Gabapentinoids Pregablin and 4-methylpregablin cross tolerance?

[don_cab]

I use pregabalin occasionally, maybe like 2 or 3 days in a row every few weeks. I don't feel anything close to the first few times of course, but sometimes it randomly hits just right. 900mg is generally my threshold (and limit) dose now, usually works pretty damn good the first day, and then the days after are pretty much a coin flip.

ANYWAYS, I used a lot this weekend and probably messed up my tolerance. I redosed both days, which I normally never do, anywhere from about 200 to 500mg, probably twice both days, and still didn't feel jack. I can get my hands on some 4-methylpregabalin, which is said to be very similar, and much stronger by weight than pregabalin. I had it once before and I remember I did dose less, but not by much.

Anyways, would there be a cross tolerance between the two? I've noticed that once you get a hefty enough tolerance to anything, all the bigger doses and redoses in the world won't help you reach that high. It's a shame that pregabalin has such an exponential type tolerance, plus the whole risk of seizures and devastating withdrawals, cause god does it feel good. If I could experience that high 24/7 I'd be a much happier, more productive and all around better person, lol.

 

[don_cab]

So based off my very limited research (a quick search of 4-methylpregabalin on here) i would assume they do indeed have a cross tolerance. Supposedly I read that pregabalin is converted into 4-methylpregabalin in the body (along with something else but 4-meth is the significant one) the small amount that isn't just wasted and discharged, anyway. Going off that, I'd think it's obvious that they'd have a cross tolerance, am I wrong?

 

[Vesicle]

Yes, pregabalin and 4-methyl-pregabalin should have cross-tolerance as they are both ligands of the alpha(2)-delta sub-unit of voltage gated calcium ion channels.

Also, as far as I know, 4-methyl-pregabalin is not a metabolite of pregabalin, it is a separate drug that was being developed by Pfizer. You may be thinking of N-methyl-pregabalin as the metabolite?

Structure-activity relationships of pregabalin and analogues that target the alpha(2)-delta protein - PubMed

Pregabalin exhibits robust activity in preclinical assays indicative of potential antiepileptic, anxiolytic, and antihyperalgesic clinical efficacy. It binds with high affinity to the alpha(2)-delta subunit of voltage-gated calcium channels and is a substrate of the system L neutral amino acid...

pubmed.ncbi.nlm.nih.gov