Sex and gender differences in pain

Women carry a higher risk of many chronic pain conditions and show greater experimental pain sensitivity, and some pain mechanisms differ by sex, so research and drug targets must include both sexes.

1. Women have more clinical pain. Epidemiologic studies show women are at substantially greater risk for many clinical pain conditions, and postoperative and procedural pain may be more severe in women ¹.
2. Experimental sensitivity is higher in females. Across most modalities, including temporal summation and intramuscular algesic injection, females show greater pain sensitivity than males ¹.
3. Other differences are inconsistent. Evidence on sex differences in endogenous pain modulation, brain imaging of pain, and responses to drug and nondrug treatments is mixed; proposed mechanisms are biopsychosocial, spanning hormones, genetics, anxiety and coping ¹.
4. Mechanisms can differ qualitatively. In mice, microglia were required for nerve-injury mechanical hypersensitivity in males but not females, who used adaptive immune cells, likely T lymphocytes ².
5. Male animals are not proxies. Microglia-to-neuron signaling had been considered essential to chronic pain hypersensitivity, yet Sorge and colleagues concluded that this dimorphism means male mice cannot stand in for females in pain research ².
6. Funders require both sexes. NIH expects sex as a biological variable to be factored into the design, analysis and reporting of vertebrate animal and human studies, with strong justification for single-sex studies ³.

A drug target validated only in male animals may fail in women; check whether preclinical evidence included both sexes, with sex-disaggregated analysis, before extrapolating results to female patients ²³.

• Temporomandibular pain is more prevalent in women across the lifespan and in many countries ¹.
• Headache and migraine prevalence is higher in women than men ¹.
• In one community study, fibromyalgia point prevalence was 4.9% in women versus 1.6% in men ¹.
• Studies of mixed-action kappa opioids such as nalbuphine and pentazocine after oral surgery found greater analgesia in women ¹.
• Psychological factors matter: gender roles and anxiety mediated sex differences in heat temporal summation, and catastrophizing explained differences in conditioned pain modulation ¹.
• Back pain is more prevalent in women, but evidence that women are at greater risk of chronicity is limited ¹.
• Adequate inclusion of both sexes and sex-disaggregated data allow sex-based comparisons ³.
• The NIH policy applied to applications from the January 25, 2016 due date onward ³.

• Assuming pain mechanisms are identical in both sexes ².
• Treating sex differences in analgesic response as settled; findings are inconsistent ¹.
• Accepting a single-sex study without justification ³.
• Attributing every sex difference to biology alone when psychological factors such as catastrophizing can mediate it ¹.