ReviewInsights into the mechanisms and the emergence of sex-differences in pain

•Sex and gender influence the occurrence of pain and the response to treatments.•Women are overrepresented in most clinical pain conditions.•Biological and psychological factors are acting on sex and gender pain modulation.•Sex and gender are essential factors in personalized pain medicine.

Recent studies describe sex and gender as critical factors conditioning the experience of pain and the strategies to respond to it. It is now clear that men and women have different physiological and behavioral responses to pain. Some pathological pain states are also highly sex-specific. This clinical observation has been often verified with animal studies which helped to decipher the mechanisms underlying the observed female hyper-reactivity and hyper-sensitivity to pain states. The role of gonadal hormones in the modulation of pain responses has been a straightforward hypothesis but, if pertinent in many cases, cannot fully account for this complex sensation, which includes an important cognitive component. Clinical and fundamental data are reviewed here with a special emphasis on possible developmental processes giving rise to sex-differences in pain processing.