Pain is a complex and subjective experience that varies among individuals. However, there is increasing evidence that men and women differ in their response to pain, with an increased pain sensitivity and risk of clinical pain commonly being observed among women. The International Association for the Study of Pain has designated 2024 as the ‘Global Year About Sex and Gender Disparities in Pain’ (1). Throughout 2024, IASP aims to examine what is known about sex and gender differences in pain perception and modulation, and address sex- and gender-related disparities in both the research and treatment of pain. Understanding why the experience of pain varies between people is central to the development of more targeted, and personalised, treatments for pain.
Women are more likely to experience chronic pain
Studies have consistently highlighted that women are at greater risk of developing many chronic pain-causing conditions, compared to men. For example, fibromyalgia, a condition characterised by chronic widespread pain, is significantly more prevalent in women (80-90% of diagnosed cases) (2). Other conditions that disproportionately affect women include migraine headache, temporomandibular disorders (TMD), irritable bowel syndrome (IBS), osteoarthritis, rheumatoid arthritis and chronic pelvic pain.
Mood disorders, in particular anxiety, play an important role in the exacerbation of pain perception in all clinical settings, and women also demonstrate higher rates of these anxiety disorders. It is well established that anxiety is associated with a greater severity of pain and, in turn, the presence of chronic pain can cause higher levels of anxiety, creating a devastating positive feedback loop (3).
Women feel pain more intensely than men
The female body has a more intense natural response to painful stimuli, indicating a sex difference in the way pain systems function. According to research by the American Society
of Plastic Surgeons, women possess a higher nerve density than men, with 35 nerve fibres per centimetre of skin, while men average 17 (4). These findings indicate that women’s lower pain tolerance and threshold may also be physical.
Despite this, The Gender Pain Gap Index Report, commissioned by Nurofen in 2023, revealed over half of UK women (56%) feel their pain is ignored or dismissed by healthcare professionals (5). When they are in pain, women wait longer in emergency departments (6) and are 25% less likely to have their pain adequately treated (7). It takes women longer to receive a diagnosis, healthcare professionals diagnose them with the least confidence and they are twice as likely to be alternatively diagnosed with a mental illness, relative to men reporting the same
symptoms (8).
Nearly half (48%) of UK adults believe there is a ‘gap’ in the identification and treatment of pain between sexes, and this gap is widening (6). These reports highlight the urgent need to address the stark inequalities around women’s pain.
Effects of sex steroid hormones on pain
Overwhelming evidence supports the multitude of sex-specific biological mechanisms that underlie pain at both a physiological and pathophysiological level. For example, hormones can exert an influence on pain in a variety of ways, including:
Altering sensitivity to pain by influencing pain processing pathways (e.g., descending modulation)
Altering biological processes associated with pain (e.g., inflammation)
Driving hormonally dependent pathologies (e.g., endometriosis)
Impacting mood to alter/exacerbate the pain experience
Oestrogen, in particular, plays a significant role in modulating pain perception. At high concentrations, oestrogen has a pain-suppressing effect via activation of inhibitory pathways in the spinal cord (9). Increased oestrogen levels have also been found to protect against pain conditions like musculoskeletal (10) or posttraumatic pain (11).
Whilst it is commonly believed that women have a higher pain tolerance, because they can ‘endure childbirth’, it is, in fact, the opposite. Pregnancy (a time of very high oestrogen and progesterone) is associated with a marked reduction in pain sensitivity (12). This “pregnancy-induced analgesia” has been consistently demonstrated in animal models, even in male rats injected with pregnancy hormones.
Three well-studied findings relating to sex differences in pain hypersensitivity have been described in detail:
The male-specific role of spinal microglia. Microglia do not contribute to pain hypersensitivity in female mice. Instead, adaptive immune cells perform an analogous role in females (13).
The female-specific role of calcitonin gene-related peptide (CGRP). CGRP has a preferential pain-promoting effect in female rodents but has limited impact in males (14).
The female-specific role of prolactin and its receptor. The Prolactin/Prolactin Receptor System sensitises nociceptors to promote pain selectively in females (15).
Gaps in the research
Although most patients with chronic pain are women, the majority of our knowledge about pain mechanisms has been derived from preclinical studies on male rodents. Between 1996 and 2005, 79% of preclinical rodent studies published in the journal, Pain, tested male rats or mice only, with an additional 3% of studies not stating the sex of their subjects (16). Pain is not an exception in this regard. Male animals dominate preclinical research subjects in neuroscience, with the percentage of published studies using male rodents increasing between 2010 and 2014. Decades of study of, primarily male, rodents have led to the pain literature being male-biased (17). Sex differences should be considered in the investigation of pain.
Common misconceptions about including female animals in preclinical studies
Could it not be argued that, by including female animals, it would make the research more clinically relevant, especially considering over half of the population is female? What are some of the common arguments against using females in preclinical research, and are these realistic or not?
‘Females are more variable because of their oestrous cycle’
It has empirically been shown, both in pain research and in other fields, that this is not true. The oestrous cycles are short in these animals and even if the cycle does add to variability in female animals, researchers should acknowledge that male animals have dominance hierarchies in their cages, which adds a source of variability.
‘If I use both sexes, then I’m going to have to use double the animals’
Again, this is not true from an experimental design point of view. Researchers should use a factorial design (18), with sex being considered a factor.
‘You can’t blind for sex in your experiments’
It isn’t always possible to blind for everything. In this case, using both sexes, even without blinding, is worth it to improve the study.
However, with major funding agencies around the world advocating for sex to be included as a biological variable in all aspects of research they fund, from study design to data analysis and dissemination, there is hope that we can better understand pain in women.
References:
IASP, 2024 Global Year about Sex and Gender Disparities in Pain (https://www.iasp-pain.org/advocacy/global-year/sex-and-gender-disparities-in-pain/).
Arout, C. A., Sofuoglu, M., Bastian, L. A., & Rosenheck, R. A. (2018). Gender Differences in the Prevalence of Fibromyalgia and in Concomitant Medical and Psychiatric Disorders: A National Veterans Health Administration Study. Journal of Women’s Health, 27(8), 1035–1044.
De La Rosa, J. S., Brady, B. R., Ibrahim, M. M., Herder, K. E., Wallace, J. S., Padilla, A. R., & Vanderah, T. W. (2024). Co-occurrence of chronic pain and anxiety/depression symptoms in U.S. adults: Prevalence, functional impacts, and opportunities. Pain, 165(3), 666–673.
Mowlavi, A., Cooney, D., Febus, L., Khosraviani, A., Wilhelmi, B. J., & Akers, G. (2005). Increased cutaneous nerve fibres in female specimens. Plastic and Reconstructive Surgery, 116(5), 1407–1410.
Nurofen, Gender Pain Gap Index Report 2023 (https://www.nurofen.co.uk/static/nurofen-gender-pain-gap-index-report-2023-94a5039e65c1051240cc359d8bc2787a.pdf).
Banco, D., Chang, J., Talmor, N., Wadhera, P., Mukhopadhyay, A., Lu, X., Dong, S., Lu, Y., Betensky, R. A., Blecker, S., Safdar, B., & Reynolds, H. R. (2022). Sex and Race Differences in the Evaluation and Treatment of Young Adults Presenting to the Emergency Department with Chest Pain. Journal of the American Heart Association, 11(10).
Chen, E., Shofer, F., Dean, A., Hollander, J., Baxt, W., Robey, J., Sease, K., Mills, A. (2008) Gender disparity in analgesic treatment of emergency department patients with acute abdominal pain, Acad. Emerg. Med, 15(5), 414-8.
Maserejian, N. N., Link, C. L., Lutfey, K. L., Marceau, L. D., & McKinlay, J. B. (2009). Disparities in Physicians’ Interpretations of Heart Disease Symptoms by Patient Gender: Results of a Video Vignette Factorial Experiment.
Chen, Q., Zhang, W., Sadana, N., & Chen, X. (2021). Estrogen receptors in pain modulation: cellular signalling. Biology of Sex Differences 12(1).
De Kruijf, M., Bos, D., Huygen, F. J. P. M., Niessen, W. J., Tiemeier, H., Hofman, A., Uitterlinden, A. G., Vernooij, M. W., Ikram, M. A., & Van Meurs, J. B. J. (2016). Structural brain alterations in community dwelling individuals with chronic joint pain. American Journal of Neuroradiology, 37(3), 430–438.
Obo, J. J., McLean, S. A., Tungate, A. S., Peak, D. A., Swor, R. A., Rathlev, N. K., Hendry, P. L., & Linnstaedt, S. D. (2021). Polygenic risk scoring to assess genetic overlap and protective factors influencing posttraumatic stress, depression, and chronic pain after motor vehicle collision trauma. Translational Psychiatry, 11(1).
Onodera, Y., Kanao-Kanda, M., Kanda, H., Sasakawa, T., Iwasaki, H., & Kunisawa, T. (2017). Pregnancy suppresses neuropathic pain induced by chronic constriction injury in rats through the inhibition of TNF-α. Journal of Pain Research, 10, 567–574.
Sorge, R. E., Mapplebeck, J. C. S., Rosen, S., Beggs, S., Taves, S., Alexander, J. K., Martin, L. J., Austin, J. S., Sotocinal, S. G., Chen, D., Yang, M., Shi, X. Q., Huang, H., Pillon, N. J., Bilan, P. J., Tu, Y., Klip, A., Ji, R. R., Zhang, J.,Mogil, J. S. (2015). Different immune cells mediate mechanical pain hypersensitivity in male and female mice. Nature Neuroscience, 18(8), 1081–1083.
Paige, C., Plasencia-Fernandez, I., Kume, M., Papalampropoulou-Tsiridou, M., Lorenzo, L. E., David, E. T., He, L., Mejia, G. L., Driskill, C., Ferrini, F., Feldhaus, A. L., Garcia-Martinez, L. F., Akopian, A. N., De Koninck, Y., Dussor, G., & Price, T. J. (2022). A Female-Specific Role for Calcitonin Gene-Related Peptide (CGRP) in Rodent Pain Models. Journal of Neuroscience, 42(10), 1930–1944.
Chen, Y., Navratilova, E., Dodick, D. W., & Porreca, F. (2020). An Emerging Role for Prolactin in Female-Selective Pain. In Trends in Neurosciences, 43(8), 635-648.
Mogil, J. S., & Chanda, M. L. (2005). The case for the inclusion of female subjects in basic science studies of pain. Pain, 117(1-2), 1-5.
Mogil, J. (2016). Equality need not be painful. Nature, 535(7611).
NC3Rs Experimental Design Assistant- EDA (https://nc3rs.org.uk/our-portfolio/experimental-design-assistant-eda)
This article was written by Neave Smith and edited by Rebecca Pope, with graphics produced by Neave Smith and Ginevra Sperandio. If you enjoyed this article, be the first to be notified about new posts by signing up to become a WiNUK member (top right of this page)! Interested in writing for WiNUK yourself? Contact us through the blog page and the editors will be in touch.
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