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Does tolerance/dependence build slower to partial agonists compared to full agnonists

K

Kdem

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Mar 14, 2015
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In particular benzodiazepines,

In particular comparing clonazepam and diazepam on the one hand (full agonists) vs. desmethyldiazepam (as in Tranxene) which is a partial agonist ?
What I've read is rather mixed. 'it doesn't matter' vs. 'much slower'
 
I will try to find what my textbook said later but what I recall was that concerning chronic administration of things that bind to the benzodiazepine site there is some sort of change in the ratio of the different subunits that creates a borderline permanent tolerance to benzos (but no tolerance to endogenous GABA), and the authors of the textbook thought that this might not occur with partial agonists.
 
Found the entry in my book, "The molecular mechanisms that underlie tolerance and dependence elicited by benzodiazepines are still not understood despite a great deal of research. Tolerance and dependence likely are not associated with changes in total levels of GABA-A Receptors, but may involve altered phosphorylation of receptor subunits, altered subunit composition of the receptors, or adaptations in any of several other neurotransmitter systems."

I sadly cannot find any studies to support this but the book itself is written by prestigious authors and is titled "molecular neuropharmacology, a foundation for clinical neuroscience"

I also sadly can't find anything regarding partial agonists. But I could tell you from theory that if the benzo tolerance is permanent then even if a partial agonist somehow did not build tolerance in the same way you would still be hindered by the tolerance that is already present.
 
Heya,

I'm not sure about benzos - I don't know a lot about partial vs full agonists working the GABA pathway...however...I have considerable experience with opiates and have also observed a lot of opiate activity among associates.

The most commonly used partial opiate agonist is buprenorphine (Subutex, Suboxone). Apologies if you already know this...

I have noticed that when I have used Subutex (or Suboxone), my tolerance builds incredibly rapidly.

For example, if you can get high on 2mg, you will need 4mg after about 4 or 5 days. Then 8mg four days later. Then 16mg. Before you know it you can be on the maximum dose of 32mg and you won't feel a thing.

Compared to methadone or morphine or oxycodone this is just plain strange.

So, with opiates at least, it *seems* partial agonists build tolerance faster.


​Peace :)
 
'I also sadly can't find anything regarding partial agonists. But I could tell you from theory that if the benzo tolerance is permanent then even if a partial agonist somehow did not build tolerance in the same way you would still be hindered by the tolerance that is already present.'

True.

However, I am dealing with a practical issue.
The dependence and tolerance on/to clonazepam is already there. Diazepam is mostly a different drug. It feels and acts as if it is.
When I tried that foolish lorazepam taper, it went fine till I developed tolerance/dependence to its sedative, hypnotic and amnestic properties. After that, it went to hell.

I am very, very concerned about 'quitting' clonazepam, developing tolerance/dependence to/on diazepam and being even worse off ! Not to mention that I find diazepam a nasty, dirty, messy drug than again is quite different than clonazepam. And 40 mg is not a low dose.

(tapering directly is an issue (!), if possible it would likely be some forced bizarre taper)

So, I have been thinking about Tranxene (desmethyldiazepam). My guess is that it is 'weaker' than diazepam (sedation), it's still a somewhat dirty drug (accumulation, but less so than with diazepam).

I'm just wondering about (and worried about!) the developing tolerance/dependence part.

For me, 'a benzo is not a benzo'.
 
I think you consider using a sodium channel antagonist or even Gabapentin to assist with a taper. I know both Gabapentin and depakote increase GABA synthesis a little bit without being direct agonists so you wouldn't have to worry about the specific tolerance associated with benzos there.
 
Yeah it probs is different. I do know that tolerance to benzos in general builds pretty quick. Like really quick. Doctors always say they are relatively ineffective for long-term anxiety treatment. I find the best thing for my anxiety, long term, is an SSRI (currently fluvoxamine) and.....methadone, of all things. Sounds odd but it seems the best combo and I've tried a lot.

Note: I am NOT recommending introducing another category of psychoactive into your regime to combat anxiety, especially one as addictive as an opiate. I'm just saying what works for me

peace :)
 
Based on the implications of switching to a "partial agonist" benzo like tranxene (which has the full agonist oxazepam as a metabolite) there will not likely be any benefits like reduced tolerance... chances are, the required dose to prevent the worst of the withdrawal symptoms during a taper would be enough to maintain the tolerance you already have. Ultimately, you're just changing to diazepam metabolites. I doubt it would be worse to taper off desmethyldiazepam, but switching could result in some acute withdrawal effects.

Good luck tapering by the way
 
I'm not sure if I understand. Since clonazepam and diazepam are different drugs regarding tolerance/dependence ('incomplete cross tolerance'), would a partial agonist be less likely to induce tolerance/dependence ?

'I doubt it would be worse to taper off desmethyldiazepam, but switching could result in some acute withdrawal effects.'
Are you saying it is more likely to cause 'acute withdrawal effects' than a full agonist like diazepam ?
 
willy33 said:
Heya,

I'm not sure about benzos - I don't know a lot about partial vs full agonists working the GABA pathway...however...I have considerable experience with opiates and have also observed a lot of opiate activity among associates.

The most commonly used partial opiate agonist is buprenorphine (Subutex, Suboxone). Apologies if you already know this...

I have noticed that when I have used Subutex (or Suboxone), my tolerance builds incredibly rapidly.

For example, if you can get high on 2mg, you will need 4mg after about 4 or 5 days. Then 8mg four days later. Then 16mg. Before you know it you can be on the maximum dose of 32mg and you won't feel a thing.

Compared to methadone or morphine or oxycodone this is just plain strange.

So, with opiates at least, it *seems* partial agonists build tolerance faster.


​Peace :)
Click to expand...

I am on Suboxone and can't say anything in regards to getting high on Suboxone but on maintenance doses it appears that the tolerance to the narcotic effects does build quite rapidly but someone can be on the same maintenance dose for many years and it will still hold them. Maintenance is quite different as people are not chasing a high, just the stability and the safety net of the blockade effect of buprenorphine. When I was put on it I ensured I was put on a dose lower than my tolerance level and there was a long adjustment period, but in this way I achieved stability and it eventually ended up holding me without having a lot of the negative side effects typical of opioids. I find it more therapeutic than if I were to go on Methadone, at least when dosed in this way because there is no pacifying narcotic effects and it doesn't seem to interupt hormone production as either full agonists or a higher dose of buprenorphine might, anxiety and depression got really overwhelming while I was getting adjusted to this dose. So one is, not technically sober but is mostly as the dose is enough to keep them functional without the narcotic effects due to tolerance but being able to be held on the same dose for years at a time. I am curious as to why that is.

Methadones blockade effect happens around 80mgs I believe (don't quote me on that) and people stop getting pleasurable narcotic effects after a few doses or at least I did when I was abusing it. It stopped being recreational and I couldn't use any other opioids while on it either. But Methadone still has people with low testosterone levels and it does seem to still keep them somewhat pacified/opiated.
 
IDK, IME if you don't continue to raise your dose of buprenorphine, it continues to act almost like a full agonist like methadone, for instance dosages under 8mg to me always felt exactly like a 30-40mg dose of methadone.

Anyway, I don't know much in terms of the partial agonist in question here, but I always thought clonazepam was a weird benzo, in that it acts a lot like methadone where past a certain dose it seems that it saturates the GABA receptors so you can't get any more therapeutic effect out of it like you can when you increase your dose of Alprazolam. It seems to plateau its anxiolytic effects and will just black you out or cause respiratory depression or both. Has anyone else noticed that? I'm not saying it blocks other benzo's like Methadone, just itself..
 
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