Paracetamol and Pain Modulation by TRPV1, UGT2B15, SULT1A1 Genotypes: A Randomized Clinical Trial in Healthy Volunteers

Pain Med. 2020 Apr 1;21(4):661-669. doi: 10.1093/pm/pnz037.


Background: The influence of the genetic polymorphism of enzymes and receptors involved in paracetamol metabolism and mechanism of action has not been investigated. This trial in healthy volunteers investigated the link between paracetamol pain relief and the genetic polymorphism of 23 enzymes and receptors.

Design: This randomized double-blind crossover controlled pilot study took place in the Clinical Pharmacology Department, University Hospital, Clermont-Ferrand, France. Forty-seven Caucasian volunteers were recruited. The trial consisted of two randomized sessions one week apart with oral paracetamol or placebo, and pain changes were evaluated with mechanical pain stimuli. The genetic polymorphism of 23 enzymes and receptors was studied, and correlations were made with pain relief. All tests are two-sided with a type I error at 0.05.

Results: Paracetamol was antinociceptive compared with placebo (222 ± 482 kPaxmin vs 23 ± 431 kPaxmin; P = 0.0047), and the study showed 30 paracetamol responders and 17 paracetamol nonresponders. Responders were characterized by TRPV1rs224534 A allele, UGT2B15rs1902023 TT genotype, and SULT1A1rs9282861 GG genotype (P < 0.05 for all). These findings confirm for the first time the involvement of a specific TRPV1 rs224534 variant in paracetamol antinociception. They also reveal a new antinociceptive role for specific variants of hepatic phase II enzymes associated with paracetamol metabolism.

Conclusions: The study warrants larger clinical trials on these potential genomic markers of paracetamol analgesia in patients. Confirmation of the present findings would open the way to effective individualized pain treatment with paracetamol, the most commonly used analgesic worldwide.

Trial registration: NCT01520792.

Keywords: Genetic Polymorphism; Healthy Volunteers; Pain; Paracetamol.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Acetaminophen / pharmacology
  • Acetaminophen / therapeutic use*
  • Adult
  • Alleles
  • Analgesics, Non-Narcotic / pharmacology
  • Analgesics, Non-Narcotic / therapeutic use*
  • Arylsulfotransferase / genetics
  • Back Pain / prevention & control*
  • Cross-Over Studies
  • Genotype
  • Glucuronosyltransferase / genetics
  • Healthy Volunteers
  • Humans
  • Male
  • Nociception / drug effects
  • Pain Threshold / drug effects
  • Pharmacogenomic Variants
  • Polymorphism, Genetic
  • Random Allocation
  • TRPV Cation Channels / genetics
  • Young Adult


  • Analgesics, Non-Narcotic
  • TRPV Cation Channels
  • TRPV1 protein, human
  • Acetaminophen
  • Glucuronosyltransferase
  • UDP-glucuronosyltransferase 2B15, human
  • Arylsulfotransferase
  • SULT1A1 protein, human

Associated data