Chapter 9 - Sex and gender differences in pain and analgesia

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Abstract

It is a clinical reality that women make up the large majority of chronic pain patients, and there is now consensus from laboratory experiments that when differences are seen, women are more sensitive to pain than men. Research in this field has now begun to concentrate on finding explanations for this sex difference. Although sex differences in sociocultural, psychological, and experiential factors likely play important roles, evidence largely from animal studies has revealed surprisingly robust and often qualitative sex differences at low levels of the neuraxis. Although not yet able to affect clinical practice, the continued study of sex differences in pain may have important implications for the development of new analgesic strategies.

Introduction

Sex and gender differences in pain and analgesia—fully cognizant of definitional issues (Institute of Medicine, 2001), we will hereinafter use the term “sex” for convenience—are simultaneously of great interest and largely ignored. On the one hand, the study of sex differences has exploded as a subfield of pain research. The interest largely stemmed from a few review articles in the mid-1990s pointing out that interest was lacking despite overwhelming evidence of the differential clinical pain experience of men and women (Berkley, 1997, Fillingim and Maixner, 1995, Unruh, 1996). The topic was championed by the US National Institutes of Health (NIH), which responded by organizing a scientific conference, a Request for Proposals, and the awarding of two P50 (Specialized Centers of Interdisciplinary Research) grants. At the 1996 World Congress on Pain, a special interest group of the International Association for the Study of Pain (IASP) was established. This same group published a consensus report on the topic in 2006 (Greenspan et al., 2007). The growth in the subfield can be appreciated by considering that a PubMed search for “(sex OR gender) AND pain” yields 1753 published papers between 1990 and 1995 but 6741 published papers between 2005 and 2010 (see also Fig. 1 in Fillingim et al., 2009).

At the same time, despite high interest by funders and some pain researchers, and consistent interest shown by the media, the topic of sex differences in pain and analgesia has continued to be steadfastly ignored by the wider pain research community. Clinical trials are, of course, now required by many governments to be conducted in both men and women (in the United States, since 1994), but there is no such requirement for basic and translational research. We surveyed the basic science of pain literature from 1996 to 2005 by considering papers using rats or mice as subjects in the flagship journal, Pain, and discovered that 79% of all published papers tested male subjects exclusively. In addition, 5% of papers tested both sexes but did not report any analyses of possible sex differences, and 3% did not report the sex of their subjects. There were no apparent trends toward increased use of female subjects in this decadal period. In fact, the only sign of progress was that subject sex was reported in 97% of papers, in contrast to Karen Berkley’s survey of neuroscience papers from 1991 in which subject sex was reported in only 55% (Berkley, 1992). The male bias in basic science research is by no means limited to the pain field (Beery and Zucker, 2010).

Why are female subjects avoided by pain researchers even though a clear majority (perhaps 70%) of chronic pain patients are women (Berkley, 1997)? There appear to be three explanations. The first is simple inertia; pain researchers are loathe to change their choice of subjects in the middle of their research careers for fear that new data will not be easily comparable with old data. Second, female subjects are avoided based on the expectation that hormonal cyclicity will add to experimental variability, necessitating larger sample sizes to obtain statistically significant differences. There may in fact be gonadal hormone effects on pain and analgesic sensitivity (see Fillingim and Ness, 2000 for review), but as an empirical fact, in at least two major algesiometric assays in the mouse (the tail-flick and formalin tests) data sets obtained in female subjects do not feature increased variability compared to males (Mogil and Chanda, 2005), perhaps due to the fact that male rodents have sex-specific variability as well (i.e., cage dominance). Finally, pain researchers often view sex differences in pain as small, contradictory, and inconsequential. We obviously believe this view to be false, and will attempt to demonstrate this in the sections that follow.

Section snippets

Clinical epidemiology of pain

The consensus from the many population studies that have been conducted is that, even apart from menstruation, pregnancy, and childbirth, women are more likely to report the presence (point, period, and lifetime prevalence) of pain, higher severity of pain, higher frequency of pain, pain in more anatomical regions, and longer duration of pain than men (see Fillingim et al., 2009, LeResche, 2000, Unruh, 1996 for reviews). The median prevalence (current to 12-month) in 10 relevant epidemiological

Laboratory studies of sex differences in pain

The epidemiological realities described above may or may not suggest that females have increased sensitivity to pain. Women in fact have higher morbidity from acute and chronic diseases across the board, and are far more likely than men to seek medical care (Briscoe, 1987). Thus, the idea that women are overrepresented as chronic pain patients because they are more sensitive to pain is an empirical hypothesis that needs to be directly tested in the laboratory. A large number of such experiments

Sociocultural

The masculine gender role has been associated with an increased tolerance to pain among males in experimental studies (Myers et al., 2003, Otto and Dougher, 1985, Sanford et al., 2002), and decreased chronic pain complaints in clinical studies (Applegate et al., 2005, Trudeau et al., 2003), although other studies have shown no differences. It is usually assumed that this is due to social roles for men encouraging and rewarding stoicism (and punishing overt pain expression), whereas females are

Why should sex differences in pain exist?

We turn finally to the ultimate (rather than proximate) causes of sex differences in pain and analgesia; that is, why should they exist. To our knowledge there are three competing hypotheses: (1) pregnancy-induced analgesia (PIA) as a female-specific system; (2) separate adaptive pressures in males versus females; and (3) the “reproductive spandrel” hypothesis.

Alan Gintzler’s laboratory has for many years studied the phenomenon of PIA, whereby the nociceptive sensitivity of rats to electric

Conclusions

Although much is left to be explained with respect to sex differences in pain and analgesia, we believe the existing data make a compelling case for the inclusion of both sexes in all biomedical research on pain, even at the basic science level. It can be readily admitted that the existing data have had limited clinical impact thus far. However, the increasing evidence of qualitative sex differences in this domain presages a day when sex-specific analgesic therapies might be developed.

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