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N&PD Moderators: Skorpio | thegreenhand
Is it possible to switch from a 1,4 benzodiazepine to a 1,5 benzodiazepine ?
- Thread starter Kdem
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I do not recall where I read that such a switch is not possible. However, (wikipedia) '
Like other 1,5-benzodiazepines (e.g., arfendazam, lofendazam, CP-1414S), it has less affinity for the α1-allosteric binding site on the GABAA receptor compared to the 1,4-benzodiazepines. It has higher affinity for the α2 site, where it has agonistic activity.[25]
In a double-blind placebo-controlled trial published in 1990 comparing it to clonazepam, 10 mg; of clobazam was shown to be less sedating than either 0.5 mg or 1 mg of clonazepam'
Aside from being a different drug, it is less sedating. I can't say I find clonazepam sedating ...
Like other 1,5-benzodiazepines (e.g., arfendazam, lofendazam, CP-1414S), it has less affinity for the α1-allosteric binding site on the GABAA receptor compared to the 1,4-benzodiazepines. It has higher affinity for the α2 site, where it has agonistic activity.[25]
In a double-blind placebo-controlled trial published in 1990 comparing it to clonazepam, 10 mg; of clobazam was shown to be less sedating than either 0.5 mg or 1 mg of clonazepam'
Aside from being a different drug, it is less sedating. I can't say I find clonazepam sedating ...
Solipsis
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Don't focus on them being 1,4 or 1,5 benzodiazepines or triazolo or thienodiazepines etc, but on the pharmacological profile.
I think I would advise against 'very' partial cross-tolerance issues where you don't really have proper overlap of effects but instead trade in effects for different ones on different GABA subtypes. (Say going from an a1 selective to a2 selective drug)
The lack of sedation for clobazam can indeed be explained by being less heavy on the a1 which is a target for hypnotics, while a2 is considered the main anxiolysis target.
Clonazepam has low to moderate a1 (sedation / hypnotic effect) affinity and a study shows it is not as selective for a2 (anxiolysis) over a1.
Switching may lead to some insomnia as you may basically withdraw from not having as much a1 effect from clobazam.. but withdrawal is inevitable at some point if this is a step towards quitting entirely.
I think I would advise against 'very' partial cross-tolerance issues where you don't really have proper overlap of effects but instead trade in effects for different ones on different GABA subtypes. (Say going from an a1 selective to a2 selective drug)
The lack of sedation for clobazam can indeed be explained by being less heavy on the a1 which is a target for hypnotics, while a2 is considered the main anxiolysis target.
Clonazepam has low to moderate a1 (sedation / hypnotic effect) affinity and a study shows it is not as selective for a2 (anxiolysis) over a1.
Switching may lead to some insomnia as you may basically withdraw from not having as much a1 effect from clobazam.. but withdrawal is inevitable at some point if this is a step towards quitting entirely.
Nakajima, Hiroyuki (2001). "A pharmacological profile of clobazam (Mystan), a new antiepileptic drug". Folia Pharmacologica Japonica 118 (2): 117–22. doi:10.1254/fpj.118.117
binds to a2 subunit - 1,4 benzos bind to a1 subunit.
Beware - even the specialist I went to didn't know and wouldn't slowly cross over. I sent him a bundle of printed refs and told him that if is ignorance is the cause of death or serious injury, he had been told. Sent recorded delivery so HE had to sign for it. I kept a copy and told him so. ANY seizure deaths in this burg & I'm going straight to the press & RCM and get the guy back into general practice - practice he obviously NEEDS!
binds to a2 subunit - 1,4 benzos bind to a1 subunit.
Beware - even the specialist I went to didn't know and wouldn't slowly cross over. I sent him a bundle of printed refs and told him that if is ignorance is the cause of death or serious injury, he had been told. Sent recorded delivery so HE had to sign for it. I kept a copy and told him so. ANY seizure deaths in this burg & I'm going straight to the press & RCM and get the guy back into general practice - practice he obviously NEEDS!
Solipsis
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Care to venture a guess as to what part of the incomplete cross-tolerance precipitates in that withdrawal? I guess it's possible - even if it feels nearly as bad as just completely withdrawing from the clonazepam - that the clobazam still covers part of the effects, preventing some withdrawal like fits or insomnia?
Lack of 'a1 sedation' surely feels terrible, but I imagine the gamma activation to be important too if its so important for physical dependency?
Lack of 'a1 sedation' surely feels terrible, but I imagine the gamma activation to be important too if its so important for physical dependency?
It does appear that clobazam is more forgiving - I can forget a dose and 12 hours later, I still feel OK (unlike a missed 10mg of diazepam). Could be the way to go for less dependence-forming benzos since it's effects are less but on more subreceptors. People have found that adding a '2-halide increases potency as does the tetracyclic derivatives.