Gender Differences in Pain

The pain field has moved from debating whether sex differences in pain exist to recognizing the importance of these differences ( Table 1 ). Attention is now directed toward understanding (1) which conditions lead to the sex and gender difference, (2) which mechanisms are responsible, and (3) should these differences inform clinical management of pain.

Shinal and Fillingim’s study of gender differences in orofacial pain states “Orofacial pain refers to a large group of disorders, including TMDs, headaches, neuralgia, pain arising from dental or mucosal origins such as burning mouth syndrome (BMS), and idiopathic pain affecting 10% of adults and up to 50% of the elderly.” There is a higher prevalence of clinical pain conditions in women than in men (see Tables 3 and 4 ). The prevalence in females increases during the pubertal period. Pereira and colleagues assessed TMD in 508 12-year-olds (330 girls and 228 boys) and found that gender was related to TMD but menarche, malocclusion, and oral habits were not.

We consider the target group for TMD to be women of childbearing age (20–40 years old). Other pain conditions that present as TMD comorbidities, such as migraine headaches, decline in prevalence after the fourth decade of life. Interstitial cystitis, joint pain, and fibromyalgia (FM) seem to persist until later ages. The OPPERA (Orofacial Pain Prospective Evaluation and Risk Assessment) study ( Box 1 ) identified which TMD risk factors influence the incidence of TMD/orofacial pain.

Gender Differences in Musculoskeletal Function

Cause of TMD

Manfredini and colleagues’ meta-analysis on TMD diagnosis had 3463 clinical subjects (female/male ratio 3.3), including 45.3% with muscle disorders (group [Gp] I diagnoses), 41.1% with DD (Gp II), and 30.1% with joint disorders (Gp III). Studies from the community studied 2491 individuals, with an overall 9.7% prevalence for Gp I, 11.4% for Gp IIa, and 2.6% for Gp IIIa diagnoses. Myofascial pain (MFP) was the most common diagnosis in TMD patient populations, and DD with reduction in community samples.

The diagnostic discrepancy between a clinical and community TMD population could indicate the chronicity of muscle pain. It seems that joint sounds, which identify a community-based patient with TMD, often are asymptomatic, thus reserving the clinic visit for the female patient with chronic muscle pain. In contrast, recent OPPERA (see Box 1 ) data showed that the most common patient with TMD was age 60 years, female, and had osteoarthritis (OA) of the temporomandibular joint (TMJ). The OPERRA investigators found that greater age, female gender, and white racial/ethnic group were all associated with increased odds of TMD, whereas higher educational achievement was just modestly associated.

Chronic dull aching pain in TMD is associated with MFP and the presence of myofascial trigger points (MTrPs). MTrPs develop through local afferent nerve sensitization from inflammatory mediators such as calcitonin gene-related peptide, bradykinin, and substance P.

TMJ dysfunction

TMJ disk displacement (DD) occurs more often in women. This has been attributed to gender differences in joint laxity, type of collagen in TMJ retrodiskal tissues, and increased intra-articular pressure. Women have more hypermobility, and hypermobile TM joints have more DD, which leads to more TMJ dysfunction. A difference in collagen type exists in people with painful versus asymptomatic DD.

Abubaker and colleagues suggest that sex steroids influence the content of collagen and protein in the rat TMJ disk. Type III collagen, a more easily distorted type of collagen, was identified in the posterior disk attachments of humans. It has been speculated that women have more type III collagen in the posterior TMJ disk attachment than men because women have more DD.

The association between joint laxity and TMD symptoms has been evaluated. Wang and colleagues measured the function of multiple joints in 66 young female patients with TMJ internal derangement (ID) evident on magnetic resonance imaging (MRI) and in 30 age-matched female controls. The Beighton score (a measure of joint laxity) did not differentiate between individuals with and without TMJ ID. Perrini evaluated 32 asymptomatic volunteers and 62 symptomatic patients. Joint laxity was diagnosed if the Beighton test was greater than 4. Thirteen percent of controls and 37% of patients with TMD had joint laxity. There was no difference in the ratio of women compared with men who had TMD and an increased Beighton score.

Yamada and colleagues found decreased steepness in the articular eminence associated with DD without red, whereas a steeper posterior slope was associated with DD with red.

The significance of occlusal factors in cause of TMD will forever be debated. However, it is generally accepted that occlusal instability can lead to an unequal distribution of functional forces, thereby increasing the risk for arthralgia, myalgia, or increased trigeminal stimulation affecting neuropathic pain.

There is evidence that loss of posterior support can contribute to changes in TMJ structure and symptoms of TMD. Localized pressure in the TMJ potentially affects its adaptive capabilities, leading to signs and symptoms of TMJ arthralgia.

Huber and Hall found no significant gender differences in TMJ dysfunction and occlusal discrepancies. Warren and Fried states that an equal number of men and women have joint morphology changes, but women still report having more pain, report pain more frequently, and seek care more than men. Is this related to hormonal factors?

Li and colleagues found a role for sex hormones in the TMJD inflammatory cascade. Estradiol increased the synthesis of interleukin 1 and interleukin 6, but testosterone did not. Estrogen coupled with changes in dietary loading affected cartilage degradation with increased TMJ pain and swelling in females, whereas testosterone increased inflammation-sparing plasma extravasation in males. Rats treated with estrogen replacement experienced excitability of afferent innervations of the TMJ and masticatory muscles. Gender differences in TMJ nociception were established further when levels of C-Fos, an early response transcription factor in neural tissue, in the brainstem were most increased after TMJ stimulation in female rats with high hormone levels. Prolactin induces the release of estradiol in female mice to exacerbate collagen-induced arthritis.

Human studies also support gender-based risk factors for TMJ arthralgia. Wiese and colleagues found gender differences in the clinical presentation of TMD. Age, gender (OR ≥2.36), and coarse crepitus, but no pain-related variables, were associated with an increased risk of degenerative findings in TMJ tomograms. Cadaver studies indicate that more DD exists in women compared with men, that there are more estrogen receptors (ER) in the TMJs of women, and that cartilage and bone metabolism are affected by estrogen and progesterone. Relaxin, a female hormone associated with joint laxity during pregnancy and the last days of the menstrual cycle, is believed to affect cartilage-degrading enzymes. Prolactin was associated with accelerated condylysis in pregnant women.

LaResche and colleagues found that low estrogens levels during the menstrual cycle were related to TMD pain and TMD symptoms during pregnancy decreased at the end of pregnancy when hormone levels are high. The influence of estrogen may depend on the particular type of ER that a woman expresses at the genetic level. Milam proposes that ER polymorphisms may be associated with a higher prevalence of osteophoresis, rheumatoid arthritis (RA), and breast cancer in women.

A gender difference has not been established in polymorphisms affecting how types of collagen maintain articular surface integrity.

Parafunctional habits

Parafunctional habits are routinely considered a cause associated with TMD. Michelotti and colleagues identified female gender as a significant risk factor for MFP (OR = 3.8) but not arthralgia/arthritis/arthrosis when assessing the frequency of diurnal clenching or grinding and nail-biting habits.

Bruxism, defined as nonfunctional contact of the teeth, is considered by many to be the major cause triggering expression of orofacial disease in susceptible individuals. In the general population, the awareness of night-time bruxism is 8%, clenching 20%, with no evident gender differences; however, there does seem to be a genetic predisposition for nocturnal parafunctions such as sleep bruxism or restless legs syndrome. The phenotypic variance of bruxism attributed to genetic influences is estimated to be 39% in males and 53% in females.

TMJ arthridites

There is a genetic predisposition for the development of arthridites. Certain systemic arthridites affect men more than women ( Table 2 ). Ankylosing spondylitis is twice as common in men as in women and presents in the third to fifth decades as lower back pain.

Women are more likely than men to develop RA and suffer greater disability from it. The reasons for this sexually dimorphic pattern of disease is unknown; however, women may be more susceptible to RA because of sex-specific differences in body composition and structure. Lupus affects women more than men, affecting 1.8 to 7.6 per 100,000 persons. In patients with systemic lupus erythematosus (SLE), 33% have TMJ symptoms, 22% clinical signs, and 11% radiographic signs of TMJ arthopathy.

Hallert and colleagues and Jawaheer and colleagues found differences in disease progression and response to treatment in females compared with men in early versus chronic RA.

These results are consistent with the OPPERA findings of increased arthritis in older women, pointing to a gender difference in the disability associated with chronic TMJ symptoms from both types of arthritis.

Idiopathic condylar resorption

Those who manage adolescent females with idiopathic condylar resorption (ICR) recognize it as a gender disability. This problem is generally found in women in their second and third decades or as they reach puberty. A common initial sign of ICR is a changing bite, with the sensation of biting posteriorly. Retrognathism, clockwise rotation of the mandible, and an anterior open bite eventually develop. Risk factors include long-faced females with large mandibular plane angles, history of steroid use, RA, SLE, and sclerodema. History of orthognathic surgery is also a risk factor; these surgical patients have a 7% to 12.2% chance of developing ICR, especially if it is advanced more than 10 mm. Activation of ERs promoting TMJ arthritis may also be a risk factor. Alternatively, some suggest that ICR is a problem of osteonecrosis caused by disruption of the blood supply to the condyle. Previous orthodontic appliance therapy promoting a posterior force on the condyles may be an initiating factor. Collaboration of the ICR diagnosis is aided by testing for RA factor (80% positive in patients with RA, 33% in patients with scleroderma).

Summary: TMD musculoskeletal pain

TMJD and MFP both have complex causes with many risk factors. Most patients (80%) respond to nonoperative therapy targeting jaw or orofacial dysfunction. However, many (5%–20%) remain refractive to treatment. Does a gender-based problem explain the poor response? Recent studies suggest that the most important factors in identifying whether a person has a long-term problem with TMJ arthralgia or TMD MFP are psychosocial and affected by gender, such as catastrophizing, depression, anxiety, sleep quality, and pain-coping mechanisms. Prolonged nociception in such patients could lead to peripheral or central nervous system (CNS) sensitization, resulting in pain perception long after the physical findings initiating the pain have disappeared.

Central Sensitivity Syndrome

Evidence points to the conclusion that MFP and TMJD are different but related disorders under the heading TMD. Recently, Woolf reviewed research findings indicating that OA in the TMJ and other joints, rather than being primarily a degenerative disease associated with morphologic and functional factors, has characteristics of a central sensitization syndrome (CSS) much like TMD muscular pain and its associated comorbidities.

Box 2 reviews TMD and orofacial pain comorbidities.

There are gender differences in peripheral pain perception. Riley and colleagues’ meta-analysis found that females have higher threshold and tolerance measures to pressure pain and electrical stimulation, but not to thermal stimuli. As for deep tissue pain, females did show a lower pain threshold in visceral pain tests measuring esophageal distension but not for mechanical thresholds in rectal stimulation studies.

Gender Differences in Experimentally Induced Hyperalgesia

Studies of experimentally induced hyperalgesia have found robust sex differences. In animals, the sex differences found in acute pain models depend on the type of animals tested. This finding also applies to chronic pain models used in nerve ligation and arthritis studies.

It is clear that more than morphologic differences exist between patients with and without TMD pain and that females commonly experience more pain than males. The fact that imaging findings of TMJ disease do not always correlate with symptoms points to a difference in how symptomatic and asymptomatic patients process pain. Chronically symptomatic patients have signs and symptoms consistent with a neuropathic pain presentation.

Neuropathic Pain

Neuropathic pain is pain that arises after injury to nerves or to sensory transmitting systems in the spinal cord and brain. A key feature of neuropathic pain is the combination of sensory loss with hypersensitivity. After mandibular osteotomy, only 10% of patients with severe intraoperative nerve damage developed clinically significant neuropathic pain. Nerve damage seems necessary for the initiation of postsurgical persistent pain, but is not always sufficient by itself to cause neuropathic pain development. There exists genetic susceptibility to the experience of neuropathic pain, elucidated by high pain levels and response to analgesics. An example is postherpetic neuralgia preceded by severe zoster pain. Findings of several studies show that women have higher postoperative pain than men. Cairns offers evidence for sex-related differences in the response of afferent fibers and second-order trigeminal sensory neurons that innervate tissues associated with chronic pain conditions. Further, pain modulation by opioidergic receptor mechanisms seems dependent on gender.

Tables 3 and 4 list gender-based differences in pain affecting ion channels and neurotransmitters, respectively.

There are indications that patients can be tested and then their susceptibility for chronic pain symptoms predicted. Studies have noted a positive correlation between preoperative pain response and degree of early postoperative pain. Preoperative catastrophizing has been correlated with acute but not postoperative pain intensity. Pinto and colleagues found that presurgical anxiety, emotional illness representation, and pain catastrophizing predicted persistent postsurgical pain 4 months after hysterectomy.

Wind-up pain

Postsurgical neuropathic pain that develops because of nerve damage is often attributed to receptor field spreading involving interneurons at the second-order neuron level in the CNS. The resulting CNS sensitization is referred to as wind-up pain. Wind-up is a transient upregulation, whereas central sensitization is a long-term upregulation, of postsynaptic response to a wider range of inputs. Wind-up could be considered as a gateway to central sensitization. The psychophysical correlate of wind-up is believed to be temporal summation (TS) of pain. Like wind-up pain, TS requires 3 factors: C-fiber stimulation, short interstimulus intervals, and N -methyl- d -aspartate (NMDA) receptor activation.

Greater TS was found in women with chronic pain conditions such as FM and TMD and was observed even in asymptomatic body sites, pointing toward a central pain-processing problem.

Stress reaction

Reaction to stress is credited with causing enhanced pain perception in many patients with chronic pain. The cause for this connection is dysfunction in the hypothalamus-pituitary-adrenal (HPA) axis. Support for this concept exists: 40% to 70% of patients with chronic pain have a history of abuse. In these patients, emotions and thoughts create a physiologic response just like a real stressor. These deep-seated memories upregulate the autonomic nervous system, resulting in a state of hypervigilance with corresponding secretion of norepinephrine and epinephrine targeting nociceptors so as to heighten pain perception. Studies examining the stress response in women with TMD and FM support the concept of a turned-on HPA axis in these patients.

Martenson and colleagues give a neural-based explanation for stress-induced hyperalgesia, whereas King and colleagues show similar dysfunctional pain responses in patients with both TMD and IBS.

Milam points toward a gender difference in stress response for the antinociception discrepancy between sexes. One difference involves an increase in nerve growth factor (NGF) levels in times of stress. NGF levels are associated with muscle, neuropathic, sympathetically maintained pain, and reflex sympathetic dystrophy pain. Females are more sensitive to NGF than males, and the difference is believed to involve NGF and its primary tyrosine kinase A (TRKA) receptor. These receptors respond to estrogen. Women produce more TRKA receptors than men, which can account for women’s increased sensitivity to NGF.

Stress turns on the HPA axis, which is sustained in patients with a history of physical abuse (predominantly females). Such prolonged HPA activity in times of stress has also been correlated to increased rates of obesity, depression, and memory loss.

Pain processing in patients with TMD

Dysregulation of cortisol and adrenaline levels seems to be associated with heightened pain awareness and limited pain modulation abilities in individuals with TMD. This difference could be genetically programmed and in some cases gender based. Through the human genome project, more than 13 million polymorphisms have been identified that can affect the absorption, distribution, metabolism, and excretion of enzymes and medications. Specifically, some women have an SNP, resulting in a 40% increase in metabolism of endogenous opioids. Also, the catechol- O -methyltransferase (COMT) enzyme, which affects catecholamine metabolism via adrenergic and dopaminergic pathways, is reduced 3 to 4 times in those persons with an SNP at the Val158Met COMT gene. Zubieta and colleagues showed that the pain response of individuals whose TMJs were injected with saline was related to levels of COMP activity. The relative risk for developing TMD after orthodontic treatment was associated to a variant of the COMT gene. Diatchenko and colleagues identified 3 genetic COMT variants (haplotypes). These investigators designated them as low pain sensitivity (LPS), average pain sensitivity, and high pain sensitivity. They found that the presence of a single LPS haplotype diminished the risk of developing myogenous TMJ disorder (MFP).

Others found an association between pain and epinephrine metabolism in response to a polymorphism at the β ₂ adrenergic ADRB2 receptor. Rogers found that differences in pain tolerance can explain women’s overall response to treatment when compared with men, whereas catastrophizing seems important in understanding sex differences in daily pain levels. Possibly, these studies explain why women with TMJD, TMD, or FM can have a heightened response to painful stimuli that indicates hyperalgesia; these studies also highlight the role that neuropathic pain mechanisms play in the development of chronic TMJ arthralgia and TMD. In addition to understanding how nociception develops in TMJ arthritis and MFP of the masticatory muscles, development of neuropathic pain must be understood to diagnose and treat chronic TMD effectively.