Fibromyalgia 318049 225897292 2008-07-15T22:30:06Z Ratel 672103 Revert to revision 225788140 dated 2008-07-15 12:05:03 by 212.64.173.211 using [[:en:Wikipedia:Tools/Navigation_popups|popups]] {{Infobox_Disease | Name = Fibromyalgia | Image = | Caption = | DiseasesDB = <!-- no entry --> | ICD10 = {{ICD10|M|79|7|m|70}} | ICD9 = {{ICD9|729.1}} | ICDO = | OMIM = | MedlinePlus = 000427 | eMedicineSubj = med | eMedicineTopic = 790 | eMedicine_mult = {{eMedicine2|med|2934}} {{eMedicine2|ped|777}} {{eMedicine2|pmr|47}} | MeshID = D005356 }} '''Fibromyalgia''' (FM) is a human disorder classified by the presence of chronic widespread [[pain]] and tactile [[allodynia]].<ref name="Wolfe">{{cite journal | last=Wolfe | first=F | coauthors=Smythe HA, Yunus MB et al. | title=The American College of Rheumatology 1990 Criteria for the Classification of Fibromyalgia. Report of the Multicenter Criteria Committee | journal=Arthritis and Rheumatism | volume=33 | issue=2 | pages=160–172 |date=February 1990 | pmid=2306288 | doi=10.1002/art.1780330203 }}</ref> While the [[criteria]] for such an entity have not yet been thoroughly developed, the recognition that fibromyalgia involves more than just pain has led to the frequent use of the term "fibromyalgia [[syndrome]]". It is not [[Infectious disease|contagious]], and recent studies suggest that people with fibromyalgia may be [[genetics|genetically]] predisposed.<ref>{{cite journal |author=Buskila D, Sarzi-Puttini P |title=Biology and therapy of fibromyalgia. Genetic aspects of fibromyalgia syndrome |journal=Arthritis Res. Ther. |volume=8 |issue=5 |pages=218 |year=2006 |pmid=16887010 |doi=10.1186/ar2005 |url=http://arthritis-research.com/content/8/5/218 |accessdate=2008-05-21}}</ref> The disorder is not directly life-threatening. The degree of symptoms may vary greatly from day to day with periods of flares (severe worsening of symptoms) or remission; however, the disorder is generally perceived as [[non-progressive]].<ref>{{cite web | author=McBride CR |title=Fibromyalgia |work=Clinical Vignette |date=2000-07-03 |url=http://www.med.ucla.edu/modules/wfsection/article.php?articleid=141 |publisher=UCLA Department of Medicine}}</ref> ==Signs and symptoms== The defining symptoms of fibromyalgia are chronic, widespread pain and tenderness to light touch. Other symptoms can include moderate to severe fatigue, a heightened and painful response to gentle [[Somatosensory system|touch]] ([[allodynia]]), needle-like tingling of the skin, [[Myalgia|muscle aches]], prolonged [[Spasm|muscle spasms]], [[Muscle weakness|weakness]] in the limbs, [[Neuropathy|nerve pain]], functional bowel disturbances,<ref name="pmid15361320">{{cite journal |author=Wallace DJ, Hallegua DS |title=Fibromyalgia: the gastrointestinal link |journal=Curr Pain Headache Rep |volume=8 |issue=5 |pages=364–8 |year=2004 |month=October |pmid=15361320 |doi= |url= |accessdate=2008-05-21}}</ref> and chronic [[Sleep disorder|sleep disturbances]].<ref name="pmid169541">{{cite journal |author=Moldofsky H, Scarisbrick P, England R, Smythe H |title=Musculosketal symptoms and non-REM sleep disturbance in patients with "fibrositis syndrome" and healthy subjects |journal=Psychosom Med |volume=37 |issue=4 |pages=341–51 |year=1975 |pmid=169541 |doi= |url=http://www.psychosomaticmedicine.org/cgi/pmidlookup?view=long&pmid=169541 |accessdate=2008-05-21}}</ref> Sleep disturbances may be related to a phenomenon called ''alpha-delta sleep'', a condition in which deep sleep (associated with [[delta wave]]s) is frequently interrupted by bursts of [[alpha wave]]s, which normally occur during wakefulness. [[Slow-wave sleep]] is often dramatically reduced.{{Fact|date=May 2008}} Many patients experience cognitive dysfunction<ref name="pmid17092441">{{cite journal |author=Glass JM |title=Cognitive dysfunction in fibromyalgia and chronic fatigue syndrome: new trends and future directions |journal=Curr Rheumatol Rep |volume=8 |issue=6 |pages=425–9 |year=2006 |month=December |pmid=17092441 |doi= |url= |accessdate=2008-05-21}}</ref> (known as "brain fog" or "fibrofog"), which may be characterized by impaired concentration,<ref name="pmid17041327">{{cite journal |author=Leavitt F, Katz RS, Mills M, Heard AR |title=Cognitive and Dissociative Manifestations in Fibromyalgia |journal=J Clin Rheumatol. |volume=8 |issue=2 |pages=77–84 |year=2002 |pmid=17041327|doi=10.1097/00124743-200204000-00003}}</ref> problems with [[Short-term memory|short]]<ref name="pmid17894922">{{cite journal |author=Buskila D, Cohen H |title=Comorbidity of fibromyalgia and psychiatric disorders |journal=Curr Pain Headache Rep |volume=11 |issue=5 |pages=333–8 |year=2007 |month=October |pmid=17894922 |doi= |url= |accessdate=2008-05-21}}</ref><ref name="pmid17041327"/> and [[long-term memory]], short-term memory consolidation,<ref name="pmid17894922"> impaired speed of performance,<ref name="pmid17041327"/><ref name="pmid17894922"> inability to multi-task, cognitive overload,<ref name="pmid17894922"><ref name="pmid17041327"/> diminished [[attention span]] and [[anxiety]] and [[Clinical depression|depressive]] symptoms.<ref name="pmid17894922"> "Brain fog" may be directly related to the sleep disturbances experienced by sufferers of fibromyalgia.{{Fact|date=January 2008}} Other symptoms often attributed to fibromyalgia that may possibly be due to a [[comorbidity|comorbid]] disorder include [[myofascial pain syndrome]], diffuse non-dermatomal [[paresthesia]]s, functional bowel disturbances and [[irritable bowel syndrome]] (possibly linked to lower levels of [[ghrelin]],<ref name="pmid17689128">{{cite journal |author=Tander B, Atmaca A, Aliyazicioglu Y, Canturk F |title=Serum ghrelin levels but not GH, IGF-1 and IGFBP-3 levels are altered in patients with fibromyalgia syndrome |journal=Joint Bone Spine |volume=74 |issue=5 |pages=477–81 |year=2007 |month=October |pmid=17689128 |doi=10.1016/j.jbspin.2007.01.024 |url=http://linkinghub.elsevier.com/retrieve/pii/S1297-319X(07)00183-2 |accessdate=2008-05-21}}</ref> [[Urinary system|genitourinary]] symptoms and [[interstitial cystitis]], [[Dermatology|dermatological]] disorders, [[headache]]s, [[Myoclonus|myoclonic twitches]], and symptomatic [[hypoglycemia]]. Although fibromyalgia is classified based on the presence of chronic widespread pain, pain may also be localized in areas such as the [[shoulder]]s, [[neck]], low [[back]], [[hip]]s, or other areas. Many sufferers also experience varying degrees of facial pain and have high rates of comorbid [[temporomandibular joint disorder]]. Not all patients have all symptoms. Symptoms can have a slow onset, and many patients have mild symptoms beginning in childhood, that are often misdiagnosed as [[growing pains]]. {{Fact|date=January 2008}} Symptoms are often aggravated by unrelated illness or changes in the weather. {{Fact|date=January 2008}}They can become more tolerable or less tolerable throughout daily or yearly cycles; however, many people with fibromyalgia find that, at least some of the time, the condition prevents them from performing normal activities such as driving a car or walking up stairs. The disorder does not cause [[inflammation]] as is characteristic of [[rheumatoid arthritis]], although some [[non-steroidal anti-inflammatory drug]]s may temporarily reduce pain symptoms in some patients. Their use, however, is limited, and often of little to no value in pain management.<ref name="Yahoo health">{{cite web |author=Shannon Erstad | title=Nonsteroidal anti-inflammatory drugs for fibromyalgia |url=http://health.yahoo.com/topic/pain/resources/article/healthwise/hw196001 |date=2005-11-10 |publisher=Health Yahoo |accessdate=2007-10-25}}</ref> ===Variability of symptoms=== The following factors have been proposed to exacerbate symptoms of pain in patients: * Increased [[psychosocial]] [[Stress (medicine)|stress]]<ref>{{cite book |author= |title=Puzzling Symptoms: How to Solve the Puzzle of Your Symptoms |publisher=Cable Publishing |location= |year=2008 |pages= |isbn=1-934980-11-0 |oclc= |doi= |accessdate=}}</ref> * Excessive physical exertion (exercise seems to decrease the pain threshold of people with fibromyalgia but increase it in healthy individuals)<ref>{{cite journal | author = Staud R, Robinson ME, Price DD | title = Isometric exercise has opposite effects on central pain mechanisms in fibromyalgia patients compared to normal controls | journal = Pain | volume = 118 | issue = 1-2 | pages = 176–84 | year = 2005 | pmid = 16154700 | doi = 10.1016/j.pain.2005.08.007}}</ref> * Lack of [[slow-wave sleep]] * Changes in humidity and barometric pressure {{Fact|date=January 2008}} ==Causes== The cause of fibromyalgia is unknown. However, several hypotheses have been developed, which are discussed below. === Genetic Predisposition === There is evidence that genetic factors may play a role in the development of fibromyalgia. For example, there is a high aggregation of FM in families.<ref> Stormorken H, Brosstad F. Fibromyalgia: family clustering and sensory urgency with early onset indicate genetic predisposition and thus a "true" disease. Scand J Rheumatol. 1992;221:207. </ref><ref> Arnold LM, Hudson JL, Hess EV, Ware AE, Fritz DA, Auchenbach MB, Starck LO, Keck PE Jr. Family study of fibromyalgia. Arthritis Rheum. 2004;50:944–952. doi: 10.1002/art.20042. </ref> The mode of inheritance is currently unknown , but it is most probably polygenic.<ref> Buskila D, Sarzi-Puttini P. Biology and therapy of fibromyalgia. Genetic aspects of fibromyalgia syndrome. Arthritis Res Ther. 2006;8(5):218.</ref> Research has demonstrated that FM is associated with polymorphisms of genes in the serotoninergic,<ref> Cohen H, Buskila D, Neumann L, Ebstein RP. Confirmation of an association between fibromyalgia and serotonin transporter promoter region (5-HTTLPR) polymorphism, and relationship to anxiety related personality traits. Arthritis Rheum. 2002;46:845–847. doi: 10.1002/art.10103. </ref> dopaminergic<ref> Buskila D, Cohen H, Neumann L, Ebstein RP. An association between fibromyalgia and the dopamine D4 receptor exon III repeat polymorphism and relationship personality traits. Mol Psychiatry. 2004;9:730–731. doi: 10.1038/sj.mp.4001506. </ref> and catecholaminergic systems.<ref> Zubieta JK, Heitzeg MM, Smith YR, Bueller JA, Xu K, Xu Y, Koeppe RA, Stohler CS, Goldman D. COMT val158met genotype affects muopioid neurotransmitter responses to a pain stressor. Science. 2003;299:1240–1243. doi: 10.1126/science.1078546. </ref> However, these polymorphisms are not specific for FM and are associated with a variety of allied disorders (e.g. chronic fatigue syndrome,<ref> Narita M, Nishigami N, Narita N, Yamaguti K, Okado N, Watanabe Y, Kuratsune H. Association between serotonin transporter gene polymorphism and chronic fatigue syndrome. Biochem Biophys Res Commun. 2003;311:264–266. doi: 10.1016/j.bbrc.2003.09.207. </ref> irritable bowel syndrome<ref> Camilleri M, Atanasova E, Kim HJ, Viramontes BE, Mckinzie S, Urrutia R. Serotonin-transporter polymorphism pharmacogenetics in diarrhea-predominant irritable bowel syndrome. Gastroenterology. 2002;123:425–432. doi: 10.1053/gast.2002.34780. </ref>) and with depression.<ref> Hudson JI, Mangweth B, Pope HG JR, De COL C, Hausmann A, Gutweniger S, Laird NM, Biebl W, Tsuang MT. Family study of affective spectrum disorder. Arch Gene Psychiatry. 2003;60:170–177. doi: 10.1001/archpsyc.60.2.170. </ref> === Stress === Studies have shown that [[Stress (medicine)|stress]] is a significant precipitating factor in the development of fibromyalgia,<ref>{{cite journal | author = Anderberg UM, Marteinsdottir I, Theorell T, von Knorring L | title=The impact of life events in female patients with fibromyalgia and in female healthy controls | journal=Eur Psychiatry | month=Aug| year=2000 | pages=33–41 | volume=15 | issue=5 | pmid=10954873 | doi = 10.1016/S0924-9338(00)00397-7}}</ref> and that [[PTSD]] is linked with fibromyalgia.<ref>{{cite journal | author= Amital D, Fostick L, Polliack ML, Segev S, Zohar J, Rubinow A, Amital H | title=Posttraumatic stress disorder, tenderness, and fibromyalgia syndrome: are they different entities? | journal=J Psychosom Res | month=Nov | year=2006 | pages=663–9 | volume=61 | issue=5 | pmid=17084145 | doi= 10.1016/j.jpsychores.2006.07.003}}</ref><ref>{{cite journal | author= Raphael KG, Janal MN, Nayak S | title=Comorbidity of fibromyalgia and posttraumatic stress disorder symptoms in a community sample of women | journal=Pain Med. | month=Mar| year=2004 | pages=33–41 | volume=5 | issue=1 | pmid=14996235 | doi= 10.1111/j.1526-4637.2004.04003.x}}</ref> The Amital study found that 49% of PTSD patients fulfilled the criteria for FMS, compared with none of the controls. Stress can alter the function of the [[HPA axis]] and change [[cortisol]] levels in the body, leading to widespread pain.<ref> {{cite journal|title=Hypothalamic-pituitary-adrenal stress axis function and the relationship with chronic widespread pain and its antecedents|journal=Arthritis Res Ther. |date=|first=|last=|coauthors=|volume=|issue=|pages=|pmid=16207340 |url=|format=|accessdate=2008-06-03 }}</ref> An alternate hypothesis regarding the development of fibromyalgia in relationship to stress proposes that the disorder may be a [[psychosomatic illness]] has been described by [[John E. Sarno]]'s "[[tension myositis syndrome]]", which hypothesizes that [[chronic pain]] is caused by the mind's [[subconscious]] strategy of distracting painful or dangerous emotions. Education, attitude change, and in some cases, psychotherapy are proposed as treatments.<ref>{{cite book |last=Sarno|first=Dr. John E. et al,| title=The Divided Mind: The Epidemic of Mindbody Disorders |year=2006 |isbn=0-06-085178-3 |pages=21-22,235-237,294-298}}</ref> ===Sleep disturbance=== [[Electroencephalography]] studies have shown that people with fibromyalgia lack [[slow-wave sleep]] and circumstances that interfere with stage four sleep (pain, depression, serotonin deficiency, certain medications or [[anxiety]]) may cause or worsen the condition.<ref>{{cite web |title=Fibromyalgia &ndash; An Information Booklet |url=http://www.arc.org.uk/arthinfo/patpubs/6013/6013.asp |date=October 2004 |publisher=[[Arthritis Research Campaign]]}}</ref> According to the sleep disturbance hypothesis, an event such as a trauma or illness causes sleep disturbance and possibly initial chronic pain that may initiate the disorder. The hypothesis supposes that stage 4 sleep is critical to the function of the [[nervous system]], as it is during that stage that certain neurochemical processes in the body 'reset'. In particular, pain causes the release of the [[neuropeptide]] [[substance P]] in the [[spinal cord]] which has the effect of amplifying pain and causing nerves near the initiating ones to become more sensitive to pain. Under normal circumstances, areas around a wound to become more sensitive to pain but if pain becomes chronic and body-wide this process can run out of control. The sleep disturbance hypothesis holds that deep sleep is critical to reset the substance P mechanism and prevent this out-of-control effect. The sleep disturbance/substance P hypothesis could explain "tender points" that are characteristic of fibromyalgia but which are otherwise enigmatic, since their positions don't correspond to any particular set of nerve junctions or other obvious body structures.{{Fact|date=June 2007}} The hypothesis proposes that these locations are more sensitive because the sensory nerves that serve them are positioned in the spinal cord to be most strongly affected by substance P. This hypothesis could also explain some of more general neurological features of fibromyalgia, since substance P is active in many other areas of the nervous system. The sleep disturbance hypothesis could also provide a possible connection between fibromyalgia, [[chronic fatigue syndrome]] (CFS) and [[post-polio syndrome]] through damage to the ascending reticular activating system of the [[reticular formation]]. This area of the brain, in addition to apparently controlling the sensation of fatigue, is known to control sleep behaviors and is also believed to produce some neuropeptides, and thus injury or imbalance in this area could cause both CFS and sleep-related fibromyalgia. Critics of the hypothesis argue that it does not explain slow-onset fibromyalgia, fibromyalgia present without tender points, or patients without heightened pain symptoms, and a number of the non-pain symptoms present in the disorder.{{Fact|date=January 2008}} ===Dopamine abnormality=== [[Dopamine]] is a [[catecholamine]] [[neurotransmitter]] perhaps best known for its role in the pathology of [[schizophrenia]], [[Parkinson's disease]] and [[addiction]]. There is also strong evidence for a role of dopamine in [[restless leg syndrome]],<ref name="pmid16816393">{{cite journal |author=Cervenka S, Pålhagen SE, Comley RA, ''et al'' |title=Support for dopaminergic hypoactivity in restless legs syndrome: a PET study on D2-receptor binding |journal=Brain |volume=129 |issue=Pt 8 |pages=2017–28 |year=2006 |month=August |pmid=16816393 |doi=10.1093/brain/awl163 |url=http://brain.oxfordjournals.org/cgi/pmidlookup?view=long&pmid=16816393 |accessdate=2008-05-21}}</ref> which is a common co-morbid condition in patients with fibromyalgia.<ref name="pmid8646049">{{cite journal |author=Yunus MB, Aldag JC |title=Restless legs syndrome and leg cramps in fibromyalgia syndrome: a controlled study |journal=BMJ |volume=312 |issue=7042 |pages=1339 |year=1996 |month=May |pmid=8646049 |doi= |url=http://bmj.com/cgi/pmidlookup?view=long&pmid=8646049 |accessdate=2008-05-21}}</ref> In addition, dopamine plays a critical role in pain perception and natural analgesia. Accordingly, musculoskeletal pain complaints are common among patients with Parkinson's disease,<ref name="pmid15043802">{{cite journal |author=Sage JI |title=Pain in Parkinson's Disease |journal=Curr Treat Options Neurol |volume=6 |issue=3 |pages=191–200 |year=2004 |month=May |pmid=15043802 |doi= |url=http://www.treatment-options.com/1092-8480/6/191 |accessdate=2008-05-21 |format={{dead link|date=June 2008}} &ndash; <sup>[http://scholar.google.co.uk/scholar?hl=en&lr=&q=intitle%3APain+in+Parkinson%27s+Disease&as_publication=Curr+Treat+Options+Neurol&as_ylo=2004&as_yhi=2004&btnG=Search Scholar search]</sup>}}</ref> which is characterized by drastic reductions in dopamine owing to neurodegeneration of dopamine-producing neurons, while patients with schizophrenia, which is thought to be due (in part) to hyperactivity of dopamine-producing neurons, have been shown to be relatively insensitive to pain.<ref name="pmid18093615">{{cite journal |author=Potvin S, Stip E, Tempier A, ''et al'' |title=Pain perception in schizophrenia: No changes in diffuse noxious inhibitory controls (DNIC) but a lack of pain sensitization |journal=J Psychiatr Res |volume= |issue= |pages= |year=2007 |month=December |pmid=18093615 |doi=10.1016/j.jpsychires.2007.11.001 |url=http://linkinghub.elsevier.com/retrieve/pii/S0022-3956(07)00187-2 |accessdate=2008-05-21}}</ref><ref name="pmid18160219">{{cite journal |author=Potvin S, Marchand S |title=Hypoalgesia in schizophrenia is independent of antipsychotic drugs: A systematic quantitative review of experimental studies |journal=Pain |volume= |issue= |pages= |year=2007 |month=December |pmid=18160219 |doi=10.1016/j.pain.2007.11.007 |url=http://linkinghub.elsevier.com/retrieve/pii/S0304-3959(07)00676-8 |accessdate=2008-05-21}}</ref> Patients with restless legs syndrome have also been demonstrated to have [[hyperalgesia]] to static mechanical stimulation.<ref name="pmid14985260">{{cite journal |author=Stiasny-Kolster K, Magerl W, Oertel WH, Möller JC, Treede RD |title=Static mechanical hyperalgesia without dynamic tactile allodynia in patients with restless legs syndrome |journal=Brain |volume=127 |issue=Pt 4 |pages=773–82 |year=2004 |month=April |pmid=14985260 |doi=10.1093/brain/awh079 |url=http://brain.oxfordjournals.org/cgi/pmidlookup?view=long&pmid=14985260 |accessdate=2008-05-21}}</ref> Fibromyalgia has been commonly referred to as a "stress-related disorder" due to its frequent onset and worsening of symptoms in the context of stressful events.<ref name="pmid16174484">{{cite journal |author=Van Houdenhove B, Egle U, Luyten P |title=The role of life stress in fibromyalgia |journal=Curr Rheumatol Rep |volume=7 |issue=5 |pages=365–70 |year=2005 |month=October |pmid=16174484 |doi= |url= |accessdate=2008-05-21}}</ref><ref name="pmid12849719">{{cite journal |author=Clauw DJ, Crofford LJ |title=Chronic widespread pain and fibromyalgia: what we know, and what we need to know |journal=Best Pract Res Clin Rheumatol |volume=17 |issue=4 |pages=685–701 |year=2003 |month=August |pmid=12849719 |doi= |url= |accessdate=2008-05-21}}</ref> It was proposed that fibromyalgia may represent a condition characterized by low levels of central dopamine that likely results from a combination of genetic factors and exposure to environmental stressors, including psychosocial distress, physical trauma, systemic viral infections or inflammatory disorders (e.g. [[rheumatoid arthritis]], [[systemic lupus erythematosus]]).<ref name="pmid14975515">{{cite journal |author=Wood PB |title=Stress and dopamine: implications for the pathophysiology of chronic widespread pain |journal=Med. Hypotheses |volume=62 |issue=3 |pages=420–4 |year=2004 |pmid=14975515 |doi=10.1016/j.mehy.2003.10.013 | url = http://linkinghub.elsevier.com/retrieve/pii/S0306987703003748 |accessdate=2008-05-21}}</ref> This conclusion was based on three key observations; fibromyalgia is associated with stress, chronic exposure to stress results in a disruption of dopamine-related neurotransmission<ref name="pmid9355111">{{cite journal |author=Finlay JM, Zigmond MJ |title=The effects of stress on central dopaminergic neurons: possible clinical implications |journal=Neurochem. Res. |volume=22 |issue=11 |pages=1387–94 |year=1997 |month=November |pmid=9355111 |doi= |url= |accessdate=2008-05-21}}</ref> and dopamine plays a critical role in modulating pain perception and central [[analgesia]] in such areas as the [[basal ganglia]]<ref name="pmid7715939">{{cite journal |author=Chudler EH, Dong WK |title=The role of the basal ganglia in nociception and pain |journal=Pain |volume=60 |issue=1 |pages=3–38 |year=1995 |month=January |pmid=7715939 |doi= |url=http://linkinghub.elsevier.com/retrieve/pii/0304-3959(94)00172-B |accessdate=2008-05-21}}</ref> including the [[nucleus accumbens]],<ref name="pmid10597883">{{cite journal |author=Altier N, Stewart J |title=The role of dopamine in the nucleus accumbens in analgesia |journal=Life Sci. |volume=65 |issue=22 |pages=2269–87 |year=1999 |pmid=10597883 |doi= |url=http://linkinghub.elsevier.com/retrieve/pii/S0024320599002982 |accessdate=2008-05-21}}</ref> [[insular cortex]],<ref name="pmid10234044">{{cite journal |author=Burkey AR, Carstens E, Jasmin L |title=Dopamine reuptake inhibition in the rostral agranular insular cortex produces antinociception |journal=J. Neurosci. |volume=19 |issue=10 |pages=4169–79 |year=1999 |month=May |pmid=10234044 |doi= |url=http://www.jneurosci.org/cgi/pmidlookup?view=long&pmid=10234044 |accessdate=2008-05-21}}</ref> [[anterior cingulate cortex]],<ref name="pmid15327817">{{cite journal |author=López-Avila A, Coffeen U, Ortega-Legaspi JM, del Angel R, Pellicer F |title=Dopamine and NMDA systems modulate long-term nociception in the rat anterior cingulate cortex |journal=Pain |volume=111 |issue=1-2 |pages=136–43 |year=2004 |month=September |pmid=15327817 |doi=10.1016/j.pain.2004.06.010 |url=http://linkinghub.elsevier.com/retrieve/pii/S0304395904002982 |accessdate=2008-05-21}}</ref> [[thalamus]],<ref name="pmid1611515">{{cite journal |author=Shyu BC, Kiritsy-Roy JA, Morrow TJ, Casey KL |title=Neurophysiological, pharmacological and behavioral evidence for medial thalamic mediation of cocaine-induced dopaminergic analgesia |journal=Brain Res. |volume=572 |issue=1-2 |pages=216–23 |year=1992 |month=February |pmid=1611515 |doi= |url=http://linkinghub.elsevier.com/retrieve/pii/0006-8993(92)90472-L |accessdate=2008-05-21}}</ref> [[periaqueductal gray]]<ref name="pmid15275769">{{cite journal |author=Flores JA, El Banoua F, Galán-Rodríguez B, Fernandez-Espejo E |title=Opiate anti-nociception is attenuated following lesion of large dopamine neurons of the periaqueductal grey: critical role for D1 (not D2) dopamine receptors |journal=Pain |volume=110 |issue=1-2 |pages=205–14 |year=2004 |month=July |pmid=15275769 |doi=10.1016/j.pain.2004.03.036 |url=http://linkinghub.elsevier.com/retrieve/pii/S0304395904001733 |accessdate=2008-05-21}}</ref> and [[spinal cord]].<ref name="pmid6314870">{{cite journal |author=Lindvall O, Björklund A, Skagerberg G |title=Dopamine-containing neurons in the spinal cord: anatomy and some functional aspects |journal=Ann. Neurol. |volume=14 |issue=3 |pages=255–60 |year=1983 |month=September |pmid=6314870 |doi=10.1002/ana.410140302 |url= |accessdate=2008-05-21}}</ref><ref name="pmid15975975">{{cite journal |author=Tamae A, Nakatsuka T, Koga K, ''et al'' |title=Direct inhibition of substantia gelatinosa neurones in the rat spinal cord by activation of dopamine D2-like receptors |journal=J. Physiol. (Lond.) |volume=568 |issue=Pt 1 |pages=243–53 |year=2005 |month=October |pmid=15975975 |doi=10.1113/jphysiol.2005.091843 |url=http://www.jphysiol.org/cgi/pmidlookup?view=long&pmid=15975975 |accessdate=2008-05-21}}</ref> In support of the dopamine [[hypothesis]] of fibromyalgia, a reduction in dopamine synthesis has been reported by a study that used [[positron emission tomography]] (PET) and demonstrated a reduction in dopamine synthesis among fibromyalgia patients in several brain regions in which dopamine plays a role in inhibiting pain perception, including the [[mesencephalon]], thalamus, insular cortex and anterior cingulate cortex.<ref name="pmid17023218">{{cite journal |author=Wood PB, Patterson JC, Sunderland JJ, Tainter KH, Glabus MF, Lilien DL |title=Reduced presynaptic dopamine activity in fibromyalgia syndrome demonstrated with positron emission tomography: a pilot study |journal=J Pain |volume=8 |issue=1 |pages=51–8 |year=2007 |month=January |pmid=17023218 |doi=10.1016/j.jpain.2006.05.014 |url=http://linkinghub.elsevier.com/retrieve/pii/S1526-5900(06)00843-1 |accessdate=2008-05-21}}</ref> A subsequent PET study demonstrated that, whereas healthy individuals release dopamine into the [[caudate nucleus]] and [[putamen]] during a tonic experimental pain stimulus (i.e. hypertonic saline infusion into a muscle bed),<ref name="pmid17050717">{{cite journal |author=Scott DJ, Heitzeg MM, Koeppe RA, Stohler CS, Zubieta JK |title=Variations in the human pain stress experience mediated by ventral and dorsal basal ganglia dopamine activity |journal=J. Neurosci. |volume=26 |issue=42 |pages=10789–95 |year=2006 |month=October |pmid=17050717 |doi=10.1523/JNEUROSCI.2577-06.2006 |url=http://www.jneurosci.org/cgi/pmidlookup?view=long&pmid=17050717 |accessdate=2008-05-21}}</ref> fibromyalgia patients fail to release dopamine in response to pain and, in some cases, actually have a reduction in dopamine levels during painful stimulation.<ref name="pmid17610577">{{cite journal |author=Wood PB, Schweinhardt P, Jaeger E, ''et al'' |title=Fibromyalgia patients show an abnormal dopamine response to pain |journal=Eur. J. Neurosci. |volume=25 |issue=12 |pages=3576–82 |year=2007 |month=June |pmid=17610577 |doi=10.1111/j.1460-9568.2007.05623.x |url=http://www.blackwell-synergy.com/openurl?genre=article&sid=nlm:pubmed&issn=0953-816X&date=2007&volume=25&issue=12&spage=3576 |accessdate=2008-05-21}}</ref> Moreover, a substantial subset of fibromyalgia patients respond well in controlled trials to [[pramipexole]], a [[dopamine agonist]] that selectively stimulates dopamine D2/D3 receptors and is used to treat both Parkinson's disease and restless legs syndrome.<ref name="pmid16052595">{{cite journal |author=Holman AJ, Myers RR |title=A randomized, double-blind, placebo-controlled trial of pramipexole, a dopamine agonist, in patients with fibromyalgia receiving concomitant medications |journal=Arthritis Rheum. |volume=52 |issue=8 |pages=2495–505 |year=2005 |month=August |pmid=16052595 |doi=10.1002/art.21191 |accessdate=2008-05-21}}</ref> ===Serotonin=== [[Serotonin]] is a [[neurotransmitter]] that is known to play a role in regulating sleep patterns, mood, feelings of well-being, concentration and descending inhibition of pain. Accordingly, it has been hypothesized that the [[pathophysiology]] underlying the symptoms of fibromyalgia may be a dysregulation of serotonin metabolism, which may explain (in part) many of the symptoms associated with the disorder. This [[hypothesis]] is derived in part by the observation of decreased serotonin metabolites in patient [[plasma]]<ref>[http://www.ncbi.nlm.nih.gov/pubmed/1313504?ordinalpos=4&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsPanel.Pubmed_RVDocSum Platelet 3H-imipramine uptake receptor density and...[J Rheumatol. 1992&#93; - PubMed Result<!-- Bot generated title -->]</ref> and [[cerebrospinal fluid]].<ref>[http://www.ncbi.nlm.nih.gov/pubmed/1374252?ordinalpos=1&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsPanel.Pubmed_RVDocSum Cerebrospinal fluid biogenic amine metabolites in ...[Arthritis Rheum. 1992&#93; - PubMed Result<!-- Bot generated title -->]</ref> However, [[selective serotonin reuptake inhibitors]] (SSRIs) have met with limited success in alleviating the symptoms of the disorder, while drugs with activity as mixed [[serotonin-norepinephrine reuptake inhibitor]]s (SNRIs) have been more successful<ref>[http://www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pubmed&pubmedid=16762044 Biology and therapy of fibromyalgia. New therapies in fibromyalgia<!-- Bot generated title -->]</ref>. Accordingly, [[duloxetine]] ([[Cymbalta]]), a SNRI originally used to treat depression and painful [[diabetic neuropathy]], has been demonstrated by controlled trials to relieve symptoms of some patients. Eli Lilly and Company, the manufacturer of duloxetine has submitted a supplementary new drug application (sNDA) to the [[FDA]] for approval of it use in the treatment of FM. The relevance of dysregulated serotonin metabolism to the pathophysiology is a matter of debate.<ref>[http://www.ncbi.nlm.nih.gov/pubmed/17693607?ordinalpos=1&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsPanel.Pubmed_RVDocSum Serum serotonin levels are not useful in diagnosin...[Ann Rheum Dis. 2007&#93; - PubMed Result<!-- Bot generated title -->]</ref> Ironically, one of the more effective types of medication for the treatment of the disorder (i.e. serotonin [[5-HT3 antagonist]]s) actually block some of the effects of serotonin.<ref>[http://www.ncbi.nlm.nih.gov/pubmed/12122920?ordinalpos=3&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsPanel.Pubmed_RVDocSum Current experience with 5-HT3 receptor antagonists...[Rheum Dis Clin North Am. 2002&#93; - PubMed Result<!-- Bot generated title -->]</ref> ===Human growth hormone=== An alternate hypothesis suggests that stress-induced problems in the [[hypothalamus]] may lead to reduced sleep and reduced production of [[human growth hormone]] (HGH) during [[slow-wave sleep]]. People with fibromyalgia tend to produce inadequate levels of HGH. Most patients with FM with low IGF-I levels failed to secrete HGH after stimulation with clonidine and l-dopa.{{Fact|date=January 2008}} This view is supported by the fact that those hormones under the direct or indirect control of HGH, including [[IGF-1]], [[cortisol]], [[leptin]] and [[neuropeptide Y]] are abnormal in people with fibromyalgia,<ref>{{cite journal | last = Anderberg | first = UM | coauthors = Liu Z, Berglund L, Nyberg F | pmid = 10700334 | title = Elevated plasma levels of neuropeptide Y in female fibromyalgia patients | journal = European Journal of Pain | volume = 3 | issue = 1 | year = 1999 | pages = 19–30 | doi = 10.1016/S1090-3801(99)90185-4}}</ref> In addition, treatment with exogenous HGH or growth hormone secretagogue reduces fibromyalgia related pain and restores slow wave sleep<ref> {{ cite journal | last = Jones | first = KD | coauthors = Deodhar P, Lorentzen A, Bennett RM, Deodhar AA | title = Growth hormone perturbations in fibromyalgia: a review | journal = Seminars in Arthritis and Rheumatism | year = 2007 | volume = 36 | issue = 6 | pages = 357–79 | pmid = 17224178 | doi = 10.1016/j.semarthrit.2006.09.006 }}</ref><ref>{{cite journal | last = Shuer | first = ML | title = Fibromyalgia: symptom constellation and potential therapeutic options | journal = Endocrine | volume = 22 | issue = 1 | pages = 67–76 | pmid = 14610300 | doi = 10.1385/ENDO:22:1:67 | year = 2003 }}</ref><ref>{{cite journal | last = Yuen | first = KC | coauthors = Bennett RM, Hryciw CA, Cook MB, Rhoads SA, Cook DM | journal = Growth hormone & IGF research | title = Is further evaluation for growth hormone (GH) deficiency necessary in fibromyalgia patients with low serum insulin-like growth factor (IGF)-I levels? | volume = 17 | issue = 1 | year = 2007 | pages = 82–8 | pmid = 17289417 | doi = 10.1016/j.ghir.2006.12.006 }}</ref><ref>{{cite journal | last = Bennett | first = RM | coauthors = Cook DM, Clark SR, Burckhardt CS, Campbell SM. | pmid = 9228141 | title = Hypothalamic-pituitary-insulin-like growth factor-I axis dysfunction in patients with fibromyalgia | volume = 24 | issue = 7 | pages = 1384–9 | journal = of Rheumatology }}</ref> though there is disagreement about the proposition.<ref>{{cite journal | last = McCall-Hosenfeld | first = JS | coauthors = Goldenberg DL, Hurwitz S, Adler GK. | title = Growth hormone and insulin-like growth factor-1 concentrations in women with fibromyalgia | journal = Journal of Rheumatology | volume = 30 | issues = 4 | pages = 809–14 | pmid = 12672204 }}</ref> ===Comorbidity=== Cutting across several of the above hypotheses is the proposition that fibromyalgia is almost always a [[comorbidity|comorbid]] disorder, occurring in combination with some other disorder (or trauma) that likely served to "trigger" the fibromyalgia in the first place. In some cases, the original disorder abates on its own or is separately treated and cured, but the fibromyalgia remains. This is especially apparent when fibromyalgia seems triggered by major surgery.{{Fact|date=May 2008}} A large percentage of chronic fatigue syndrome patients are reported to develop fibromyalgia between onset and the second year of illness.<ref>{{cite journal | author = Friedberg F, Jason LA | title = Chronic fatigue syndrome and fibromyalgia: clinical assessment and treatment | journal = J Clin Psychol. | volume = 57 | issue = 4 | pages = 433–55 | year = 2001 | pmid = 11255201 | doi = 10.1002/jclp.1040 }}</ref> Other possible triggers are [[gluten sensitivity]] and/or irritable bowel. Irritable bowel is found at high frequency in fibromyalgia,<ref name="pmid16042909">{{cite journal | author = Frissora CL, Koch KL | title = Symptom overlap and comorbidity of irritable bowel syndrome with other conditions | journal = Current gastroenterology reports | volume = 7 | issue = 4 | pages = 264–71 | year = 2005 | pmid = 16042909| doi = 10.1007/s11894-005-0018-9}}</ref> and a large support group survey of adult celiacs revealed that 9% had fibromyalgia.<ref name="pmid12741468">{{cite journal | author = Zipser RD, Patel S, Yahya KZ, Baisch DW, Monarch E | title = Presentations of adult celiac disease in a nationwide patient support group | journal = Dig. Dis. Sci. | volume = 48 | issue = 4 | pages = 761–4 | year = 2003 | pmid = 12741468| doi = 10.1023/A:1022897028030}}</ref> ===Deposition disease=== The 'deposition hypothesis of fibromyaglia' posits fibromyalgia is due to intracellular [[phosphate]] and [[calcium]] accumulations that eventually reaches levels sufficient to impede the [[Adenosine triphosphate|ATP]] process, possibly caused by a [[kidney]] defect or missing [[enzyme]] that prevents the removal of excess phosphates from the blood stream. Accordingly, proponents of this hypothesis suggest that fibromyalgia may be an inherited disorder, and that phosphate build-up in cells is gradual but can be accelerated by trauma or illness. [[Diagnosis]] is made with a specialized technique called ''mapping'', a gentle palpitation of the [[muscle]]s to detect lumps and areas of spasm thought to be caused by an excess of [[calcium]] in the [[cytosol]] of the cells. The mapping technique is notably different from the manual tenderpoint examination<ref>[http://www.ncbi.nlm.nih.gov/pubmed/9035000?ordinalpos=1&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsPanel.Pubmed_RVDocSum A standardized manual tender point survey. I. Deve...[J Rheumatol. 1997&#93; - PubMed Result<!-- Bot generated title -->]</ref> upon which a diagnosis of fibromyalgia depends and is purportedly different from the detection of [[trigger point]]s that characterize the [[myofascial pain syndrome]].{{Fact|date=January 2008}} While this hypothesis does not identify the causative mechanism in the kidneys, it proposes a treatment known as [[guaifenesin therapy]]. This treatment involves administering the drug guaifenesin to a patient's individual dosage, avoiding [[salicylic acid]] in medications or on the skin. Often products for [[salicylate sensitivity]] are very helpful. If the patient is also hypoglycemic, a diet is designed to keep [[insulin]] levels low. Of note, guaifenesin is also a central acting [[muscle relaxant]] used in veterinary anaesthesia<ref>[http://www.ncbi.nlm.nih.gov/pubmed/2282545?ordinalpos=13&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsPanel.Pubmed_RVDocSum Intravenous anesthesia. [Vet Clin North Am Equine Pract. 1990&#93; - PubMed Result<!-- Bot generated title -->]</ref> that is structurally related to [[methocarbamol]], a property that might explain its utility in some fibromyalgia patients. A controlled trial of guaifenesin for the treatment of fibromyalgia demonstrated no evidence for efficacy of this medication.<ref name="Bennett">{{cite journal |author=Bennett RM, De Garmo P, Clark SR |title=A Randomized, Prospective, 12 Month Study To Compare The Efficacy Of Guaifenesin Versus Placebo In The Management Of Fibromyalgia |journal=Arthritis and Rheumatism |volume=39 |pages=S212 |year=1996 |url=http://www.myalgia.com/guaif2.htm |format=reprint |doi=10.1002/art.1780391004}}<br/>Lay summary and report: * {{cite web |author=Kristin Thorson |work=Fibromyalgia Network |title=Is One Placebo Better Than Another? &ndash; The Guaifenesin Story |url=http://www.fmnetnews.com/resources-alert-product6.php |date=1997 |publisher=Fibromyalgia Network}}</ref> However, this study has been criticized by the chief proponent of the deposition hypothesis for not limiting salicylic acid exposure in patients, and for studying the effectiveness of only guaifenesin, not the entire treatment method.<ref>{{cite journal | url = http://www.fibromyalgiatreatment.com/Research_Oregon.htm | title = A Response To The Oregon Study's Implication | accessdate = 2007-06-23 | first = R. Paul | last = St. Amand | journal = Clinical Bulletin of Myofascial Therapy | volume = 2 | issue = 4 | year = 1997 }}</ref> ===Other hypotheses=== Other hypotheses have been proposed related to various [[toxin]]s from the patient's environment, [[virus|viral]] causes such as the [[Epstein-Barr Virus]], [[growth hormone]] deficiencies possibly related to an underlying (maybe autoimmune) disease affecting the hypothalamus gland, an aberrant immune response to [[intestinal bacteria]],<ref name="ClinExpDermatol2004-KendallSN">{{cite journal | author=Kendall SN | title=Remission of rosacea induced by reduction of gut transit time | journal=Clin Exp dermatol. | month=May | year=2004 | pages=297–9 | volume=29 | issue=3 | pmid=15115515 | doi=10.1111/j.1365-2230.2004.01461.x}}</ref><ref name="AnnRheumDis2004-PimentalM">{{cite journal | author=Pimental M, Wallace D, Hallegua D et.al | title=A link between irritable bowel syndrome and fibromyalgia may be related to findings on lactulose breath testing | journal=Ann Rheum Dis. | month=April | year=2004 | pages=450–2 | volume=63 | issue=4 |pmid=15020342 | doi=10.1136/ard.2003.011502}}</ref> [[neurotransmitter]] disruptions in the [[central nervous system]], and erosion of the protective chemical coating around sensory nerves. A 2001 study suggested an increase in fibromyalgia among women with extracapsular silicone gel leakage, compared to women whose implants were not broken or leaking outside the capsule.<ref name="Brown2001">{{cite journal | author=Brown SL, Pennello G, Berg WA, Soo MS, Middleton MS | title=Silicone gel breast implant rupture, extracapsular silicone, and health status in a population of women | journal=J Rheumatol | year=2001 | pages=996–1003 | volume=28 | issue=5 | pmid=11361228}}</ref><ref>{{cite web |title=Study of Silicone Gel Breast Implant Rupture, Extracapsular Silicone, and Health Status in a Population of Women |url=http://www.fda.gov/cdrh/breastimplants/extracapstudy.html |date=2001-05-29 |publisher=FDA}}</ref> This association has not repeated in a number of related studies,<ref name=Lipworth>{{cite journal | author=Lipworth L, Tarone RE, McLaughlin JK.| title=Breast implants and fibromyalgia: a review of the epidemiological evidence| journal=Ann Plast Surg. | year=2004 | pages=284–7| volume=52 | issue=3 |pmid=15156983 | doi=10.1097/01.sap.0000116024.18713.28}}</ref> and the US-FDA concluded "the weight of the epidemiological evidence published in the literature does not support an association between fibromyalgia and breast implants."<ref>{{cite web |title=FDA Breast Implant Consumer Handbook 2004 |url=http://www.fda.gov/cdrh/breastimplants/handbook2004/diseases.html#1 |date=2004-06-08 |publisher=FDA}}</ref> Due to the multi-systemic nature of illnesses such as fibromyalgia and [[chronic fatigue syndrome]] (CFS/ME), an emerging branch of medical science called [[psychoneuroimmunology]] (PNI) is looking into how the various hypotheses fit together. Still another hypothesis on the cause of symptoms in fibromyalgia states that patients suffer from [[vasomotor]] dysregulation causing improper [[Blood vessel|vascular]]flow and [[hypoperfusion]] (decreased blood flow to a given tissue or organ).<ref name="pmid17376601">{{cite journal |author=Katz DL, Greene L, Ali A, Faridi Z |title=The pain of fibromyalgia syndrome is due to muscle hypoperfusion induced by regional vasomotor dysregulation |journal=Med Hypotheses. |volume=(Epub ahead of print) |issue= |pages=517|year=2007 |month=19 March |pmid=17376601 |doi=10.1016/j.mehy.2005.10.037}}</ref> ==Pathophysiology== '''Sleep disturbances''' The first objective findings associated with the disorder were reported in 1975 by Moldofsky and colleagues who reported the presence of anomalous alpha wave activity (typically associated with arousal states) on sleep electroencephalogram (EEG) during non-rapid-eye-movement sleep.<ref>Moldofsky H, Scarisbrick P, England R, Smythe H. Musculosketal symptoms and non-REM sleep disturbance in patients with "fibrositis syndrome" and healthy subjects. Psychosom Med. 1975 Jul-Aug;37(4):341-51.</ref> In fact, by disrupting stage IV sleep consistently in young, healthy subjects Moldofsky was able to reproduce a significant increase in muscle tenderness similar to that experienced by fibromyalgia but which resolved when the subjects were able to resume their normal sleep patterns.<ref> Moldofsky H, Scarisbrick P. Induction of neurasthenic musculoskeletal pain syndrome by selective sleep stage deprivation. Psychosom Med. 1976 Jan-Feb;38(1):35-44. </ref> Since that time a variety of other EEG sleep abnormalities have also been reported in subgroups of fibromyalgia patients.<ref> Drewes AM, Gade K, Nielsen KD, Bjerregård K, Taagholt SJ, Svendsen L. Clustering of sleep electroencephalographic patterns in patients with the fibromyalgia syndrome. Br J Rheumatol. 1995 Dec;34(12):1151-6.</ref> '''Poly-modal sensitivity''' Results from studies examining responses to experimental stimulation have shown that fibromyalgia patients display sensitivity to pressure, heat, cold, electrical and chemical stimulation.<ref> Desmeules JA, Cedraschi C, Rapiti E, Baumgartner E, Finckh A, Cohen P, Dayer P, Vischer TL. Neurophysiologic evidence for a central sensitization in patients with fibromyalgia. Arthritis Rheum. 2003 May;48(5):1420-9.</ref> Experiments examining pain regulatory systems have shown that fibromyalgia patients also display a dysregulation of diffuse noxious inhibitory control,<ref> Kosek E, Hansson P. Modulatory influence on somatosensory perception from vibration and heterotopic noxious conditioning stimulation (HNCS) in fibromyalgia patients and healthy subjects. Pain. 1997 Mar;70(1):41-51</ref> an exaggerated wind-up in response to repetitive stimulation,<ref> Staud R, Vierck CJ, Cannon RL, Mauderli AP, Price DD. Abnormal sensitization and temporal summation of second pain (wind-up) in patients with fibromyalgia syndrome. Pain. 2001 Mar;91(1-2):165-75.</ref> and an absence of exercise-induced analgesic response.<ref> Staud R, Robinson ME, Price DD. Isometric exercise has opposite effects on central pain mechanisms in fibromyalgia patients compared to normal controls. Pain. 2005 Nov;118(1-2):176-84. Epub [[September 9]], [[2005]].</ref> Together these results point to dysregulation of the nociceptive system at the central level. '''Neuroendocrine disruption''' Patients with fibromyalgia have been demonstrated to have a disruption of normal neuroendocrine function, characterized by mild hypocortisolemia,<ref> Gur A, Cevik R, Sarac AJ, Colpan L, Em S. Hypothalamic-pituitary-gonadal axis and cortisol in young women with primary fibromyalgia: the potential roles of depression, fatigue, and sleep disturbance in the occurrence of hypocortisolism. Ann Rheum Dis. 2004 Nov;63(11):1504-6. </ref> hyperreactivity of pituitary adrenocorticotropin hormone release in response to challenge, and glucocorticoid feedback resistance.<ref> Griep EN, Boersma JW, Lentjes EG, Prins AP, van der Korst JK, de Kloet ER. Function of the hypothalamic-pituitary-adrenal axis in patients with fibromyalgia and low back pain. J Rheumatol. 1998 Jul;25(7):1374-81.</ref> A progressive reduction of serum growth hormone levels has also been documented—at baseline in a minority of patients, while most demonstrate reduced secretion in response to exercise or pharmacological challenge.<ref> Bennett RM. Adult growth hormone deficiency in patients with fibromyalgia. Curr Rheumatol Rep. 2002 Aug;4(4):306-12.</ref> Other abnormalities include reduced responsivity of thyrotropin and thyroid hormones to thyroid-releasing hormone,<ref> Neeck G, Riedel W. Thyroid function in patients with fibromyalgia syndrome. J Rheumatol. 1992 Jul;19(7):1120-2.</ref> a mild elevation of prolactin levels with disinhibition of prolactin release in response to challenge<ref> Riedel W, Layka H, Neeck G. Secretory pattern of GH, TSH, thyroid hormones, ACTH, cortisol, FSH, and LH in patients with fibromyalgia syndrome following systemic injection of the relevant hypothalamic-releasing hormones. Z Rheumatol. 1998;57 Suppl 2:81-7.</ref> and hyposecretion of adrenal androgens.<ref> Dessein PH, Shipton EA, Joffe BI, Hadebe DP, Stanwix AE, Van der Merwe BA. Hyposecretion of adrenal androgens and the relation of serum adrenal steroids, serotonin and insulin-like growth factor-1 to clinical features in women with fibromyalgia. Pain. 1999 Nov;83(2):313-9.</ref> These changes might be attributed to the effects of chronic stress, which, after being perceived and processed by the central nervous system, activates hypothalamic corticotrophin-releasing hormone neurons. Thus, the multiple neuroendocrine changes evident in fibromyalgia have been proposed to stem from chronic overactivity of corticotropin-releasing hormone releasing neurons, resulting in a disruption of normal function of the pituitary-adrenal axis and an increased stimulation of hypothalamic somatostatin secretion, which, in turn, inhibits the secretion of a multiplicity of other hormones.<ref> Neeck G, Crofford LJ. Neuroendocrine perturbations in fibromyalgia and chronic fatigue syndrome. Rheum Dis Clin North Am. 2000 Nov;26(4):989-1002</ref> '''Sympathetic Hyperactivity''' Functional analysis of the autonomic system in patients with fibromyalgia has demonstrated disturbed activity characterized by hyperactivity of the sympathetic nervous system at baseline<ref> Martinez-Lavin M. Biology and therapy of fibromyalgia. Stress, the stress response system, and fibromyalgia. Arthritis Res Ther. 2007;9(4):216.</ref> with reduced sympathoadrenal reactivity in response to a variety of stressors including physical exertion and mental stress.<ref> Giske L, Vøllestad NK, Mengshoel AM, Jensen J, Knardahl S, Røe C. Attenuated adrenergic responses to exercise in women with fibromyalgia&mdash;a controlled study. Eur J Pain. 2008 Apr;12(3):351-60.</ref><ref> Nilsen KB, Sand T, Westgaard RH, Stovner LJ, White LR, Bang Leistad R, Helde G, Rø M. Autonomic activation and pain in response to low-grade mental stress in fibromyalgia and shoulder/neck pain patients. Eur J Pain. 2007 Oct;11(7):743-55. </ref> Fibromyalgia patients demonstrate lower heart rate variability, an index of sympathetic/parasympathetic balance, indicating sustained sympathetic hyperactivity, especially at night.<ref> Martínez-Lavín M, Hermosillo AG, Mendoza C, Ortiz R, Cajigas JC, Pineda C, Nava A, Vallejo M. Orthostatic sympathetic derangement in subjects with fibromyalgia. J Rheumatol. 1997 Apr;24(4):714-8.</ref> In addition, plasma levels of neuropeptide Y, which is co-localized with norepinephrine in the sympathetic nervous system, have been reported as low in patients with fibromyalgia,<ref> Anderberg UM, Liu Z, Berglund L, Nyberg F. Elevated plasma levels of neuropeptide Y in female fibromyalgia patients. Eur J Pain. 1999 Mar;3(1):19-30. </ref> while circulating levels of epinephrine and norepinephrine have been variously reported as low, normal and high.<ref> van Denderen JC, Boersma JW, Zeinstra P, Hollander AP, van Neerbos BR. Physiological effects of exhaustive physical exercise in primary fibromyalgia syndrome (PFS): is PFS a disorder of neuroendocrine reactivity? Scand J Rheumatol. 1992;21(1):35-7. </ref><ref> Adler GK, Kinsley BT, Hurwitz S, Mossey CJ, Goldenberg DL. Reduced hypothalamic-pituitary and sympathoadrenal responses to hypoglycemia in women with fibromyalgia syndrome. Am J Med. 1999 May;106(5):534-43. </ref> Administration of interleukin-6, a cytokine capable of stimulating the release of hypothalamic corticotropin-releasing hormone which in turn stimulates activity within the sympathetic nervous system, results in a dramatic increase in circulating norepinephrine levels and a significantly greater increase in heart rate over baseline in fibromyalgia patients as compared to healthy controls.<ref> Torpy DJ, Papanicolaou DA, Lotsikas AJ, Wilder RL, Chrousos GP, Pillemer SR. Responses of the sympathetic nervous system and the hypothalamic-pituitary-adrenal axis to interleukin-6: a pilot study in fibromyalgia. Arthritis Rheum. 2000 Apr;43(4):872-80.</ref> '''Cerebrospinal fluid abnormalities''' The most reproduced laboratory finding in patients with fibromyalgia is an elevation in cerebrospinal fluid levels of substance P, a putative nociceptive neurotransmitter.<ref> Russell IJ, Orr MD, Littman B, Vipraio GA, Alboukrek D, Michalek JE, Lopez Y, MacKillip F. Elevated cerebrospinal fluid levels of substance P in patients with the fibromyalgia syndrome. Arthritis Rheum. 1994 Nov;37(11):1593-601.</ref><ref> Vaerøy H, Helle R, Førre O, Kåss E, Terenius L. Elevated CSF levels of substance P and high incidence of Raynaud phenomenon in patients with fibromyalgia: new features for diagnosis. Pain. 1988 Jan;32(1):21-6.</ref><ref> Evengard B, Nilsson CG, Lindh G, Lindquist L, Eneroth P, Fredrikson S, Terenius L, Henriksson KG. Chronic fatigue syndrome differs from fibromyalgia. No evidence for elevated substance P levels in cerebrospinal fluid of patients with chronic fatigue syndrome. Pain. 1998 Nov;78(2):153-5.</ref> Metabolites for the monoamine neurotransmitters serotonin, norepinephrine, and dopamine—all of which play a role in natural analgesia—have been shown to be lower,<ref> Russell IJ, Vaeroy H, Javors M, Nyberg F. Cerebrospinal fluid biogenic amine metabolites in fibromyalgia/fibrositis syndrome and rheumatoid arthritis. Arthritis Rheum. 1992 May;35(5):550-6.</ref> while concentrations of endogenous opioids (i.e., endorphins and enkephalins) appear to be higher.<ref> Vaerøy H, Nyberg F, Terenius L. No evidence for endorphin deficiency in fibromyalgia following investigation of cerebrospinal fluid (CSF) dynorphin A and Met-enkephalin-Arg6-Phe7. Pain. 1991 Aug;46(2):139-43.</ref> The mean concentration of nerve growth factor, a substance known to participate in structural and functional plasticity of nociceptive pathways within the dorsal root ganglia and spinal cord, is elevated.<ref> Giovengo SL, Russell IJ, Larson AA. Increased concentrations of nerve growth factor in cerebrospinal fluid of patients with fibromyalgia. J Rheumatol. 1999 Jul;26(7):1564-9.</ref> There is also evidence for increased excitatory amino acid release within cerebrospinal fluid, with a correlation demonstrated between levels for metabolites of glutamate and nitric oxide and clinical indices of pain.<ref> Larson AA, Giovengo SL, Russell IJ, Michalek JE. Changes in the concentrations of amino acids in the cerebrospinal fluid that correlate with pain in patients with fibromyalgia: implications for nitric oxide pathways. Pain. 2000 Aug;87(2):201-11.</ref> '''Brain imaging studies''' Evidence of abnormal brain involvement in fibromyalgia has been provided via functional neuroimaging. The first findings reported were decreased blood flow within the thalamus and elements of the basal ganglia and mid-brain (i.e., pontine nucleus).<ref> Mountz JM, Bradley LA, Modell JG, Alexander RW, Triana-Alexander M, Aaron LA, Stewart KE, Alarcón GS, Mountz JD. Fibromyalgia in women. Abnormalities of regional cerebral blood flow in the thalamus and the caudate nucleus are associated with low pain threshold levels. Arthritis Rheum. 1995 Jul;38(7):926-38.</ref><ref> Kwiatek R, Barnden L, Tedman R, Jarrett R, Chew J, Rowe C, Pile K. Regional cerebral blood flow in fibromyalgia: single-photon-emission computed tomography evidence of reduction in the pontine tegmentum and thalami. Arthritis Rheum. 2000 Dec;43(12):2823-3</ref> Differential activation in response to painful stimulation has also been demonstrated.<ref> Gracely RH, Petzke F, Wolf JM, Clauw DJ. Functional magnetic resonance imaging evidence of augmented pain processing in fibromyalgia. Arthritis Rheum. 2002 May;46(5):1333-43</ref> Brain centers showing hyperactivation in response to noxious stimulation include such pain-related brain centers as the primary and secondary somatosensory cortex, anterior cingulate cortex and insular cortex, while relative hypoactivation at subjectively equal pain levels appears to occur within the thalamus and basal ganglia. In addition, patients exhibit neural activation in brain regions associated with pain perception in response to nonpainful stimuli, in such areas as the prefrontal, supplemental motor, insular, and cingulate cortices.<ref> Cook DB, Lange G, Ciccone DS, Liu WC, Steffener J, Natelson BH. Functional imaging of pain in patients with primary fibromyalgia. J Rheumatol. 2004 Feb;31(2):364-78.</ref> Patients with fibromyalgia have evidence of hippocampal disruption indicated by reduced brain metabolite ratios.<ref> Emad Y, Ragab Y, Zeinhom F, El-Khouly G, Abou-Zeid A, Rasker JJ. Hippocampus Dysfunction May Explain Symptoms of Fibromyalgia Syndrome. A Study with Single-Voxel Magnetic Resonance Spectroscopy. J Rheumatol. [[May 15]], [[2008]]. [Epub ahead of print] </ref> An acceleration of normal age-related brain atrophy has likewise been demonstrated using voxel-based morphometry (VBM) with areas of reduced gray matter located in the cingulate cortex, insula and parahippocampal gyrus.<ref> Kuchinad A, Schweinhardt P, Seminowicz DA, Wood PB, Chizh BA, Bushnell MC. Accelerated brain gray matter loss in fibromyalgia patients: premature aging of the brain? J Neurosci. [[April 11]], [[2007]];27(15):4004-7.</ref> Studies utilizing positron emission tomography have demonstrated reduced dopamine synthesis in the brainstem and elements of the limbic cortex,<ref> Wood PB, Patterson JC 2nd, Sunderland JJ, Tainter KH, Glabus MF, Lilien DL. Reduced presynaptic dopamine activity in fibromyalgia syndrome demonstrated with positron emission tomography: a pilot study. J Pain. 2007 Jan;8(1):51-8. </ref> disruption of dopaminergic reactivity to tonic pain stimulus<ref> Wood PB, Schweinhardt P, Jaeger E, Dagher A, Hakyemez H, Rabiner EA, Bushnell MC, Chizh BA. Fibromyalgia patients show an abnormal dopamine response to pain. Eur J Neurosci. 2007 Jun;25(12):3576-82.</ref> and a reduced availability of mu-opioid receptors in the ventral striatum/nucleus accumbens and cingulate cortex.<ref> Harris RE, Clauw DJ, Scott DJ, McLean SA, Gracely RH, Zubieta JK. Decreased central mu-opioid receptor availability in fibromyalgia. J Neurosci. [[September 12]], [[2007]];27(37):10000-6.</ref> ==Diagnosis== There is still debate over what should be considered essential diagnostic criteria. The most widely accepted set of classification criteria for research purposes were elaborated in 1990 by the Multicenter Criteria Committee of the [http://www.rheumatology.org/ the American College of Rheumatology]. These criteria, which are known informally as "the ACR 1990" define fibromyalgia according to the presence of the following criteria: *A history of widespread pain lasting more than three months—affecting all four quadrants of the body, i.e., both sides, and above and below the waist. *Tender points—there are 18 designated possible tender or trigger points (although a person with the disorder may feel pain in other areas as well). During diagnosis, four [[kilogram-force|kilograms-force]] (39 [[newton]]s) of [[force]] is exerted at each of the 18 points; the patient must feel pain at 11 or more of these points for fibromyalgia to be considered.<ref>{{cite web |author=National Institute of Arthritis and Musculoskeletal and Skin Diseases |title=Questions and Answers About Fibromyalgia &ndash; How Is Fibromyalgia Diagnosed? |url=http://www.niams.nih.gov/hi/topics/fibromyalgia/fibrofs.htm#fib_d |date=June 2004 |publisher=National Institutes for Health}}</ref> Four kilograms of force is about the amount of pressure required to blanch the thumbnail when applying pressure. This set of criteria was developed by the American College of Rheumatology as a means of classifying an individual as having fibromyalgia for both clinical and research purposes. While these criteria for classification of patients were originally established as inclusion criteria for research purposes and were not intended for clinical diagnosis, they have become the ''de facto'' diagnostic criteria in the clinical setting. It should be noted that the number of tender points that may be active at any one time may vary with time and circumstance. ==Prevention== Patients with fibromyalgia benefit from scheduled lives.{{Fact|date=June 2008}} Eating at the same time every day, going to bed at the same time, and getting the same amount of sleep every night can help minimize symptoms.{{Fact|date=June 2008}} Also, patients tend to fare better in warmer, dryer climates as compared to colder, wetter ones.{{Fact|date=June 2008}} Changes in temperature can increase pain for patients.{{Fact|date=June 2008}} Regular exercise (but not excessive exercise) can help lessen symptoms, although a disease flare is possible in the first few weeks.{{Fact|date=June 2008}} {{Expand-section|date=May 2008}} ==Treatment== As with many other syndromes, there is no universally accepted cure for fibromyalgia, though some physicians claim to have found cures.<ref>{{cite book |author=Selfridge, Dr. Nancy, and Peterson, Franklynn|title=Freedom from Fibromyalgia: The 5-Week Program Proven to Conquer Pain |year=2001| isbn=0-8129-3375-3 }}</ref> However, a steady interest in the disorder on the part of academic researchers as well as pharmaceutical interests has led to improvements in its treatment, which ranges from symptomatic prescription medication to [[alternative medicine|alternative]] and [[complementary medicine]]. The European League Against Rheumatism (EULAR) issued the first guidelines<ref>EULAR 9 Point Treatment plan [url=http://www.fibromyalgia-associationuk.org/content/view/220/1/]</ref> for the treatment of fibromyalgia syndrome (FMS) and published them in the [[September 17]] On-line First issue of the Annals of the Rheumatic Diseases. ===Pharmaceutical=== ====Analgesics==== A number of [[analgesics]] are used to treat the pain symptoms resulting from fibromyalgia. This includes [[NSAID]] medications over the counter, COX-2 inhibitors, and [[tramadol]] in prescription form for more advanced cases. Recently, [[pregabalin]] (marketed as Lyrica) has been given FDA approval for the treatment of diagnosed fibromyalgia.<ref name="Rooks">{{cite journal |author=Rooks DS |title=Fibromyalgia treatment update |journal=Curr Opin Rheumatol |volume=19 |issue=2 |pages=111–7 |year=2007 |month=March |pmid=17278924 |doi=10.1097/BOR.0b013e328040bffa |url=}}</ref> ====Muscle relaxants==== Muscle relaxants, such as [[cyclobenzaprine]] (Flexeril) or [[tizanidine]] (Zanaflex), may be used to treat the muscle pain associated with the disorder.<ref>[http://www.webmd.com/fibromyalgia/Cyclobenzaprine-hydrochloride-for-fibromyalgia Cyclobenzaprine hydrochloride for fibromyalgia<!-- Bot generated title -->]</ref><ref>[http://www.fibromyalgia-reviews.com/Drg_Zanaflex.cfm Zanaflex for Fibromyalgia<!-- Bot generated title -->]</ref><ref>[http://www.intelihealth.com/IH/ihtIH/WSIHW000/8310/8310.html InteliHealth:<!-- Bot generated title -->]</ref> ====Tricyclic antidepressants ==== Traditionally, low doses of sedating antidepressants (e.g. [[amitriptyline]] and [[trazodone]]) have been used to reduce the sleep disturbances that are associated with fibromyalgia and are believed by some practitioners to alleviate the symptoms of the disorder. Because depression often accompanies chronic illness, these antidepressants may provide additional benefits to patients suffering from depression. [[Amitriptyline]] is often favoured as it can also have the effect of providing relief from neuralgenic or [[Neuropathy|neuropathic pain]].{{Fact|article|date=June 2007}} It is to be noted that Fibromyalgia is not considered a depressive disorder; antidepressants are used for their sedating effect to aid in sleep. ====Selective serotonin reuptake inhibitors ==== Research data consistently contradict the utility of agents with specificity as serotonin reuptake inhibitors for the treatment of core symptoms of fibromyalgia.<ref name="pmid7478688">{{cite journal |author=Nørregaard J, Volkmann H, Danneskiold-Samsøe B |title=A randomized controlled trial of citalopram in the treatment of fibromyalgia |journal=Pain |volume=61 |issue=3 |pages=445–9 |year=1995 |month=June |pmid=7478688 |doi= |url=http://linkinghub.elsevier.com/retrieve/pii/0304395994002184 |accessdate=2008-05-21}}</ref><ref name="pmid10833553">{{cite journal |author=Anderberg UM, Marteinsdottir I, von Knorring L |title=Citalopram in patients with fibromyalgia&mdash;a randomized, double-blind, placebo-controlled study |journal=Eur J Pain |volume=4 |issue=1 |pages=27–35 |year=2000 |pmid=10833553 |doi=10.1053/eujp.1999.0148 |url= |accessdate=2008-05-21}}</ref><ref name="pmid17466657">{{cite journal |author=Patkar AA, Masand PS, Krulewicz S, ''et al'' |title=A randomized, controlled, trial of controlled release paroxetine in fibromyalgia |journal=Am. J. Med. |volume=120 |issue=5 |pages=448–54 |year=2007 |month=May |pmid=17466657 |doi=10.1016/j.amjmed.2006.06.006 |url=http://linkinghub.elsevier.com/retrieve/pii/S0002-9343(06)00685-1 |accessdate=2008-05-21}}</ref> Moreover, SSRIs are known to aggravate many of the comorbidities that commonly affect patients with fibromyalgia including restless legs syndrome and sleep [[bruxism]].<ref name="pmid9416386">{{cite journal |author=Caley CF |title=Extrapyramidal reactions and the selective serotonin-reuptake inhibitors |journal=Ann Pharmacother |volume=31 |issue=12 |pages=1481–9 |year=1997 |month=December |pmid=9416386 |doi= |url= |accessdate=2008-05-21}}</ref><ref name="pmid8909330">{{cite journal |author=Leo RJ |title=Movement disorders associated with the serotonin selective reuptake inhibitors |journal=J Clin Psychiatry |volume=57 |issue=10 |pages=449–54 |year=1996 |month=October |pmid=8909330 |doi= |url= |accessdate=2008-05-21}}</ref><ref name="pmid9640489">{{cite journal |author=Gerber PE, Lynd LD |title=Selective serotonin-reuptake inhibitor-induced movement disorders |journal=Ann Pharmacother |volume=32 |issue=6 |pages=692–8 |year=1998 |month=June |pmid=9640489 |doi= |url=http://www.theannals.com/cgi/pmidlookup?view=long&pmid=9640489 |accessdate=2008-05-21}}</ref> ====Anti-seizure medication==== Anti-seizure drugs are also sometimes used, such as [[gabapentin]]<ref name="pmid17393438">{{cite journal |author=Arnold LM, Goldenberg DL, Stanford SB, ''et al'' |title=Gabapentin in the treatment of fibromyalgia: a randomized, double-blind, placebo-controlled, multicenter trial |journal=Arthritis Rheum. |volume=56 |issue=4 |pages=1336–44 |year=2007 |month=April |pmid=17393438 |doi=10.1002/art.22457 |accessdate=2008-05-21}}</ref> and [[pregabalin]] (Lyrica). [[Pregabalin]], originally used for the nerve pain suffered by diabetics, has been approved by the American [[Food and Drug Administration]] for treatment of fibromyalgia. A [[randomized controlled trial]] of [[pregabalin]] 450 mg/day found that a [[number needed to treat]] of 6 patients for one patient to have 50% reduction in pain.<ref name="pmid15818684">{{cite journal |author=Crofford LJ, Rowbotham MC, Mease PJ, ''et al'' |title=Pregabalin for the treatment of fibromyalgia syndrome: results of a randomized, double-blind, placebo-controlled trial |journal=Arthritis Rheum. |volume=52 |issue=4 |pages=1264–73 |year=2005 |pmid=15818684 |doi=10.1002/art.20983}}</ref> ====Dopamine agonists==== [[Dopamine agonists]] (e.g. [[pramipexole]] (Mirapex) and [[ropinirole]](ReQuip)) have been studied for use in the treatment of fibromyalgia with good results.<ref name="pmid16052595">{{cite journal |author=Holman AJ, Myers RR |title=A randomized, double-blind, placebo-controlled trial of pramipexole, a dopamine agonist, in patients with fibromyalgia receiving concomitant medications |journal=Arthritis Rheum. |volume=52 |issue=8 |pages=2495–505 |year=2005 |month=August |pmid=16052595 |doi=10.1002/art.21191 |accessdate=2008-05-21}}</ref> A trial of transdermal [[rotigotine]] is currently on going<ref>[http://clinicaltrials.gov/ct2/show/NCT00464737 A Double-Blind Multicenter Proof of Concept Trial to Assess the Efficacy and Safety of Rotigotine in Subjects With Fibromyalgia Syndrome - Full Text View - ClinicalTrials.gov<!-- Bot generated title -->]</ref>. ====Combination therapy==== A controlled clinical trial of [[amitriptyline]] and [[fluoxetine]] demonstrated utility when used in combination.<ref name="pmid8912507">{{cite journal |author=Goldenberg D, Mayskiy M, Mossey C, Ruthazer R, Schmid C |title=A randomized, double-blind crossover trial of fluoxetine and amitriptyline in the treatment of fibromyalgia |journal=Arthritis Rheum. |volume=39 |issue=11 |pages=1852–9 |year=1996 |pmid=8912507|doi=10.1002/art.1780391111}}</ref> ====Central nervous system stimulants==== Cognitive dysfunction in fibromyalgia, often referred to as "brain fog," may be treated with low doses of [[central nervous system]] (CNS) [[stimulant]]s such as [[modafinil]], [[adderall]] or [[methylphenidate]]. These stimulants are also used to treat the chronic fatigue that is characteristic of fibromyalgia.<ref>http://www.immunesupport.com/fibromyalgia-treatment.htm</ref><ref>http://www.askdrjones.com/2006/11/13/determining-the-best-stimulants/</ref> Stimulants may be habit forming and can have other serious side effects, so it is important to note that other treatments may be effective.<ref>{{cite web | url = http://www.rcpsych.ac.uk/training/cpd/adhd/therapy/methylphenidate/contraindications/adverse/effects.aspx | title = Unwanted effects and Adverse Events with Methylphenidate: Further information on unwanted effects | publisher = [[Royal College of Psychiatrists]] | accessdate = 2008-05-21 }}</ref> Care should be taken with any prescription, as people with fibromyalgia are known to be sensitive to medications.<ref>http://www.fmnetnews.com/articles-hot.php</ref> ====Cannabis and cannabinoids==== Fibromyalgia patients frequently self-report using [[cannabis (drug)|cannabis]] therapeutically to treat symptoms of the disorder.<ref name="pmid16202145">{{cite journal |author=Swift W, Gates P, Dillon P |title=Survey of Australians using cannabis for medical purposes |journal=Harm reduction journal |volume=2 |issue= |pages=18 |year=2005 |pmid=16202145 |doi=10.1186/1477-7517-2-18 |url=http://www.biomedcentral.com/content/pdf/1477-7517-2-18.pdf |format=PDF}}</ref> Writing in the July 2006 issue of the journal Current Medical Research and Opinion, investigators at Germany's University of Heidelberg evaluated the analgesic effects of oral THC ([[tetrahydrocannabinol|∆<sup>9</sup>-tetrahydrocannabinol]]) in nine patients with fibromyalgia over a 3-month period. Subjects in the trial were administered daily doses of 2.5 to 15 mg of THC, but received no other pain medication during the trial. Among those participants who completed the trial, all reported a significant reduction in daily recorded pain and electronically induced pain.<ref name="pmid16834825">{{cite journal |author=Schley M, Legler A, Skopp G, Schmelz M, Konrad C, Rukwied R |title=Delta-9-THC based monotherapy in fibromyalgia patients on experimentally induced pain, axon reflex flare, and pain relief |journal=Current medical research and opinion |volume=22 |issue=7 |pages=1269–76 |year=2006 |pmid=16834825 |doi=10.1185/030079906X112651}}</ref> Previous clinical and preclinical trials have shown that both naturally occurring and endogenous cannabinoids hold analgesic qualities,<ref>{{cite journal |author=Burnes TL, Ineck JR |title=Cannabinoid Analgesia as a Potential New Therapeutic Option in the Treatment of Chronic Pain |journal=Annals of Pharmacotherapy |year= 2006|volume=40 |issue=2 |pages=251–60 |doi=10.1345/aph.1G217 |url=http://www.theannals.com/cgi/content/full/40/2/251 |pmid=16449552}}</ref> particularly in the treatment of cancer pain and neuropathic pain,<ref name="pmid15757410">{{cite journal |author=Radbruch L, Elsner F |title=Emerging analgesics in cancer pain management |journal=Expert opinion on emerging drugs |volume=10 |issue=1 |pages=151–71 |year=2005 |pmid=15757410|doi=10.1517/14728214.10.1.151}}</ref><ref name="pmid15096238">{{cite journal |author=Notcutt W, Price M, Miller R, ''et al'' |title=Initial experiences with medicinal extracts of cannabis for chronic pain: results from 34 'N of 1' studies |journal=Anaesthesia |volume=59 |issue=5 |pages=440–52 |year=2004 |pmid=15096238 |doi=10.1111/j.1365-2044.2004.03674.x}}</ref> both of which are poorly treated by conventional opioids. As a result, some experts have suggested that cannabinoid agonists would be applicable for the treatment of chronic pain conditions unresponsive to opioid analgesics such as fibromyalgia, and they propose that the disorder may be associated with an underlying clinical deficiency of the [[endocannabinoid system]].<ref name="pmid15159679">{{cite journal |author=Russo EB |title=Clinical endocannabinoid deficiency (CECD): can this concept explain therapeutic benefits of cannabis in migraine, fibromyalgia, irritable bowel syndrome and other treatment-resistant conditions? |journal=Neuro Endocrinol. Lett. |volume=25 |issue=1-2 |pages=31–9 |year=2004 |pmid=15159679 |doi=}}</ref><ref>{{cite web |title=Fibromyalgia |url=http://norml.org/index.cfm?Group_ID=7007 |publisher=NORML (The National Organization for the Reform of Marijuana Laws) |accessdate=2007-10-25}}</ref> ===Non-drug treatment=== ====Physical treatments==== Studies have found exercise improves fitness and sleep and may reduce pain and fatigue in some people with fibromyalgia.<ref name="pmid12137713">{{cite journal |author=Busch A, Schachter CL, Peloso PM, Bombardier C |title=Exercise for treating fibromyalgia syndrome |journal=Cochrane database of systematic reviews (Online) |volume= |issue=3 |pages=CD003786 |year=2002 |pmid=12137713|doi=10.1002/14651858.CD003786}}</ref> Many patients find temporary relief by applying heat to painful areas. Those with access to [[physical therapy]], [[massage]], or acupuncture may find them beneficial.<ref name="pmid10086765">{{cite journal |author=Berman BM, Ezzo J, Hadhazy V, Swyers JP |title=Is acupuncture effective in the treatment of fibromyalgia? |journal=The Journal of family practice |volume=48 |issue=3 |pages=213–8 |year=1999 |pmid=10086765 |doi=}}</ref> Most patients find exercise, even low intensity exercise to be extremely helpful.<ref name="pmid14770100">{{cite journal |author=Gowans SE, deHueck A |title=Effectiveness of exercise in management of fibromyalgia |journal=Current opinion in rheumatology |volume=16 |issue=2 |pages=138–42 |year=2004 |pmid=14770100|doi=10.1097/00002281-200403000-00012}}</ref> [[Osteopathic Manipulative Medicine|Osteopathic manipulative therapy]] can also temporarily relieve pain due to fibromyalgia.<ref name="pmid12090649">{{cite journal |author=Gamber RG, Shores JH, Russo DP, Jimenez C, Rubin BR |title=Osteopathic manipulative treatment in conjunction with medication relieves pain associated with fibromyalgia syndrome: results of a randomized clinical pilot project |journal=The Journal of the American Osteopathic Association |volume=102 |issue=6 |pages=321–5 |year=2002 |pmid=12090649 |doi= |url=http://www.jaoa.org/cgi/reprint/102/6/321.pdf |format=PDF}}</ref> ====Psychological/behavioral therapies==== [[Cognitive behavioral therapy]] has been shown to improve quality of life and coping in fibromyalgia patients and other sufferers of chronic pain.<ref name="Chakrabarty"/> [[Neurofeedback]] has also shown to provide temporary and long-term relief.{{Fact|date=June 2008}} Biofeedback and self-management techniques such as pacing and stress management may also be helpful for some patients. {{Fact|date=June 2008}} Because the nature of fibromyalgia is not well understood, some physicians believe that it may be [[Psychosomatic illness|psychosomatic]] or [[Psychogenic disease|psychogenic]].<ref>{{cite book |last=Sarno|first=Dr. John E, et al|authorlink=John E. Sarno| title=The Divided Mind: The Epidemic of Mindbody Disorders|publisher=ReganBooks|year=2006 |isbn=0-06-085178-3 |pages=21-22, 235-237, 264-265, 294-298, 315, 319-320, 363}}</ref> Accordingly, some doctors have claimed to have successfully treated fibromyalgia when a psychological cause is accepted.<ref>{{cite book |last=Leonard-Segal|first=Dr. Andrea| title=The Divided Mind: The Epidemic of Mindbody Disorders|chapter=A Rheumatologist's Experience With Psychosomatic Disorders|publisher=ReganBooks|year=2006 |isbn=0-06-085178-3 |pages=264-265 }}</ref> ====Dietary treatment==== In a 2001 review of four case studies, symptoms were alleviated by minimizing consumption of [[monosodium glutamate]].<ref>{{cite journal |author=Smith JD, Terpening CM, Schmidt SO, Gums JG |title=Relief of fibromyalgia symptoms following discontinuation of dietary excitotoxins |journal=Ann Pharmacother |volume=35 |issue=6 |pages=702–6 |year=2001 |month=June |pmid=11408989 |doi= |url=http://www.theannals.com/cgi/pmidlookup?view=long&pmid=11408989}}</ref> There are few other studies linking diet and the disease. ===Investigational treatments=== [[Milnacipran]], a [[serotonin-norepinephrine reuptake inhibitor]] (SNRI), is available in parts of Europe where it has been safely prescribed for other disorders. [[as of 2007|On May 22nd, 2007]], a Phase III study demonstrated statistically significant therapeutic effects of [[Milnacipran]] as a treatment of fibromyalgia syndrome. At this time, only initial top-line results are available and further analyses will be completed in the coming weeks. If ultimately approved by the [[FDA]], [[Milnacipran]] could be distributed in the United States as early as [[as of 2008|summer, 2008]].<ref>{{cite web |author=Forest Laboratories |title=Forest Laboratories, Inc. and Cypress Bioscience, Inc. Announce Positive Results of Phase III Study for Milnacipran as a Treatment for Fibromyalgia Syndrome |url=http://www.frx.com/news/PressRelease.aspx?ID=1005671 |date=2007-05-22}}</ref> Among the more controversial therapies involves the use of [[guaifenesin]]; called St. Amand's protocol or the [[guaifenesin protocol]]<ref name="Longley">{{cite web | title=Are phosphates the hidden enemy? |author=Kathy Longley |year=2004 |url=http://www.fibromyalgia-associationuk.org/component/option,com_docman/task,doc_download/gid,4/Itemid,40/ |format=PDF |publisher=Fibromyalgia Association UK}}</ref> the efficacy of guaifenesin in treating fibromyalgia has not been proven in properly designed research studies. Indeed, a controlled study conducted by researchers at Oregon Health Science University in Portland failed to demonstrate any benefits from this treatment,<ref name="Bennett">{{cite journal |author=Bennett RM, De Garmo P, Clark SR |title=A Randomized, Prospective, 12 Month Study To Compare The Efficacy Of Guaifenesin Versus Placebo In The Management Of Fibromyalgia |journal=Arthritis and Rheumatism |volume=39 |pages=S212 |year=1996 |url=http://www.myalgia.com/guaif2.htm |format=reprint |doi=10.1002/art.1780391004}}<br/>Lay summary and report: * {{cite web |author=Kristin Thorson |work=Fibromyalgia Network |title=Is One Placebo Better Than Another? &ndash; The Guaifenesin Story |url=http://www.fmnetnews.com/resources-alert-product6.php |date=1997 |publisher=Fibromyalgia Network}}</ref> and the lead researcher has suggested that the anecdotally reported benefits where due to placebo suggestion.<ref>{{cite web |author=Robert Bennett |title=Speculation as to the mechanism whereby some of Dr. St. Amand's fibromyalgia patients experienced improvement while taking guaifenesin |url=http://www.myalgia.com/Treatment/guaifspe.htm |date= |publisher=Fibromyalgia Information Foundation |accessdate=2008-01-06}}</ref> The results of the study have since been contested by Dr St. Amand, who was a co-author or the original research report.<ref>{{cite journal | url = http://www.fibromyalgiatreatment.com/Research_Oregon.htm | title = A Response To The Oregon Study's Implication | accessdate = 2007-06-23 | first = R. Paul | last = St. Amand | journal = Clinical Bulletin of Myofascial Therapy | volume = 2 | issue = 4 | year = 1997 }}</ref> [[Dextromethorphan]] is an over-the-counter cough medicine with activity as an [[NMDA receptor antagonist]]. It has been used in the research setting to investigate the nature of fibromyalgia pain;<ref name="pmid15890634">{{cite journal |author=Staud R, Vierck CJ, Robinson ME, Price DD |title=Effects of the N-methyl-D-aspartate receptor antagonist dextromethorphan on temporal summation of pain are similar in fibromyalgia patients and normal control subjects |journal=The journal of pain: official journal of the American Pain Society |volume=6 |issue=5 |pages=323–32 |year=2005 |pmid=15890634 |doi=10.1016/j.jpain.2005.01.357}}</ref><ref> {{cite web |title=''Cough Drug May Help Fibromyalgia Pain: Findings Could Affect Other Chronic Pain Conditions'' |author=Salynn Boyles |url=http://www.webmd.com/content/article/106/108142 |publisher= WebMD |date=2005-05-23}}</ref> however, there are no controlled trials of safety or efficacy in clinical use. ==Prognosis== Fibromyalgia can affect every aspect of a person's life. While neither degenerative nor fatal, the chronic pain associated with fibromyalgia is pervasive and persistent. FMS can severely curtail social activity and recreation, and as many as 30% of those diagnosed with fibromyalgia are unable to maintain full-time employment.{{Fact|date=November 2007}} Like others with disabilities, individuals with FMS often need accommodations to fully participate in their education or remain active in their careers.{{Fact|date=June 2008}} In the [[United States]], those who are unable to maintain a full-time job due to the condition may apply for Social Security Disability benefits. Although fibromyalgia has been recognized as a genuine, severe medical condition by the government{{Fact|date=June 2008}}, applicants are often denied benefits, since there are no formal diagnostic criteria or medically provable symptoms. In the [[United Kingdom]], the [[Department for Work and Pensions]] recognizes fibromyalgia as a condition for the purpose of claiming benefits and assistance.<ref>[http://www.fibromyalgia-associationuk.org/content/view/57/2/ The Fibromyalgia Association of the UK]</ref> ==Epidemiology== Fibromyalgia is seen in about 2% of the general population<ref name="Chakrabarty">{{cite journal | last=Chakrabarty | first=S | coauthors=Zoorob R | title=Fibromyalgia | journal=American Family Physician | volume=76 | issue=2 | pages=247–254 |date=July 2007 | url=http://www.aafp.org/afp/20070715/247.html | pmid=17695569 | accessdate=2008-01-06 }}</ref> and affects more females than males, with a ratio of 9:1 by ACR criteria.<ref>Fibromyalgia {{eMedicine|med|790}}</ref> It is most commonly diagnosed in individuals between the ages of 20 and 50, though onset can occur in childhood. ==History== Fibromyalgia has been studied since the early 1800s and referred to by a variety of former names, including '''muscular rheumatism''' and fibrositis.<ref>{{cite web |author=Health Information Team |title=Fibromyalgia |url=http://hcd2.bupa.co.uk/fact_sheets/mosby_factsheets/fibromyalgia.html |date=February 2004 |Publisher=BUPA insurance}}</ref> The term ''fibromyalgia'' was coined in 1976 to more accurately describe the symptoms, from the [[Latin]] ''fibra'' (fiber)<ref>{{cite web | url = http://dictionary.reference.com/browse/fibro- | title = Fibro- | publisher = Dictionary.com | accessdate = 2008-05-21 }}</ref> and the [[Greek language|Greek]] words ''myo'' (muscle)<ref>[http://www.bartleby.com/61/94/M0509400.html Meaning of myo]</ref> and ''algos'' (pain).<ref>[http://www.bartleby.com/61/59/A0195900.html Meaning of algos]</ref> Dr. Muhammad B. Yunus, considered the father of the modern view of fibromyalgia, published the first [[Clinical trial|clinical]], controlled study of the characteristics of fibromyalgia syndrome in 1981.<ref name=Winfield>{{cite journal |author=Winfield JB |title=Fibromyalgia and related central sensitivity syndromes: twenty-five years of progress |journal=Semin. Arthritis Rheum. |volume=36 |issue=6 |pages=335–8 |year=2007 |month=June |pmid=17303220 |doi=10.1016/j.semarthrit.2006.12.001 |url=http://linkinghub.elsevier.com/retrieve/pii/S0049-0172(06)00180-6 |accessdate=2008-05-21}}</ref><ref name=sciencedaily>{{cite news | url = http://www.sciencedaily.com/releases/2007/06/070625095756.htm | title = Further Legitimization Of Fibromyalgia As A True Medical Condition | publisher = [[Science Daily]] | date = 2007-06-25 | accessdate = 2008-05-21 }}</ref> Yunus' work validated the known [[symptom]]s and tender points that characterise the condition, and proposed data-based criteria for diagnosis. In 1984, Yunus proposed the interconnection between fibromyalgia syndrome and other similar conditions, and in 1986 demonstrated the effectiveness of [[serotonergic]] and [[Norepinephrine|norepinephric]] drugs.<ref name=Inanici>{{cite journal |author=Inanici F, Yunus MB |title=History of fibromyalgia: past to present |journal=Curr Pain Headache Rep |volume=8 |issue=5 |pages=369–78 |year=2004 |month=October |pmid=15361321 |doi= |url= |accessdate=2008-05-21}}</ref> Yunus later emphasized the "[[Biopsychosocial model|biopsychosocial perspective]]" of fibromyalgia, which synthesized the contributions of [[Genetics|genes]], personal and [[medical history]], [[Stress (medicine)|stress]], [[Posttraumatic stress disorder|posttraumatic]] and [[mood disorder]]s, [[coping skill]]s, self-efficacy of [[pain management]] and [[social support]] towards the functioning and dysfunctioning of the [[central nervous system]] in relation to [[pain]] and [[Fatigue (medical)|fatigue]].<ref name=Winfield/><ref name=sciencedaily/> Fibromyalgia was recognized by the [[American Medical Association]] as an illness and a cause of disability in 1987.{{Fact|date=January 2008}} In an article the same year, in the [[Journal of the American Medical Association]], a physician named Dr. Don Goldenberg also called the disorder fibromyalgia.{{Fact|date=January 2008}} The [[American College of Rheumatology]] (ACR) published a criteria for fibromyalgia in 1990, and developed [[Neurohormone|neurohormonal]] mechanisms with central [[sensitization]] in the 1990s.<ref name=Inanici/> ==Controversies== The validity of fibromyalgia as a unique clinical entity is a matter of some contention among researchers in the field. For example, it has been proposed that the pathophysiology responsible for the symptoms that are collectively classified as representing "fibromyalgia" is poorly understood, thereby suggesting that the fibromyalgia [[phenotype]] may result from several different disease processes that have global [[hyperalgesia]] and [[allodynia]] in common,<ref>http://www.springerlink.com/content/1271314042w8405g/ Mueller W, et al. The classification of fibromyalgia syndrome. Rheumatol Int. [[July 25]], [[2007]]</ref><ref>The association or otherwise of the functional somatic syndromes.Psychosom Med. 2007 Dec;69(9):855-9. Review. PMID: 180400</ref><ref>Comorbidity of fibromyalgia and psychiatric disorders.Curr Pain Headache Rep. 2007 Oct;11(5):333-8. Review. PMID: 17894922</ref> an observation that has led to the proposition that current diagnostic criteria are insufficient to differentiate patient groups from each other.<ref>An integrated model of group psychotherapy for patients with fibromyalgia.Int J Group Psychother. 2007 Oct;57(4):451-74</ref> Alternatively, there is evidence for the existence of differing pathophysiological processes within the greater fibromyalgia construct<ref>[http://www.ncbi.nlm.nih.gov/pubmed/17084146?ordinalpos=4&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsPanel.Pubmed_RVDocSum Psychophysiological responses in patients with fib...[J Psychosom Res. 2006&#93; - PubMed Result<!-- Bot generated title -->]</ref><ref>[http://www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pubmed&pubmedid=16356200 Heterogeneity of psychophysiological stress responses in fibromyalgia syndrome patients<!-- Bot generated title -->]</ref>, which may be interpreted to represent evidence for the existence of biologically distinct "sub-types" of the disorder akin to conditions such as [[epilepsy]], [[schizophrenia]] and [[major depressive disorder]]. In essence, fibromyalgia may actually be composed of several clinical entities, ranging from a mild, [[idiopathic]] [[inflammatory]] process in some individuals, to a [[somatoform disorder]] resulting from [[clinical depression]] in others, with probable overlaps in between.<ref>http://www.springerlink.com/content/1271314042w8405g/ Mueller W, et al. The classification of fibromyalgia syndrome. Rheumatol Int. [[July 25]], [[2007]]</ref> Current diagnostic criteria are insufficient to differentiate these entities. == Timeline == {{SectOR|date=June 2008}} -1800s The study of muscular rheumatism begins. -1976 The term fibromyalgia was coined to more accurately describe the symptoms, from the Latin fibra (fiber), the Greek words myo (muscle)and algos (pain). -1981 Dr. Muhammad B. Yunus published the "first controlled study of the clinical characteristics" of the fibromyalgia syndrome, for which he is considered "the father of our modern view of fibromyalgia." His work was the "first controlled clinical study" of fibromyalgia with validation of known symptoms and tender points, and he also proposed "the first data-based criteria." -1984 Dr. Muhammad B. Yunus proposed the important concept that the fibromyalgia syndrome and other similar conditions are interconnected. -1986 Dr. Muhammad B. Yunus showed serotonergic and norepinephric drugs to be effective. Yunus later emphasized a "biopsychosocial perspective" of fibromyalgia, which is considered the "only way to synthesize the disparate contributions of such variables as genes and adverse childhood experiences, life stress and distress, posttraumatic stress disorder, mood disorders, self-efficacy for pain control, catastrophizing, coping style, and social support into the evolving picture of central nervous system dysfunction vis-a-vis chronic pain and fatigue." -1987 Fibromyalgia was recognized by the American Medical Association as an illness and a cause of disability. -1987 In an article of the Journal of the American Medical Association, a physician named Dr. Don Goldenberg also called the disorder 'fibromyalgia'. -1990 The ACR American College of Rheumatology published a criteria for fibromyalgia and developed neurohormonal mechanisms with central sensitization. -1997 National Fibromyalgia Foundation(NFA) is founded in Orange, California, by Lynne Matallana and Karen Lee Richards. It is the largest nonprofit organization working to support people with fibromyalgia and other chronic pain illnesses. - 1999 The Annual Fibromyalgia Awareness Day Proclamation Program is established. 2000 (May) - 2006 (March) The National Fibromyalgia Foundation hosted six international conferences, each providing a venue for leading fibromyalgia authorities to share their research and expertise with patients and health care professionals alike. -2001 In a review of four case studies, symptom alleviation was found by minimizing consumption of monosodium glutamate. -2005 Pfizer began selling Lyrica in the United States. -2006 (July) In the issue of Current Medical Research and Opinion, investigators at Germany's University of Heidelberg evaluated the analgesic effects of oral THC (∆9-tetrahydrocannabinol) in nine patients with fibromyalgia over a 3-month period. Subjects in the trial were administered daily doses of 2.5 to 15 mg of THC, but received no other pain medication during the trial. Among those participants who completed the trial, all reported a significant reduction in daily recorded pain and electronically induced pain. -2007 ([[June 21]]) The F.D.A. approves Pfizer's request to market the drug Lyrica as a fibromyalgia treatment. -2007 (July) "Facing Fibromyalgia, Finding Hope," a national educational campaign aimed at increasing the understanding of fibromyalgia among patients, healthcare providers and the public, was launched. The public service announcement, distributed through print, radio and television outlets, reached more than 37 million people in the United States. -2008 (Monday, May 10th) To garner support for ACR 112, more than 100 fibromyalgia patients and their supporters from across California turned out at the state capitol of Sacramento to participate in the first Fibromyalgia Legislation Day coordinated by the National Fibromyalgia Association. -2008 (Monday, May 19th) Resolution (ACR) 112 continues on its successful path, passing the California Assembly. It will now go before the California Senate for a vote. The resolution, written by Assembly member Mervyn Dymally, calls on members of the State Assembly, State Senate and the National Fibromyalgia Association to appoint a 14-member task force. In addition to establishing a public outreach campaign for fibromyalgia, the Task Force aims to work with other state and local agencies to promote fibromyalgia education and training programs for physicians and other health professionals, and hold a Fibromyalgia Summit in 2009-2010. -2008 (Friday, June 20th) The FDA approves Cymbalta® (duloxetine HCl) for the management of fibromyalgia. ==References== {{reflist|2}} ==Further reading== * [http://fm-cfs.ca/pharmacists.pdf Fibromyalgia for Pharmacists, a medication guide] ==External links== <!-- BEFORE inserting new links here you should first post it to the talk page, otherwise your edit is likely to be reverted--> * [http://www.rheumatology.org/public/factsheets/fibromya_new.asp?aud=pat American College of Rheumatology Fibromyalgia factsheet] * [http://www.fda.gov/consumer/updates/fibromyalgia062107.html Living with Fibromyalgia, First Drug Approved] at US Food and Drug Administration * [http://www.niams.nih.gov/Health_Info/Fibromyalgia Questions and Answers About Fibromyalgia] by the National Institute of Arthritis and Musculoskeletal and Skin Diseases *{{dmoz|/Health/Conditions_and_Diseases/Musculoskeletal_Disorders/Connective_Tissue/Fibromyalgia/}} {{Diseases of the musculoskeletal system and connective tissue}} [[Category:Rheumatology]] [[Category:Diseases involving the fasciae]] [[Category:Syndromes]] [[Category:Ailments of unknown etiology]] [[ca:Fibromiàlgia]] [[de:Fibromyalgie]] [[es:Fibromialgia]] [[eu:Fibromialgia erreumatiko]] [[fr:Fibromyalgie]] [[it:Fibromialgia]] [[he:דאבת השרירים]] [[nl:Fibromyalgie]] [[ja:線維筋痛症]] [[no:Fibromyalgi]] [[pl:Fibromialgia]] [[pt:Fibromialgia]] [[fi:Fibromyalgia]] [[sv:Fibromyalgi]]