Epidemiology and Sex Prevalence of Painful Diseases

Clinical and epidemiological studies have shown that many more painful diseases demonstrate a higher female prevalence than a male prevalence (Box 15-1), particularly for pain conditions involving the head and neck, of musculoskeletal or visceral origin, and of autoimmune cause. Furthermore, considering pain of unspecified or uncertain origin, epidemiological studies consistently reveal that women report more severe levels of pain, more frequent pain, pain in more areas of the body, and pain of longer duration than that reported by men (Unruh 1996, Berkley 1997, Dao and LeResche 2000, Isacson and Bingefors 2002).

 

Some of the higher female prevalence can be accounted for by female-specific problems that occur during a woman’s reproductive years and involve sex-specific organs, as opposed to fewer male-specific disorders. In many other cases, however, the differences are not as straightforward as they might seem. First, the overall prevalence patterns in both sexes for many types of pain (such as those of temporomandibular disorder [TMD], fibromyalgia, migraine, and gastrointestinal, abdominal, back, and joint pain) change across the life span. In some of these cases, the sex prevalence ratio changes with age, sometimes even reversing (LeResche 2000). Other influences that might bias sex difference estimates are differences in the symptoms and signs of some disorders, such as irritable bowel syndrome (IBS), acute appendicitis, migraine, rheumatoid arthritis, and coronary artery disease (Box 15-2; see also Berkley 1997, Weyand et al 1998, Weitzel et al 2001, Chang et al 2006). However, several pain conditions typically do not demonstrate sex differences in pain. One example is cancer pain, for which several studies report no sex differences (Turk and Okifuji 1999, Miaskowski 2004, van den Beuken-van Everdingen et al 2007), whereas fewer reports describe small and inconsistent sex differences in some aspect of cancer pain (Reyes-Gibby et al 2006, Valeberg et al 2008).

 

Other factors that contribute to higher female prevalence in several chronic pain conditions include gender-related psychological and sociocultural issues. It is recognized that women are more willing to report pain than men are and are more willing to seek health care (Isacson and Bingefors 2002). Thus, the apparent female sex prevalence of some conditions is consistently greater in clinical populations (i.e., among patients seeking health care) than in community ones. For example, the IBS female-to-male prevalence ratio in Western cultures is reduced from as high as 4:1 in patient populations to 2:1 or 1:1 in community-based samples (Hungin et al 2003). A similar reduction from 9:1 to 2:1 has been reported for TMD (LeResche 2000). Cultural differences are also relevant, though less studied. For example, IBS has a greater male than female prevalence in some Asian populations (Chial and Camilleri 2002, Chang et al 2006).

Sex and Gender Differences in Experimental Pain Sensitivity

Well over 100 papers have been published that report on sex or gender differences in experimental pain sensitivity. The majority of studies have reported that women have greater pain sensitivity than men do. However, a sizable number of experimental studies report no significant sex differences. It is not clear why studies differ in their findings in this regard. It has been suggested that sex differences are more likely to be found with certain types of stimuli or certain types of protocols. Two recent reviews suggest some ideas why such differences are normally, but not always, found (Table 15-1; Fillingim et al 2009, Racine et al 2012a). Thermal, pressure, electrical, and algesic chemical stimuli tend to reveal greater pain sensitivity in women. In contrast, studies using ischemic and exercise-induced myalgic stimuli largely fail to show sex differences in pain sensitivity. The few studies that have evaluated sex differences in the temporal summation of pain have reported greater female sensitivity more often than not. Pain thresholds and ratings reveal greater female sensitivity in about half the studies, with less pain tolerance found in approximately 75% of the studies. Thus, these factors of stimulus modality and perceptual level seem to have some relevance to the expression of sex differences in pain but do not fully explain the phenomenon.

An important point is that the differences between men and women in any of these pain measures is relatively small in comparison to the full range of variability found in the population. An apt analogy is the sex difference in height. We all recognize that on average, men are taller than women. At the same time we recognize that the range in heights within each sex provides a large amount of overlap in the populations. A graphic representation of thresholds, as one example, demonstrates this perspective (Fig. 15-1). Even though the mean (and median) pressure pain thresholds is higher in men than in women, the distributions are largely overlapping. One can easily see from such distributions that a particular sampling may or may not actually result in a statistically significant difference.

Related to this issue is that of sample size. Given the distribution of pressure pain thresholds derived from the OPPERA study (Greenspan et al 2011; depicted in Fig. 15-1), a power analysis indicated that a sample size of 49 per group is needed to identify a sex difference at α = 0.05 and a power of 0.80. As elaborated in previous reviews, most studies of sex differences in experimental pain used smaller sample sizes (Fillingim et al 2009, Racine et al 2012a).

Given this modest difference between the sexes, it is reasonable to ask whether this represents a biologically or clinically meaningful difference. One perspective is as follows. The lower end of this distribution represents the most pain-sensitive segments of the population. Considering the lowest 10% of the population’s distribution (Fig. 15-1), we find 4.8 times more women than men. Arguably, this segment of the population is the most susceptible to clinical pain problems by virtue of finding noxious and near-noxious events more painful than the rest of the population does. Consequently, it may be that the tail of this distribution is most relevant to the greater female prevalence of many clinical pain problems despite the large overlap in the populations as a whole.

Sex Differences in Nociception Derived from Animal Studies

Many factors contribute to the expression of sex differences in nociceptive behavior in animals. Biological variables such as genetics or gonadal hormone differences and experimental variables (e.g., type of test and tissue, flexion reflex or complex behavior, hormonal manipulation) all appear to play a role in the expression of sex differences, but not always in a consistent pattern. Consider the type of stimulus and measured end point. Mechanical or thermal cutaneous stimuli evoke a reflex withdrawal or coordinated movement when the stimulus reaches the nociceptive threshold. Radiant heat, a hot plate, or mechanical probing of the hindpaw or tail in normal animals (i.e., in the absence of injury) more often than not reveals sex differences, but the direction of effect varies depending on the strain and species (Mogil et al 2000, Terner et al 2003, Cook and Nickerson 2005, LaCroix-Fralish et al 2005a, Ribeiro et al 2005, Banik et al 2006, Wang et al 2006). In contrast, following inflammation or nerve injury, hyperalgesia in general is more robust (magnitude and/or duration) in females than in males (complete Freund’s adjuvant: Cook and Nickerson 2005, Wang et al 2006; formalin: Kim et al 1999, Gaumond et al 2002, but see Pajot et al 2003; capsaicin: Lu et al 2009b; nerve injury: LaCroix-Fralish et al 2005b, Dominguez et al 2009; temporomandibular joint [TMJ] and muscles of mastication: Cairns et al 2002, Bereiter et al 2005b, Gazerani et al 2010).

In contrast, in studies of visceral tissues, in the absence of injury females are more sensitive to noxious stimulation of common viscera (colon: Holdcroft et al 2000, Ji et al 2006; bladder: Ness et al 2001; ureter: Affaitati et al 2011, Aloisi et al 2010). One explanation for the predominantly greater sensitivity of females to visceral stimuli than to somatic stimuli may be the type of stimulation. Organ distention is typically longer in duration (tens of seconds), and test stimuli are usually above the noxious threshold and inescapable. The quantitative metric is not a withdrawal reflex, but rather a pseudo-affective response (e.g., visceromotor response, pressor response) or writhing behavior. The prolonged noxious visceral input could evoke central sensitization similar to mild somatic inflammatory stimuli with greater female sensitivity. Indeed, NMDA receptor signaling contributes to spinal processing of acute visceral, but not somatic, stimuli (Ji and Traub 2001, Traub et al 2002).

Human Studies

To a large extent, mechanistic studies related to sex differences in human pain have involved investigating the role of gonadal hormones. A meta-analysis of seven studies evaluating effects of the menstrual cycle on experimental pain identified some trends (Riley et al 1999). For most stimulus modalities, thresholds were higher during the follicular phase than during later phases of the cycle. Electrical stimulation–evoked pain thresholds, in contrast, were higher during the luteal phase. A subsequent review found that the literature had become more conflicting and concluded that there was little evidence for an effect of the menstrual cycle phase on experimental pain, with the possible exception of electrically evoked pain (Sherman and LeResche 2006). Since publication of these reviews, several other studies have addressed this topic. Many of them failed to find a significant difference in experimental pain measures across the menstrual cycle with the use of pressure (Sherman et al 2005, Vignolo et al 2008), heat (Granot et al 2001, de Leeuw et al 2006, Soderberg et al 2006, Klatzkin et al 2010, Teepker et al 2010), cold (Kowalczyk et al 2006, Klatzkin et al 2010), and ischemic stimuli (Straneva et al 2002, Sherman et al 2005, Klatzkin et al 2010). A smaller number of studies reported significant effects of the menstrual cycle on experimental pain, although the pattern of effects was quite different across studies (Hellstrom and Lundberg 2000, Bajaj et al 2002, Isselée et al 2002, Tassorelli et al 2002, Gazerani et al 2005, Stening et al 2007, Teepker et al 2010). Indeed, it is still not possible to make a general statement on the pattern of menstrual cycle effects that would apply to a majority of these and earlier studies. Even within a given study, significant cycle effects could be found for one measure but not another.

Only a small number of the aforementioned studies measured hormone levels at the time of testing. Of these, two reported no relationship between either estrogens or progesterone and any of their pain measures (Kowalczyk et al 2006, Soderberg et al 2006), some relationships for some measures but not others (Fillingim et al 1997, Teepker et al 2010), or a complex relationship between both estrogens and progesterone on pain measures that varied according to the measure (Stening et al 2007). Taken together, this literature provides little evidence of consistent gonadal hormonal influence on experimental pain sensitivity in the context of normal menstrual fluctuations in healthy women.

Fewer studies have addressed the topic of menstrual cycle and gonadal hormone effects on clinical pain. The severity of symptoms for headache (Arjona et al 2007, Keenan and Lindamer 1992), TMD (LeResche et al 2003), IBS (Heitkemper and Jarrett 1992, Kane et al 1998, Heitkemper et al 2003), and fibromyalgia (Pamuk and Çakir 2005) has been reported to vary significantly across the menstrual cycle. A common finding across these studies is greater pain during the perimenstrual phase. However, findings of no effects of the menstrual cycle on fibromyalgia pain (Alonso et al 2004, Okifuji and Turk 2006) and IBS (Lee et al 2007) have also been reported. Studies of peri- and postmenopausal women have produced variable results with respect to the effects of hormone replacement therapy (HRT). Several studies indicate that HRT is associated with increased TMD pain (LeResche et al 1997) and back pain (Symmons et al 1991, Brynhildsen et al 1998, Musgrave et al 2001). However, discontinuation of HRT has also been associated with increased musculoskeletal pain (Ockene et al 2005) and increased migraine frequency (Somerville 1972, Lichten et al 1996), but a large epidemiological study failed to find a relationship between HRT and musculoskeletal pain (Macfarlane et al 2002). Potentially rapid and large changes in hormone levels—either increases or decreases—could be the key factor by which estrogens and/or progesterone influences clinical pain.

Animal Studies

Sex Differences in Neural Processing of Pain as Revealed by Human Neuroimaging

Only about a dozen neuroimaging studies have addressed the question of sex differences in human pain processing (Table 15-2). The first of these studies, an ¹⁵O-positron emission tomography (PET) study using noxious heat stimuli, reported greater response in women than in men in several brain regions (Paulson et al 1998). However, a fixed-intensity stimulus was used, which evoked more intense pain in the women than in the men, thus leaving open the question of whether this was a sex difference or an intensity difference (Coghill et al 2003). Most subsequent studies applied stimuli that were perceived as being equally painful to the men and women, which often meant that the stimuli were of lesser intensity when applied to women. These studies tended to report greater activation for men than for women in some brain regions; however, there is considerable variability in results across studies. Two studies reported greater activation for men in some brain regions and greater activation for women in other regions, although the specific brain regions were not the same in the two studies (Derbyshire et al 2002, Naliboff et al 2003). One common finding across most of the PET and functional magnetic resonance imaging (fMRI) studies is greater activation in the insula for men than for women. There is no strongly consistent pattern for any other brain region.

Two fMRI studies evaluated heat pain–related responses at two different phases of the menstrual cycle (Choi et al 2006, de Leeuw et al 2006). Even though significant differences in pain-related activation were reported in both studies, there was little commonality in results (see Table 15-2).

Psychological, Social, and Cultural Factors Related to Sex and Gender Differences in Pain

Whereas the preceding sections focused on biological mechanisms underlying sex differences in pain, it is quite clear that psychological, social, and cultural factors influence the experience of pain. Consequently, these factors are potentially capable of influencing the sexes differentially.

Clinical Studies

Sex differences in response to analgesic medications have been explored in several studies (as reviewed by Kest et al 2000, Craft 2003, Fillingim and Gear 2004, Niesters et al 2010, Rasakham and Liu-Chen 2011). Though not a direct measure of analgesic response, studies of self-administration of opioids using patient-controlled analgesia (PCA) have been used to investigate sex differences in opiate analgesia. Several early studies revealed lower postoperative opioid consumption in women than in men (Miaskowski and Levine 1999). Along with the most direct interpretation of these results—greater analgesic efficacy in women—this lower opioid consumption in women could be driven by other factors, such as increased adverse effects, which have been documented in women (Fillingim et al 2005). Subsequent studies have provided a mixed picture of sex differences in opioid analgesia (Joels et al 2003, Gagliese et al 2008).

Recently, a systematic review of the literature on this topic considered 25 clinical studies on μ-opioids and found no significant sex–analgesia association (Niesters et al 2010). Restricting analysis to PCA studies identified greater analgesia in women (n = 15, effect size = 0.22, 95% confidence interval [CI] = 0.02–0.42, P = 0.028). Further restricting the analysis to morphine PCA studies yielded an even greater effect in women (n = 11, effect size = 0.36, 95% CI = 0.17–0.56, P = 0.003). A further analysis indicated that the longer the duration of PCA, the greater the difference between the sexes.

Others have investigated analgesic responses to mixed-action opioid agonist–antagonists in women relative to men. In several studies of pain after oral surgery, women have shown more robust and longer-lasting analgesic responses than have men in response to κ-opioid agonists such as pentazocine, nalbuphine, and butorphanol (Gear et al 1999, 2003). After endodontic surgery, women showed significantly greater pain relief with a pentazocine-naloxone combination than did men (Ryan et al 2008). In contrast, no sex differences in butorphanol analgesia were observed in patients treated in the emergency department for trauma-related pain (Miller and Ernst 2004).

Human Experimental Studies

Only a handful of studies have examined sex differences in analgesic responses using experimental pain models. As with clinical pain, most of these studies examined μ-opioid–mediated analgesia. A recent systematic review of this topic reported that women had greater antinociception from opioids (n = 11, effect size = 0.35, 95% CI = 0.01–0.69, P = 0.047), which was predominantly derived from six morphine studies (Niesters et al 2010). A previous review found little evidence of sex differences in opiate hypoalgesia for experimental pain and warned against interpreting data without reference to placebo effects (Fillingim et al 2009). One of the studies showing significantly greater hypoalgesia in women’s response to morphine also found a significantly greater hypoalgesic response to placebo. Adjusting for the placebo response eliminated the sex difference in morphine response (Pud et al 2006).

Three studies have reported on sex differences in the hypoalgesic effects of non-opioid pain medications in response to experimental pain. Two studies using non-steroidal anti-inflammatory drugs produced mixed results, with one showing greater effects of ibuprofen for electrical stimuli in men than in women (Walker and Carmody 1998) and another study showing no sex differences in effects on tolerance of cold pain (Compton et al 2003). In this latter study, men showed substantially increased tolerance in response to both placebo and ketorolac, whereas females showed no placebo response and a very modest increase in response to ketorolac. A third study reported that lidocaine iontophoresis produced greater cutaneous anesthesia to pressure pain in men than in women (Robinson et al 1998). These few and very different studies prevent any general statement at this time.

Another aspect of experimental pain sensitivity that has been evaluated with respect to sex differences is the ability to evoke endogenous analgesia. This has been evaluated most often in the context of conditioned pain modulation (CPM; previously termed diffuse noxious inhibitory control [DNIC]) (Yarnitsky et al 2010), in which one painful stimulus is administered to evaluate its effect on the pain evoked by another painful stimulus. In other studies, stressors are administered to evaluate their effects on experimental pain perception. Based on recent reviews of this literature (Fillingim et al 2009, Popescu et al 2010, Racine et al 2012b), 9 of 19 CPM studies showed a significantly greater analgesic effect in men, and all but 1 of the other studies showed no sex difference. In contrast, four of six studies evaluating the effects of stress on experimental pain found a significantly greater analgesic effect in women, whereas two studies reported no sex difference (Table 15-3). Given the multiple systems involved in these types of studies (attentional, stress related, cognitive), it is easy to envision that results can vary from study to study, even when using the same protocol. For example, one study reported no sex difference in the degree of endogenous analgesia provoked in a CPM protocol, yet the relationship between the self-reported stressfulness of the protocol and the degree of analgesia was very different for men and women (Quiton and Greenspan 2007). In another instance, a sex difference in CPM analgesia could be eliminated if the results were statistically corrected for catastrophizing (Weissman-Fogel et al 2008). Both these studies exemplify the important role that psychological factors play in pain assessment, even in the context of a controlled experimental environment.

One research group used PET with radiolabeled carfentanil (a μ-opioid receptor agonist) to evaluate the cerebral mechanisms underlying endogenous analgesic mechanisms. In the absence of pain, μ-opioid–binding measures were found to be higher for women than for men in several brain regions. Interestingly, this difference decreased with age, with levels tending to be reduced in older women (Zubieta et al 1999). In the presence of pain, men showed greater activation of the μ-opioid system than did women in regions such as the thalamus, amygdala, and basal ganglia, and women showed a reduction in μ-opioid activation in the nucleus accumbens (Zubieta et al 2002). These results suggest greater engagement of the endogenous opioid system in men than in women when experiencing pain. A third study evaluated the endogenous opioid system in response to painful stimulation when women were in the follicular phase of their cycle, either with or without estradiol supplementation (Smith et al 2006). When tested in the high-estradiol condition, women reported lower pain ratings and showed greater μ-opioid activation in the thalamus, nucleus accumbens, and amygdala. Perhaps counterintuitively, the high-estradiol condition resulted in a response profile that was more similar to the male response than the low-estradiol condition was. Nonetheless, the explicit manipulation of estradiol levels, rather than relying on menstrual cycle effects, allowed the authors to conclude that estradiol functioned in an antinociceptive manner that involved engagement of components of the endogenous opioid system.

Animal Studies

The effects of sex, hormones, and genotype on analgesic mechanisms in rodents, especially opioids, have been extensively reviewed (Fillingim and Ness 2000, Kest et al 2000, Craft 2003, Craft et al 2004, Fillingim and Gear 2004, Dahan et al 2008, Hurley and Adams 2008, Loyd and Murphy 2009, Bodnar and Kest 2010). One main point is that sex differences and hormonal effects are inversely correlated with opioid efficacy and intensity of the noxious stimulus: the more effective the opioid or the more intense the stimulus, the less obvious are differences based on sex or hormonal milieu. When sex differences are found, they tend to indicate that μ- and κ-opioid agonists produce greater antinociception/analgesia in males than in females. Several factors contribute to this finding. Males express more μ-opioid receptor protein in the spinal cord and midbrain, especially when compared with females in proestrus (Kren et al 2008, Loyd et al 2008, Murphy et al 2009). The greater antinociception in males is also due in part to the activational effects of testosterone; Craft and colleagues (2004) reported on 16 studies in rodents and found greater (7/16, 44%) or equal (6/16, 37%) morphine antinociception in intact males and gonadectomized males with testosterone replacement than in gonadectomized males without replacement. In females, estrogen appears to decrease morphine analgesia; ovariectomy increased morphine’s effect (more pronounced at shorter times following ovariectomy), which was reversed by estradiol replacement (Craft et al 2004, Stoffel et al 2005, Ji et al 2007). However, increasing or decreasing morphine antinociception may be dose and time dependent (Craft et al 2008). Other opioids follow a similar pattern of testosterone increasing antinociception and estradiol decreasing antinociception (Stoffel et al 2005, Claiborne et al 2006).

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