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Long acting benzodiazepines (not 'half life'), suitable for tapering

Maybe it's a bit off topic considering the section of this forum:
Direct taper off clonazepam. Nutshell: it is a problem drug, with a harsh effect/side effect profile. If I were still healthy and high functioning, I could do it. Dose-dependent and unique effects. Both tablets and liquid have their own problems. I doubt a crash-and-burn taper makes sense ... It should be tapered very slowly, for about 6 months, while continuing to live normally ... Not going to happen. I have tried several 'schedules' but some medical issues (that needed treatment) got in the way.
I foolishly went along with a lorazepam taper (which went wrong when I developed tolerance/dependence to its hypnotic, sedative and amnestic effects). These days, I get the 'what am I tapering, clonazepam or lorazepam' question when tapering clonazepam. Let's just say something else is terribly wrong, but it's partly guesswork as to what that is.

Diazepam. Completely different. More like a calming tablet. Originally, I took the clonazepam as a muscle relaxant. Very off-label.
Diazepam's duration of action is much shorter. I did try it in January for about a week but was concerned about its effects. Tinnitus etc. 4-5 hours sleep. It raised the question: is 'not dying' good enough ? In a nutshell: it offers a completely different type of sedation.

While I could say more about that: for me, it's not a 'habit'. I believe that to fully heal I need to get the last benzo molecule out of my body ... As far as diazepam's metabolites go, I believe that my body will try to adjust to whatever benzodiazepine molecules are in my system. So the long elimination period of two months is not a plus.

I didn't take it for anxiety. The closes thing to anxiety would be 'physical anxiety', but that hardly describes the issue.

I see no advantage of Librium over diazepam. Tranxene ? Being considered. RCs ? I would need to obtain a large quantity, and I have absolutely no experience with that 'scene'. Diclazepam is 'super-diazepam', diazepam with a chloride molecule attached.

If anyone wants to comment on the supposed 60-80 mg Tranxene equivalence for 2 mg clonazepam ...

Probably a bit off topic for the 'Neuroscience and Pharmacology Discussion' .
 
Kdem said:
Maybe it's a bit off topic considering the section of this forum:
Direct taper off clonazepam. Nutshell: it is a problem drug, with a harsh effect/side effect profile. If I were still healthy and high functioning, I could do it. Dose-dependent and unique effects. Both tablets and liquid have their own problems. I doubt a crash-and-burn taper makes sense ... It should be tapered very slowly, for about 6 months, while continuing to live normally ... Not going to happen. I have tried several 'schedules' but some medical issues (that needed treatment) got in the way.
I foolishly went along with a lorazepam taper (which went wrong when I developed tolerance/dependence to its hypnotic, sedative and amnestic effects). These days, I get the 'what am I tapering, clonazepam or lorazepam' question when tapering clonazepam. Let's just say something else is terribly wrong, but it's partly guesswork as to what that is.

Diazepam. Completely different. More like a calming tablet. Originally, I took the clonazepam as a muscle relaxant. Very off-label.
Diazepam's duration of action is much shorter. I did try it in January for about a week but was concerned about its effects. Tinnitus etc. 4-5 hours sleep. It raised the question: is 'not dying' good enough ? In a nutshell: it offers a completely different type of sedation.

While I could say more about that: for me, it's not a 'habit'. I believe that to fully heal I need to get the last benzo molecule out of my body ... As far as diazepam's metabolites go, I believe that my body will try to adjust to whatever benzodiazepine molecules are in my system. So the long elimination period of two months is not a plus.

I didn't take it for anxiety. The closes thing to anxiety would be 'physical anxiety', but that hardly describes the issue.

I see no advantage of Librium over diazepam. Tranxene ? Being considered. RCs ? I would need to obtain a large quantity, and I have absolutely no experience with that 'scene'. Diclazepam is 'super-diazepam', diazepam with a chloride molecule attached.

If anyone wants to comment on the supposed 60-80 mg Tranxene equivalence for 2 mg clonazepam ...

Probably a bit off topic for the 'Neuroscience and Pharmacology Discussion' .
Click to expand...

Based on this it sounds to me, and I mean this with all respect for your problem as I've been there, like you need to man up and just move forward. The longer you delay action based on the equivocation on what the "proper" benzo to taper with is. Many, many people have gotten off with tapers on every long-acting benzo mentioned in this thread, and I am starting to wish I hadn't taken part in this discussion. Many will tell you, you are not going to feel normal while tapering, maybe you adjust by the last few days before your dose drop, but that's idealistic. Benzo tapers are difficult, persistent and unforgiving. You will likely have to stop all other drugs (if I took ANYTHING, opiates, lyrica, etc. it would exacerbate everything and send me into panic) and come to terms with the fact that if you don't start tapering soon you could become stuck on the so called "dirty" benzos you're on, whether that's clonazepam or diazepam. Fundamentally, long-acting (whether duration of action or half-life) in essence means it builds up and has active metabolites. Until you conceed to the fact that this all seems like one big delay tactic to avoid the inevitable, no progress will be made.
 
Maybe it's best to set aside the personal, and go back to the 'neuroscience and pharmacology' character of this section.
 
Difficulty is:

based on the more general benzo matters, it's no surprise that you keep getting responses of people who basically don't understand why you insist on avoiding certain benzo's or why you don't just get on with it. The reasons explaining why it isn't so simple as it appears are I'd say mostly personal and symptoms are deeply intertwined with your own medical condition, a part of it may have little to do with benzo's directly and that is confusing to people. I appreciate that you have limits regarding privacy, but for people to try and follow what your medical situation and case its about... they for a good part really need those proper explanations and background info.
You certainly have serious dillema's to deal with and I won't reveal private matters concretely without your consent... but it can get pretty unclear what 'neuroscience and pharmacology' questions remain and are crucial without the obscuring personal dilemma's out of the way?
For the best advice when it gets very complicated, a sec question often won't do. The bigger picture becomes important to solve the puzzle. Also the misunderstandings very obviously demotivate people to keep following up with advice.
 
Well, I did find the theoretical matters interesting. And I honestly wouldn't mind a continuation of that. I've always been interested in science.

As for the personal, it seems I'm looking at either a substitute for the clonazepam (sufficient duration of action, right properties, not problem drugs, not accumulating too much/too 'dirty') or some way to 'tame' the clonazepam. I don't know how to put my issues in one sentence, but for me this was a dangerous drug from the start. Aside from muscle issues, I only took hypnotic benzos (infrequently) for years, never anti-anxiety drugs. In fact, I don't tolerate 'benzos' that well at all. The same goes for most drugs ...

My health is bad, I'm low functioning. I could say I'm ill. Doctors treated me like crap (most of them), I recently learned why. What is done cannot be undone ... Normally, I should be in good health before tapering this drug. I had two past attempts (years ago), both failed because I made certain mistakes (like using one glass of alcohol for sleep for months ...)
Tapering this drug would mean a declining health even under the best circumstances. Loss of muscle mass, inability to exercise (real exercise), needing an almost perfect day/night rhythm.
I'm rather messed up. (body doesn't respond normally to food, exercise, cognitive issues etc) Normally, I'd have no business tapering considering the circumstances, but the drug makes me sick.
Over the past months I noticed that whenever I became less functional (not related to tapering) the harsh (side) effects of the drug came to the fore. It's really not a 'GABA' issue. Maybe I have an undiagnosed affliction to the CNS, peripheral nervous system ('crappy internist') ? Not everything that can be considered a symptom of 'benzo withdrawal' is 'benzo withdrawal'.

Honestly I don't like the idea of taking RCs. I've never even bought one. Of course, if there were an ideal candidate ...

My options are limited. Crash-and-burn taper of clonazepam or something close. Diazepam, Tranxene, (alternative ?) Forced taper or not. Bottom line, I don't tolerate most drugs well at all, I never did. It's not a 'habit', I took this drug at 2 mg a day for too many years. Regarding tapering, I have been unable to find a doc that knows even 5 % of what I do. Yet, they often want to make the decisions.
I want to be as well-informed as I can since I'll have to do something soon. It's pretty much a devastating drug.
 
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Kdem said:
Maybe it's best to set aside the personal, and go back to the 'neuroscience and pharmacology' character of this section.
Click to expand...

I agree. Though I still wish you the best in trying to taper.

Your aversion to RCs could be holding you back, because like you said, doctors who understand benzo withdrawal are few and far between. But there are other issues that crop up with RC use too, so I understand your position (though RC benzos are probably some of the safest RCs when used properly with respect for potency/duration).

If you could pinpoint your health issue it would probably make things easier, and might provide the neuroscience and pharmacology explanation you're looking for. I know nothing of the diagnostics you've undergone, but a metabolic disorder could change the way metabolites form, and could even explain why diazepam seems to have such a short "duration of action" for you, when others, like myself, can feel a dose for a solid 48 hours. I get toxic feelings from Xanax, and without too much testing, I can estimate I may metabolize it differently because the metabolite they usually test for doesn't show up for me in drug screens. Maybe ask for a blood test/urine test to see if you have "normal" metabolites/ratios??

NOTE: My drug screens are done by the infamous University of Colorado toxicology lab that basically invented the tests for new drugs, and they do the WADA testing for professional athletes, olympians, etc. They have tests for most RCs, and when I get my results it tells me if I have nicotine, acetominophen, naproxen, trazadone, and like 26 different benzodiazine metabolites (even zolpidem and zopiclone). So the chances that the times I should have tested hot for xanax were testing errors are very low
 
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I have the same response to Clonazepam versus Alprazolam, Diazepam, and most of all Lorazepam. I've found that the Klonopin, with it's extensive half life, works the absolute best for me. Xanax works very well short term.
 
I have tried Tranxene for two days. 40 mg (tablets) taken twice daily. 80 mg a day.

Aside from it being a very different drug, have a side effect that is difficult to describe, it is much weaker and it is mostly short acting. For some reason I could do with two doses a day, but these days were long days ... it peters out quickly.

There is a clear peak after ingestion, and it would seem that the drug quickly redistributes. Into fat tissue ?
Of course I still had clonazepam in my system, and I would have had a different experience if it were not for that ...

It is supposed to have a long 'duration of action'. Not just 'half life'. Would anyone have an explanation ? Up to a point, it seemed to act shorter than diazepam.
 
Reviving an old thread for a question, see bold 'Diazepam is a broad spectrum benzo in that it bind all alpha (1-5) subunits and therefore will induce a PKA/CREB-induced downregulation of all GABAARs.'

'PKA/CREB' Would anyone clarify ? I know that taking lorazepam did downregulate GABA (putting it simply). Horrible mistake.
Diazepam is often touted as the wonder drug, yet I wonder if it doesn't also 'downregulate GABA' (?)

Pharmokinetictal said:
It's been a while since I took physical chem but I am currently a neuropsychopharmacologist. I got off 6mg clonazepam after 5yrs daily use and mixing with Xanax (I could take 120mg of Xanax at once and not notice it). It took 7 months but I did it with clonazepam. I'd failed before but only because of when I administered my doses. So at first I dose dumped in the morning because you have to remember that sleep disrupts the effective therapeutic half life of drugs because anaebolic metabolism helps redistribute the drug back into the blood.

I'm against Valium as a tapering agent because it IS 'dirty.' Diazepam alone does not have a particularly long half life. It's fast acting but is quickly oxidized and reduced to much less efficacious metabolites like oxazepam and nordiazepam and desmethyldiazepam. As a drug alone, diazepam is great...but it's lipophilicity makes it a terrible prodrug to metabolites that are even less effective and now exist mainly plasma protein and lipid bound at insignificant quantities.

Stick with clonazepam. Even lorazepam isn't worth trying.

However! There is a recognized beneficial practice many docs don't do but should. You seem very educated on BZDs so you may know this: the GABAa receptor is a pentameric construct. Drugs like alprazolam preferentially bind the alpha1 subunit and one other associated with hypnotic properties. Diazepam is a broad spectrum benzo in that it bind all alpha (1-5) subunits and therefore will induce a PKA/CREB-induced downregulation of all GABAARs. One practice is to frequently shift from one benzo to another--preferably two with different affinities for their respectively loving alpha subunits. That will prevent tolerance built, ironically during tapering.

So clonazepam to lorazepam to alprazolam (qid++), to clonazepam again. Docs don't like it cuz it looks weird to pharmacists but it is recognized in literature as effective for opioids and BZDs.

My method was to cut my dose by roughly 0.25mg/2 weeks and 0.5mg per month. So if I were at 2mg, I'd be using the 1mg tablets--maybe even the 0.5mg tabs. I would take 1mg in the morning, 0.5 at ~4pm, and 0.5mg at bedtime. The second week, I would do 0.5mg QID. Then I'd be ready for 1.25mg...'dump' 0.50mg in the morning, 0.50mg afternoon, 0.25mg bedtime first week. Then 0.5mg morning and 0.25mg at noon, afternoon, and bedtime and so forth.

Finally...look into etizolam. I don't know if docs can prescribe it but it can reverse tolerance, so says the literature! Good luck!
Click to expand...
 
That's very complicated stuff. I've been trying to understand it, but well ....

Could/would lorazepam have done the same ? I've been on that for 2-3 months, misguided taper. It was definitely more hypnotic, amnestic and sedating than clonazepam at the equivalent dose of 4 mg (2mg BID). After some time, those preperties disappeared, while the clonazepam still does something. But clonazepam has been 'weaker' ever since that failed lorazepam taper.

Maybe a question that is impossible to answer: are there any drugs that reverse that pathway ?
 
Kdem said:
Given my issues, I want to give this question another go.

Obviously, there is a difference between 'duration of action' and 'half life'. While diazepam has a very long half life, I would need to dose 3 x a day to 'cover' one dose of clonazepam. For me, clonazepam lasts a full day.
In my experience it seems I'm a 'duration of action' type of guy, once that is over it is not doing much.

Benzodiazepines other than clonazepam, that have a long duration of action (>11 hours). Once, I followed a foolish suggestion of my doc to switch to lorazepam. Taking it twice a day worked well, till I developed tolerance to and dependence on the drug, making it fairly short/medium acting (peaks and vallleys).

I don't want to take a research chemical, maybe I can import something (legally) if it can work.
I have this list from wikipedia: https://en.wikipedia.org/wiki/List_of_benzodiazepines which unfortunately doesn't say anything about the 'duration of action'.
Obviously such a drug would need to meet certain criteria, for example a strong hypnotic would not be suitable.

Anyone ?
Click to expand...


Valium 3 times a day -- Heather Ashton -- the word of GOD regarding how to taper off benzos -- says cross-over to valium or librium

Unless you just cant tolerate the crossover then you titrate the klonopin with milk

the active netabolites of valium are nordiazepam (Nordaz), Oxazepam (Serax) and Temeazepam (restoril)

I speak from experience --

http://www.benzo.org.uk/manual/

pick a taper schedule -- don't go too fast -- 1 mg kpins = 20 mg valium
 
#129, #131

Really what I wanted to know.

As for #132: how would you go from 2 mg once a day (evening) to diazepam (much shorter acting drug) TID ?
And blood plasma levels does not equal duration of action/biological activity.
 
From the no longer existing forum benzo exodus:

'Of course, clonazepam is both long acting and has a long half life. Here is what one source says (I think I got it from a no longer existing benzo site benzo exodus):
'Valium is 98% bound to plasma proteins. It rapidly crosses the blood-brain barrier and peaks within 2 hours following administration. Following the peak, the initial distribution phase in the brain is one hour. Since Valium is highly bound to plasma proteins, the drug is rapidly redistributed to adipose (fat) tissue. It is stored there, and slowly eliminated over a period of 4 days (or one month for prolonged use). Given that it is redistributed throughout the body, the duration of action following a single dose is 6-8 hours (average 6). The actual half-life of the drug (which is 30-100 hours) means very little.

Additionally, the so called "active metabolites" (Oxazepam and Temazepam) are glucuronidated during the metabolic process and are excreted rapidly via the kidneys. So, they are not "active", and they do not count as part of Valium's overall pharmacological effect. Valium's active metabolite is Desmethyldiazepam. This is what exerts an effect. The concept of several active metabolites is praised often with regard to Valium's half life, but what it really means is that the drug is "dirty", i.e. deposits in adipose tissue, hanging around in the body longer than its actual intended use and action. Librium was Sternbach's first creation, and was even dirtier. Then Valium followed. Today, we now have been given the creation of Tranxene (pure Desmethyldiazepam), which is the cleanest Diazepam variant.

By comparison, Klonopin is 86% bound to plasma proteins. Therefore, it is less lipophilic (attracted to fats) than Valium, Librium or Tranxene. It also takes longer to peak (2-4 hours). The initial distribution phase is the same as Valium, however, Klonopin is not redistributed to fat tissue like Valium. For this reason, the duration of action is prolonged to 12-18 hours. Klonopin is the longest-acting benzodiazepine that is currently marketed. The half-life ranges from 18-50 hours (mean 34 hours). Klonopin has both a long half-life and very prolonged duration of action. It is also the drug of choice for tapering off of higher-potency benzodiazepines, such as Ativan and Xanax. Valium has little to no affinity for alpha subunits 2 and 3 (which Ativan, Klonopin and Xanax bind to), therefore Valium is more problematic to substitute in place of them. Valium is less selective and binds to alpha subunits 1 and 5, as do all of the low-potency benzodiazepines.'
 
Kdem said:
Today, we now have been given the creation of Tranxene (pure Desmethyldiazepam), which is the cleanest Diazepam variant.
Click to expand...

I doubt nordazepam (N-desmethyldiazepam) is sold anywhere under the name Tranxene. Tranxene is a brand name for clorazepate (or more specifically clorazepate dipotassium) which is 3-carboxynordazepam, but clorazepate is a prodrug for nordazepam, it is rapidly decarboxylated in stomach, so it is effectively as if you took nordazepam itself.

As to why you felt a very short-lasting effect from clorazepate, I suppose it may be because you took it while being on clonazepam, nordazepam is a partial benzodiazepine receptor agonist, so if you're on a full agonist clonazepam which is also much more potent, it is likely that a dose of clorazepate added only a weak short-lasting effect before being overpowered by excess unbound clonazepam. You would need to switch to it to appreciate its long-lasting effect (in my experience longer-lasting than clonazepam). When I switched to clorazepate, I was off 0.5-0.25mg of clonazepam and already in mild withdrawal, a single dose of 15mg of clorazepate was as a matter of fact enough to make me feel all right for two days before I would feel withdrawal again.
 
Ah that does explain well why I felt very little of clorazepate when I tried it.

I am pretty sure nordazepam is or at least was sold illicitly... kdem are you saying you are not getting the bad reaction from clorazepate that you get from diazepam? If so, congrats on finding a way to remedy your situation... although not sure if there have been developments. That's private i guess.
 
Doctors ... the only thing that works for clonazepam is clonazepam ...

Taking it daily for a few weeks, a few months or even a year is a very different thing from taking it daily long term and having relevant health problems.

I know the theory that Tranxene needs to build up. Just like diazepam needs to build up. People forget, that clonazepam itself needs to build up ! The active substance of Tranxene, desmethyldiazepam is weaker than diazepam and shorter acting.
Clonazepam itself has a very long half life. My experience with diazepam is that it can work a bit as long as you have enough clonazepam left in the body. They potentiate.

In theory, a different high potency benzodiazepine could substitute for clonazepam. But (not counting the hypnotics) beyond lorazepam and alprazolam there are no options. Not counting RCs like diclazepam (not sure what it would do) etc. Correct me if I´m wrong.
 
And as a final question, sort of.

Again: duration of action (how long the drug works, typically single dose) vs. half life.

I take it that there are no high or even medium potency benzos that have favorable pharmacokinetic properties: medium to long duration of action, no excessive accumulation as with diazepam, no active metabolites. ? I did not investigate drugs like clonitrazolam, but I didn't think that clonazepam-derivates would make sense ...

Even bromazepam turned out to be diazepam-like, in the sense that it didn't 'last' beyond a couple of hours and it was stored in fatty tissues and slowly eliminated as with diazepam (I could actually feel that).
 
Have you tried augmenting your taper with a non-addictive GABA-ergic drug like kava? There hasn't been a whole lot of research on which modes of action are really responsible for kava's effects, but it might help relax you and relieve some of the withdrawal symptoms as you do your taper.
 
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