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

I keep seeing references to first order and higher order kinetics. In reality, zero-order kinetics are the gold standard that pharmaceutical companies try to achieve with controlled drug delivery. However, there is never a constant rate at which the drug leaves the blood stream, so biochemists do their best to create a delivery method that at least approximately maintains the desired plasma concentration in most people. It is important that we understand biological half life refers to the time it takes for the organism to eliminate half of the drug. It doesn't refer to plasma concentrations unless you're specifically referring to a plasma concentration half life. But, as previously mentioned, steady state reaction kinetics are typically non-existent in terms of plasma concentration. Duration of action is definitely the best indicator of the presence active metabolites in the blood stream. Elimination half lives can contribute to the length and acute severity of withdrawal. You shouldn't worry about drugs accumulating indefinitely. We have all sorts of great ways to get rid of things, even if it can ultimately kill the desired effect :/
 
Thnx for clarifying your effects, don't know if you are experiencing the known paradoxical effects that occasionally happen or for some individuals more structurally... or if its something different and a result of fluctuating blood levels, or metabolites?.. hmm anyway part of what you mention *can* be 'known' side-effects I think. Perhaps not all but yeah I understand that it's disturbing. Apart from that, I know from experience that living with benzo use - scripted or any habit i.e. structural use - is not an easy and careless life.. Yeah side effects start to suck more and more, and you just cant keep it up cause of tolerance.

Otherwise for some merited cases it wouldn't even be such a bad idea to go on them indefinitely.

I hated bromazepam, because it had very mood-destabilizing / depressing action for me, sort of consistently...

Is phenazepam that much more of a research chemical than diclazepam? Why? I wouldn't think so...
Again! Not that I advocate phenazepam in general, but it seems to address your 'requirements'. Who says diclazepam has a 'duration of action of 12 h' ? and what does that mean anyway for you, do you have to notice it - or do you (hopefully) count the warding away of withdrawal symptoms as enduring action as well?

I don't really get why people consider diazepam as having such a short duration of action, or compared to its half-life. What do you hope to achieve or avoid in the long tail end of that duration?

If you taper, its all really to maintain but less and less, and hold you over without having to deal with seizures and truly fucked up shit, but it still tends to be very difficult.

If you want your duration of action and quality of action covered then I don't think you are tapering, you are just maintaining and going nowhere...

I'm currently using etizolam, and I want to stop asap hoping that it will be doable since its only become a habit recently. Don't even know how long after a dose I can expect serious w/d if they come at all.. its rather short acting.
 
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http://www.benzo.org.uk/manual/index.htm

I think the person suggesting diclazepam once a day has a smaller habit they are treating by taking MORE. Diclazepam lasts 12 hours. If you take 1/2 every 12 hours, you might find you don't need as much. IF you can get reliable 1mgs, you can use a pill cutter to get into 1/4s but even this is 2.5mg diazepam. The Ashton manual (above) shows how slowly you have to go. Trust me when I say I've been on MORE diclazepam than anyone I've heard of - 24mg/day. I got down to 2mg/day (in 2 doses) and went to my doctor where 5 & 2mg diazepam can get you down - it's SLOW. Screw up and it causes seizures (I know) so someone with even a 2x2mg/day clonazepam habit has a BIG problem. It took me 15 months to get here.
 
Solipsis, diclazepam BID: 'Diclazepam and active metabolites have longest T1/2 - can be detected for 24 days after single dose. Of course, the ADME cycle means that a BID reduction works (diazepam is often TID).'

Is that incorrect ?

'I don't really get why people consider diazepam as having such a short duration of action, or compared to its half-life. What do you hope to achieve or avoid in the long tail end of that duration?'
The half life of a single dose of diazepam is 1-2 days. After accumulation, that gets, for practical purposes, longer. Then there is the active metabolite desmethyldiazepam which is formed right up till the last diazepam molecule has left the fat cells.
For me, the duration of action is relatively short. In the past BID was't quite enough. Even in the best of cases I had to sneak in a small dose between the two larger doses. it's more a TID drug. The diazepam may do a litte after the duration of action is over, but not much ! Clonazepam is such a powerful drug.
Of course, if you have no benzo tolerance or dependence at all and a doc gives you a 20 mg diazepam dose ... I can imagine that you can feel some effects for 48 hours !
 
Slow_Mobius,

'It is important that we understand biological half life refers to the time it takes for the organism to eliminate half of the drug. It doesn't refer to plasma concentrations unless you're specifically referring to a plasma concentration half life.'
A very good point. When the half life of a drug is discussed in medical or pseudo-medical sources, which definition is used ?

'Duration of action is definitely the best indicator of the presence active metabolites in the blood stream.'
In the case of diazepam, Ashton's theory is that the accumulation of diazepam will provide a steady half life.
I gave diazepam a try for a couple of days (40 mgs!), and once the 'duration of action' was over there was a weak after effect, but it was weak. Then again, clonazepam is a powerful and long acting (24 hrs) drug and once it is gone ...
 
Well plasma concentrations and biological half lives are significant in their own regard. Both would typically be studied for any new drug. Half life without specification would refer to bioloigical half life unless it is previously defined otherwise. However, plasma concentration half lives are usually more significant for dosing and drug design. They're more commonly and more easily studied. Of course, this is assuming they can extrapolate (or sort of extrapolate) a first order kinetic elimination profile.

With drugs that have long biological half lives, like diazepam, there will probably be a relatively insiginificant amount that is released into he bloodstream well after the typical duration of action is over, unless there is accumulation via relatively large doses or a relatively large number of doses in a small period of time. A long biological half life would suggest that there will be small amounts of the active drug still re-entering the blood stream well beyond the typical duration of action, so in theory, there could be significant plasma concentrations well after cessastion. The longer half life would only help in maintaining constant plasma concentrations after cessation, and while still dosing on the drug, it could potentially complicate the issue of maintaining a therapeutic window.
 
So, after that 'duration of action' the drug is not excreted but bound to plasma protein and tissue - thereby not reaching active levels in the brain anymore... and that is the reason why you need more redoses a day - to keep active brain levels high enough?

Hmm if that is true, silly of me not to realize it until now - I always kind of thought that it would just make the drug more 'time-release' like, assuming that the drug will immediately be as bound/caught up in tissue after administration as it will ever be. Instead though, it will just follow its tendencies more and more over time...

Still, diazepam seems rather good for tapering - I still think that even if the above is true, active diazepam levels won't drop off *that* quickly, it and nordazepam lingering still seem to have significance otherwise the long winded decline would not have such effect.
Fyi, at most I got BID when tapering with diazepam.

And yes clonazepam is IMO very powerful, I can imagine it feeling very sensitive to not be covered by maintaining dosages - but while long durations for steady blood levels are important, you gotta face the music sometimes so like I said: it not feeling like 'quite enough' is also part of the taper?

How functional do you have to be these days? Cause withdrawing should be expected to be severely debilitating. Don't want to make you nervous but I feel obliged to tell you, cause I tried tapering and quitting all by myself while having a stressful job, and I couldn't sleep and it nearly destroyed me. Had to do it professionally.

If you notice that if you try such Heather Ashton tapering schemes yourself and feel that it is humanly impossible to bear especially if you have responsibilities to keep up, just check in and get the help you need and get it over with... I mean: be confident and quit, but don't expect to be superman, managing the impossible.
That said, everyone's mind and situation is different, so see what is realistic.
 
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My doctor cut all my meds.30mg diazepam a day for over 12 years. 20mg Prozac and 5-6 Percocet/day for 5-1/2years. I don't know what to do. I needed the anxiety medication the worst! PTSD and GAD. Any advice would be so greatly appreciated.
Buddyx
 
Wt actual f

that is so irresponsible of your doc...

I would phone any other possible doctor explaining your situation and that it's a medical fact that quitting diazepam or prozac cold turkey is likely to cause a withdrawal syndrome that can for a good part be avoided with tapering. Even if there is a valid reason why you would better discontinue treatment (in any case discontinuing two such psychiatric medications at the same time is always bad practice), it should always be with tapering - the diazepam with more increments than prozac, and the last tiny bit is the trickiest.. Stopping like this, abruptly and with 2 medications important to your condition will do more harm than good - and thats on your doc.
Continue phoning docs and shrinks (or have someone do it for you if you are too anxious or cannot find a temporary anxiety med solution) until you find one who is actually aware of this being unacceptable - get some help / advice from them how to solve it in terms of convincing your current doc or switching to another one, which seems like a good plan anyway... what a dick

(I mention 2 meds and not the percocet because technically withdrawing from that is just terrible and not the best plan in terms of cravings and relapse chances - I've been through opium withdrawal - but it's not really harmful. In practice though, I'd expect that it worsens the problems from stopping diazepam and prozac - which beyond terrible feelings are a real concern physically not to mention mentally.)

Good luck, I'm really sorry you are at the mercy of a douchebag.. :(
 
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Post#46:

'for any new drug'. But both clonazepam and diazepam are old drugs ... Not much is known, right ? In this country, clonazepam was introduced in the early 1970s ... Formal indication, epilepsy-only.

Let me guess ... for diazepam, the stated half life is the biological half life ? When Heather Ashton discusses the importance of the half life, she must refer to blood plasma levels. Which should be relatively stable after extended dosing. But let me guess, the blood plasma levels are probably relatively low after the 'duration of action' has passed.
Maybe that's also why she wants people to switch to once-daily dosing after a gradual crossover ? Taking diazepam TID does cause ups and downs ...
My impression is that accumulation of 40 mg daily (building up to 5-8 times the daily dose) would cause the presence of a massive amount of diazepam in the body, with relatively low blood plasma levels after the duration of action has passed.

Am I getting this right ? I need to give this some further thought.

Solipsis,

The pharmacokinetics of clonazepam are complicated. Aside from unknown issues, like whether the plasma protein binding is truly reversible (as has been stated), and unbound vs. bound fraction, the duration of action is long, period.

And for practical purposes, I am already low-functioning. They don't know how to do a real benzo detox here (aside from the issue that it's bad!), they load you up with diazepam and do a 6 week taper. They don't know how to do a pheno detox, they have no experience with clonazepam.

Note: Heather Ashton did not switch anyone from clonazepam to diazepam in her famous study. There are lots of claims, but in practice (experiences of other people) switching from clonazepam to diazepam seems to be more problematic than switching from other benzodiazepines to diazepam.
 
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What do you consider a 'real' benzo detox? Ashton as well as my experience here in The Netherlands at a what I would say was a good high quality clinic in the middle of what modest nature we have here (though perhaps not the pay yourself elite spa type)... the understanding is that you switch from any other benzo than diaz, to diazepam.

Do you mean pheno as in phenobarbital? I thought that was more old school for any GABAergic / sedative detox, in any case:

Results of a retrospective chart review of benzodiazepine-dependent patients undergoing inpatient detoxification showed that results with phenobarbital and a long-acting benzodiazepine were similar.
Click to expand...

http://www.medscape.com/viewarticle/823979

So I wonder what you mean by 'load you up' with diazepam. If loading up means attempting to find a diazepam equipotent to your clonazepam regimen and then tapering - then yeah that seems reasonable and normal.

So what problem remains?

Diazepam is not anxiolytic enough? (have you actually tried it?) So you insist on something with more overlap of effect, to avoid partial acute withdrawal when switching to the taper medication? (The 'incomplete cross-tolerance mentioned in the article')
 
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Normally, benzodiazepines should be tapered. A C/T at home can be done, as long as the patient is in good health and the dose is not too high.

A carbamazepine or oxcarbazepine detox or - assisted taper can be an option, even at home. A bit late for me, given my situation.

Detox is just detox. Getting the toxin out of the body. Making sure the patient doesn't die, avoiding medical complications and possibly alleviating suffering.
Why then loading people up with diazepam ? I don't know the specifics, but if you start out with 40 mg diazepam in the first week, maybe 30 mg in the second week you'll still have a lot on your system a few weeks later ! Meaning, the real detox starts at home. Again, assuming the diazepam was well-tolerated. I don't see the point in using a different benzo, acting in different degrees on different benzodiazepine receptors while rapidly changing the dose during a few weeks ! And given diazepam's accumulating aspects, it is just messy.

I am not in favor of a detox, but if you do it can it be done right ? What a local addiction doc called 'fast tapering' is basically some kind of detox. If you have been physically dependent on 2 mg clonazepam for years ... That protocol is not a real taper.
I know phenobarbital is not without disadvantages. A least it doesn't act on the 'benzo receptors'.

That's a good reference you have there (medscape).
The language used in the article is a bit messy. On the one hand, they use the phrase 'dependence'. Elsewhere, the word addiction is used.
'These substances are highly addictive' What do we mean by that ? Craving, uncontrollable dose escalation ?
'abused substance'. Really ? By whom, the 'patient' or a doctor ?
What is the sample population like ? Real patients, getting their drug prescribed or recreational drug users ? No offense to anyone, I can see why at least in some situations a 'detox' might be more appropriate for the latter group. When doctors manage to get their patients on 8 mg of Klonopin or 12 mg of Xanax a detox might be appropriate in some cases ...

I'm well-aware of the Ashton manual. I'm glad it works for some people. But not everyone tolerates diazepam well. And not 'all benzos do the same'. Although the Ashton manual refers to switching people from clonazepam to diazepam, she did not do that herself in even a single instance.

I have tried diazepam and it is very different from clonazepam. That's the short version. Almost a different class of drug. It is not about emotions (although diazepam can be depressing), it has very different physiological effects. I'm not sure how else to put it in a few words.

The Ashton manual calls phenobarbital detoxes barbaric - but why are diazepam detoxes not barbaric ? Not everyone tolerates the drug well, and actually Ashton doesn't call for a 'detox' but slow tapering.

Actually, the article refers to long acting benzodiazepines. My guess is that something typical is going on here, confusing 'half life' with 'duration of action'. Switching from midazolam to diazepam may be stabilizing. Switching from a long acting drug like clonazepam to diazepam ? ...

Maybe this has been off topic ...
 
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Yes, my taper took a 8 week stay! It's REALLY shitty but it appears that's how it is with withdrawing and resetting your GABAergic system. You make it not only sound very bad (which it honestly is), but also like there are alternatives. If there would be a way around it then I'd be killing a few people over why in the relatively developed western country I live in, they are not up to date.

But yeah I understand if it's about diazepam being too different from clonazepam - so indeed the incomplete cross-tolerance. They might try to compensate for that by giving you a relatively high diazepam dose and theoretically it should work. I guess that would be the 'loading you up', for real.

What other options do you have? Have someone administer you your daily doses like a mailman? I wouldn't recommend trying it on your own, I don't know if I would have made it - probably not enough self discipline since it takes an agonizingly long time - that's a long tension curve to withstand during w/d assault.

I personally used up to 13 different benzo's including clonazepam before I quit, but I never took them recreationally - just wanted to try a lot and use each one 'appropriately' for what I thought would be most fitting for my symptoms. I didn't really go over 2-2.5 standard doses, and that is due to, but also despite tolerance which could have really shot me up so much higher in dosage if I let myself go with abuse.

Was aware of incomplete cross-tolerance, they didn't put me on unreasonably high diazepam - perhaps just reserved with regard to estimated equivalency... but I found that coming off the last bit was somehow hardest, more challenging, while in the start it was devastating but I was cared for and it was doable to get myself through it.

If you know they can care for you professionally if you have complications when switching, but I don't really know about switching becoming a really serious problem - just hard.

So what is the consideration you have left, realistically?

Not trying to persuade you even if it seems like that - it's cause you suggest many problems but I wonder about the solutions. It doesn't sound like you can keep postponing, so what options are you left with?

Addictiveness of a drug refers to the tendency of the drug to cause dependency with repeated use. Whether people abuse it recreationally or get them prescribed, that is not the point here - they end up in a similar way: dependent and in this case in taper/detox programs. We ignore for now that drug abusers and patients dependent from scripts have different motivations, but it may be more subtle than we think sometimes: self-medication, or professional medication still based on the patient having a problem that asks for medication. I think that abusers and self-medicating people may be more at risk to relapse due to circumstances, bad things happening or feeling particularly bad... patients with chronic problems may feel a more constant structural issue pressing. Internal or external triggers have different challenges, it depends which one is more serious.

In any case I wouldn't worry about wording in the article, or the semantics. It's not really the point I think, besides it is not personal and nobody is saying anything about whose fault it is - the patient's, the doctor's, the junkie's, the system's, the random bad things that happen in our lives or our psychiatric conditions.

"Detox" is getting clean, for most other drugs - as I experienced in the clinic - it's a lot faster and it's the first week or so that people are not bothered much with things and are given rest to get the drugs out of their bodies just waiting over time. I was an exception, doing that long a taper. So yes the terms can be confusing here since with benzo's the timing doesn't apply just like a number of other aspects.

No doubt about it though: I am glad I did it and it gave me strength and self-confidence, and I averted disasters for my health since other drug abuse came to a stop, incidentally or no - my main reason for going there was inability to taper and quit at home while desperate and answering to responsibility for a job etc.
 
Addiction vs dependence, that can be a sensitive issue. I don't want to make an issue of it, but it there really is a difference between people having a strong physical dependency because they were prescribed the drug at 'therapeutic' doses for years, and people who cannot control themselves and go on a binge, crave the drug and have no self control.

I didn't 'buy' the drug (although the pharmacy doesn't give it away for free) and while the original dose was lower it has not been increased for a very long time. Intermittent use is actually much less likely to cause serious dependence than long term daily use.

I would say that 2 mg clonazepam is way beyond any standard dose - for someone who doesn't suffer from epilepsy. The 'equivalent' dose is 40 mg diazepam, although clonazepam is much stronger in some regards. Anyway, I think that if I were to do that - and some addiction doc offered me a three week inpatient detox- it would be a disaster. Clonazepam being so unique and such. While in theory that could load me up with megadoses of diazepam, there are strict protocols and obviously the real withdrawal would begin at home, even if the diazepam was tolerated easily ! Another local addiction doc was honest and claimed a 30 % success rate. Anyway, they have NO experience with clonazepam at all. And very, very little with detoxing benzodiazepine 'patients' in inpatient settings.

'What other options do you have? Have someone administer you your daily doses like a mailman?' What do you mean ? Daily doses of what ?

Of course, the real objective is recovery. In some ways, it seems that the 'protracted benzodiazepine withdrawal syndrome' has already begun.
 
I'd like to get back to post #50, in particular the section that I marked bold. Am I getting that right ? Any comments ?
 
I don't think that's right...

If what you say were true and after 12 or less hours of 'action' the blood levels would be very low - then how come after up to 100 or more hours still half is found in the blood (after the biological half life i mean), the long half life means that it takes that long for the blood levels to halven so in 12 hours or maybe 1/10th of that half-life blood levels are still high. Maybe up to 97-98% is blood protein bound, reversibly - but I am not sure how quickly this happens, I think it wouldn't take that long after distribution.
While for some drugs it is perhaps a real issue of bioaccumulation (with a long taper it should be fine as long as you don't suddenly burn a lot of bodyfat?), but for the most part I think that even besides bioavailability, often only a small portion of administered drugs make it to the brain (especially with oral - enteral use), I think for LSD the part that makes it of that already absolutely miniscule dose, is even tinier. But that is apparently how little it takes.

So seems like a common thing with drugs, partially accounted for as a standard phenomenon.

Maybe what you call the short duration of action has the best noticeable effects, and those may feel positive relieving or satisfying... but I guess that is just the short period after administration of a slight upswing before you are on that very slow steady decline again, tolerant to the initial effects and only left with therapeutic maintenance.

I think you are strongly exaggerating in your understanding or interpretation - at least from what I know/understand personally - in that you would get mega-dosed and most would just be lost somewhere in your tissue and inactivated.

With such long half-life and relatively small dip in (pretty much steady state) levels after 24 hours, once-daily dose of diazepam is enough - there is just no point in 3 times a day that I know of, so is there an issue?
 
Slow_Mobius, I would appreciate that.

Solipsis,

That 100 hours number probably includes desmethyldiazepam. And actually, for as far as I know the acute effects of a dose of diazepam hits the brain massively but only for a short time.
In my case, the clonazepam has a really long duration of action, pretty much a full 24 hours. You can't beat that.
'With such long half-life and relatively small dip in (pretty much steady state) levels after 24 hours, once-daily dose of diazepam is enough - there is just no point in 3 times a day that I know of, so is there an issue?' If that were true, I could take a huge bolus dose, and then switch to diazepam taken once a day.

Most sources don't state clearly if they refer to the biological half life or plasma half life of diazepam. I've seen the phrase, 'terminal half life'. I'm not even sure if the authors are aware of the differences (using old sources, it was much easier to introduce drugs in those days).

What people 'feel' subjectively is not relevant here. As long as I continue to take the same dose of clonazepam I would still feel some subtle effects of a 30 mg dose of diazepam 24 hours later.
 
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If I were to look for a replacement benzo for clonazepam that has at least a medium duration of action, besides the RCs the following benzos are available where I live:

Flunitrazepam (it's a hypnotic and I assume it is not suitable), several other hypnotics that I skip: oxazepam (6-7 hours with a peak of 3 hours, mild after effect), lorazepam, alprazolam (including XR), bromazepam (duration of action ??), Librium, Tranxene, diazepam, flurazepam (hypnotic?), prazepam, clobazam. And clonazepam, obviously. Or possibly, I might be able to import something from another country in the EU.
Aside from sources, contamination, supply issues, one disadvantage of taking a RC on my own that I can get into difficult situations if I had to tell a doc that I had been taking a RC. (other health issues)
Any suggestions at all ? If I were to switch to a different benzo I would prefer a benzo with a medium/long duration of action, that does not accumulate (much).
 
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