The science behind pain, sex, and gender: do we need sex-specific treatments for chronic pain?
Written by: Denis Duagi
Art by: Wenanlan Jin
Pain is a complex experience that is influenced by many variables in the body – from how much inflammation is in your body to how the brain can dampen or amplify the pain experience.
Experimental reports of women experiencing pain differently compared to men date all the way back to 1967. It has since been debated that women generally complain more or that women do not accurately report their pain. Much attention has been drawn to this subject in the scientific community, and both clinical and experimental studies have surfaced solid evidence for the sex differences in pain.
What is the evidence?
There are two main arguments that support the idea of different pain processing in males and females. Firstly, clinical studies show that women are at substantially greater risk of developing certain pain conditions such as neuropathic pain, migraine, and fibromyalgia, a chronic condition that causes widespread pain. Strikingly, migraine is more than twice as prevalent in women, and in certain geographical regions, the incidence of widespread pain and fibromyalgia is between four to eight times higher in women than in men. Secondly, women are not only more prone to developing certain pain disorders, but there is also evidence that they are more sensitive to various experimental pain modalities such as heat and electrical stimulation.
Biological sex or social gender?
Despite such compelling evidence, many confounders need to be taken into account in this field of research. One has to consider that pain is not just a simple biological response, but rather a very complex experience known to be influenced by both biological factors such as age and stress, and socio-economic status. Willingness to report pain is the main source of subjectivity in pain research. In a large-scale meta-analysis, researchers found that women reported higher pain intensity across all 14 pain disorders investigated. The obvious question that arises when considering differences in pain processing between men and women is whether physiology or behaviour is the main driving force. Gender roles seem to play an important part in the pain response, with the masculine gender norm dictating increased tolerance of pain among males, whereas feminine gender norms accept pain as a normal part of life and are more permissive of pain expression.
American researchers investigating social norms and behaviour prediction developed an experimental protocol that can assess the participant’s knowledge of gender norms regarding pain tolerance and determine how strongly the participant identifies with their gender group. They found that both men and women agreed that the “ideal” man should tolerate more pain than the “ideal” woman. They also demonstrated that men who strongly identified with male gender norms had a higher electrical pain tolerance than men who did not. On the other hand, such gender norm identification was not associated with pain tolerance in women. Furthermore, several studies found that the reported pain intensity was higher in men if the research investigator was female. Together, these findings point out that gender expectations might lead men to report less pain. For women, on the contrary, it seems less likely to be influenced by gender norms. Hence, biological pathways involved in pain are likely to function differently in men and women.
What are the mechanisms?
Distinct, but not mutually exclusive hypotheses have been put forward to explain sex bias in pain. Sex hormones such as estrogen have been shown to have modulatory effects on pain sensitivity, although the exact mechanism remains unknown. The endogenous opioid system is also a major candidate, as one study identified differences between men and women in mu-opioid receptor-mediated analgesic responses, with men exhibiting higher pain-related receptor bindings. Activation of the NMDA receptor, an ion channel well-known for its role in enhancing pain responses, was also shown to elicit a higher neuronal activation in women.
Recently, Dr. Simon Beggs and his collaborators from UCL’s Paediatric Pain Research Group uncovered a cellular mechanism underlying pain processing in the spinal cord that is sexually dimorphic in mice. Microglia, the central nervous system’s immune cells, become activated following nerve injury and facilitate excitation of the pathways involved in pain processing. These cells appear to play an important role only in male mice. Whereas in female mice, increased sensitivity to pain is dependent on T cells.
Decades of research have demonstrated differences in pain perception between men and women. Recent studies showed that there is indeed a difference in the underlying neurological mechanisms that mandate women to experience more pain. This raises the concern that by using mostly males as subjects for clinical and pharmacological research, the currently available analgesic treatments may not work as effectively in women. In order to combat these sex differences in pain, sex-specific drug development is necessary as women are constantly undertreated for their pain. Without such treatments, the gap between men and women with chronic pain will be constantly widening.
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