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Dr. Bob is Robert Hsiung, MD,
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Posted by Squiggles on August 9, 2007, at 16:05:45
In reply to Re: Tolerance to Benzo Anxiety Effects, posted by FredPotter on August 9, 2007, at 15:52:08
> I'm not sure how withdrawal symptoms appear even in the presence of the drug. Is this another way of saying tolerance and needing a progressively higher dose?
Tolerance means that a higher dose than the initial one given for condition x, becomes necessary with time. Time varies according to type of benzo (with its half-life), length of time taken, and amount.
Withdrawals from the above conditions, will also vary, but are more like a corrollary to that and not the same as tolerance. So, you can have withdrawals of a different type and severity even with a small dose of say Xanax after 3 months.
Squiggles
Posted by Phillipa on August 9, 2007, at 21:50:05
In reply to Re: Tolerance to Benzo Anxiety Effects » FredPotter, posted by Squiggles on August 9, 2007, at 16:05:45
Squiggles going on 40 years and I take less than in the beginning. Love Phillipa ps we're all different
Posted by Quintal on August 10, 2007, at 3:50:53
In reply to Re: Tolerance to Benzo Anxiety Effects, posted by FredPotter on August 9, 2007, at 15:52:08
>I'm not sure how withdrawal symptoms appear even in the presence of the drug. Is this another way of saying tolerance and needing a progressively higher dose?
This is an interesting explanation:
__________________________________________________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.[5] Study subjects had been benzodiazepine free for between 1 month and 5 years but all reported persisting withdrawal effects to varying degrees. Persistent symptoms included clouded thinking, tiredness, muscular symptoms such as neck tension, 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 0.2-2mg 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.
http://en.wikipedia.org/wiki/Benzodiazepine_withdrawal_syndrome
--------------------------------------------------Although the underlying mechanisms of benzodiazepine dependence are still not entirely understood, research in animals points to the clinical potential for the benzodiazepine antagonist flumazenil (Ro 15-1788) to reverse benzodiazepine dependence and tolerance and prevent withdrawal (Whitwam, 1988). Administration of flumazenil reverses tolerance and dependence to benzodiazepines (Gonsalves and Gallager, 1985) but precipitates recognizable withdrawal symptoms . However, if given during chronic treatment flumazenil can, by similarly reversing tolerance, prevent subsequent withdrawal syndromes in primates (Gallager, Heninger and Heninger, 1986) and in rats (Baldwin, Hitchcott and File, 1990). One explanation for this is the antagonism and depletion of an endogenous benzodiazepine receptor ligand with inverse agonist and thus anxiogenic activity by the antagonist flumazenil (Baldwin, Hitchcott and File, 1990). However, levels of the proposed 'anxiety peptide' ligand associated with diazepam binding inhibitor (DBI) were not found to be increased by the administration of diazepam in rats (Ball et al., 1987). An alternative explanation is that chronic agonist use causes a persistent conformational change and thus a shift in benzodiazepine receptor efficacy in the direction of inverse agonist function (Little, Nutt and Taylor, 1987) and that flumazenil resets the receptor's sensitivity (Nutt and Costello, 1988). In binding to the benzodiazepine receptor flumazenil may alter the coupling of the elements of the GABA/benzodiazepine macromolecular complex modified by benzodiazepine binding, thus restoring the GABA recognition site to its pre-drug affinity (Gonsalves and Gallager, 1985).
http://www.bcnc.org.uk/flumazenil.html
__________________________________________________Q
Posted by Squiggles on August 10, 2007, at 4:30:49
In reply to Re: Tolerance to Benzo Anxiety Effects » FredPotter, posted by Quintal on August 10, 2007, at 3:50:53
That's really interesting. The conformation part is a biological concept i don't understand. But regarding the prolonged withdrawal symptoms is a well-observed phenomenon above. In my case i am pretty sure, that since K w/d the gastro problem began and never stopped. It would be interesting if flunozetol were tried on me.
I know people who took benzos many yrs. ago and have some of the symtpoms above and they never stopped, nor could various drs. discover the cause, but i bet it was withdrawal.
One thing that I did not pick up was the withdrawal with tolerance situation. I have spoken about inter-dose withdrawal, but mostly i thought that tolerance is managable with a constantly increased dose, but withdrawal was a different beast altogether that could not easily be reversed on some benzos. But here, it seems that you can have mixed tolerance/withdrawal. Interesting.
Squiggles
Posted by sometimesblue on August 10, 2007, at 9:24:39
In reply to Re: Tolerance to Benzo Anxiety Effects » Quintal, posted by Squiggles on August 10, 2007, at 4:30:49
I find that I build up a tolerance to benzos very quickly and was constantly self medicating and increasing my doses. The first time a took a break from it the withdrawal was non-existant. However the second time was hell! I had all the book-marked symtoms of a benzo withdrawal...it was completely awful...i thought i was going to have seizures. But strangely, I had been on the medication longer the second time around, but not at such high doses like the first time. Go figure.
-SB
Posted by Squiggles on August 10, 2007, at 9:47:03
In reply to Re: Tolerance to Benzo Anxiety Effects, posted by sometimesblue on August 10, 2007, at 9:24:39
> I find that I build up a tolerance to benzos very quickly and was constantly self medicating and increasing my doses. The first time a took a break from it the withdrawal was non-existant. However the second time was hell! I had all the book-marked symtoms of a benzo withdrawal...it was completely awful...i thought i was going to have seizures. But strangely, I had been on the medication longer the second time around, but not at such high doses like the first time. Go figure.
>
> -SB
Which benzo were you on?I had a strange experience too, with the early
stages of taking clonazepam-- say the first year or so. I was taking a min. dose of 0.5 and i stopped. I experienced an electric shock down my arm and numbness on the left side of my head. I decided to better get back on. And it took about a month for these slight withdrawal effects to go away.Much later, when I tried on the same dose, the effects were far worse, and later than than that, say 7 yrs. unbearable. Still, the 30-day mark of recovery seemed to be consistent, with the exception of the last try, where they would not stop without reinstatement after about 18 mos. And then, to recover again it took about 30-60 days. But the withdrawals on this try were severe and i was bed-ridden for the time, as if after a stroke.
It seems that with clonazepam at least, it just got worse and worse every time i tried to withdraw, even though the range for about 15 yrs was 0.5-1.0mg (.5 added later to stop the w/d's.).
Don't know what's going there. Those articles by Lader et al look good, if you can understand them.
Squiggles
Posted by boveni3 on August 10, 2007, at 9:55:52
In reply to Re: Tolerance to Benzo Anxiety Effects » sometimesblue, posted by Squiggles on August 10, 2007, at 9:47:03
Have read Ashton's manual?
http://www.benzo.org.uk/manual/index.htm
Posted by Squiggles on August 10, 2007, at 10:10:27
In reply to Re: Tolerance to Benzo Anxiety Effects, posted by boveni3 on August 10, 2007, at 9:55:52
> Have read Ashton's manual?
> http://www.benzo.org.uk/manual/index.htmI haven't seen this revised version. I read
the first edition some years ago when i participated at benzo.org. I'm glad to see that the benzo group's findings are now becoming respectable in medical communities and health care bodies. I recall at that time, there was a lot of opposition, and for my part, a lot of paranoia and scepticism from friends. Cognitive dissonance, indeed, and it is just like personal and political conflicts of world-views. But, as Ray Nimmo used to say "the truth will out".Squiggles
Posted by Squiggles on August 10, 2007, at 11:25:08
In reply to Re: Someone Prove Ashton Wrong!!!!!!!!!!....Please, posted by boveni3 on August 5, 2007, at 22:14:29
> "I still believe that under the care of the right doctor, benzodiazepines are among the safest psychoactive drugs purely due to their very long history, over barbiturates, reducing the chance of overdosage."
>I agree with much of that, and I think Dr. Ashton
has a chapter on the Rational Use of Benzos. The
problem is that they have been taken lightly due to the marketing promotion over the old barbiturates. They do need monitoring for tolerance, withdrawal, and dose, especially for older people who may fall or have car accidents or other mishaps due to cognitive and motor effects of benzos; and if they are living alone, there is always the problem of forgetting the right dose.They're just overused and once used, constanty used.
Squiggles
Posted by Phillipa on August 10, 2007, at 20:43:33
In reply to Re: Someone Prove Ashton Wrong!!!!!!!!!!....Please » boveni3, posted by Squiggles on August 10, 2007, at 11:25:08
As I've said before I've taken for years then just stopped no withdrawal and when thyroid started had to start the benzos again will die with benzos. Don't care as it could be alchohol or a car wreck. Love Phillipa
Posted by Squiggles on August 10, 2007, at 20:57:02
In reply to Re: Someone Prove Ashton Wrong!!!!!!!!!!....Please » Squiggles, posted by Phillipa on August 10, 2007, at 20:43:33
> As I've said before I've taken for years then just stopped no withdrawal and when thyroid started had to start the benzos again will die with benzos. Don't care as it could be alchohol or a car wreck. Love Phillipa
Which benzo?
What dose?
How long taken?
What was it taken for?
What other medications were taken concurrently?
How long did you stop for?
Did you start again at the same dose?
How often were you taking the benzo before
stopping (daily, weekly, every other day)?Generalizations about drugs can be misleading.
Posted by Phillipa on August 10, 2007, at 22:36:31
In reply to Re: Someone Prove Ashton Wrong!!!!!!!!!!....Please » Phillipa, posted by Squiggles on August 10, 2007, at 20:57:02
Squiggles various benzos have been on valium l5mg total with miltown back when and just stopped the miltown when felt better and no withdrawal with that. The I took 5mg of valium three times a day and gradually cut down to 5mg a day for the three years in nursing school. Then .25 of ativan for a couple of years then drug free for about a year. Moved to virginia by myself and was then on xanax took .5 to sleep. Then when I met Greg was on .125 of xanax. I moved to NC and my thyroid went two years later up to .25 of xanax twice a day and a half at bedtime. Then I went back on valium as the xanax was making me tired and now on it 20mg going down to l5mg with 50mg of luvox cutting that down to 25mg soon. Oh all the other years no other meds. Magna cum laude in nursing school a divorce after 21years three kids and an Aerobic Dance Business. So I don't think they are addictive for me. Love Phillipa
Posted by Squiggles on August 11, 2007, at 7:59:50
In reply to Re: Someone Prove Ashton Wrong!!!!!!!!!!....Please » Squiggles, posted by Phillipa on August 10, 2007, at 22:36:31
I can't explain it. Maybe the devil is in the details.
Squiggles
Posted by Phillipa on August 11, 2007, at 20:32:50
In reply to Re: Someone Prove Ashton Wrong!!!!!!!!!!....Please » Phillipa, posted by Squiggles on August 11, 2007, at 7:59:50
Squiggles me either it just is what it is. No complaints from me. Love Phillipa
Posted by FredPotter on August 11, 2007, at 20:39:44
In reply to Re: Tolerance to Benzo Anxiety Effects » FredPotter, posted by Quintal on August 10, 2007, at 3:50:53
Thanks Quintal I've saved that. On the face of it that looks like wonderful news. If benzos can control anxiety long-term as a result of Flumazenil I don't see a future for SSRIs being used for that purpose (with all their side effects). Whatever side effects there are with benzos I don't think they're as bad as those for SSRIs
Posted by boveni3 on August 11, 2007, at 20:56:48
In reply to Re: Tolerance to Benzo Anxiety Effects » Quintal, posted by FredPotter on August 11, 2007, at 20:39:44
This states that Flumazenil appears to curb protracted withdrawal symptoms, with potential “to reverse benzodiazepine dependence and tolerance and prevent withdrawal eliminate dependency.”
This compilation was written in the 1980’s, that is over twenty years ago! If Flumazenil had the stated potential, it would be in use today and this thread would not exist.
Posted by Quintal on August 11, 2007, at 21:02:26
In reply to Re: Tolerance to Benzo Anxiety Effects » Quintal, posted by FredPotter on August 11, 2007, at 20:39:44
Posted by Quintal on August 11, 2007, at 21:13:11
In reply to Re: Tolerance to Benzo Anxiety Effects, posted by boveni3 on August 11, 2007, at 20:56:48
I think the problem is that you have to withdraw from benzos first in order to use flumazenil safely - it could cause convulsions (not to mention extreme distress) in people who are dependent on them. A similar strategy is sometimes used with the opioid receptor antagonist naltrexone as a rapid detox from, you guessed it, opiates. http://en.wikipedia.org/wiki/Naltrexone
With benzos, there's still the problem of cognitive impairment and amnesia to contend with though, tolerance to which also will be reset by flumazenil.
Q
Posted by boveni3 on August 11, 2007, at 21:29:20
In reply to Re: Tolerance to Benzo Anxiety Effects » boveni3, posted by Quintal on August 11, 2007, at 21:13:11
I think you may want to read more about this drug. All benzodiazapines have longer half-lives making its use is very limited. See below:
Flumazenil (also known as flumazepil, code name Ro 15-1788, trade names Anexate, Lanexat, Mazicon, Romazicon) is a benzodiazepine antagonist, used as an antidote in the treatment of benzodiazepine overdose. It reverses the effects of benzodiazepines by competitive inhibition at the benzodiazepine binding site on the GABAA receptor. It was introduced in 1987 by Hoffmann-La Roche under the trade name Anexate.
The onset of action is rapid and usually effects are seen within one to two minutes. The peak effect is seen at six to ten minutes. The recommended dose for adults is 200 μg every 1-2 minutes until the effect is seen, to a maximum of 3 mg per hour. It is available as a clear, colourless solution for intravenous injection, containing 500 μg in 5 mls.
All benzodiazepines (including midazolam) have longer half-lives than flumazenil. Therefore, repeat doses of flumazenil may be required to prevent recurrent symptoms of overdosage once the initial dose of flumazenil wears off. It is hepatically metabolised to inactive compounds which are excreted in the urine. Subjects who are physically dependent on benzodiazepines may suffer benzodiazepine withdrawal symptoms, including seizure, upon administration of flumazenil.
Posted by Quintal on August 11, 2007, at 21:36:53
In reply to Re: Tolerance to Benzo Anxiety Effects, posted by boveni3 on August 11, 2007, at 21:29:20
Yes, that's why I said in my previous post flumazenil probably didn't catch on because people have to withdraw from benzos first, or suffer withdrawal symptoms and possibly seizures, making it dangerous in people who are dependent on them.
Q
Posted by barbaracat on August 12, 2007, at 15:50:51
In reply to Re: Tolerance to Benzo Anxiety Effects » boveni3, posted by Quintal on August 11, 2007, at 21:36:53
I've noticed a progressive tolerance building up now that I've been taking benzos more frequently because of some stresses. I take clonazepam and lorazepam, interchanging them. It's getting to where I could easily take a small handful and hardly feel it.
This has happened periodically and I'll usually ramp down on the doses. I usually find no withdrawal problems, but I never just discontinue, only reduce slowly.
I find that gabapentin will help in these situations. It binds to the GABA receptors differently and even though it has a very short tolerance life, the action seems different and I can at least get some relief when benzos have pooped.
What I'm searching for now is a way to replenish the GABA naturally and have been trying various aminos and herbs. Amino GABA doesn't do squat since it doesn't cross the bbb, but L-theanine, an amino acid, may be a contender. Another is rosavin, a high mountain flower which strengthens the adrenals and lifts the mood. I order Ameriden brand over the net.
One thing that's become clear is the importance of Omega 3's and 6's, fish oil, flax oil and evening primrose oils for example. These keep the fatty surfaces of the cell membranes fluid and permeable so the neurons can do their work of receiving and releasing molecules in a more healthy state.
- BarbCat
Posted by boveni3 on August 12, 2007, at 16:19:54
In reply to Tolerance to Benzo Anxiety Effects - suggestions, posted by barbaracat on August 12, 2007, at 15:50:51
Hi Barbcat
"Amino GABA doesn't do squat since it doesn't cross the bbb, but L-theanine, an amino acid, may be a contender."
My reasearch found that benzos do not deplete or inhibit GABA, it interferes with the reuptake of GABA. Additionally, new research shows that long-term us of benzos may cause this to be a permanent problem.
Unfortunately, taking GABA has no value.
Posted by barbaracat on August 12, 2007, at 19:45:25
In reply to Re: Tolerance to Benzo Anxiety Effects - suggestions, posted by boveni3 on August 12, 2007, at 16:19:54
Yes, as I found out with the amino form. What I wonder is if this tolerance is with all variants of the GABA receptor/molecules or just the subtypes of that particular benzo. Why would the re-uptake pump not eventually revert back to it's genetically encoded behavior if the aggravating substance was absent? I also wonder about the longevity of the neuron itself. Since we now know that neurons can possibly replace themselves, what is the lifespan of a particular cell and do they or don't they revert back to their original coding?
I particularly wonder about this same situation existing in regards to SSRIs. I don't know of a single person, myself included, who has had a long-term (note 'long-term', as in years) relationship with an SSRI who has been able to stay off them permanently. One could say 'well, that shows you need them'. I'm not so sure. I suspect there is a long-term (I cringe to use 'permanent') modification of the actual cell mechanism that prevents/destroys the cell/brain system from physically readapting to it's pre-SSRI functioning.
What particularly strikes me are those people who were not endogenously but situationally depressed, i.e., grief, trauma - and just fine before taking the med. However, after a moderate stint on an SSRI as a temporary coping measure, they found that eventually they had to go back on. Something had changed and they were now chronically depressed. Who knows how long this would have lasted if they white-knuckled it longer, or if it was now a permanent maladaption?
This stuff concerns me greatly, but I have faith in the plasticity of our wondrous brains and hope they knows what they're supposed to do given the right conditions. That's why I preach Omega 3 & 6 oils to give them every chance of help possible.
Best wishes and keep in touch,
-BarbCat
Posted by Quintal on August 12, 2007, at 20:12:46
In reply to Re: Tolerance to Benzo Anxiety Effects - suggestio » boveni3, posted by barbaracat on August 12, 2007, at 19:45:25
Well I took benzos for about five years more or less continuously (only stopped them for a week or a few days each time) and I've now been off them for a year. At the height of my addiction I took 20mg Klonopin a day (very briefly), but my usual dose was around 4mg. I also took SSRIs and related rugs for most of that time. I have no lingering problems from having been on these drugs, though I managed to get off them in the time-honoured way of replacing one addiction with another - opiates, codeine to be specific. Codeine does a much better job than all of the above put together.
I think it's possible for people to come off these drugs and make a full recovery, but the withdrawal needs to be managed carefully. It's interesting about the inverse agonist theory, and I wonder if something similar is happening when people have lingering withdrawal symptoms from SSRIs etc.? There's no evidence as yet that benzos cause permanent brain damage, but there may be functional changes at the receptors, and the same could be true for SSRIs.
Q
Posted by Squiggles on August 12, 2007, at 20:18:29
In reply to Re: Tolerance to Benzo Anxiety Effects - suggestio, posted by Quintal on August 12, 2007, at 20:12:46
I'm glad i didn't take SSRIs. I was actually offered them when I withdrew from Xanax (piece of cake) on the idea i think, that i would have continued to have panic attacks. But the panic attacks were due to hyperthyroidism from Synthroid.
I don't know how Dr. Preskorn does polypharmacy. I think he's a real drugstore cowbody. :-)
Squiggles
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