

I just read an article on Facebook: https://www.facebook.com/groups/benzodiazapineclassactionlawsuit/permalink/925889540799654/

 

The summary is that the benzo GABA-A receptor is special.  According to the author, that site is normally used by the body by the action of endozepines which DO NOT make us calm and sleepy, but rather block the GABA-A altogether to make us run for our lives.

 

Benzos hijack that site, and now its function is reversed.  Supposedly, flumazenil sets it back to the way it is supposed to be.

 

As for administration, I heard someone had an implant, similar to the way birth control implants work thus no frequent injections/IV.

 

What do my fellow neurology geeks think about the site functionality reversal idea in general?

 

Be well and good luck,

 

Ramcon1

I'm not a member of Facebook, so for as far as I know I cannot access that.

 

Is there a reference to a scientific study or could you highlight part of the story ?

Dear All,

 

I just posted on protrcated before stumbling across this excelent post.  Great job pers, as always.

 

I just read an article on Facebook: https://www.facebook .com/groups/benzodiazapineclassactionlawsuit/permalink/925889540799654/

 

The summary is that the benzo GABA-A receptor is special.  According to the author, that site is normally used by the body by the action of endozepines which DO NOT make us calm and sleepy, but rather block the GABA-A altogether to make us run for our lives.

 

Benzos hijack that site, and now its function is reversed.  Supposedly, flumazenil sets it back to the way it is supposed to be.

 

As for administration, I heard someone had an implant, similar to the way birth control implants work thus no frequent injections/IV.

 

What do my fellow neurology geeks think about the site functionality reversal idea in general?

 

Be well and good luck,

 

Ramcon1

 

Yeah, benzos bind to an allosteric site on the GABA receptor which is NOT the primary (orthosteric) location. The allosteric site is obviously used for something endogenously, otherwise it wouldn't exist.

 

This theory could prove true and I'm sure there is some data to suggest this is the case.

 

 

With chronic administration, benzos are thought to cause damage - via the conformational change they exert - on receptor (post-synaptic) cells. Through dosing (up-regulation), the cells respond by down-regulating.

 

HOWEVER, flumazenil could help to increase an excitatory response, especially in benzo WD, leading to seizures, insomnia, excitability, etc.

 

In short, flumazenil's half-life is way too short and it would take repeated dosing over time, if it had any effect, whatsoever.

 

More research is needed. But altered gene expression is what should be looked at in protracted cases...

Dear Fault,

 

Thank you for the response.  I am inclined to think it is possible as well.  I am not sure why you think administration would result in excitory bad effects.  Please explain if you can.  Also, I recall a memebr say s/he was going to receive a dissolving implant, which for our purposes would be the best for of administration.

 

Do you really think there is a way to favorable alter gene expression to help us heal?

 

I am of the unpopular belief that in a small percentage of us, this is just not going to get better.  I have only gotten sicker in 40 months.  Granted, I drank a lot on years 1 and 2, but if this theory is true, that should not have made a difference as alcohol binds to the primary sites of GABA A.

 

I am just at wits end with this, and looking for a way to end it.  If it is in fact permanent, I often wonder out loud (read "rant") on this board if we should just stay on low dose valium for the rest of our lives, and if that would even work.

 

Thank you again,

 

Ramcon1

Dear Fault,

 

Thank you for the response.  I am inclined to think it is possible as well.  I am not sure why you think administration would result in excitory bad effects.  Please explain if you can.  Also, I recall a memebr say s/he was going to receive a dissolving implant, which for our purposes would be the best for of administration.

 

Do you really think there is a way to favorable alter gene expression to help us heal?

 

I am of the unpopular belief that in a small percentage of us, this is just not going to get better.  I have only gotten sicker in 40 months.  Granted, I drank a lot on years 1 and 2, but if this theory is true, that should not have made a difference as alcohol binds to the primary sites of GABA A.

 

I am just at wits end with this, and looking for a way to end it.  If it is in fact permanent, I often wonder out loud (read "rant") on this board if we should just stay on low dose valium for the rest of our lives, and if that would even work.

 

Thank you again,

 

Ramcon1

 

Ram,

 

            Thanks for the reply, also.

 

Since flumazenil binds to the central benzodiazepine site as an antagonist, it reverses (temporarily, unless continuously infused) the sedative, anticonvulsant, and anxiolytic effects of the medication.  As a therapy for benzo withdrawal, this might increase the seizure threshold, exacerbate tremors, and lead to increased excitability in the patient.

 

------->  http://www.ncbi.nlm.nih.gov/pubmed/8306565

 

 

Since many benzo withdrawal patients are already experiencing increases in glutamate binding or receptor up-regulation due to the brain's compensatory action of dealing with the inhibitory effects of benzos, flumazenil COULD make things worse initially, or may need to be held until the patient stabilizes to some degree.

 

Benzo sites (allosteric sites) are thought to exist to accommodate an endogenous compound called 'endozepines,' which could have two different effects; they may work like benzodiazepine meds (positive allosteric modulators), OR work to bring about an acute stress response (ie. 'fight or flight'). Much of this is still theory, however.

 

My point is that flumazenil binds to the same sites that can preclude or elicit a stress response.

 

This does not rule flumazenil out as a treatment for BWS.

 

I ABSOLUTELY DO BELIEVE THAT, THROUGH ALTERED GENE EXPRESSION, OR 'RE-ALTERED' GENE EXPRESSION , WE CAN RETURN TO A PRE-BENZO BASELINE AND LIVE WITH PEACE IN OUR MINDS AND HEARTS!

 

Cells constantly undergo change as a means of adapting to a stimulus or environmental factor. Just as the brain changed once to adapt, so can it change again to re-adapt.

 

This means creating as advantageous an environment within our bodies as possible.

 

Ram, I would try everything, bud, and only return to meds as a last resort. Light therapy, cognitive behavioral therapy, diet, and exercise are great places to start.

 

In terms of the alcohol thing, all I know is alcohol is non-selective at GABA sites and it is highly recommended that patients consume as little alcohol as possible.

 

I believe that the longer one is on benzos, the worse things are in both the long and short run.

 

Since you're 40 months off, I would challenge you to look at your lifestyle and find things that are not helping.

 

I know people 5 years+ that still have waves and windows.

 

Please message me back with your thoughts.

Thank you again.  I will be PM you in a few days.

One place in the US called the Coleman Institute does Flumazenil treatment and they say they can get you past the acute withdrawal in 8 days with a 98% success rate and 0% death rate. However, it cost $6,000 is an outpatient program and they don't accept insurance. They give you a pump to carry around that gives you a slow infusion of it. Somehow this drug reverses benzo tolerance. I called them before and they said it can help with protracted withdrawal too because of the growth of new receptors. This is what I'm going to do if my taper fails.

fault and Jx,

 

First, here is a link describing endozepines and their possible negative modulation at the benzo recpetor og GABA A.

 

https://books.google.com/books?id=Xz4yFpdSRrwC&pg=PA762&lpg=PA762&dq=endozepines+and+negative+allosteric+modulator&source=bl&ots=0WN8NmZGmv&sig=ONRfum3dHEL29-Uo7_1TuN_SigA&hl=en&sa=X&ved=0ahUKEwiVsJeayvTJAhUBOSYKHQUUCx8Q6AEINzAE#v=onepage&q=endozepines%20and%20negative%20allosteric%20modulator&f=false

 

 

Second, I wrote the following email to the Coleman institute.  I will let you know if they call me:

 

Dear Sir or Madam,

 

My name is XXXX.  I successfully tapered off benzodiazepines 40 months ago.  I was an Ativan addict, and used the diazepam taper method.  Forty months later, I still have many physical, mental, and psychological symptoms.

 

I am a member of the benzobuddies.org user group.  The topic of flumazenil comes up.  We understand how it works for getting thru the acute phase.  We have heard that some of your staff believe it can treat the post acute, or for many of us protracted withdrawal where our neurology is still very damaged.

 

I would appreciate a call to discuss this after the new year.  Please have a neurologist on your staff call me to explain the theory of how this can help, and present at least a few success stories for people who had post acute withdrawal and were helped by your flumazenil method.

 

Please note, and I mean this in the nicest possible way, a call from a neurologist on your staff prepared with the information I requested above is the ONLY way I would  consider paying the $6000.  You can reach me anytime after January 4th at XXX-XXX-XXXX.

 

Thank you, Happy Holidays, and Happy New Year.

 

Sincerely,

 

 

edited personal info

I assume that's not your real phone number.

fault and Jx,

 

First, here is a link describing endozepines and their possible negative modulation at the benzo recpetor og GABA A.

 

https://books.google.com/books?id=Xz4yFpdSRrwC&pg=PA762&lpg=PA762&dq=endozepines+and+negative+allosteric+modulator&source=bl&ots=0WN8NmZGmv&sig=ONRfum3dHEL29-Uo7_1TuN_SigA&hl=en&sa=X&ved=0ahUKEwiVsJeayvTJAhUBOSYKHQUUCx8Q6AEINzAE#v=onepage&q=endozepines%20and%20negative%20allosteric%20modulator&f=false

 

 

Second, I wrote the following email to the Coleman institute.  I will let you know if they call me:

 

Dear Sir or Madam,

 

My name is XXXX.  I successfully tapered off benzodiazepines 40 months ago.  I was an Ativan addict, and used the diazepam taper method.  Forty months later, I still have many physical, mental, and psychological symptoms.

 

I am a member of the benzobuddies.org user group.  The topic of flumazenil comes up.  We understand how it works for getting thru the acute phase.  We have heard that some of your staff believe it can treat the post acute, or for many of us protracted withdrawal where our neurology is still very damaged.

 

I would appreciate a call to discuss this after the new year.  Please have a neurologist on your staff call me to explain the theory of how this can help, and present at least a few success stories for people who had post acute withdrawal and were helped by your flumazenil method.

 

Please note, and I mean this in the nicest possible way, a call from a neurologist on your staff prepared with the information I requested above is the ONLY way I would  consider paying the $6000.  You can reach me anytime after January 4th at XXX-XXX-XXXX.

 

Thank you, Happy Holidays, and Happy New Year.

 

Sincerely,

 

Ram,

 

              Thanks for the link regarding endozepines. According to that research, it seems like those little guys act more as NAM's,  implicated more in pathophysiologies. Scary. I'll consider that when dispensing advice and what I know next time.

 

 

 

edited to remove personal info from quote

Here is what an emergency medicine doctor thinks about flumazenil:

 

Flumazenil is currently not recommended to treat chronic benzodiazepines by the American College of Medical Toxicology.

 

There is a very real risk that rapid reversal of benzodiazepines can lead to refractory seizures only treatable with barbiturates as flumazanil binds to GABA receptors with greater affinity, which could lead to unopposed glutamate stimulation. Benzodiazepine tapers are better.

 

Dr. Glenn Burns

Emergency Medicine

Here is what an emergency medicine doctor thinks about flumazenil:

 

Flumazenil is currently not recommended to treat chronic benzodiazepines by the American College of Medical Toxicology.

 

There is a very real risk that rapid reversal of benzodiazepines can lead to refractory seizures only treatable with barbiturates as flumazanil binds to GABA receptors with greater affinity, which could lead to unopposed glutamate stimulation. Benzodiazepine tapers are better.

 

Dr. Glenn Burns

Emergency Medicine

 

He´s completely right, but not addressing the use of flumazenil for PROTRACTED benzo WD. It´s a serious risk if you are taking benzos still, not months or years after discontinuation.

Here is what an emergency medicine doctor thinks about flumazenil:

 

Flumazenil is currently not recommended to treat chronic benzodiazepines by the American College of Medical Toxicology.

 

There is a very real risk that rapid reversal of benzodiazepines can lead to refractory seizures only treatable with barbiturates as flumazanil binds to GABA receptors with greater affinity, which could lead to unopposed glutamate stimulation. Benzodiazepine tapers are better.

 

Dr. Glenn Burns

Emergency Medicine

 

He´s completely right, but not addressing the use of flumazenil for PROTRACTED benzo WD. It´s a serious risk if you are taking benzos still, not months or years after discontinuation.

 

You have a point, Laudante, but the inherent problem in protracted withdrawal is what you touched upon in your first sentence. Basically: 

 

There IS no protocol or approach in addressing ANY solutions for patients in protracted withdrawal.

 

All the current literature and treatment modalities that exist pertain to patients in inter-dose or acute benzodiazepine withdrawal.

 

Why?

 

Probably because the various inter-disciplinary medical communities are utterly mystified by the concept of someone experiencing crippling protracted withdrawal 7 years off a controlled taper.

 

 

There IS no protocol or approach in addressing ANY solutions for patients in protracted withdrawal.

 

All the current literature and treatment modalities that exist pertain to patients in inter-dose or acute benzodiazepine withdrawal.

 

Why?

 

Probably because the various inter-disciplinary medical communities are utterly mystified by the concept of someone experiencing crippling protracted withdrawal 7 years off a controlled taper.

 

That´s right. I¨m 22 months off and completely crippled. If I had a possibility of trying flumazenil I would do it, no doubt.