|Year : 2014 | Volume
| Issue : 2 | Page : 167-172
Psychoneuroimmunological disorders and temporomandibular joint pain: A review
Ranjani Shetty, Ashok Lingappa
Department of Oral Medicine and Radiology, Bapuji Dental College and Hospital, Davangere, Karnataka, India
|Date of Submission||01-Aug-2014|
|Date of Acceptance||17-Oct-2014|
|Date of Web Publication||30-Oct-2014|
Department of Oral Medicine and Radiology, Bapuji Dental College and Hospital, Davangere - 577 004, Karnataka
Source of Support: None, Conflict of Interest: None
| Abstract|| |
Psychoneuroimmunology characterizes a disease entity that combines psychological components, central nervous system regulation, and immunology, to explain the etiological complexity of a disease. Temporomandibular disorders (TMDs) include a heterogeneous group of painful conditions that involve the temporomandibular joint (TMJ), muscles of mastication, and the adjacent anatomic structures. This review focuses on the psychoneuroimmunological diseases and disorders that mimic the symptoms of TMDs. The differentiation of these disorders is of great significance to the oral physician - differentiating and diagnosing the cause of TMJ pain and treating it effectively to benefit the patient.The literature for this review was taken from Medline/PubMed, other indexed journals, standard text books, and online material.
Keywords: Hypothalamic-pituitary-adrenal (HPA) axis, psychoneuroimmunology (PNI), temporomandibular joint disorders (TMDs)
|How to cite this article:|
Shetty R, Lingappa A. Psychoneuroimmunological disorders and temporomandibular joint pain: A review
. J Indian Acad Oral Med Radiol 2014;26:167-72
|How to cite this URL:|
Shetty R, Lingappa A. Psychoneuroimmunological disorders and temporomandibular joint pain: A review
. J Indian Acad Oral Med Radiol [serial online] 2014 [cited 2019 Mar 26];26:167-72. Available from: http://www.jiaomr.in/text.asp?2014/26/2/167/143693
| Introduction|| |
The field of psychoneuroimmunology (PNI) has developed over the past 30 years. This is a field that joins immunology and neurobiology and considers the influence of the central nervous system (CNS) on the immune system and vice versa.  It is the study of interactions between behavior, the brain, and the immune system.  The immune modulation by psychosocial stressors and/or interventions can lead to actual health changes. No disease is exempt from psychological influences - as a corollary all diseases have psychological repercussions.  It has been stated that the temporomandibular disorder (TMD) is a medical entity that has symptoms common to other medical disorders and there are at least nine syndromes that have symptoms common with TMDs.  Psychoneuroimmunology deals with the effects of stress on the hypothalamic-pituitary-adrenal (HPA) axis. Reduced levels of hormones and neurotransmitters within the HPA-axis, due to stress, can lead to a large number of diseases and disorders. Therefore, it is of great importance for the oral physician to be well versed with PNI and the HPA-axis, in order to make an accurate diagnosis of TMD. 
The literature for the review of this topic has been taken mainly from a key article published by Auvenshine RC, 'Psychoneuroimmunology and its relationship to the differential diagnosis of temporomandibular disorders. Dent Clin North Am 1997;41:279-96'  and the other material for this review has been collected from Medline/PubMed, other online indexed journals, standard text books, and the Internet.
| Historical Background|| |
Psychoneuroimmunology has a history of development since several thousand years ago and goes beyond many cultures. Age-old mystics, logicians, and therapists were amused about the impact of a person's mental well-being on physical health and the other way around.  Studies in human PNI began around 1919, but a systematic approach was not used until the work of Solomon in the 1960s. Recently, the new speciality achieved relative independence due to considerable data acquisition.  The name psychoneuroimmunology was coined in 1975, by Dr. Robert Ader, Director of the Division of Behavioral and Psychosocial Medicine, at New York's University of Rochester. Dr. Ader believed that there was a link between what we thought (our state of mind), our health, and our ability to heal ourselves. , Over the past ten years, studies have shown that stress and depression could cause immune alterations, such as decreased numbers of immunocompetent cells and reduced lymphocyte and natural killer cell activity.  Historically, the field of TMDs has concentrated on two theories: The tooth muscle theory and psychophysiological theory. 
| Hypothalamic-Pituitary-Adrenal Axis and Psychoneuroimmunology|| |
In the course of daily life, there is a continuous interaction between the individual and the environment. Likewise, there is a constant physiological interaction between the central nervous system and the endocrine glands to maintain homeostasis. This interaction involves a close anatomical and physiological relationship between the limbic system and the pituitary gland. The role of the limbic system is to integrate behavior and also to lend emotional coloration to the cognitive processes in times of stress. The HPA-axis [Figure 1], as its name indicates, is a feedback loop, which includes the hypothalamus, pituitary, and adrenal glands, regulatory neural inputs, and a variety of releasing factors and hormones.  During physical or psychological stress, the HPA-axis is activated. The hypothalamus secretes two hormones, the corticotropin-releasing hormone (CRH) and arginine vasopressin. The corticotropin-releasing hormone acts on the pituitary to stimulate adrenocorticotropic hormone (ACTH) release. The adrenocorticotropic hormone reaches the adrenal cortex through the systemic circulation and interacts with the receptors on the adrenocortical cells stimulating the production and release of cortisol.  In stressful circumstances, there appears to be an increase in the circulating levels of the hormones produced within the HPA-axis, which prepares the animal to meet the demands of the stressful situation. Conversely, there is a reciprocal inhibition of secretion of hormones that is counteractive to the anabolic effects of the endocrine system. As stress is a major factor in the catabolic reactions within the HPA-axis, rest and sleep bring about an anabolic effect. In syndromes or disorders that affect sleep patterns, there is a failure of the HPA-axis to undergo anabolic activity. This brings about alterations in the immune system because of the depletion in cortisol; when there is a continuous stressful situation there is disharmony in homeostasis. Stress leads to thoughts and emotions that influence both the central nervous system and the immune system, which initiates a cascade of reactions throughout the human body. These reactions upregulate and downregulate the immune system by increasing or decreasing the levels of the neurotransmitters and hormones, which results in closely related psychoneuroimmunological disorders. ,
| Diseases and Disorders that Elicit Symptomatology of Temporomandibular Disorders|| |
A 'temporomandibular disorder' is a collective term embracing a number of clinical problems that involve the masticatory musculature, the temporomandibular joint (TMJ), and the associated structures, or both. Pain associated with TMDs can be clinically expressed as masticatory muscle pain or TMJ pain. TMD-related facial pain has been reported in 4-12% of the general population (female:male ratio is 2:1). Many aspects of the etiology of TMDs are unclear. In contrast to a dental/occlusal cause, there is a definite support for a bio-psychosocial and multifactorial background, illustrating the complex interaction between biological (e.g., hormonal) mechanisms, psychological states and traits, environmental conditions, and macro- or micro-trauma. 
A temporomandibular disorder is said to be a medical entity that has symptoms common to other medical disorders, and thus, it has been titled 'The Great Imposter'. , There are at least nine diseases or syndromes related to PNI, as mentioned below, which elicit symptoms of TMDs among female patients between the age group of 20 and 40 years.
Fibromyalgia (FM) is a syndrome characterized by widespread chronic pain affecting the musculoskeletal system. The American College of Rheumatology has developed diagnostic criteria for FM, based on the identification of defined musculoskeletal tender points.  Fibromyalgia shares many symptomatic complaints with TMDs, and most TMDs involve masticatory muscle myalgia.  Fibromyalgia has been reported primarily in women, with a female-male ratio of 9:1.  The overlap between these two conditions has led to the suggestion that patients with muscular TMDs may represent a subgroup of FM.  The commonly presenting symptoms of FM are myalgia, headaches, myofacial pain, depression, fatigue, and poor sleep.  It has been reported that in a sample of 60 patients with FM, 75% had fulfilled the criteria for muscular TMDs and 18.4% of the patients with TMDs had fulfilled the criteria for FM.  A prospective cohort study showed an increased risk for the onset of clinically significant TMJ pain in subjects having FM or widespread pain and also widespread pain was related to the onset of dysfunctional TMJ pain. This study found that FM and widespread pain both constituted factors that would complicate the management of TMDs, and thus, needed to be considered in both the evaluation and management of TMDs. 
Chronic fatigue syndrome
Chronic fatigue syndrome (CFS) is an illness characterized by profound disabling fatigue lasting for at least six months, accompanied by numerous rheumatological, infectious, and neuropsychiatric symptoms.  According to Bombardier and Buchwald, it seems likely that CFS is a heterogeneous disease, with different pathophysiological disturbances that manifest with similar symptoms. Regardless of the pathogenesis, persons with CFS, like those with other chronic diseases, have a substantially impaired functional status that results in significant personal and economic morbidity.  Chronic fatigue syndrome is a disorder of the execution of sensory input by the brain. Information from inside and outside the body is misinterpreted, resulting in inappropriate sensations. Touch may be painful, odors may cause illness, and climbing stairs can be like climbing a hill. This propensity of misinformation is due to decreased norepinephrine and increased substance P secretion by the brain. The symptoms associated with this disorder include, fatigue, headaches, paresthesia, depression, fever, myalgia, inadequate sleep, arthritis, and weight loss.  Indeed, most persons who receive a diagnosis of CFS are 30-40 years of age, and most surveys support a female preponderance.  The symptoms of CFS, often co-occur with the other so-called functional illnesses, such as, FM, multiple chemical sensitivities, irritable bowel syndrome, and TMDs.  According to the study by Korszun, out of the 92 patients who fulfilled the criteria for chronic fatigue syndrome or fibromyalgia (or both), 39 (42%) patients reported a prior diagnosis of TMD.
Depression, is 'a common mental disorder that presents with depressed mood, loss of interest or pleasure, feelings of guilt or low self-worth, disturbed sleep or appetite, low energy, and poor concentration', and has recently been acknowledged as a major contributor to the global burden of disease.  It has been seen that TMDs are demonstrable in 71% of these patients, but the remaining 29% have no objective physical findings.  Women have more symptoms, or a more severe type of depression, than men. , Women undergo premenstrual and postmenstrual endocrine changes and compared to men have high levels of monoamino-oxidase (the enzyme needed to degrade neurotransmitters considered important for mood).  Screening for symptoms of substance P secretion depression must be an integral part of the evaluation of all patients with chronic facial pain, even when the masticatory muscle or TMDs are identified.  When the screening tools point toward a high probability of depressive disorder, the patient should be referred to a psychiatrist for further evaluation and treatment. At present 40% of the patients are refractory to TMD therapies,  and identification and treatment of a comorbid depressive disorder may make a significant impact on the treatment outcome of these patients.  The prevalence of depression in patients with chronic pain is usually higher in the elderly than in younger individuals.  Although the precise relationship between pain and depression is still under debate, there is sufficient evidence suggesting that depression is more frequently a consequence rather than the cause of persistent pain. 
Hypothyroidism is due to a deficient production of thyroid hormones, which can lead to many structural and functional abnormalities. It can be caused by loss or atrophy of the thyroid tissue, insufficient stimulation of an intrinsically normal gland, and compensatory goitrogenicity, as a result of defective hormone biosynthesis. Of the three causes, insufficient stimulation of the normal gland and compensatory goitrogenicity are the most common causes of hypothyroidism.  The symptoms related to hypothyroidism are headache, fatigue, high blood pressure, dizziness, depression, lethargy, emotional disturbances, sleep disturbances, decreased libido, irritability, feeling cold, weight gain, dry skin and hair, constipation, and menstrual irregularities. , Hypothyroidism is the most common thyroid disorder. It occurs more often in women, it increases with age, and it runs in families. Blood tests can measure the levels of the thyroid-stimulating hormone (TSH) and thyroid hormone (T4). Hypothyroidism is present when the TSH is high and low T4 levels are present in the blood. In very early or mild hypothyroidism, the TSH level will increase above normal level before the T4 drops below normal. Of the two blood tests, TSH is more important.  The symptoms related to hypothyroidism may sometimes coincide with TMDs, and thus, should be considered in the differential diagnosis of TMDs.
Wilson's syndrome is a condition with common and undetailed symptoms, such as, a comparatively low body temperature; but with normal thyroid hormone levels in the blood. This syndrome is named after Dr. E. Denis Wilson. According to him, this is a form of thyroid hormone deficiency, which reacts well to treatment with triiodothyronine (T3).  Wilson's syndrome constitutes insufficient active thyroid interaction with the nuclear membrane receptors of the cells to produce desirable body temperature patterns.  Low thyroid hormones result in a body temperature below 98.6°F measured in the morning immediately after waking up, in the axillary region. If the temperature falls below 98.6°F, chemical reactions do not take place. The symptoms include those of premenstrual syndrome such as, depression, headache, weight gain, fatigue, panic attacks, sleep disorders, irritability, decreased memory, and concentration.  The prevalence of signs and symptoms associated with Wilson's syndrome has been reviewed recently. It has been seen that more than 20% of the adults show fatigue and 30% have typical musculoskeletal symptoms. Moreover, the affected individual suffers from any one of the symptoms every four to six days, and in a duration of two to four weeks, more than 80% of them have one of these symptoms.  These symptoms have been given different names and have been associated to an array of causes by others for more than a century, including syndromes, such as, neurasthenia, CFS, FM, multiple chemical sensitivities, chronic Ebstein Barr disease and chronic candidiasis. 
Prolactin feedback disorder
The pituitary gland produces the hormone prolactin, which has a major role in lactation. The other functions of prolactin include action on the reproductive system, influence on behavior, and regulation of the immune system. Its secretion is controlled by the hypothalamus. Dopamine, produced by the hypothalamus is one of the main regulators of the production of prolactin from the pituitary gland. Dopamine (prolactin inhibiting factor) restrains prolactin production. As more dopamine is produced, the release of prolactin is reduced. Another key regulator of prolactin is oestrogen (prolactin releasing factor), which increases the secretion of prolactin from the pituitary gland.  Prolactin plays a major role in regulating the estrogen - progesterone cycle in women. The patients who suffer from prolactin feedback disorder, which leads to lack of prolactin secretion, usually complain of symptoms such as depression, headaches, breast tenderness, abdominal bloating, irregular menses, menstrual changes, nausea, fatigue, sleep disturbances, emotional changes, loss of ambition, irritability, and low self-image. ,
Mitral valve prolapse dysautonomia (MVP)
Approximately 10% of the women in the 20- to 40-year-old age group have a prolapse of the mitral valve or insufficiency of mitral valve closure. The diagnosis of mitral valve prolapse is made through auscultation of the heart sounds. Ten percent of those with mitral valve prolapse have symptoms linked to dysautonomia. This syndrome is a merger of mitral valve prolapse (a minor disorder of a heart valve, which occasionally causes a small amount of blood to move backward through the heart) with another condition called dysautonomia (an imbalance of the autonomic nervous system). Most people with mitral valve prolapse dysautonomia have a normal amount of epinephrine in their blood, but have too much of a related hormone, norepinephrine. This has been labeled as the heart - brain connection. The symptoms related to mitral valve prolapse dysautonomia are rapid resting heart rate, fatigue, physical stress, chest palpitations, dizziness, nausea, migraine headaches, depression, sleep disorders, and blood clotting.  Dysautonomia can also cause visual discrepancy and digestive ailments. Mitral valve prolapsed dysautonomia patients display a higher rate of fibrocystic breast disorder, tinnitus, TMJ, and other joint problems, FM, premenstrual syndrome (PMS), seasonal affective disorder (SAD), altitude, and seasickness. The dysautonomia syndrome includes CFS, vasovagal (or neurocardiogenic) syncope, panic attacks and FM. To make a diagnosis in patients complaining of such symptoms, by advising different tests, physicians have found that a fraction of these challenging patients have MVP.
Premenstrual syndrome in women
Premenstrual syndrome (PMS) has been defined as premenstrual changes that are physical and psychological. They include fluid retention, acne, cravings for sweet or salty foods, aches and pains in the muscles or joints, fatigue, irritability, tension, anxiety, sadness, moodiness, feeling out of control, insomnia, and alterations in sex drive. Although not all women have any experience with these symptoms, some women do, and report that these experiences have an effect on their daily lives and identities.  Generalized symptoms related to PMS also include breast tenderness, abdominal bloating, headaches, weight gain, and depression. This syndrome is related to fluctuations in estrogen and progesterone.  A study had concluded that the TMJ disk, in some men and women, is targeted potentially by the female sex hormone.  According to the study by Korszun, out of the original 92 patients, of whom 42% reported TMDs, 42% had histories of premenstrual syndrome. 
Androgen excess syndromes in women
Elevated levels of testosterone can appear in women between the ages of 30 and 60 years. Testosterone can be produced in women with the androgen excess syndrome. The clinical signs of androgen excess syndrome are depression, loss of self-esteem, loss of libido, and polyendocrine dysfunction. This condition may also mimic the TMD.  Studies have also suggested that estrogen and progesterone are associated with the synthesis of collagen and elastin, and the protein content within the fibrocartilaginous disk of the TMJ. The transduction of psychological events into physiological and endocrine changes have been evaluated by blood assays in clinical trials.  Therefore, blood assays for different hormones is very useful to differentiate these disorders from the TMDs.
Irritable bowel syndrome
Irritable bowel syndrome (IBS) is a symptom-based disease with chronic pain in the abdomen, discomfort, bloating, and erratic bowel habits without any organic cause. Most of the IBS patients have extraintestinal symptoms, such as, rashes, tension headaches, and muscle pains. According to the study by Korszun, out of the original 92 patients, of whom 42% reported TMDs, 46% had histories of irritable bowel syndrome.  It was also seen that almost 60% of the IBS patients suffered from fibromyalgia syndrome. Similarly, as many as 70% of the FM patients reported symptoms of IBS. They occurred most often in women and were associated with a stressful event in life. They are functional disorders in which cognitive behavior therapy and certain types of drugs are effective.  IBS or FM patients respond to pain in a different manner than other persons. 
Other diseases and disorders that mimic TMDs include, sleep disorders, connective tissue disorders and autoimmune disorders, which may also be the central problem of the HPA-axis, which over a period of years causes an imbalance of the hormones and neurotransmitters, similar to the other disorders mentioned above, leading the body defense mechanism to either upregulate or downregulate the target organ, leading to diseases. 
| Conclusion|| |
In conclusion, the patients suffering with chronic pain often experience high levels of stress, demoralization, and depression. They tend to use a variety of prescribed and self-administered drugs that may alter immune processes. Temporomandibular pain dysfunction syndrome is associated with substantial functional morbidity, and itself acts as a stressor. TMD-related pain can, in many cases, become a chronic pain condition, and as such shares many features with other common psychoneuroimmunological conditions as mentioned above. This review states that clinically significant TMJ pain can be part of a generalized pain syndrome. Dentists can play an important role in the early diagnosis of these common and debilitating conditions by addressing the generalized symptoms in their evaluation of patients with TMDs. A multidisciplinary clinical approach that cuts across the traditional boundaries of such medical disciplines like Dentistry, Rheumatology, Gastroenterology, Endocrinology, and Psychiatry will lead to a more rational approach to clinical diagnosis and treatment options for these complex conditions. The overlap of clinical symptoms among all these conditions shows a shared underlying pathophysiological cause, which involves deregulation of the hypothalamic - pituitary - adrenal stress hormone axis in liable individuals. Any effective treatment is advocated on a foundation of patient - physician respect and trust, and treatment must be demarcated by understanding the TMD's relationship with PNI.
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