Epidemiology of orofacial pain

Orofacial pain refers to a large group of disorders, including temporomandibular disorders (TMDs), headaches, neuralgia, pain arising from dental or mucosal origins, and idiopathic pain . The classification and epidemiology of orofacial pain presents challenges because of the many anatomic structures involved, diverse causes, unpredictable pain referral patterns and presenting symptoms, and a lack of consensus regarding differential diagnostic criteria . Despite these obstacles, several investigators and professional associations have made progress in developing diagnostic criteria . For example, the International Association for the Study of Pain and the International Headache Society have developed widely used orofacial pain diagnostic criteria . Similarly, Dworkin and LeResche have proposed Research Diagnostic Criteria for TMD, including a dual axis system for classifying patients according to the predominant pain source (eg, muscle pain, disk displacement, joint condition) and any associated psychosocial features (eg, disability, depression, somatization). The often weak association between pain and observable tissue pathology has prompted researchers and clinicians to use a multidimensional approach for studying this widespread problem .

Chronic orofacial pain affects approximately 10% of adults and up to 50% of the elderly . There is evidence that sex differences in masticatory muscle pain and tenderness emerge as early as 19 years of age . Women of reproductive age, with a concentration of women in their 40s, seek treatment for orofacial pain more frequently compared to men by a 2:1 ratio . Moreover, a greater proportion of women seek treatment for other pain conditions, such as migraine and tension-type headaches, fibromyalgia, autoimmune rheumatic disorders, chronic fatigue, orthopedic problems, and irritable bowel syndrome . Women are more likely to seek medical care for pain; however, they also report more pain for which they do not seek treatment . This holds true for all bodily symptoms, and for those with unknown etiology . Women also experience more symptom recurrences and more intense pain. These differences persist when apparent confounding factors, such as sex differences in the prevalence rates of medical conditions and gynecologic pain, are controlled statistically .

Kohlmann noted that, among patients who presented with orofacial pain lasting at least a week, more than 90% complained of pain in other body areas as well. Patients who have orofacial pain share many similarities with other patients who have chronic pain, such as a moderate correlation between reported symptoms and objective pathologic findings, maladaptive behaviors (eg, parafunctions), social and psychologic distress, impairment of daily activities, occupational disability, and higher rates of health care use . The result is a diminished quality of life that is constrained by pain experiences.

Numerous factors with varying degrees of empiric support have been posited to explain sex differences in pain prevalence. These include differences in descending central nervous system pathways that modulate pain signal transmission , genetics , and the effects of gonadal hormones . Also, a vast literature addresses psychosocial sex differences in symptom appraisal, socialization and gender roles, abuse and trauma, depression and anxiety, gender bias in research and clinical practice, and race and ethnicity .

Sex differences in responses to experimental pain

Although numerous factors inevitably contribute to sex differences in the prevalence and severity of clinical pain, the senior author and colleague previously suggested that sex differences in the processing of pain-related information could play an important role. That is, a higher level of pain sensitivity among women may serve as a risk factor for developing certain pain disorders, including chronic orofacial pain. A robust and expanding literature that addresses sex differences in experimental pain sensitivity is available, and these findings are discussed below.

Sex differences in responses to experimental pain

Although numerous factors inevitably contribute to sex differences in the prevalence and severity of clinical pain, the senior author and colleague previously suggested that sex differences in the processing of pain-related information could play an important role. That is, a higher level of pain sensitivity among women may serve as a risk factor for developing certain pain disorders, including chronic orofacial pain. A robust and expanding literature that addresses sex differences in experimental pain sensitivity is available, and these findings are discussed below.

Brain imaging studies

A rapidly expanding body of research uses functional brain imaging in an attempt to identify cerebral responses that are associated with the experience of pain . Several brain regions have emerged consistently as areas that are activated during acute exposure to noxious stimuli. Acute painful events often elicit activity in the primary and secondary somatosensory cortices, insular cortex, anterior cingulate, and prefrontal cortices . Bilateral thalamic and brain stem activation have been associated with general arousal (eg, attention) in response to noxious stimuli , whereas limbic system components (eg, anterior cingulate, medial prefrontal, insular cortices) are believed to reflect emotional aspects of pain anticipation and processing . The periaqueductal gray, regions of the anterior cingulate, and the orbitofrontal cortex are implicated in endogenous pain modulation .

A small body of evidence addresses sex differences in brain activation patterns in the contralateral insula, thalamus, and prefrontal cortex in response to experimentally evoked pain. For example, in response to a painful thermal stimulus, patterns of pain-related brain activation showed similarity between the sexes; however, women showed greater activation in the contralateral prefrontal cortex, contralateral insular and anterior cingulate cortex, and cerebellar vermis compared with men . In contrast, Derbyshire and colleagues reported greater heat pain–related activation among men versus women in bilateral parietal cortex, and in contralateral primary and secondary somatosensory, prefrontal, and insular cortices. Women showed greater activation in ipsilateral perigenual cortex. This conflicting pattern of results likely reflects differences in stimulus characteristics. Specifically, Paulson and colleagues used an identical (50°C) contact heat stimulus, which was rated as more painful by women, whereas Derbyshire and colleagues adjusted the intensity of their laser stimulus to be equally painful across sexes.

Several studies have examined sex differences in cerebral responses to stimuli delivered to deep abdominal body tissues (ie, visceral stimulation). Berman and colleagues found that, compared with women who had irritable bowel syndrome (IBS), men who had IBS showed greater bilateral insular cortex activation to rectal pressure. These investigators subsequently showed that rectal distention produces greater activation in ventromedial prefrontal and right anterior cingulate cortex, and left amygdala among women who had IBS, whereas men who had IBS showed greater activation in right dorsolateral prefrontal cortex, insula, and periaqueductal gray . In contrast, Hobson and colleagues found no sex differences in cortical activity evoked from esophageal stimuli in healthy subjects.

Thus, these findings involving somatic and visceral stimuli indicate substantial overlap in brain areas that are involved in acute pain processing between men and women. The variable sex differences that have emerged across studies likely depend upon the stimulus properties and population characteristics.

Sex differences in analgesic systems

Many organisms, including humans, possess natural pain control mechanisms (ie, endogenous systems). Nonhuman animal studies have revealed sex differences for at least one form of endogenous pain modulation: stress-induced analgesia (SIA). In rodents, mildly stressful events (eg, brief swims in tepid water) recruit endogenous opiate systems, whereas intensely stressful events (eg, forced cold-water swims) recruit nonopioid systems (eg, NMDA glutamate receptors) more heavily . Given the same stressor, female rodents usually have equal or less SIA than do males. Blocking opioid or NMDA receptors reverses SIA in male and ovariectomized female mice, but not in intact female mice. This suggests that the neurochemical and hormonal mechanisms that support SIA might differ for female and male animals .

Methods for investigating endogenous pain inhibition also are available in humans. One frequently used method is assessment of diffuse noxious inhibitory controls (DNIC). DNIC, or counterirritation, refers to the process whereby one noxious stimulus inhibits the perception of a second painful stimulus. This phenomenon is believed to reflect descending inhibition of pain signals . DNIC is presumed to operate through activation of descending supraspinal inhibitory pathways that are initiated by release of endogenous opioids . Several studies have investigated sex differences in the efficacy of DNIC, with mixed results. France and Suchowiecki reported that ischemic arm pain produced equal reductions in the nociceptive flexion reflex (NFR, a pain-related reflex in the biceps femoris in response to electrical stimulation of the lower extremity) activity in women and men, which indicated no differences in DNIC. Serrao and colleagues recorded the NFR and pain intensity for 36 healthy adults randomized to a baseline, nonpainful control or a painful cold pressor DNIC condition. As expected, women, on average, had lower NFR temporal summation thresholds than did men. The cold pressor produced greater increases in the stimulus intensity at which temporal summation elicited a reflex in men compared with women, which indicated greater DNIC among men. In contrast, Baad-Hansen and colleagues found no sex differences in the ability of an ice-water DNIC to modulate intraoral pain that was induced by the application of a topical irritant (ie, capsaicin) in healthy participants.

Responses to analgesic medication (ie, exogenous analgesia) also might differ as a function of sex, although the findings are far from consistent. For example, clinical studies have indicated greater morphine analgesia among women , among men , and others have reported no sex differences in morphine analgesia . Consistent sex differences have been reported in the analgesic effects of mixed action opioids (eg, pentazocine, butorphanol, nalbuphine), which produce analgesia, in part, by binding of κ-receptors . This class of medications also has partial agonist action at δ-receptors and antagonist action at μ-receptors, which complicates the side effect profile . Among patients who experienced postoperative pain after third molar extraction, Gear and colleagues demonstrated that pentazocine and butorphanol produced greater and longer-lasting analgesia among women versus men. Subsequently, these investigators found that a 5-mg dose of nalbuphine had paradoxic antianalgesic effects on men . To obtain analgesia, men required higher doses (20 mg) than did women (10 mg). This trend persisted when body weight was included as a covariate. Men also had more pain by the end of the study protocol, whereas women, on average, did not return to their baseline pain levels. This study demonstrates that subtle sex differences exist in response to κ-opioids.

Experimental pain models also have been used to explore sex differences in opioid analgesia. With an electrical pain assay, women have shown greater analgesic potency but slower onset and offset of morphine analgesia than did men , although these investigators failed to include a placebo condition and subsequently observed no sex differences in analgesic responses to morphine-6-glucuronide, an active metabolite of morphine . Zacny reported that μ-opioid agonists (eg, morphine, meperidine, hydromorphone) produced greater analgesic responses among women using cold pressor pain, but no sex differences in analgesia emerged for pressure pain. The authors’ group found no sex differences in morphine analgesia using pressure, heat, and ischemic pain. Regarding mixed action opioids, Zacny and Beckman reported that men experienced slightly, though not significantly, greater analgesia in response to butorphanol. The authors and colleagues reported no sex differences in pentazocine analgesia; however, the melanocortin-1-receptor genotype ( MC1R ) was associated with pentazocine analgesia in a sex-dependent manner . Specifically, women with two variant MC1R alleles, associated with red hair and fair skin, reported significantly greater analgesia with the κ-opioid pentazocine during thermal and ischemic pain testing compared with women with one or no variant MC1R allele; MC1R genotype was not associated with analgesic responses among men.

In summary, evidence from clinical and experimental pain models present a mixed picture of sex differences in response to opioids, and the presence of sex differences likely depends on multiple factors, including the specific opioid agonist and dose used, the pain model tested, and the timing of postdrug assessments. Moreover, human and nonhuman animal data suggests that sex-by-genotype interactions may influence the findings of such studies.

Clinical relevance of experimental pain responses

It has not been determined whether common mechanisms underlie sex differences in the epidemiology of clinical pain and sensitivity to experimental pain; however, this possibility is supported by increasing evidence that experimental pain sensitivity predicts clinical pain responses . Indeed, patients who have certain chronic pain disorders, such as TMD , IBS , headache pain , and fibromyalgia , exhibit increased sensitivity to a variety of experimental pain stimuli. Moreover, some evidence suggests that within populations that have chronic pain, greater experimental pain sensitivity is associated with greater severity of clinical symptoms .

Fillingim and colleagues investigated the relationship between heat pain tolerance and threshold in healthy adults, and reports of daily pain in the month preceding pain testing. Consistent with previous studies, women reported more pain sites (but not more pain episodes) and greater health care use in the month preceding experimental testing. Women also displayed increased sensitivity to thermal pain after adjusting for baseline sensitivities in warmth detection. Women who reported higher levels of clinical pain during the month preceding testing exhibited lower thermal pain thresholds and tolerances than did those who reported less clinical pain; however, men showed no significant relationship between clinical and experimental pain.

Growing evidence also suggests that experimental pain sensitivity may predict future pain severity and response to treatment. Indeed, several studies now indicate that laboratory pain sensitivity that is assessed presurgically predicts severity of postsurgical pain . Also, pretreatment ischemic pain tolerance predicted pain reductions following multidisciplinary treatment among women, but not among men, who had chronic pain . More recently, pretreatment heat pain thresholds predicted the effectiveness of opioids for neuropathic pain . Taken together, these findings support the clinical relevance of experimental pain assessment, which implies that sex differences in experimental pain sensitivity are related to sex differences in clinical pain.

Responses to nonpharmacologic treatment

Women and men may respond differently to pharmacologic pain treatment, but little is known about sex differences in the effectiveness of nonpharmacologic interventions for pain. In a study of orofacial pain, women who had TMD showed significant decreases in pain 2 years after multidisciplinary treatment, whereas pain reports among men who had TMD remained unchanged . In the experimental setting, a cognitive intervention encouraging a sensory focus aimed at pain reduction significantly attenuated pain intensity among men but not women . Also, exercising on a treadmill reduced cold pressor pain ratings in women but not men, whereas playing video games decreased pain in men but not women . In the clinical setting, conventional physical therapy was more effective for men who had back pain, whereas intensive dynamic back exercises produced greater pain reduction among women . In another study, women who had back pain showed significant improvements in health-related quality of life with cognitive behavioral treatment and the combination of cognitive behavioral treatment plus physical therapy, whereas men showed no benefit . Other recent findings indicate similar treatment gains for women and men following active rehabilitation for chronic low back pain , and one study reported better outcomes from multidisciplinary treatment among men . Thus, these findings are mixed, but, on balance, they suggest greater treatment responses for women, especially when treatments are multimodal.

Mechanisms underlying sex differences in pain perception

Several mechanisms have been proposed to explain gender differences, including “biologic” factors, such as genetic and hormonal influences as well as sex differences in endogenous pain modulation. In addition, “psychosocial” processes have been suggested, including gender roles and other cognitive/affective influences. Before discussing these putative explanatory mechanisms, it is worth noting that this distinction between “psychosocial” and “biologic” contributions is artificial, because psychosocial variables can reflect or alter the underlying biologic processes that are involved in the modulation of pain. In addition, sex differences in pain inevitably are driven by multiple mechanisms; therefore, reductionistic attempts to identify the reason for sex differences likely will be unsuccessful.

Gonadal hormones may contribute to sex differences in pain modulation and opioid analgesia. Experimental pain perception varies across the menstrual cycle in healthy women, with the greatest pain sensitivity occurring perimenstrually . The severity of some pain disorders fluctuates with the menstrual cycle . For example, in patients who have TMD, peak pain occurs perimenstrually and at the time of ovulation . It is hypothesized that rapidly dropping estrogen levels may be associated with heightened symptoms in this population. Hormone replacement therapy also has been associated with an increased risk for developing TMDs and back pain , and women who were using exogenous hormones reported more severe orofacial pain compared with women who were not using hormones . Furthermore, postmenopausal women who were taking hormone replacement showed lower pain thresholds and tolerances compared with women who were not taking hormone replacement and men . Thus, endogenous and exogenous hormonal events affect clinical and experimental pain responses.

Psychosocial factors also contribute to sex differences in responses to pain. Psychologic distress is common among patients who have orofacial pain . Several studies indicate that psychologic factors play a larger role when TMD pain is myogenic (as opposed to arthrogenic), perhaps because of more parafunctional behaviors in the former group . Regarding emotion, two dimensions seem to be especially important for pain modulation: valence—whether an emotion is positive or negative, and arousal—how intensely the emotion is experienced . Although negative and positive emotions can influence pain, more research has addressed the effect of negative emotions. For example, fear is a high-intensity negative emotion that is associated with threat or perception of imminent harm. The fear response is characterized by autonomic arousal and temporary pain attenuation (ie, “fight, flight, or freeze”). Fear-based analgesia is not studied readily in humans because of ethical considerations. In comparison, anxiety is a lower-intensity negative emotion that often heightens pain sensitivity . Thus, an emotional stimulus can attenuate or amplify pain depending upon how it is perceived.

Aggregate findings suggest that, given the same negative stimuli (eg, upsetting photographs, startling noise), women display more intense affective reactions compared with men. In addition, women report higher base rates of depression and anxiety than do men, which often are associated with increased pain and other physical symptoms . These negative affective states generally predict greater sensitivity pain in the laboratory . Thus, higher levels of affective distress might account for some of the increased pain sensitivity among women. Robinson and colleagues found that sex differences in temporal summation of heat pain became nonsignificant after controlling for anxiety, indicating that anxiety mediates gender differences. Several studies suggest that anxiety more strongly predicts experimental pain responses in men than in women, however . Similar results have been reported for clinical pain . Thus, it seems that anxiety more strongly predicts clinical and experimental pain among men. Clearly, more investigation is warranted concerning the role of negative emotions during pain processing.

In addition to emotional factors, cognitive variables, such as self-efficacy, anticipation, expectancies, perceived ability to control pain, and coping strategies, can contribute to gender differences in pain perception and treatment outcomes . Orofacial patients who have positive pretreatment expectations, and who use adaptive cognitive coping strategies, report better treatment satisfaction . Relative to men, women report more worry and catastrophizing in laboratory and clinical pain settings . Turner and colleagues found that a catastrophizing coping style was associated with extraoral muscle and joint palpation pain, activity interference, and higher health care use in patients who had TMDs. Despite a greater tendency to catastrophize, Unruh and colleagues found that women use a broader repertoire of coping strategies. Furthermore, men and women seem to derive differential benefits from coping skills training, which highlights the importance of tailoring treatments to meet individual needs .

Stereotypic gender roles also should be considered because traditional Western feminine roles may enable reporting pain, whereas masculine roles discourage such complaints. Among men, masculinity has been associated with higher pain thresholds . One study found that men reported less pain to an attractive female experimenter than to a male experimenter, whereas experimenter gender did not influence women’s pain reports . Two studies that used standardized measures of gender role demonstrated that gender roles are associated with experimental pain responses, but gender role measures did not account for sex differences in pain . More recently, a subscale that assesses willingness to report pain was found to mediate sex differences partially in temporal summation of heat pain . Also, feminine gender role and threat appraisal mediated sex differences in cold pressor pain . Thus, gender roles seem to contribute to sex differences in pain sensitivity.