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

PINKoPANaTHER and Pharmokinetictal,

I appreciate that but clonazepam is such a gruesome drug ... I'm fairly sure that my health is in play as well, although I'm not sure what exactly is going on. And the drug has a nasty effect/side effect profile, 'mixed' if not paradoxical effects. Pharmacokinetics/ probably plays a role as well.

The point is that clonazepam is my problem drug. It's not easy or neutral by any means.
Regarding subunits: I already have full tolerance/dependence to clonazepam. I have full tolerance to the hypnotic, amnestic and sedative effects of lorazepam. Diazepam still has some sedative properties, I have taken it for only a few days.
I'm very sensitive to when I take the clonazepam, I have to take it in the evening. It's a hardcore dependence ...

'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.'
Diazepam's half life, at the top of my head, 1-2 days ? Long enough. 'duration of action' is a different matter. It seems to matter for some people, not for others.
It is dirty, though. It indeed accumulates up to 5-8 times the daily dose (I guess that makes for an 'effective' half life that is longer?), which makes it difficult to adjust the taper. The desmethyldiazepam also accumulates into fat, and indeed desmethyldiazepam/diazepam together tends to require very slow tapers, with difficulty in making adjustments. And what if you lose body fat ? ... Release of 'benzo' Btw, nordiazepam=desmethyldiazepam ...
Any opinions about Tranxene ?
 
Flubromazolam?

or maybe Flubromazepam...
Flubromazepam lasts for 3 days, or so I have read.
 
Firstly, thank you, kdem for the naming correction--you are correct and I should know better. Nonetheless!

Yes Clonazepam sucks due to its highly unique molecular composition/active substituent--the 7-Nitro group. Regarding CLZ coming in 'two forms,' I have never heard of that. the NO2 group has resonance through redisribution of its negative charge on its oxide and positive Nitrogen. Because that benzene group cannot rotate, there are technically 'two' forms that exist in equilibrium--but as far as I know, they make no difference.

Unfortunately, most doctors are idiots--as is our FDA and DEA and pharmacists. BZDs have over 40 derivatives and we limit ourselves to the use of essentially 4: diazepam, lorazepam, alprazolam, and clonazepam. Occassionally we get temazepam and oxazepam, but the former is dangerous and the latter is junk. Clorazepate and chlordiazepoxide are generally replaced by diazepam in prescriptions. So, there aren't really any 'long acting and fast onset' BZDs with an elimination half life perceivably equal to its therapeutic one. I remember doctors giving me valium and saying "oh yes the half life is 200+ hours!!, so you won't feel a thing." And the FDA caps the daily dosage of DZP at 40-60mg despite the fact that an equipotent dose of CLZ is ~ 10mg DZP: 0.5mg CLZ. And you can't get 80mg of DZP.

So having been daily a user, binger, and poly drug abuser of BZDs with strong opioids for 6 years, it took a long time to get it right. And for me...I realized I had two goals:
1) Get off Clonazepam without experiencing protracted withdrawal syndrome
2) Don't try to 'feel' the drug again because then I'll never succeed. I had to taper slowly enough that once I was good and dependent/tolerant (way past cognitive addiction...just pure dependence on what now felt like a sugar pill), the aim was to maintain that disappointing feeling of no-effect at every dose drop along the way in the 7-8 months it took me to get off it. If you felt high from it, your tolerance is reversing, but that's not good because it means you're taking too high a taper dosage. If you feel like youre about to have a seizure, then you're going too fast. It's different for everyone. I had to play mine by ear and I was always 2 weeks behind my doctors schedule, but he trusted me to listen to my body. I used to take all 4mg CLZ in the morning when I woke--so I also tried tapering the same way. It was a disaster 5 times in a row.

Then I spread them out over an 18hr period with a minor 'dose dump' in the morning as I described in my earlier post and it worked. From November, 2013 -- June 2014, I did this..dropping 0.25mgs every 2 weeks. I made sure I either had brand name Klonopin or the generic TEVA brand (which is the best). A lot of doctors and pharmacists will deny that generics are different. But the FDA stipulates that any generic medication can have +/- 25% of its active ingredient in the pill. That's shameful. So for someone needing careful regulation of their declining dosage, the fact that Rite-Aid carries the Purepac generic (which feels markedly different than Teva because their 2mg tablets legally contain only 1.5mg) is a bit perturbing and will end up in the doc office 1-2 weeks early asking for a refill they think you abused. So in summary, I think it's best to stick to CLZ or witch to either CLZ or lorazepam (intermediate duration) for any BZD taper and research the best generic companies and which pharms use them :)
 
I think Kdem is talking about why drugs are weak acids or bases. Kdem, this isnt really two separate forms of a drug, just that most drugs are either weak acids or bases because they are only partially ionized and partially not depending on the pH of where they are in the body. Drug need to be able to both disolve in biologic fluids and pass through cell membranes and the ionized form dissolves better and the unionized can permeate membranes more thoroughly.
 
The pharmaceutical industry should really develop a long-acting depot injection formulation of a benzo or other potent GABA-A positive allosteric modulator, possibly a decanoate ester of a neuroactive steroid or potent benzo that has a hydroxy group in its structure (just like decanoate and other long-chain carboxylic acid esters of testosterone and some antipsychotics are used as depot injection). There are lots of people who have comorbid severe anxiety disorders and addictive tendencies and can't be given benzos in pill form to control their anxiety because they would just compulsively pop the pills and abuse a months worth of benzos in a week, running out of the meds early and run a risk of seizures when they go in withdrawal. If the anxiolytic could be administered by injection once a month, in a controlled setting, there would be much less risk of abuse. Preferably the pharmacokinetics of the formulation would be such that the injection maintains a steady blood concentration of the drug for a few weeks, and then the concentration would drop slowly enough to prevent significant withdrawal.

Actually, a depot injection form of buprenorphine has already been developed so that opioid maintenance patients would not have to go to the addiction clinic every day to get their dose: http://www.ncbi.nlm.nih.gov/pubmed/16499515 . This idea has just not yet been applied to other meds with abuse potential, namely benzos and dopaminergic ADHD meds (pipradrol decanoate, anyone?).

Maybe I should write a scientific article about this idea and publish it in Medical Hypotheses to be able to claim intellectual property if someone actually develops a depot injection benzo.
 
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polymath said:
The pharmaceutical industry should really develop a long-acting depot injection formulation of a benzo or other potent GABA-A positive allosteric modulator, possibly a decanoate ester of a neuroactive steroid or potent benzo that has a hydroxy group in its structure (just like decanoate and other long-chain carboxylic acid esters of testosterone and some antipsychotics are used as depot injection). There are lots of people who have comorbid severe anxiety disorders and addictive tendencies and can't be given benzos in pill form to control their anxiety because they would just compulsively pop the pills and abuse a months worth of benzos in a week, running out of the meds early and run a risk of seizures when they go in withdrawal. If the anxiolytic could be administered by injection once a month, in a controlled setting, there would be much less risk of abuse. Preferably the pharmacokinetics of the formulation would be such that the injection maintains a steady blood concentration of the drug for a few weeks, and then the concentration would drop slowly enough to prevent significant withdrawal.

Actually, a depot injection form of buprenorphine has already been developed so that opioid maintenance patients would not have to go to the addiction clinic every day to get their dose: http://www.ncbi.nlm.nih.gov/pubmed/16499515 . This idea has just not yet been applied to other meds with abuse potential, namely benzos and dopaminergic ADHD meds (pipradrol decanoate, anyone?).

Maybe I should write a scientific article about this idea and publish it in Medical Hypotheses to be able to claim intellectual property if someone actually develops a depot injection benzo.
Click to expand...
The problem with your idea is that benzodiazepines are not approved for long term use. In fact, the current medical consensus is that they shouldn't be used
daily for long periods, although it does happen. The FDA won't approve a depot version of a drug that is not approved for long-term use.

By contrast, buprenorphine is supposed to be used for months at a time. There are also medical concerns about compliance that make depot buprenorphine a good idea (i.e., the depot formulations make it difficult to discontinue buprenorphine on the spur of the moment in preparation for relapse).

Depot administration of stimulants is a horrible idea -- not sleeping for a month is a good way to induce stimulant psychosis.
 
^ Yeah, here in Finland benzos are recommended for at most 3 weeks use too. In practice, however, there are lots of people who have been on benzos for something like 10 years. Lyrica is approved for long-term use for generalized anxiety disorder, and it too has abusability problems involved, but unfortunately the potency of pregabalin per milligram is so low that it wouldn't be feasible to inject a months dose of pregabalin at once.

Is it really impossible to have a constant small concentration of a stimulant in one's blood, that would be sufficient to relieve ADHD symptoms but not large enough to prevent sleep?
 
polymath said:
Is it really impossible to have a constant small concentration of a stimulant in one's blood, that would be sufficient to relieve ADHD symptoms but not large enough to prevent sleep?
Click to expand...
Some people that take ADD medications have problems with insomnia. If the dose is high enough to relieve symptoms then it will keep some people awake.

Stimulants aren't needed when people are sleeping. The goal is to expose patients to the smallest amount of drug possible while sill relieving symptoms.
 
Thats basically what I was saying, Kdem. When it is in open ring form at low pH as in the stomach, they are more polar and absorption would be poor. But fortunately absorption occurs in the intestines where pH is higher and the surface area is so much larger it overcomes any drug that still may be ionized (the pH increases as you move down the small intestine, the duodenem is still slightly acid so some will remain in open ring form). But the pH of the blood is about 7.4, so most will be in the closed ring form and be able to penetrate the membranes of tissues.
 
polymath said:
The pharmaceutical industry should really develop a long-acting depot injection formulation of a benzo or other potent GABA-A positive allosteric modulator, possibly a decanoate ester of a neuroactive steroid or potent benzo that has a hydroxy group in its structure (just like decanoate and other long-chain carboxylic acid esters of testosterone and some antipsychotics are used as depot injection). There are lots of people who have comorbid severe anxiety disorders and addictive tendencies and can't be given benzos in pill form to control their anxiety because they would just compulsively pop the pills and abuse a months worth of benzos in a week, running out of the meds early and run a risk of seizures when they go in withdrawal. If the anxiolytic could be administered by injection once a month, in a controlled setting, there would be much less risk of abuse. Preferably the pharmacokinetics of the formulation would be such that the injection maintains a steady blood concentration of the drug for a few weeks, and then the concentration would drop slowly enough to prevent significant withdrawal.

Actually, a depot injection form of buprenorphine has already been developed so that opioid maintenance patients would not have to go to the addiction clinic every day to get their dose: http://www.ncbi.nlm.nih.gov/pubmed/16499515 . This idea has just not yet been applied to other meds with abuse potential, namely benzos and dopaminergic ADHD meds (pipradrol decanoate, anyone?).

Maybe I should write a scientific article about this idea and publish it in Medical Hypotheses to be able to claim intellectual property if someone actually develops a depot injection benzo.
Click to expand...

They already have transdermal patches of buprenorphine and methylphenidate. They are probably better than a depot injection for the reasons serotonin2a said as well as ease of administration.
 
Pharmacokinetical,

'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 have never heard of this anabolic effect that would help redistribute the drug. Do you have any information about it ?
Any ideas about Tranxene vs. diazepam ?
I just don't know if I can do clonazepam directly, and I never recovered from the attempted taper by means of lorazepam, which was more hypnotic, sedating and had stronger amnestic properties.
 
Ok, let me finish. First, regarding redistribution at night, I too would be interested in seeing these results. I know that there has been studies done regarding time-dependent kinetics (chronokinetics) of diazepam and midazolam, but cannot find any info on clonazepam. I will use diazepam to illustrate some of the effects of time of administration. In IV and oral dosing, cmax was higher and tmax was shorter in morning vs evening doses. But free fraction (% unbound to plasma proteins) did increase at night, which is suggestive of distribution affecting the PK parameters (it was shown absorption and elimination werent the culprits for reasons I wont go into). This correlates well with known circadian changes in levels of plasma proteins with more circulating during the day then at night. Less circulating protein means less binding of drug to protein and thus increased free fraction. But this may have relatively minor effects (the actual total plasma concentration and free concentration were still higher in the morning despite %unbound being increased at night in one of the studies). It seems this increased free fraction and thus distribution in general would only be relevent in regards to the chronokinetics of drugs that are highly protein bound and have small Vd or a narrow therapeutic index, which really describes no benzodiazepine. I cannot find much more than this and nothing for clonazepam so would be interested.

Now onto accumulation. I am going to assume steady state, which may not be true but with help explain. The equations for steady state kinetics of oral dosing are as followed:

Css=AUC/t

AR= 1/1-e-kel*t or AR= AUCmd/AUCsd

with Css being concentration at steady state, AR the accumulation factor, kel the elimination rate constant, t the dosing interval, AUCmd the AUC after multiple doses and AUCsd the AUC after single dose (you could also use Cmax or Cmin in place of AUC.

If you look, t is in the denominator of two of the equations and it is the variable as AUC is an observed data point (it can change obviously but wont for a single observation) and kel is a constant either derived experimentally or calculated from other data. This is important as only the frequency of dosing will affect both the Css and the AR. With Css its pretty obvious. A shorter t gives you a larger Css. But its a little less obvious with the AR. Again though, a shorter dosing frequency leads to greater accumulation. So in essence, you can minimize how much drug accumulates by taking doses further apart. With a taper as you want, you would have to be extremely careful as too great a t, would lead to less plasma concentration potentially inducing withdrawal. But as others have mentioned, the PD of benzos also is important with tolerance, down-regulated receptors and the like potentially offsetting a lower plasma concentration but it is difficult with benzos as there isnt really an agreed on plasma concentration for therapeutic monitoring and tolerance plays a huge role.

The second equation for AR is one that can calculate the amount of accumulation from measured blood sample and a little math. This is useful as you will always be able to draw blood and measure levels and the kel may not be known making the first equation useless but also you could calculate the kel after getting the AR from the second equation.

Just to be thorough, these equations, while extremely useful, are rather idealistic and drugs including benzos behave in ways that require different models and mathematics. Remember back to the two compartment model I talked about and how the compartments dont necessarily equate to physiologic organs. Well benzos still fit at least a two or three compartment model which has consequences on accumulation and distribution.

I was going to talk about rates of distribution, but think it is better to discuss them here, in terms of accumulation. I threw up that equation that you said you werent going to learn. I agree, I dont know it by heart but can see the usefulness of its components. All the k's, k10, k12,k21 etc are the micro rate constants of distribution between compartments. k12 is the rate out of the central and into the peripheral compartmemt while k21 is the rate from the peripheral back into the central. These are not necessarily the same. In the case of benzos, the k12 is probably much greater than the k21. This goes back to the lipophilicity of benzos (yes they vary and clonazepam is one of the lower but compared to other drugs it is still very lipophilic) and how adipose tissue behaves as a sink. This is quite obvious (although I do not think modern kinetics would use the term sink, it suits us fine though) from looking at the Vd of benzos in obese people. Because they have increased adipose tissue, the amount of benzos distributed to the fat increases and the rate at which it redistributes back to the blood is slower in the obese. So yes, even though clonazepam is a lower lipophilic benzo, it is sufficiently fat soluble to still distribute extensively into the fat.

But what does any of this have to do with accumulation? Well, a lot. Since the rates into a compartment can be significantly higher than the rate out, more drug can accumulate there. It may take days, weeks or even months for equilibrium to be reached between a peripheral compartment and the central. And with each new dose, more drug is pouring into this compartment than is being redistributed out, which leads to accumulation. There are equations for this, which I would be more than happy to post after I look them up (Im not a PK genius by any means) but I dont think you would get any more insight into accumulation from them without studying them and knowing how they are derived.

But an example may be helpful. There is a drug for cardiac arrhythmias called amiodarone. It is a narrow therapeutic index drug and quite nasty stuff with thyroid and pulmonary toxicities. It is quite lipohilic and generally dosed once daily. Its kinetics has been described by a four compartment model. One of the compartments is indeed the adipose tissue and its measures of accumulation are about 20 times higher there than in any of the other three compartments and takes about 100 days to reach equilibrium. This is very important with this drug because some off the toxicities do not manifest for months after starting therapy and could very well be attributed to the slow rate of distribution and high amount of accumulation in the adipose tissue. Remember, unlike benzos, amiodarone is a narrow therapeutic index drug, so the small amounts redistributing back into the circulation from the huge amount accumulated in the fat could explain such long times for these side effects to occur.

I think that is it. There is much more I didnt even really touch on like elimination rather than redistribution from peripheral compartments, how much protein binding has an effect on a drug's kinetics (could be a lot) or dynamics (usually minimal) and more advanced PK-PD modeling. And worst of all, I barely mentioned clonazepam at all. But let me say this about Klonopin. I do not think it is all that different than most benzos and we can calculate all the kinetics and infer all we want on how they may affect its dynamics. But in the end, you are the best judge of how any drug hits you. Go as slow as you need to taper. Assuming you have access to the drug, does it matter if it takes a day, a week, or a month or more? I dont think so.
 
Thanks, this has been an interesting and complicated thread. If anyone wants to add something I'll read it.
It's just that I don't see how to taper clonazepam directly, given the whole effect/side effect profile, health, pharmacokinetics/pharmacodynamics and whatever else may be going on. Not a 'vanilla' taper, anyway.

Kittycat5, if you feel like finishing that Tranxene thread ... I understand if you're done.
 
The Ashton Manual is what you want to read. http://www.benzo.org.uk/manual/

Depending where you are, Diclazepam are x10 diazepam used in an acute manner, but the metabolites build up so on chronic administration, it's x15 diazepam as I have found out. I got down to ½ a 2mg tablet [BID] only to find that 10mg diazepam [TID] was required. I sent off to 2 sites for the 1mg tablets and both times they were blank and in any case, even cutting the 1mg ones in half, you still have a big drop at the end so, frankly, I fessed up to my GP who read the info off the patents and agreed to help me down with yellows and whites.

My only caveat is that the clobazam entry is plain WRONG. 1,5-benzos bind at a different junction as I discovered when swapping from clonazepam to clobazam for epilepsy. I took the trouble to tell both her and the neurologist and neither knew and whoever is actually running the site hasn't bothered to add the data... hope this is of use to some people. Never break rule 1
 
Kdem said:
Thanks, this has been an interesting and complicated thread. If anyone wants to add something I'll read it.
It's just that I don't see how to taper clonazepam directly, given the whole effect/side effect profile, health, pharmacokinetics/pharmacodynamics and whatever else may be going on. Not a 'vanilla' taper, anyway.

Kittycat5, if you feel like finishing that Tranxene thread ... I understand if you're done.
Click to expand...


I will. I need to read it closer first. I think its essence says it accumulates similarly to diazepam though. Tonight I will read again.
 
I honestly do find all of the information in this thread useful and interesting, but I will state my concerns again... all this talk of theory surrounding effective half-lives and duration of action is not going to do a bit of good until you attempt to taper. There is such a thing as a titration-taper where one drug is added slowly (titrated) concurrently to another that is simultaneously tapered, where you slowly add the new drug until you stop taking the first one - this could ease your switch from clonazepam to another benzo. Both Chlordiazepoxide and Chorazepate have long half lives (but also build up with prolonged use) which makes your plan theoretically difficult as long half lives usually (and i mean USUALLY) means a build up of either the primary drug or active metabolites.

BUT - If you are really seeking to taper off of all benzos completely, or switch to a lower dose of another, you'll have to either have regular appointments with your doctor to regularly switch doses/drugs (especially if you do a titration-taper followed by a taper) or source RC benzos online and volumetrically dose out your meds with 0.02 to 0.05 mg drops a day (equaling either 1mg per 50 days or 20 days depending on what you can handle).

The key is to take action and quit debating the proper substitutes, because only you can find what works for you (I LOVE temazepam, diazepam and flubromazolam where many people hate or get nothing out of them, or just cannot use them to taper - specifically diazepam in your situation). Until you have tried other substitutes to taper with, you will be stuck, but I think things would go easily if you use a titration-taper to gradually decrease your clonazepam while increasing to an equivalent or slightly higher dose of the drug which you will ultimately taper off.

Again good luck with this, and I'd like to know any progress if you would please (i.e. new benzos used, dosage drops, doctor comments, anything regarding this) I have tapered off benzos at least 4-5 times, but usually only after binges of a few to several months (at extreme doses equivalent to 20-40mg clonazepam). So I am a little interested in the outcome. If my research institution will fund it I may try to author a paper on benzo dependency and withdrawal, discussing chiefly the successes and failures of different tapers, CT detoxes with seizure meds, varying drugs etc.)
 
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Clubcard and PINKoPANaTHER,

I recall having read about a problem regarding substituting 1,4 benzodiazepines with 1,5 benzodiazepines. But is it absolutely impossible ?

And no offense, but there are so many things that are wrong with the Ashton manual. Like the complete omission of the concept of 'duration of action'. And a bit about Klonopin (clonazepam) vs Valium: ''All the benzodiazepines are non-selective and act on all types of GABA/benzodiazepine receptors. Valium acts on exactly the same receptors as Klonopin etc.' At the very least there are relative differences. Also, I have found statements about Klonopin binding to receptors that other benzodiazepines do not bind to.

'The main reason that benzodiazepines have somewhat different structures is not so much that they act on different receptors (they don't) but so that the drug companies can call them different drugs.' Nonsense.

'Binding of clonazepam to receptors that do not bind to other benzodiazepines and action on sodium channel conductors are relevant to anticonvulsant effects, not tranquillising effects.' So what ? I don't have an anxiety disorder.

'Since clonazepam has a relatively short half life, from 18 to 50 hours' Are you kidding ??
Source: http://www.benzo.org.uk/ashvtaper.htm
There are other differences as well. And in her crossover schedules she has patients taking clonazepam three times a day, who are gradually switched over to the 'long acting' diazepam.
In her famous (n=300?) study in which she switched people to diazepam, zero subjects were on clonazepam.

It seems that in the real world many people who are on clonazepam have great difficulty switching to diazepam.

About titrating one drug to the other: in my very limited experience mixing diazepam with clonazepam causes problems. Hard to put in a few words. In some respects diazepam greatly potentiates clonazepam, or the other way.

From a practical point of view: there are very major issues tapering clonazepam (health issues, not being able to 'function'), a diazepam taper would have to be 'forced' (is not dying enough?), Tranxene ?? I wish I had done a C/T a few years ago, before my health was so messed up. I followed bad medical advice, and have healthcare from the stone age.
At least the French got it right when they banned clonazepam in 2012: https://fr.wikipedia.org/wiki/Clonazépam
 
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I need to get some things straight here... I am not recommending anything based on the Ashton Manual. I am a moral relativist, and think anything treated like a bible (the big book of AA for example) is bound to become out of date and ultimately damaging when people try to get years old information out of it. Had she had access to many of the RC benzos brought back to market, it would be a different story, plus there are other partial agonist now (I can't remember the name off the top of my head - I will look it up) so you take what you can from it but do not treat it as sacred or the only possible way to do it.

Most importantly, what all drugs, dosage schemes, taper plans etc. have you tried? I still stand firm on my advice that the only way to proceed is to try a few things you haven't and committ to a certain time period you'll try it for - as your individual body chemistry is unique and substantially different from many of us on here based on all reports of your trials. I think you brushed off the siuggestion to try flubromazepam and diclazepam, but have you tired them? All of us could provide better advice/experience if you gave a complete history of everything you've done to try and get off benzos (in a brief format). If you are so stuck you won't try anyting new to attempt to get off, I have to be blunt and say maybe you're better off sticking with the benzos for life, as some do it with success if there is no abuse involved.

Please take action on your own behalf and let us know how it goes (along with history of attempts - oh, and try the taper-titration, I kicked a 120mg/day temazepam habit by taper titrating to an equivalent clonazepam dose then dropping that as quickly as was safe, total time ~2-3 months for the whole process, but that's just the way my body works)

{Edit} - Though not the drugs I was thinking of - Pagoclone and Bretazenil are chemicals that do not have the tolerance and withrawal liability of full agonist benzos, as they are partial agonists that have been shown to substitute for diazepam in dependent non-human primates. Not sure on if they are approved for marketing yet, but just something to consider when discussing the contemporary value of the Ashton Manual (not hating on it, just pointing out things change with time...)
 
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Kdem said:
PINKoPANaTHER and Pharmokinetictal,

I appreciate that but clonazepam is such a gruesome drug ... I'm fairly sure that my health is in play as well, although I'm not sure what exactly is going on. And the drug has a nasty effect/side effect profile, 'mixed' if not paradoxical effects. Pharmacokinetics/ probably plays a role as well.

The point is that clonazepam is my problem drug. It's not easy or neutral by any means.
Regarding subunits: I already have full tolerance/dependence to clonazepam. I have full tolerance to the hypnotic, amnestic and sedative effects of lorazepam. Diazepam still has some sedative properties, I have taken it for only a few days.
I'm very sensitive to when I take the clonazepam, I have to take it in the evening. It's a hardcore dependence ...

'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.'
Diazepam's half life, at the top of my head, 1-2 days ? Long enough. 'duration of action' is a different matter. It seems to matter for some people, not for others.
It is dirty, though. It indeed accumulates up to 5-8 times the daily dose (I guess that makes for an 'effective' half life that is longer?), which makes it difficult to adjust the taper. The desmethyldiazepam also accumulates into fat, and indeed desmethyldiazepam/diazepam together tends to require very slow tapers, with difficulty in making adjustments. And what if you lose body fat ? ... Release of 'benzo' Btw, nordiazepam=desmethyldiazepam ...
Any opinions about Tranxene ?
Click to expand...

I don't know why you are so against Clonazepam and Diazepam. I find them to be the best benzos for anxiety and i have been taking Clonazepam for over 10 years to treat my anxiety, Trigeminal Neuralgia and Mania with little to no problems. I can go about 2 days without taking a dose before withdrawal symptoms really set it so missing a dose for me is not a big problem even though i am on 6mg's a day. Clonazepam can be used for tapering in some people as it has a medium half life of 48 hours but this like everything else varies from person to person. I have had to get by a few times on lower doses of Clonazepam and i have not noticed a huge difference in dropping a mg or 2 for a few days to a week. Though i don't seem to be very susceptible to Benzo withdrawal anyway.

Valium's metabolites Nordiazepam, Temazepam and Oxazepam have a half life of about 200 hours when they build up and this is the reason why Valium is often the benzo of choice for tapering off other benzos. While Chlordiazepoxide has a long half life as well and is used sometimes for tapering but since it's active metabolites are responsible for it's long half life i don't see the difference between it and Valium. Also Librium's low potency is a problem especially if tapering off high potency benzos such as Clonazepam or Alprazolam.
 
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