Influence of Genetic Polymorphisms on the Response to Tramadol, Ibuprofen, and the Combination in Patients With Moderate to Severe Pain After Dental Surgery.

Purpose: We aimed to elucidate the influence on analgesic effect of genetic polymorphisms in enzymes responsible for biotransformation of tramadol and ibuprofen or other possible genes involved in their mechanism of action.
Methods: The study population comprised 118 patients from a multicenter, randomized, double-blind, placebo-controlled, Phase III clinical trial that assessed the analgesic efficacy and tolerability of a single dose of ibuprofen (arginine)/tramadol 400/37.5 mg compared with ibuprofen arginine 400 mg alone, tramadol 50 mg alone, and placebo in patients with moderate to severe pain after dental surgery. We analyzed 32 polymorphisms in the cytochrome P450 (CYP) enzymes COMT, ABCB1, SLC22A1, OPRM1, and SLC22A1.
Findings: We did not find any statistically significant difference among CYP2C9 phenotypes related to ibuprofen response, although CYP2C9 poor metabolizers had a longer effect (higher pain relief at 6 hours). Likewise, we did not find any statistically significant difference among PTGS2 genotypes, contradicting previously publications.
Implications: There was not a clear effect of CYP2D6 phenotype on tramadol response, although CYP2D6 poor metabolizers had a slower analgesic effect. Concerning the transport of CYP2D6, we observed a better response in individuals carrying ABCB1 mutated alleles, which might correlate with higher tramadol plasma levels. Finally, we found a statistically significant better response in patients carrying the OPRM1 A118G G allele, which contradicts the previous reports. Measuring the active metabolite O-desmethyl-tramadol formation would be of great importance to better evaluate this association because O-desmethyl-tramadol has a higher μ-opioid receptor affinity compared with the parent drug. EudraCT.ema.europa.eu identifier: 2013-004637-33.
Competing Interests: Disclosures Francisco Abad-Santos and Dolores Ochoa have been consultants or investigators in clinical trials sponsored by the following pharmaceutical companies: Abbott, Alter, Chemo, Cinfa, FAES, Farmalíder, Ferrer, GlaxoSmithKline, Galenicum, Gilead, Italfarmaco, Janssen-Cilag, Kern, Normon, Novartis, Servier, Silverpharma, Teva, and Zambon. Antonio J. Carcas and Alberto M. Borobia have been consultants or investigators in clinical trials sponsored by the following pharmaceutical companies: GlaxoSmithKline, Janssen, Daichii, Mundipharma, Farmalider, and Menarini. The authors have indicated that they have no other conflicts of interest regarding the content of this article.
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