Pain and Temporomandibular Disorders

Gender is the biggest risk factor in the development of temporomandibular disorders (TMD) and orofacial pain. Gender differences in pain thresholds, temporal summation, pain expectations, and somatic awareness exist in patients with chronic TMD or orofacial pain. There are gender differences in pharmacokenetics and pharmacodynamics of medications used to treat pain. A better understanding of the mechanisms that contribute to the increased incidence and persistence of chronic pain in females is needed. Future research will elucidate the sex effects on factors that protect against developing pain or prevent debilitating pain. Gender-based treatments for TMD and orofacial pain treatment will evolve from the translational research stimulated by this knowledge.

Key points

  • Genetic studies indicate that the genetic contribution to the development of temporomandibular disorders (TMD) and orofacial pain is a small part of the overall risk for these disorders. However, gender is the most significant risk factor.

  • Gender differences in pain thresholds, temporal summation, pain expectations, and somatic awareness can exist in patients with chronic TMD or orofacial pain.

  • A better understanding of the mechanisms that contribute to the increased incidence and persistence of chronic pain in females is needed. Future research needs to elucidate the sex effects on factors that protect against developing pain or prevent pain from becoming debilitating pain.

  • Gender-based treatments for TMD and orofacial pain treatment will evolve from the translational research stimulated from understanding the gender differences in pain modulation and perception.

Introduction

A clinician must understand the cause of the problem that they are treating. Does the patient fit into a normal pattern of presentation for the disorder in terms of age, sex, race, and so forth? Epker and colleagues’ assessment of masticatory muscle pain found that individuals with a pain intensity of 7 out of 10 or greater remain symptomatic despite treatment. Is this poor prognosis related to sex/gender differences or comorbidities? Is an innate pain-processing problem responsible? This article provides an evidence-based review of temporomandibular disorders (TMD) and pain in relation to:

  • 1.

    Gender-based effects on musculoskeletal disorders

  • 2.

    Pain-processing disorders leading to TMD and its comorbidities

  • 3.

    Neuropathic pain affecting the trigeminal distribution: is this process gender specific?

  • 4.

    Genetic influences on orofacial pain

  • 5.

    Pharmacokinetics/pharmacodynamics of medications for orofacial pain

Introduction

A clinician must understand the cause of the problem that they are treating. Does the patient fit into a normal pattern of presentation for the disorder in terms of age, sex, race, and so forth? Epker and colleagues’ assessment of masticatory muscle pain found that individuals with a pain intensity of 7 out of 10 or greater remain symptomatic despite treatment. Is this poor prognosis related to sex/gender differences or comorbidities? Is an innate pain-processing problem responsible? This article provides an evidence-based review of temporomandibular disorders (TMD) and pain in relation to:

  • 1.

    Gender-based effects on musculoskeletal disorders

  • 2.

    Pain-processing disorders leading to TMD and its comorbidities

  • 3.

    Neuropathic pain affecting the trigeminal distribution: is this process gender specific?

  • 4.

    Genetic influences on orofacial pain

  • 5.

    Pharmacokinetics/pharmacodynamics of medications for orofacial pain

Epidemiology of gender and TMD/orofacial pain

TMD is a collection of musculoskeletal disorders of the head and neck. Epidemiologic studies have shown that 40% to 70% of individuals can show signs and symptoms of TMD, whereas 80% have or have had facial pain. Approximately 6% of these persons have symptoms severe enough to require treatment. Community studies show there is a 2:1 to 3:1 predilection in favor of women, and women seek care at an 8:1 ratio over men. The pain characteristics of men who present for treatment are similar to women in treatment.

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.

Table 1
Sex prevalence in pain disorders
Female Prevalence Male Prevalence No Sex Prevalence
Head and Neck Pain
Migraine headache with aura Migraine without aura Acute tension headache
Chronic tension headache Cluster headache Cluster-tic syndrome
Postdural puncture headache Posttraumatic headache Jabs and jolts syndrome
Hemicrania continua SUNCT syndrome Secondary trigeminal neuralgia
Cervicogenic headache Raeder paratrigeminal syndrome Nervus intermedius neuralgia
Tic douloureux Painful ophthalmoplegia
Temporomandibular joint disorder Toothache caused by pulpitis
Occipital neuralgia Cracked tooth syndrome
Periapical periodontitis and abscess Dry socket
Atypical odontalgia Vagus nerve neuralgia
Burning tongue Stylohyoid process syndrome
Carotidynia
Chronic paroxysmal hemicrania
Temporal arteritis
Generalized Syndromes
Carpal tunnel syndrome Ankylosing spondylitis Thoracic outlet syndrome
Raynaud disease Pancreatic disease Familial Mediterranean fever
Chilblains Lateral femoral cutaneous neuropathy Acute herpes zoster
Causalgia Postherpetic neuralgia
Reflex sympathetic dystrophy Hemophilic arthropathy
Multiple sclerosis Brachial plexus avulsion
Rheumatoid arthritis Lateral femoral cutaneous neuropathy
Pain of psychological origin
Visceral Pain
Irritable bowel syndrome Abdominal migraine Esophageal motility disorders
Interstitial cystitis Duodenal ulcer Chronic gastric ulcer
Twelfth rib syndrome Crohn disease
Gallbladder disease Diverticular disease of colon
Chronic constipation Carcinoma of the colon
Pyriformis syndrome
Data from Berkley KJ. Sex differences in pain. Behav Brain Sci 1997;20:371–80; and Dao TT. Pain and gender. In: Lund J, Lavingne G, Dubner R, et al, editors. Orofacial pain: from basic science to clinical management. Chicago: Quintessence; 2001. p. 131.

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.

Box 1

Recently, the OPPERA study published its first findings from the baseline case-control study of the OPPERA program, a series of studies designed to identify risk factors for the onset and persistence of painful TMD. Phenotypic and genotypic data were collected for TMD arthralgia, myalgia, or both cases (TMD) and people who were found not to have TMD (controls). The basic premise of OPPERA hypothesizes that clinical manifestation of TMD is driven by 2 global intermediate phenotypes: psychological distress and pain amplification, which are both influenced by genetic factors and environmental exposures. Phenotypic data were collected across multiple domains: sociodemographic, clinical, psychosocial, pain sensitivity, and autonomic function risk factors were associated with increased odds of TMD. Genetic associations to biological pathways that may contribute to TMD pathophysiology were also identified. The strongest associations with TMD were measures related to bodily tenderness (eg, pressure pain thresholds) and salience of symptoms (eg, somatic awareness). Odds ratios (ORs) were smaller for measures of other phenotypes, to include mood, autonomic function, impaired temporal regulation of pain, and genetic variants (8 gene single nucleotide polymorphism [SNPs] had an allele frequency of 20% and OR at 1.5 or 0.6 [protective]).

The OPPERA study

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.

Table 2
Clinical conditions presenting with polyarthralgia that may accompany TMJ arthritis and screening evaluation for them
Illness/Condition Screening Appropriate Test
Rheumatic disease
Systematic lupus erythematosus Hx and Px ANA, ESR
Rheumatoid arthritis Hx and Px RF, ESR
Sjögren syndrome Hx and Px ANA, ASSA, ASSB
Polymyositis Hx and Px CPK, EMG, Bx
Chronic infection/inflammation
Tuberculosis Hx and Px PPD, ESR
Chronic syphilis Hx and Px VDRL, FTA
Bacterial endocarditis Hx and Px Blood culture, ESR
Lyme disease Hx and Px Lyme serology, PCR
Acquired immunodeficiency Hx and Px AIDS serology, CD 4
Breast implantation Hx and Px Possible serology
Endocrine disorders
Hypothyroidism Hx and Px T 4 , TSH, CPK
Hypopituitary Hx and Px Prolactin, others
Abbreviations: ANA, antinuclear antibody; ASSA, antibody to SSA; ASSB, antibody to SSB; Bx, biopsy of labial minor salivary glands; CD4, lymphocytes positive for the CD4 surface antigen; CPK, creatine phosphokinase; EMG, electromyography; ESR, erythrocyte sedimentation rate; FTA, fluorescent treponemal antibody; Hx and Px, insightful medical history and physical examination; PCR, polymerase chain reaction; PPD, delayed hypersensitivity skin test for tuberculosis; RF, rheumatoid factor; T4, thyroid hormone; TSH, thyroid-stimulating hormone; VDRL, serologic test for syphilis.
Data from Mense S, Simons D, Russel IJ, editors. Muscle pain: understanding its nature, diagnosis and treatment. Philadelphia: Lippincott Williams & Wilkins; 2001. p. 302; and Russell IJ. Fibromyalgia syndrome: approach to management. Bull Rheum Dis 1996;45(3):1–4.

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.

Gender differences in pain processing

Widespread pain is a risk indicator for painful TMD, and predicts treatment response.

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.

Box 2

Comorbidity is defined as the co-occurrence of 2 or more diseases at a rate higher than expected by chance. A large population-based cross-sectional study, which included 189, 977 people, showed that 83% of 8964 individuals suffering from TMD pain reported a comorbid pain condition. Females were 1.4 times more likely than males to report at least comorbid pain conditions. Hispanics and Afro-Americans report more comorbidities and have the greatest risk for developing chronic TMD. Recent OPERRA data contradict this assumption, pointing toward a higher TMD prevalence in older white women rather than in minority populations.

Headaches/migraine are common among people with TMD and all 3 are more common in women. Marcus found that 14% of women with migraine have it only with their menses. Estrogen replacement therapy increases migraine and TMD prevalence by 30% and oral contraceptives also increase TMD and migraine prevalence. Gupta and colleagues reviewed the mechanisms through which female sex steroids might influence the trigeminal nociceptive pathways involved with migraine. There has been only 1 study evaluating the prevalence of various comorbid conditions with TMD at the same time. Hoffman and colleagues’ study surveyed 1511 people with TMD and found that 70% had tension headaches, 60% had allergies, 50% had migraines, 50% had tinnitus, 40% had chronic fatigue syndrome, 25% had irritable bowel syndrome (IBS), and 20% had FM. MFP seems to have a higher rate of comorbidities than TMJD.

MFP can be more difficult to treat than TMJD, and poor response to treatment is a consistent factor in other CSS disorders. Patients with MFP are known to have higher levels of somatization, depression, and anxiety than TMJD. Such risk factors associated with MFP also have a higher prevalence in women than men.

Comorbidity, CSS, and TMD

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.

Table 3
Pain-related genes associated with ion channel and receptor function
Gene Name Channel Type Affected Phenotype Locus
SCN9A Voltage-gated Na + channels ↑ Chronic pain in mixed cohort (sciatica, OA, pancreatitis, lumbar diskectomy, and phantom limb)
↑ Sensitivity for experimental pain
OPRD1 Opioid receptor 1p35.3
OPRM1 Opioid receptor 6q25.2
ATP1A2 Na and K channels at plasma membrane Maintains electrochemical gradient 1q23.3
MC1R κ opioid receptor Receptor protein for melanocyte stimulating hormone 16q24.3
KCNS1 Voltage-gated K + channels ↑ Chronic pain in 5 cohorts (sciatica, lumbar pain, amputation, phantom limb)
↑ Sensitivity for experimental pain
CACNA2D3 Voltage-gated Ca 2+ channels ↑ Sensitivity to thermal pain
↑ Chronic postsurgical pain (diskogenic)
CACNG2 Voltage-gated Ca 2+ channels ↑ Chronic postsurgical pain (mastectomy)
CACNA1A Voltage-gated Ca channels Mediates entry of Ca into neuronal tissue cells 19p13.13
Data from Oakley M, Vieira AR. The many faces of genetics contribution to temporomandibular joint disorder. Orthod Craniofac Res 2008;11:125–35; and Young EE, Lariviere WR, Belfer I. Genetic basis of pain variability: recent advances [review]. J Med Genet 2012;49:1–9.

Table 4
Pain-related genes associated with neurotransmitter systems and inflammation
Gene Name Neurotransmitter System Affected Phenotype Locus
GCH1 Serotonin, dopamine, norepinephrine and epinephrine, NO ↓ Sensitivity to pain ↓ postsurgical pain
SLC6A4 Serotonin ↑ Risk for CWP ↑ facilitation 17q11
ADRB2 Epinephrine ↑ Risk for CWP 5q33.1
HTR2A Serotonin ↑ Risk for CWP ↑ postsurgical pain 13q14.2
PTGS2 Prostaglandin ↑, ↓ prostaglandin biosynthesis 1q25.2-q25.3
IL10 Cytokine Immunoregulation and inflammation 1q32.1
IL1B Cytokine Mediates cell proliferation, differentiation 2q13
IL1RN Cytokine Inhibits interleukin 1A activity 2q13
IL1A Cytokine Immune response, inflammation, hematopoiesis 2q13
CYP19A1 Isoenzyme Cholesterol, steroid metabolism and synthesis 15q21.1
CYP2D6 Isoenzyme Cholesterol, steroid metabolism and synthesis 22q13.1
CCL7 Attracts macrophages 17q12
CCF3 Controls differentiation/function of granulocytes 17q21.1
Abbreviation: CWP, chronic widespread pain.
Data from Oakley M, Vieira AR. The many faces of genetics contribution to temporomandibular joint disorder. Orthod Craniofac Res 2008;11:125–35; and Young EE, Lariviere WR, Belfer I. Genetic basis of pain variability: recent advances [review]. J Med Genet 2012;49:1–9.

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.

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Oct 29, 2016 | Posted by in General Dentistry | Comments Off on Pain and Temporomandibular Disorders
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