Sonya K. Christianson
SEX DIFFERENCES IN PAIN
Do men and women experience pain differently? Understanding and alleviating pain is a universal endeavor that is constantly evolving, revealing new information and new questions. The pain phenomenon incorporates an enormity of contributions that are currently being studied. These include, among many others, a person’s age, hormones, culture, medical comorbidities, psychological state, social dynamics and stressors, family structure, and physical environment. As the field of studying pain continues to advance, the complexity of the pain experience becomes more apparent. There have been many new interesting observations made, such as sex-specific changes in hemodynamic and autonomic measures in acute pain (1) and differences in spatial pattern seen in cortical imaging (2–4). Polymorphisms or mutations in certain genes may play a role in sex differences, as well as the influence of past experience of pain (5–8).
Understanding pain is crucial to comprehensive sports medicine. As providers, we strive to diagnose and treat pain in our athletes to maximize their performance and to keep them safe from injury. The idea that there are differences in the pain experience that are specific to a person’s sex is well recognized and generally accepted. However, the question of how this contributes to the mosaic of the pain experience remains difficult to delineate in our clinical practice. Perhaps this merely serves to stir our excitement for exploration and a more complete understanding of pain in men and women.
Pain in the General Population
Very few studies have specifically looked at sex differences in athletes with pain. In general, there is evidence that athletes have a higher tolerance for pain than nonathletes, the reasons for which are multifactorial and still being studied (9,10). Pain management in sports medicine is a rapidly growing field, but clear and consistent answers regarding sex differences in pain for athletes still remain as elusive as they do for the general population. For the time being, we will have to derive our understanding of sex differences in pain from this still limited but larger pool of literature addressing the general population of men and women.
Across many studies, pain has been shown to be more prevalent in women than in men. Higher pain prevalence in women is consistently observed, and the pain that women report is more severe, more frequent, more diffuse, and of longer duration than that reported by men. This difference appears to be consistent across nations, race, and culture (11–19). There are some specific pain disorders that are seen more commonly in women than in men. These include fibromyalgia, inflammatory bowel disease, back pain, migraine, tension headaches, neck pain, temporomandibular joint disorders, osteoarthritis, and rheumatoid arthritis (20). Women are also more likely than men to experience multiple pains simultaneously (21–23).
It seems that these sex differences in pain prevalence emerge during adolescence. In boys and girls who have similar experiences in pain, it was found that girls recalled a higher pain intensity of the experience than boys did (24). As girls go through puberty, increasing rates of pain conditions were found in girls. In contrast, the rates of pain conditions in boys remained stable or increased at a slower rate (25).
As people age, these sex differences in the prevalence of pain are found to persist. In the elderly population, there is a higher prevalence of pain in females than in males—similar to the overall prevalence in younger patients (26). Although this overrepresentation of women is consistently seen, it is not well understood. Herein lie the questions that many have attempted to answer over the last few decades. There has been a wealth of research supporting a variety of theories for these sex differences in pain.
Laboratory Studies in Pain
Sport-related pain is more complex than the pain studied in artificial laboratory conditions. The pain that athletes experience usually arises from multiple different stimuli under highly varied environments. For example, a marathon runner could be experiencing lower extremity pain simultaneously from generalized muscle fatigue, hypoxic muscle cramping, tendinopathy, a pressure ulcer, and a sunburn. The pain in any one of these components could be considered a combination of heat/cold pain, ischemic pain, chemical pain, or pressure pain. With many varied factors at hand, it is quite difficult to study the true experience of athletes’ pain in controlled, calculated environments. The best data we have come from highly isolated situations yielding results that are limited and vague in application to our targeted population of athletes. The application of available data in clinical practice is subjective and varies by clinician—this must be understood as we review the available data on sex-specific pain differences in the laboratory setting.
Laboratory studies in pain utilize a variety of nociceptive stimuli: cold pain, heat pain, pressure pain, ischemic pain, muscle pain, chemical pain, electrical pain, or visceral pain. In response to one or more of these stimuli, outcome measures include pain threshold, pain tolerance, pain intensity, and pain unpleasantness. Pain threshold is defined as the least experience of pain that can be identified by a subject; pain tolerance is defined as the highest level of pain that a subject is ready to tolerate (27). For example, we can consider the pain threshold of a ballet dancer standing en pointe (on toe). A dancer with a high pain threshold would be able to stand for a longer period of time before beginning to identify pain. In contrast, pain tolerance would be considered the amount of time the dancer continues to stand en pointe while experiencing increasing amounts of pain.
Pain intensity and unpleasantness are subjective scales that can be assessed with validated instruments such as the visual analogue scale (VAS), numerical rating scale (NRS), or verbal rating scale (VRS) (28). Because pain is subjective, standardized scales are difficult to design and remain prone to intersubject variability. For example, in the numerical rating scale, the subject is instructed to consider a 10 the “worse pain you can possible imagine” and 0 as “no pain.” One can envision that the “worse pain you can possibly imagine” may actually be quite different from person to person. Perhaps it is even dependent on how big an imagination the person has! Despite this, we can rely on consistency within one subject across successive ratings (29).
Pain tolerance and threshold in athletes has been compared to nonathletes. A meta-analysis of 15 studies found that athletes consistently show a higher pain tolerance than normally active control subjects (30). In contrast, differences in pain threshold were not found to be significant. It appears that athletes actually feel the same initial pain that everyone else does. The difference is that they are able to tolerate it more significantly or continue despite the pain to higher levels of performance. Whereas some people may stop running at the first leg cramp, athletes will “push through” the pain to climb the next hill.
There have been very few, small studies that seem to support male athletes having a higher pain threshold and tolerance than female athletes (31,32). This reflects some of the studies of nonathletes in the general population; some general population studies have shown sex-specific differences in pain, but clear and consistent patterns across studies have not been seen (33,34). Sex differences in response to pain stimuli are variable as a function of the type of stimuli used and the outcome being measured. As mentioned previously, the wide variety of nociceptive stimuli used and the inconsistency of outcomes measured are problematic in drawing general conclusions. A review of 10 years of research suggests that males and females have comparable thresholds for chemical pain and ischemic pain, while pressure pain thresholds were lower in females. In terms of tolerance, there is strong evidence that females tolerate less pressure and thermal pain than males, but tolerance for ischemic pain is comparable between men and women (35). Studies that measured subjective pain intensity and unpleasantness found no sex differences across many different pain stimuli (36–38). Because of the variability of these studies, it is difficult to draw generalized conclusions about gender differences for the pain experience in a laboratory setting. If we were to try and apply these data clinically, would this mean that females were more vulnerable to pain from pressure ulcers? Do they perform more poorly in the hot sun or in snowy conditions? It is difficult to know what data are truly applicable for our patients, and more research is needed for further education.
Animal and Rodent Studies
Pain in animals is measured by observing animals’ aversive behavior in response to stimuli. Pain stimuli used in many rodent studies include formalin administration, exposure to complete freund’s adjuvant (CFA), injection of carrageenan, and others. Some examples of observed pain behavior include flinching responses, writhing behavior, or licking/shaking of their paws. Different animal models have been developed to mimic human pain syndromes, such as inflammatory pain, temporomandibular disorder pain, and neuropathic pain (39).
Animal and rodent studies have shown differences between the sexes in the pain experience. Compared to human studies, rodent studies have demonstrated more consistent sex differences in pain. Female rats have demonstrated a lower pain threshold by showing increased pain behaviors in response to pain stimuli (39,40). Male mice were also found to have a general higher level of activity in the endogenous analgesic system compared to females, including a stronger analgesic response to mu-opioid receptor agonists. There is some small evidence that female rats have lower levels of stress-induced analgesia (41).
Nociception and Analgesics
Opioids are sometimes considered illegal drugs during competition. However, the role of opioids in athletic performance is more complicated than we think. An interesting simulation was demonstrated in a study by Benedetti, Pollo, and Colloca in 2007 (42). During the precompetition training phase, repeated doses of morphine were administered to subject athletes. On the day of competition, the morphine was replaced with placebo and induced opioid-mediated increase of pain endurance and physical performance. This pharmacologic conditioning may have practical implications and brings to question whether opioid-mediated placebo responses are ethically acceptable in sports competitions.
Commonly known as the “runners’ high,” it is known that the release of endogenous opioids, or endorphins, in response to exercise is a significant physiologic phenomenon. Elevated levels of endorphins have been linked to changes in pain perception, mood, and hormonal responses (43,44). Nociception refers to the neurobiological receptors and connectivity of the somatosensory nervous system that constitute the pathways of the pain experience (27). Several opioid receptors have been identified and studied as significant components of nociception, the originally classified receptors being the mu-, delta-, and kappa-opioid receptors (45). There may be some sex-specific differences in the activation of these receptors. Sex differences in the opioid, dopaminergic, serotoninergic, and other endogenous pain-related systems have been documented (46–49). The mechanisms that mediate these phenomena are poorly understood and still being studied. Most studies have been performed using animal models or in laboratory settings using healthy human volunteers. The resulting evidence has been mixed, and consistent data to support sex-related differences have not yet been found.
For thousands of years, opioid receptors have been the target for pain treatment and are the most widely used analgesics in clinical practice. One might think that we could further our understanding of the pain experience by studying how opioid medications are utilized and consumed between men and women. However, the results are varied. Overall, there is mixed evidence for differences between men and women in the efficacy and use of morphine and other opioids. When men and women of equal pain scores were compared postoperatively, opioid consumption was found to be higher in men (50). In cancer pain, no significant sex differences were found in analgesic prescriptions or intake of analgesic medications (51). A study with epidural steroid injections showed no sex differences in the magnitude of treatment response (52). There is relatively stronger evidence for greater analgesic efficacy in women of mixed opioid agonist-antagonists (pentazocine, nalbuphine, and butorphanol) (53–63). Women do experience increased adverse reactions to opioid medications as compared to men, particularly nausea and vomiting (64–66).
Opioid Prescription and Aberrant Behavior
There has been concern that athletes are at higher risk for being chronic users of opioid medications. National Football League (NFL) players with injury-related pain are at increased risk for opioid use and misuse, resulting in medical, psychiatric, and social problems. Players who misused opioid medications during their NFL careers were more likely to misuse them after their careers were finished (67). Over 100,000 people have died from prescribed opioids in the United States since the late 1990s. In adults age 35 to 54, these deaths have exceeded mortality from firearms and motor vehicle accidents (68). From 1997 to 2006, the number of fatal overdoses from prescription opioids quadrupled, exceeding those from heroin or cocaine (69,70). In the treatment of chronic pain, providers can be heavily scrutinized in the prescription of scheduled medications, and the fear of addiction or misuse of these medications is an issue that commonly arises.
Among chronic pain patients, some aberrant prescription use behaviors may be sex-specific. Aberrant behaviors that are associated with risk for abuse include lack of adherence to prescription instructions, use via unintended routes (oral versus crushing and snorting), a higher number of prescriptions from the emergency department (ED), multiple or overlapping prescriptions, illegitimate prescriptions, drug dependence disorders, functional impairment, and psychiatric comorbidities (71).
Studies reveal that both men and women have been observed with aberrant behaviors and are at risk for medication abuse. Women are more likely to be regular and long-term opioid users (69,70). More women are prescribed opioids in the ED, have higher dosages prescribed in the ED, and are more likely to have multiple and overlapping prescriptions (72). However, women are more likely than men to use opioids consistent with their prescription instructions, are more likely to use via the intended route of administration, and are more likely than men to have first obtained opioids via legitimate prescriptions (73).
Men acknowledge more misuse of prescription analgesics compared with women (74). Adult men are two to three times more likely than women to have drug dependence disorders, but the rate of escalation of drug use is higher in women (75). Women prone to opioid misuse exhibit greater functional impairment, more psychiatric comorbidities, and higher likelihood of using opioids to cope with psychiatric symptoms and pain than men.
Social and Cultural Influences
Some cultures and societies treat male and female athletes quite differently (76) and create significant differences in athletes’ perceptions and expectations (77). Some people postulate that the gender differences in the pain experience are due to the social and cultural expectations that women have versus men. Some people suggest that it is more socially acceptable for women to express or exhibit signs of pain, or that perhaps men are socially discouraged to express or report pain (78,79).
The social interaction between research subjects and investigators has also been studied. Clinicians themselves can have gender-specific stereotypes, whether conscious or unconscious, and it seems that this can influence their treatment decisions for pain (80). One study found that female providers were more likely to recommend psychosocial treatments instead of opioid medications for female pain patients (81). In addition, patients have been observed to report their pain differently with male and female providers. One study found that male and female patients reported higher pain scores to female practitioners than male practitioners (82). Interestingly, another study found that women reported higher levels of pain to their clinician when in the presence of a woman friend. The authors suggest that this higher social support may reinforce pain syndromes in women (83). Alternatively, men were shown to report lower pain intensity with higher social support (84).
Although it has not been studied to date, these social influences on pain reporting raise interesting questions in reference to team versus individual sports. How are team dynamics influential in the experience of pain? Some have suggested that team sports elicit more aggressive behavior than individual sports (85). There are interesting areas for future research: Would male athletes who play team sports be less likely to report pain? Also, would females report more pain if they are involved in team sports or in the presence of fellow female athletes?
Some people highlight the attribution of anxiety or depression to the pain experience, both of which have shown differences between men and women. It is often clinically difficult to differentiate the cause/effect of pain or anxiety. Is it primarily the anxiety that is making pain worse, or is it pain that is causing feelings of anxiety? Or is it a mutual synergistic effect, breeding a compound suffering of both anxiety and pain? These same questions can be asked of depression or other comorbidities such as insomnia and poor sleep quality (86).
Little is known about mental health disorders in athletes and may be missed in clinical assessments. We know that the prevalence of mental health problems in athletes is high (87,88). In particular, female athletes have been found to have greater odds of experiencing symptoms of depression than male athletes (89,90). Women may be particularly vulnerable psychologically, as compared to men, when faced with acute pain (91). Optimal interventions for anxiety- or depression-related pain are still being studied, but may differ by patient sex (92,93). For example, one study found that higher anxiety was correlated with more pain relief in men but less pain relief in women (94). The authors suggest that this may be due to sex differences in coping strategies. Clearly the relationship between anxiety and pain is quite complex, and how to apply this knowledge clinically in treating our male and female athletes remains to be studied.
Researchers have investigated gonadal hormones as a plausible explanation for sex differences in pain, particularly the role of estrogen. Women have major fluctuations in estrogen and progesterone levels related to their menstrual cycles, as well as significant deficits as they enter menopause. In men, androgens such as testosterone are the predominant gonadal hormones essential for the male reproductive system. Although poorly understood, estrogen, progesterone, and other gonadal hormones have a complex role in inflammatory processes and the pain response (95,96).
Estrogen and Progesterone
Several studies have measured pain during various stages of the menstrual cycle. The average woman’s menstrual cycle ranges from 28 to 35 days in length and has a cyclic fluctuation in serum levels of estrogen and progesterone. In the beginning of the cycle, estrogen and progesterone levels are low. Estrogen levels increase during the follicular phase, peak right before ovulation, and then have a smaller peak during the luteal phase. Progesterone levels peak during the luteal phase approximately 6 to 10 days after ovulation. At the end of the luteal phase, both estrogen and progesterone levels decrease (97,98).
As mentioned with previous studies in pain, there are difficulties in drawing generalized conclusions because of variations in pain stimuli modalities and outcomes measured. In addition, studies have been of relatively small magnitude, and there have been methodological inconsistencies in regard to experimental session timing. The timing of measurement across the menstrual cycle was inconsistent; biological markers were not used to specifically track the stages of the cycle. Given these difficulties, measuring pain sensitivity across the menstrual cycle has had minimal or conflicting results (48).
Some studies support a correlation with higher pain occurring during times of low estrogen and lower pain at times of high estrogen. This has been demonstrated in several ways: (a) pain sensitivity is higher during luteal phase (low estrogen); (b) there are increased reports of migraine headaches, temporomandibular pain, and low back pain during luteal phase (low estrogen) as compared to the follicular phase (rising estrogen); (c) higher pain thresholds were found during the follicular phase (rising estrogen); (d) lower pain was reported during late pregnancy (high estrogen) (99–104).
The mechanism for estrogen’s influence in pain is poorly understood and still being studied. One study found weaker emotional modulation of pain associated with low estradiol (105). Another interesting study demonstrated that females with low estrogen states showed significantly less regional activation of the endogenous opioid system (106). Rodents have also been observed for pain behavior during menstruation; female rodents have a similar estrous cycle that lasts about 4 days (107). As in human studies, variability in pain stimuli and measured outcomes yielded a range of results, making general comparisons difficult across studies. However, several studies support a significant role for gonadal hormones in pain. Similar to human studies, some studies in rats have supported a correlation between higher estrogen states and less pain (108,109).
Some researchers have studied low estrogen states by comparing women with regular menstrual cycles versus postmenopausal women. If estrogen and progesterone indeed play a role in the pain experience, it would be useful to study pain in the population of postmenopausal women as their endogenous levels of these hormones decline. Women with an oophorectomy are also a comparable population to study as compared to women with regular menses. These studies have produced conflicting results. Some studies have shown increased levels of pain in perimenopausal and postmenopausal women (110). Cranial and orofacial pain conditions were also shown to be more prevalent in these subjects (111). In contrast, however, prevalence rates of joint pain, chronic widespread pain, and fibromyalgia were higher in menstruating women than postmenopausal women. Migraine headaches and temporomandibular disorder pain have also been observed to peak in prevalence during reproductive years (112).
Though not well studied, menstruation in young female athletes has some significance in their sports performance (113). We do know that high-intensity sports combined with inadequate caloric intake can lead to several types of menstrual abnormalities (114). The interrelationship among energy availability, menstrual function, and bone health is called the female athlete triad and has been extensively studied (115). The idea that low estrogen is also associated with higher reported pain makes this syndrome all the more compelling.
If indeed low estrogen levels were associated with higher levels of pain, one would postulate that exogenous estrogen administration might be a possible treatment for said pain. However, results have been mixed or insignificant. When comparing pain in female users versus nonusers of oral contraceptives, many studies did not account for the types of oral contraceptives used, and sample sizes were limited. No correlation was found between oral contraceptive use and chronic widespread pain, and estrogen replacement showed inconsistent results in acute pain assays (116–119).
Testosterone has a significant role in men and women. Biologically normal secretion of testosterone is important for athletic performance (120). Exogenous testosterone administration has been banned from competition because of its performance-enhancing capabilities (121). Although not well understood, there appears to be a relationship between testosterone and the pain experience. There is some evidence that opioid therapy can lower testosterone and cortisol levels (122). Particularly in patients chronically using opioids, long-term testosterone impairment has been observed. In patients with low testosterone, testosterone replacement has produced improvements in pain (123). Whether this provides any insight into sex-related differences in the pain experience remains to be studied.
Cortisol is a steroid hormone secreted by the adrenal gland that is a key component of stress adaptation. Both testosterone and cortisol can enhance changes in muscle growth and performance, especially in resistance training (124). Scientists have noticed that upon repeated exposure to stressful stimuli, a phenomenon of pain suppression occurs. Higher cortisol levels have been associated with this stress-induced analgesia; there is evidence that cortisol influences nociception via peripheral and central nervous system pathways (125). A few small studies have compared male versus female cortisol concentrations related to pain, and some sex differences have been seen. In response to acute pain, women were observed to have a different moderation of their adrenocortical response (126). Males showed an increased cortical reactivity in comparison to females (127). Rodent studies have reflected similar differences. Serum levels of corticosterone were shown to significantly increase after pain stimuli in male rats. Accordingly, stress-induced analgesia was shown to be greater among male rodents than female rodents (128,129).