Effect sizes in experimental pain produced by gender, genetic variants and sensitization procedures.

BACKGROUND: Various effects on pain have been reported with respect to their statistical significance, but a standardized measure of effect size has been rarely added. Such a measure would ease comparison of the magnitude of the effects across studies, for example the effect of gender on heat pain with the effect of a genetic variant on pressure pain. METHODOLOGY/PRINCIPAL FINDINGS: Effect sizes on pain thresholds to stimuli consisting of heat, cold, blunt pressure, punctuate pressure and electrical current, administered to 125 subjects, were analyzed for 29 common variants in eight human genes reportedly modulating pain, gender and sensitization procedures using capsaicin or menthol. The genotype explained 0-5.9% of the total interindividual variance in pain thresholds to various stimuli and produced mainly small effects (Cohen's d 0-1.8). The largest effect had the TRPA1 rs13255063T/rs11988795G haplotype explaining >5% of the variance in electrical pain thresholds and conferring lower pain sensitivity to homozygous carriers. Gender produced larger effect sizes than most variant alleles (1-14.8% explained variance, Cohen's d 0.2-0.8), with higher pain sensitivity in women than in men. Sensitization by capsaicin or menthol explained up to 63% of the total variance (4.7-62.8%) and produced largest effects according to Cohen's d (0.4-2.6), especially heat sensitization by capsaicin (Cohen's d = 2.6). CONCLUSIONS: Sensitization, gender and genetic variants produce effects on pain in the mentioned order of effect sizes. The present report may provide a basis for comparative discussions of factors influencing pain.

Capsaicin or menthol sensitization induces quantitative but no qualitative changes to thermal and mechanical pain thresholds.

AIM: To analyze whether sensitization procedures employed in experimental human pain models introduce additional components to pain measurements resulting in a different kind of pain or whether they are limited to quantitative changes resulting in the same pain at higher intensity. METHODS: Heat, mechanical (von Frey hairs), and cold stimuli were applied to 69 men and 56 women, aged 18 to 46 years, prior and subsequently to sensitization by dermal capsaicin or menthol application. RESULTS: Sensitization decreased the fraction of censored data, that is, thresholds at the technical limit of 52.5 degrees C or 0 degrees C or 300 g von Frey hairs, from 38 to 21 patients with von Frey hairs, from 30 to 19 patients with cold stimuli (chi(2) tests: P<0.001), whereas pain thresholds to heat never reached its technical maximum. In the 75 patients without censored data, capsaicin sensitization decreased the heat pain thresholds from 44.7+/-2.1 degrees C to 36.8+/-3.3 degrees C, the von Frey pain thresholds from 78.2+/-74 g to 33.9+/-37.8 g, and menthol sensitization decreased cold pain thresholds from 13+/-8.4 degrees C to 19.3+/-9.2 degrees C (paired comparisons: all P<0.001). However, for each stimulus, only 1 single principal component of the variance of nonsensitized and sensitized thresholds with an eigenvalue >1 was identified by principal component analysis, explaining 64.8%, 84.8%, and 94.4% of the total variance for heat, mechanical, and cold stimuli, respectively, and indicating that nonsensitized and sensitized pain thresholds shared the same main source of variance. CONCLUSIONS: The main effect of sensitization by capsaicin or menthol application is a quantitative decrease in thermal and mechanical pain threshold with the methodologic benefit of decreasing the incidence of censored data. A qualitative change in pain thresholds by sensitization is not supported by the present statistical analysis at level of primary hyperalgesia.

Principle components analysis of pain thresholds to thermal, electrical, and mechanical stimuli suggests a predominant common source of variance.

We addressed the question whether pain thresholds to different stimuli measure independent aspects of pain or one common phenomenon. In the first case, different stimuli are required to completely characterize a subject's pain sensitivity. In the second case, different stimuli are redundant and can be used to calculate composite scores across pain modalities. We measured pain thresholds to several stimuli (heat, heat/capsaicin, cold, cold/menthol, blunt pressure, 5-Hz sine-wave electric current (0-20mA), punctate pressure (von Frey hairs), and von Frey hairs plus capsaicin application) in 45 healthy men and 32 healthy women (aged 20-44 years). We observed that pain thresholds were significantly correlated with each other. Principal component analysis indicated that their variance was attributable more to the difference in subjects (variance estimate: 0.393) than to the difference in pain stimuli within a subject (variance estimate: -0.008). Among three principal components of the intercorrelation matrix with eigenvalues >1, the first, explaining 48% of the total variance, carried high loadings from all stimuli indicating that they shared a common source of half of their variance. Only minor variance components, each explaining <14% of the total variance, indicated a distinction of pain stimuli. There, a pattern of similarities and dissimilarities emerged agreeing with known distinct mechanisms of nociceptive responses to different stimuli. We conclude that characterizing a person as being generally stoical or complaining to any painful stimulus appears to be justified at least at pain threshold level.