Sex differences in analgesic response to ibuprofen are influenced by expectancy: A randomized, crossover, balanced placebo‐designed study

Abstract

To determine whether there is a sex difference in placebo and ibuprofen analgesia expectancy. We measured detection and tolerance thresholds for electrically induced pain in the ear lobe in healthy subjects (10 male, 10 female) to study sex differences in expectancy following either ibuprofen 800 mg or placebo in four different expectancy states. Subjects took ibuprofen or placebo in a two-by-two factorial design (the balanced placebo design). We randomly assigned subjects to start in one of the four expectancy states. We analysed the results using analysis of variance for repeated measures with baseline pain as a covariate. We found no sex difference in baseline pain threshold or tolerance levels. When partitioned by sex and expectancy state, analgesia only occurred in males during positive expectancy states at 2, 3 and 4 h post-placebo, and at 1 and 2 h post-ibuprofen. The time course of analgesic action in males was as expected considering the pharmacokinetic profile of ibuprofen. Our study found that dosages of 800 mg of ibuprofen are ineffective in producing analgesia in women regardless of their expectations. We hypothesize that ibuprofen analgesia is produced by a combination of specific pharmacological effects and a non-specific beta endorphin-mediated placebo effect. Whatever the mechanism responsible for the analgesic response seen in males, this research re-emphasizes the importance of psychological factors in determining drug response. It also shows that these factors can differ between men and women, and thus the contribution of psychological factors on analgesia needs to be seriously re-evaluated.