Sex/Gender Biases in Pain Research and Clinical Practice

What Are Sex/Gender Biases in Pain Research and Clinical Practice?

• Sex/gender biases describe a tendency to (un)favor a group of individuals over another based on their sex/gender categorization [1]. They reflect unjustified stereotypical preconceptions and prejudiced attitudes towards females/women, males/men, or gender-diverse people, that may lead to discriminatory actions. In patriarchal societies, such biases often reflect a tendency to favor males/men over females/women and gender-diverse people. They are culture-bound, contextual and intersect with other social positions and identities like age, ethnicity, sexual orientation and/or socioeconomic status. 
• Sex/gender biases can be explicit (i.e., conscious) or implicit (i.e., unconscious). Explicit and implicit biases can be contradictory [1]. For example, health care professionals or researchers may be explicitly committed to egalitarian values but implicitly hold gender stereotypical beliefs that shape their clinical judgements or their conceptual/methodological approaches, respectively.
• Two main types of sex/gender biases can be found in the health field [2]:
  • Disregarding real or potentially relevant sex/gender differences under the assumption that females/women and males/men are “the same” or have similar needs, e.g., when females/women are excluded from clinical trials under the assumption that findings may be generalizable from male/men samples.
  • Assuming differences between the sexes/genders when similarities should be acknowledged, e.g., underassessing a woman’s pain compared to a man’s pain despite similar complaints and needs.

Are There Sex/Gender Biases in Pain Research? 

Sex Biases in Preclinical Research:

• Preclinical studies of pain have been historically performed exclusively in male rodents (rats and mice), because of the fear that cycling gonadal hormones (i.e., estrogen and progesterone) would “complicate” things in females and lead to higher levels of variability in the data, necessitating the use of more animals and raising costs. This fear was shown to be unfounded in studies of pain [3] and in biomedicine more generally. If anything, it is male rodents that feature higher levels of variability. 
• A review of preclinical research published in the journal Pain from 1996–2005 showed that 79% of studies featured the exclusive use of male rats/mice, with an additional 3% of studies not even specifying the sex of the research subject [3]. A similar review of Pain papers published in 2015 showed that nothing had changed over 20 years; again, 79% of studies used males only [4]. 
• This use of male rodents to model conditions overwhelmingly affecting women is clearly unethical. In response, funding agencies around the world are instituting sex-as-a-biological-variable (SABV) mandates, i.e., policies recognizing sex as a variable to consider in research design, analysis and reporting. At the National Institutes of Health in the U.S., such a mandate was announced in 2014 and went into effect in 2016 [5] .
• A review of preclinical papers published in Pain from 2015–2019 showed that by 2019, only 50% of papers used males only [6]. However, of 127 identified studies in which both sexes were tested, and the experimental manipulation was found to “work” in one sex but not the other, 72% of the time it worked in males but not females [6]. This suggest that the literature is now thoroughly biased such that findings in males generate hypotheses that are found to be true only in males. We are thus likely only at early stages of understanding female pain biology in animal models.

Sex/Gender Biases in Clinical Research:

• Most current pain theories do not integrate sex/gender factors and most pain research with humans does not analyze nor report sex/gender differences. A systematic review of publications in Pain from 2012-2021 concluded that less than 20% presented data disaggregated by sex [7].
• Although recent studies have a more balanced representation of the sexes [7], sampling bias can still be found. As females/women are more likely to seek support or attend pain clinics, there is an overrepresentation of females/women in clinical studies. Conversely, experimental studies have a higher proportion of males/men in their samples, as masculine-identifying individuals are more likely to volunteer for experimental pain studies [8].
• Assessment of demographic characteristics is still often unable to tap the diversity of the sexes and gender identities, going little beyond “female/woman, male/man, other”. Furthermore, gender-diverse populations are often lumped together or excluded from the data analysis, contributing to their marginalization in knowledge production [8].
• Dominant stereotypical sex/gender binary views still shape most research conceptual assumptions and designs [8]. For example, within-sex variations in biological factors (e.g., sex hormones) that may be linked to pain experiences have been less investigated. Also, research has mostly been focused on traditional western conceptions of femininity and masculinity, sometimes seen as mutually exclusive, instead of coexisting within all human beings. Indeed, little pain research has explored the diversity and fluidity of femininities and masculinities, which are often shaped by situational cues and other social positions (e.g., age, culture, ethnicity, social class). 

Are There Sex/Gender Biases in Clinical Practice?

• Sex/gender biases can influence pain communication, assessment and treatment decisions occurring within clinical encounters. Many studies have shown sex/ and gender biases in acute and chronic pain contexts.
• Regarding acute pain, various studies have been conducted in emergency medical settings and post-operative pain contexts:
  • A scoping review of articles published from 1960-2021 on biases in emergency medical services (EMS) in the US [9] concluded that although women are quicker in recognizing the signs and symptoms of acute coronary syndromes (such as chest pain), they wait longer to access the EMS system after seeking help compared to men. However, there was no clear consensus on sex/gender biases in prehospital interventions for acute coronary syndrome (e.g., ECG, aspirin or nitroglycerin) nor prehospital pain management. 
  • A systematic review of studies on biases in post-operative pain and pain management published from 1992-2022 [10] showed women reported higher postoperative pain scores than men in most studies but received less pain medication than men in more than half the studies.
• Regarding chronic pain, a theory-driven review of quantitative and qualitative studies published from 2000-2015 on gender bias in pain care [11] showed that, compared to men, women more often:
  • must struggle for their pain to be seen as legitimate in the context of clinical encounters: their pain is more psychologized, mistrusted and judged as unreliable depending on their appearances (e.g., looking too good or not looking good enough) .
  • receive more referrals to psychological treatments, less effective pain relief, fewer opioid analgesics, and more antidepressants. 
• This review [11] also showed that pain-related gender norms – stereotypical expectations regarding how men and women are and should behave when in pain – may partially account for such sex/gender biases in clinical practices. Indeed, there are widely shared expectations across various cultures that, in public spaces such as the clinical encounter:
  • men with chronic pain are stoic, autonomous, in control, pain tolerant, avoid talking about pain and seeking help. They are also expected to prioritize paid work over household duties.
  • women with chronic pain are often described in comparison with men (andro-normativity), being perceived as more sensitive to pain, more willing to report pain and sometimes as hysterical, malingerers or feigning the pain. They are also expected to engage in self-care practices more than men.
• Although implicit prejudice (e.g., unconscious negative attitudes) may also be an underlying mechanism of sex/gender biases in clinical practices, it has been much less investigated. A scoping review of articles published between 2011 and 2021 on health professionals’ unconscious bias in different regions of the world [12] showed that only 13% of studies focused on gender biases and a minority of those did so in pain contexts.
• Although many studies show biases against women in acute and chronic pain contexts, some studies suggest the absence of biases or even (although less frequently) biases against men. For example, a systematic review  and meta-analysis [13] showed that, health care providers significantly underestimate  patients’ pain, especially when most of the patients in the study sample were males/men (vs. females/women). This suggests that sex/gender biases in clinical practice are variable and most likely context dependent [14].

How can we Minimize Sex/Gender Biases in Pain Research and Clinical Practice?

• To minimize sex/gender biases in pain research, researchers can familiarize themselves with existing guidelines and recommendations to integrate sex and gender in health (and pain) research, such as the:
  • Sex- and Gender-Based Analysis (SGBA) approach of the CIHR Institute of Gender and Health.
  • Sex and Gender Equity in Research (SAGER) Guidelines [15].
  • recent recommendations by Keogh and Boerner [8] on how to embed and integrated sex and gender perspective in pain research.
• The Genderful Research Consortium Platform is an example of a particularly useful initiative that “provides an overview of key resources per stage of biomedical, clinical and public health research”. 
• As for clinical practice, the first step to counter sex/gender biases is to raise awareness about them. There is, however, a lack of effective evidence-based interventions to overcome or reduce gender biases in clinical practice in general [16].
• Nonetheless, some tools can be found that aim to facilitate this process in pain contexts, such as the “gender equality tool” [17] that supports the analysis of gendered and social processes in the clinical assessment of pain through questions addressed at workplaces and professionals directly. 
• Increased awareness about sex/gender bias in clinical practice is an ongoing process and it is important that health care organisations, colleagues and every individual professional find procedures and routines for how to discuss explicit and not least implicit biases continuously. 

References:

1. Brewer MB. Intergroup discrimination: Ingroup love or outgroup hate? In CG Sibley,  FK Barlow (eds.), The Cambridge Handbook of the Psychology of Prejudice. Cambridge: Cambridge University Press, 2017, pp. 90–110.
2. Risberg G, Johansson E, Hamberg K: A theoretical model for analyzing gender bias in medicine. Int J Equity Health 2009: 28, 1-8.
3. Mogil JS, Chanda ML: The case for the inclusion of female subjects in basic science studies of pain. Pain 2005; 117: 1-5.
4. Mogil JS. Equality need not be painful. Nature 2016; 535:S7.
5. Clayton JA, Collins, FS. Policy: NIH to balance sex in cell and animal studies. Nature 2014; 509 (7005): 282-283.
6. Mogil JS. Qualitative sex differences in pain processing: Emerging evidence of a biased literature. Nat Rev Neurosci 2020; 21: 353-365.
7. Plumb AN, Lesnak JB, Berardi G, Hayashi K. Janowski AJ,  Smith AF,  Bailey D, Kerkman C, Kienenberger Z, Martin B,; Patterson E, Van Roekel H,  Vance CGT,  Sluka A:  Standing on the shoulders of bias: lack of transparency and reporting of critical rigor characteristics in pain research. PAIN 2023; 164(8):1775-1782.
8. Keogh E, Boerner KE. Challenges with embedding an integrated sex and gender perspective into pain research: Recommendations and opportunities. Brain Behav Immun 2024;117:112–121.
9. Farcas AM, Joiner AP, Rudman JS, Ramesh K, Torres G, Crowe RP, Curtis T, Tripp R, Bowers K, von Isenburg M, Logan R, Coaxum L, Salazar G, Lozano M Jr, Page D, Haamid A. Disparities in Emergency Medical Services Care Delivery in the United States: A Scoping Review. Prehosp Emerg Care. 2023;27(8):1058-1071.
10. Thurston KL, Zhang SJ, Wilbanks BA, Billings R, Aroke EN: A Systematic Review of Race, Sex, and Socioeconomic Status Differences in Postoperative Pain and Pain Management. J Perianesth Nurs. 2023;38(3):504-515.
11. Samulowitz A, Gremyr I, Eriksson E, Hensing G:  “Brave men” and “emotional women#: A theory-guided literature review on gender bias in health care and gendered norms towards patients with chronic pain. Pain Res Manag 2018; ID6358624.
12. Meidert U, Dönnges G, Bucher T, Wieber F, Gerber-Grote A: Unconscious Bias among Health Professionals: A Scoping Review. Int J Environ Res Public Health. 2023 12;20(16):6569.
13. Ruben, MA, Blanch-Hartigan, D., & Shipert JC: To know another’s pain: A meta-analysis of caregivers’ and healthcare providers’ pain assessment accuracy. Annals Behav Med 2018; 52 (8): 662-685.
14. Bernardes SF, Lima ML: On the contextual nature of sex-related biases in pain judgments: The effects of pain duration, patient’s distress and judge’s sex. Eur J Pain 2011; 15(9): 950–957.
15. Heidari S, Babor TF, De Castro P et al. Sex and Gender Equity in Research: rationale for the SAGER guidelines and recommended use. Res Integr Peer Rev 2016; 1, 2.
16. Alcalde-Rubio L., Hernandéz-Aguado I, Parker LA, Bueno-Vergara E, Chilet-Roselt E: Gender disparities in clinical practice: A there any solutions? Scoping review of interventions to overcome or reduce gender bias in clinical practice. Int J Equity Health 2020; 19: 166.
17. Hammarström A, Wiklund M, Stålnacke BM, Lehti A, Haukenes I, et al: Developing a Tool for Increasing the Awareness about Gendered and Intersectional Processes in the Clinical Assessment of Patients – A Study of Pain Rehabilitation. PLOS ONE 2016; 11(4): e0152735.