Sex-gender differences in pain perception is still a poorly understood subject, despite receiving greater scientific and clinical interest in recent years. Although there is still a lack of unequivocal evidence of gender specificities in pain processing, there are many reports that strongly indicate that there are indeed significant differences in the way men and women experience pain.

Such differences can be observed, for instance, in the sensitivity to pain therapy. Females seem to be more sensitive to some neuroblocking agents and to opioid receptor agonists, whereas males tend to be more susceptible to propofol and to general anesthesia, from which they take longer to wake up.

The sensitivity to pain itself also differs widely. Overall, there seems to be greater pain sensitivity and higher prevalence of most pain modalities in women; females have a higher incidence of clinical pain conditions and more severe postoperative and procedural pain, and show lower pain thresholds, higher pain ratings, and less tolerance to painful stimuli.

An intuitive explanation for such differences is that sex hormones may have a role in pain modulation. Sex hormones do actually play important parts in many biological functions besides reproduction and sexual differentiation. Estrogens, the primary female hormones, can modulate cardiovascular function, bone formation, thermal regulation of the body, feeding behavior, metabolic rate, memory, motivation and mood, among others. The central nervous system is a major target for estrogens, where they can have neuroprotective actions, act as vasodilators to increase blood flow to the brain, and regulate neurotransmission and sensory perception.

Research in animal models has provided considerable evidences of sex differences in pain processing and its hormonal regulation. It has been shown that estrogen receptors are present in areas of the central nervous system where pain is modulated and that there is a direct action of estrogens in the modulation of pain in the spinal cord. Estrogen receptors are also expressed in the peripheral nervous system; in the sensory neurons that detect nociceptive stimuli. Studies in mice lacking estrogen receptors demonstrated that the differences in pain thresholds between male and female mice were eliminated in the absence of those receptors, supporting their role in nociception in female mice.

In vitro studies have also shown a direct effect of estrogens in the production and activation of other molecules involved in pain signaling. An important mechanism for the action of estrogens in pain processing seems to be the interaction with the endogenous opioid system, which is crucial in pain modulation.

But there are also studies in humans that support sex differences and hormonal regulation of pain. For instance, in some clinical deep tissue pain conditions, it was observed that the severity of pain was higher in women and that it was associated with the phase of the menstrual cycle, sustaining the hypothesis of a regulation of pain perception by female sex hormones.

Pain is also strongly modulated by emotion. A recent neuroimaging study on sex differences in pain has shown that the rating of pain unpleasantness is associated with different pain-evoked brain responses in men and women. Interestingly, it demonstrated that men preferentially mobilize threat control circuits, whereas women recruit emotion-processing areas of the brain.

There is still a great need for more research on this subject, but understanding the specificities of pain processing in men and women can be a great advance in the optimization of pain relief and in the individualization of pain therapy.

References

Amandusson Å, & Blomqvist A (2013). Estrogenic influences in pain processing. Frontiers in neuroendocrinology, 34 (4), 329-49 PMID: 23817054

Bartley EJ, & Fillingim RB (2013). Sex differences in pain: a brief review of clinical and experimental findings. British journal of anaesthesia, 111 (1), 52-8 PMID: 23794645

Campesi I, Fois M, & Franconi F (2012). Sex and gender aspects in anesthetics and pain medication. Handbook of experimental pharmacology (214), 265-78 PMID: 23027455

Fillingim RB, King CD, Ribeiro-Dasilva MC, Rahim-Williams B, & Riley JL 3rd (2009). Sex, gender, and pain: a review of recent clinical and experimental findings. The journal of pain : official journal of the American Pain Society, 10 (5), 447-85 PMID: 19411059

Girard-Tremblay L, Auclair V, Daigle K, Léonard G, Whittingstall K, & Goffaux P (2014). Sex differences in the neural representation of pain unpleasantness. The journal of pain : official journal of the American Pain Society PMID: 24887007

Traub RJ, & Ji Y (2013). Sex differences and hormonal modulation of deep tissue pain. Frontiers in neuroendocrinology, 34 (4), 350-66 PMID: 23872333

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