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Fibromyalgia: all stressed out.

Fibromyalgia is a poorly understood condition that is characterized by widespread pain and stiffness in the soft tissues, including muscles, tendons, and ligaments, and generally includes fatigue and difficulty sleeping. Diagnosis is made when pain is noted in specific patterns and locations at 11 or more of 18 tender points, although it is often referred to as a "diagnosis of exclusion," or rather one that is made when many other possible conditions have been ruled out yet ongoing pain persists.

Because there is no specific diagnostic test and pain is inherently subjective, many of the patients who suffer from the chronic and often debilitating symptoms of fibromyalgia are treated by both friends and family, as well as some in the medical community, as if they were being overly dramatic, seeking attention, or making things up. This mindset is often propagated when patients with fibromyalgia are portrayed on popular television shows as hypochondriacs or treated with placebo. (1) Years of experience with this attitude only add to the stress and depression that are often rampant in this population. Developments in functional, genetic, and metabolite testing may provide these patients and their physicians with new insight into the etiology and predisposition for this condition, as well as some consolatory validation of symptoms.

It is well established that fibromyalgia is often triggered by stress, including physical, emotional, infectious, and chemical stressors, and is also more prevalent among those who experience a stressful childhood or have a history of trauma. (2-4) However, equal stimuli may have no effect in some people while causing debilitating symptoms in others. What would explain the dramatic individual variance in the ability to "handle" or recover from stress? First we must review the basic physiology of a stress response, including an overview of the various hormones and neurotransmitters involved, and discuss ways to measure and compare stress responses.

When the brain identifies a stressor, or a threat to homeostasis, a cascade of events takes place. A stress response has both a hormonal component and a neuronal component. When a stress is identified, the hypothalamus releases corticotrophin-releasing hormone (CRH) via a portal system to the nearby pituitary gland, where it stimulates the release of adrenocorticotropic hormone (ACTH) that subsequently travels via the bloodstream to the adrenal cortex and prompts additional output of the hormones cortisol and DHEA. Though the stress hormone cortisol is very well studied, this is just part of the picture, as there is a simultaneous activation of the sympathetic nervous system that stimulates an increased output of catecholamines (epinephrine and norepinephrine) in both the brain and the adrenal medulla. It's important to note that CRH also plays a role in activating the sympathetic nervous system through the noradrenergic neurons of the locus ceruleus (a location in the brainstem that is involved in response to stress and is the primary source of norepinephrine in the brain). (5) Norepinephrine in turn also stimulates additional release of CRH from the paraventricular nucleus (PVN); therefore the two hormones and the two branches of a stress response mutually stimulate each other. (6) These events are controlled by negative feedback loops and other regulatory mechanisms that prevent the response from spiraling out of control and return stress hormones to baseline following a reaction to the primary stressor.

There is significant evidence to support a connection between an abnormal stress response and a diagnosis of fibromyalgia, and in fact investigations into the biomarkers of a stress response may aid in diagnosis of the disease. Though most people have little trouble describing what a stress response feels like: increased perspiration, quickened pulse, flushing of skin, increased breath rate, and so on, measuring stress is a much more difficult task. The scientific community has used a variety of ways to try to quantify stress. Stress questionnaires are often employed; however, response is subjective and it is often difficult to separate current symptoms from those experienced recently, making this method relatively insensitive to real-time data. Measuring the hormones of stress response including cortisol levels and catecholamines has been done for a number of years in research circles and is becoming more common in clinical practice. Additional biomarkers, including orthostatic blood pressure, vagal tone, and heart rate variability, also offer objective, in-the-moment data. As we explore these methods for measuring a stress response, we can compare the responses in control populations versus those patients who have been diagnosed with fibromyalgia.

Salivary Cortisol

Saliva is an effective medium for measuring cortisol because its ease of collection allows for assessment of multiple levels throughout the day and therefore the evaluation of the diurnal rhythm. Furthermore, it doesn't require venipuncture, which can affect cortisol levels independently; and the levels of the hormone present in saliva are the fraction that are unbound to carrier proteins, which is the best assessment of hormone that is available for tissues. (7) At-home collection of saliva also allows for an early a.m. collection time. Cortisol levels typically peak approximately 30 minutes after awakening, and this value is referred to as the cortisol awakening response (CAR). Fibromyalgia patients have been found to have a blunted CAR compared with both healthy controls as well as patients with more localized pain. (8), (9) There are a number of theories regarding the pathogenesis of the blunted cortisol production with chronic pain, including the possibility that inflammatory cytokines and/or substance P (a neuropeptide associated with pain and inflammation) may suppress the output of CRH, causing a downstream reduction in cortisol. (10) Other studies have indicated that fibromyalgia patients exhibit an elevation in CRH levels in addition to a blunted CAR, pointing at probable disruptions in feedback or control mechanisms. (11) Regardless of the mechanism, these patients are left with a compromised ability to deal with additional stress, and the underproduction of cortisol also inhibits their ability to control inflammation.

Urinary Catecholamines

Though much less established than salivary cortisol levels, measurement of catecholamines, including dopamine, epinephrine, and norepinephrine as well as other neurotransmitters in urine, is emerging as an effective way to assess the neuronal component of the stress response. There are few studies that relate to fibromyalgia directly; however, correlation with other disorders of the stress response, including insomnia, anxiety, depression, and PTSD, have been noted. (12-14)

Heart Rate Variability Analysis

This easy to measure marker of stress looks at the variance between the R peaks on electrocardiogram (ECG) and can also be measured through pulse monitoring with a photoplethysmograph, essentially an instrument that uses light to measure changes in volume of an organ. Most familiar of these devices is a pulse oximeter. While this sounds like "fancy" technology, there are applications that can be installed on many smartphones that use the camera lens to read changes in blood volume in the fingertip and monitor the rate of variance of the pulse, giving an indication of heart rate variability (HRV). While this feature may be interesting as a novelty, it is not intended as a clinical diagnostic tool, as the duration of "phone study" is typically 2 minutes compared with the 30-minute to 24-hour analysis more commonly done for complete clinical assessment.

The variability in heart rate is caused by the balance between sympathetic and parasympathetic control of the sinus node. Low HRV is associated with risk of heart disease, as well as increased sympathetic tone, indicative of stress. HRV analysis of patients who have been diagnosed with fibromyalgia indicates significant sympathetic hyperactivity (and therefore low HRV). Most of the studies were done in women, and one study did not note the same effect in men. (15-17)

In addition to the fact that fibromyalgia frequently occurs after a traumatic event or stress and functional tests such as HRV indicate increased sympathetic tone in fibromyalgia patients, further evidence to support the fact that fibromyalgia is a sympathetically maintained pain syndrome is indicated by an exacerbation of pain induced by injection of norepinephrine. (18) It is also true that fibromyalgia is often treated with selective serotontin and norepinephrine reuptake inhibitors (SNRIs), indicating that increasing the norepinephrine in the synapse may decrease the pain signal. However, these medications have only been shown to decrease pain by approximately 30010 in 1 out of 4 to 6 people who take them, so direct causality is difficult to ascertain. (19)

There are several ways that a clinician can assess a patient's reaction to stress and level of sympathetic activity, and although the increased sympathetic tone may be a significant contributor to the pain experienced by fibromyalgia patients, it doesn't necessarily explain why some people are more susceptible to this disruption in the stress response while others may not be. There are, however, some genetic variances that may help to explain predisposition to dysfunction.

Genetic Variance

After a stressful event has passed, the body should return to homeostasis and stress hormones that have been secreted should return to near baseline levels. In the case of catecholamines, the metabolism and clearance from circulation throughout the body is facilitated by the COMT (catechol-0-methyltransferase) enzyme. Recent research has found a number of polymorphisms in this enzyme in fibromyalgia patients, meaning that some people have genetic copies of the enzyme that are up to 11 times less efficient than others. (20-21) The COMT polymorphism is by no means specific to fibromyalgia, as the enzyme occurs throughout the body and acts on a wide variety of substrates including dopamine, epinephrine, norepinephrine, estrone, and others. There is ongoing research regarding genetic variance in this area as it pertains to a variety of conditions including prefrontal cognition, back pain, ADHD, and more. (23-25) Screening for this may, however, give some insight to why some patients are experiencing upregulated sympathetic tone; and providing them with additional cofactor support including methyl donors (methylcobalamin, methyltetrahydrofolate, SAMe, etc.) may be of use clinically. Until recently testing has primarily been done for investigational uses only, although some labs around the country are providing this analysis, including the Mayo Clinic. (26)

As with the COMT enzyme, there is genetic variance in the adrenergic receptors seen with fibromyalgia patients, indicating that it may not simply be a case of increased sympathetic signal via elevated catecholamines, but the receptors may vary in concentration, which can cause further increase in sympathetic activity. (27)

Analysis of sympathetic tone, adrenal cortical output, and testing for genetic predisposition to stress dysfunction are objective markers of dysfunction in the body and may provide much-needed validation for a population whose pain is often dismissed because it is difficult to identify its source. Furthermore the strong connection between an abnormal stress response and a diagnosis of fibromyalgia indicate that this population would likely gain great clinical benefit from lifestyle modifications and nutritional and supplemental support for stress, and patients with a strong family history of fibromyalgia and chronic pain should take extra precautions to limit their stress and cultivate a pattern of regular relaxation techniques.

Notes

(1.) Kaplow L. House. Paternity. Season 1, episode 2. Aired November 23,2004.

(2.) Buskila D, Neumann L, Vaisberg G, Alkalay D, Wolfe F. Increased rates of fibromyalgia following cervical spine injury. A controlled study of 161 cases of traumatic injury. Arthritis Rheum. 1997;40:446-452.

(3.) Weissbecker I, Floyd A, Dedert E, Salmon P, Sephton S. Childhood trauma and diurnal cortisol disruption in fibromyalgia syndrome. Psychoneuroendocrinology. 2006 Apr;31(3):312-24. Epub 2005 Nov 7.

(4.) Jones GT, Nicholl BI, McBeth J, et al. Road traffic accidents, but not other physically traumatic events, predict the onset of chronic widespread pain: results from the EpiFunD study. Arthritis Care Res. 2011;63(5):696701.

(5.) Valentino RJ, Foote SL, Aston-Jones G: Corticotropin-releasing factor activates noradrenergic neurons of the locus coeruleus. Brain Res. 1983;270:363-367.

(6.) Calogero AE, Gallucci WT, Gold PW, Chrousos GP: Multiple feedback regulatory loops upon rat hypothalamic corticotropin-releasing hormone secretion. Potential clinical implications. J. Clin Invest. 1988;82:767-774.

(7.) Vining RF et al. Salivary cortisol: a better measure of adrenal cortical function than serum. Ann Clin Biochem. 1983;20:329-335.

(8.) Riva R, Mork PJ, Westgaard RH, Lundberg U. Comparison of the cortisol awakening response in women with shoulder and neck pain and women with fibromyalgia. Psychoneuroendocrinology. 2012 Feb;37(2):299-306.

(9.) Riva R, Mork PJ, Westgaard RH, Re M, Lundberg U. Fibromyalgia syndrome is associated with hypocortisolism. Intl Behav Med. 2010 Sep;17(3):223-233.

(10.) O'Connor TM, O'Halloran DJ, Shanahan F. The stress response and the hypothalamic-pituitary-adrenal axis: from molecule to melancholia. QJ Med 2000; 93:323- 333.

(11.) Neeck G. Pathogenic mechanisms of fibromyalgia. Ageing Res Rev. 2002 Apr;1(2):243-255.

(12.) Delahanty D, Nugent N, Christopher N, Walsh M. Initial urinary epinephrine and cortisol levels predict acute PTSD symptoms in child trauma victims. Psychoneuroendocrinology. 2004;30(2):121-128.

(13.) Hughes )W, Watkins L, Blumenthal JA, Kuhn C, Sherwood A. Depression and anxiety symptoms are related to increased 24-hour urinary norepinephrine excretion among healthy middle-aged women. J Psychosom Res. 2004;57:353-358.

(14.) Vgontzas AN, Tsigos C, Bixler E0, et al. Chronic insomnia and activity of the stress system: a preliminary study. J Psychosom Res. 1998;45:21-31.

(15.) Stein PK, Domitrovich PP, Ambrose K, et al. Sex effects on heart rate variability in fibromyalgia and Gulf War illness. Arthritis Rheum 2004;51:700-708.

(16.) Cohen H, Neumann L, Shore M, Amir M, Cassuto Y, Buskila D. Autonomic dysfunction in patients with fibromyalgia: application of power spectral analysis of heart rate variability. Semin Arthritis Rheum. 2000;29:217-227.

(17.) Ulas UH, Unlu E, Hamamcioglu K, Odabasi Z, Cacki A, Vural 0. Dysautonomia in fibromyalgia syndrome: sympathetic skin responses and RR interval analysis. Rheumatol Int 2006;26:383-387.

(18.) M. Martinez-Lavin, M. Vidal, R. E. Barbosa, C. Pineda, J. M. Casanova, and A. Nava, Norepinephrine-evoked pain in fibromyaIgia. A randomized pilot study [ISCRTN70707830]. BMC Musculoskelet Disord. 2002;3(1)1-6.

(19.) WebMD quote from National Fibromyalgia Association President Lynne Matallana.

(20.) Diatchenko L, Slade GD, Nackley AG, et al. Genetic basis for individual variation of pain perception and the development of a chronic pain condition. Hum Mol Genet. 2005;14:135-143.

(21.) Vargas-AlarcOn G, Fragoso JM, Cruz-Robles D, et al. Catechol-O-methyl transferase (COMT) gene haplotypes in Mexican and Spanish patients with fibromyalgia. Arthritis Res Ther. 2007;9(5):R110.

(22.) Barbosa FR, Matsuda JB, Mazucato M, et al. Influence of catechol-O-methyltransferase (COMT) gene polymorphisms in pain sensibility of Brazilian fibromialgia patients. Rheumatol Int.

(23.) Malhotra AK, Kestler LJ, Mazzanti C, Bates JA, Goldberg T, Goldman T. A Functional Polymorphism in the COMT Gene and Performance on a Test of Prefrontal Cognition. Am) Psychiatry. 2002;159:652.

(24.) Omair A, Lie BA, Reikeras 0, Holden M, Brox JI. Genetic contribution of catechol-O-methyltransferase variants in treatment outcome of low back pain: a prospective genetic association study. BMC Musculoskelet Disord. 2012 May 21;13(1):76.

(25.) Choudhry Z, Sengupta 5, Thakur G, et al. Catechol-0-methyltransferase gene and executive function in children with ADHD. J Atten Disord. 2012 Mar 26.

(26.) Mayo Clinic. COMT: catechol-0-methyltransferase genotype [Web page]. http://www.mayomedicallaboratories.com/test-catalog/Clinical + and + Interpretive/83301. Accessed July 15,2012.

(27.) Vargas-Alarc6n G, Fragoso JM, Cruz-Robles D, et al. Association of adrenergic receptor gene polymorphisms with different fibromyalgia syndrome domains. Arthritis Rheum. 2009 Jul;60(7):2169-2173.

by Sara G. Wood, ND

Dr. Wood grew up in Colorado and obtained her undergraduate degree in biochemistry from Colorado College. An enthusiasm for science but a passion for people led her to medicine, and a desire to treat the cause of disease, not just the symptoms, led her to naturopathy. After completing her doctorate at the National College of Naturopathic Medicine, Dr. Wood stayed in Oregon and has a private practice focused on endocrine imbalance, digestive dysfunction, immune support, and cardiovascular health.

In addition to her clinical practice, Dr. Wood is a staff physician with Labrix Clinical Services Inc., where she educates physicians and health-care providers around the country about hormonal balancing through development of educational materials, contributions to a webinar series, and lectures at local and national conferences. In 2008 she coauthored a book on andropause titled His Change of Life: Male Menopause and Healthy Aging with Testosterone.
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Date:Nov 1, 2013
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