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2 P. Sarzi-Puttini et al.The meeting held in Rome in February 2008 wasthe first gathering of health professionals from differentspecialties within the field of FM in Italy.Three international experts joined us for this occasionand gave a strong contribution to this successfulexpert consensus.The papers produced in this supplement representthe outcome of this meeting and should constitute,according to the participants, the first Italian consensusspecific to FM.There is still a long road ahead, one that requiresgood physicians and health care personnel, but italso requires assistance from the health care system,which must contribute resources to this syndrome.In the next few years, we expect officialrecognition of this syndrome and therapeutic strategiesto be delivered through the national health caresystem. The patient association is also growing,and we know that this association is valuable forits political strength.In conclusion, we need to reshape the pain perceptionof our FM patients and the perception ofhealth care personnel toward patients. Moreover,we need to give patients the chance to be treatedproperly; none of these patients should be ignoredor left to face such an invisible and debilitating diseasewithout help.REFERENCES1. Mease P, Arnold LM, Bennett R, Boonen A, BuskilaD, Carville S, Chappell A, et al. Fibromyalgia syndrome.J Rheumatol 2007; 34: 1415-25.2. Williams DA, Gracely RH. Biology and therapy of fibromyalgia.Functionalmagnetic resonance imagingfindings in fibromyalgia. Arthritis Res Ther 2006; 8(6): 224.3. Abeles M, Solitar BM, Pillinger MH, Abeles AM. Updateon fibromyalgia therapy. Am J Med 2008; 121:555-61.4. Sarzi-Puttini P, Buskila D, Carrabba M, Doria A,Atzeni F. Treatment Strategy in Fibromyalgia Syndrome:Where are we now? Semin Arthritis Rheum2008; 37: 353-65.5. Cazzola M, Sarzi-Puttini P, Buskila D, Atzeni F. Pharmacologicaltreatment of fibromyalgia. Reumatismo2007; 59: 280-91.6. Goldenberg DL. Multidisciplinary modalities in thetreatment of fibromyalgia. J Clin Psychiatry 2008; 69Suppl. 2: 30-4.7. Carville SF, Arendt-Nielsen S, Bliddal H, Blotman F,Branco JC, Buskila D, et al. EULAR evidence-basedrecommendations for the management of fibromyalgiasyndrome. Ann Rheum Dis 2008; 67: 536.8. Lachapelle DL, Lavoie S, Boudreau A. The meaningand process of pain acceptance. Perceptions of womenliving with arthritis and fibromyalgia. Pain Res Mansag2008; 13: 201-10.

ORIGINAL ARTICLEReumatismo, 2008; 60: Supplemento 1: 3-14Fibromyalgia syndrome:definition and diagnostic aspectsLa sindrome fibromialgica: definizione ed aspetti diagnosticiM. Cazzola 1 , P. Sarzi Puttini 2 , S. Stisi 3 , M. Di Franco 4 , L. Bazzichi 5 , R. Carignola 6 , R.H. Gracely 7 ,F. Salaffi 8 , F. Marinangeli 9 , R. Torta 10 , M.A. Giamberardino 11 , D. Buskila 12 , M. Spath 13 , G. Biasi 14 ,G. Cassisi 15 , R. Casale 16 , L. Altomonte 17 , G. Arioli 18 , A. Alciati 19 , A. Marsico 20 , F. Ceccherelli 21 ,G. Leardini 22 , R. Gorla 23 , F. Atzeni 2 (Italian Fibromyalgia Network)1Unit of Rehabilitative Medicine “Hospital of Circolo”, Saronno (VA), Italy; 2 Rheumatology Unit, L. Sacco University Hospital, Milan,Italy; 3 Rheumatology Unit, “G. Rummo” Hospital, Benevento, Italy; 4 Chair of Rheumatology, University la Sapienza Rome, Rome,Italy; 5 Department of Internal Medicine, Division of Rheumatology, S. Chiara Hospital, University of Pisa, Italy; 6 S.C.D.U. InternalMedicine I, Department of Clinical and Biological Science, University of Turin, Italy; 7 Department of Medicine, University of MichiganHealth System, Ann Arbor, Michigan, USA; 8 Department of Rheumatology, Polytechnic University of the Marche Region, Ancona, Italy;9Department of Anesthesiology and Pain Medicine, L'Aquila University, L'Aquila, Italy; 10 Department of Neuroscience, University ofTurin, A.S.O. San Giovanni Battista of Turin, Turin, Italy; 11 Ce.S.I. “G. D’Annunzio” Foundation, Department of Medicine and Scienceof Aging, “G. D’Annunzio”, University of Chieti , Italy; 12 Department of Medicine H, Soroka Medical Center and Faculty of HealthSciences, Ben Gurion University, Beer Sheva, Israel; 13 Friedrich-Baur-Institute, University of Munich, Germany; 14 Unit ofRheumatology, University of Siena, Siena, Italy; 15 Rheumatology Branch, Specialist Outpatients’ Department, Belluno, Italy;16Department of Clinical Neurophysiology and Pain Rehabilitation Unit, Foundation Salvatore Maugeri, IRCCS, Scientific Institute ofMontescano, Montescano (PV), Italy; 17 UOC of Rheumatology Hospital S. Eugenio, Rome, Italy; 18 Division of Rehabilitative Medicineand Rheumatology, General Hospital of Pieve di Coriano (Mantua), Italy; 19 Department of Psychiatry, L. Sacco University Hospital,Milan, Italy; 20 Rheumatology Unit, Hospital of Taranto, Taranto, Italy; 21 IOV (Veneto Cancer Institute) - IRCCS, - Department ofPharmacology and Anesthesiology, University of Padua, Italy; 22 Rheumatology Unit, SS Giovanni e Paolo Hospital , Venice, Italy;23Rheumatology and Clinical Immunology, Spedali Civili and University of Brescia, ItalyCompeting interests: none declaredRIASSUNTOFin dalla prima descrizione la FM è stata considerata tra le diagnosi più controverse in ambito reumatologico, dalmomento che non tutti accettano l’esistenza della FM come un’entità clinica indipendente. La sensibilità e la specificitàdei criteri diagnostici sono ancora oggetto di discussione tra i vari specialisti (non solo tra i reumatologi), chesollevano come critica principale il fatto che i criteri dell’American College del 1990 identificano solamente un subsetdi pazienti non rappresentativo della pratica clinica quotidiana. Inoltre, i sintomi caratteristici della FM sono similia quelli osservati in altre condizioni cliniche. Negli ultimi anni, questo ha portato a considerare la FM sempremeno come un’ entità clinica indipendente e sempre più come una possibile manifestazione tipica delle alterazioni delsistema psico-neuroendocrino (lo spettro dei disturbi affettivi) o del sistema di reazione allo stress (sintomi disfunzionali).Recentemente, sono stati sollevati dubbi su queste classificazioni; e attualmente sembra corretto includere laFM tra le sindromi di “sensibilizzazione del sistema nervoso centrale”, che considerano il meccanismo patogeneticocausa di sindromi muscolari ed extra-muscolari della FM o delle altre sindromi disfunzionali.Reumatismo, 2008; 60: Supplemento 1: 3-14INTRODUCTIONAlthough the term “fibromyalgia” (FM) is relativelynew, the condition characterised bychronic musculoskeletal pain that is accompaniedCorresponding author:Fabiola Atzeni, MD, PhDRheumatology UnitL. Sacco University Hospital, Milan, ItalyE-mail: atzenifabiola@hotmail.comby numerous extra-skeletal symptoms has been describedin the medical literature for many years underdifferent names. The term “fibrositis,” whichwas originally used in 1904 by Sir William Gowersto define a type of lumbalgia, became a synonymfor diffuse musculoskeletal pain until 1976(1). In the mid-1970s, Smythe and Moldofsky usedthe term “fibrositic syndrome” to describe the presenceof tender points (TPs), sleep disturbances andother accompanying symptoms such as asthenia

4 M. Cazzola et al.(2). In the early 1980s, Yunus replaced “fibrositis”with “fibromyalgia” in order to underline the absenceof phlogistic alterations in the muscle thatwere repeatedly reported in published histologicalstudies (3). In 1990, under the aegis of the AmericanCollege of Rheumatology (ACR), a multicentrestudy of 558 patients with fibromyalgia wasconducted with the aim of standardising the diagnosticcriteria of the syndrome (4). This studyfound that the combination of pain induced by 4kg./cm 2 of pressure in at least 11 of the 18 consideredTPs and a history of diffuse musculoskeletalpain for at least three months provided the mostsensitive, specific and accurate criteria for diagnosingboth primary and secondary FM.However, the use of the 1990 ACR criteria in clinicalpractice soon highlighted their limitations; inparticular, they were not able to distinguish FMfrom other syndromes that are characterised by organor systemic symptoms without detectable morphologicalalterations, such as chronic fatigue syndrome(CFS) and myofascial syndromes (5-7).Many of these symptoms overlap to the extent thatthe same patient will often satisfy the diagnosticcriteria for two or more syndromes. In 1989, Popeand Hudson postulated the concept of a “spectrumof affective disorders” based on the observationthat many of these conditions showed a certain clinicalresponse only to antidepressants (8). Followingsimilar reasoning concerning the syndromes’clinical characteristics and mutual associations, andconsidering the most accredited pathogenetic hypothesesfor each, Yunus coined the definition of a“spectrum of dysfunctional syndromes” in whichthe term “dysfunctional” referred to the supposedunderlying psycho-neuro-immuno-endocrine alterations(9). More recently, these attempts at classificationhave been questioned and supplanted bythe concept of a “central pain syndrome” or, better,“central sensitisation” (10, 11). Central sensitisationis based on the latest experimental evidenceconcerning the role that central nervous systemmodifications, which are induced by the environmentin genetically predisposed subjects, play inthe onset of many previously defined “algodysfunctional”syndromes, including FM (12).DEFINITIONIn 1989, Wolfe defined FM as “a painful musculoskeletaldisorder characterised by core clinicalfeatures that are always present (widespread chronicpain and tenderness), features that are present inmore than 75% of cases (fatigue, non-refreshingsleep and morning stiffness), and features that arepresent in more than 25% of cases (for example,paresthesia, irritable bowel syndrome and functionaldisability)” (13). Constitutional symptomshave not been considered since the 1990 ACR diagnosticcriteria; and the main symptom that distinguishesFM is now pain, which must be diffuse(affecting both sides of the body, above and belowthe waist, and the axial skeleton involving at leastone of the cervical, dorsal and lumbar regions of thespine), chronic (present for at least three months),and capable of being evoked by pressure at specificsites (TPs) (4). In our view, developments in ourknowledge of the pathogenetic mechanisms of thecentral pain syndromes, together with the reducedimportance of TPs for diagnostic purposes, now allowthe definition to be reformulated as follows:“Fibromyalgia is a central sensitisation syndromecharacterised by dysfunctions in the neurocircuitsinvolving the perception, transmission and processingof nociceptive afferents, with the prevalentmanifestation of pain at the level of the musculoskeletalsystem. In addition to pain, there may bea multitude of accompanying symptoms (asthenia,sleep disturbances, abdominal pains…) that arecommon to other central sensitisation syndromes.Particular genetic characteristics and a reduced individualcapacity to tolerate “stressors” predisposeindividuals to the onset of the disease”.DIAGNOSTIC CRITERIAIn 1990, the ACR carried out a study involving 558FM patients attending 16 centres with the aim ofstandardising the syndrome’s diagnostic criteria(4); this study identified the most sensitive, specificand accurate criteria for diagnosing FM:1) A history of widespread pain: chronic, widespread,musculoskeletal pain lasting longer thanthree months in all four quadrants of the body(“widespread pain” was defined as pain above andbelow the waist, and on both sides of the body),with the additional presence of axial skeletal painin the cervical spine, anterior chest, thoracic spineor low back.2) Pain in 11 of 18 tender sites upon digital palpation:there are 18 TPs that doctors assess to confirmthe diagnosis of FM (see Figure 1), and accordingto the ACR requirements, a patient must

Fibromyalgia syndrome: definition and diagnostic aspects 5A) Occiput: bilateral, at the suboccipital muscle insertions.B) Low cervical: bilateral, at the anterior aspects of the intertransversespaces at C5-C7.C) Trapezius: bilateral, at the midpoint of the upper border.D) Supraspinatus: bilateral, at origins, above the scapula spinenear the medial border.E) Second rib: bilateral, at the second costochondral junction, justlateral to the junctions on upper surfaces.F) Lateral epicondyle: bilateral, 2 cm distal to the epicondyles.G) Gluteal: bilateral, in upper outer quadrants of buttocks in anteriorfold of muscle.H) Greater trochanter: bilateral, posterior to the trochantericprominence.I) Knee: bilateral, at the medial fat pad proximal to the joint line.Figure 1 - Fibromyalgia tender points identified by the American Collegeof Rheumatology in 1990 (at digital palpation with an approximateforce of 4 kg).endorse at least 11 as painful upon application ofapproximately four kg/cm 2 of pressure.As the ACR criteria suggest, a diagnosis of FM requiresthe “hands-on” evaluation of a patient by askilled medical professional, typically a rheumatologist,although other specialists are becomingquite knowledgeable in this area. Patients are usuallyaware of the specific anatomical origins of thepain in their bodies; however, self-diagnosis is notadvised.The authors also stated that, from a clinical perspective,primary and secondary FM were indistinguishableand, therefore, they proposed abolishingthe term “secondary fibromyalgia”. A diagnosisof FM may be present concomitant with otherrheumatic diseases, but in this way, the “secondary”FM remains clinically indistinguishablefrom the primary form and is an unnecessary classification.In the absence of diagnostic laboratory tests or X-rays, the ACR diagnostic criteria were a milestonein the recognition and study of FM. For the firsttime, researchers around the world could identifyand study FM patients using standardised measures,thus enabling comparison of results. In the clinicsetting, patients who had fallen through the cracksof medical science could finally be diagnosed.Nevertheless, the criteria were not without theirdrawbacks:• the TP paradigm suggested that FM patients onlyexperienced pain in anatomically-specificsites, but later studies (such as those reported byGranges and Littlejohn in 1993) suggested thatthey were sensitive to painful stimuli throughoutthe body. Today, widespread body pain is commonlyassociated with FM (14);• it quickly became evident that tenderness variedfrom day to day and from month to month, whichmeant that TP counts fluctuated above and belowthe required 11 depending on when the countwas made. Furthermore, patients did not alwaysmanifest pain in all four body quadrants: somehad unilateral pain, and/or pain solely in the upperor lower half of the body;• Staud has shown that, although everyone withFM has TPs, the number of TPs does not reflectthe level of pain patients experience; in short,TPs do not correlate with pain (15);• Clauw and Crofford have commented that theACR criteria focus only on pain and do not includemany other FM symptoms (fatigue, cognitivedisturbance, irritable bowel syndrome, etc.);as a result, the criteria “fail to capture the essenceof the FM syndrome” and allow for “greater variabilityin studies of physiologic mechanisms otherthan pain processing” (16);• the number of TPs is greatly influenced by thedemographic and psychological characteristicsof patients with FM. Women are only 1.5 timesmore likely to experience chronic widespreadpain but are 11 times more likely to have 11 ormore TPs, which means that they are approximately10 times more likely to satisfy the ACRcriteria. However, most men who experiencechronic widespread pain but are not tender

6 M. Cazzola et al.enough to meet FM criteria probably have thesame underlying pathophysiology;• another unintended consequence of diagnosingFM on the basis of chronic widespread pain andat least 11 TPs is that many people with FM experiencehigh levels of distress. Wolfe has describedTPs as a “sedimentation rate for distress”because population-based studies have shownthat TPs are more common in distressed individuals(17). Distress is considered a combinationof somatic and anxiety and/or depressionsymptoms, and it has been assumed that, as TPsare associated with distress, the same is true oftenderness (i.e., sensitivity to mechanical pressure).However, recent evidence suggests that theassociation is probably due to the standard TPtechnique of applying steadily increasing pressureuntil reaching 4 kg and, in this situation,people who are anxious or “expectant” have atendency to “bail out” and report tenderness;• TP examinations require skill and, when performedincorrectly (in the wrong place or withtoo much or too little digital pressure), they leadto erroneous results. Unfortunately, the TPs ofFM are also sometimes confused with the triggerpoints of myofascial pain syndrome (MPS), andthe two are not uncommonly mistaken for eachother.To complicate the clinical picture further, FM patientsoften have symptoms that overlap with thoseof other systemic syndromes (CFS, psychogenicsyndrome, etc) or localised syndromes (MPS, irritablebowel syndrome, etc.), and many rheumatologistsdoubt that the current 1990 ACR criteria definea specific disease.Setting aside the philosophical issue raised byHazemeijer and Rasker concerning the need for aspecific change in the social setting, or “therapeuticdominion”, it has always been clear that patientsdiagnosed as having FM on the basis of the1990 ACR criteria fall into a series of heterogeneoussubgroups.Fukuda, et al., studied Air Force veterans from thefirst Gulf War in 1990-1991, and defined the complexof symptoms as “chronic multisymptom illness“(21). In 1996, Turk, et al. (22), first demonstratedthe existence of “subsets” of FM patientsthat could be identified using the MultidimensionalPain Inventory (MPI) and that would respond todifferent therapies. In addition to psychosocial andcognitive factors, they identified a number of specificneurobiological factors that could better explainthe fundamental mechanism of the pain causinghyperalgesia and allodynia.In 2003, Giesecke, et al. (23), more precisely separatedFM patients on the basis of differences intheir perception of pain and other psychologicalfactors. They studied 117 FM patients aged 18-60years (88% women) by evaluating the characteristicsand perception of pain (VAS, individual painthresholds, the number of tender points), and theway in which it was interpreted emotionally (anxiety,depression and catastrophising) (see Figure2). They quantitatively analysed six parameters foreach patient (anxiety, depression, catastrophising,ability to control pain, pain scale, and tendernessto a light touch) and identified three different clusters.The most frequent (51.5%) was cluster 1 (longdashed line), in which all levels of all parametersCLINICAL SUBSETSIn 2003, first Hazemeijer and Rasker (18), and thenEhrlich (19), raised considerable doubts about thevery existence of FM. In particular, Ehrlich consideredit only a mental construct: “When one hastuberculosis, one has tuberculosis, whether or notit is diagnosed. The same is true for cancer,rheumatoid arthritis, hookworm infestation - really,of the gamut of diseases. But not for FM. Noonehas FM until it is diagnosed.“However, given the indisputable existence of peopleaffected by a central painful syndrome, the positivistposition of Wolfe has a point: “fibromyalgiawill always exist regardless of the name given tothe syndrome” (20).Rescalated values7.06.05.04.03.02.01.00.0AnxietyDepressionCaatastrphizingControl overpainDolorimeterFigure 2 - Subgrouping of fibromyalgia patients on the basis of pressure-painthresholds and psychological factors (23).MRS

Fibromyalgia syndrome: definition and diagnostic aspects 7were medium. This probably represents the majorityof patients who consult a general practitioner(GP) because of widespread pain and who generallyrespond better to prescribed medical therapy.Cluster 2 (continuous line) represents 32% of theenrolled patients, a group that was characterised byhigh levels of anxiety, depression and catastrophising,the lowest level of control over pain,and significant tenderness to light touch.Cluster 3 (dotted line) accounted for only 16.5% ofthe patients, a group that showed the lowest levelsof anxiety, depression and catastrophising, but alsothe lowest pain threshold (see Figure 3).This study showed that patients diagnosed on thebasis of the 1990 ACR criteria fall into differentcategories and may have different reactions to theavailable therapeutic options.However, it also strongly suggested that, althoughthey had represented an unquestioned diagnosticplatform for more than ten years, the 1990 ACRcriteria alone were not sufficient to define FM patientsand, therefore, necessitated further research.At the beginning of 2006, the ACR criteria wereused by Katz, et al. (24) to verify their concordancewith the clinical diagnosis alone and with the “surveycriteria.” To this end, they studied 206 patientsevaluated on the basis of TPs using the pooled diagnosisof FM (Regional Pain Scale score >8 andfatigue score >6) and clinical history, and foundthat 49% met the criteria for a clinical diagnosis,29.1% met the 1990 ACR criteria, and 40.3% metthe survey criteria. The clinical and survey criteriawere concordant in 74.8% of cases; the clinical and1990 ACR criteria were concordant in 75.2% ofGroup 1 (n = 50)• Low tenderness• Moderate depression/anxiety• Moderate catastrophizing• Moderate control over painGroup 3 (n = 16)• High tenderness• High depression/anxiety• High catastrophizing• High control over painGroup 2 (n = 31)• High tenderness• High depression/anxiety• High catastrophizing• Low control over painFigure 3 - Subgrouping of fibromyalgia patients on the basis of pressure-painthresholds and psychological factors (23).cases; and the survey and 1990 ACR criteria wereconcordant in 72.3% of cases. Tenderness to lighttouch of at least 11 of the 18 ACR TPs was not presentin the clinical and survey diagnostic criteria butwas shown to be very useful in the clinical diagnosis.Therefore, the authors concluded that thethree sets of criteria (clinical, ACR and survey)were moderately concordant (72-75%).As there is no diagnostic “gold standard” for FM,all of the mentioned criteria are equally useful, andthe survey criteria have the undoubted advantage ofnot requiring a physical examination.DIAGNOSISIt is clear that a diagnosis of FM cannot be basedexclusively on the 1990 ACR criteria. Many subjectsmay not have pain throughout the body or atleast 11 TPs upon physical examination, but theirpsychological characteristics and associated symptomsclearly suggest a form of FM or, at any rate,a central sensitisation syndrome of which FM isclearly a part. As there are no specific laboratorymarkers, imaging techniques or objective signs,constitutional symptoms are the only parametersthat can be used.Characteristics of painIn clinical practice, FM should be suspected in allpatients describing multifocal pain that has an originwhich is not justified by the presence of tissuedamage or inflammation at the painful sites. Inmany cases, the main clinical manifestation is musculoskeletalpain; but it may be much more generalisedbecause it is known that mechanisms of sensoryamplification underlie pain of central origin.This explains why chronic headache, atypical chestpain, and chronic abdominal or pelvic pain are verycommon findings in FM patients; FM should besuspected in all patients who complain of chronicpain sine materia at these sites. As pain is the fundamentalelement of FM, it is necessary to investigateits characteristics and to differentiate it frompain induced by other diseases. Fibromyalgia painis typically diffuse or multifocal, varies in intensityduring the course of the day, and sometimes migratesfrom one body region to another; its exacerbationsare influenced by various external physicaland/or psychological factors. These are thecharacteristics of central pain, which differ fromthe more constant localization and intensity of peripheralpain. Patients sometimes perceive stimuli

8 M. Cazzola et al.Table I - Characteristics of central and peripheral pain.CentralPeripheralSite Diffuse LocalisedIntensity Variable ConstantStimulus/response ratio Non-proportional ConservedModifying factors Environmental and/or psychological factors Mechanical factorsConcomitant sensitivity alterations (dysesthesia/paresthesia) Present Absentthat are usually innocuous, such as wearing clothes,as painful; if adequately questioned, they frequentlyreport associated paresthesia or dysesthsia(Tab. I).Other symptomsPain may be accompanied by numerous othersymptoms that are apparently unrelated. Asthenia,sleep disturbances, weakness, labile attention andmemory deficits, intolerance of cold or heat, visualand hearing disorders, vestibular symptoms, thesensation of dry mucosae, and inexplicable changesin weight are only the most frequent. “Allergic”phenomena such as rhinitis, sinusitis, nasal congestionand lower respiratory airway symptoms arereported more frequently by FM patients than controls,although these are almost always due to hypersensitivityand not immunoglobulin E (IgE)-mediated immune reactions. The most frequent comorbiditiesin women are dysmenorrhea, interstitialcystitis, vestibulitis and vulvodynia; in men,non-bacterial prostatitis is most common.Physical examinationPhysical examination is usually negative with theexception of hyperpathia upon pressure, particularlyat the TPs. However, the semiology of themusculoskeletal system must always be completedfor the purposes of differential diagnosis.Laboratory testsGenerally, lab tests are not useful except for differentialdiagnosis. One criterion for decidingwhich and how many laboratory tests to perform isthe duration of the disease: if the diagnosis wasmade several years ago, it is possible to limit thenumber of tests, whereas more recent or currentdiagnosis may require thorough investigation foraccuracy (Tab. II).Other investigationsThese are not usually necessary unless indicated onthe basis of findings from the physical examinationand laboratory screening (see Figure 4).Table II - Laboratory tests recommended at first observation.Symptom onset 12 monthsERSHemochromeTSHFibromyalgia-like symptoms >3 monthsEvaluate for other disordersComplete physical examination:• Check ESR, CRP, chemistry panel, TSH• Avoid ANA, RF unless indicatedNormal work-upDiagnose or “label”fibromyalgiaAbnormal work-upManage accordingly(may have comorbidfibromyalgia)Figure 4 - Algorithm for the diagnosis of fibromyalgia. Modified from:Clauw D. Fibromyalgia: defining the disorder and its diagnostic andtreatment approach. www.medscape.com, 2007.FM is often part of a wider syndrome encompassingmany symptoms from different organs otherthan muscles. Its clinical diagnosis is not easy becausefibromyalgia-like symptoms are frequentlyfound, and differential diagnosis with other causesof chronic pain is essential (Tabs. III, IV). When

Fibromyalgia syndrome: definition and diagnostic aspects 9the pain involves a large number of joints, it maybe confused with the widespread pain of FM. Thedegree of pain as measured by a visual analoguescale is not helpful in distinguishing FM from otherconditions such as arthritis or osteoarthritis (25).Furthermore, as FM can exist in association withimmunoinflammatory diseases, many rheumaticand non-rheumatic diseases can easily be misdiag-Table III - Possible causes of muscle pain.Causes of focal muscle painWith swelling or indurationNeoplasmTrauma (hematoma)Torn tendonRuptured Baker’s cystThrombophlebitisInfectionStreptoccal myositisGas gangrenePyomyositisTrichinosis, hydatid cyst, sparganosisPainful weakness in children with influenzaInflammationLocalised nodular myositisProliferative myositisPseudo-malignant myositis ossificansEosinophilic fasciitisSarcoidosis (nodular)IschemiaMuscle necrosis due to arterial occlusionDiabetes (thigh muscle infarction)Embolism (marantic endocarditis)Azotemic hyperparathyroidismToxic and metabolic disordersAcute alcoholic myopathyMyoglobinuria in drug-induced comaDrug-induced damageEffort-induced muscle damage (in normal subjectsor subjects with metabolic myopathies)Motor unit hyperactivity (stiff man syndrome, tetanus,strychnine poisoning)Without swelling or indurationEffort myalgiaNormal subjectsClaudicatio intermittensMetabolic myopathiesAcute brachialgiaIschemic mononeuropathyParkinsonismResting leg pain of obscure causeGrowing painsRestless legsPainful legs and tips of the fingersIdiopathic leg painCauses of generalised muscle painWith muscle weaknessInflammation (dermatomyositis and polymyositis)InfectionToxoplasmosisTrichinosisToxic myopathy (viral infections, leptospirosis,Gram-negative infections, toxic shock syndrome,Kawasaki’s syndrome)PoliomyelitisToxic and metabolic disordersAcute alcoholic myopathyHypophosphatemiaPotassium deficiencyTotal parenteral nutritionCarcinoma-induced necrotic myopathyHypothyroid myopathyDrugs (e-aminocaproic acid, clofibrate, emetine)Carnitine palmitoyltransferase deficiencyAmyloidosisBone pain and myopathy (osteomalacia,hyperparathyroidism)Acute polyneuropathy (Guillain-Barré syndrome, porphyria)Without muscle weaknessRheumatic polymyalgiaPainful muscle fasciculation syndromeMyalgia in infections or feverMyalgia in collagenovascular diseaseDiscontinuation of steroidsHypothyroidismPrimary myalgiaFabry’s diseaseParkinsonismModified from: Layzer RB: Muscle pain, cramps and fatigue. In Engel AG, Banker BQ (eds.): Myology. New York, McGraw-Hill, 1986, pp. 1907-1922.

10 M. Cazzola et al.Table IV - Conditions that simulate fibromyalgia.CommonHypothyroidismPolymyalgia rheumaticaEarly in course of autoimmunedisorders: e.g. rheumatoid arthritisor SLESjogren’s syndromeLess commonHepatitis CSleep apneaChiari malformationnosed as FM. A recent study (26) has providedsome evidence concerning inaccuracy in diagnosingFM in a cohort of patients referred to a rheumatologyclinic: FM was confirmed in only 34% ofpatients presenting with musculoskeletal pain, witha 66% diagnostic error rate. TPs (p

Fibromyalgia syndrome: definition and diagnostic aspects 11Table V - Clinical criteria for a diagnosis of myofascial pain syndrome caused by active trigger points.To make a clinical diagnosis of myofascial pain syndrome, the findings should include the five main criteria and at least one of the threeminor criteria. The five main criteria are:1. Reported symptom of regional pain.2. Symptoms of pain or altered sensation in the expected distribution, or pain transferred from a myofascial trigger point.3. Palpable tense fascia in an accessible muscle.4. Point of great tenderness along the tense fascia.A certain limitation in the amplitude of movement, when measurable.The three minor criteria are:1. Clinical symptom of pain or altered sensitivity reproduced by pressure on the tender point.2. Provocation of local contraction response by means of sharp transversal palpation on the tender point, or the insertion of a needle inthe tender point of the tense fascia.3. Pain relived by lengthening (stretching) the muscle or by injecting the tender point (trigger point).Note: Additional symptoms are often present, such as sensitivity to the weather, disturbed sleep and depression, but they are not diagnostic because they may be attributable tochronic severe pain perpetuated by numerous mechanical and/or systemic factors. From: Simons AG: Muscular pain syndromes. In : Friction JR, Awad EA (eds.), Advances inPain Research and Therapy, Vol. 17: Myofascial Pain and Fibromyalgia. New York, Raven Press, 1990, p. 18.Table VI - Diagnostic criteria for chronic fatigue syndrome.• Clinically ascertained, persistent, recurrent and unexplainablechronic fatigue• of recent onset or temporally identifiable• not due to an ongoing period of effort• not relievd by rest• occupationally, socially or personally disabling.The concomitant presence of at least four of the followingsymptoms, each of which must have been present continuouslyor have recurred occasionally for at least six or more consecutivemonths of disease, and not prevailing over the fatigue:• patient report of a deterioration in short-term memory thatis sufficiently severe as to cause a reduction in previousworking, scholastic, social or personal activities• pharyngodynia• cervical or axillary lymphadenopathy• muscle pain• polyarticular pain without tumefaction or reddening• headaches with new characteristics or of different severity• unrefreshing sleep• malaise following effort and lasting more than 24 hours.whether HCV infection is associated with FM,since there is no proof of an epidemiological linkbetween the two (44).CFS frequently overlaps FM (Tab. VI). More than70% of FM patients have CFS symptoms, and thepatients who meet the criteria for both FMS andCFS have a worse overall health status (45).Myofascial pain syndrome has been defined aschronic pain accompanied by trigger points (TrPs)in one or more muscles or group of muscles (Tab.V). TrPs may easily be mistaken for TPs and, thus,lead to the overdiagnosis of FM; therefore, physiciansmust be able to distinguish TrPs and TPs withthe aid of a pain drawing (25).CONCLUSIONSIn the light of current knowledge, we can defineFM as a “central sensitisation syndrome characterisedby dysfunction in the neurocircuits involvingthe perception, transmission and processing ofnociceptive afferents, with the prevalent manifestationof pain at the level of the musculoskeletalsystem”.Together with pain, which is characterised by hyperalgesiaand allodynia, symptoms of debilitatingfatigue, disrupted or non-restorative sleep, functionalbowel disturbances, and a variety of neuropsychiatricproblems including cognitive dysfunction,anxiety and depressive symptoms combineto define FM (46). Women are the most affected,and the disease has a familial connectionlinked to genetic variances in the serotonin,dopamine and catecholamine intracerebral system(47). The physical symptoms of FM express themselvesprimarily in the presence of a psychologicalcondition that reduces the individual capacity totolerate stessors (48).Despite widespread criticism, the diagnostic criteriaof FM are still based on the 1990 ACR recommendations,which require a specific case history(widespread pain lasting more than three months,sleep disturbance, debilitating fatigue, paresthesia),and tenderness upon pressure (4 kg/cm 2 ) in at least11 of the 18 TPs distinguishing the disease, on bothsides of the body and simultaneously above and belowthe waist. On the basis of these diagnostic cri-

12 M. Cazzola et al.teria, three subsets of FM patients can be identifiedbased on individual pain-emotional and neurobiologicalcharacteristics that respond differently tospecific therapeutic strategies.Many common musculoskeletal conditions canmimic FM and, thus, may be misdiagnosed as FM.Moreover, many patients do not completely satisfythe FM criteria; rather, they only present with afew symptoms. FM may co-occur or overlap severalrheumatic and non-rheumatic conditions. Inpatients with widespread pain and fatigue, it is necessaryto rule out the presence of any other medicalcondition or disease known to cause thesesymptoms (27, 28).A simple and rational approach to evaluating thesepatients should include a complete clinical history,a physical examination and laboratory tests; andpatients with a history that suggests FM should undergofurther investigation of their vital signs; TPs;joints and tendons; neurological, abdominal andthyroid status; and signs of connective tissue orother concomitant diseases (49). Laboratory assessmentsshould include a complete blood cellcount for common anemias, infections and bonemarrow diseases. Although ESR and C-reactiveprotein are non-specific, they can help to confirmsystemic inflammation or infection. Patients presentingwith fatigue and widespread pain shouldundergo routine thyroid function tests. A standardchemistry panel (liver and kidney function, serumfasting glucose, blood lipids) is useful to evaluateoverall systemic health. If the physical examinationfindings suggest joint involvement and soft tissueinflammation, additional serological tests such asrheumatoid factor, ANAs or others should be performed(27). There is agreement that the differentialdiagnosis of FM should be ruled out as far aspossible by adding a number of simple blood teststo the physical examination, which would be justifiedif the history and physical examination suggestanother concomitant or associated condition.Finally, FM should be diagnosed on the basis of itsown characteristics and not just by exclusion; thepresence of a concomitant disease such as arthritisor hypothyroidism does not exclude a diagnosis ofFM (25,49).SUMMARYEver since it was first defined, fibromyalgia (FM) has been considered one of the most controversial diagnoses in thefield of rheumatology, to the point that not everybody accepts its existence as an independent entity. The sensitivityand specificity of the proposed diagnostic criteria are still debated by various specialists (not only rheumatologists),whose main criticism of the 1990 American College of Rheumatology criteria is that they identify subsets of particularpatients that do not reflect everyday clinical reality. Furthermore, the symptoms characterising FM overlap withthose of many other conditions classified in a different manner. Over the last few years, this has led to FM being consideredless as a clinical entity and more as a possible manifestation of alterations in the psychoneuroendocrine system(the spectrum of affective disorders) or the stress reaction system (dysfunctional symptoms). More recently, doubtshave been raised about even these classifications; and it now seems more appropriate to include FM among the centralsensitisation syndromes, which identify the main pathogenetic mechanism as the cause of skeletal and extra-skeletalsymptoms of FM and other previously defined “dysfunctional” syndromes.Key words - Diagnosis, ACR criteria, overlap syndrome, dysfunctional syndromes.Parole chiave - Diagnosi, criteri ACR, sindrome da overlap, sindromi disfunzionali.REFERENCES1. Gowers WR. Lumbago: its lessons and analogues. BrMed J, 1904; 1: 117-21.2. Smythe HA, Moldofsky H. Two contributions to understandingof the fibrositis syndrome. Bull Rheum Dis1977; 28: 928-31.3. Yunus M, Masi AT, Clabro JJ, Miller KA, FeigenbaumSL. Primary fibromyalgia (fibrositis): clinical study of50 patients with matched normal controls. SeminArthritis Rheum 1981; 11: 151-71.4. Wolfe F, Smythe HA, Yunus MB, Bennett RM, BombardierC, Goldenberg DL, et al. The American Collegeof Rheumatology 1990 criteria for the classification offibromyalgia. Report of the multicenter criteria committee.Arthritis Rheum 1990; 2: 160-72.5. Tunks E, McCain GA, Hart LE, Teasell RW, GoldsmithCH, Rollman GB, et al. The reliability of examinationsfor tenderness in patients with myofascial pain,chronic fibromylagia and controls. J Rheumatol 1995;22: 944-52.6. Wolfe F, Smons DG, Fricton J, Bennett RM, Golden-

Fibromyalgia syndrome: definition and diagnostic aspects 13berg DL, Gerwin R, et al. The fibromyalgia and myofascialpain syndromes: a preliminary study of tenderpoints and trigger points in persons with fibromyalgia,myofascial pain syndromes and no disease. J Rheumatol1992; 19: 944-51.7. Croft P, Schollum J, Silman A. Population study of tenderpoints counts and pain as evidence of fibromyalgia.BMJ 1994; 309: 944-511.8. Hudson JI, Pope HG Jr. Fibromyalgia and psychopathology:is fibromyalgia a form of “affective spectrumdisorder?” J Rheumatol 1989; 19: 15-22.9. Yunus MB. Dysfunctional Spectrum Syndrome: a unifiedconcept for many common maladies. FibromyalgiaFrontiers 1996; 4: 3.10. Yunus MB. Fibromyalgia and overlapping disorders:the unifying concept of central sensitivity syndromes.Semin Arthritis Rheum 2007; 36: 339-56.11. Winfield JB. Fibromyalgia and related central sensitivitysyndromes: twenty-five years of progress. SeminArthritis Rheum 2007; 36: 335-8.12. Yunus MB. Central sensitivity syndromes: a new paradigmand group nosology for fibromyalgia and overlappingconditions, and the related issue of disease versusillness. Semin Arthritis Rheum 2008 [Epub aheadof print].13. Wolfe F. Fibromyalgia: the clinical syndrome. RheumDis Clin North Am 1989; 15: 1-18.14. Granges G, Littlejohn G. Pressure pain threshold inpain-free subjects, in patients with chronic regional painsyndromes, and in patients with fibromyalgia. ArthritisRheum 1993; 36: 642-6.15. Staud R. The abnormal central pain processing mechanismin patients with fibromyalgia. FibromyalgiaFrontiers 2002; 10: 18.16. Crofford LJ, Clauw DJ. Fibromyalgia: where are we adecade after the American College of Rheumatologyclassification criteria were developed? Editorial. ArthritisRheum 2002; 46: 1136-7.17. Wolfe F. The relation between tender points and fibromyalgiasymptom variables: evidence that fibromyalgiais not a discrete disorder in the clinic. AnnRheum Dis 1997; 56: 268-71.18. Hazemeijer I, Rasker JJ. Fibromyalgia and the therapeuticdomain. A philosophical study on the origins offibromyalgia in a specific social setting. Rheumatology2003; 42: 507-15.19. Ehrlich GE. Pain is real; fibromyalgia isn't. J Rheumatol.2003; 30: 1666-7.20. Wolfe F. The fibromyalgia problem. J Rheumatol 1997;24: 1247-9.21. Fukuda K, Nisenbaum R, Stewart G, Thompson WW,Robin L, Washko RM, et al. Chronic multisymptom illnessaffecting Air Force veterans of the Gulf War. JA-MA 1998; 280: 981-8.22. Turk DC, Okifuji A, Sinclair JD, Starz TW. Pain, disability,and physical functioning in subgroups of patientswith fibromyalgia. J Rheumatol 1996; 23: 1255-62.23. Giesecke T, Williams DA, Harris RE, Cupps TR, TianX, Tian TX, et al. Subgrouping of fibromyalgia patientson the basis of pressure-pain thresholds and psychologicalfactors. Arthritis Rheum 2003; 48: 2916-22.24. Katz RS, Wolfe F, Michaud K. Fibromyalgia diagnosis:a comparison of clinical, survey, and AmericanCollege of Rheumatology criteria. Arthritis Rheum2006; 54: 169-76.25. Bliddal H, Danneskiold-Samsøe B. Chronic widespreadpain in the spectrum of rheumatological diseases.BestPract Res Clin Rheumatol 2007; 21: 391-402.26. Fitzcharles MA, Boulos P. Inaccuracy in the diagnosisof fibromyalgia syndrome: analysis of referrals.Rheumatology 2003; 42: 263-7.27. Schneider MJ, Brady DM, Perle SM. Commentary: differentialdiagnosis of fibromyalgia syndrome: proposalof a model and algorithm for patients presenting withthe primary symptom of chronic widespread pain. JManipulative Physiol Ther 2006; 29: 493-501.28. Martínez-Lavín M. Overlap of fibromyalgia with othermedical conditions.Curr Pain Headache Rep 2001;5: 347-50.29. Bennett R. The concurrence of lupus and fibromyalgia:implications for diagnosis and management. Lupus1997; 6: 494-9.30. Middleton GD, McFarlin JE, Lipsky PE. The prevalenceand clinical impact of fibromyalgia in systemiclupus erythematosus. Arthritis Rheum 1994; 37: 1181-8.31. Morand EF, Miller MH, Whittingham S, Littlejohn GO.Fibromyalgia syndrome and disease activity in systemiclupus erythematosus. Lupus 1994; 3: 187-91.32. Akkasilpa S, Goldman D, Magder LS, Petri M. Numberof fibromyalgia tender points is associated withhealth status in patients with systemic lupus erythematosus.J Rheumatol 2005; 32: 48-50.33. Kötter I, Neuscheler D, Günaydin I, Wernet D, KleinR. Is there a predisposition for the development of autoimmunediseases in patients with fibromyalgia? Retrospectiveanalysis with long term follow-up. RheumatolInt 2007; 27: 1031-9.34. Buskila D, Press J, Abu-Shakra M. Fibromyalgia insystemic lupus erythematosus: prevalence and clinicalimplications. Clin Rev Allergy Immunol 2003; 25:25-8.35. Bonafede RP, Downey DC, Bennett RM An associationof fibromyalgia with primary Sjogren’s syndrome: aprospective study of 72 patients. J Rheumatol 1995;22: 133-6.36. Wolfe F, Hawley DJ, Wilson K. The prevalence andmeaning of fatigue in rheumatic disease. J Rheumatol1996; 23: 1407-17.37. Hidding A, van Santen M, De Klerk E, Gielen X, BoersM, Geenen R, et al Comparison between self-reportmeasures and clinical observations of functional disabilityin ankylosing spondylitis, rheumatoid arthritisand Fibromyalgia. J Rheumatol 1994; 21: 818-23.38. Proven A, Gabriel SE, O'Fallon WM, Hunder GG.Polymyalgia rheumatica with low erythrocyte sedimentationrate at diagnosis. J Rheumatol 1999, 26:1333-7.39. Helfgott SM, Kieval RI: Polymyalgia rheumatica in pa-

14 M. Cazzola et al.tients with a normal erythrocyte sedimentation rate.Arthritis Rheum 1996, 39: 304-7.40. Daoud KF, Barkhuizen A. Rheumatic mimics and selectedtriggers of fibromyalgia. Curr Pain HeadacheRep 2002, 6: 284-28.41. Reginato AJ, Falasca GF, Pappu R, McKnight B, AghaA. Musculoskeletal manifestations of osteomalacia: reportof 26 cases and literature review. Semin ArthritisRheum 1999; 28: 287-304.42. Bazzichi L, Rossi A, Giuliano, et al. Association betweenthyroid autoimmunity and fibromyalgic diseaseseverity. Clin Rheumatol 2007; 26: 2115-20.43. Dinerman H, Steere AC. Lyme disease associated withfibromyalgia. Ann Intern Med 1992; 117: 281-5.44. Lormenau C, Falgarone G, Roulot D, Boisser MC.Rheumatologic manifestation of chronic hepatitis C infection.Joint Bone Spine 2006; 73: 633-8.45. Aaron LA, Buchwald D. Chronic diffuse musculoskeletalpain, fibromyalgia and co-morbid unexplainedclinical condition. Best Pract Res Clin Rheumatol2003; 17: 563-74.46. Häuser W, Zimmer C, Felde E, Köllner V. What are thekey symptoms of fibromyalgia? Results of a survey of theGerman Fibromyalgia Association. Schmerz 2007; 21.47. Buskila D, Sarzi-Puttini P. Biology and therapy of fibromyalgia.Genetic aspects of fibromyalgia syndrome.Arthritis Res Ther 2006; 8: 218.48. Martinez-Lavin M. Biology and therapy of fibromyalgia.Stress, the stress response system, and fibromyalgia.Arthritis Res Ther 2007; 9: 216.49. Yunus MB. Role of central sensitization in symptomsbeyond muscle pain, and the evaluation of a patientwith widespread pain. Best Pract Res Clin Rheumatol2007; 21: 481-97.

ORIGINAL ARTICLEReumatismo, 2008; 60: Supplemento 1: 15-24Symptoms and signs in fibromyalgia syndromeI segni e i sintomi della sindrome fibromialgicaG. Cassisi 1 , P. Sarzi-Puttini 2 , A. Alciati 3 , R. Casale 4 , L. Bazzichi 5 , R. Carignola 6 , R.H. Gracely 7 ,F. Salaffi 8 , F. Marinangeli 9 , R. Torta 10 , M.A. Giamberardino 11 , D. Buskila 12 , M. Spath 13 , M. Cazzola 14 ,M. Di Franco 15 , G. Biasi 16 , S. Stisi 17 , L. Altomonte 18 , G. Arioli 19 , G. Leardini 20 , R. Gorla 21 ,A. Marsico 22 , F. Ceccherelli 23 , F. Atzeni 2 (Italian Fibromyalgia Network)1Rheumatology Branch, Specialist Outpatients' Department, Belluno, Italy; 2 Rheumatology Unit, L.Sacco University Hospital, Milan,Italy; 3 Department of Psychiatry, L. Sacco University Hospital, Milan, Italy; 4 Department of Clinical Neurophysiology and PainRehabilitation Unit, Foundation Salvatore Maugeri, IRCCS, Scientific Institute of Montescano, Montescano (PV), Italy; 5 Department ofInternal Medicine, Division of Rheumatology, S. Chiara Hospital, University of Pisa, Italy; 6 S.C.D.U. Internal Medicine I, Departmentof Clinical and Biological Science, University of Turin, Italy; 7 Department of Medicine, University of Michigan Health System, AnnArbor, USA; 8 Department of Rheumatology, Polytechnic University of the Marche Region, Ancona, Italy; 9 Department ofAnesthesiology and Pain Medicine, L'Aquila University, L'Aquila, Italy; 10 Department of Neuroscience, University of Turin, A.S.O.San Giovanni Battista of Turin, Turin, Italy; 11 Ce.S.I. “G. D’Annunzio” Foundation, Department of Medicine and Science of Aging,“G. D’Annunzio”, University of Chieti, Italy; 12 Department of Medicine H, Soroka Medical Center and Faculty of Health Sciences,Ben Gurion University, Beer Sheva, Israel; 13 Friedrich-Baur-Institute, University of Munich, Germany; 14 Unit of RehabilitativeMedicine “Hospital of Circolo”, Saronno (VA), Italy; 15 Chair of Rheumatology, University la Sapienza Rome, Rome, Italy;16Unit of Rheumatology, University of Siena, Siena, Italy; 17 Rheumatology Unit, “G. Rummo” Hospital, Benevento, Italy;18UOC of Rheumatology Hospital S. Eugenio, Rome, Italy; 19 Division of Rehabilitative Medicine and Rheumatology, General Hospitalof Pieve di Coriano (Mantua), Italy; 20 Rheumatology Unit, SS Giovanni e Paolo Hospital, Venice, Italy; 21 Rheumatology and ClinicalImmunology, Spedali Civili and University of Brescia, Italy; 22 Rheumatology Unit, Hospital of Taranto, Taranto, Italy;23IOV (Veneto Cancer Institute), IRCCS, Department of Pharmacology and Anesthesiology, University of Padua, ItalyCompeting interests: none declaredRIASSUNTO67,814La sindrome fibromialgica (FM) è una comune condizione di dolore cronico che interessa almeno il 2% della popolazione.Il dolore cronico diffuso è l’elemento caratterizzante la FM, ma i pazienti possono riferire una varietà di altrisintomi, compresi disturbi del sonno, astenia, sindrome da colon irritabile, cefalea, e disturbi del tono dell’umore.L’eziologia della FM non è completamente conosciuta e la sindrome viene influenzata da una varietà di fattori qualistress, malattie mediche e una molteplicità di condizioni dolorose. Stabilire la diagnosi può essere difficile a causadella natura multiforme della sindrome e della sovrapposizione con altre sindromi dolorose croniche. Un’ipotesi unificatriceè che la FM risulti dalla sensibilizzazione del sistema nervoso centrale; questo nuovo concetto potrebbe giustificarela varietà di caratteristiche cliniche della sindrome. I sintomi della FM possono essere muscolo scheletrici,non-muscoloscheletrici o una combinazioni di entrambi e molti pazienti sperimentano un insieme di sintomi o condizionicliniche. I criteri classificativi ACR si focalizzano solamente sul dolore e non considerano altri sintomi importanti,ma tre sintomi-chiave, dolore, astenia e disturbi del sonno sono presenti praticamente in ogni paziente affettoda FM. Parecchi altri disturbi associati comprendenti i sistemi circolatorio, nervoso, digestivo, e genito-urinatio sonoprobabilmentre parte della cosiddetta sindrome da sensibilizzazione centrale. Una minoranza dei pazienti (30-40%)ha un significativo disturbo psicologico. I disturbi psichiatrici più comunemente descritti sono i disturbi del tonodell’umore, ma le patologie psichiatriche non costituiscono un fattore necessario nella eziopatogenesi della FM.Reumatismo, 2008; 60: Supplemento 1: 15-24INTRODUCTIONFibromyalgia (FM) is currently classified aschronic widespread pain with widespread al-Corresponding author:Fabiola Atzeni, MD, PhDRheumatology UnitL. Sacco University Hospital, Milan, ItalyE-mail: atzenifabiola@hotmail.comlodynia/hyperalgesia to pressure pain and is categorizedamong the large group of soft-tissue painsyndromes. FM remains an elusive condition ofunknown etiology in which patients report not onlychronic widespread pain but also a variety ofother complaints, so that it is one of several relativelycommon overlapping syndromes characterizedby otherwise unexplained chronic pain and fatigue(1, 2).

16 G. Cassisi et al.The cardinal features are chronic widespread painin the presence of multiple tender points throughoutthe body on physical examination.FM, as defined by the American College ofRheumatology (ACR) 1990 definition for clinicaltrials, is a chronic widespread pain condition withcharacteristic tender points on physical examination,often associated with a constellation of symptomssuch as fatigue, sleep disturbance, headache,irritable bowel syndrome, and mood disorders. TheACR defined 2 major compulsory criteria for classifyingFM in adults. The first criterion is a historyof widespread pain for at least 3 months. Thesecond criterion requires patient report of tendernessin at least 11 of 18 defined tender points whendigitally palpated with about 4 kg per unit area offorce (3).Diagnosis is on the contrary made by a combinationof patient history, physical examination, laboratoryevaluations, and exclusion of other causesfor symptoms attributed to FM.It has also been noted that the ACR classificationcriteria focus only on pain and disregard other importantsymptoms of FM, including fatigue, cognitivedisturbance, sleep disturbance, and psychologicaldistress, and that focusing strictly on painmay fail to capture the “essence” of this syndrome(4). Three key features pain, fatigue and sleep disturbanceare present in virtually every patient withFM (5) even if the hallmark symptom that differentiatesFM from most other medical conditions isthe pronounced tenderness to even mildest palpationor physical touch, i.e. allodynia (6, 7).A recent study provided some evidence of the seriousnessof improper diagnosis, criticizing the disturbingdiagnostic error rate (66%) (8). With regardto this, the principal author of the 1990 ACR Criteriarecently published an editorial article entitled“Stop using the ACR Criteria in the Clinic” (9).In a very recent study, in order to develop a newdefinition of FM based on symptoms and withouttender points, the authors concluded that the keysymptoms are chronic widespread pain, nonrestorativesleep and subjective disabilities, implyingthat FM is more than just a pain disorder(10).In the late ’80s, Yunus proposed that preliminaryclinical criteria for FM should include some historicalfeatures besides the tender point count, adescription of pain as “hurt all over,” anxiety andstress, non restorative sleep, fatigue, irritable bowelsymptoms, and pain referred by patients in sevensites (11).Table I - Full OMERACT 8 group responses in percentages (13).Domain A B CPain 94 3 3Fatigue 86 13 1Patient Global 81 12 7Sleep 64 26 10Multidimensional function 60 28 12HRQOL 52 34 14Tenderness 50 27 24Depression 44 34 21Treatment side effects 40 34 26Anxiety 22 43 35Dyscognition 21 42 37Stiffness 13 3552A: essential for core set for all clinical studie. B: necessary but not mandatory forIn 1992 a consensus document (the Copenhagendeclaration) identified FM is part of a wider syndromeinvolving headaches, bruxism, irritable bowel,irritable bladder, sleep disorders, dysmenorrhea,depression and anxiety disorders, cold sensitivity,Raynaud’s phenomena, restless legs, atypical patternsof numbness and tingling, complaints ofweakness, exercise intolerance, cognitive dysfunction,autonomic nervous system or neuroendocrinedysregulation (12).Temporomandibularpain anddysfunctionsyndromeRegionalfibromyalgia/MyofascialpainsyndromeRestlesslegssyndromePeriodic limbmovementdisorderFibromyalgiasyndromeCSSChronicfatiguesyndromePrimarydysmenorrheaIrritablebowelsyndromeMultiplechemicalsensitivityTensiontypeheadacheMigraineFigure 1 - Central Sensitivity Syndrome and its members with overlappingfeatures. From Yunus MB.Psychological aspects of fibromyalgiasyndrome: a component of the dysfunctional spectrumsyndrome. Baillieres Clin Rheumatol. 1994; 8(4): 811-37. In RachlinES, Rachlin IS. Myofascial Pain and Fibromyalgia, Trigger Point Management.2nd ed. St. Louis: Mosby, 2002 (adapted).

Symptoms and signs in fibromyalgia syndrome 17OMERACT 8 workshop on FM in 2006, of whichthe principal objective was to work towards consensuson core domains for assessment in FM studies,identified key domains of pain, fatigue, sleepdisturbance, multidimensional function, quality oflife, mood disorders, and cognitive dysfunction.An additional domain highlighted by patients wasstiffness (13) (Table I). At last we cannot ignore theevolving idea of central sensitivity syndrome(CSS), which is based on neuroendocrine aberrationsinteracting with psychosocial factors. CSSbecomes an important new concept that embracesthe biopsychosocial model of disease as a usefulparadigm and an appropriate terminology for FMand related conditions (14, 15) (Fig. 1).THE SYMPTOMSThe most common and characteristic symptoms ofFM are generalized pain, stiffness, fatigue, andpoor sleep. Other symptoms are a swollen feelingin soft tissue and paresthesia. Several associated illnesses,more common in FM patients than in normalpopulation (as well as in those with otherchronic pain conditions) have been well described(16).MUSCULOSKELETAL SYMPTOMSPainAs mentioned, the defining symptom of FM remainswidespread chronic pain that lasts at leastthree months, usually present in all four limbs, aswell as the upper or lower back. About two thirdsof the patients state that they “hurt all over”; thissymptom has been found to be useful in differentiatingFM from other conditions (11).Pain may be described as any combination of burning,searing, tingling, shooting, stabbing, deepaching, sharp and feeling bruised all over (17).Some authors, using an adapted McGill Pain Questionnaire,found that pain in FM had a greater spatialdistribution and involved a greater number ofpain descriptors compared to other pain syndromes(18).Common sites of pain are low back, neck, shoulderregion, arms, hands, knees, hips, thighs, legs,feet (19), and anterior chest (20). However, pain isusually generalized and in “non-anatomical” distributionor regional; it does not follow any definitestructural or nerve root distributions, it is perceivedas originating in the muscle or deep in bones (17),although in a subgroup of patients it is predominantlyarticular (21).Characteristics of FM pain include allodynia, hyperalgesia,persistent pain, summation effects, hyperpatiain the skin and tenderness on examination.Pain is often aggravated, like stiffness, by cold orhumid weather, anxiety or stress, overuse or inactivity,poor sleep (19, 22) and noise (20). The worsttimes for an FM patient are in the morning, the latterhalf of the afternoon, and evening (23).Myalgia and muscle dysfunctionsPain often includes widespread myalgia that is notnecessarily confined to the tender points, and withcharacteristics that vary widely even in an individualpatient. It can also appear as low back pain,sometimes simulating sciatica; in this case theremay be a concomitant myofascial pain syndrome(piriformis, gluteus).Approximately 40% of FM patients reported legcramps in comparison to 2% of controls (24).Myalgia can be accompanied by muscle weaknessand fasciculations with or without general weakness.Muscle function is globally impaired (most ofall aerobic processes) (25) and strength is generallyreduced in the hand and quadriceps, in particular(26).Many studies failed to demonstrate typical and specificmuscle abnormalities. Bioptic studies (27-29)revealed only non-specific signs of muscle pathologywithout pathognomonic flags of FM. Needleelectromyography found minor and, again, nonspecificchanges looking for pathological evidenceof motor unit recruitment (no loss of motor unitsand no fiber degeneration) (30). Multichannel surfaceelectromyography seems to be of some interest,giving original information about acute alterationof motor unit recruitment strategies andchronic modification of muscle fiber type distribution,number or size (31, 32). Muscle alterationthat is clinically expressed as fatigue could be theperipheral aspect of a central alteration of the sensory-motorinteraction.Muscles in a patient with FM probably undergo apathologic remodelling related to an alteredsuprasegmental control (33). Because of this, theirfunction is incorrect and ineffective.However, these results are not strictly related to fibromyalgicmuscle; they have also been recorded,for example, in healthy, deconditioned elderly populations(34).

18 G. Cassisi et al.StiffnessIn FM patients, stiffness, typically, is not only articularbut also generalized (global stiffness) and iscommon; but unlike in rheumatoid arthritis, it isworse upon awakening and in the evening. The incidenceof morning stiffness lasting more than fifteenminutes has been reported in as many as 83%of patients (35).Morning stiffness does not correlate with severityof FM (19), but it does correlate with pain (36).Swollen feeling in tissueSwelling of the hands and feet is often present inFM and is sometimes accompanied by numbnessand tingling. Generalized swelling may be presentas the result of inactivity as well.In many patients, the sensation of swelling is present(22), even if no objective joint swelling is presenton physical examination. In some patients, theskin overlying a muscle with known myofascialpain syndrome can exhibit the characteristic orangepeel skin; however, trophic edema does not“pit” upon digital pressure in these cases.NON-MUSCULOSKELETAL SYMPTOMSFatigueFatigue is quite common in FM; it is generallyworse in the morning and patients often awakenfeeling more exhausted than when they went tobed. Moderate or severe fatigue occurs in about75% to 90% of patients (35, 36). Patients will typicallydescribe their fatigue using the expression,“I’m always tired.” Other descriptors for fatigueinclude exhaustion, tiredness, lack of energy, andsometimes, a global feeling of general weakness.Fatigue in these patients seems to be unexpected orinappropriate with a delayed reactivity followingphysical exertion (next day or even later). After exerciseFM patients can feel worse rather than better.Normal physical or intellectual exertion maytake an inordinate amount of time to regain the preexertionlevel of function and competence. Fatiguemay be generated by many different mechanisms.Arousal fatigue is a typical cause of fatigue in FM;it results from an inadequate quantity or quality ofsleep or from some medications. Muscular fatigueis commonly seen in FM, and motivational fatigueis usually associated with depression, which is presentin about 30% or more of FM patients (17). Fatigueis also associated with pain severity and functionaldisabilities (37).Sleep dysfunctionNon restorative sleep is common in FM. About75% of patients describe sleep disturbances thatmay include early, middle or late insomnia; hypersomnia;frequent awakening; light sleep with irregulardiurnal rest; or reversed or chaotic sleeprhythms. Poor sleep may aggravate pain and mayalso contribute to disturbed sleep. There is a relationship,in fact, between poor sleep and pain, andsleep disturbances are important in the genesis oftender points (37, 38).Loss of deeper phases of sleep (stages three andfour) is characteristic of FM and leads to the lossof restorative feelings on awakening.Polysomnographic studies have shown that, comparedto controls, FM patients experience a reducedportion of deep sleep, REM sleep, and total sleeptime, a greater number of awakenings and a significantpattern indicating the intrusion of alphawaves on delta rhythm (39).Some researchers have suggested that alpha intrusionis an intrinsic characteristic of non-REM sleepin FM patients (40-42). Others, however, do notagree because this phenomenon may be observedin normal individuals and in patients with otherchronic pain syndromes, such as rheumatoid arthritisand chronic fatigue syndrome (41, 43). Still otherresearchers have demonstrated a poor presenceof alpha waves intrusion during deep sleep in FMpatients (44, 45).From these varied studies, a reasonable conclusionis that fragmented sleep is an important factor forthe physiopathology of FM symptoms; and althoughan excess of alpha intrusion is not specificfor FM, it may be considered a sensitive marker fornon-restorative sleep nevertheless.Restless legs syndrome or periodic limb movementdisorder may also contribute to sleep disturbances.Restless legs syndrome has been reported in approximately30% of FM patients compared to 2%of controls (24). Periodic limb movement disorderis another common sleep disturbance that affectsabout 30% of patients over the age of 50. It is oftenindependent of the presence of FM and is characterizedby transient episodes (0.5 to 5 seconds)of partial bending of the ankles, knees, or hips (46).This disorder is common, but is not as significantin FM patients.Sleep apnea syndrome and other breathing conditions,like periodic breathing during sleep, might beobserved in FM patients. Sleep apnea syndrome ischaracterized by recurring episodes of upperbreathing apparatus (mouth and nose) obstruction

Symptoms and signs in fibromyalgia syndrome 19during sleep with significant ipopnea or apnea (47).About 2% of women and 44% of men with FM areaffected by sleep apnea syndrome (48). In spite ofthis, apneas are unlikely culprits for FM symptoms(49).ParesthesiaParesthesia has been shown to appear in as manyas 84% of FM patients (50) and occurs predominantlyin the extremities. In some patients thesesymptoms can be quite severe but without sensorydeficits on physical examination. This symptom isdescribed as tingling, “pins and needles,” or numbness.Paresthesia may have a radiating quality thatmimics a neurologic disorder but without radiculardistribution. Electromyographic and nerve conductionvelocity studies are normal in these patients(50).ADDITIONAL CLINICAL SYMPTOMSThe clinical presentation of FM may vary somewhat,and the additional symptoms, though not requiredfor ACR criteria, are still clinically important(Table II).Neurologic manifestationsFM patients often report symptoms that are neurologicalin nature. Muscle dysfunction often manifestsas a hypertonic or hypotonic state, an abnormaltwitch response, cramps, weakness and fasciculation.Headaches, temporomandibular joint disorder,perceptual disturbances, spatial and temporalinstability and sensory overload phenomena oftenoccur. In particular, the patient may be hypersensitiveto light, sound, noise, speed, odours andother mixed sensory modalities. Perceptual disturbancesmay include dizziness, numbness, tinnitus,nausea or shooting pain (17).Neurocognitive manifestationsNeurocognitive disturbances are usually present inFM patients. These include impaired concentrationand short-term memory consolidation, reduced performancespeed, inability to multi-task, distractibilityand cognitive overload. Complaints ofcognitive “fog” (fibro-fog) or simple confusion,linguistic performance impairment, dyslexia whenfatigued, and difficulty with writing, reading, mathematics,word retrieval and speaking are especiallycommon. It is easy for patients to lose track ofthings and to forget many things (17).Table II - Symptoms in Fibromyalgia Syndrome Based on Several LargeSeries.SymptomsMean*MusculoskeletalPain at multiple sites 100Stiffness 78“Hurt all over” 64Swollen feeling in tissue 47NonmusculoskeletalGeneral fatigue 86Morning fatigue 78Poor sleep 65Paresthesia 54Associated syndromeHeadaches 53Dysmenorrhea 43Irritable bowel syndrome 40Restless legs syndrome 31Sicca syndrome 15Raynaud’s phenomenon 13Female urethral syndrome 12*Mean values derived from percentage figures reported in several studies. In RachlinES e Rachlin IS Myofascial pain and fibromyalgia: trigger point management(30). Modified from Yunus MB, Masi AT: Fibromyalgia, restless legs syndrome,periodic limb movement disorder and psychogenic pain. In McCart DJ Jr, KoopmanWJ (eds): Arthritis and Allied Conditions: A Textbook of Rheumatology, 12thed. Philadelphia, Lea & Febiger, 1993, pp 1383-1405.FM patients have cognitive function that is worsethan that in age-matched controls (51) and similarto that in adults 20 years older with respect to longtermmemory and working memory (i.e. theamount of information a person can store andprocess simultaneously) (52).FM patients are able to perform at a similar levelas healthy controls, but this is only due to more extensiveneural activation in frontal and parietalbrain regions (53). This supports the hypothesisthat FM patients show an aging effect that requiresincreased use of cognitive resources to maintaincomparable levels of performance as their sameagedpeers.The finding of an acceleration of age-related brainchanges has been supported by the observation thatFM patients had significantly less total gray mattervolume and 3.3 times greater age-associated decreasein gray matter than healthy controls. Thelonger the individuals had had fibromyalgia, thegreater the gray matter loss, with each year of fibromyalgiabeing equivalent to 9.5 times the lossin normal aging (54).This is probably due to the mechanism of neurotoxicity(neuronal apoptosis).

20 G. Cassisi et al.Autonomic and neuroendocrine manifestationsThese manifestations indicate a general loss of internalhomeostasis and adaptation. They includecardiac arrhythmias, hypotension, dizziness, senseof lightheadedness, vertigo, vasomotor instability,sicca syndrome, temperature instability, heat orcold intolerance, respiratory disturbances, intestinaland bladder motility disturbances, dysmenorrhea,loss of adaptability and tolerance for stress,emotional flattening, and reactive depression (17).Associated symptoms and conditions and centralsensitivity syndromeChronic headaches, irritable bowel, irritable bladderand female urethral syndromes, primary dysmenorrhea,restless legs syndrome, and sicca syndromehave been often described in FM, more commonthan in pain-free normal controls (3). But severalother similar syndromes, including FM, arenow considered to form a spectrum of illnesseswith central sensitivity, described previously asCSS (15) (Table III).Psychiatric disorders and psychological factorsPsychological factors are an important determinantof any form of pain including chronic pain,irrespective of the cause, and FM is no exception.Psychological distress perpetuates pain, andchronic pain may cause psychological disturbance.Table III - Symptoms that may be present, not included as part of the criteria for diagnosis (17).Musculoskeletal systemGeneralized stiffnessMuscle crampsChest pressure and painTMJ dysfunctionNervous systemPersistent fatigueLack of enduranceMigraines or new onset headachesSensoryHypersensitivity to painHyperresponsiveness to noxious stimulusPerceptual and dimensional distortionsFeeling of burning or swellingSensory overload phenomenaLoss of cognitive mapDyspneaCognitiveDifficulties processing informationSlowness in cognitive processingConcentration problemsDifficulties with word retrievalConfusion and word mix-upsShort-term memory difficultiesMotor and balanceMuscle weakness and paralysisPoor balance, ataxia and tandem gaitClumsiness and tendency to drop thingsDifficulty in tandem gaitAtypical numbness or tinglingNeuroendocrine systemMarked weight changeHeat/cold intoleranceNeuropsychologicalMood swing, anxietyReactive depressionVisual and auditory disturbancesVisual changes or eye painDouble, blurred and wavy visionDry or itchy eyesPhotophobiaTinnitus-buzzing or ringing in earsHyperacusis and interference from background noiseSleep disturbancesSleep disorder, hyper or insomniaNon-refreshing sleepCirculatory systemNeurally-mediated hypotensionFainting or vertigoPalpitations and tachycardiaFluid retentionBruisingDigestive systemLump in throatNauseaHeart burnAbdominal painIrritable bowel syndromeUrinary systemIrritable bladderOveractive bladderReproductive syndromeDysmenorrheaPre-menstrual syndrome or irregular cyclesLoss of sexual libido or impotenceAnorgasmia

Symptoms and signs in fibromyalgia syndrome 21A minority subgroup of patients (30-40%) has asignificant psychological disturbance (55).Several studies provide evidence that psychiatricdisorders occur at significantly higher rates in subjectswith FM compared with other pain patients orhealthy controls. Other studies contend that the frequencyof such distress is similar to that in otherchronic disease, such as rheumatoid arthritis (55).Studies examining psychiatric comorbidity in communitysamples of subjects with FM found elevatedlevels of psychopathology (56, 57), althoughpsychiatric illness is not a necessary factor in theetiopathogenesis of FM.Psychiatric disorders most commonly describedare mood disorders.Current major depression has been detected in 14-36% of patients with FM (58, 59) compared to 6.6% of healthy subjects in a community sample (60).Family history studies indicate a higher prevalenceof mood disorders in first degree relatives of patientswith FM compared to first degree relatives ofpatients with rheumatoid arthritis and healthy controls(61, 62).Subjects with FM report childhood traumatic experiencesmore frequently than medically ill orhealthy controls; and they report a high prevalenceof emotional neglect or abuse (48%) and physicalmaltreatment (23%) as well (63).Job-related stress or or physical stressors may actas precipitating factors, but the impact of thesestressors may only be realized if they have strongpersonal significance. An etiopathogenetic link betweenFM and life stress is also suggested by thecomorbid occurrence of post-traumatic stress disorder.Post-traumatic stress disorder symptoms werefounded in 56% of patients with FM (64).Research on personality traits in FM has yielded inconsistentresults, but no personality disorders havebeen associated with FM (65).Despite all of this, cognitive styles are increasinglybeing recognized as important factors in the experienceof pain. For example, catastrophizing,which is characterized by pessimistic beliefs aboutoneself, others, and the future and by defining painas awful and unbearable, is a common cognitivestyle that is known to modulate pain reports andpain-related disability. It seems to play a substantialrole in the development of pain chronicity andin the experience of chronic pain and pain-relateddisability. It is an independent factor that is onlypartially associated with depression.Catastrophizers hardly shift their attention awayfrom painful or threatening stimuli, and they attachmore threator harm to non-painful stimuli thanis warranted (66).THE SIGNSThe most significant finding related to FM is thepresence of multiple tender points (3). Tenderpoints are best elicited by manual palpation, specificallyby digital pressure using an approximate totalforce of four Kg. A small subgroup of patientsis diffusely tender all over. It is necessary to underlinethat the tender point never aches spontaneously.Other physical signs, though not necessary for diagnosis,are skinfold tenderness, which is assessedby pinching a fold of skin and subcutaneous tissueon tender point sites, cutaneous hyperaemiaat the tender point site after examination, andreticular discoloration (livedo reticularis) in theextremities.Negative findings are the absence of joint swelling,a normal range of joint motion and muscle strength,and normal sensory function and reflexes (56).CONCLUSIONFM is a chronic pain condition in which patientsreport not only widespread pain but also a varietyof other complaints. The cardinal features arechronic widespread pain in the presence of multipletender points throughout the body on physicalexamination. The ACR 1990 definition for clinicaltrials proposed compulsory criteria for classifyingFM in adults and was not intended to be used forclinical diagnosis.On the contrary, diagnosis is made by a combinationof patient history, physical examination, laboratoryevaluations, and exclusion of other causesfor symptoms attributable to FM.Three key features - pain, fatigue and sleep disturbance- are present in virtually every patient withFM. The hallmark symptom that differentiates FMfrom most other medical conditions is allodynia toeven the mildest palpation or physical touch. Thetender point, which never aches spontaneously, isthe only cardinal sign, and it can be elicited bymanual palpation via digital pressure.FM symptoms can be summarized in musculoskeletal,non-musculoskeletal, and additionalclinical symptoms.

22 G. Cassisi et al.Associated symptoms and conditions must be consideredin patient’s evaluation because several associatedillnesses are more common in FM patientsthan in the normal population.The evolving idea of CSS, which is based on neuroendocrineaberrations interacting with psychosocialfactors, will be an important new conceptto consider in the daily diagnosis of FM and relatedconditions.The Wolfe editorial entitled “Stop using the ACRCriteria in the Clinic” is a great article that will encouragephysicians to obtain complete knowledgeof all common and uncommon FM symptoms tominimize improper diagnosis.SUMMARYFibromyalgia syndrome (FM) is a common chronic pain condition that affects at least 2% of the adult population. Chronicwidespread pain is the defining feature of FM, but patients may also exhibit a range of other symptoms, includingsleep disturbance, fatigue, irritable bowel syndrome, headaches, and mood disorders. The etiology of FM is not completelyunderstood and the syndrome is influenced by factors such as stress, medical illness, and a variety of pain conditions.Establishing diagnosis may be difficult because of the multifaceted nature of the syndrome and overlap withother chronically painful conditions. A unifying hypothesis is that FM results from sensitization of the central nervoussystem; this new concept could justify the variety of characteristics of the syndrome. FM symptoms can be musculoskeletal,non-musculoskeletal, or a combination of both; and many patients will also experience a host of associatedsymptoms or conditions. The ACR classification criteria focus only on pain and disregard other important symptoms;but three key features, pain, fatigue and sleep disturbance, are present in virtually every patient with FM. Severalother associated syndromes, including circulatory, nervous, digestive, urinary and reproductive systems are probablya part of the so called central sensitivity or sensitization syndrome. A minority subgroup of patients (30-40%) hasa significant psychological disturbance. Psychological factors are an important determinant of any type of pain, andpsychological comorbidity is frequent in FM. Psychiatric disorders most commonly described are mood disorders, butpsychiatric illness is not a necessary factor in the etiopathogenesis of FM.Key words - Fibromyalgia, symptoms, sleep disorders, restless leg syndrome, chronic pain, fatigue.Parole chiave - Fibromialgia, sintomi, disturbi del sonno, syndrome delle gambe senza riposo, dolore cronico, fatica.REFERENCES1. Clauw DJ. Elusive syndromes: treating the biologic basisof fibromyalgia and related syndromes. Cleve ClinJ Med 2001; 68: 830, 832-4.2. Bennett R. Fibromyalgia, chronic fatigue syndrome,and myofascial pain. Curr Opin Rheumatol 1998; 10:95-103.3. Wolfe F, Smythe HA, Yunus MB, et al. The AmericanCollege of Rheumatology 1990 Criteria for the Classificationof Fibromyalgia. Report of the Multicenter CriteriaCommittee. Arthritis Rheum 1990; 33: 160-72.4. Crofford LJ, Clauw DJ. Fibromyalgia: where are we adecade after the American College of Rheumatologyclassification criteria were developed? Arthritis Rheum2002; 46: 1136-8.5. Aaron LA, Buchwald D. A review of the evidence foroverlap among unexplained clinical conditions. AnnIntern Med 2001; 134: 868-81.6. Schneider MJ, Brady DM, Perle SM. Commentary: differentialdiagnosis of fibromyalgia syndrome: proposalof a model and algorithm for patients presenting withthe primary symptom of chronic widespread pain. JManipulative Physiol Ther 2006; 29: 493-501.7. Cöster L, Kendall S, Gerdle B, Henriksson C, HenrikssonKG, Bengtsson A. Chronic widespread musculoskeletalpain - A comparison of those who meet criteriafor fibromyalgia and those who do not. Eur J Pain2008; 12: 600-10.8. Fitzcharles MA, Boulos P. Inaccuracy in the diagnosisof fibromyalgia syndrome: analysis of referrals.Rheumatology (Oxford) 2003; 42: 263-7.9. Wolfe F. Stop using the American College of Rheumatologycriteria in the clinic. J Rheumatol 2003; 30:1671-2.10. Häuser W, Zimmer C, Felde E, Köllner V. What are thekey symptoms of fibromyalgia?: Results of a survey ofthe German Fibromyalgia Association. Schmerz 2008;22: 176-83.11. Yunus MB, Masi AT, Aldag JC. Preliminary criteria forprimary fibromyalgia syndrome (PFS): multivariateanalysis of a consecutive series of PFS, other pain patients,and normal subjects. Clin Exp Rheumatol 1989;7: 63-9.12. Jacobsen S, Danneskiold-Samsoe B, Lund B. Consensusdocument on fibromyalgia: the Copenhagen declaration.J Musculoske Pain 1993; 1: 295-312.13. Mease P, Arnold LM, Bennett R, et al. Fibromyalgiasyndrome. J Rheumatol 2007; 34: 1415-25.14. Yunus MB. Fibromyalgia and overlapping disorders:the unifying concept of central sensitivity syndromes.Semin Arthritis Rheum 2007; 36 (6): 339-56.15. Yunus MB. Central Sensitivity Syndromes: A new paradigmand group nosology for fibromyalgia and over-

Symptoms and signs in fibromyalgia syndrome 23lapping conditions, and the related issue of disease versusillness. Semin Arthritis Rheum. 2008 [Epub aheadof print].16. Wolfe F, Hawley DJ, Cathey MA, Caro X, Russell IJ.Fibrositis: symptom frequency and criteria for diagnosis.An evaluation of 291 rheumatic disease patientsand 58 normal individuals. J Rheumatol 1985; 12:1159-63.17. Jain KA, Carruthers M, Van De Sande MI, et al. FibromyalgiaSyndrome: Canadian clinical working CaseDefinition, diagnostic and treatment protocols – A consensusdocument. J Musculoske Pain 2004; V. 11: 3-107.18. Leavitt F, Katz RS, Golden HE, Glickman PB, LayferLF. Comparison of pain properties in fibromyalgia patientsand rheumatoid arthritis patients. Arthritis Rheum1986; 29: 775-81.19. Yunus MB, Masi AT, Aldag JC. A controlled study ofprimary fibromyalgia syndrome: clinical features andassociation with other functional syndromes. J RheumatolSuppl 1989; 19: 62-71.20. Pellegrino MJ. Atypical chest pain as an initial presentationof primary fibromyalgia. Arch Phys Med Rehabil1990; 71: 526-8.21. Reilly PA, Littlejohn GO. Peripheral arthralgic presentationof fibrositis/fibromyalgia syndrome. JRheumatol 1992; 19: 281-3.22. Campbell SM, Clark S, Tindall EA, Forehand ME, BennettRM. Clinical characteristics of fibrositis. I. A“blinded,” controlled study of symptoms and tenderpoints. Arthritis Rheum 1983; 26: 817-24.23. Moldofsky H. Chronobiological influences on fibromyalgiasyndrome: theoretical and therapeutic implications.Baillieres Clin Rheumatol 1994; 8: 801-10.24. Yunus MB, Aldag JC. Restless legs syndrome and legcramps in fibromyalgia syndrome: a controlled study.BMJ 1996; 312: 1336-9.25. Maquet D, Croisier JL, Renard C, Crielaard JM. Muscleperformance in patients with fibromyalgia. JointBone Spine 2002; 69: 293-9.26. Dombernowsky T, Dreyer L, Bartels EM, Danneskiold-Samsøe B. Muscular strength in patients with fibromyalgia.A literature review. Ugeskr Laeger 2008;170: 217-24.27. Sprott H, Salemi S, Gay RE, et al. Increased DNA fragmentationand ultrastructural changes in fibromyalgicmuscle fibres. Ann Rheum Dis 2004; 63: 245-51.28. Gronemann ST, Ribel-Madsen S, Bartels EM,Danneskiold-Samsoe B, Bliddal H. Collagen and musclepathology in fibromyalgia patients. Rheumatology(Oxford) 2004; 43: 27-31.29. Takahashi M, Oikawa M, Nagano A. Effect of age andmenopause on serum concentrations of pentosidine, anadvanced glycation end product. J Gerontol A Biol SciMed Sci 2000; 55: M137-40.30. Zidar J, Bäckman E, Bengtsson A, Henriksson KG.Quantitative EMG and muscle tension in painful musclesin fibromyalgia. Pain 1990; 40: 249-54.31. Casale R, Farina D, Merletti R, Rainoldi A. Myoelectricmanifestations of fatigue during a twelve day exposureto hypobaric hypoxia. Muscle Nerve 2004; 30:618-35.32. Rainoldi A, Casale R, Hodges P, Jull G. Applicationsin rehabilitation medicine and related fields. In: MerlettiR, Parker P, editors. Electromyography Physiology,engineering and non invasive applications. Hoboken,New Jersey, USA: J. Wiley/IEEE Press Publication2004; 403-33.33. Casale R, Sarzi-Puttini P, Gazzoni M, Fundarò C, RainoldiA. Central motor control failure in fibromyalgia: asurface electromyography study. E J Appl Phys (underreview 2008).34. Casale R, Rainoldi A, Nilsson J, Bellotti P. Can continuousphysical training counteract aging effect onmyoelectric fatigue? A surface electromyographystudy application. Arch Phys Med Rehabil 2003; 84:513-7.35. Lessard JA, Russell IJ: Fibrositis/fibromyalgia in privaterheumatology practice; systematic analysis of apatient data base. 1989 (unpublished) Reported in: Fibrositis/fibromyalgia(Chapter 23), in The Clinical andScientific Basis of Myalgia Encephalomyelitis/ChronicFatigue. Syndrome. Editors: Hyde BM, Goldstein J,Levine P. The Nightingale Research Foundation, Ottawa,Canada, 1992.36. Russell IJ: Fibrositis/fibromyalgia (Chapter 23), in TheClinical and Scientific Basis of Myalgia Encephalomyelitis/ChronicFatigue. Syndrome. Editors:Hyde BM, Goldstein J, Levine P. The Nightingale ResearchFoundation, Ottawa, Canada, 1992.37. Yunus MB, Inanici F, Aldag JC, Mangold RF. Fibromyalgiain men: comparison of clinical features withwomen. J Rheumatol 2000; 27: 485-90.38. Moldofsky H, Scarisbrick P, England R, Smythe H.Musculosketal symptoms and non-REM sleep disturbancein patients with “fibrositis syndrome” and healthysubjects. Psychosom Med 1975; 37: 341-51.39. Moldofsky H. The significance, assessment, and managementof non-restorative sleep in fibromyalgia syndrome.CNS Spectr 2008; 13: 22-6.40. Moldofsky H, Scarisbrick P. Induction of neurasthenicmusculoskeletal pain syndrome by selective sleep stagedeprivation. Psychosom Med 1976; 38: 35-44.41. Branco J, Atalaia A, Paiva T. Sleep cycles and Alpha -Delta Sleep in Fibromyalgia Syndrome. J Rheumatol1994; 21: 1113-7.42. Drewes AM,Nielsen KD,Taagholt SJ, Bjerregard K,Svendsen L, Gade J. Sleep intensity in fibromyalgia: focuson the microstructure of the sleep process. Br JRheumatol 1995; 34: 629-35.43. Roizenblatt S, Moldofsky H, Benedito-Silva AA, TufikS. Alpha sleep characteristics in fibromyalgia.Arthritis Rheum 2001; 44: 222-30.44. Lentz MJ, Landis CA, Rothemel J, et al. Effect of selectiveslow wave alwwp diaruption on musculoskeletalpain and fatigue in middle aged women. J Rheumatol1999; 26: 1586-92.45. Sergi M, Rizzi M, Braghiroli A, et al. Periodic breathingduring sleep in patients affected by fibromyalgiasindrome. Eur Resp J 1999; 14: 203-8.

24 G. Cassisi et al.46. Coleman RM, Pollak CP, Weitzman ED. Periodicmovement in sleep (nocturnal myoclonus): relation tosleep disorders. Ann Neurol 1980; 8: 416-21.47. De Backer WA. Central sleep apnoea, pathogenesis andtreatment: an overview and perspective. Eur Respir J1995; 8: 1372-83.48. May KP, West SG, Naker MR, Everett DW. Sleep apneain male patients with the fibromyalgia syndrome.Am J Med 1993; 94: 505-8.49. Lario BA, Teran J, Alonso JL, et al. Lack of associationbetween fibromyalgia and sleep apnoea syndrome.Ann Rheum Dis 1992; 51: 108-11.50. Simms RW, Goldenberg DL. Symptoms mimickingneurologic disorders in fibromyalgia syndrome. JRheumatol 1988; 15: 1271-3.51. Grace GM, Nielson WR, Hopkins M, Berg MA. Concentrationand memory deficits in patients with fibromyalgiasyndrome. J Clin Exp Neuropsychol 1999;21: 477-87.52. Park DC, Glass JM, Minear M, Crofford LJ. Cognitivefunction in fibromyalgia patients. Arthritis Rheum2001; 44: 2125-213.53. Bangert AS, Glass JM, Welsh RC, Crofford LJ, TaylorSF, Park DC. Functional magnetic resonance imagingof working memory in fibromyalgia. Arthritis Rheum2003; 48: S90.54. Kuchinad A, Schweinhardt P, Seminowicz DA, WoodPB Chizh BA, Bushnell MC. Accelerated brain graymatter loss in fibromyalgia patients: premature aging ofthe brain? J Neurosci 2007; 27: 404-7.55. Rachlin ES, Rachlin IS. Myofascial Pain and Fibromyalgia,Trigger Point Management. 2 nd ed. St.Louis: Mosby, 2002.56. Wolfe F, Ross K, Anderson J, Russell IJ. Aspects of fibromyalgiain the general population: sex, pain threshold,and fibromyalgia symptoms. J Rheumatol 1995;22: 151-6.57. White KP, Nielson WR, Harth M, Ostbye T, SpeechleyM. Chronic widespread musculoskeletal pain withor without fibromyalgia: psychological distress in a representativecommunity adult sample. J Rheumatol2002; 29: 588-94.58. Buskila D, Cohen H. Comorbidity of fibromyalgia andpsychiatric disorders. Curr Pain Headache Rep 2007;11: 333-8.59. Ahles TA, Khan SA, Yunus MB, Spiegel DA, MasiAT. Psychiatric status of patients with primary fibromyalgia,patients with rheumatoid arthritis, and subjectswithout pain: a blind comparison of DSM-III diagnoses..Am J Psychiatry 1991; 148: 1721-6.60. Kessler RC, Berglund P, Demler O, et al. The epidemiologyof major depression: results from the NationalComorbidity Survey Replication (NCS-R). JA-MA 2003; 289: 3095-105.61. Hudson JH, Arnold LM, Keck PE Jr, et al. Family studyof fibromyalgia and affective spectrum disorders. BiolPsychiatry 2004; 56: 884-91.62. Raphael KG, Janal MN, Nayak S et al. Familial aggregationof depression in fibromyalgia: a community - basedtest of alternate hypotheses. Pain 2004; 110: 449-60.63. Van Houdenhove B, Neerinckx E, Lysens R et al. Victimizationin chronic fatigue syndrome and fibromyalgiain tertiary care: a controlled study on prevalence andcharacteristics. Psychosomatics 2001; 42: 21-8.64. Sherman JJ, Turk DC, Okifuji A. Prevalence and impactof posttraumatic stress disorder-like symptoms onpatients with fibromyalgia syndrome. Clin J Pain 2000;16: 127-34.65. Thieme K, Turk DC, Flor H. Comorbid depression andanxiety in fibromyalgia syndrome: relationship to somaticand psychosocial variables. Psychosom Med2004; 66: 837-44.66. Geisser ME, Casey KL, Brucksch CB, Ribbens CM,Appleton BB, Crofford LJ. Perception of noxiousand innocuous heat stimulation among healthywomen and women with fibromyalgia: associationwith mood, somatic focus, and catastrophizing. Pain2003; 102: 243-50.

ORIGINAL ARTICLEReumatismo, 2008; 60: Supplemento 1: 25-35Etiopathogenetic mechanisms of fibromyalgia syndromeMeccanismi eziopatogenetici della sindrome fibromialgicaS. Stisi 1 , M. Cazzola 2 , D. Buskila 3 , M. Spath 4 , M.A.Giamberardino 5 , P. Sarzi-Puttini 6 , G. Arioli 7 ,A. Alciati 8 , G. Leardini 9 , R. Gorla 10 , A. Marsico 11 , F. Ceccherelli 12 , L. Bazzichi 13 , R. Carignola 14 ,R.H. Gracely 15 , F. Salaffi 16 , F. Marinangeli 17 , R. Torta 18 , M. Di Franco 19 , G. Biasi 20 , G. Cassisi 21 ,R. Casale 22 , L. Altomonte 23 , F. Atzeni 6 (Italian Fibromyalgia Network)1Rheumatology Unit, “G.Rummo” Hospital, Benevento, Italy; 2 Unit of Rehabilitative Medicine “Hospital of Circolo”, Saronno (VA),Italy; 3 Department of Medicine H, Soroka Medical Center and Faculty of Health Sciences, Ben Gurion University, Beer Sheva, Israel;4Friedrich-Baur-Institute, University of Munich, Germany; 5 Ce.S.I. “G. D’Annunzio” Foundation, Department of Medicine and Scienceof Aging, “G. D’Annunzio”, University of Chieti, Italy; 6 Rheumatology Unit, L. Sacco University Hospital, Milano, Italy; 7 Division ofRehabilitative Medicine and Rheumatology, General Hospital of Pieve di Coriano (Mantua), Italy; 8 Department of Psychiatry, L. SaccoUniversity Hospital, Milan, Italy; 9 Rheumatology Unit, SS Giovanni e Paolo Hospital , Venice, Italy; 10 Rheumatology and ClinicalImmunology, Spedali Civili and University of Brescia, Italy; 11 Rheumatology Unit, Hospital of Taranto, Taranto, Italy; 12 IOV (VenetoCancer Institute), IRCCS, Department of Pharmacology and Anesthesiology, University of Padua, Italy; 13 Department of InternalMedicine, Division of Rheumatology, S. Chiara Hospital, University of Pisa, Italy; 14 S.C.D.U. Internal Medicine I, Department ofClinical and Biological Science, University of Turin, Italy; 15 Department of Medicine, University of Michigan Medical School, AnnArbor, Michigan, USA; 16 Department of Rheumatology, Polytechnic University of the Marche Region, Ancona, Italy; 17 Department ofAnesthesiology and Pain Medicine, L'Aquila University, L'Aquila, Italy; 18 Department of Neuroscience, University of Torino,A.S.O. San Giovanni Battista of Turin, Turin, Italy; 19 Chair of Rheumatology, University la Sapienza Rome, Rome, Italy;20Unit of Rheumatology, University of Siena, Siena, Italy; 21 Rheumatology Branch, Specialist Outpatients’ Department, Belluno, Italy;22Department of Clinical Neurophysiology and Pain Rehabilitation Unit, Foundation Salvatore Maugeri, IRCCS, Scientific Instituteof Montescano, Montescano (PV), Italy; 23 UOC of Rheumatology Hospital S. Eugenio, Rome, ItalyCompeting interests: none declaredRIASSUNTOLa sindrome fibromialgica (FMS) è una comune condizione cronica di dolore diffuso con meccanismi causali largamentesconosciuti, ma la sua patogenesi appare associata ad una alterazione del sistema nocicettivo a livello del sistemanervoso centrale. La FMS è spesso scatenata da influenze ambientali negative, specialmente se presenti nell’infanzia.In un feto, questi triggers ambientali possono influenzare lo sviluppo del sistema nervosa autonomo (ASN) edell’asse ipotalamo-ipofisi-surrene (HPA). Frequente è la comorbidità di condizioni psicologiche che comprendonola depressione, gli attacchi di panico, l’ansia e il disturbo post-traumatico da stress (PTSD). Recenti evidenze suggerisconoche fattori genetici possano giocare un ruolo nella patogenesi della FMS. La sensibilizzazione centrale è statada tempo associata con il dolore fibromialgico. Questo fenomeno descrive l’aumentata eccitabilità dei neuroni dellecorna dorsali, che porta alla trasmissione di alterate informazioni nocicettive al cervello. La comprensione dellevie patogenetiche della FMS è supportata dall’osservazione delle risposte dei pazienti alle terapie neurofisiologicamentemirate e dalla ricerca di base.Reumatismo, 2008; 60: Supplemento 1: 25-35INTRODUCTIONFibromyalgia syndrome (FMS) is a commonchronic condition of widespread pain withcausal mechanisms that are largely unknown. It ischaracterized by moderate to severe musculoskel -Corresponding author:Piercarlo Sarzi-Puttini, MDDirector of Rheumatology UnitL. Sacco University Hospital, Milan, ItalyE-mail: sarzi@tiscali.itetal pain and allodynia, but its pathogenesis appearsconfined to the nociceptive structures of thecentral nervous system.From a pathogenetic point of view, indeed, no clearmuscle pathology has been demonstrated in FMS(1, 2), while increasing evidence suggests a disturbancein pain perception that is genetically conditioned.In our review we will consider five “keypoints”that we think determine the origin andmaintenance of the pain syndrome that we defineas fibromyalgia: “triggers,” “genetics,” “central

26 S. Stisi et al.sensitization,” “neuroendocrine abnormalities” and“nervous autonomic amplification.” (Fig. 1).The “triggers”Fibromyalgia is often triggered by negative environmentalinfluences, especially if they occur inchildhood. In a fetus, these environmental triggersmay influence the development of the autonomicnervous system (ANS) and the hypothalamic-pituitary-adrenalaxis (HPA), which represent the keycomponents of the neuroendocrine response tostressors. Their functional alteration constitutes themain factor that predisposes individuals to developmany stress-related diseases in adulthood, includingFMS (3).Low birth weight also correlates with hyperactivityof the HPA in males and sympathetic hypertonein females; therefore, it seems that these individualshave a more intense cardiovascular response tostressors (4). A history of childhood adversity, violenceor stressors may cause a higher incidence ofcertain co-morbid conditions in adult patients withFMS such as major depression (5, 6).Likely the reaction to the stress induced by thesetraumatic events, which occurs in a critical periodfor the development of specific synapses, inducesalterations in the central nervous system (7).Although a direct causal relationship between infectiousdiseases and FMS has not been demonstrated,it seems reasonable, however, that infectionscan, in some way, act as triggering agents.The onset of FMS, in fact, has been allied withmultiple vaccinations for infectious diseases, virusesor bacteria (8). It is possible that the hypotheticalinfectious, natural or attenuated agent acts byindirectly stimulating production of cytokines thattake part in the multiple physiological functionsthat are altered in patients with FMS.Evidence supports a high prevalence of FMSamong patients with numerous chronic infections,including Epstein Barr virus, herpes 6-virus, HIVand, recently, HTLV-I virus (9, 10).Sleep disturbance could trigger mechanisms ofFMS. Moldofsky (11), in fact, artificially reproducedfibromyalgia-like symptomatology inhealthy volunteers by using an acoustic stimulus ofan intensity that was insufficient to provoke awakeningyet was able to disturb non-REM sleep. However,just as altering sleep physiology can inducethe appearance of musculoskeletal pain, the inverseis also true: nociceptive muscular stimulation appliedto healthy volunteers during sleep can alterEEG patterns (12).The risk of developing FMS seems to be increasedin patients with chronic painful conditions of anothernature; more than 80% of patients, in fact, reportthat they have suffered from a chronic localizedpainful condition before the generalization ofpain (13). In patients affected by symptomatic hiposteoarthritis abnormalities of the inhibitory systemfor nociception, similar to that documented in FMSpatients, have been found; these abnormalities normalizefollowing successful prosthetic treatmentof the hip (14). Nociceptive persistent inputs aresufficiently intense; therefore, they could inducethe generalization of pain and insurgence of FMSin predisposed subjects.A particular sensitivity to multiple chemical substanceswould be the cause of multiple chemicalsensitivity syndrome, a dysfunctional syndromethat is closely associated with FMS and chronicfatigue syndrome. Mercury, nickel, and silicone,which is commonly used in surgical breast implants,are substances that are frequently cited aspossible causes of dysfunctional syndromes, suchas FMS (15, 16).Of particular importance as triggers of FMS arepsychological conditions that can lead to catastrophizingof pain (17, 18) or life events and, therefore,cause additional stress. There is increasingevidence supporting the comorbidity of FMS andpsychological conditions. These conditions includedepression, panic disorders, anxiety, and post-traumaticstress disorder (PTSD). The nature of the relationshipbetween depression and FMS is not fullyunderstood. Depression is a common denominatoramong chronic painful conditions (15); it hasbeen hypothesized that chronic pain causes depression,or vice versa, and that chronic pain syndromesare variants of depression. A link betweenPTSD symptoms and FMS has been reported, andboth conditions share similar symptomatology andpathogenetic mechanisms (19).The preexistence of chronic stressful conditionsprior to the onset of FMS is frequently demonstrated.The symptomatology that is reported by fibromyalgiapatients seems to be influenced negativelyby chronic stressful situations, while positivecorrelations with acute stressful events have notbeen found (20). In addition, FMS patients showhigher levels of stress compared to controls (21).GeneticsRecent evidence suggests that genetic factors mayplay a role in the pathogenesis of FMS (22-24).Certain environmental factors (“stressors”) may

Etiopathogenetic mechanisms of Fibromyalgia Syndrome 27trigger the development of FMS in genetically predisposedindividuals (25).A number of studies published over recent yearshave documented increased incidence of FMSamong family members of patients suffering fromthis syndrome (26-28).Buskila et al. found that 28% of offspring of FMSpatients fulfill the American College of Rheumatology(1990) classification criteria for the diagnosisof FMS (26). Buskila et al. reported anotherstudy, we reported that the prevalence of FMSamong blood relatives of patients with FMS was26%, and that FMS prevalence in male and femalerelatives was 14% and 41%, respectively (27).Arnold and colleagues (28) tested the hypothesesthat FMS and measures of pain and tenderness aggregatein families and that FMS co-aggregateswith major mood disorder. They performed a familyinterview study of 78 probands with FMS and40 probands with rheumatoid arthritis (RA). Theyassessed FMS and major mood disorder in a totalof 533 first degree relatives of FMS probands anda total of 272 first degree relatives of RA probands.FMS was found to aggregate strongly in families: theodds ratio measuring the odds of FMS in a relativeof a proband with FMS versus the odds of FMS inrelative of a proband with RA was 8.5. The clear familialaggregation in FMS and related conditionsmay represent either genetic or environmental influence,or most likely a combination of both.Based on the strong evidence of a familial aggregationin FMS, a considerable amount of researchhas been conducted in search of the genetic underpinningsof this phenomenon. At present no evidencehas emerged to suggest a monogenic modeof transmission, and a multifactorial mode of transmissionis generally presumed.Research done in recent years has demonstrated arole for polymorphisms of genes in the serotonergic,dopaminergic and catecholaminergic systemsin the etiology of FMS.Offenbaecher and colleagues (29) analyzed thegenotypes of the promoter region of the serotonintransporter gene (5-HTT) in 62 patients with FMSand 110 healthy controls. A significantly higherfrequency of the S/S genotype of the serotonintransporter promoter region was found in FMS patients(31%) compared with healthy controls(16%). The S/S subgroup exhibited higher meanlevels of depression and psychological distress. Itwas suggested that the results support the notion ofaltered serotonin metabolism in at least a subgroupof patients with FMS.In another study, these researches reported on asignificantly different genotype distribution in FMSpatients with a decrease in T/T and an increase inboth T/C and C/C genotypes compared to the controlpopulation (30).Cohen and colleagues (31) performed genotypingin a group of 99 female FMS patients from two Israeliethnic groups. Additionally, each patient wasassessed with the Tridimensional Personality Questionnaire(TPQ). The results of this study confirmthe association between FMS and the serotonintransporter promoter region (5 - HTTLPR) polymorphismin two ethnic groups in Israel, Jewishand Bedouins. A significant association between 5- HTTLPR polymorphism and anxiety-related personalitytraits was found as well (31).Zubieta and colleagues (32) examined the influenceof a common functional genetic polymorphismaffecting the metabolism of catecholamineson the modulation of responses to sustained painin humans. Individuals homozygous for the Met158 allele of the catechol - O methyltransferase(COMT) polymorphism (Val 158 Met) show diminishedregional mu-opioid system responses topain compared with heterozygotes. These effectswere accompanied by higher sensory and affectiveratings of pain and a more negative internal affectivestate.It was concluded that the COMT Val 158 Met polymorphisminfluences the human experience of painand may underlie interindividual differences in theadaptation and responses to pain and other stressfulstimuli (32).Gursory and colleagues (33) have reported on theinvolvement of COMT gene polymorphism in patientswith FMS. Recently, Vargas-Alarcon et al.(35) reported that in a group of Spanish patients,there was an association between FMS and theCOMT haplotype. However, this association wasnot observed in Mexican patients.Buskila and colleagues (35) reported a significantdecrease in the frequency of the 7 repeat allele inexon III of the DR receptor gene in FMS patientsand also demonstrated an association between thepolymorphism and the low novelty seeking personalitytrait. Altogether, recent evidence suggestsa role for polymorphism of genes in the serotonergic,dopaminergic and catecholaminergic systemsin the etiopathogenesis of FMS.Thus recent evidence suggests a role for geneticand familial factors in the development of FMS.The mode of inheritance in FMS is unknown, butit is most probably polygenic. Recognition of these

28 S. Stisi et al.Sum oflife-eventsstressorsCentralsensitizationTriggersGeneticsCentral sensitizationChronic painand symptomsNeuroendocrineabnormalitiesPersonalityChildhoodadversitiesandviolences1 2NervousautonomicamplificationsFigures 1 - Modified from Van Houdenhove (106) - and 2 synthesize our proposal for the pathogenesis of FMS. From exposed it’s probable thattriggers cause a central sensitization when they interact in genetically predisposed individuals. Then central sensitization creates a vicious circleby provoking neuroendocrine abnormalities and nervous autonomic amplifications, which subsequently cause a chronic maintenance painfulsyndrome.gene polymorphisms may help to better subgroupFMS patients and to guide a more rational pharmacologicapproach.Central sensitizationCentral sensitization has long been considered to beassociated with FMS pain (36) (Fig. 1). It describesenhanced excitability of dorsal horn neurons, thentransmission of altered nociceptive information tothe brain. “Wind-up“ (temporal summation) is thesecond mechanism increasing pain: a painful stimulusis applied steadily but the pain is perceived asincreasing in intensity while applied subsequently(37, 38). Receptor fields increase as well, resultingin a larger distribution of the pain (39-41).These phenomena of functional neuroplasticity arepredominantly mediated by activation of N-methyl-D-aspartate (NMDA) receptors (42-44). Persistentactivation of NMDA receptors may lead into structuralalterations/reorganisation of the whole dorsalhorn synapse. Again, the result may be chronicspinal amplification of the nociceptor input.A descending pain inhibitory system originates inneurons of the periaqueductal gray matter, with descendingprojections to the nucleus raphe magnusand other nuclei in the rostral medulla. The neuronsin these nuclei project via the dorsolateral funiculusto the spinal dorsal horn with projections in differentnuclei of the rostral medulla, where they inhibitnociceptive neurons by releasing (among otherneuropeptides) serotonin. But also noradrenergicneurons in the medulla are involved. NE and 5-HT are key neurotransmitters in descending inhibitorypain pathways. Increasing the availabilityof NE and 5-HT may promote pain inhibition centrally(45-48).As the system acts predominantly on the nociceptiveinput from deep tissues, an impairment of thedescending inhibition will increase the ongoing activityand excitability particularly in dorsal hornneurons that process information from deep nociceptors.In patients, this may result in spontaneouspain and tenderness mainly in deep tissues. As theterminations of the descending neurons have awidespread distribution in the spinal cord, a dysfunctionof the descending system may result in, orcontribute to, the symptom of widespread pain observedin FMS (49).A recent study by Harris et al. (50) compared a sampleof 17 FMS patients and 17 age- and sex-matchedhealthy controls using mu-opioid receptor (MOR)positron emission tomography. It demonstrated thatFMS patients display reduced MOR within severalregions that play an important role in pain regulation,such as the nucleus accumbens, the dorsal cingulate,and the amygdala. These results indicate alteredendogenous opioid analgesic activity in FMSand explain why exogenous opiates appear to havereduced efficacy in this population.A previous study by the same group (51) suggestedthat pain catastrophizing is significantly associatedwith increased activity in some brain areas relatedto anticipation of pain (medial frontal cortex, cerebellum),attention to pain (dorsal ACC, dorsolateralprefrontal cortex), and emotional aspects of pain(claustrum, closely connected to amygdala). Theseresults suggest that catastrophizing influences painperception by altering attention and anticipation,and heightening emotional responses to pain.Also some neurotransmitters play an important rolein the central sensitization of the widespread painthat characterizes FMS. Serotonin is crucial in me-

Etiopathogenetic mechanisms of Fibromyalgia Syndrome 29diating pain pathways; it was the first neuropeptideto be studied extensively in FMS and hypothesizedto be involved in abnormal pain processing (52,53). The co-morbidity of psychiatric conditions,such as depression, and the alterations of sleepwakecycles, mediated by 5-HT, seemed to support5-HT dysregulation (54).Levels of 5-HT, its precursor tryptophan, and itsmetabolites 5-HIAA and 5-HTP were measured inthe blood, in the cerebrospinal fluid (CSF), and inthe urine of FMS patients. The most consistent resultsof all attempts to confirm an abnormality in5-HT neurotransmission were derived from CSFsamples. The pioneering studies did not measure 5-HT directly but found decreased levels of 5-HIAAin FMS patients as compared to controls, includingboth pain-free and low back pain subjects (55-57). The results from studies measuring 5-HT levelsin the serum of patients with FMS were lessconsistent. One group documented higher 5-HTlevels in FMS patients versus controls (58), evenusing platelet-rich plasma for the assay, whereasanother group found lower serum 5-HT levels inFMS than in RA patients (54). The hypothesis wasthat increased platelet activation may lead to a releaseof 5-HT into the plasma fraction. FMS patientswith a high plasma-to-serum 5-HT ratio presentedwith a higher frequency of orofacial painand anxiety (59). Similarly in another study, thenumber of tender points and serum 5-HT levelssignificantly correlated inversely, comparing FMSpatients with both RA patients and healthy controls(52). Whether or not the inconsistency may beexplained by changes within the serotonin transporterhas been discussed. A polymorphism in the5-HT transporter gene regulatory region (S/S genotype)is associated with decreased 5-HT transportermessenger RNA transcription and decreased 5-HTuptake in vitro. As mentioned previously, this polymorphismhas been shown to have a significantlyhigher distribution in FMS cohort (29).To summarize, a dysregulation of 5-HT metabolismin FMS is likely but has not been proven to bethe sole cause of central sensitization of FMS.Substance P, an 11-amino-acid neuropeptide, actsas a neuromodulator via the NK1 receptor. It sensitizesthe neurons to the effects of other neuromodulators.Stimulating the release of 5-HT in thespinal cord decreases the release of substance P intothe spinal cord (60).Substance P levels in the CSF of FMS patients havebeen found to be reproducibly high in five differentstudies (61-64). A trend toward correlation ofCSF substance P levels and pain severity in FMSover time has been suggested (65). Other chronicpain states, such as low back pain and painful neuropathy,present with low levels of CSF substanceP (66-69). High CSF concentration of substance Prepresents the most prominent neurochemical abnormalityfound in FMS patients.There are significant negative correlations betweenlevels of substance P and 5-HT, its precursor tryptophan(TRP), and its primary metabolite 5-HIAAin the serum of patients with FMS. High serumconcentrations of 5-HIAA and TRP showed a significantrelation to low pain scores. Low levels of5-HIAA and high concentrations of substance Pwere both positively correlated with more severesleep disturbance (70). Nerve growth factor (NGF),which stimulates the production of substance P insmall, afferent, unmyelinated neurons, was foundto be elevated in the CSF of FMS patients with primaryFMS, but not in FMS with an associatedpainful inflammatory condition (secondary FMS)(71). This finding addresses the clinical finding ofsubgroups in FMS (72-74). Elevated CSF substanceP could be a common link between primaryand secondary FMS, but the groups differ withregard to the mechanism responsible for the elevatedsubstance P. In primary FMS, NGF seems toinduce the elevated CSF substance P from centralinterneurons. In secondary FMS, the peripheral inflammation,so characteristic of the underlyingrheumatic or infectious conditions, may be responsiblefor the elevated CSF substance P. Forthese reasons, NGF could be critical to the initiationor perpetuation of the painful symptoms ofprimary but not secondary FMS (71).Neuroendocrine abnormalitiesThe neuroendocrine system, together with the autonomicnervous system and immune system, playsa fundamental role in the maintenance of the homeostasisof the organism in a large variety of environmentalsituations, namely stressful events ofboth physical and psychological origin. FMS is frequentlyassociated with a rich history of stressful/traumaticevents (75) and is characterized by anumber of symptoms similar to those typical ofstress-related conditions, such as irritable bowelsyndrome or chronic fatigue syndrome.The hypothalamic-pituitary-adrenal axis(HPA-axis)FMS patients have been shown to present withHPA axis alterations (76-80). Compared to con-

30 S. Stisi et al.trols, they present low 24-h serum cortisol levels;abnormal circadian pattern of cortisol concentrationand blunted serum cortisol responses to corticotropin-releasinghormone (CRH), i.e., whenCRH is released by the hypothalamus, there is adisproportionately high release of corticotrophinby the pituitary gland and disproportionately smallrelease of cortisol by the adrenal gland. This latterresult suggests an abnormal response of FMS patientsto stress, and thus, an inadequate reaction toa number of stressful events, such as trauma or infection(81). Interestingly, when synthetic CRH isinjected in FMS patients this abnormal response isnot present, and the patients behave like normalcontrol subjects. This suggests that there might bea different sensitivity of adrenal tissue to endogenousand exogenous CRH in FMS. On the whole,however, there is no evidence to support any structuralabnormality in the endocrine organs whichcomprise the HPA axis; thus, it seems that thechanges found in hormone production under activationof the axis are functional in patients withFMS (82).Dysregulation of the HPA axis can potentially accountfor several symptoms in FMS, including fatigue,primarily, as well as depression and sleepdisturbance; these symptoms are often present insubjects with a reduced activity of the axis (as inwithdrawal from glucocorticoid therapy, or in Addison’sdisease) or in individuals with geneticallyaltered HPA axis function (83). A link with pain isalso present. For instance, a recent study byMcLean et al. (84) showed a significant associationbetween levels of CRH in CSF and pain levels inpatients with FMS.Increased central levels of CRH also produce analgesiain animals (85). Activation of the HPA axisstimulates the release of the opioid beta-endorphin,corticotrophin, and cortisol, which, thanks to itsanti-inflammatory properties, has the potential ofreducing pain (83), though it should be underlinedthat in FMS, specifically, corticosteroids are noteffective (86).The hypothalamic-pituitary-thyroid axis(HPT-axis)The hypothalamic-pituitary-thyroid axis functionwould seem altered in FMS patients as the releaseof thyrotropin-releasing hormone stimulates lessthyrotropin, triiodothyronine and thyroxin productionthan normal. This is possibly the result of somepituitary dysfunction secondary to the documentedimpaired stress response in FMS (87).The hypothalamic-pituitary-gonadal axis(HPG-axis)Though not many studies have been performed inthis area, the results of those available so far provideno evidence for any abnormality in gonadotropinsecretion or gonadal steroid levels inFMS (88, 89). Thus a deficit of sex hormones doesnot appear to be part of the manifestations of FMS.Growth hormone (GH)A number of research studies have been devoted toevaluation of circulating levels of growth hormonein FMS. These levels tend to be normal duringwaking hours and are slightly reduced during sleep.It is well known that stage 4 of sleep is disruptedin FMS, and this is the phase when GH is secreted;it remains to be established if the decreasedGH is the consequence of disrupted sleep or of adecreased GH-stimulation by sleep. FMS patientshave increased levels of corticotrophin, and corticotrophinincreases hypothalamic somatostatin secretion.Since somatostatin is one of the hormonesthat inhibits GH via the hypothalamic-pituitary portalsystem this may also contribute to their relativeGH insufficiency. Supplementation with GH hasprovided relatively positive results, at least in asubpopulation of FMS patients; however, the highcosts of the hormone, combined with the unpleasantnessof the modality of administration do not encouragethe use of this therapy on a large scale(90).FMS patients have been shown to present withmany neurochemical alterations, e.g., norepinephrinedeficit, lower concentrations of beta-endorphinin peripheral blood mononuclear cells (91), lowserum serotonin levels and low level of the serotoninmetabolite (5-HIAA) (92) in the CSF, increasedlevels of substance P and nerve growth factor(NGF) - a promoter of substance P synthesis -in CSF (93, 94), abnormal dopaminergic transmission.Regarding the latter, a recent review by Wood(95) focused on the mesolimbic dopaminergic systemas a possible contributor to central pain states;in animals acute stress activates mesolimbicdopamine neurons inducing analgesia; however,prolonged stress decreases mesolimbic dopaminergicoutput and creates a hyperalgesic state. A recentstudy by Malt et al (96) compared the responseof female patients with FMS and healthy controlsto buspirone, showing an increased prolactin responsein the FMS group, a result that was attributedby the researchers to altered dopamine sensitivityin FMS.

Etiopathogenetic mechanisms of Fibromyalgia Syndrome 31Collectively, these neurotransmitter abnormalitiesmay play a role in HPA function and control in FMS(97).To date, however, the means by which HPA axisdysfunction develops in FMS still remains unclear.Autonomic nervous system (ANS)amplificationThe ANS is the principal regulatory system of thebody; it maintains essential involuntary functions,e.g., the vital signs (blood pressure, pulse, respiration,and temperature) and balances the function ofall internal organs. It is a complex network activatedby nerve centers located in the spinal cord,brain stem, hypothalamus and thalamus; centersthat also receive input from the limbic area andother higher brain regions.Emotions such as fear or anger, therefore, produceimmediate biological responses, such as pupil dilatationor tachycardia. Through their neurotransmitters(catecholamines for the sympathetic system),the two divisions of the peripheral autonomicsystem, sympathetic and parasympathetic, haveantagonistic actions on most functions of the body,but their proper balance is essential to preservehomeostasis (98).A number of studies have demonstrated alterationsof the ANS in FMS, the most recent ones usingmethodologies such as power spectrum analysis ofheart rate variability (HRV) and tilt table test.Vaeroy, et al. (99) demonstrated a decreased sympatheticresponse to painful and auditory stimuli.Studies with power spectrum analysis of HRVshowed decreased 24-h HRV with persistent nocturnalsympathetic hyperactivity associated withincreased number of awakenings, decreased sympatheticresponse to several stressors and abnormalsympathovagal responses during postural changes.The HRV studies reflect a basal autonomic state ofhyperactivation characterized by increased sympatheticand decreased parasympathetic tone (i.e., asympathetic basal hyperactivity with hyporeactivity)(100, 101). Abnormal HRV in FMS, consistentwith excessive sympathetic activity, especially inwomen, has been reported by several investigators(99). In a recent study, Furlan, et al. (102) investigatedwhether FMS is characterized by alterationsin the cardiovascular autonomic response to gravitationalstimulus (using the stepwise tilting); theyfound a reduced ability to enhance the sympatheticactivity to the vessels and withdraw the vagalmodulation to the sino-atrial node.The dysautonomia in FMS would thus be characterizedas a sympathetic nervous system that ispersistently hyperactive but is hyporeactive tostress. This apparent paradox (sympathetic hyperactivitywith hyporeactivity) nevertheless agreeswith the basic physiological principle showing thatchronic hyperstimulation of the beta-adrenergicreceptors leads to receptor desensitization anddown-regulation (99). It has been suggested thatthe dysautonomia in FMS could be at least in partresponsible for the pain of the syndrome - similarlyto what happens in classic sympathetic-maintainedpain conditions.ANS dysfunction may also explain a number ofthe other clinical symptoms of FMS. Due to a ceilingeffect, the hyperactive sympathetic nervoussystem in FMS would become unable to further respondto different stressors, thus explaining theconstant fatigue and morning stiffness. Relentlesssympathetic hyperactivity may explain sleep disorders,anxiety, pseudo-Raynaud’s phenomenon,sicca symptoms, and intestinal irritability.Further studies support the altered sympatheticfunction in FMS. Anderberg, et al. (103) foundhigh serum levels of neuropeptide Y (NPY) in FMSvs healthy controls, which was interpreted as a signof increased sympathetic activity (prolonged and/orrepeated stress) since NPY is co-released with noradrenalinefrom sympathetic neurons. Wallace, etal. (104) showed high serum concentrations of IL-8 in FMS vs healthy controls, another interestingfinding since IL-8 has been associated with sympatheticallydependent hyperalgesia. Along thesame line, Martinez-Lavin (98) showed that a subcutaneousinjection of noradrenaline induced painmore frequently and with a higher intensity in FMSpatients vs RA patients or vs healthy controls.The HPA axis and the ANS have multiple sites ofinteraction. At present it is not clear if decreasedANS activity and altered neuroendocrine functionmay contribute to the pain and related symptomsof the syndrome or if they are the consequence ofpain.It is frequent for FMS patients to present a historyof emotional or physical trauma before the onset ofFMS symptoms (105). Stress is known to reduce theneuroendocrine and ANS stress response; therefore,stressful events may represent the triggering factorfor the neuroendocrine and ANS abnormality inFMS. However, it is also possible that the symptomsof FMS (pain, sleep disturbance, fatigue, etc.), experiencedon a chronic basis, may affect the functionof the HPA axis and ASN. As a matter of fact,a number of studies have shown that a reduction of

32 S. Stisi et al.stress, obtained, for instance, through relaxationtraining or exercise training, produces a decrease inthe sympathetic activity (as evaluated via spectralanalysis, resting heart rate, circulating levels of catecholamines).Pain may also explain the reduced neuroendocrineand ANS responsiveness since there is a high levelof substance P in the CSF in FMS, and substance Pis a potent inhibitor of CRH.CONCLUSIONSUnderstanding of pathogenetic pathways in FMShas advanced from observing patient responses toneurophysiologically targeted therapies and basicresearch. The model of central sensitization representsthe most common and most accepted hypothesesabout the underlying mechanisms in thepathogenesis of FMS.SUMMARYFibromyalgia syndrome (FMS) is a common chronic condition of widespread pain with causal mechanisms that are largelyunknown. It is characterized by moderate to severe musculoskeletal pain and allodynia, but its pathogenesis appearsconfined to the nociceptive structures of the central nervous system. FMS is often triggered by negative environmentalinfluences, especially if they occur in childhood. In a fetus, these environmental triggers may influence the developmentof the autonomic nervous system (ANS) and the hypothalamic-pituitary-adrenal axis (HPA). Increasing evidence supportsthe comorbidity of psychological conditions including depression, panic disorders, anxiety, and post-traumaticstress disorder (PTSD). Recent evidence suggests that genetic factors may play a role in the pathogenesis of FMS. Centralsensitization has long been associated with FMS pain. It describes enhanced excitability of dorsal horn neurons, whichleads to transmission of altered nociceptive information to the brain. Understanding of pathogenetic pathways in FMShas advanced beyond observing patient responses to neurophysiologically targeted therapies and basic research.Key words - Central sensitization, neuroendocrine abnormalities, genetic factors, autonomic nervous system.Parole chiave - Sensibilizzazione centrale, alterazioni neuroendocrine, fattori genetici, alterazioni del sistema nervoso.REFERENCES1. Sarnoch H, Adler F, Scholz OB. Relevance of muscularsensitivity, muscular activity, and cognitive variablesfor pain reduction associated with EMG feedbackin fibromyalgia. Percept Mot Skills 1997; 84:1043-50.2. Jacobsen S, Petersen IS, Danneskiold-Samsoe B.Clinical features in patients with chronic muscle painwith special reference to fibromyalgia. Scand JRheumatol 1993; 22: 69-76.3. Kajantie E. Fetal origins of stress-related adult disease.Ann NY Acad Sci 2006; 1083: 11-27.4. Phillips DI and Jones A. Fetal programming of autonomicand HPA function: do people who were smallbabies have enhanced stress response? J Phisiol 2006;572: 45-50.5. McBeth J, Morris S, Benjamin S, Silman AJ, MacfarlaneGJ. Associations between adverse events inchildhood and chronic widespread pain in adulthood:are they explained by differential recall? J Rheumatol2001; 28: 2305-9.6. Imbierowicz K, Egle UT. Childhood adversities inpatients with fibromyalgia and somatoform pain disorder.Eur J Pain 2003; 7: 113-9.7. Crofford LJ. Violence, stress, and somatic syndromes.Trauma Violence Abuse 2007; 8: 299-313.8. Ablin JN, Shoenfeld Y, Buskila D. Fibromyalgia, infectionand vaccination: two more parts in the etiologicalpuzzle. J Autoimmun 2006; 27: 145-52.9. Goldenberg DL: Do infections trigger fibromyalgia?(editorial). Arthritis Rheum 1993; 36: 1489-92.10. Cruz BA, Catalan-Soares B, Proietti F. Higher prevalenceof fibromyalgia in patients infected with humanT cell lymphotropic virus type I. J Rheumatol 2006;33: 2300-3.11. Moldofsky H, Scarisbrick P, England R, Smythe H.Musculoskeletal symptoms and non-REM sleep disturbancein patients with “fibrositis syndrome” andhealthy subjects. Psychosom Med 1975; 47: 341-51.12. Lavigne G, Brousseau M, Kato T Mayer P, ManziniC, Guitard F, et al. Experimental pain perception remainsequally active over all sleep stages. Pain 2004;110: 646-55.13. Burckhardt CS, Clark SR, Campbell SM, O’ReillyCA and Bennett RM. Events and comorbidities associatedwith the onset of fibromyalgia. J MusculoskelPain 1995; 3: 71.14. Kosek E and Ordeberg G. Abnormalities of somatosensoryperception in patients with painful osteoarthritisnormalize following successful treatment.Eur J Pain 2000; 4: 229-38.15. McBeth J and Silman AJ. The role of psychiatric disordersin fibromyalgia. Curr Rheumatol Reports 2001;3: 157-64.16. Bell IR, Baldwin CM, Schwartz GE. Illness from low

Etiopathogenetic mechanisms of Fibromyalgia Syndrome 33levels of environmental chemicals: relevance to chronicfatigue syndrome and fibromyalgia. Am J Med1998; 105: 74S-82S.17. Vasey FB, Zarabadi SA, Seleznick M, Ricca L. Wherethere’s smoke there’s fire: the silicone breast implantcontroversy continues to flicker: a new disease thatneeds to be defined. J Rheumatol 2003; 2092-4.18. Gracely RH, Geisser ME, Giesecke T, Grant MA,Petzke F, Williams DA, Clauw DJ. Pain catastrophizingand neural responses to pain among personswith fibromyalgia. Brain 2004; 127: 835-43.19. Buskila D, Cohen H. Comorbidity of fibromyalgiaand psychiatric disorders. Curr Pain Headache Rep2007; 11: 333-8.20. Hazlett DJ, Haines SN. Fibromyalgia: a time seriesanalysis of the stressor-physical symptom association.J Behav Med 1992; 15: 541-8.21. Kosek E, Fibromyalgia. In: F Cervero and TS Jensen(Eds), Handbook of Clinical Neurology, Vol 81 (3 rdseries), Elsevier, Edinburgh, London, New York, Oxford,Philadelphia, St Louis, Sydney, Toronto, 2006;763-77.22. Buskila D, Neumann L. Genetics of fibromyalgia.Curr Pain Headache Rep 2005; 9: 313-5.23. Buskila D, Neumann L, Press J. Genetic factors inneuromuscular pain. CNS Spectr 2005; 10: 281-4.24. Buskila D, Sarzi Puttini P. Genetic aspects of fibromyalgiasyndrome. Arthr Res Ther 2006; 8: 218-25.25. Clauw DJ, Crofford LJ. Chronic widewspread painand fibromyalgia, what we know and what we needto know. Best Pract Res Clin Rheumatol 2003; 17:685-701.26. Buskila D, Neumann L, Hazanov I, Carmi R. Familialaggregation in the fibromyalgia syndrome. SeminArthritis Rheum 1996; 26: 605-11.27. Buskila D, Neumann L. Fibromyalgia Syndrome(FM) and nonarticular tenderness in relatives of patientswith FM. J Rheumatol 1997; 24: 941-4.28. Arnold LM, Hudson J, Hess EV, Ware AE, Fritz DA,Auchenbach MB, et al. Family study of fibromyalgia.Arthritis Rheum 2004; 50: 944-52.29. Offenbaecher M, Bondy B, de Jong S, Glalzender K,Kruger M, Schoeps P, Ackenheil M. Possible associationof fibromyalgia with a polymorphism in the regulatoryregion. Arthritis Rheum 1999; 42: 2482-8.30. Bondy B, Spaeth M, Offenbaecher M, Glatzeder K,Stratz T, Schwarz M, et al. The T 102 C polymorphismof the 5-HT2A receptor gene in fibromyalgia.Neurobiol Dis 1999; 6: 433-39.31. Cohen H, Buskila D, Neumann L, Ebstein RP. Confirmationof an association between fibromyalgia andserotonin transporter promoter region (5-HTTLPR)polymorphism and relationship to anxiety related personalitytraits. Arthritis Rheum 2002; 46: 845-7.32. Zubieta JK, Heitzeg M, Smith YR. COMT Val 158Met genotype affects mu-opioid neurotransmitter responsesto a pain stressor. Science 299; 5610: 1240-3.33. Gursoy S, Erdal E, Herken H, Ma denci E, Ala B,Erdal N. Significance of catechol - O - methyl - transferasegene polymorphism in fibromyalgia syndrome.Rheumatol Int 2003; 23: 104-7.34. Vargas - Alarcon G, Fragosos JM, Gruz - Robeles D,Vergas A, Lao - Villadoniga JI, Garcia - Fructuoso F.Catechol - O - methyltransferase gene haplotypes inMexican and Spanish patients with fibromyalgia.Arthritis Res Ther 2007; 9: R 110.35. Buskila D, Cohen H, Neumann L, Ebstein RP. An associationbetween fibromyalgia and the dopamine D4receptor exon III repeat polymorphism and relationshipto personality traits. Mol Psychiatry 2004; 9: 730-1.36. Yunus MB. Towards a model of pathophysiology offibromyalgia: aberrant central pain mechanisms withperipheral modulation. J Rheumatol 1992; 19: 846-50.37. Staud R, Vierck CJ, Cannon RL, Mauderli AP, PriceDD. Abnormal sensitization and temporal summationof second pain (wind-up) in patients with fibromyalgiasyndrome. Pain 2001; 91: 165-75.38. Li J, Simone DA, Larson AA. Windup leads to characteristicsof central sensitization. Pain 1999; 79: 75-82.39. Schadrack J, Zieglgänsberger W. Activity-dependentchanges in the pain matrix. Scand J Rheumatol 2000;113: 19-23.40. Sorensen J, Graven-Nielsen T, Henriksson KG,Bengtsson M, Arendt-Nielsen L. Hyperexcitability infibromyalgia. J Rheumatol 1998; 25: 152-5.41. Zieglgansberger W, Herz A. Changes of cutaneous receptivefields of spino-cervical-tract neurones and otherdorsal horn neurones by microelectrophoreticallyadministered amino acids. Experimental Brain Research1971; 13: 111-26.42. Davies SN, Lodge D. Evidence for involvement of N-methylaspartate receptors in ‘wind-up’ of class 2 neuronesin the dorsal horn of the rat. Brain Res 1987;424: 402-6.43. Dickenson AH. Spinal cord pharmacology of pain.Br J Anaesth 1995; 75: 193-200.44. Dickenson AH, Sullivan AF. Evidence for a role ofthe NMDA receptor in the frequency dependent potentiationof deep rat dorsal horn nociceptive neuronesfollowing C fibre stimulation. Neuropharmacology1987; 26: 1235-8.45. Staud R, Domingo M. Evidence for abnormal painprocessing in fibromyalgia syndrome. Pain Med 2001;2: 208-15.46. Gebhart GF. Descending modulation of pain. NeurosciBiobehav Rev 2004; 27: 729-37.47. Kosek E, Hansson P. Modulatory influence on somatosensoryperception from vibration and heterotopicnoxious conditioning stimulation (HNCS) in fibromyalgiapatients and healthy subjects. Pain 1997;70: 41-51.48. Kranzler JD, Gendreau JF, Rao SG. The psychopharmacologyof fibromyalgia: a drug development perspective.Psychopharmacol Bull 2002; 36: 165-213.49. Mense S. Neurobiological concepts of fibromyalgia -the possible role of descending spinal tracts. Scand JRheumatol 2000; 29: 24-9.

34 S. Stisi et al.50. Harris RE, Clauw DJ, Scott DJ, McLean SA, GracelyRH, Zubieta JK. Decreased central mu-opioid receptoravailability in fibromyalgia. J Neurosci 2007;27: 10000-6.51. Gracely RH, Geisser ME, Giesecke T, Grant MA,Petzke F, Williams DA, Clauw DJ. Pain catastrophizingand neural responses to pain among personswith fibromyalgia. Brain 2004; 127: 835-43.52. Hrycaj P, Stratz T, Muller W. Platelet 3H-imipramineuptake receptor density and serum serotonin levels inpatients with fibromyalgia/fibrositis syndrome. JRheumatol 1993; 20: 1986-8.53. Yunus MB, Dailey JW, Aldag JC, Masi AT, Jobe PC.Plasma tryptophan and other amino acids in primaryfibromyalgia: a controlled study. J Rheumatol 1992;19: 90-4.54. Moldofsky H. Sleep and musculoskeletal pain. Am JMed 1986; 81: 85-9.55. Russell IJ. Neurochemical pathogenesis of fibromyalgia.Z Rheumatol 1998; 57: 63-6.56. Russell IJ, Michalek JE, Vipraio GA, Fletcher EM,Wall K. Serum amino acids in fibrositis/fibromyalgiasyndrome. J Rheumatol 1989; 19: 158-63.57. Russell IJ, Vaeroy H, Javors M, Nyberg F. Cerebrospinalfluid biogenic amine metabolites in fibromyalgia/fibrositissyndrome and rheumatoid arthritis.Arthritis Rheum 1992; 35: 550-6.58. Legangneux E, Mora JJ, Spreux-Varoquaux O, ThorinI, Herrou M, Alvado G, et al. Cerebrospinal fluid biogenicamine metabolites, plasma-rich platelet serotoninand [3H]imipramine reuptake in the primary fibromyalgiasyndrome. Rheumatology (Oxford) 2001;40: 290-6.59. Ernberg M, Voog U, Alstergren P, Lundeberg T,Kopp S. Plasma and serum serotonin levels and theirrelationship to orofacial pain and anxiety in fibromyalgia.J Orofac Pain 2000; 14: 37-46.60. Murphy RM, Zemlan FP. Differential effects ofsubstance P on serotonin-modulated spinal nociceptivereflexes. Psychopharmacology (Berl) 1987;93: 118-21.61. Bradley LA, Alberts KR, Alarcon GS. Abnormalbrain regional cerebral blood flow (rCBF) and cerebrospinalfluid (CSF) levels of substance P (SP) in patientsand non-patients with fibromyalgia (FM).Arthritis Rheum [abstract] 1996; 39: 212.62. Russell IJ, Orr MD, Littman B, Vipraio GA, AlboukrekD, Michalek JE, et al. Elevated cerebrospinalfluid levels of substance P in patients with the fibromyalgiasyndrome. Arthritis Rheum 1994; 37:1593-601.63. Vaeroy H, Helle R, Forre O, Kass E, Terenius L. ElevatedCSF levels of substance P and high incidenceof Raynaud phenomenon in patients with fibromyalgia:new features for diagnosis. Pain 1988; 32: 21-6.64. Welin M, Bragee B, Nyberg F, Kristiansson M. Elevatedsubstance P levels are contrasted by a decreaseinmetenkephalin-ARG-PHE levels in CSF from fibromyalgiapatients. J Musculoske Pain 1995; 3: 4.65. Russell IJ. Advances in fibromyalgia: possible role forcentral neurochemicals. Am J Med Sci 1998; 315:377-84.66. Almay BG, Johansson F, Von Knorring L, Le GrevesP, Terenius L. Substance P in CSF of patients withchronic pain syndromes. Pain 1988; 33: 3-9.67. Fischer HP, Eich W, Russell IJ. A possible role forsaliva as a diagnostic fluid in patients with chronicpain. Semin Arthritis Rheum 1998; 27: 348-59.68. Sjostrom S, Tamsen A, Hartvig P, Folkesson R, TereniusL. Cerebrospinal fluid concentrations of substanceP and (met)enkephalin-Arg6-Phe7 duringsurgery and patient-controlled analgesia. AnesthAnalg 1988; 67: 976-81.69. Tsigos C, Diemel LT, White A, Tomlinson DR,Young RJ. Cerebrospinal fluid levels of substance Pand calcitonin-gene-related peptide: correlation withsural nerve levels and neuropathic signs in sensory diabeticpolyneuropathy. Clin Sci (Lond) 1993; 84: 305-11.70. Schwarz MJ, Späth M, Müller-Bardorff H, PongratzDE, Bondy B, Ackenheil M. Relationship of substanceP, 5-hydroxyindole acetic acid and tryptophanin serum of fibromyalgia patients. Neuroscience Letters1999; 259: 196-8.71. Giovengo SL, Russell IJ, Larson AA. Increased concentrationsof nerve growth factor in cerebrospinalfluid of patients with fibromyalgia. J Rheumatol 1999;26: 1564-9.72. Giesecke T, Williams DA, Harris RE, Cupps TR, TianX, Tian TX, et al. Subgrouping of fibromyalgia patientson the basis of pressure-pain thresholds andpsychological factors. Arthritis Rheum 2003; 48:2916-22.73. Muller W, Schneider EM, Stratz T. The classificationof fibromyalgia syndrome. Rheumatol Int 2007; 27:1005-10.74. Turk DC, Okifuji A, Sinclair JD, Starz TW. Pain, disability,and physical functioning in subgroups of patientswith fibromyalgia. J Rheumatol 1996; 23: 1255-62.75. Stisi S, Venditti C, Sarracco I, Prevalenza di stressorspercepiti in pazienti con fibromialgia primaria. Progressiin Reumatologia Clinica 2007; 1 (Suppl. 1):67.76. Dessein PH, Shipton EA, Stanwix AE, Joffe BI. Neuroendocrinedeficiency-mediated development andpersistence of pain in fibromyalgia: a promising paradigm.Pain 2000; 86:213-5.77. Martinez-Lavin M. Biology and therapy of fibromyalgia.Stress, the stress response system and fibromyalgia,Arthritis Res Ther 2007; 9: 216-25.78. Riedel W, Schlapp U, Leck S, Netter P, Neeck G.Blunted ACTH and cortisol responses to systemic injectionof corticotropine-releasing hormone (CRH) infibromyalgia. Ann NY Acad Sci 2002; 966: 483-90.79. Tsigos C, Chrousos GP. Hypothalamic-pituitaryadrenalaxis, neuroendocrine factors and stress. J PsychosomRes 2002; 53: 865-71.80. Wingenfeld K, Wagner D, Schmidt I, MeinlschmidtG, Hellhammer DH, Hein C. The low-dose dexam-

Etiopathogenetic mechanisms of Fibromyalgia Syndrome 35ethasone suppression test in fibromyalgia. J PsychosomRes 2007; 62: 85-91.81. Crofford LJ. Neuroendocrine abnormalities in fibromyalgiaand related disorders. Am J Med Sci 1998;315: 359-66.82. Tanriverdi F, Karaca Z, Unluhizarci K, Kelestimur F.The hypothalamo-pituitary-adrenal axis in chronic fatiguesyndrome and fibromyalgia syndrome. Stress2007; 10: 13-25.83. Sarzi-Puttini P, Atzeni F, Diana A, Doria A, FurlanR. Increased Neural sympathetic activation in fibromyalgiasyndrome. Ann NY Acad Sci 2006; 1069:109-17.84. McLean SA, Williams DA, Stein PK, Harris RE, LydenAK, Whalen G, et al. Cerebrospinal fluid corticotropin-releasingfactor concentration is associatedwith pain but not fatigue symptoms in patients withfibromyalgia. Neuropsychopharmacology 2006; 31:2776-82.85. Lariviere WR, Melzack R. The role of corticotrophinreleasingfactor in pain and analgesia. Pain 2000; 84:1-14.86. Abeles AM, Pillinger MH, Solitar BM, Abeles M.Narrative Review: The Pathophysiology of Fibromyalgia.Ann Int Med 2007; 146: 726-34.87. Neeck G. Thyroid function in patients with fibromyalgiasyndrome. J Rheumatol 1992; 19: 1120-2.88. Korszun A, Young EA, Engleberg NC, Masterson L,Dawson EC, Spindler K, et al. Follicular phase hypothalamicpituitary-gonadal axis function in womenwith fibromyalgia and chronic fatigue syndrome. JRheumatol 2000; 27: 1526-30.89. Samborski W, Sobieska M, Pieta P, Drews K, BrzoskoM. Normal profile of sex hormones in womenwith primary fibromyalgia. Ann Acad Med Stetin2005; 51: 23-6.90. Jones KD, Deodhar P, Lorentzen A, Bennett RM, DeodharAA. Growth hormone perturbations in fibromyalgia:a review. Semin Arthritis Rheum 2007;36: 357-79.91. Panerai A, Vecchiet J, Panzeri P, Meroni PL, ScaroneS, Pizzigallo E, et al. Peripheral Blood MononuclearCell [beta]-Endorphin Concentration Is Decreased inChronic Fatigue Syndrome and Fibromyalgia but Notin Depression: Preliminary report. Clin J Pain 2002;18: 270-3.92. Russell IJ, Vaeroy H, Javors M, Nyberg F. Cerebrospinalfluid biogenic amine metabolites in fibromyalgia/fibrositissyndrome and rheumatoid arthritis.Arthritis Rheum 1992; 5: 550-6.93. Giovengo S, Russell I, Larson A. Increased concentrationof nerve growth factor in cerebrospinal fluid ofpatients with fibromyalgia. J Rheumatol 1999; 26:1564-9.94. Russell IJ. The promise of substance P inhibitors infibromyalgia. Rheum Dis Clin N Am 2002; 28: 329-42.95. Wood PB. Stress and dopamine: implications for thepathophysiology of chronic widespread pain. MedHypotheses 2004; 62: 420-4.96. Malt EA, Olafsson S, Aakvaag A, Lund A, Ursin H.Altered dopamine D2 receptor function in fibromyalgiapatients: a neuroendocrine study with buspirone inwomen with fibromyalgia compared to female populationbased controls. J Affect Disord 2003; 75: 77-82.97. Buskila D, Press J. Neuroendocrine mechanisms in fibromyalgia-chronicfatigue. Best Pract Res ClinRheumatol 2001; 15: 747-75.98. Martinez-Lavin M. Biology and therapy of fibromyalgia.Stress, the stress response system and fibromyalgia,Arthritis Res Ther 2007; 9: 216.99. Vaeroy H, Qiao Z-G, Morkrid L, Forre O. Alteredsympathetic nervous system response in patients withfibromyalgia (Fibrositis syndrome). J Rheumatol1989; 16: 1460-5.100. Cohen H, Neumann L, Kotler M, Buskila D. Autonomicnervous system derangement in fibromyalgiasyndrome and related disorders. IMAJ 2001; 3:755-60.101. Kooh M, Martinez-Lvin M, Meza S, Martin-del-CampoA, Hermosillo AG, Pineda C, Nava A, Amigo MC,Drucker-Colin R. Concurrent heart rate variability andpolysomnography analyses in fibromyalgia patients.Clin Exp Rheumatol 2003; 21: 529-30.102. Furlan R, Colombo S, Perego F, Atzeni F, Diana A,Barbic F, Porta A, et al. Abnormalities of cardiovascularneural control and reduced orthostatic tolerancein patients with primary fibromyalgia. J Rheumatol2005; 32: 1787-93.103. Anderberg UM, Liu Z, Berglund L, Nyberg F. Elevatedplasma levels of neuropeptide Y in female fibromyalgiasyndrome patients. Eur J Pain 1999; 3:19-30.104. Wallace D, Linker-Israeli M, Hallegua D, SilvermanS, Silver D, Weisman M. Cytokines play an aetiopathogeneticrole in fibromyalgia: a hypothesis andpilot study. Rheumatology 2001; 40: 743-9.105. Abeles AM, Pillinger MH, Solitar BM, Abeles M.Narrative Review: The Pathophysiology of Fibromyalgia.Ann Int Med 2007; 146: 726-34.106. Van Houdenhovea B, Egle U.T. - Fibromyalgia: astress disorder? - Psychother Psychosom 2004; 73:267-75.

ORIGINAL ARTICLEReumatismo, 2008; 60: Supplemento 1: 36-49The evaluation of the fibromyalgia patientsLa valutazione del paziente fibromialgicoF. Atzeni 1 , F. Salaffi 2 , L. Bazzichi 3 , R.H. Gracely 4 , R. Carignola 5 , R. Torta 6 , R. Gorla 7 , A. Marsico 8 ,F. Ceccherelli 9 , M. Cazzola 10 , D. Buskila 11 , M. Spath 12 , M. Di Franco 13 , G. Biasi 14 , G. Cassisi 15 ,S. Stisi 16 , R. Casale 17 , L. Altomonte 18 , G. Arioli 19 , A. Alciati 20 , G. Leardini 21 , F. Marinangeli 22 ,M.A. Giamberardino 23 , P. Sarzi-Puttini 1 (Italian Fibromyalgia Network)1Rheumatology Unit, L. Sacco University Hospital, Milan, Italy; 2 Department of Rheumatology, Polytechnic University of the MarcheRegion, Ancona, Italy; 3 Department of Internal Medicine, Division of Rheumatology, S. Chiara Hospital, University of Pisa, Italy;4Department of Medicine, University of Michigan Health System, Ann Arbor, Michigan, USA; 5 Department of Neuroscience, Universityof Turin, A.S.O. San Giovanni Battista of Turin, Turin, Italy; 6 Department of Neuroscience, University of Turin, A.S.O. San GiovanniBattista of Turin, Turin, Italy; 7 Rheumatology and Clinical Immunology, Spedali Civili and University of Brescia, Italy; 8 RheumatologyUnit, Hospital of Taranto, Taranto, Italy; 9 IOV (Veneto Cancer Institute), IRCCS, Department of Pharmacology and Anesthesiology,University of Padua, Italy; 10 Unit of Rehabilitative Medicine “Hospital of Circolo”, Saronno (VA), Italy; 11 Department of Medicine H,Soroka Medical Center and Faculty of Health Sciences, Ben Gurion University, Beer Sheva, Israel; 12 Friedrich-Baur-Institute,University of Munich, Munich, Germany; 13 Chair of Rheumatology, University la Sapienza Rome, Rome, Italy; 14 Unit of Rheumatology,University of Siena, Siena, Italy; 15 Rheumatology Branch, Specialist Outpatients’ Department, Belluno, Italy; 16 Rheumatology Unit,“G.Rummo” Hospital, Benevento, Italy; 17 Department of Clinical Neurophysiology and Pain Rehabilitation Unit, Foundation SalvatoreMaugeri, IRCCS, Scientific Institute of Montescano, Montescano (PV), Italy; 18 UOC of Rheumatology Hospital S. Eugenio, Rome, Italy;19Division of Rehabilitative Medicine and Rheumatology, General Hospital of Pieve di Coriano (Mantua), Italy;20Department of Psychiatry, L. Sacco University Hospital, Milan, Italy; 21 Rheumatology Unit, SS Giovanni e Paolo Hospital, Venice,Venice, Italy; 22 Department of Anesthesiology and Pain Medicine, L'Aquila University, L’Aquila, Italy;23Ce.S.I. “G. D’Annunzio” Foundation, Department of Medicine and Science of Aging, “G. D’Annunzio”, University of Chieti, ItalyCompeting interests: none declaredRIASSUNTOLa sindrome fibromialgica (FM) è una condizione di frequente riscontro nella pratica clinica caratterizzata da doloremuscoloscheletrico cronico e diffuso, sensazione di tensione e/o di rigidità muscolare e articolare, affatticabilità,disturbi del sonno, alterazioni del tono dell’umore e dolore alla digitopressione di almeno 11/18 tender points (TPs).Fino ad oggi, non disponiamo né di esami strumentali né di marcatori specifici per effettuare la diagnosi di FM; infatti,la maggior parte degli esami attualmente disponibili sono utili solo ai fini di ricerca. La maggior parte delle diagnosidifferenziali può essere effettuata mediante un accurato esame clinico e anamnestico. Se consideriamo il possibileoverlap tra la FM ed altre malattie, il medico curante dovrebbe sottoporre tutti i pazienti con sospetta FM a radiografiadel torace ed ecografia dell’addome, oltre ad un accurato esame obiettivo. La risonanza magnetica funzionaleha messo in evidenza diverse alterazioni sovraspinali nei pazienti affetti da FM, una condizione clinica a patogenesisconosciuta. Nei pazienti affetti da FM sono diversi i trattamenti utilizzati, ma valutarne il loro effetto è difficilepoiché questa sindrome presenta molteplici aspetti. Al fine di identificare un “core outcome domains”, l’iniziativadell’ IMMPACT e il workshop OMERACT ha convocato un meeting per sviluppare le raccomandazioni utili per itrials clinici sul dolore cronico.Reumatismo, 2008; 60: Supplemento 1: 36-49Corresponding author:Fabiola Atzeni, MD, PhDRheumatology UnitL. Sacco Hospital, Milan, ItalyE-mail atzenifabiola@hotmail.comINTRODUCTIONFibromyalgia (FM) is a rheumatic disease characterizedby musculoskeletal pain, chronic diffusetension and/or stiffness from joints and muscles,easy fatigue, sleep and emotional disturbances,and pressure pain sensitivity in at least 11 of 18 tenderpoints (TP) (1, 2). This disease has an incidenceof 2% in the general population, but it is found moreoften in middle-aged women (3.4%) (3, 4). Theetiopathogenesis of FM has not been clarified yet.FM patients have a dysregulation of pain neurotransmittersand neurohormone-mediated associationwith irregularities in the physiology of sleep.The American College of Rheumatology (ACR)

The evaluation of the fibromyalgia patients 37SerumCompared to healthy subjects or patients with otherdiseases, FM patients present with high antipolymerantibodies (APA) (12) and antiserotoninantibody (13) values, with contrasting results inthe Italian population. The APA positivity in a recentwork appears to be less than that evidenced inthe USA, and it appears to correlate with the severityof the disease; this result could be due to a differentethnic origin of the populations studied. Otherantibodies (antiganglioside and antiphospholipids)were identified in FM patients compared tohealthy subjects, but the sensitivity and specificitywas not clear. Patients with FM have a higher frequencyof anti-thyroid antibodies, and their valuesseem to be correlated with the presence of certainsymptoms (14). Recent studies have shown higherhyaluronic acid values in FM patients compared tohealthy controls, but this data has not been confirmed(15, 16). Alterations of branched-chainamino acids (valine, leucine, isoleucine), phenycriteriadiagnostic criteria for FM are based uponchronic widespread pain and tenderness in 11 of 18defined muscular sites (1). Recent evidence suggeststhat the tenderness component of FM is notconfined to these sites; rather, it is present throughoutthe body, including non-muscular sites such asthe thumb. The widespread nature of spontaneouspain in FM implicates general mechanisms that mayinvolve spinal or supraspinal modulation of normalperipheral input, or effector mechanisms that alterpain sensitivity at the periphery. These mechanismsare likely observed at supraspinal sites. Functionalneuroimaging of the brain has opened a window intothe supraspinal processes in health and disease(5). With a few exceptions, these methods inferneural activity in the brain by changes in regionalcerebral blood flow (rCBF). This inference is basedon the principle that localized brain activity signalsa discreet increase in rCBF to meet the metabolicdemands of this increase in neural activity. The increasein rCBF occurs after a hemodynamic delayof a few seconds and is closely coupled to the magnitudeand duration of the activity. Most functionalimaging methods are based on the evaluation ofthe time course of changes in rCBF throughout thebrain (6).The absence of anatomopathological lesions andbiohumoral abnormalities, demonstrated with classicalinstrumental methods, has led to considerabledifficulties in diagnosis. The diagnostic criteria frequentlyoverlap with those of other diseases; infact, some patients with chronic fatigue syndrome(CFS) meet the criteria for FM, and an FM-likeframework may be present even in non-rheumaticdiseases.For example, patients with hypothyroidism showmusculoskeletal pain that is similar FM. The diagnosisbased on the ACR criteria, therefore, must beaccompanied by the exclusion of diseases that havesymptoms, but not causes, in common with FM asevidenced by the evaluation of markers and humoralscans (miositis, rheumatic polmyalgia,spondyloarthritis, etc.) (7). Often, FM is comorbidwith other diseases that act as confounding and aggravatingfactors (Sjögren, systemic lupus eriythematosus(SLE), rheumtoid arthritis (RA), thyroiddisease). There are no instrumental tests to confirmthe diagnosis of FM; and many differential diagnosesmay be excluded by an extensive clinicalexamination and patient history. Considering theoverlap of FM with other medical conditions, treatingphysicians should be vigilant: chest-X-rays andabdominal ultrasonography are the first steps to-ward general evaluation of all patients with suspectedFM. An individualized, multidisciplinaryrange of treatments should be employed to treatthe various symptoms that patients experience. Althoughsome of these therapies have been tested inrandomized controlled trials (RCT), there has beenlittle standardization in the approach to these trialsand in the outcome measures used. Evaluating therapeuticeffects in FM patients is difficult becauseof the many facets of the syndrome. To address theidentification of core outcome domains, the Initiativeon Methods, Measurement, and Pain Assessmentin Clinical Trials (IMMPACT) (8) and OutcomeMeasures in Rheumatoid Arthritis ClinicalTrials (OMERACT) (9) workshop convened ameeting to develop consensus recommendationsfor chronic pain clinical trials.LABORATORY AND INSTRUMENTALEVALUATIONS IN PATIENTS WITH FMIn clinical studies and observational research studies,FM is usually diagnosed by application of theACR criteria (1). Moreover, diagnosis is made by acombination of patient history, physical examination,laboratory evaluations and exclusion of othercauses for symptoms attributed to FM (10, 11).BIOMARKERS IN FM

38 F. Atzeni et al.lalanine (17), and collagen cross links, and particularly,a reduction in the ratio of pyridinoline to deoxypyridinolineas well as decreased levels of hydroxipyroline(18) were also found. Neopterin hasbeen suggested as an inflammation marker, whichhas an inversely proportional relationship with L-tryptophan availability. Other studies showed lowserum levels of 5-HT in FM patients compared toboth healthy controls and patients with rheumaticdiseases such as RA. These studies provide indirectevidence supporting the alteration of 5-HT metabolismin FM subjects. In a recent study, FM patientsexhibited a tendency to have lower serotonin levelsthan patients with RA and healthy controls; butthe variation of serotonin levels within the diseasegroups is too broad to differentiate FM from otherconditions, especially depression (19). There is alsoevidence to suggest that FM patients may havealterations in the expression of 5-HT transportersdue to a transcriptional polymorphism in the regionthat could lead to an increase of the same transcriptionalregion (20). Another study has suggestedthat an alteration of the growth hormone(GH), an indirect modulator of the immune systemthat interacts with the hormonal system, seems toprotect the body from the immunosuppressive effectsof glucocorticoids during stress (21) andfavours IGF1-mediated muscle repair. Alteredserum cortisol and melatonin levels were found;these hormone secretions are closely associatedwith the circadian rhythms. The study also foundalterations of 5-HT, somatomedin C, calcitoningene-related peptide, calcitonin and cholecystokininwhich are possible indicators of FM widespreadpain (22). Studies conducted on FM patientsshowed an increase in plasma levels of IL-6 and IL-8 compared to healthy controls, an increased productionof IL-1 and TNF-alpha, and a reduced productionof IL-2 and IFN-alpha, which highlights animmune activation and a down-regulation of theHPA. A study showed an increase in plasma IL-10,IL-8 and TNF-alpha in FM patients independent ofthe presence of psychiatric comorbidity; this supportsthe hypothesis of an activation of the immunesystem (23). Abnormal levels of ACTH, 5-HT,IGF-1 and FT4 were found, which suggests an alterationof the endocrine system in this disease(14). The role of free radicals in FM is controversial,as this could suggest that FM is also an oxidativedisorder; studies have shown high levels ofmalondialdehyde, markers of oxidative damage,and low levels of superoxide dismutase, an intracellularantioxidant (24) in FM.UrineThe stress factor is probably crucial in this conditionand alterations of the urinary corticotropin-releasingfactor (CRF)-L1, catecholamine, cortisol,with the haplotypes of catecholamine COMT gene(25) were recently found; as in the serum, crosslinksof collagen, a reduction in the ratio of pyridinolineto deoxypyridinoline and decreased levels ofhydroxyproline (18) were found in the urine.Cerebrospinal fluidIn FM subjects, substance P levels increase in cerebrospinalfluid and this event leads to the releaseof IL-6. Substance P induces the production of IL-8, a pro-inflammatory cytokine, which stimulatesthe passage of neutrophils through the vascularwalls. Altered levels of serotonin and increasedcorticotropin-releasing hormone (CRH) and a poolof proteins (alpha-1-macroglobulina, keratin 16,orosomucoide, amyloid precursors etc.) were alsofound in the cerebrospinal fluid of FM patients(26). Among FM patients, pain, but not fatigue,was associated with the concentration of CRF inthe cerebrospinal fluid (27).These data support the hypothesis that abnormalitiesin the stress response are associated withFM pain. In FM subjects, a reduction of glial cellderivedneurotophic factor was also found (28);this result could be related to the role of this neurotophicfactor in preventing and reversing abnormalitiesthat develop in chronic pain conditions.Somatostatin levels appear to be reduced in thecerebrospinal fluid of FM patients and significantlycorrelated with reduced levels of neurotophicfactor.Isolated cellsAlterations of the immune cells have been studiedin FM patients, highlighting an abnormal lymphocyteand cytokine (IL-6-8-10 TNF-alpha) responserelated to FM. Specifically, the number of T lymphocytesand the immunoglobulin M level appearto be altered, and the number of natural killer cellsappears to be reduced. In FM patients, reduced activationof T lymphocytes was also found. The cellreceptors, especially the peripheral benzodiazepinereceptor (PBR), the 5-HT receptors and the 5-HTre-uptake system were altered. Studies conductedon platelets have shown a reduced receptor densityand functionality of 5-HT and its carrier, whichwere identified by lower 5-HT re-uptake rate fromthe synaptic cleft (29). Other research has shown

The evaluation of the fibromyalgia patients 39an up-regulation of PBR, also related to the severityof illness (30). In the platelets of FM patientsincreased intracellular concentrations of calciumand magnesium ions and decreased ATP levelswere also found. In a recent study (31), a comparisonwas made between FM patients, subjects withcomplex regional pain syndrome (CRPS) andhealthy controls regarding the influence of pain onsubpopulations, lymphocyte number, and the ratioof Th1 to Th2 cytokine in T lymphocytes. The lymphocytenumber did not differ between groups, butthere was a significant reduction of cytotoxic CD8+lymphocytes in FM and CRPS patients.TissuesIn skin biopsies an increase of activated mast cellshas been observed (25). It appears that muscle tissuedoes not exhibit alterations at the cellular level;and while the data appear inconsistent, inflammatoryinfiltrates have not been found. The skin ofFM patients shows unusual patterns of unmyelinatednerve fibers as well as Schwann cells; if theseresults are replicated in a larger study, these abnormalitiesmay contribute to the lower pain thresholdof FM subjects (32).INSTRUMENTAL STUDIESStudies that employ existing or innovative testingdevices or methodologies are usually negative, andthese testing methodologies are not recommendedfor purposes of screening or diagnosis (33); however,imaging tests can be used to exclude concomitantillnesses that could resemble FM.The following overview of comorbidities highlightsthe need for improved instruments for accurate assessmentof FM. Environmental factors can influenceboth the development of FM and a number of“stressors” that are temporally correlated with theonset of the syndrome, including trauma, infections(e.g., hepatitis C virus, HIV, and Lyme disease),emotional stress, catastrophic events (e.g.,war), autoimmune diseases and other pain conditions(34, 35). FM has been reported to coexist in25% of patients with RA, 30% of patients withSLE and 50% of patients with Sjogren’s syndrome(36-38).The most common rheumatic diseases that couldoverlap and be confused with FM are: osteoarthritis(OA), RA, ankylosing spondylitis (AS),polymyalgia rheumatica (PMR), SLE, Sjogren’ssyndrome, osteomalacia, polymyositis.OA is observed most often in people over age 50(most of them are asymptomatic); OA, togetherwith FM, is among the most prevalent (7%)rheumatic syndromes in clinical practice (39). OAcan be confused with FM because it causes arthralgiasof the whole body and could be associatedwith significant limitation of activity. It has a clearpredilection for certain joints, in particular, the firstcarpometacarpal joints, cervical and lumbar spine,hips, knees and metatarsophalangeal joints (40).Radiographically, OA has classic changes that includeosteophyte formation, joint space narrowing,subchondral sclerosis, and subchondral cysts (41).It may seem reasonable to study the painful regionon radiograph, but radiographs are not necessarilycorrelated with clinical symptoms and must be interpretedcorrectly in the clinical context.RA is an inflammatory arthritis; the patients presentwith inflammatory symptoms. The historicalevaluation and the physical examination are fundamentalto determine, for example, if real synovitisis present. The radiographic manifestationsof RA have been well described (marginal erosions,joint space narrowing, joint destruction), and disease-specificalterations that can be seen during theclinic visit (e.g., soft tissue swelling, deformities,subluxations) could be partially found on radiographs.In fact, it takes months or years to developthese alterations, which emphasizes the importanceof developing new instrumental assessmentsthat will facilitate early diagnosis of RA. Magneticresonance imaging (MRI) is the gold standard forconfirming the diagnosis of RA, but is too expensivefor normal management. Muscoloskeletal ultrasonographyis easy to perform, can be repeatedwithout X-ray exposure risks for patient, and representsthe best compromise between cost and result(42-44). The ultrasonography evaluation of thepatient could help the clinician to identify the elementsfor RA or FM diagnosis.AS usually begins with an insidious onset of chronicinflammatory back pain symptoms in adolescenceor early adulthood (45). AS can be easilymistaken for FM, because both diseases occur inyoung patients who may have constitutional symptomssuch as malaise, fatigue and impaired sleep(45). The hallmark of AS is sacroiliitis as identifiedradiographically via conventional pelvic X-ray, although this condition may not be evident inthe early stages of the illness (46). Sacroiliitis doesnot occur in FM, though, so its presence is fundamentalin distinguishing AS from FM. Recent reportsindicate that the role of MRI has become

40 F. Atzeni et al.clearer and it may be a better tool for early identificationof these patients (47).PMR is characterized by widespread pain and profoundmorning stiffness. Patient’s historical factors(age, distribution of pain and stiffness) andlaboratory tests can help to distinguish FM fromPMR. The response to prednisone therapy is dramaticin PMR (24 to 48 hours), whereas no responseis present in FM. Instrumental tests are nothelpful to diagnose both diseases.FM could mimic SLE as demographic and clinicalfeatures overlap: young women, fatigue, dermatologicalinvolvement, arthralgias (48, 49). However,organ system involvement such as malar rashand photosensitivity, fever, serositis, haematologicalalterations, and neurological signs typically occurin SLE whereas these elements are not presentin FM (50). Conventional X-rays, ultrasonography,computed tomography, MRI help clinicians to diagnoseSLE and to distinguish SLE from FM.Fatigue and generalized arthralgias are common forSjogren’s syndrome and FM. The fundamental clinicalfeatures of Sjogren’s syndrome are dry eyesand dry mouth. In FM mucosal dryness is relatedto sympathetic hyperactivity (51). Sjogren’s syndromeis also characterized by damage to the eyeepithelium whereas no damage is evident in patientswith FM. Rose bengal and/or fluorescein dyes areused by oculists to identify this hallmark feature. Inrecent years, salivary gland ultrasonography becamea simple and noninvasive test for the detectionof gland involvement in Sjogren’s syndrome; colordoppler sonography can also increase diagnosticaccuracy (52). Both methods are important to differentiateSjogren’s syndrome from FM.The radiographic evidence of osteopenia with pseudofracturesdistinguishes osteomalacia from FM(24). Bone density in FM patients is comparable tohealthy controls (53).Profound proximal muscle weakness with mildpain is typical of polymyositis. The muscle biopsyis the gold standard in the diagnosis of this inflammatorymyopathy. The histological features ofpolymyositis include variability in muscle fibersize, scattered necrotic and regenerating fibers andendomysial inflammation with invasion of nonnecroticmuscle fibers (54). Use of electromyographyincreases spontaneous and insertional activitywith fibrillation potential, complex repetitive discharges,positive sharp waves, small polyphasicmotor unit potentials and early recruitment (54).Muscle biopsy and electromyography are normalin FM patients.Nonrheumatic syndromes that could overlap and beconfused with FM include thyroid dysfunction andhepatitis B and C virus infection.Thyroid dysfunction. Hypo- and hyperthyroidismare characterized by profound fatigue and muscleweakness. Anxiety may be presented in hyperthyroidism.There are significant similarities between the clinicalfindings in FM and the symptoms of thyroiddysfunction (55). Many studies report that a considerableproportion of FM patients has problemsin the production or utilization of thyroid hormones(56); therefore, signs of thyroid dysfunction mustbe investigated in FM patients. When clinically indicated,thyroid function tests may be performed.Gland ultrasonography can be helpful, but the instrumentalresults are not necessarily indicative ofdisease as thyroid tissue abnormalities can be presentin healthy subjects, too.Hepatitis B and C virus (HBV/HCV) infection. Patientswith HCV infection may frequently presentsome rheumatologic manifestations such as FM(57). Diffuse musculoskeletal pain is present in approximatelyhalf of HB antibody positive patientsand approximately 25% of HB antigen positive patientspresent with FM syndrome (58). Hepatic ultrasonographyindicates liver alterations and is animportant test for differentiating FM from hepatitisB or C infections.Generalized pain is a feature of many malignantdiseases, including multiple myeloma, andmetastatic breast, lung and prostatic cancer (59).Usually FM does not predict cancer, but an increasedrisk of breast cancer was found amongthose female patients that did not satisfy the ACRcriteria for FM (60). Clinicians must be vigilant ofthose patients that develop any symptoms of breastmalignancy and thoroughly screen using proceduressuch as mammography.Tilt testThe tilt table test is another useful tool to study orthostaticintolerance and syncope. The method isbased on the physiological changes that occur afteradopting an upright posture with pooling of approximately700 ml blood in the lower parts of thebody. In normal circumstances, the autonomic nervoussystem quickly compensates for this relativevolume loss by increasing vascular tone and cardiacoutput. This mechanism serves to prevent hypotensionand inadequate cerebral perfusion. Tilttable testing examines this response in a controlledenvironment.

The evaluation of the fibromyalgia patients 41With passive orthostasis, additional stress is exertedon the sympathetic nervous system by blockingthe influence of muscle contraction that could increasevenous return. Subjects are supine for 30minutes in the first step. The subject is then tiltedupright for 30-45 minutes at an angle of 60-80°.Pharmacological stimulation with isoproterenol issometimes used as an additional step. The normalresponses to tilting consist of an increase in heartrate of 10-15 beats per minute, an elevation of diastolicblood pressure of about 10 mmHg, and littlechange in systolic pressure. There are two typesof abnormal responses. One response is orthostatichypotension, defined as a reduction of systolicblood pressure of at least 20 mmHg or a reductionof diastolic blood pressure of at least 10 mmHg.This hypotension may induce syncope (61). Theother type of abnormal response is postural orthostatictachycardia, which consists of a sustained increasein heart rate of at least 30 beats per minuteor a sustained pulse rate of 120 beats per minute.Tilt table testing has been used mostly to studysyncope in patients with no evidence of structuralheart disease. Furlan et al. (62) showed that, whilerecumbent, patients with FM seemed to experiencea global increase of central cardiovascular sympatheticactivity and a blunted enhancement of sympatheticactivity. A blunted enhancement of sympatheticmodulation to the vessels and impairedcardiac vagal withdrawal characterized their autonomicprofiles during gravitational stress and mayhave accounted for the excessive rate of syncopethey experienced upon standing.PolysomnographyPatients with FM often complain of poor sleepquality. Polysomnography (PSG) is a recording ofsleep stages and architecture that is used to investigateunderlying pathology, including sleep apnea.Sarzi-Puttini et al. (63) reported that FM patientscomplaining of daytime hypersomnolence had ahigher number of TPs, a greater score of subjectivepain and more fatigue than FM patients with nodaytime hypersomnolence. Moreover, hypersomnolentpatients slept significantly less efficiently,had a lower proportion of stages 3 and 4 sleep, andhad twice as many arousals per hour of sleep comparedto patients with no hypersomnolence. Rizziet al. (64) reported that FM patients experience anincreased cyclic alternating pattern (CAP) rate,which indicates poorer quality of sleep. Further,these data are strongly correlated with severity ofsymptoms.FUNCTIONAL NEUROIMAGINGThe first studies that used functional neuroimagingto evaluate brain processing in fibromyalgia patientsused the method of single photon emissioncomputed tomography (SPECT). SPECT quantifiesregional cerebral blood flow (rCBF) by detectingthe distribution of a radioactive tracer thatis infused before the scan. Mountz et al. (65) evaluatedbaseline levels of rCBF in ten patients withFM and in seven healthy control subjects. After thetracer infusion the participants sat quietly for theduration of the 32-minute SPECT scan. Thismethod produced images with a resolution of about8.5 mm in predefined regions of interest (ROI) correspondingto the right and left thalamus and rightand left head of the caudate nucleus. Patients, relativeto controls, had lower rCBF in both the rightand left thalamus and in both the right and left caudatenucleus. Kwiatek et al. (66) subsequently performeda similar study using SPECT in 17 patientswith FM and in 22 healthy control subjects andfound decreased rCBF in the right thalamus but nodecreases in either the left thalamus or in the caudatenuclei of FM patients. Additional activationswere found in the inferior pontine tegementum andnear the right lentiform nucleus of patients. Theconsistent finding of reduced baseline rCBF in theright thalamus was replicated by Cohen-Gadol etal. (67) and has been observed in patients with painassociated with traumatic peripheral neuropathy(68) and metastatic breast cancer (69).During the time of these initial SPECT studies inFM, functional magnetic resonance imaging (fM-RI) methods were being developed to assess brainactivity with greater temporal and spatial resolutionthan either SPECT or positron emission tomography(PET). The commonly used fMRI method ofblood oxygen level dependent (BOLD) imaginghas the further advantage of not requiring the infusionof a radioactive tracer. The first study to applyfMRI to the evaluation of FM evaluated brainresponses to painful blunt pressure applied to thethumb (6). This study assessed the pressure painsensitivity in patients and control subjects beforeand during the fMRI experiments. For each of 16FM and 16 control participants, this study determinedpressures that evoked pain described as near“slightly intense” on a calibrated pain scale (6, 70).The comparison of the effects of these subjectivelyequal evoked pain sensations (produced by approximatelyhalf the pressure in the fibromyalgiapatients) defined the equal pain contrast. The

42 F. Atzeni et al.healthy control subjects received an additional scanin which they received the same low pressures thatwere delivered to the patients (equal pressure contrast).These pressures provoke ratings of “slightlyintense” pain by the FM patients, and ratings of“not painful” or “faintly painful” by the controlsubjects. Pressures were applied to the thumbnailby a 1-cm diameter hard rubber probe attached toa hydraulic cylinder. The thumb site was chosen forits dense innervation and its large representation inthe primary somatosensory cortex. The thumb wasalso chosen to test the concept that tenderness inFM is not due to muscle sensitivity or confined tomuscles at specific tender point sites, but rather, itis a property of deep tissue and is found throughoutthe body in these patients.The patients underwent an fMRI scan during which30 seconds of painful pressure (e.g., 2 kg) was alternatedwith 30 seconds of non-painful pressure(e.g., 0.5 kg) for the duration of the 10–minutescan. Control participants underwent the same typeof scan whereby painful pressure alternated withnonpainful pressure (equal pain control), and anadditional scan in which the painful pressure wasreduced to the values delivered to the patients(equal pressure control). All participants also receiveda conventional anatomical MRI of the headto facilitate localization of the fMRI-derived brainactivity. During the anatomical session completefunctional images of the entire brain and cerebellumwere obtained every 5 seconds, with a resolutionof 3 mm in all three dimensions. These datawere processed by standard methods (6), and theresult is a statistical volume, or map, of each subject’sbrain that represents the statistical results ofthe difference between painful and nonpainful pressure.To perform group analyses, each of these volumeswas converted to standard coordinates andpresented as group activity for each group or as astatistical difference between groups. The resultsshow that a similar experience of pain (the equalpain contrast), which was produced using abouthalf the amount of pressure in patients comparedto controls, was associated with similar activationsin a number of brain regions that are usually activatedin pain imaging experiments. These includecontralateral primary (SI) and secondary (SII) somatosensorycortex, insular cortex and inferiorparietal lobule. In this case the brain response appearsto be consistent with the verbal reports of thesubjects. A second analysis evaluated the effects ofthe equal pressure contrast by identifying regionsin which the same pressure produced greater effectsin one of the groups. The relatively low pressure of2 kg evoked significantly greater activity in a numberof brain regions in FM patients, including bothregions found in the first analysis and additional regionssuch as anterior cingulate cortex.This result with painful pressure has been foundwith painful heat as well. Cook et al. (5) administeredsimilarly painful, 10-second heat stimuli tothe left hand of nine female FM patients and ninefemale healthy controls. The reduced heat toleratedby patients (mean 47.4°C) compared to controls(48.3 °C) resulted in no significant differences inbrain activation. This study also showed evidenceof increased activity in the contralateral insular cortexof patients.Additional studies have characterized regions thatshow graded responses to stimulus intensity and regionsthat appear to show a binary response topainful stimulation, i.e., turning on at some thresholdlevel of stimulation (71). Both patients and controlshave shown graded responses to stimulus pressurein regions that are involved in processing thesensory-discriminative dimension of pain sensation,including contralateral (right) thalamus, andprimary (SI) and secondary (SII) somatosensorycortex.These initial studies explored the effects of theamount of painful stimulation on the pattern andmagnitude of brain responses. A large body of evidenceindicates that pain perception and behaviorare much more complex and influenced by a numberof variables such as mood and cognition. Anadditional group of studies have begun to investigatethis complexity by using fMRI to evaluate themodulation of evoked pain by mood or cognitivevariables that have been shown to influence painand pain behavior.Depression is a significant factor in the expressionof pain and response to treatment. Giesecke, et al.(72) evaluated the effects of depression on brain responseto pressure pain in FM. Thirty FM patientsand 7 control participants received fMRI scans duringalternating pressure and no pressure stimulationusing methods similar to the initial fMRI study describedabove by Gracely, et al. (6). However, insteadof comparing two groups, the first analysiscompared three groups: 7 age- and gender-matchedcontrol subjects, 7 FM patients diagnosed with majordepressive disorder, and 7 matched fibromyalgiapatients without major depressive disorder.Equally painful stimuli, produced by significantlylower stimulus pressures in the FM patients, resultedin similar activations in all three groups.

The evaluation of the fibromyalgia patients 43These activations were in regions implicated in processingthe sensory-discriminative dimension ofpain, including contralateral SI and SII. The patientswith major depressive disorder showed additionalactivations in bilateral amygdala and in aspecific region of the contralateral anterior insula.A second analysis examined the influence of depressionusing a correlational method in all 30 FMpatients in which the level of pain-induced brain activationfor each subject was correlated with thesymptoms of depression, as measured by the Centerfor Epidemiological Studies Depression Scale(CES-D). No associations between depression andpressure pain sensitivity were found in brain regionsassociated with processing the sensory discriminativedimensions of pain. CES-D scores,however, were significantly associated with painevokedactivity in brain regions implicated in processingthe motivational-affective dimensions ofthe pain experience, specifically the contralateralanterior insula and bilateral amygdale, the sameregions identified in the between groups analysis.These results suggest that depression modulatespain-evoked activity in structures involved in processingaffective characteristics of pain experience.Similar correlation analyses have been applied tothe cognitive variable of catastrophizing, which isemerging as a significant variable predicting painchronicity and poor treatment response (73). Sincethis cognitive style has been linked to depression,the analysis controlled for depression statistically.The results correlating catastrophizing with painevokedactivity in each subject found significant associationsin brain regions related to the anticipationof (contralateral medial frontal cortex, ipsilateralcerebellum) and attention to (contralateral anteriorcingulate gyrus, bilateral dorsolateral prefrontalcortex) pain, and to both emotional (ipsilateralclaustrum, interconnected to the amygdala)and motor (contralateral lentiform nuclei) responses(74). These results suggest that the effectsof negative cognitions are mediated through a numberof separate mechanisms. Successful treatmentmay involve identification of the relevant and mostresponsive mechanisms.The field of brain neuroimaging continues to advanceat a fast pace, and both old and new methodshave been applied to the evaluation of FM. Inan application of the older method of structuralMRI, Kuchinad, et al. (75) have found that the sizeof specific brain regions is significantly reduced inpatients with FM. A PET study of opioid receptorsshowed significant differences in endogenous opioidactivity in FM (76), and the neuroimagingmethod of magnetic resonance spectroscopy(MRS) showed differences in the concentrationsof metabolites related to neural activity in the insula(Harris, unpublished observations). Newer fM-RI methods such as arterial spin labeling (ASL)have indentified insular mechanisms in patients thatare related to increased activity at rest in the absenceof painful stimulation and differences in theinterconnections of the pain network at rest. A recentmulti-center European trial has found that longterm treatment with milnacipran results in changesin pain-evoked brain activity not observed withplacebo treatment.CLINIMETRIC APPROACHESIN FIBROMYALGIAA range of treatments are employed to treat thevarious symptom facets of FM. Although some ofthese therapies have been tested in randomizedcontrolled trials (RCT), there has been little standardizationof an approach to trials or of the outcomemeasures used, and evaluating therapeuticeffects on widely varying symptoms is difficult. Toaddress the identification of core outcome domains,the Initiative on Methods, Measurement, and PainAssessment in Clinical Trials (IMMPACT) (9) andOutcome Measures in Rheumatoid Arthritis ClinicalTrials (OMERACT) (8) workshop convened ameeting to develop consensus recommendationsfor chronic pain clinical trials. The consensus ofthese groups has been that key outcomes should includepain, physical functioning, emotional functioning,patient global ratings of satisfaction,health-related quality of life, and adverse events(8, 9).Pain AssessmentChronic generalized pain is a core feature of FM(77, 78). A number of tools are available for the assessmentof pain, including the visual analoguescale, the daily pain diary, and the McGill PainQuestionnaire (MPQ). Important issues that mayinfluence assessment of pain in patients with FMinclude recall bias, use of paper versus electronicdiaries to assess pain experiences, and pain scalingmethods (79). The standard visual analogue scaleis a 10 cm scale with a border on each end. The leftend may be anchored by a numeric (i.e., “0”) and/orverbal (e.g., “No pain at all”) indicator. The rightend may be anchored by a numeric (e.g., “10”)

44 F. Atzeni et al.and/or verbal (e.g., “Pain as bad as it could be”) indicator.There are occasional distortions throughphotocopying and printing, but adjustments can bemade so that the highest score is 10. Huskisson etal. (80) also suggested that an alternative descriptivepain relief scale based on the indications “completerelief” “moderate relief,” “slight relief” and“no pain relief” was possible, but this would bemuch less sensitive than the visual analogue scale.A number of studies have established that data fromself-report visual analogue scales are reproducible.With the development of optical scanning technologyfor the automated computer entry of scores, visualanalogue scales can be presented in a format of 11small boxes or circles for patients to assess their painfrom 0-10 (or 100) (81). Although formal direct comparativestudies have not been performed to analyzethe results of automated optical scanning, this scalingformat appears to have criterion validity.The visual analogue pain scale has proven to be agreat advance in the assessment of pain. A daily diaryhas been used to assess the impact of pain inpatients with FM and has been reported to be usefulfor demonstrating the manner in which pain influencesactivities of daily living in these individuals.The MPQ can provide detailed information onthe characteristics of pain in FM (82). It includes78 pain adjectives that are divided into 4 major categories(sensory, affective, evaluative, and miscellaneoussensory) (82, 83). This index takes 10 to15 minutes to complete. Tender point assessmentis a demonstrably useful part of the official ACRcriteria for the diagnosis of FM. However, TPs arenot unique to the syndrome. Tenderness is widespreadin patients with FM rather than being confinedto specific anatomic regions, and these individualsmay also demonstrate more hypersensitivityto heat, cold, and electrical stimulation. Somemethods of assessing tenderness (e.g., dolorimetry)may demonstrate increased pain sensitivity in patientswith FM more objectively than palpation andare relatively independent of biasing factors or patientdistress. In addition to tender point count, assessmentof tender point intensity or score has beendeveloped as an assessment tool. For example, theFM Intensity Score (FIS) is obtained by averagingthe pain intensity scores (on a 0-10 scale) for the18 sites assessed in the Manual Tender Point Survey(84).Psychological and behavioural assessmentPsychological evaluation of the patient can provideuseful information about the psychological and behaviouralfeatures that may influence their pain anddysfunction and, conversely, provide a sense of theimpact of pain, fatigue, and other symptoms on theirpsychological health (85, 86). It is often presumedthat patients with greater psychological impairmentand/or psychiatric pathology may be more symptomaticor resistant to improvement with therapeuticintervention. However, this assumption may be trueonly in some cases. Both in clinical practice and indrug trials, it is important to diagnose and effectivelytreat concomitant depression, anxiety, bipolarstates, and especially, suicidal tendencies. In additionto a careful history, a number of screeningtools are available for both clinical and researchpurposes, including the Multidimensional Pain Inventory,the Pain Behaviour Scale, the DartmouthPain Questionnaire, the Coping Strategies Questionnaire,the Ways of Coping Scale and the IllnessBehaviour Questionnaire (79, 85).Fatigue assessmentFatigue is one of the core features of FM, and itsmeasurement is important in both research andclinical settings. A variety of measures exist andhave proven useful in measuring fatigue in otherrheumatic diseases, such as RA and AS (87). Theseinclude the Multidimensional Fatigue Index, whichmeasures various types of fatigue including physicaland emotional (87); the Functional Assessmentof Chronic Illness Therapy (FACIT) system, whichhas been validated in a number of disease states andmay be customized to certain disease indications(88); And the Fatigue Severity Scale, which wasoriginally developed for multiple sclerosis and lupusfatigue assessment (89). The advantage of suchtools is their ability to explore the multiple dimensionsof fatigue. More simple, single-question fatigueassessments are embedded within such compositeinstruments as the FM Impact Questionnaire(FIQ).Sleep assessmentMultiple dimensions of sleep quality have been assessedin FM trials, including quantity, quality, easeof falling asleep, frequency of waking, and feelingrefreshed upon awakening. Sleep quality can beassessed on a 100 mm linear scale with “sleep isno problem” at one extreme and “sleep is a majorproblem” at the other extreme. Similar scales canbe used to rate number of awakenings, and “restedness”on awakening in the morning. The MedicalOutcome Study (MOS) sleep scale is an exampleof an instrument used in an FM trial.

The evaluation of the fibromyalgia patients 45Quality of life and functional assessmentMeasurement of global sense of well being, qualityof life, and functional capacity in multiple dimensions(physical, vocational, social, emotional)is a key area of assessment and is considered essentialby regulatory agencies when contemplatingapproval of medications for chronic pain states(90, 91). Assessment with the MOS Short Form-36 (SF-36) Health Survey (SF-36) has shown thatpatients with FM have reduced physical functioning,physical role functioning, body pain, generalhealth, vitality, and social functioning compared tohealthy subjects.The SF-36 is a generic instrument with scores thatare based on responses to individual questions,which are summarized in eight scales (bodily pain,physical functioning, general health perception,role function - physical aspect, role function - emotionalaspect, vitality, social functioning, and mentalhealth), each of which measures a health concept(92). These scales, weighed according to normativedata, are scored from 0 to 100, with higherscores reflecting a better quality of life. The SF-36has been validated for use in Italy, and it can becompleted within 15 min by most people. The NottinghamHealth Profile (NHP) is intended for primaryhealth care to provide a brief indication of apatient’s perceived emotional, social and physicalhealth problems (93).The questionnaire consisted of two parts, but onlypart I is now used: it contains 38 yes/no items thatcan be grouped into 6 domains (physical mobility,pain, sleep, social isolation, emotional reactions, andenergy level) with each question weighted for severity.The sum of all weighted values in a given domainrepresents a continuum between 0 (best health)and 100 (worst health). The FM Impact Questionnaire(FIQ) is an assessment instrument designed tomeasure the components of health status that are believedto be most affected by FM patients. It is composedof 20 items and is used to measure FM patientstatus, progress and outcomes (93, 94). The FIQ isa brief, self-administered instrument that takes approximately5 minutes to complete (90, 91).Table I - Proposed preliminary response criteria for fibromyalgia.Improvement in at least 3 of the 4 measures; and at least 3 ofthe post-treatment scores must satisfy the respective cutoffs:1. FIQ score

46 F. Atzeni et al.for study purposes only. The presence of these factors,however, helps researchers and clinicians tounderstand the pathogenetic mechanisms and toidentify patient subgroups. Some of these factorscould be used as indices of disease severity. Thecurrent literature is engaged in identifying and suggestingserological alterations or instrumental investigationsas new, specific markers of FM; but itis necessary to identify precise biomarkers of diseasein accordance with the criteria of feasibilityand reproducibility for diagnostic and therapeuticpurposes. Unfortunately, the symptoms of FM arenot specific and there are no instrumental diagnostictests for FM. Many differential diagnoses maybe excluded via extensive clinical examination andpatient history, and considering the overlap of FMwith other medical conditions, treating physiciansshould be vigilant: chest-X-rays and abdominal ultrasonographyare the first steps of general evaluationfor all patients with suspected FM. Functionalneuroimaging methods have revealed a large numberof supraspinal effects in FM, a disorder mediatedby mechanisms that are essentially unknown.The goal of future studies will be to assess whetherthese findings are associated with the mechanismsthat initiate and maintain this disorder, or whetherthey represent supraspinal consequences of theseunknown mechanisms. Evaluating therapeutic effectsin FM is difficult because of the many facetsof the syndrome. To address the identification ofcore outcome domains, the IMMPACT andOMERACT workshops are working to developconsensus recommendations for chronic pain clinicaltrials.SUMMARYFibromyalgia (FM) is a rheumatic disease characterized by musculoskeletal pain, chronic diffuse tension and/or stiffnessin joints and muscles, easy fatigue, sleep and emotional disturbances, and pressure pain sensitivity in at least 11of 18 tender points. At present, there are no instrumental tests or specific diagnostic markers for FM; in fact, many ofthe existing indicators are significant for research purposes only. Many differential diagnoses may be excluded by anextensive clinical examination and patient history. Considering overlap of FM with other medical conditions, the treatingphysicians should be vigilant: chest-X-rays and abdominal ultrasonography are the first steps of general evaluationfor all the patients with suspected FM. Functional neuroimaging methods have revealed a large number ofsupraspinal effects in FM, a disorder mediated by mechanisms that are essentially unknown. Many treatments are usedin FM patients, but evaluating their therapeutic effects in FM is difficult because the syndrome is so multifaceted. Toaddress the identification of core outcome domains, the Initiative on IMMPACT and OMERACT workshop conveneda meeting to develop consensus recommendations for chronic pain clinical trials.Key words - Biomarkers, functional magnetic resonance, clinimetric approaches, polysomnography, tilting test.Parole chiave - Biomarkers, risonanza magnetica funzionale, clinimetria, polisonnografia, tilting test.REFERENCES1. Wolfe F, Smythe HA, Yunus MD. The American Collegeof Rheumatology 1990 Criteria for the Classificationof Fibromyalgia. Report of the Multicenter CriteriaCommittee. Arthritis Rheum 1990; 33: 160-72.2. Magaldi M, Moltoni I, Biasi G, Marcolongo R. Modificationsof calcium and magnesium ions in the intracellularfibromialgica pathophysiology of the syndro -me. Minerva Med 2000; 91: 137-40.3. Wolfe F, K Ross, Russell AJ, Herbert L. The prevalenceand characteristics of fibromyalgia in the general population.Arthritis Rheum 1995; 38: 19-28.4. Salaffi F, De Angelis R, Stancati A, Grassi W, ArchePain M. Prevalence Investigation Group (MAPPING)study. Health-related quality of life in multiple musculoskeletalconditions: a cross-sectional population basedepidemiological study. II. The MAPPING study. ClinExp Rheumatol 2005; 23: 829-39.5. Cook DB, Lange G, Ciccone DS, Liu WC, Steffener J,Natelson BH. Functional imaging of pain in patientswith primary fibromyalgia. J Rheumatol. 2004, 31: 364-78.6. Gracely RH, Petzke F, Wolf JM, Clauw DJ. Functionalmagnetic resonance imaging evidence of augmentedpain processing in fibromyalgia. Arthritis Rheum. 2002,46: 1333-43.7. Buskila D, Sarzi-Puttini P, Atzeni F, Stisi S, CarrabbaM. La sindrome fibromialgica: recenti acquisizioni.Progres Reum 2005; 6 (suppl 1): 148-57.8. Turk DC, Dworkin RH, Allen RR, Bellamy N, BrandenburgN, Carr DB, et al. Core outcome domains forchronic pain clinical trials: IMMPACT recommendations.Pain 2003; 106: 337-45.

The evaluation of the fibromyalgia patients 479. Mease PJ, Clauw DJ, LM. Arnold, Goldenberg DL,Witter J, Williams DA, et al. Fibromyalgia syndrome.OMERACT 7 Workshop. J Rheumatol 2005; 32:2270-7.10. Mease P. Fibromyalgia syndrome. review of clinicalpresentation, pathogenesis, outcome measures andtreatment. J Rheumatol 2005; 32: 6-21.11. Sarzi-Puttini P, Atzeni F. La sindrome fibromialgica.Riabilitazione reumatologica approccio multidisciplinare.Ed. S. Maddali Bongi. 2008; 979-94.12. Wilson RB, Gluck OS, Tesser JR, Rice JC, Meyer A,Bridges AJ. Antipolymer antibody reactivity in a subsetof patients with fibromyalgia correlates with severity.J Rheumatol 1999; 26 : 402-7.13. Werle And Fischer HP, Muller A, Fiehn W, Eich W.Antibodies against serotonin have no diagnostic relevancein patients with fibromyalgia syndrome. J Rhe -umatol 2001; 28: 595-600.14. Bazzichi L, Rossi A, Giuliano T, De Feo F, GiacomelliC, Consensi A, et al. Association between thyroid autoimmunityand fibromyalgic disease severity. ClinRheumatol 2007; 9.15. Werle And Jakel HP, Muller A, Fischer HP, Fiehn W.Eich Serum Hyaluronic acid levels are elevated inarthritis patients, but normal and not associated withclinical data in patients with fibromyalgia syndrome.Lab Clin 2005; 51: 11-19.16. Wigley RD, B, EM Chambers. Hyaluronic acid serumlevels in fibromyalgia, non-specific arm disorder, andcontrols. J Rheumatol 2001; 28: 2563.17. Maes M, Verkerk R, Delmeire L, Van Gastel A, VanHunsel F, Scharpe S. Serotonergic markers and loweredplasme branched-chain amino-acid concentrations infibromyalgia. Psychiatry Res 2000; 97 : 11-20.18. Sprott H, A Muller, H. Heine. Collagen cross-links infibromyalgia syndrome. Z. Rheumatol 1998; 57 : 52-5.19. Jaschko G, Hepp U, Berkhoff M, Schmet M, MichelBA, Gay S, Sprott H. Serum serotonin levels are notuseful in diagnosing fibromyalgia. Ann Rheum Dis2007; 66: 1267-8.20. Offenbaecher M, Bondy B, De Jonge St, Glatzeder K,Krüger M, Schoeps P, et al. Possible association of fibromyalgiawith a polymorphism in the serotonin transportergene regulatory region. Arthritis Rheum 1999;42: 2482-8.21. Dorshkind K, Horseman ND. The roles of prolactin,growth hormone, insulin-like growth factor-1, and thyroidhormones in lymphocyte development and function: insightsfrom genetic models of hormone and hormone receptordeficiency. Endocr Rev 2000; 21: 292-312.22. Hocherel K, Farber L, S Ladenburger, Vosshage D,Stratz T, Muller W, Grobecker H. Effect of tropisetronon circulating catecholamines and other putative biochemicalmarkers in serum of patients with fibromyalgia.Scand J Rheumatol 2000; 113: 46-8.23. Bazzichi L, Rossi A, MassimettiG, Giannaccini G, GiulianoT, De Feo F, et al. Cytokine patterns in fibromyalgiaand their correlation with clinical manifestations.Clin Exp Rheumatol 2007; 25: 225-30.24. Bagis S, Tamer L, Sahin G, Bilgin R H Guler, ErcanB, Erdogan C. Free radicals and antioxidants in primaryfibromyalgia: an oxidative stress disorder? RheumatolInt 2005; 25: 188-90.25. Lund I Lundeberg T, Carleson J, H Sonnerfors, UhrlinB Svensson E. Corticotropin releasing factor in theurine: a possible biochemical markers of fibromyalgia.Responses to massage and guided relaxation. NeurosciLett 2006; 403: 166-71.26. Baraniuk JN, Casado B, H Maibach, Clauw DJ, PannellLK, Hess SS. A chronic fatigue syndrome-relatedproteome in human cerebrospinal fluid. BMC Neurol2005; 5: 22.27. McLean S, Williams DA, Stein PK, Harris RE, LydenAK, Whalen G, et al. Cerebrospinal fluid corticotropinreleasingfactor concentration is associated with painbut not fatigue symptoms in patients with fibromialgia.Neuropsychopharmacology 2006; 31: 2776-82.28. Sarchielli P, Alberti A, Candeliere A, Floridi A, CapocchiG, Calabresi P. Glial cell line-derived neurotrophicfactor and somatostatin levels in cerebrospinal fluidof patients affected by migraine and fibromialgia.Cephalalgia 2005; 26: 409-15.29. Bazzichi L, Giannaccini G, Betti L, Mascia G, FabbriniL, Italiani P, et al. Alteration of serotonin transporterdensity and activity in Fibromyalgia. Arthritis Res Ther2006; 8: R99 (doi: 10.1186/ar1982).30. Bazzichi L, Giannaccini G, Betti L, Italiani P, FabbriniL, De Feo F, et al. Peripheral benzodiazepine receptorson platelets of fibromyalgia patients. Clin Biochem2006, 39: 867-72.31. Kaufmann I, Eisner C, Richter P, Huge V, Beyer A,Chouker A, et al. Lymphocyte subsets and the role ofTh1/Th2 balance in stressed chronic pain patients. Neuroimmunomodulation2008; 14: 272-80.32. Kim SH, Kim DH, Oh DH, Clauw DJ. Characteristicelectron microscopic findings in the skin of patientswith fibromialgia-preliminary study. Clin Rheumatol.2008; 27: 219-23.33. Nampiaparampil DE, Shmerling RH. A review of fibromyalgia.Am J Manag Care 2004; 10: 794-800.34. Clauw DJ, Crofford LJ. Chronic widespread pain andfibromyalgia: what we know and what we need know.Best Pract Res Clin Rheumatol 2003;17:685-701.35. Daoud KF, Barkhuizen A. Rheumatic mimics and selectedtriggers of fibromyalgia. Curr Pain HeadacheRep 2002; 6: 284-288.36. Wolfe F, Cathey MA, Kleinheksel SM. Fibrositis (fibromyalgia)in rheumatoid arthritis. J Rheumatol 1984;11: 814-8.37. Middleton GD, McFarlin JE, Lipsky PE. The prevalenceand clinical impact of fibromyalgia in systemiclupus erythematosus. Arthritis Rheum 1994; 37:1181-8.38. Bonafede RP, Downey DC, Bennetr RM. An associationof fibromyalgia with primary Sjogren’s syndrome:a prospective study of 72 patients. J Rheumatol 1995;22: 133-6.39. Wolfe F, Cathey MA. Prevalence of primary and secondaryfibrositis. J Rhematol 1983; 33: 160-72.40. Esther H, Barkhuizen A. Update on Rheumatologic

48 F. Atzeni et al.mimics of fibromyalgia. Curr Pain Head Rep 2006; 10:327-332.41. Klippel JH, Crofford LJ, Stone JH, Weyand CM, eds.Primer on the rheumatic diseases. Atlanta: ArthritisFoundation; 2001.42. Ostergaard M., Ejbjerg B, Szkudlarek M. Imaging inearly rheumatoid arthritis: roles of magnetic resonanceimaging, ultrasonography, conventional radiographyand computed tomography. Best Pract Res Clin Rheum -atol 2005; 19: 91-116.43. Joshua F, Lassere M, Bruyn GA, Szkudlarek M, NaredoE, Schmidt WA, et al. Summary findings of a systematicreview of the ultrasound assessment of synovitis.J Rheumatol 2007; 34: 839-47.44. Grassi W, Filippucci E. Ultrasonography and therheumatologist. Curr Opin Rheumatol 2007; 19: 55-60.45. Khan MA. Update on spondyloarthropathies. Ann InternMed 2002; 136: 896-907.46. Fitzcharles MA, Esdaile J. The overdiagnosis of fibromyalgiasyndrome. Am J Med 1997; 103: 44-50.47. Zochling J, Baraliakos X, Hermann KG, Braun J. Magneticresonance imaging in ankylosing spondylitis. CurrOpin Rheumatol 2007; 19: 346-52.48. Cervera R, Khamashta MA, Font J, Sebastiani GD, GilA, Lavilla P, et al. Morbidity and mortality in systemiclupus erythematosus during a 10-year period. Medicine2003; 82: 299-308.49. Fitzpatrick TB, Johnson RA, Wolff K, eds et al. ColorAtlas and Synopsis of Clinical Dermatology. NewYork: The McGraw-Hill Companies; 1997.50. Martinez-Lavin M. Overlap of Fibromyalgia with othermedical conditions. Curr Pain Head Rep 2001; 5:347-50.51. Martinez-Lavin M, Hermosillo AG. Autonomic nervoussystem dysfunction may explain the multi-systemfeatures of fibromyalgia. Semin Arthritis Rheum 2000;29: 197-9.52. Salaffi F, Carotti M, Argalia G, Salera D, GiuseppettiGM, Grassi W. Usefulness of ultrasonography and colorDoppler sonography in the diagnosis of major salivarygland diseases. Reumatismo 2006; 58: 138-56.53. Al-Allaf AW, Mole PA, Paterson CR, Pullar T. Bonehealth in patients with fibromyalgia. Rheumatology2003; 42: 1202-6.54. Briani C, Doria A, Sarzi-Puttini P, Dalakas MC. Updateon idiopatic inflammatory myopathies. Autoimmunity2006; 39: 161-70.55. Pamuk ON, Cakir N. The frequency of thyroid antibodiesin fibromyalgia patients and their relationshipwith symptoms. Clin Rheumatol 2007; 26: 55-9.56. Garrison RL, Breeding PC. A metabolic basis for fibromyalgiaand its related disorders: the possible role ofresistance to thyroid hormone. Med Hypotheses 2003;61: 182-9.57. Buskila D. Hepatitis C-associated arthritis. Curr OpinRheumatol 2000; 12: 295-9.58. Adak B, Tekeoglu I, Ediz L, Budancamanak M, YazganT, Karahocagil K, et al. Fibromyalgia frequency inhepatitis B carriers. J Clin Rheumatol 2005; 11: 157-9.59. Reilly PA. The differential diagnosis of generalizedpain. Baillieres Best Pract Res Clin Rheumatol 1999;13: 391-401.60. Dreyer L, Mellemkjaer L, Kendall S, Jensen B,Danneskiold-Samsøe B, Bliddal H. Increased cancerrisk in patients referred to hospital with suspected fibromyalgia.J Rheumatol 2007; 34: 201-6.61. Martinez-Lavin M. Biology and therapy of fibromyalgia.Stress, the stress response system, and fibromyalgia.Arthritis Res Ther 2007; 9: 216 (doi: 10.1186/ar2146).62. Furlan R, Colombo S, Perego F, Atzeni F, Diana A,Barbic F, et al. Abnormalities of cardiovascular neuralcontrol and reduced orthostatic tolerance in patientswith primary fibromyalgia. J Rheumatol. 2005; 32:1787-93.63. Sarzi-Puttini P, Rizzi M, Andreoli A, Panni B, Pecis M,Colombo S, et al. Hypersomnolence in fibromyalgiasyndrome. Clin Exp Rheumatol 2002; 20: 69-72.64. Rizzi M, Sarzi-Puttini P, Atzeni F, Capsoni F, AndreoliA, Pecis M, et al. Cyclic alternating pattern: a newmarker of sleep alteration in patients with fibromyalgia?J Rheumatol 2004; 31: 1193-9.65. Mountz JM, Bradley LA, Modell JG, Alexander RW,Triana-Alexander M, Aaron LA, et al. Fibromyalgia inwomen. Abnormalities of regional cerebral blood flowin the thalamus and the caudate nucleus are associatedwith low pain threshold levels. Arthritis Rheum 1995;38: 926-38.66. Kwiatek R, Barnden L, Tedman R, Jarrett R, Chew J,Rowe C, Pile K. Regional cerebral blood flow in fibromyalgia:single-photon-emission computed tomographyevidence of reduction in the pontine tegmentumand thalami. Arthritis Rheum. 2000; 43: 2823-33.67. Cohen-Gadol AA, Bradley CC, Williamson A, KimJH, Westerveld M, Duckrow RB, et al. Normal magneticresonance imaging and medial temporal lobeepilepsy: the clinical syndrome of paradoxical temporallobe epilepsy. J Neurosurg 2005; 103: 768-9.68. Iadarola MJ, Max MB, Berman KF, Byas-Smith MG,Coghill RC, Gracely RH, Bennett G. Unilateral decreasein thalamic activity observed with positron emissiontomography in patients with chronic neuropathicpain. Pain 1995; 63: 55-64.69. Di Piero V, Jones AK, Iannotti F, Powell M, Perani D,Lenzi GL, Frackowiak RS. Chronic pain: A PET studyof the central effects of percutaneous high cervical cordotomy.Pain 1991; 46: 9-12.70. Petzke F, Clauw DJ, Ambrose K, Khine A, GracelyRH. Increased pain sensitivity in fibromyalgia: effectsof stimulus type and mode of presentation. Pain 2003;105: 403-13.71. Grant MA, Farrell MJ, Kumar R, Clauw DJ, GracelyRH. fMRI evaluation of pain intensity coding in fibromyalgiapatients and controls. Arthritis Rheum2001; 44.72. Giesecke T, Gracely R H, Williams DA, Geisser M,Petzke F, Clauw DJ. The relationship between depression,clinical pain, and experimental pain in a chronicpain cohort. Arthritis Rheum 2005; 52: 1577-84.73. Burton AK, Tillotson KM, Main CJ, Hollis S. Psy-

The evaluation of the fibromyalgia patients 49chosocial predictors of outcome in acute and subchroniclow back trouble. Spine 1995; 20: 722-8.74. Gracely RH, Geisser ME, Giesecke T, Grant MA, PetzkeF, Williams DA, Clauw DJ. Pain catastrophizingand neural responses to pain among persons with fibromyalgia.Brain 2004; 127: 835-43.75. Kuchinad A Scweinhardt P Seminowicz DA Wood PBChizh BA Bushnell MC. Accelerated brain gray matterloss in fibromyalgia patients: premature. J Neurosci2007; 27: 4004-7.76. Harris RE, Clauw DJ, Scott DJ, McLean SA, Gracely RH,Zubieta JK. Decreased central mu-opioid receptor availabilityin fibromyalgia. J Neurosci 2007; 2: 10000-6.77. Mäntyselkä P, Kumpusalo E, Ahonen R, Kumpusalo A,Kauhanen J, Viinamäki H, et al. Pain as a reason to visitthe doctor; a study in Finnish primary health care.Pain 2001; 89: 175-80.78. Macfarlane GJ, Morris S, Hunt IM, Benjamin S, Mc-Beth J, Papageorgiou AC, et al. Chronic widespresdpain in the community: the influence of psychologicalsymptoms and mental disorder on healthcare seekingbehavior. J Rheumatol 1999; 26: 413-9.79. Salaffi F, Carotti M. Semeiotica e valutazione del doloremuscoloscheletrico. In “Clinimetria delle malattiemuscoloscheletriche. Scale e punteggi” Ed Mattioli1885; 19-58, 2007.80. Scott-Huskisson EC. Graphic Representation of pain.Pain 1976; 2: 175-84.81. Salaffi F, Stancati A, Silvestri CA, Ciapetti A, GrassiW. Minimal clinically important changes in chronicmusculoskeletal pain intensity measured on a numericalrating scale. Eur J Pain 2004; 8: 283-91.82. Melzack R. The McGill Pain questionnaire: major propertiesand scoring methods. Pain 1985; 1: 85-92.83. Salaffi F, Nolli M, Cavalieri F, Ferraccioli GF. Confrontotra indici algometrici nella valutazione dell'esperienzaalgica in Reumatologia. Utilità della versioneitaliana del questionario algologico McGill. Reumatismo1990; 42: 19-31.84. Sinclair D, Starz T, Turk D. The manual Tender PointSurvey. [Internet]. [Accessed July, 2005]. Availablefrom National Fibromyalgia Association: http://fmaware.org/doctor/tenderpt.htm85. Fordyce WE, Lansky D, Calsyn DA, Shelton JL, StolovWC, Rock DL. Pain measurement and pain behavior.Pain 1984; 18: 53-69.86. Scudds RA, Rollman GB, Harth M, McCain A. Pain perceptionand personality measures as discriminations in theclassification of fibrositis. J Rheumatol 1987; 14: 563-9.87. Belza BL, Henke CJ, Yelin EH, Epstein WV, GillisCL. Correlates of fatigue in older adults with rheumatoidarthritis. Nurs Res 1993; 42: 93-9.88. Webster K, Cella D, Yost K. The Functional Assessmentof Chronic Illness Therapy (FACIT) MeasurementSystem: properties, applications, and interpretation.Health Qual Life Outcomes 2003; 1: 79.89. Krupp LB, LaRocca NG, Muir-Nash J, Steinberg AD.The Fatigue Severity Scale. Application to patients withmultiple sclerosi and systemic lupus erythematosus.Arch Neurol 1989; 46: 1121-3.90. Hays R, Stewart A. Measuring functioning and well-being.In: Stewart A, Ware J, editors. Durham, NC: DukeUniversity Press; 1992: 232-59.91. Franchignoni F, Salaffi F. Generic and specific measuresfor outcome assessment in orthopaedic and rheumatologicrehabilitation. In: Assessment in Physical Medicineand Rehabilitation - Advances in Rehabilitation. M.Barat, F. Franchignoni Eds. 2004; 16: 45-77.92. Ware JE Jr, Sherbourne CD. The MOS 36-item shortform health survey (SF-36). Conceptual frame-workand item selection. Med Care 1992; 30: 473-81.93. Hunt SM, McEven J, McKenna SP. Measuring healthstatus: a new tool for clinicians and epidemiologists. JRoy Coll Gen Pract 1985; 35: 185-8.94. Burckhardt CS, Clark SR, Bennett RM. The FibromyalgiaImpact Questionnaire: development andvalidation. J Rheumatol 1991; 18: 728-33.95. Sarzi-Puttini P, Atzeni F, Fiorini T, Panni B, RandisiG, Turiel M, et al. Validation of an Italian version ofthe Fibromyalgia Impact Questionnaire (FIQ-Q). ClinExp Rheumatol 2003; 21: 459-64.96. Simms RW, Felson DT, Goldenberg DL. Developmentof preliminary criteria for response to treatment in fibromyalgiasyndrome. J Rheumatol 1991; 18: 1558-63.97. Dunkl PR, Taylor AG, McConnell GG, Alfano AP,Conaway MR. Responsiveness of fibromyalgia clinicaltrial outcome measures. J Rheumatol 2000; 27:2683-91.

ORIGINAL ARTICLEReumatismo, 2008; 60: Supplemento 1: 50-58Fibromyalgia syndrome:the pharmacological treatment optionsIl trattamento farmacologico della sindrome fibromialgicaP. Sarzi-Puttini 1 , R. Torta 2 , F. Marinangeli 3 , G. Biasi 4 , M. Spath 5 , D. Buskila 6 , R.H. Gracely 7 ,M.A. Giamberardino 8 , L. Bazzichi 9 , M. Cazzola 10 , M. Di Franco 11 , S. Stisi 12 , F. Salaffi 13 , R. Casale 14 ,G. Leardini 15 , R. Gorla 16 , A. Marsico 17 , R. Carignola 18 , L. Altomonte 19 , F. Ceccherelli 20 , G. Cassisi 21 ,G. Arioli 22 , A. Alciati 23 , F. Atzeni 1 (Italian Fibromyalgia Network)1Rheumatology Unit, L. Sacco University Hospital, Milan, Italy; 2 Department of Neuroscience, University of Turin, A.S.O. San GiovanniBattista of Turin, Turin, Italy; 3 Department of Anesthesiology and Pain Medicine, L'Aquila University, L’Aquila, Italy; 4 Unit ofRheumatology, University of Siena, Siena, Italy; 5 Friedrich-Baur-Institute, University of Munich, Munich, Germany; 6 Department ofMedicine H, Soroka Medical Center and Faculty of Health Sciences, Ben Gurion University, Beer Sheva, Israel; 7 Department of Medicine,University of Michigan Health System, Ann Arbor, Michigan, USA; 8 Ce.S.I. “G. D’Annunzio” Foundation, Department of Medicine andScience of Aging, “G. D’Annunzio”, University of Chieti , Italy; 9 Department of Internal Medicine, Division of Rheumatology, S. ChiaraHospital, University of Pisa, Italy; 10 Unit of Rehabilitative Medicine “Hospital of Circolo”, Saronno (VA), Italy; 11 Chair of Rheumatology,University la Sapienza Rome, Rome, Italy; 12 Rheumatology Unit, “G.Rummo” Hospital, Benevento, Italy; 13 Department of Rheumatology,Polytechnic University of the Marche Region, Ancona, Italy; 14 Department of Clinical Neurophysiology and Pain Rehabilitation Unit,Foundation Salvatore Maugeri, IRCCS, Scientific Institute of Montescano, Montescano (PV), Italy; 15 Rheumatology Unit, SS Giovanni ePaolo Hospital , Venice, Italy; 16 Rheumatology and Clinical Immunology, Spedali Civili and University of Brescia, Italy; 17 RheumatologyUnit, Hospital of Taranto, Taranto, Italy; 18 Department of Neuroscience, University of Turin, A.S.O.San Giovanni Battista of Turin, Turin, Italy; 19 UOC of Rheumatology Hospital S. Eugenio, Rome, Italy;20IOV (Veneto Cancer Institute), IRCCS, Department of Pharmacology and Anesthesiology, University of Padua, Italy; 21 RheumatologyBranch, Specialist Outpatients’ Department, Belluno, Italy; 22 Division of Rehabilitative Medicine and Rheumatology, General Hospital ofPieve di Coriano (Mantua), Italy; 23 Department of Psychiatry, L. Sacco University Hospital, Milan, ItalyCompeting interests: none declaredRIASSUNTOIl trattamento farmacologico della sindrome fibromialgica (FM) si è gradualmente arricchito di nuove molecole; tuttavia,nessun farmaco da solo è in grado di controllare completamente la costellazione dei sintomi che caratterizzanotale sindrome. Attualmente non è possibile trarre conclusioni definitive sul migliore approccio farmacologico pertrattare la FM, poiché i risultati degli studi clinici controllati presentano limitazioni metodologiche e vi è una consistenteeterogeneità nelle strategie terapeutiche, che rendono gli studi di difficile confronto. Una varietà di trattamentifarmacologici, che comprendono antidepressivi, farmaci antiinfiammatori non steroidei (FANS), oppioidi, sedativi,rilassanti muscolari e anti-epilettici vengono utilizzati per trattare la FM con risultati contrastanti. In questa review,si parlerà principalmente dei farmaci che hanno mostrato i risultati clinici più significativi. La natura della FM suggerisceche un approccio terapeutico a più livelli, sia farmacologico che non farmacologico, sembra costituire attualmentela decisione terapeutica più appropriata.Reumatismo, 2008; 60: Supplemento 1: 50-58INTRODUCTIONFibromyalgia (FM), also known as fibromyalgiasyndrome (FMS), is a frequently observed systemicdisorder characterized by widespread musculoskeletalpain (1, 2). Its prevalence in the generalCorresponding author:Piercarlo Sarzi-Puttini, MDDirector of Rheumatology UnitL. Sacco University Hospital, Milan, ItalyE-mail: sarzi@tiscali.itpopulation is 1-3%, and it is more common amongfemales than males. The American College ofRheumatology (ACR) classification criteria definesit as widespread pain with patients endorsing at least11 of 18 tender points as painful (3). Although itsdefining feature is chronic, widespread pain, FM patientsmay also have a number of other symptomsincluding sleep disturbance, fatigue, irritable bowelsyndrome, headache and mood disorders (1).Current evidence advocates a multifaceted programemphasizing patient education, medications for im-

Fibromyalgia syndrome: the pharmacological treatment options 51proving symptoms, and aggressive use of exerciseand cognitive-behavioural approaches to retain orrestore function (4-6). Physicians and patientsshould be educated about current theories regardingthe underlying pathophysiologic mechanismsof FM, and then set realistic goals for all modalitiesof treatment.However, it is not possible to draw definite conclusionsconcerning the best approach to managingFM because results of randomized clinical trialspresent methodological limitations, and therapeuticprograms are consistently heterogeneous, whichrenders them difficult to compare (7,8). However,a variety of pharmacological treatments, includinganalgesics, antidepressants, antiepileptics andmany other drugs have been used to treat symptomsof FM with mixed results (8). In this review, wewill discuss those drugs that have produced themost significant clinical results in treating FM patients.AnalgesicsThe use of steroids and nonsteroidal anti-inflammatorydrugs (NSAIDs) in FM has had disappointingoutcomes (1, 8). NSAIDs, which are commonlyused for arthritic conditions, may be less effectivefor FM because pain associated with FM isnot caused by muscle or joint inflammation. Thereis no scientific evidence that NSAIDs are effectivewhen used alone in FM patients, although they maybe useful adjuncts for analgesia when combinedwith tricyclic medications (1); the combination ofNSAIDs with benzodiazepines, however, gave inconsistentresults (1, 7-9).The central nervous system (CNS) mechanisms forthe disorder, specifically, central sensitization, centraldisinhibition and a dysfunctional hypothalamic-pituitary-adrenalaxis, could justify the relativelyreduced efficacy of NSAIDs and opioids, thelatter being more effective for “peripheral” pain(7). However, NSAIDs can be helpful in reducingpain that flares with excessive physical activity,tendinitis or bursitis; but they should be used onlyas needed to avoid side effects. COX 2inhibitorshave much fewer side effects, but have less efficacyin pain.Acetaminophen acts differently for FM patients; ithas a degree of strength for FM and is safe for useover long periods (9). Wolfe et al. surveyedrheumatic disease patients about their preferencesfor NSAIDs versus acetaminophen in terms of efficacyand side effects (10). There was a considerableand statistically significant preference forNSAIDs among patients; but the authors stress thatif safety and costs are issues, then the recommendationof the American College of Rheumatologythat acetaminophen be the first choice, primarilyfor mild pain, seems appropriate given the long durationof safe use (11).The use of NSAIDs or acetaminophen, with orwithout opioids, is always justified when patientswho already suffer from FM have other peripheralsources of pain (osteoarthritis, inflammatory arthritis,degenerative disk disease) (11).Opioids are meant to improve function in FM patientswho are impaired by pain, even though thereis an open debate about their usefulness and safetyas a “specific” medication for fibromyalgia patients(12-14).Few clinical trials exist that address the use of opioidsto treat persistent pain in FM patients, butthose trials show that these drugs are helpful for relievingFM pain; moreover, opioids can help to reducesleep disturbances, anxiety and depressionand to increase mobility and enjoyment of life (13,15).Potential side effects tend to decline over time, andaddiction has been disproven by the scientific literature.Opioids that are available on the Italian market includecodeine, tramadol, oxycodone, hydromorphon,morphine, buprenorphine and fentanyl.Furlan et al. (15) conducted a meta-analysis of 41randomized trials (6019 patients, 7% affected byFM) to evaluate the efficacy of opioids ranging induration from 1-16 weeks. They found that opioidswere more effective than placebo for both painand functional outcomes; and strong opioids weresignificantly superior to naproxen and nortriptyline,but only for pain relief. Despite the relativebrevity of the trials, more than 1/3 of the participantsabandoned treatment (15).Tramadol, in particular, was beneficial for FM patients(8, 9, 12-14). It is an atypical pain relieverthat differs from other narcotics in its action on thecentral nervous system, specifically, on reuptakeof serotonin and norepinephrine. Its most commonside effects are drowsiness, dizziness, constipationand nausea, and it should not be given in combinationwith tricyclic antidepressants.Tramadol, used alone or in combination with acetaminophen,is commonly prescribed for relief offibromyalgia pain (16-18) in a dose of 200-300mg/d. A small double-blind, placebo-controlled trialinitially suggested that tramadol was effectiveand well-tolerated in patients with FM (16).

52 P. Sarzi-Puttini et al.A larger RCT (n=69) reported decreased visualanalogue pain scores, improved pain relief and decreasedpain threshold after tramadol treatment.Another study compared a combination of 37.5 mgtramadol/325 mg acetaminophen tablets withplacebo in 315 patients with FM. Pain and physicalfunctioning improved significantly in the tramadol/acetaminophen-treatedsubjects. The averagedose of tramadol/acetaminophen was 4.0±1.8tablets per day with an attrition rate of 19% (n=29)due to adverse events. The attrition rate in theplacebo-treated subjects was 12% (n=18). Thisstudy suggested that the combination of tramadol/acetaminophenwas effective in treating FMpatients’ pain without causing serious adverseevents (17).Bennett et al. (18) examined efficacy data to comparethe impact of tramadol/acetaminophen versusplacebo on quality of life; the authors concluded thatmoderate-to-severe fibromyalgia pain significantlyimpairs health-related quality of life (HRQOL) inplacebo-treated patients.A recent study has demonstrated that transdermalbuprenorphine, a strong opioid, has beneficial effectson severe widespread pain (VAS >6/10), butit is less effective on other symptoms that are typicalof the disease (19).FM that is diagnosed according to the ACR criteriaseems to include patients with different painprocessing mechanisms. Screening for disordersthat may initiate or exacerbate symptoms of FM iscritical; if comorbid disorders are not identifiedearly and treated appropriately, therapies that targetFM, only, may be ineffective.In fact, there is a subset of FM patients that do notrespond to opioids, while other patients, who mayhave overlapping conditions such as diabetes,chronic myofascial pain, temporomandibular jointdisorder, arthritis, degenerative disc disease andother diseases, may benefit quite significantly fromopioids (8, 18).Physicians should obtain a careful medical and psychologicalprofile of the patient before prescribingopioids (17, 18). Therapy with these drugs shouldbe initiated after an adequate trial of acetaminophenfor nociceptive pain and of tricyclic antidepressantsor anticonvulsants.To obtain a synergistic effect on analgesia, somepatients may be prescribed combinations of differentpain relievers (multimodal analgesia) with differenteffects on pain pathways, but not for managingside effects. Patients should be asked to giveinformed consent for treatment; even though it isnot necessary for legal purposes, it would help toeducate patients and give them a sense of responsibility(18).It is appropriate to increase doses of immediate-releaseopioids slowly until pain reduction isachieved and then switch patients to controlled-releaseopioids, considering that most patients withchronic, non-malignant pain can be managed with

Fibromyalgia syndrome: the pharmacological treatment options 53be considered as a systemic disease that is relatednot only to neurotransmission imbalance, but alsoto other neurotrophic, neurosteroidal, CNS hormonalmodifications and diffuse, autonomic, immunologic,and metabolic somatic changes (8, 21).According to this hypothesis, antidepressants restoreneurotransmitter levels and modulate receptorexpression in the hypothalamus, which normalizeshyperactivity of the hypothalamic-pituitary-adrenal(HPA) axis (18, 1). An over-activationof the HPA axis is observed in depression and inchronic stress, both of which are frequently presentin patients with long-term pain disorders. Conversely,the response to stress is considered to playa crucial role in the pathogenesis of several syndromes,such as FM, chronic fatigue syndrome andirritable bowel syndrome (22, 23). Similarly, autonomicsystem alterations, such as sympatheticoveractivity, are present in both depression and FM(21). Finally, pro-inflammatory cytokines withinthe CNS play a role in the pathophysiology ofmood disorders (and pain), and modulating thesecytokines via chronic antidepressant treatment contributeto improve depression (and pain) (24).Several studies reported high frequency of mooddisorders in FM patients (25, 26) compared to controls(27). Short-term clinical studies have shownefficacy for antidepressants in the treatment of FM(28).Abnormalities in central monoaminergic neurotransmissionthat are observed in depression mightplay a role in FM pathophysiology because dysfunctionof 5-HT– and NE-mediated descendingpain-inhibitory pathways is an important mechanismrelated to the pain experienced by FM patients.Antidepressants that increase 5-HT and NEmediatedneurotransmission are commonly used totreat FM and other chronic pain conditions, particularlyneuropathic pain. Inhibition of both the 5-HTand NE reuptake transporters using tricyclic antidepressants(TCA) or SNRIs (serotonergic and noradrenergicreuptake inhibitors), seems more effectivein treating pain, and FM, in general, than inhibitionof either transporter alone using selectiveserotonergic (SSRIs) or noradrenergic (NARIs) reuptakeinhibitors (29-31).However, the efficacy of TCAs is counterbalancedby side effects (32, 33), while the better-toleratedSSRIs demonstrate less effectiveness in treating fibromyalgia(34-37).Antidepressants acting both on NE and 5HT inducea contextual increase of the endogenous opioidsystem response that raises the pain thresholdat the periacqueductal level and increases the gatecontrol of nociception at the spinal cord level (38).Antidepressants usually produce a fast, direct analgesiceffect (on opioid, enkephalinergic, substanceP) that is independent of mood state; it first appearsafter a few hours and can be achieved withlow doses.After a longer period of 2-3 weeks, a more robustanalgesic effect develops when antidepressantshave a more profound influence on mood and anxiety,and the affective and cognitive components ofpain become regulated. This effect can only be producedwith full doses that are easier to achieve withthe new generation of antidepressants, such as SS-RIs and SNRIs (39, 40).Concerning the use of antidepressants in fibromyalgia,Perrot and colleagues (41) identifiedforty-nine publications on the use of antidepressantsto treat painful rheumatologic conditions (including37 studies and 12 meta-analyses) that wereconsidered valid and used to develop the followingconsiderations: the analgesic effect is higher forTCAs than SSRIs; clear evidence concerning doseresponsedoes not exist; the onset of action occurswithin a week; the route of administration is oral;and side effects are more prevalent in TCAs thanSSRIs. Unfortunately, this review included studiesTable I - Summary of the controlled studies of dual reuptake inhibitors (SNRI).Authors References Drug N. Pts Weeks Dose Outc. ResultsArnold, 2004 43 DUL vs PLA 207 12 120 FIQ DUL > PLARussell, 2008 44 DUL vs PLA 520 24 20-120 BPIPGIDUL > PLAVitton et al., 2005 45 MIL vs PLA 125 4 200 PGIFIQMIL > PLAArnold, 2005 46 DUL > PLA 354 12 60-120 BPI DUL > PLAVLF = venlafaxine; DUL = duloxetine; MIL = milnacipran; dose in mg/day; outc. = outcome measures: VAS = Visual Analog Scale; FIQ = Fibromyalgia Impact Questionnaire;

54 P. Sarzi-Puttini et al.from 1966 to 2003 and did not consider new antidepressantssuch as SNRIs that are less effectivethan TCAs but remarkably more tolerated, particularlyin long-term treatment (42).Antidepressants that act on both NE and 5HT, i.e.,SNRIs (Serotonergic and Noradrenergic ReuptakeInhibitors), are venlafaxine, duloxetine and milnacipran(milnacipran is not marketed in Italy).Only a few controlled studies are available to date;these are summarized in Table I (43-46). All ofthese controlled studies demonstrated a significantsuperiority of the SNRI over placebo, and reportedfew and mild side effects (more frequent nausea,dry mouth and constipation in the first twoweeks of treatment) (47).Cyclobenzaprine, a tricyclic muscle relaxant, hasalso proven to be moderately effective in FM patientsat a dose of 10-40 mg/day (48). This has recentlybeen confirmed by a meta-analysis of fiverandomised, placebo-controlled trials (49), whichshowed that patients treated with cyclobenzaprinewere approximately three times as likely to reportsymptom improvement, but there was a highdropout rate and the duration of the studies wasshort (49).In our experience treating cancer pain with antidepressants,we have found that the impact of antidepressantson emotion and cognition is quite interesting:after a month of treatment, especiallywhen brief psychotherapy is also included, patientswho have pain as well as maladaptive coping styles(such as despair or hopelessness) begin to adoptpositive coping styles (such as fighting spirit). Thischange is obtained by improving mood and reshapingbeliefs about pain, both of which are extremelyimportant in malignant pain diseases (50).A final consideration involves the placebo effect inpain treatment.In a medical model placebo is manly considered aninert substance, and at present, it is well knownthat the placebo effect on pain is mediated by anopioid mechanism (51).In clinical practice, however, we consider that aplacebo effect is also an adjunct response to an activedrug: the individual expectation of a positiveresponse will increase the pharmacological actionof the drug, while a negative expectation will reducethe effectiveness of the therapy (nocebo effect).The placebo effect is highly related to the relationshipbetween patient and physician (52), a relationshipthat is also important in affecting pharmacologicaltreatments as well.Anticonvulsants/antiepileptic drugsAntiepileptic drugs (i.e., gabapentin and pregabalin)act at a number of sites that may be relevantto pain. The precise mechanism of their analgesiceffect remains unclear, but it is thought that theylimit neuronal excitation and enhance inhibition(53). The relevant sites of action include voltagegatedion channels (i.e., sodium and calcium channels),ligand-gated ion channels, excitatory receptorsfor glutamate and Nmethyl-D-aspartate, theinhibitory receptors for gamma-aminobutyric acid(GABA) and glycine (54).In preclinical pain models, gabapentin is a structuralanalogue of the neurotransmitter GABA; it exertsrobust analgesic and anti-allodynic effects insyndromes that are secondary to sensitization ofpain responses but has minimal effects in modelsof acute, transient pain (55). Taylor, et al. (56) suggestedthat gabapentin did not appear to reduceacute pain from injury, but appeared to be effectivein reducing abnormal hypersensitivity (allodyniaand hyperalgesia) induced by inflammatory responsesor nerve injury. The antinociceptive effectsof gabapentin are hypothesized to be mediated bymodulation of calcium channels via 2binding, modulationof transmission of GABA, and possibly otheradditional unidentified mechanisms.Arnold, et al. (57) conducted a 12-week, randomized,double-blind study that was designed to comparegabapentin (1,200-2,400 mg/day; n=75 patients)versus placebo (n=75 patients) for efficacyand safety in treating pain associated with FM. Patientswho were treated with gabapentin displayedsignificantly greater improvements in the BriefPain Inventory (BPI) average pain interferencescore, the Fibromyalgia Impact Questionnaire(FIQ) total score, the Clinical Global Impression ofSeverity, the Patient Global Impression of Improvement,the Medical Outcomes Study (MOS)Sleep Problems Index, and the MOS Short Form 36vitality score; but they did not show improvementsin the mean tender point pain threshold or theMontgomery Asberg Depression Rating Scale.Gabapentin was generally well tolerated by theseFM patients.Pregabalin is an α 2-δ ligand that has analgesic, anxiolytic-like,and anticonvulsant activity in animalmodels. Biochemical studies identified α 2-δ (type1) as the primary binding site for both pregabalinand the related compound, gabapentin (57). Alpha2-delta is an auxiliary protein associated withvoltage-gated calcium channels. Potent binding ofpregabalin at the α 2-δ site reduces calcium influx

Fibromyalgia syndrome: the pharmacological treatment options 55at nerve terminals (58) and, therefore, reduces therelease of several neurochemicals, including glutamate,noradrenaline, and substance P (58, 59).The reduced neurotransmitter release caused bydrug binding at the α 2-δ site is presumed to accountfor the the analgesic, anticonvulsant, andanxiolytic-like actions of pregabalin in animalmodels. Reduction of neurotransmitter release fromneurons in the spinal cord and brain is also proposedas the mechanism of action that may resultin clinical benefit for patients with FM. In an 8-week, multicentre, double-blind, randomised,placebo-controlled clinical trial, Crofford, et al.(61) compared the effects of pregabalin (150, 300and 450 mg/day) on pain, sleep, fatigue and healthrelatedquality of life in 529 FM patients, and foundthat it was superior to placebo in reducing thescores for pain, SF-MPQ, sleep index, fatigue, patientand clinician global impression of change,and four of the eight SF-36 domains. The most frequentadverse events were dizziness and somnolence.Arnold, et al. (62) conducted a study to assesssymptoms of anxiety and depression in a large cohortof FM patients to determine the impact ofthese symptoms on pain during a course of pregabalintreatment. The results indicated that anxietysymptoms were more common than depressivesymptoms in this cohort, and that the pain treatmenteffect of pregabalin did not depend on baselineanxiety or depressive symptoms, which suggeststhat pregabalin improves pain in patients with orwithout these symptoms. Finally, much of the painreduction appears to be independent of improvementsin anxiety or mood symptoms.In a multicenter, double-blind, placebo-controlledtrial, Mease, et al. (63) randomly assigned 748 FMpatients to receive placebo or pregabalin (300, 450,or 600 mg/day, dosed twice daily) for 13 weeks.The pregabalin groups showed statistically significantimprovements in mean pain score and in PatientGlobal Impression of Change (PGIC) comparedto the placebo group. Improvements in FIQ-Total Score for the pregabalin groups were numericallybut not significantly greater than those for theplacebo group. Compared with placebo, all pregabalintreatment groups showed statistically significantimprovement in assessments of sleep and inpatients’ impressions of their global improvement.Dizziness and somnolence were the most frequentlyreported adverse events. The study concludedthat pregabalin monotherapy provides clinicallymeaningful benefit to patients with FM.Other drugsSerotonergic receptors have been implicated in processinginformation and in the development of painin FM, and randomised, controlled trials havefound that tropisetron, a 5-hydroxytryptophan intermediatemetabolite of L-tryptophan, is more effectivethan placebo (64, 65)In a pilot study, Papadopoulos, et al. (66) found thattropisetron might be effective in treating pain in FMpatients, but Koeppe, et al. (67) did not observeany significant change in the intensity of habitualpain following local injection of tropisetron in FMpatients who took part in a pre- and post-treatment,double-blind study of pain perception and centralprocessing.In an open trial of pindolol, a mixed serotonin (5-HT)(1A) presynaptic autoreceptor/beta-adrenergicreceptor antagonist, at a dose of 7.5 mg/day (titratedto a maximum of 15 mg/day) for a total of 90days in 20 female FM patients, Wood, et al. (68)demonstrated a significant improvement in primarytender point counts (p

56 P. Sarzi-Puttini et al.rational, genotype-based, pharmacological approach(72). Subjects with the short 5HTTLPR allelein the serotonergic system may be more suitablecandidates for antidepressant treatment (73),whereas subjects with polymorphisms in thedopaminergic system, such as the dopamine D4receptor exon III repeat polymorphism, may becandidates for dopaminergic medications (73).Certainly, further randomized, controlled clinicaltrials that are conducted with subgroups of patientsusing standardized outcome measurements and sufficientlength of follow-up are necessary to observeand document changes in patient symptoms andbehaviors over time.SUMMARYPharmacological treatment has been gradually enriched by a variety of compounds; however, no single drug is capableof fully managing the constellation of fibromyalgia (FM) symptoms. Currently, it is not possible to draw definiteconclusions concerning the best pharmacological approach to managing FM because results of randomized clinical trialspresent methodological limitations and therapeutic programs are too heterogeneous for adequate comparison. However,a variety of pharmacological treatments including antidepressants, nonsteroidal anti-inflammatory drugs(NSAIDS), opioids, sedatives, muscle relaxants and antiepileptics have been used to treat FM with varying results. Inthis review, we will evaluate those pharmacological therapies that have produced the most significant clinical resultsin treating FM patients.The nature of FM suggests that an individualized, multimodal approach that includes both pharmacologic and nonpharmacologictherapies seems to be the most appropriate treatment strategy to date.Key words - Pharmacologic approach, non-pharmacologic approach, opioids, antiepileptics, nonsteroidal anti-inflammatorydrugs.Parole chiave - Terapia farmacologica, terapia non-farmacologica, oppiodi, antiepilettici, anti-infiammatori nonsteroidei.REFERENCES1. Mease P. Fibromyalgia syndrome: review of clinicalpresentation, pathogenesis, outcome measures, andtreatment. J. Rheumatol 2005; 75: 6-21.2. Shmerling RH. A review of fibromyalgia. Am. J ManagCare 2004; 10: 794-800.3. Wolfe F, Smythe HA, Yunus MD. The American Collegeof Rheumatology 1990 Criteria for the Classificationof Fibromyalgia. Report of the Multicenter CriteriaCommittee. Arthritis Rheum 1990; 33: 160-72.4. Sim J, Adams N. Physical and other non-pharmacologicalinterventions for fibromyalgia. Bailliere’s ClinRheumatol 1999; 13: 507-23.5. Offenbaecher M, Stucki G. Physical therapy in the treatmentof fibromyalgia. Scand J Rheumatol 2000; 29:78-85.6. Busch A, Schachter CL, Peloso PM, Bombardier C.Exercise for treating fibromyalgia syndrome. CochraneDatabase Syst Rev 2002 (3): CD003786.7. Keel PJ. Pain management strategies and team approach.Bailliere’s Clin Rheumatol 1999; 13: 493-506.8. Sarzi-Puttini P, Buskila D, Carrabba M, Doria A,Atzeni F. Treatment strategy in fibromyalgia syndrome:where are we now? Semin Arthritis Rheum 2008; 37:353-65.9. Cazzola M, Sarzi-Puttini P, Buskila D, Atzeni F. Pharmacologicaltreatment of fibromyalgia. Reumatismo.2007; 59: 280-91.10. Wolfe F, Zhao S, Lane N. Preference for nonsteroidalantiinflammatory drugs over acetaminophen byrheumatic disease patients: a survey of 1,799 patientswith osteoarthritis, rheumatoid arthritis, and fibromyalgia.Arthritis Rheum. 2000; 43: 378-85.11. Schnitzer TJ. Update on guidelines for the treatment ofchronic musculoskeletal pain. Clin Rheumatol 2006;25 (Suppl 1): S22-9.12. Carville SF, Arendt-Nielsen S, Bliddal H, Blotman F,Branco JC, Buskila D, et al. EULAR. EULAR evidencebasedrecommendations for the management of fibromyalgiasyndrome. Ann Rheum Dis. 2008; 67: 536-41.13. Clauw DJ. Pharmacotherapy for patients with fibromyalgia.J Clin Psychiatry. 2008; 69 Suppl 2: 25-9.14. No authors listed. Now we know: why opioids don’twork against fibromyalgia pain. Recent study revealsreduced opioid receptor availability in the brain; but anew FDA-approved drug brings relief. Health News2008; 14: 3.15. Furlan AD, Sandoval JA, Mailis-Gagnon A, Tunks E.Opioids for chronic noncancer pain: a meta-analysis ofeffectiveness and side effects. CMAJ 2006; 23, 174:1589-94.16. Biasi G, Manca S, Manganelli S, Marcolongo R. Tramadolin the fibromyalgia syndrome: a controlled clinicaltrial versus placebo. Int J Clin Pharmacol Res 1998;18: 13-9.17. Bennett RM, Kamin M, Karin R, Rosenthal N. Tramadoland acetaminophen combination tablets in the

Fibromyalgia syndrome: the pharmacological treatment options 57treatment of fibromyalgia pain. Am J Med 2003; 114:537-45.18. Bennett RM, Schein J, Kosinski MR, Hewitt DJ, JordanDM, Rosenthal NR: Impact of fibromyalgia pain onhealth-related quality of life before and after treatmentwith tramadol/acetaminophen. Arthritis Rheum 2005;53: 519-27.19. Kress HG. Clinical update on the pharmacology, efficacyand safety of transdermal buprenorphine. Eur JPain. 2008. [Epub ahead of print].20. Harris JD. Management of expected and unexpectedopioid-related side effects. Clin J Pain. 2008; 24: S8-S13.21. Sarzi-Puttini P, Atzeni F, Diana A, Doria A, Furlan RIncreased Neural Sympathetic Activationin FibromyalgiaSyndrome Ann NY Acad Sci 2006; 1069:109-117.22. Gupta A, Silman AJ. Psychological stress and fibromyalgia:a review of the evidence suggesting a neuroendocrinelink. Arthritis Res Ther 2004; 6: 98-106.23. McBeth J, Chiu YH, Silman AJ, Ray D, Morriss R,Dickens C, Gupta A, Macfarlane GJ. Hypothalamic- pituitary-adrenalstress axis function and the relationshipwith chronic widespread pain and its antecedents.Arthritis Res Ther 2005; 7: 992-1000.24. Torta R. Depression as Systemic Disease: the AntidepressantsSpectrum of Action. Psycho-Oncology 2006;15: 3-4.25. Epstein SA, Kay G, Clauw D, Heaton R, Klein D,Krupp L, Kuck J, et al. Psychiatric disorders in patientswith fibromyalgia. A multicenter investigation. Psychosomatics1999; 40: 57-63.26. Henningsen P, Zimmermann T, Sattel H. Medically unexplainedphysical symptoms, anxiety, and depression:a meta-analytic review. Psychosom Med 2003; 65: 528-33.27. Carta MG, Cardia C, Mannu F, Istilla G, Hardoy MC,Anedda C, et al. The high frequency of manic symptomsin fibromyalgia does influence the choice of treatment?Clin Pract Epidem Ment Health 2006; 2: 36.28. Goldenberg DL, Burckhardt C, Crofford L. Managementof fibromyalgia syndrome. JAMA 2004; 292:2388-95.29. Goldenberg D, Mayskiy M, Mossey C, Ruthazer R,Schmid C. A randomized, double-blind crossover trialof fluoxetine and amitriptyline in the treatment of fibromyalgia.Arthritis Rheum 1996; 39: 1852-9.30. Fishbain D. Evidence-based data on pain relief withantidepressants. Ann Med 2000; 32: 305-16.31. Maizels M, McCarberg B. Antidepressants andantiepileptic drugs for chronic non-cancer pain. AmFam Physician 2005; 71: 483-90.32. Arnold LM, Keck PE Jr, Welge JA. Antidepressant treatmentof fibromyalgia: a meta-analysis and review.Psychosomatics 2000; 41: 104-13.33. O’Malley PG, Balden E, Tomkins G, Santoro J,Kroenke K, Jackson JL. Treatment of fibromyalgia withantidepressants: a meta-analysis. J Gen Intern Med2000; 15: 659-66.34. Wolfe F, Cathey MA, Hawley DJ. A double-blindplacebo controlled trial of fluoxetine in fibromyalgia.Scand J Rheumatol 1994; 23: 255-9.35. Norregaard J, Volkmann H, Danneskiold-Samsoe B. Arandomized controlled trial of citalopram in the treatmentof fibromyalgia. Pain 1995; 61: 445-9.36. Anderberg UM, Marteinsdottir I, von Knorring L.Citalopram in patients with fibromyalgia: a randomized,double-blind, placebo-controlled study. Eur J Pain2000; 4: 27-35.37. Arnold LM, Hess EV, Hudson JI, Welge JA, Berno SE,Keck PE Jr. A randomized, placebo-controlled, doubleblind,flexible-dose study of fluoxetine in the treatmentof women with fibromyalgia. Am J Med 2002; 112:191-7.38. Torta R, Lacerenza M. Depressione e Dolore, Utet, Milano2002; 199.39. Torta R, Berra C. La terapia neuropsicofarmacologicanel dolore. In: Torta R., Mussa A: PsicOncologia. Il modellobiopsicosociale. Centro Scientifico Editore, Torino,2007.40. Arnold LM, Hess EV, Hudson JI, Welge JA, Berno SE,Keck PE Jr. A randomized, placebo-controlled, doubleblind,flexible-dose study of fluoxetine in the treatmentof women with fibromyalgia. Am J Med 2002; 112:191-7.41. Perrot S, Maheu E, Javier RM, Eschalier A, CoutauxA, LeBars M, et al. Guidelines for the use of antidepressantsin painful rheumatic conditions. Eur J Pain.2006; 10: 185-92.42. Sindrup SH, Otto M, Finnerup NB, Jensen TS. Antidepressantsin the treatment of neuropathic pain. BasicClin Pharmacol Toxicol 2005; 96: 399-409.43. Arnold LM, Lu Y, Crofford LJ, Wohlreich M, DetkeMJ, Iyengar S, Goldstein DJ. A double-blind, multicentertrial comparing duloxetine with placebo in thetreatment of fibromyalgia patients with or without majordepressive disorder. Arthritis Rheum 2004; 50:2974-84.44. Russell IJ, Mease PJ, Smith TR, Kajdasz DK, WohlreichMM, Detke MJ, et al Efficacy and safety of duloxetinefor treatment of fibromyalgia in patients with orwithout major depressive disorder: Results from a 6-month, randomized, double-blind, placebo-controlled,fixed-dose trial. Pain 2008; 136: 432-44.45. Vitton O, Gendreau M, Gendreau J, Kranzler J, Rao SG.A double-blind placebo-controlled trial of milnacipranin the treatment of fibromyalgia. Hum PsychopharmacolClin Exp 2004; 19: 27-35.46. Arnold LM, Rosen A, Pritchett YL, D’Souza DN, GoldsteinDJ, Iyengar S, Wernicke JF. A randomized, double-blind,placebo-controlled trial of duloxetine in thetreatment of women with fibromyalgia with or withoutmajor depressive disorder. Pain 2005; 119: 5-15.47. Arnold LM. Biology and therapy of fibromyalgia. Newtherapies in fibromyalgia. Arthritis Res Ther 2006; 8:212-32.48. Santandrea S, Montrone F, Sarzi-Puttini P, BoccassiniL, Caruso I. A double-blind crossover study of two cyclobenzaprineregimens in primary fibromyalgia syndrome.J Int Med Res 1993; 21: 74-80.

58 P. Sarzi-Puttini et al.49. Tofferi JK, Jackson JL, O’Malley PG. Treatment of fibromyalgiawith cyclobenzaprine: A meta-analysis.Arthritis Rheum 2004; 51: 9-13.50. Torta R, Bovero A. L’intervento integrato fra psicoterapiabreve ed antidepressivi nel dolore oncologico. IlGiornale di Psiconcologia, 2008, in press.51. Benedetti F. What do you expect from this treatment?Changing our mind about clinical trials. Pain 2007; 128:193-4.52. Colloca L, Benedetti F. Nocebo hyperalgesia: how anxietyis turned into pain. Curr Opin Anaesthesiol 2007;20: 435-9.53. Dworkin RH, Backonja M, Rowbotham MC, Allen RR,Argoff CR, Bennett GJ, et al. Advances in neuropathicpain: diagnosis, mechanisms, and treatment recommendations.Arch Neurol 2003; 60: 1524-34.54. McQuay H, Carroll D, Jadad AR, Wiffen P, Moore A.Anticonvulsant drugs for management of pain: a systematicreview. BMJ 1995; 311: 1047-52.55. Abdi S, Lee DH, Chung JM. The anti-allodynic effectsof amitriptyline, gabapentin, and lidocaine in a rat modelof neuropathic pain. Anesth Analg 1998; 87: 1360-6.56. Taylor CP, Gee NS, Su TZ, Kocsis JD, Welty DF,Brown JP, et al. A summary of mechanistic hypothesesof gabapentin pharmacology [review]. Epilepsy Res1998; 29: 233-49.57. Arnold LM, Goldenberg DL, Stanford SB, Lalonde JK,Sandhu HS, Keck PE Jr, et al. Gabapentin in the treatmentof fibromyalgia: a randomized, double blind,placebo-controlled, multicenter trial. Arthritis Rheum2007; 56: 1336-44.58. Gee NS, Brown JP, Dissanayake VU, Offord J, ThurlowR, Woodruff GN. The novel anticonvulsant drug,gabapentin (neurontin), binds to the 2subunit of a calciumchannel. J Biol Chem 1996; 271: 5768-76.59. Fink K, Dooley DJ, Meder WP, Suman-Chauhan N,Duffy S, Clusmann H, et al. Inhibition of neuronalCa(2+) influx by gabapentin and pregabalin in thehuman neocortex. Neuropharmacology 2002; 42:229-36.60. Maneuf YP, Hughes J, McKnight AT. Gabapentin inhibitsthe substance P-facilitated K(+)-evoked releaseof [ (3) H]glutamate from rat caudal trigeminal nucleusslices. Pain 2001; 93: 191-6.61. Crofford LJ, Rowbotham MC, Mease PJ, Russell IJ,Dworkin RH, Corbin AE, et al. Pregabalin for the treatmentof fibromyalgia syndrome: results of a randomized,double blind, placebo-controlled trial. ArthritisRheum 2005; 52: 1264-73.62. Arnold LM, Crofford LJ, Martin SA, Young JP, SharmaU. The effect of anxiety and depression on improvementsin pain in a randomized, controlled trial ofpregabalin for treatment of fibromyalgia. Pain Med2007; 8: 633-8.63. Mease PJ, Russell IJ, Arnold LM, Florian H, Young JPJr, Martin SA, Sharma U. A Randomized, Doubleblind,Placebo-Controlled, Phase III Trial of Pregabalinin the Treatment of Patients with Fibromyalgia. JRheumatol 2008 Feb 15 [Epub ahead of print].64. Färber L, Stratz TH, Brückle W, Späth M, Pongratz D,Lautenschläger J, et al. Short-term treatment of primaryfibromyalgia with the 5-HT3-receptor antagonist tropisetron.Results of a randomized, double-blind, placebocontrolledmulticenter trial in 418 patients. Int J ClinPharmacol Res 2001; 21: 1-13.65. Späth M, Stratz T, Färber L, Haus U, Pongratz D. Treatmentof fibromyalgia with tropisetron—dose and efficacycorrelations. Scand J Rheumatol (Suppl.) 2004;(119): 63-6.66. Papadopoulos IA, Georgiou PE, Katsimbri PP, DrososAA. Treatment of fibromyalgia with tropisetron, a5HT3 serotonin antagonist: a pilot study. Clin Rheumatol2000; 19: 6-8.67. Koeppe C, Schneider C, Thieme K, Mense S, Stratz T,Müller W, Flor H. The influence of the 5-HT3 receptorantagonist tropisetron on pain in fibromyalgia: afunctional magnetic resonance imaging pilot study.Scand J Rheumatol Suppl 2004; (119): 24-7.68. Wood PB, Kablinger AS, Caldito GS. Open trial of pindololin the treatment of fibromyalgia. Ann Pharmacother2005; 39: 1812-6.69. Jones KD, Deodhar P, Lorentzen A, Bennett RM, DeodharAA. Growth hormone perturbations in fibromyalgia:a review. Semin Arthritis Rheum. 2007;36: 357-79.70. Sörensen J, Bengtsson A, Bäckman E, Henriksson KG,Bengtsson M. Pain analysis in patients with fibromyalgia.Effects of intravenous morphine, lidocaine, and ketamine.Scand J Rheumatol 1995; 24: 360-5.71. Staud R. Are tender point injections beneficial: the roleof tonic nociception in fibromyalgia. Curr Pharm Des2006 12: 23-7.72. Buskila D, Sarzi-Puttini P, Ablin JN. The genetics offibromyalgia syndrome. Pharmacogenomics 2007; 8:67-74.73. Buskila D, Sarzi-Puttini P. Biology and therapy of fibromyalgia.Genetic aspects of fibromyalgia syndrome.Arthritis Res Ther 2006; 8: 218.

ORIGINAL ARTICLEReumatismo, 2008; 60: Supplemento 1: 59-69Non pharmacological treatments in fibromyalgiaIl trattamento non farmacologico della sindrome fibromialgicaR. Casale 1 , M. Cazzola 2 , G. Arioli 3 , R.H. Gracely 4 , F. Ceccherelli 5 , F. Atzeni 6 , S. Stisi 7 , G. Cassisi 8 ,L. Altomonte 9 , A. Alciati 10 , G. Leardini 11 , R. Gorla 12 , A. Marsico 13 , R. Torta 14 , M.A. Giamberardino 15 ,D. Buskila 16 , M. Spath 17 , F. Marinangeli 18 , L. Bazzichi 19 , M. Di Franco 20 , G. Biasi 21 , F. Salaffi 22 ,R. Carignola 23 , P. Sarzi-Puttini 6 , (Italian Fibromyalgia Network)1Department of Clinical Neurophysiology and Pain Rehabilitation Unit, Foundation Salvatore Maugeri, IRCCS, Scientific Institute ofMontescano, Montescano (PV), Italy; 2 Unit of Rehabilitative Medicine “Hospital of Circolo”, Saronno (VA), Italy; 3 Division ofRehabilitative Medicine and Rheumatology, General Hospital of Pieve di Coriano (Mantua), Italy; 4 Department of Medicine, Universityof Michigan Health System, Ann Arbor, USA; 5 IOV (Veneto Cancer Institute), IRCCS, Department of Pharmacology andAnesthesiology, University of Padua, Italy; 6 Rheumatology Unit, L.Sacco University Hospital, Milan, Italy; 7 Rheumatology Unit,“G.Rummo” Hospital, Benevento, Italy; 8 Rheumatology Branch, Specialist Out-patients Department, Belluno, Italy;9UOC of Rheumatology Hospital S. Eugenio, Rome, Italy; 10 Department of Psychiatry, L. Sacco University Hospital, Milan, Italy;11Rheumatology Unit, SS Giovanni e Paolo Hospital , Venice, Italy; 12 Rheumatology and Clinical Immunology, Spedali Civili andUniversity of Brescia, Italy; 13 Rheumatology Unit, Hospital of Taranto, Taranto, Italy; 14 Department of Neuroscience, University ofTurin, A.S.O. San Giovanni Battista of Turin, Turin, Italy; 15 Ce.S.I. “G. D’Annunzio” Foundation, Department of Medicine and Scienceof Aging, “G. D’Annunzio”, University of Chieti , Italy; 16 Department of Medicine H, Soroka Medical Center and Faculty of HealthSciences, Ben Gurion University, Beer Sheva, Israel; 17 Friedrich-Baur-Institute, University of Munich, Germany; 18 Department ofAnesthesiology and Pain Medicine, L'Aquila University, L'Aquila, Italy; 19 Department of Internal Medicine, Division of Rheumatology,S. Chiara Hospital, University of Pisa, Italy; 20 Chair of Rheumatology, University la Sapienza Rome, Rome, Italy; 21 Unit ofRheumatology, University of Siena, Siena, Italy; 22 Department of Rheumatology, Polytechnic University of the Marche Region, Ancona,Italy; 23 S.C.D.U. Internal Medicine I, Department of Clinical and Biological Science, University of Turin, ItalyCompeting interests: none declaredRIASSUNTOLa fibromialgia è una sindrome complessa associata ad una significativa riduzione della qualità di vita e della funzionecon sostanziali costi economici. Una volta che la diagnosi venga fatta, il personale sanitario dovrebbe cercaredi migliorare le funzioni del paziente e di minimizzare il dolore. I pazienti affetti da fibromialgia frequentemente utilizzanoterapia complementari, indicando con questo la loro insoddisfazione e la sostanziale inefficacia della terapiamedica tradizionale, in particolare quella farmacologica. Attualmente, le terapie farmacologiche presentano uno scoraggianterapporto costo/beneficio sia in relazione allo scarso controllo dei sintomi sia per l’alta incidenza di effetticollaterali. I programmi di terapia interdisciplinare hanno evidenziato di migliorare la sintomatologia in maniera piùsignificativa rispetto alle monoterapie. Le terapie fisiche, la riabilitazione e le terapie alternative sono generalmentepercepite per essere più “naturali”, per avere meno effetti collaterali, e in qualche modo, per essere più efficaci. Inquesta review, l’esercizio fisico e la terapia cognitivo-comportamentale multimodale sono presentate come le formepiù accettate e più efficaci nell’area della terapia non farmacologica.Reumatismo, 2008; 60: Supplemento 1: 59-69Corresponding author:Piercarlo Sarzi-Puttini, MDDirector of Rheumatology UnitL. Sacco University Hospital, Milan, ItalyE-mail: sarzi@tiscali.itINTRODUCTIONTo fully answer the complex question of whatmodes of non pharmacological treatments areuseful for fibromyalgia (FM) one should ask differentlayers of questions, and as with peeling layersof onions, be prepared to shed some tears.The first painful question, or layer of the onion, isrelated to understanding patients’ complaints. Patientswho experience recurrent as well as persistentphysical symptoms without any objective evidenceare too often classified as “psychosomaticdisorders” or worse as “non disease” (see Sarzi thisissue). This is often the case with FM. This leadsto the use of alternative medicines such as physi-

60 R. Casale et al.cal exercise and other therapies that are used infancy and pseudophilosophical ways, and it rendersevaluation of possible positive results nearly impossiblein the absence of a defined diagnosis andrecognised treatment protocols.The second onion layer is related to the possiblepresence of FM subset as well as to the erratic presentationof multiple painful muscle spots and correlatedsymptoms (1).A third layer recognizes the presence of different approachto management objectives and treatmentchoices by the various medical professionals involvedin the treatment of FM. For instance occupationaltherapists consider an increasing level of activityas the major treatment objective, followed bypain control and fatigue management while physicaltherapists are more concerned with improvingexercise tolerance and fitness followed by pain controland functional abilities. Fatigue managementand endurance exercise are the most frequent interventionaltargets across both professions (2).The last and most important layer addresses thepresence of a neuropathic component in the manifestationof pain in FM. In other words, if the painexpression in FM is only due to nociceptive pain(peripheral and related to an activation in musclenociceptors), or if the pain felt by FM patients intheir muscle is more or less dependent on functionalalteration in the sensory decoding of afferentinputs as well as in altered descending paincontrol systems. These last theories have gainedstrength recently based on several studies as wellas clinical reports (see other chapters in this issue).This is the most important point to keep in mindwhen prescribing non pharmacological treatmentsin FM, as the two types of pain, namely neuropathicand nociceptive, require different non pharmacologicalapproaches (3). Unfortunately, thisconcept is rarely considered when tailoring nonpharmacological treatments for pain control, ingeneral, and particularly, in FM. This oversight canresult in inappropriate application of otherwise usefulnon pharmacological pain control techniques..For the sake of systematic organization, the mostcommonly used forms of non pharmacologicaltreatment in FM can be divided into four majorcategories:- Physical therapies- Movement and exercises.- Cognitive-behavioural treatments.- Complementary and alternative treatments.Of note, the majority of non pharmacological treatmentstudies utilise multimodal therapies, whichrenders comparison and critical analysis on the efficacyof a single treatment difficult and a possibleguideline on these techniques a source of majorcriticism.PHYSICAL THERAPIESThe definition of physical therapies encompassesall treatment using a physical activity or techniqueto induce some therapeutic effect. These techniquesare mainly used in a rehabilitation context, althoughsome are also used as complementary andalternative treatments. These two approaches arequite divergent, however. In the rehabilitation context,physical therapies are used on the basis oftheir ascertained mechanism of action (i.e., the activationof the spinal gate, release of endogenousopiates, local metabolic action, etc.), but when usedas alternative treatments this linkage is completelylost.Physical therapies include thermal (both heat andcold), mechanical, light, electrical and magneticstimulation. In this context, acupuncture as well asmechanical stimulation that is induced by someform of massage (i.e. connective tissue massage)can be considered as particular forms of physicaltreatment. Each technique claims its own mechanismof action, although peer-reviewed evidence oftheir effectiveness in FM is lacking and recent reviewshave reached non homogeneous conclusions.While some reviews, based only on few randomized,controlled trials, are cautious in stating efficacy,they strongly suggest conducting more soundstudies and demonstrating a long-term, effectiveintervention for managing the symptoms associatedwith FM (4). Other reviews, which have includedanecdotal evidence or small, observationalphysiotherapy studies, indicate that physical therapiescan be efficacious for different symptoms (5).Heat and coldAlthough beneficial in other forms of muscle pain,local application of cold therapy by means of icecubes or cooling sprays does not seem to have anyefficacy in FM. Cold sprays are used within thestretch and spray techniques (see below). On thecontrary whole body criotherapy at -67°C seems tohave some short-term effect on the number of activetrigger points and intensity of pain. No data areavailable on its long-term efficacy (6). Superficialheat and deep heat with infrared and ultrasound applicationas well as the local thermal effect induced

Non pharmacological treatments in fibromyalgia 61by stroking massages have been always reported asbeneficial by FM patients (7, 8). When deep heathas been compared with sertraline, an antidepressant,it fails to show any better results (9). Heat isalso a fundamental factor in balneotherapy (see below).The real efficacy of both superficial as well asdeep heat is still matter for research, however.Electrical stimulation & TENSElectrical currents are, by far, the most used physicaltherapy in pain medicine. In fibromyalgia theyhave been applied transcutaneously to stimulateperipheral nerves (TENS) (10, 11) as well as totranscranially to stimulate cortical areas of the brain(12). Stimulation of motor cortex areas is betterachieved through magnetic stimulation. Preliminarybut encouraging results have been obtained bythis newly introduced methodology (13, 14). Traditionalelectrical currents have been used at highand low intensity (12) as well as at high and lowfrequency (10, 11) and by applying interferentialpatterns (7). Hydrogalvanic baths have historicalmerit, although they are evidently still in use withsome success in treating pain (15). One review articlequotes TENS as a useful methodology to controlspecific symptoms such as localised musculoskeletalpain (5) while a more recent review ismore cautious on the general efficacy of electricalcurrent (4). What can be said is that TENS and relatedtechniques can be beneficial in treating specific,contingent and localized pain problems whilethey do not have any sort of effect on FM as awhole. This concept is extensible to most of the nonpharmacological treatments considered in this review.Laser LightFew and conflicting data are available on the useof LASER in FM although a possible mechanismbasedefficacy has been demonstrated (16). Somestudies have reported no effects (17, 18) while othershave found a statistically significant reductionin both spontaneous and mechanically evoked pain(19, 20). Comparison of various treatment protocolsis difficult, however, due to varying lengths ofemission wave and emission power across different,non-standardised protocols. Moreover almostall studies that employed laser treatment used lowpower laser that cannot reach deep muscle layerswhere taught band and trigger points are usually located.As far as we know only one study has used lightbathing (exposure to a source of with light) as atherapy; however, results in FM patients did not differfrom those in the placebo group (21).MassageThe efficacy of massage varies depending on thetype and intensity of mechanical stimulation exerted.Connective tissue massage is a techniquethat applies mechanical stimulation of varying intensityin a predetermined pattern rather than followingthe trigger point sites identified by the patient.This technique uses two different stimulationintensities, and the mechanism of action relies ongate control as well as on the release of endogenousopiates. Connective tissue massage has been shownto improve pain and reduce the number of triggerpoints (22-24) while other forms of massage, i.e.,relaxation massages, only result in a general sensationof pleasantness and wellness (25); althoughthis is very much appreciated by patients (26, 27),it does not reflect a clinical improvement. Relaxationmassage, therefore, is more appropriately designatedas an alternative treatment than a physicaltherapy.AcupunctureIn single clinical trials acupuncture shows interestingresults (28, 29) that are confirmed by systematicreviews (30). Acupuncture has been shown notonly to decrease the number and intensity of painfulspots but also to modify neuro-hormonal parametersin these patients (29). It is worth noting thatsome FM patients do not like the acupuncture sensation;and in some cases, exacerbation of symptomshas been reported, which confirms the clinicalobservations of the extreme instability of thesensory-reaction system in these patients (30, 31).Dry needling is a form of acupuncture performedwith normal needles that are usually used for injectedtherapies (28 gauge). Dry needling of triggerpoints seems to have some long lasting effecton trigger-point pain in nearly 30% of patients (32);this may be due to activation of the endogenousopioid system as its analgesic effect is reversed bynaloxone. A systematic review and meta-analysisof randomised controlled trials on dry needling andacupuncture in the management of myofascial triggerpoint pain has been published recently and focuseson the substantial need for more extensive,controlled studies (33).BalneotherapyThermal therapy is one of the oldest treatmentmodalities for osteoarthropathies. Historically, the

62 R. Casale et al.definition of “balneotherapy” has been used onlyto define treatments with thermal or mineral waters,while the definition of hydrotherapy was reservedfor water therapy without particular thermal ormineral contents. More recently, the definition ofbalneotherapy has been applied to all therapeuticprocedures performed in water. This placed balneotherapymidway between physical therapy andcognitive behavioural therapy in as much as theenvironment (thermal resorts), the water temperature(37°C) and the execution of exercise can contributeto the positive results of this treatment inFM. The exact amount of efficacy of each singlecomponent has been challenged by a recent studyin which balneotherapy alone and balneotherapyplus water exercise did not differ in results (34). Torender evaluation more difficult, exercise in waterversus a dry environment does not result in substantialdifferences (35). Positive results can be perceivedafter 6 weeks to 6 months according to differentauthors (36-38). Sauna and mud bath treatmentshave been used with some positive results inuncontrolled studies; these results may be relatedto some sort of stress induced analgesia (39, 40).MOVEMENT AND EXERCISESThe majority of FM patients complain of severefunctional limitations in activities of daily living(41), and not surprisingly, most FM patients arephysically deconditioned (42). Active as well aspassive mobilization have been used although recentreviews do not provide clear results on theirefficacy. Active physical exercise, both aerobic andanaerobic, has been identified as one of the pivotaltreatments in FM, although patients quite oftenhave difficulties in starting and maintaining exerciseprograms (43).The internet provides access to so many types ofphysical training and exercises that is almost impossibleto take all them into account. Moreover,sometimes terms such as “movement” or “physicalexercise” are proposed without giving any specificsconcerning the type of exercise that should be done,the duration, or the intensity of the training. In thisrespect the term physical exercise is similar to theterm “drug”.In both cases describing a treatment as aerobic oranaerobic or drug is not enough, specific details ofthe treatment must be provided. A very recentmeta-analysis reviewed all studies that were identifiedon the Cochrane Central Register for ControlledTrials up to July 2005 suggesting moderateevidence that aerobic-only exercise training atAmerican College of Sports Medicine (ACSM)-recommended intensity levels has positive effectson global well-being and physical function, primarily,and, also a possible effect on pain and tenderpoints. Strength and flexibility remain underevaluated;however, strength training may have apositive effect on FM symptoms. This meta-analysissuggests that aerobic-only training has beneficialeffects on physical function and some FMsymptoms.Strength-only training may improve FM symptoms,but requires further study (44). Table I providesan overview of data from the Cochrane Reviewon exercise for FM (45). However, data on thelong-term efficacy of movement and exercise incontrolling the clinical picture are still lacking.Aerobic exercises can be performed in a traditional“dry” environment as well as in water via deepwater running programs, hydrokinesis therapy inheated water, and in the Spa environment (35, 46,47). In general, both aerobic and anaerobic exerciseshave been associated with educational andoccupational programs (48-52). While the shorttermefficacy of exercise is generally accepted, thecritical issue appears to be long-term compliance.Most studies report a lack of persistent effects associatedwith a failure to maintain the exercise program(53).Passive movements induced by manipulative techniqueshave been also used. They encompass severalmethodologies such as vertebral manipulations,finger pressure on trigger points, craniosacralmanipulation techniques and other forms of chiropractics.A controlled study on the efficacy of chiropracticshas shown a reduction in pain and disability levelsassessed using the Oswestry Pain Disability Indexand Neck Disability Index. Although positive, theseresults should be considered with caution and ageneralization of the efficacy of these practices isuntenable (54). Stretch and spray technique is apopular form of myofascial pain therapy in rehabilitation.The technique combines the effect of rapid coolingof the overlying skin using a vapocoolant such asfluorimethane with passive elongation of muscles.Despite its popularity only one study reports a reductionof pain at the trigger points measured bypressure algometer and VAS in myofascial pain patients;as far as we know no data are available onFM patients.

Non pharmacological treatments in fibromyalgia 63Table I - Major findings of Cochrane revision on “Exercise for treating fibromyalgia syndrome” from: Busch AJ, Barber KAR, Overend TJ, PelosoPMJ, Schachter CL. Exercise for treating fibromyalgia syndrome. Cochrane Database of Systematic Reviews 2002, Issue 3.Aerobic 4 studies Aerobic fitness/performance improved on average by 17% in patients who did aerobicexercise cycling, walking, exercises and 0.5% in patients who did notwhole body- thresholds to pain improved on average by 28% in patients who did aerobic exercisesor dance aerobics but worsened by 7% in patients who did notover 6 to 20 weeks - pain intensity decreased on average by 11% in patients who did aerobic exercises(2 studies tested but increased by 1.6% in patients who did notat 2 or 4.5 years - overall well-being improved in patients who did aerobic exercisesalso).- sleep, fatigue, sense of well-being, confidence in performing tasks and physical functionimproved in some studies but did not in other studies- psychological function, such as depression or anxiety, improved equally in patientswho exercised and in patients who did notStrength One study - pain, muscle fitness and mood improved in patients who did strength exercises more thanexercises squats, knee in patients who did notand trunk extensions - sleep and fatigue changed about equally in patients who exercised and in patientsand bench presswho did notover 21 weeksCombined One study - aerobic fitness and thresholds to pain improved more in patients who had a combinedexercises Aerobic program exercise program compared to patients who did not(walking) strengthand flexibilityexercisesover 6 weeksCombination Two studies - there were no differences between the patients who exercised with biofeedback or withoutof exercise Aerobic exercise biofeedbackand another plus educationtreatment and aerobic exerciseplus biofeedbackLonger Three studies that - One study showed that patients reported better physical function and greater confidencefollow-up tested exercises for in performing daily tasks after 1 year of exercise.longer than 21 weeks - The other study showed that patients who exercised for 6 months had greater confidencein performing daily tasks, had less fatigue and showed more improvement in the 6-minuteCOGNITIVE BEHAVIORAL THERAPYAlong with physical exercise training, cognitive behavioraltherapy is a recognized treatment for FM.Cognitive behavioral therapy (CBT) is a compositeof two approaches, cognitive therapy and behavioraltherapy. Today CBT refers to a large numberof component methods. The term CBT is nonspecificand similar to the term “drug”. Similar tothe generic term “physical exercise” discussedabove, describing a treatment as CBT or drug is notenough, specific details of the treatment must beprovided.The behavior therapy component of CBT includesa number of techniques that are centered on thecore tenants of operant and classical conditioningin psychology. In applications to treatment, theclassification is expanded to a number of methodsthat include relaxation, sleep hygiene, pacing ofactivity, scheduling social and leisure activities,pain coping, education, and assertiveness training(55). The combination of this large group of proceduresalong with cognitive therapy provides thecomponents of the CBT “toolbox”. This concept ofa toolbox is important when considering CBT forFM patients since meaningful discussion and evaluationmust take into account the specific tools thatare used.Co-morbidities including stiffness, fatigue; andproblems with sleep, concentration and memory

64 R. Casale et al.are more or less associated in almost all FM patients.It is not surprising that many patients experienceinterpersonal distress and behavioral deficits.Since CBT has been shown to be particularly effectivein distress and behavior disorders, it is logicalto apply CBT methods to FM. This approachassumes that a patient can be helped significantlyby addressing the many non-pain aspects of FM.A growing literature describes CBT treatment ofFM and has been addressed by meta analyses andreviews (55-59).A similar literature describes CBT approaches torelated disorders such as irritable bowel syndrome,and the concepts learned in these disorders are usefulfor the treatment of FM. The available evidencecan be divided into studies of CBT alone, CBT incombination with other pharmacological and nonpharmacologicaltherapies, the nature of CBT effects,patient subgrouping and tailoring CBT componentsto specific treatment.Data emerging from these reviews and meta-analysessuggest that such single method CBT (smCBT)treatments may be the least efficacious in terms ofmultiple outcome measures (60).Several studies of education programs and relaxationhave not demonstrated effects that persist infollow up evaluations. Improved results have beenobtained with multiple method CBT (mmCBT),which can include a number of components suchas cognitive restructuring, pain-coping, problemsolving, goal setting, increasing activity levels, pacing,stress management, and adjustment of painmedications in addition to education and relaxation(60, 61).The effectiveness of this approach was demonstratedin a study in which two groups received“standard” care of pharmacological therapy andexercise instruction, and one of these groups receiveda minimal package of six, one-hour groupsessions of CBT that focused on improving function.At one year, twice the number of patients receivingstandard care plus CBT reported significantimprovement in comparison to the group receivingstandard care only. At two years most patients continuedto report benefits.The principle that mmCBT is superior to smCBTcan be extended to multi-dimensional therapy inwhich mmCBT is paired with other traditional therapies.The two most common are pharmacological treatmentand exercise therapy (see this chapter). Mostreviews have discussed the positive effects of drugsassociated with various form of CBT. One issue isthat the efficacy is coupled with the short-term effectsof these drugs such that improvements maybe lost if the drug is discontinued.Many reviews of CBT for fibromyalgia concludethat the effects are modest. It is important to notethat this is true for all treatments of FMS, includingthe new generation of pharmacological agents.The fact that only one-third of participants respondto an active therapy is a challenge for the developmentof future treatments.It also raises interesting questions such as whetherthere is a small responder group that responds toany form of treatment, or a broader group, subsetsof which respond to different treatments. MmCBTtargets significant components of FM and relateddisorders, enjoys superior compliance in comparisonto exercise, and results in positive effects thatpersist after treatment.COMPLEMENTARY AND ALTERNATIVETREATMENTSAs many as 87% of the general population of tertiarycare patients have tried at least one complementaryand alternative treatment (62) (Table II).Terms such as non-conventional, complementaryand alternative treatments encompass all therapeu-Table II - Use of complementary and alternative medical treatmentsat a tertiary care center (62).Techniques and unconventional N° patients (289)treatments %Physical exercises 48Prayer 45Massage 44Chiropractics 37Weight control 20Relaxation techniques 17Aromatherapy 15Music therapy 12Acupuncture 11Counseling & therapeutic groups 11Homeopathy 10Acupressure 10Magneto therapy 9Plantar reflexology 9Pranotherapy 8Biofeedback 8Therapeutic painting 5Others 8Patients using at least one of the listed therapies 87

Non pharmacological treatments in fibromyalgia 65tic and healing techniques that are not recognizedby the scientific community due to lack of pathophysiologicalevidence and mechanisms of actionthat are able to support their supposed efficacy. Allof the treatments cited below are popular with patientsand available (with payment) on several siteson the web; our search terms simply matched thetreatment type with “fibromyalgia”.Five of these are considered complementary or alternativetreatments that are more or less openlyused in FM:a) complete theoretical systems such as homeopathy,naturopathy and anthroposophy, traditionalChinese medicine, and ayurvedic medicine;b) body-mind techniques;c) nutriceutics;d) physical manipulation;e) energetic medicine encompassing pranotherapy,reiki, and healing touch.On a recent American survey (62) the most popularalternative treatments included physical exercise(48%), prayer (45%), massage (44%), and chiropractics(37%). Along with these treatments 83%of these patients use at least one vitamin and 52%use some sort of food supplementation.Complete therapeutic systemsAmong complete therapeutic systems, homeopathyis used the most. Its efficacy in FM, as for almostof its clinical application, has never been demonstratedin clinically controlled trials (63).Ayurvedic, anthroposophy and traditional Chinesemedicine as well as homeopathy are based on principlesthat are alien to Western biology and too farfrom the writer’s competence to be reasonably andfully reported here.Body-mind techniquesThis definition encompasses those techniques thatare used to improve mental control over bodilyfunctions.Some of them have been accepted already and usedin the context of traditional Western medicine suchas behavioural and cognitive therapies, supportgroups, and music therapy in its broader meaning,while others are still outside official medicine suchas meditation, therapeutic prayer, and mentallydrivenhealing techniques.Although not considered in this review, it is worthnoting the interesting results obtained by thesebody-mind techniques: they seem to be able to diminishthe number and the pain intensity of tenderpoints, and they can improve depression, anxietyand physical performance for over two years (64).Apparently, similar results have been obtained withmeditation techniques (65).Some clinical benefits have been obtained in a therapy-resistantgroup of FM patients by means ofhypnosis (66).Nutriceutics and dietary supplementationAs many as 52% of FM patients use some form ofalimentary supplementation including vitamins C(35%), E (31%), and B complex (25%) and Magnesium(29%).Green tea (24%) is popular as an antioxidant;weight control programs (20%) are also popular.Some alimentary supplements have demonstratedsome utility in reducing pain intensity and fatiguesuch as methionin (67-69) and magnesium (70, 71),while others did not show any improvement (72).Moreover, there are various other nutraceutics thatclaim some success in controlling FM-relatedsymptoms such as sleep disturbance and early sensationof fatigue.Unfortunately, as for almost all of the treatments reportedin this section, controlled studies are lacking.Some benefits have been claimed using melatonin(73), hypericum perforatum (St. John’s wort) anddietary control (74).Physical manipulationChiropratics and other forms of manipulationbased on mobilization or even manipulation ofbody segments like manual medical techniques(Meigne) and all forms of non medical massage. Itseems that the chiropractic approach is useful in thetreatment of FM.One study compared FM patients who experienced4 weeks of treatment to patients on a wait list andregistered a temporary decrease in cervical andlumbar pain in the treated group. These patientswere also taking medication (75).CONCLUSIONSFM patients frequently use alternative therapies,strongly indicating their dissatisfaction with traditionalmedical therapies as well as the substantialineffectiveness of these traditional therapies, especiallypharmacological treatment.At present, pharmacological treatments for FMShave a rather discouraging ratio poor symptom con-

66 R. Casale et al.trol associated with a high incidence of side effects.Physical therapy, rehabilitation and alternativetherapies are generally perceived to be more“natural,” to have fewer adverse effects, and insome way, to be more effective. In this contextphysical exercise and multimodal cognitive behaviouraltherapy seem to be the more acceptedand beneficial forms of non pharmacological therapy.Anedoctal evidence and small observationalstudies using physical therapies, show some goodresults.These results are encouraging premises for larger,more systematic and methodologically sound, randomised,controlled clinical trials which will evaluatethe real effectiveness of physical therapymodalities for managing FM.It is clear that, similar to successful treatment ofother disorders, the most efficacious treatment ofFM will combine the major elements of pharmacotherapy,exercise, physical therapy and mmCBT.Evidence that efficacy is inversely related to diseaseduration suggests that this treatment programshould be initiated as quickly as possible after diagnosis.As noted above, multi-modal treatment may succeedfor a number of reasons. The results of recentstudies that have identified distinct subgroups inFM and studies that predict treatment response indicatethat it will be useful, if not essential, to tailorthe choice of treatment components to individualpatients.Current knowledge is beginning to suggest predictioncriteria for treatment success, and future studiesthat include detailed genotyping and phenotypingpromise to vastly increase the ability to matchtreatment packages to patients. Such knowledgewill also identify healthy individuals who are atrisk for developing FM and signal prophylactictreatment in a manner that is similar to current interventionsfor diabetes or heart disease. Currentevidence suggests that CBT, exercise and to a lesserextent, physical therapies will remain importantcomponents in these individualized treatments byplaying a pivotal role in the long-term managementof FM.The need for multimodal therapy in FM comesfrom different sources. It relies on several factors:first, the potential that all patients possess the samemechanistic disorder, but specific patients only respondto specific treatments and the probability ofreceiving this specific treatment is greater when amultidisciplinary approach has been planned; second,pain and dysfunction may be mediated bydifferent mechanisms, and these different mechanismsare targeted by the different therapeuticcomponents; third, specific patients may need tobe exposed to multiple methods to achieve improvement,and such multiple methods are naturallyprovided by multimodal therapies; fourth, theoutcome measures may only assess a subset of therelevant domain of the disorder, and multiplemethods are more likely to target these evaluateddomains.While there seems to be no single best treatmentoption, a multidisciplinary approach combiningthese therapies in a well-balanced program may bethe most promising strategy.Non-pharmacological treatments can be recommendedin the treatment of FM, although in the interestof time or financial restrictions it is essentialto focus medical prescriptions only on those therapiesthat are supported by scientific evidence.SUMMARYFibromyalgia is a complex syndrome associated with significant impairment in quality of life and function and withsubstantial financial costs. Once the diagnosis is made, providers should aim to increase patients’ function and minimizepain. Fibromyalgia patients frequently use alternative therapies, strongly indicating both their dissatisfaction withand the substantial ineffectiveness of traditional medical therapy, especially pharmacological treatments. At present,pharmacological treatments for fibromyalgia have a rather discouraging cost/benefit ratio in terms of poor symptomcontrol and high incidence of side effects. The interdisciplinary treatment programs have been shown to improve subjectivepain with greater success than monotherapy.Physical therapies, rehabilitation and alternative therapies are generally perceived to be more “natural,” to have feweradverse effects, and in some way, to be more effective. In this review, physical exercise and multimodal cognitivebehavioural therapy are presented as the more accepted and beneficial forms of nonpharmacological therapy.Key words - Multimodal cognitive behavioural, rehabilitation, alternative therapies.Parole chiave - Terapia cognitivo-comportamentale, riabilitazione, terapia alternativa.

Non pharmacological treatments in fibromyalgia 67REFERENCES1. Giesecke T, Williams DA, Harris RE, Cupps TR, TianX, Tian TX, Gracely RH, Clauw DJ. Subgrouping offibromyalgia patients on the basis of pressure-painthresholds and psychological factors. Arthritis Rheum2003; 48: 2916-22.2. Sim J, Adams N. Therapeutic approaches to fibromyalgiasyndrome in the United Kingdom: a surveyof occupational therapists and physical therapists. EurJ Pain 2003; 7: 173-80.3. Woolf CJ, Bennett GJ, Doherty M, Dubner R, Kidd B,Koltzenburg M, Lipton R, Loeser JD, Payne R, TorebjorkE. Towards a mechanism-based classification ofpain? Pain 1998; 77: 227-9.4. Gur A. Physical therapy modalities in management offibromyalgia. Curr Pharm Des 2006; 12: 329-59.5. Offenbächer M, Stucki G. Physical therapy in the treatmentof fibromyalgia. Scand J Rheumatol 2000; 113:78-85.6. Gutenbrunner C, Englert G, Neuen-Lahusen M, GehrkeA. Controlled study on effects of cold chamber exposures(-67°C, 3 min) in fibromyalgia. Akt Rheumatol1999; 24: 77-84.7. Citak-Karakaya I, Akbayrak T, Demirturk F et al. Shortand long-term results of connective tissue manipulationand combined ultrasound therapy in patients with fibromyalgia.J Manipulative Physiol Ther 2006; 29:524-8.8. Almeida TF, Roizenblatt S, Benedito-Silva AA, TufikS. The effect of combined therapy (ultrasound and interferentialcurrent) on pain and sleep in fibromyalgia.Pain 2003; 104: 665-72.9. Gonzalez-Viejo MA, Avellanet M, Hernandez-MorcuenteMI. A comparative study of fibromyalgia treatment:ultrasonography and physiotherapy versus sertralinetreatment. Ann Readapt Med Phys 2005; 48:610-15.10. Sunshine W, Field TF, Quintino O, Fierro K et al. Fibromyalgiabenefits from massage therapy and transcutaneouselectrical stimulation. J Clin Rheumatol1996; 2: 18-22.11. Kaada B. Treatment of fibromyalgia by low-frequencytrancutaneous nerve stimulation. Tidsskr Nor Laegeforen1989; 109: 2992-5.12. Fregni F, Gimenes R, Valle AC et al. A randomized,sham-controlled, proof of principle study of transcranialdirect current stimulation for the treatment ofpain in fibromyalgia. Arthritis Rheum 2006; 54:3988-98.13. Sampson SM, Rome JD, Rummans TA. Slow-frequencyrTMS reduces fibromyalgia pain. Pain Med2006; 2: 115-18.14. Passard A, Attal N, Benadhira R, Brasseur L, Saba G,Sichere P et al. Effects of unilateral ripetitive transcranialmagnetic stimulation of the motor cortex on chronicwidespread pain in fibromyalgia. Brain 2007; 130:2661-70.15. Gunter V, Mur E, Kinigadner U, Miller C. Fibromyalgia:the effect of relaxation and hydrogalvanic baththerapy on the subjective pain experience. ClinRheumatol 1994; 13: 573-8.16. Walker J. Relief from chronic pain by low power laserirradiation. J Neurol Transm 1977; 40: 305-8.17. Matsutani LA, Marques AP, Ferreira EA, AssumpçãoA, Lage LV, Casarotto RA, Pereira CA. Effects of musclestretching exercises with and without laser therapyat tender points for patients with fibromyalgia. ClinExp Rheumatol 2007; 25: 410-5.18. Waylonis GW, Wilke S, O’Toole D, Waylonis DA,Waylonis DB. Chronic myofascial pain: managementby low-output helium-neon laser therapy. Arch PhysMed Rehabil 1988; 69: 1017-20.19. Gur A, Karakoc M, Nas K, Cevik R et al. Effects of lowpower laser and low dose amitriptyline therapy on clinicalsymptoms and quality of life in fibromyalgia : asingle-blind, palcebo-controlled trial. Rheumatol Int2002; 22: 188-93.20. Yurtkuran M, Celiktas M. A randomized controlled trialof balneotherapy in the treatment of patients withprimary fibromyalgia syndrome. Phys Rehab Kur Med1996; 6: 109-12.21. Pearl DJ, Lue F, MacLean AW et al. The effects ofbright light treatment on the symptoms of fibromyalgia.J Rheumatol 1996; 23: 896-902.22. Casale R, Sommovigo B, Bellotti P. Connective tissuemassage (bindegewebsmassage) as a non-pharmacologicaltreatment for fibromyalgia. Rheumatic PainTreatment, IASP special interest group on rheumaticpain Freeburg, August 18-19, 2001.23. Brattberg G. Connective tissue massage in the treatmentof fibromyalgia. Eur J Pain 1999; 3: 235-45.24. Citak-Karakaya I, Akbayrak T, Demirturk F et al. Shortand long-term results of connective tissue manipulationand combined ultrasound therapy in patients with fibromyalgia.J Manipulative Physiol Ther 2006; 29:524-8.25. Haanen HCM, Hoenderdos HTW, van Romunde LKJet al. Controlled trial of hypnotherapyin the treatmentof refractory fibromyalgia. J Rheumatol 1991; 18:72-5.26. Harris RE, Claw DJ. The use of complementary medicaltherapies in the management of myofascial paindisorder. Curr Pain Headache Rep 2002; 6, 370-4.27. Pioro-Boisset M, Esdaile JM, Fitzchareles MA, AltenativeMedicine use in fibromyalgia. Arthritis Care Res1996; 9: 13-7.28. Cassisi G, Roncaglione A, Ceccherelli F, Donolato C,Gagliardi G, Todesco S. Trattamento agopunturale dellafibromialgia primaria. Confronto con mianserina.G.Ital. Riflessot. Agopunt 1994; 6: 5-9.29. Sprott H, Franke S, Kluge H, Hein G. Pain treatmentof fibromyalgia with acupuncture. Rheumatol Int 1998;18: 35-6.30. Berman BM, Ezzo J, Hadhazy V, Swyers JP. Isacupuncture effective in the treatment of fibromyalgia?J Fam Pract 1999; 48: 213-8.31. Offenbacher M, Stuki G. Physical therapy in the treatmentof fibromyalgia. Scand J Rheumatol 2000; 29 (113Suppl): 78-85.

68 R. Casale et al.32. Lewit K. The needle effect in the relief of myofascialpain. Pain 1979; 6: 83-90.33. Tough EA, White AR, Cummings TM, Richards SH,Campbell JL. Acupuncture and dry needling in themanagement of myofascial trigger point pain: a systematicreview and meta-analysis of randomised controlledtrials. Eur J Pain 2008 in print.34. Altan L, Bingol U, Aykac M et al. Investigation of theeffects of pool-based exercise on fibromyalgia syndrome.Rheumatol Int 2004; 24: 272-7.35. Assis MR, Silva LE, Alves AM, et al. A randomizedcontrolled trial of deep water running: clinical effectivenesof aquatic exercise to treat fibromyalgia. ArthritisRheum 2006; 55: 57-65.36. Donmez A, Karagulle MZ, Tercan N et al. SPA therapyin fibromyalgia: a randomised controlled clinic study.Rheumatol Int 2005; 26: 168-72.37. Buskila D, Abu-Shakra M, Neumann L et al. Balneotherapyfor fibromyalgia at the dead sea. Rheumatol Int2001; 20: 105-108.38. Gusi N, Tomas-Carus P, Hakkinen A et al. Exercise inwaist-high warm water decreases pain and improveshealth-related quality of life and strength in the lowerextremities in women with fibromyalgia. ArthritisRheum 2006; 55: 66-73.39. Piso U, Gutenbrunner C, Gehrke A. Effekte einer sechsswochingenSaunatherapie auf die Schmerzschwelle anden ACR-Tenderpoints bei der generalisierten Tendomyopathie.Phys Rehab Kur Med 1998; 8: 156.40. Fioravanti A, Perpignano G, Tirri G et al. Effects ofmud-bath treatment on fibromyalgia patients: a randomizedclinical trial. Rheumatol Int 2007; 27: 1157-61.41. Mannerkorpi K, Burckhardt CS, Bjelle A. Physical performancecharacteristics of women with fibromyalgia.Arthritis Care Res 1994; 7: 123-9.42. Bennett RM, Clark SR, Goldberg L, Nelson D,Bonafede RP, Porter J, Specht D. Aerobic fitness in patientswith fibrositis. A controlled study of respiratorygas exchange and 133xenon clearance from exercisingmuscle. Arthritis Rheum. 1989; 32: 454-60.43. Rossy LA, Buckelew SP, Dorr N et al. A meta-analysisof fibromyalgia treatment interventions. Ann BehavMed 1999; 21: 180-91.44. Busch AJ, Schachter CL, Overend TJ, Peloso PM, BarberKA. Exercise for fibromyalgia: a systematic reviewJ Rheumatol 2008; 35: 1130-44.45. Busch AJ, Barber KAR, Overend TJ, Peloso PMJ,Schachter CL. Exercise for treating fibromyalgia syndrome.Cochrane Database of Systematic Reviews2002, Issue 3.46. Munguìa-Izquierdo D, Legaz-Arrese A. Exercise inwarm water decreases pain and improves cognitivefunction in middle-aged women with fibromyalgia. ClinExp Rheumatol 2007; 25: 823-30.47. Zijlstra1, van de Laar MAFJ, Bernelot Moens HJ et al.Spa treatment for primary fibromyalgia syndrome: acombination of thalassotherapy, exercise and patienteducation improves symptoms and quality of life.Rheumatology 2005; 44: 539-46.48. Burckhardt CS, Mannerkorpi K, Hedenberg L et al. Arandomized controlled clinical trial of education andphysical training for women with fibromyalgia. J Rheumatol1994; 21: 714-20.49. Gowans SE, deHueck A, Voss S et al. A randomized,controlled trial of exercise and education for individualswith fibromyalgia. Arthritis Care Res 1999; 12:120-8.50. Martin L, Nutting A, MacIntosh BR, et al. An exerciseprogram in the treatment of fibromyalgia. J Rheumatol1996; 23: 1050-3.51. McCain GA, Bell DA, Mai FM et al. A controlled studyof the effects of a supervised cardiovascular fitnesstraining program on the manifestations of primary fibromyalgia.Arthritis Rheum 1988; 31: 1135-41.52. Wigers GH, Stiles TC, Vogel PA. Effects of aerobic exerciseversus stress management treatment in fibrom -yalgia: a 4.5 year prospective study. Scand J Rheumatol1996; 25: 77-86.53. Rossy LA, Buckelew SP, Dorr N et al. A meta-analysisof fibromyalgia treatment interventions. Ann BehavMed 1999; 21: 180-91.54. Blunt KL, Rajwani MH, Guerriero RC. The effectivenessof chiropratic management of fibromyalgia patients:a pilot study. J Manipulative Physiol Ther 1997;20: 389-99.55. Williams DA. Psychological and behavioural therapiesin fibromyalgia and related syndromes. Best Pract ResClin Rheumatol 2003; 17: 649-65.56. Goldenberg DL, Burckhardt C, Crofford L. Managementof fibromyalgia syndrome. JAMA 2004; 292:2388-95.57. Hadhazy VA, Ezzo J, Creamer P, Berman BM. Mindbodytherapies for the treatment of fibromyalgia. A systematicreview. J Rheumatol 2000; 27: 2911-8.58. Sim J, Adams N. Systematic review of randomized controlledtrials of nonpharmacological interventions for fibromyalgia.Clin J Pain 2002; 18: 324-36.59. Rossy LA, Buckelew SP, Dorr N, Hagglund KJ, ThayerJF, McIntosh MJ, Hewett JE, Johnson JC. A metaanalysisof fibromyalgia treatment interventions. AnnBehav Med 1999; 21: 180-91.60. van Koulil S, Effting M, Kraaimaat FW, van LankveldW, van Helmond T, Cats H, van Riel PL, de Jong AJ,Haverman JF, Evers AW. Cognitive-behavioural therapiesand exercise programmes for patients with fibromyalgia:state of the art and future directions. AnnRheum Dis 2007; 66: 571-81.61. Williams DA, Cary MA, Groner KH, Chaplin W, GlazerLJ, Rodriguez AM, Clauw DJ. Improving physicalfunctional status in patients with fibromyalgia: a briefcognitive behavioral intervention. J Rheumatol 2002;29: 1280-6.62. Wainer-Roedler DL, Elkin PL, Vincent A et al. Use ofcomplementary and alternative medical treatment programat a tertiary care center. Mayo Clin Proc 2005; 80:55-60.63. Gemmel H, Jacobson BH, Banfield K. HomeopathicRhus Toxicodendron in treatment of fibromyalgia. ChiropraticJ Aust 1991; 21: 2-6.

Non pharmacological treatments in fibromyalgia 6964. Bennett RM, Burkhardt CS, Clark SR. Group treatmentof fibromyalgia: a 6 month outpatient program. JRheumatol 1996; 23: 521-8.65. Kaplan KH, Goldenberg DL, Galvin-Nadeau M. The impactof a meditation-based stress reduction program onfibromyalgia. Gen Hosp Psychiatry 1993; 15: 284-9.66. Simms R.W., Controlled trials of therapy in fibromyalgiasyndrome. Balliere Clin Rheum 1994; 8:917-34.67. Jacobsen S, Danneskiold-Samsoe B, Andersen RB.Oral S-Adenosylmethionine in primary fibromyalgia: adouble-blind clinical evaluation. Scand. J Rheumatol1991; 20: 294-302.68. Tavoni A, Vitali C, Bombardieri S. Evaluation of S-adenosylmethionine in primary fibromyalgia: a doubleblind cross-over study. Am J Med 1987; 83: 107-10.69. Volkmann H, Norregard J, Jacobsen S, Danneskiold-Samsoe B, Knoke G, Nehrdich D. Double-blind, placebo-controlledcross-over study of intravenous S-adenosyl-methioninein patients with fibromyalgia. Scand JRheumatol 1997; 26: 206-11.70. Abraham G, Flechas J. Management of fibromyalgia:rationale for use of magnesium and malic acid. J NutritionalMed 1992; 3: 49-59.71. Cox IM, Campbell MI, Dowson D. Red blood cell magnesiumand chronic fatigue syndrome. Lancet 1991;337: 757-60.72. Russel IJ, Michalek JE, Flechs JD. Treatment of fibromyalgiasyndropme with super malic; a randomized,double-blind placebo controlled crossover pilot study.J Rheumatol 1995; 22: 935-58.73. Citera G, Arias A, Maldonado-Cocco Ja et al. The effectof melatonin in patients with fibromyalgia: a pilotstudy. Clin Rheumatol 2000; 19: 9 -13.74. Dykman KD, Tone C, Ford C et al. The effects of nutritionalsupplements on the symptoms of fibromyalgiaand chronic fatigue syndrome. Integr Physiol BehavSci, 1998; 33: 61-71.75. Blunt KI, Rajwani MH, Guerriero RC. The effectivenessof chiropractic management of fibromyalgia patients:a pilot study. J Manipulative Physiological Ther1997; 20: 389-9.

ORIGINAL ARTICLEReumatismo, 2008; 60: Supplemento 1: 70-77Fibromyalgia syndrome:preventive, social and economic aspectsGli aspetti preventivi, sociali ed economici della sindrome fibromialgicaL. Altomonte 1 , F. Atzeni 2 , G. Leardini 3 , A. Marsico 4 , R. Gorla 5 , R. Casale 6 , G. Cassisi 7 , S. Stisi 8 ,F. Salaffi 9 , F. Marinangeli 10 , M.A. Giamberardino 11 , M. Di Franco 12 , G. Biasi 13 , G. Arioli 14 ,A. Alciati 15 , F. Ceccherelli 16 , L. Bazzichi 17 , R. Carignola 18 , M. Cazzola 19 , R. Torta 20 , D. Buskila 21 ,M. Spath 22 , R.H. Gracely 23 , P. Sarzi-Puttini 21UOC of Rheumatology Hospital S. Eugenio, Rome, Italy; 2 Rheumatology Unit, L. Sacco University Hospital, Milan, Italy;3Rheumatology Unit, SS Giovanni e Paolo Hospital, Venice, Italy; 4 Rheumatology Unit, Hospital of Taranto, Taranto, Italy;5Rheumatology and Clinical Immunology, Spedali Civili and University of Brescia, Italy; 6 Department of Clinical Neurophysiology andPain Rehabilitation Unit, Foundation Salvatore Maugeri, IRCCS, Scientific Institute of Montescano, Montescano (PV), Italy;7Rheumatology Branch, Specialist Outpatients’ Department, Belluno, Italy; 8 Rheumatology Unit, “G. Rummo” Hospital, Benevento,Italy; 9 Department of Rheumatology, Polytechnic University of the Marche Region, Ancona, Italy; 10 Department of Anesthesiology andPain Medicine, L'Aquila University, L’Aquila, Italy; 11 Ce.S.I. “G. D’Annunzio” Foundation, Department of Medicine and Science ofAging, “G. D’Annunzio”, University of Chieti , Italy; 12 Chair of Rheumatology, University la Sapienza Rome, Rome, Italy;13Unit of Rheumatology, University of Siena, Siena, Italy; 14 Division of Rehabilitative Medicine and Rheumatology, General Hospitalof Pieve di Coriano (Mantua), Italy; 15 Department of Psychiatry, L. Sacco University Hospital, Milan, Italy;16IOV (Veneto Cancer Institute), IRCCS, Department of Pharmacology and Anesthesiology, University of Padua, Italy; 17 Department ofInternal Medicine, Division of Rheumatology, S. Chiara Hospital, University of Pisa, Italy; 18 S.C.D.U. Internal Medicine I, Departmentof Clinical and Biological Science, University of Turin, Italy; 19 Unit of Rehabilitative Medicine “Hospital of Circolo”, Saronno (VA),Italy; 20 Department of Neuroscience, University of Turin, A.S.O. San Giovanni Battista of Turin, Turin, Italy; 21 Department of MedicineH, Soroka Medical Center and Faculty of Health Sciences, Ben Gurion University, Beer Sheva, Israel; 22 Friedrich-Baur-Institute,University of Munich, Munich, Germany; 23 Department of Medicine, University of Michigan Health System, Ann Arbor, Michigan USACompeting interests: none declaredRIASSUNTODiversi sono i problemi associati al concetto di prevenzione primaria nella FM. I criteri diagnostici o classificativinon sono universalmente accettati e risulta difficile stabilire l’esordio e la durata della malattia. Nel caso della FM,la prevenzione primaria potrebbe essere intensa come il trattamento del dolore acuto o dei disturbi affettivi data lamancanza di test di laboratorio o strumentali specifici predittivi per lo sviluppo della FM. L’obiettivo della prevenzionesecondaria è nei pazienti ancora sintomatici la diagnosi e il trattmento precoce. Lo screening consente nei pazientiche possono sviluppare la FM, di identificare la malattia latente o i fattori di rischio quali i TPs, il FibromyalgiaImpact Questionnaire (FIQ), l’intensità e la sede del dolore, l’astenia e disturbi del sonno. Per prevenzione terziariasi intende trattare la malattia al fine ridurne la disabilità e le possibili complicanze. Gli obiettivi terapeutici sonoil controllo del dolore e miglioramento della funzionalità attraverso trattamenti farmacologici e non. I pazienti affettida FM determinano un utilizzano notevole delle risorse sanitarie, e conseguentemente un aumento della spesasanitaria. Il grado di disabilità e il numero delle malattie associate determina un marcato aumento dei costi. La diagnosiprecoce permettebbe di ridurre i costi e il numero delle indagini, consentendo un risparmio effettivo da partedel sistema sanitario nazionale. Tuttavia, l’intervento sociale è strettamente correlato con il livello socio-economicodella popolazione generale e la legislazione del paese nel quale il paziente risiede.Reumatismo, 2008; 60: Supplemento 1: 70-77INTRODUCTIONFibromyalgia (FM) is a central pain syndromethat is characterized, in part, by specific tenderCorresponding author:Piercarlo Sarzi-Puttini, MDDirector of Rheumatology UnitL. Sacco Hospital, Milan, ItalyE-mail: sarzi@tiscali.itpoints (TPs) in the musculoskeletal system whichare exceptionally sensitive to pressure. Pain, specificallycharacterized as hyperalgesia and allodynia,is the cardinal symptom of FM; however, most patientsalso experience additional symptoms suchas debilitating fatigue, disrupted or nonrestorativesleep, functional bowel disturbances, and a varietyof neuropsychiatric problems, including cognitivedysfunction, anxiety and depressive symptoms (1).

Fibromyalgia syndrome: preventive, social and economic aspects 71Women are the most affected and the disease hasa familial connection that is linked to the geneticvariance of serotonin, dopamine and catecholamineintra-cerebral system (2). The physical symptomsof FM often express themselves in conjunctionwith psychological conditions, which causes a reductionin the individual capacity to tolerate stressors(3).Despite some criticism, the diagnosis for FM isbased on the American College of Rheumatology(ACR) 1990 criteria, which require a specific history(widespread pain lasting more than threemonths, sleep disturbance, debilitating fatigue,paresthesia) and tenderness to light touch(4 kg/cm 2 ) of at least 11 of 18 specific tender points(4).PREVENTION OF FIBROMYALGIAFM has a general population prevalence of 2-4 %,ismore common among females than males (5), andresults from a combination of genetic aspects andstressful events. Prevention may occur in clinical,community or population settings and is often classifiedinto primary, secondary and tertiary types.Primary prevention of fibromyalgiaIn general, primary prevention includes measuresthat help avoid onset of a given health care problem(6, 7). In the case of FM, primary preventionmight include immediate care of acute painepisodes and of somatoform disturbances. At present,specific laboratory or instrumental markersof FM do not exist, and many open questions remainconcerning the concept of primary preventionin FM.Over time, several issues have arisen with the existingdiagnostic or classification criteria: a) criteriaare not likely to be applied uniformly by untrainedassessors; b) patients may have the requisiteTPs and yet not have FM; and c) TPs and widespreadpain do not capture the essence of FM; thisdisorder is known for its multiple and varyingsymptoms, which include fatigue, sleep disturbanceand cognitive dysfunction, predominantly.The road of onset and development of FM can belong and winding. In fact, there are a variety of differentclinical histories that can describe the FMroad: a female FM patient may develop headachesand dysmenorrhea in her 2 nd or 3 rd decade of lifeand present with widespread pain and tendernesslater in life; FM can also start after a stressful eventTable I - Predictors for chronicity (fibromyalgia) in recurrent widespreadpain.Recurrent pain episodesPain reports from other locationsSleep alterationsAnxietyDepressionHeadacheGenderAgeFatigueTrigger and tender pointsStress events(e.g., physical or psychological trauma); or it canbegin with localized pain (e.g., neck or low-backpain) and develop further through pain amplification(8, 9).One major problem with primary prevention stemsfrom the simple fact that no markers of disease exists;a variety of clinical symptoms can be presentat onset and chronic widespread pain may or maynot develop into FM as defined by the 1990 ACRcriteria.In conclusion, the goal of primary prevention is toreduce the incidence of FM in a population thatmay have a diathesis toward developing FM but hasnot presented with symptoms. This can be accomplishedthrough diet and exercise, prevention andcure of trauma, prevention and cure of anxiety anddepression, and finally, immunization against virusesand bacteria (Table I).Secondary prevention of fibromyalgiaThe U.S. Guide of Clinical Preventive Services(Ed. 1996) describes secondary prevention measuresas those that “identify and treat asymptomaticpersons who have already developed risk factors orpreclinical disease but in whom the condition isnot clinically apparent”.The purpose of screening is to identify an unrecognizeddisease or risk factor (10). In general,screening tests include history (e.g., asking if a patientsmokes), physical examination (e.g., bloodpressure determination), lab tests (e.g., serum cholesterollevel) and procedures (e.g., colonscopy).Such tests are not intended to be diagnostic andshould not be performed unless the patient and theclinician are committed to further investigation andtreatment of abnormal results.For patients in whom FM is suspected, preventivestrategies should be performed to identify risk factorsor predictors of chronicity.

72 L. Altomonte et al.In a clinical setting special attention should be paidto previous pain episodes, pain reports from variouslocations on the body, tender points, distress,somatisation, fatigue, and sleep disturbances. Presenceof these symptoms may predict developmentof chronic pain (8, 9).The development and persistence of chronic musculoskeletalpain may also be predicted by severalsocio-demographic, lifestyle and psychosocial riskfactors.Family history of chronic pain, low educationallevel, low socioeconomic group and lack of socialsupport are other common risk factors.Some ethic groups and immigrants have also beenshown to have an increased risk for developmentof chronic pain (11).Smoking, sedentary lifestyle and obesity are predictivefactors that could be targets for intervention(12).A number of stressors have been temporally correlatedwith the onset of the syndrome, includingtrauma, infection (e.g., hepatitis C virus, HIV, Lymedisease), emotional stress, catastrophic events(e.g., war), autoimmune diseases and other painconditions (13, 14).In conclusion, the goal of secondary prevention isto facilitate early detection of disease developmentwhen patients are asymptomatic and interventionimproves outcome. Early detection methods forFM patients include analysis of tender points, FibromyalgiaImpact Questionnaire (FIQ), pain locationand intensity, fatigue and sleep complaints(15, 16).Tertiary prevention of fibromyalgiaTertiary prevention inhibits further deterioration orreduces complications after the disease has declareditself. In FM the aim of treatment is to managesymptoms, specifically, to decrease pain and increasefunction, via multimodal therapeutic strategies,which, in most cases, include pharmacologicaland non-pharmacological interventions (17,18). As FM patients typically present with complexsymptoms and co-morbid conditions, they cannotbe managed realistically by primary care providers,alone, but require the assistance of multidisciplinaryteams with expertise in a variety of physical,cognitive, behavioural and educational strategies(17).In conclusion, prevention strategies for FM may beof paramount importance. In fact, since no cure iscurrently available, primary and secondary preventionstrategies may greatly reduce the prevalenceof this syndrome. Tertiary prevention will enablepatients to implement therapeutic approachesas early as possible, to monitor the results and toprevent the secondary effects of chronic widespreadpain and the ancillary symptoms.The economic impact of fibromyalgiaFew studies have analyzed the economic impact ofFM in terms of costs of disease and pharmacoeconomicbalance.A literature search using keywords “Fibromyalgia”and “Costs and Cost Analysis” identified only 51publications; of these, only 9 addressed pharmacoeconomicaspects (19-27) and 8 addressed diseasecosts both as direct costs, i.e., charged to publichealth systems and to patients for diagnosis andmedical assistance, and as indirect costs, i.e., financialconsequences of reduced productivity by illpatients (28-35). No publications analyzed the costor consequence of reduced quality of life for patients.Over the last decade, the annual direct costs of FMhave increased considerably. Today, these costsrange between 4.500 and 7.500€ per patient (28-35). The variability in this range is due to differentmethods being used to evaluate costs in differentyears and in different socio-economic conditions ofFM patients. The same study, however, concludesthat the most important determinant of costs are comorbidities,subjective and objective health state,emotional state and social conditions of the patient(21, 24, 28).Health costs comprise about 1/3 of direct costs, aproportion that is accompanied by several causesfor concern. First, the cost of admission to the hospitalfor diagnosis can have a significant impact onoverall costs due to the complexity of the clinicalsymptoms.Second, therapy can be quite expensive given theoverall poor response to treatment among manypatients (31, 32, 35). The lack of validated therapeuticprotocols may explain the frequent use ofphysiotherapy or alternative therapy without a correspondingincrease in costs for the public healthsystem (26).Social support, whether support groups or personalnetworks, and education programs are inexpensiveand useful avenues for facilitating psychologicalwell being and optimizing available health resources(23).The indirect costs of FM range between 2.000 to7.000 € per patient per year. Only one of threeeconomic studies in our search indicated that the

Fibromyalgia syndrome: preventive, social and economic aspects 73indirect costs of FM were higher than the directcosts, as is generally the case for other rheumaticdiseases (31, 32, 35).If the body of literature for disease costs seems insufficientfor FM, the pharmacoeconomic literatureis even more inadequate. The majority of thesestudies have described the methodology of investigationrather than analysed the specific expenses(19-25). Conclusions are not definitive and it is notpossible to define the best investment. The justificationfor this is that well-defined indicators forevaluating achievement of predetermined goals orvalidated therapeutic protocols were not available.Further, improvements from a specific therapywere too short-lived to draw meaningful conclusions(23, 26, 27).Disability and employment in FM patientsIt is difficult to assess disability and employmentin FM patients, given the limited data in the scientificliterature. Every social assessment is closelyrelated to the socio-economic level of the generalpopulation and to the legislation of the country inwhich the FM patient lives.In clinical investigations, FM is well known andstudied; the case worker, however, is accustomedto evaluating laboratory and physical data objectivelyand may have reasonable doubts in evaluatingthe FM patient for insurance purposes and abilityto work.Therefore, it is understandable that there may befundamental differences in the assessment of disabilityand employment between Italy and othercountries, just as it is understandable that there maybe differences between the clinical and medical-legalevaluation of FM patients.Several difficult issues cloud the ability to estimatethe effect of FM in Italy with accuracy. The first issueis the fundamental recognition of disease: IsFM universally recognized by physicians or is itidentified with other diseases? How many diagnosesof osteoarthtritis (OA) or how many depressivesyndromes or cases of “early arthritis” overlapwith FM in clinical practice?The second issue is the comparison of statistical data.In Italy, it is difficult to compare data from centralizeddatabases that are involved in different aspectsof public health: ISTAT (Central Statistic Institute)(36), Ministry of Health, INPS (National Instituteof Social Insurance) (37), INAIL (NationalBoard for the Insurance against Accidents in IndustrialWork, responsible for occupational diseases)(38).The ISTAT manages data from sample surveys regardingthe influence of chronic diseases; and itsuggested the atypical classification of “osteoarth -ritis-arthritis” that combines diseases which aresubstantially different. FM has no place in this classificationdespite its significant incidence amongrheumatic diseases and chronic diseases. This incidenceof FM has been reported in Italian clinicalstudies and has been confirmed in the internationalscientific literature.INPS and INAIL do not include FM in their statisticaldata concerning the granting of partial andtotal disability as paid by the two larger Italian publicinsurance institutes.In 1980, the International Classification of Impairments(ICF), Disability and Health (ICDH) includeddistinctions between impairment, disabilityand handicap. In 2001, a new International Classificationof Functioning (ICF), Disability andHealth was officially endorsed by 191 WorldHealth Organization Member States during the54th World Health Assembly as “the internationalstandard to describe and measure health and disability”(38). The general aim of ICF is to developa common metric system to describe and measureindividual health conditions and contextual factors,which are described by physical, individual, andsocial perspectives and divided into Functions,Bodily Structures, Participation and Activity. Furthermore,the classification accounts for the environmentalfactors that can impact the individual’slife and interact to determine disability, and it is definedas the consequence or the result of a complexrelationship between the health conditions, personalfactors and environmental factors representingthe circumstances where the individual lives.ICF does not simply view disability only as a “medical”or “biological” dysfunction; rather, it providesa mechanism to document the impact of the socialand physical environment on a person’s functioning.The clinical evaluation of disability involves specificassessments such as the FIQ (40), which hasbeen validated in Italy (15). Nevertheless, it is difficultto apply this and other evaluations in legalmedicine, especially if they do not refer to laboratorydata. Then the claim of disability can lead toadditional difficulty for the FM patient if she experiencesnegative feedback from official Institutionsthat may not recognize the illness.Aside from chronic pain, the FM patient may complainof various, specific symptoms that may reducework performance of the subject. For exam-

74 L. Altomonte et al.Table II - Web hits from a search of the following terms and searchengines conducted on 12/02/08.Google (Italian pages)Osteoarthritis 226.000Early arthritis 1.900Fibromyalgia 30.600Tendinitis 17.600Disability 778.000INAIL (Internal internet search)Osteoarthritis 14Rheumatoid arthritis 1Fibromyalgia 0Tendinitis 15Disability 126INPS (Internal internet search)Osteoarthritis 3Early arthritis 0Fibromyalgia 0Tendinitis 0Disability 1079ple, weakness and susceptibility to fatigue are significantin manual laborers , morning stiffness insubjects who begin working early in the morning,such as farm workers, can be debilitating to theirlivelihood; Raynaud phenomenon can pose severechallenges to operators who are exposed to suddenchanges of temperature. Patients who work in externalenvironments can be severely affected bymany weather elements such as wind, cold, andrain. Several epidemiological surveys performedin recent years in Great Britain and in Scandinaviademonstrated that FM is greatly disabling and maylead to early termination of employment, regardlessof whether this was voluntary or dictated by a medical-legaldecision.In Italy, FM is not recognized as a disabling illnessby Insurance Disability (ID), Pensionable Disability(INPS) or Accident or Professional Illness (IN-AIL). FM is not listed in the ID table of acceptedillnesses; therefore, the clinician or medical examinermay refer only to illnesses that are, in a sense,“equivalent” to FM and are included in the assessmenttable such depressive syndrome and anxiety,or neurosis with varying degrees of severity. It isnecessary to indicate comorbidity among illnesses(e.g., FM with anxious syndrome or depressivesyndrome).The same is true in INPS Pensionable Disability,although it must be said that this social Institutegrants hydrotherapy for extra-articular rheumaticdiseases, including FM. With regard to hydrotherapywe notice that INPS is granted to regular entitledworkers as a prevention of pensionable disabilityand not as non-pharmacologic therapy. InINAIL, FM is not recognized as an industrial injuryor an occupational disease, and hydrotherapy is notgranted.For some years, however, INAIL has given specialattention to working musculoskeletal disorders(WMSD) that developed from both “heavier” labor,as the manual handling of cargo, and “lighter” labor,as the poor posture or repetitive movement(RSI Repetitive Strain injury) of assembly lineworkers, monitor operators, check-out clerks (seeLegge 626/94 Title V).In INAIL it would be useful to compare WMSD ina population that is not affected by FM versus FMpatients in whom it has been reported that symptomsoften get worse as a result of having bad postureor disregarding ergonomics rules. Visitors tothe institutional INAIL site can download a usefulguide for WMSD (41). The next evaluation of disabilityand employment in FM could target differentpopulations such as housewives and students,too (42).A final consideration, which is also a concrete, positiveissue, comes from the Main Office in HealthPlan of Ministry of Health contemplated the proposedinclusion of FM in Decree 329799 on chronicdisease, as a result of the criteria provided by Decree124/98 (severity, chronicity and economic burden).It could be a first step towards a new approachto the medico-legal evaluation of FM.Table II lists web data with regard to the number ofhits from various search engines using certain termsfrom this chapter; web search dated 12/02/08.Patient associations, mass media and internetAlthough fibromyalgia is a reasonably commonclinical condition, it is often left undiagnosed. Unfortunately,this syndrome is not well known to thegeneral practitioner or to physicians, in general.Many patients have suggested the diagnosis to theirdoctor after they have discovered the syndrome onthe internet or after the reading about it in magazinesor newspapers.Prior to diagnosis, FM patients will often undergomany specialist consultations, laboratory examinations,instrumental examinations and pharmacologictherapies.Patients are often frustrated by the lack of diagnosisand the meager credibility that physicians andother family members assign to symptoms. Often,

Fibromyalgia syndrome: preventive, social and economic aspects 75self-assessment loses its credibility for patientswho face disbelief from others and quickly becomevulnerable to depression.In such cases, the satisfaction of a clear diagnosisbegins as relief from the fear of an occult neoplasia,but evolves to anger for the unnecessary timespent researching this easy diagnosis, for the moneyspent without benefit and, finally, for the lack ofrecognition of this disease.This aspect, in particular, gives patients a strongmotivation to participate in organized volunteer associations.Voluntary participation in patient associations isnot only a social obligation to encourage acknowledgementof FM but also a new social endeavorwith a substantial therapeutic benefit.Patient AssociationsThe primary mission of patient associations is todefend patient rights. The main entities to addressare governing medical Institutions (Ministry of theHealth, regional Councillor of the Health, LocalHealth Committee, Hospital Committee andRheumatology Units), and the main goal is to gainacknowledgment of FM as a clinical entity and asa rheumatic disease (43). A search of the Ministryof Health website of using the terms, “fibromyalgia”or “fibromyalgic” did not yield any results. Atpresent, the only region that recognizes FM is theTrentino-Alto Adige.The main request that FM patient associations havefor the Institutions includes exemption for expensesfor pathology, the specialized consultations necessaryfor diagnosis, for follow-up and monitoring,for rehabilitation and for the purchase of specificdrugs.From Rheumatologists, patient associations requestspecific outpatient activity for FM patients and coordinationof other professional specialists that arebeneficial to the care of the FM patient, in particular,psychologists and physiotherapists. Patientassociations may also provide information to physiciansand to the public. They may also request thatin-depth study of FM be provided in Rheumatologyand Internal Medicine courses at the University.The Associations promote collaboration betweenrheumatologists, general practitioners and otherspecialists for the early diagnosis of FM, whichcan be achieved via regular meetings sponsored theby Local Health Committee. For easy admittanceto gymnasiums and pools for patients to participatein aerobic exercise programs (44, 45), participationof the Local Sport Committee is important. Patientassociations monitor information on the internet toprotect patients against speculative or incorrect information.The fundamental solidarity of patient associationspromotes the sense of community and connectionamong patients. Patient associations promote localmeetings and also take advantage of electronic media,like chat rooms, discussion forums and selfhelpgroup training (46).To consolidate their power, FM patients may considerthemselves as rheumatic patients and coordinatetheir voluntary associations with the nationalassociations of rheumatic patients; for example,The Italian Association of FM is supported by theNational Association of Rheumatic Patients and bythe Italian Rheumatology Society.Internet and MediaOne of the most significant examples of coordinationof information, research, care and voluntary associationcame from the USA.The ACR website offers information both to doctorsand to patients (47); and it highlights theRheumatology Units and the Rheumatologists ofreference along with links to the principal patientassociations (48, 49) and the National Institute ofHealth (NIH). In this virtual strategy, the ACR informsthe medical, scientific and public communitiesabout scientific progress; the NIH manages andfunds research projects; and the associations helppatients through community initiatives, publicawareness and collection of resources for research(50).This example is not followed in Italy, however;with the exception of Rheumatology Units’ websitesand the official Italian Association of FibromyalgiaSyndrome (51), where scientific informationis available without taking advantage of thepatient news, we can find news that is without scientificmerit, is exaggerated or is directed at sellingproducts without regulatory oversight. Peoplewho suffer from an illness often believe in miraculouscures (e.g., surgical or other alternatives todrugs) that are not supported with any scientificvalidity.Scientific societies and patient associations arewatchful and denounce deceptive publicity of suchtreatments, but an official medical effort is necessaryto control or monitor nonconventional medicinesthat may be useful for FM patients. It is importantto encourage Rheumatology Units to considermeditation techniques and complementary

76 L. Altomonte et al.treatments derived from traditional Chinese medicineor from other disciplines.Finally, a website developed by Dr. Weiss (52) providesinteresting, evidence-based, accepted informationfor FM patients This site provides a videoof exercise and muscle relaxation techniques thatpatients can learn and use at home on TV; in addition,the site provides evidence for the positive effectscrio-therapy on pain perception in FM patients.CONCLUSIONPrevention may occur in clinical, community orpopulation settings and is often classified into primary,secondary and tertiary types. Few studieshave analyzed the economic impact of FM in termsof costs of disease and pharmacoeconomic balance.The internet is one of the most significant examplesof coordination of information, research, care andvoluntary patient advocacy of FM.SUMMARYThere many open questions concerning the concept of primary prevention in FM. Diagnostic or classification criteriaare not universally accepted, and this leads to difficulties in establishing the onset and duration of the disease. In thecase of FM, primary prevention may consist of the immediate care of acute pain or treatment for affective disturbancesas we do not have any specific laboratory or instrumental tests to determine risk factors of the disease. The goal of secondaryprevention is early detection of the disease when patients are largely asymptomatic and intervention improvesoutcome. Screening allows for identification of an unrecognized disease or risk factor, which, for potential FM patients,includes analysis of tender points, Fibromyalgia Impact Questionnaire (FIQ), pain location and intensity, andfatigue and sleep complaints. Tertiary prevention inhibits further deterioration or reduces complications after the diseasehas developed. In FM the aim of treatment is to decrease pain and increase function via multimodal therapeuticstrategies, which, in most cases, includes pharmacological and non-pharmacological interventions. Patients with FMare high consumers of health care services, and FM is associated with significant productivity-related costs. The degreeof disability and the number of comorbidities are strongly associated with costs. An earlier diagnosis of FM canreduce referral costs and investigations, thus, leading to a net savings for the health care sector. However, every socialassessment is closely related to the socio-economic level of the general population and to the legislation of the countryin which the FM patient resides.Key words - Prevention, economic aspects, screening, disability.Parole chiave - Prevenzione, aspetti economici, screening, disabilità.REFERENCES1. Hauser W, Zimer C, Felde E, Kollner V. What are thekey symptoms of fibromyalgia? Results of a survey ofthe German Fibromyalgia Association. Schmerz 2007.2. Buskila D, Sarzi-Puttini P. Biology and therapy of fibromyalgia.Genetic aspects of fibromyalgia syndrome.Arthtritis Res Ter 2006; 8: 218.3. Martinez-Lavin M. Biology and therapy of fibromyalgia.Stress, the stress response system and fibromyagia.Arthtritis Res Ther 2007; 9: 216.4. Wolfe F, Smythe HA, Yunus MB, Bennett RM, BombardierC, Goldenberg DL, et al. The American Collegeof Rheumatology 1990 criteria for the classification offibromyalgia: report of a multicenter criteria committee.Artrhritis Rheum1990; 33: 160-72.5. Mease P. Fibromyalgia syndrome: review of clinicalpresentation, pathogenesis, outcome measures andtreatment. J Rheumatol 2005; 75: 6-21.6. Webb R, Bramah T, Lunt M, Urwin M, Allison T, SymmonsD. Prevalence and predictors of intense, chronicand disabling neck and back pain in the UK generalpopulation Spine 2003; 28: 1195-202.7. Rao JK, Hootman JM. Prevention research and rheu -matic disease. Curr Opin Rheumatol 2004; 16: 119-24.8. Gieseke T, Gracely RH, Willams DA, Geisser ME, PetzkeFW, Clauw DJ. The relationship between depression,clinical pain and experimental pain in chronic paincohort. Arthritis Rheum 2005; 52: 1574-84.9. Theorell T, Harms-Ringdahl K, Ahlberg-Hulten G, WestinB. Psycosocial job factors and symptoms from the locomotorsystem-a multicausal analysis. Scand J RehabilMed 1991; 23: 165-73.10. McBeth J, Macfarlane GJ, Hunt IM, Silman AJ. Riskfactors for persisten chronic widespread pain: a community-basedstudy Rheumatology (Oxford) 2001; 40:95-101.11. Allison TR, Symmons DP, Brammah T, Haynes P,Rogers A, Roxby M, et al. Muscoloskeletal pain is moregeneralised among people from ethnic minorities thanamong white people in Greather Manchester. AnnRheum Dis 2002; 61: 151-6.12. Goldberg MS, Scott SC, Mayo NE. A review of the associationbetween cigarette smoking and the developmentof non specific back pain and related outcomesSpine 200; 25: 995-1014.13. Walker-Bone K, Cooper C. Hard work never hurt anyone:or did it? A review of occupational associations

Fibromyalgia syndrome: preventive, social and economic aspects 77with soft tissue musculoskeletal disorders of the neckand upper limb. Ann Rheum Dis 205; 64:1391-6.14. Bazzichi L, Rossi A, Giuliano T, De Feo F, GiacomelliC, Consensi A, el al. Association between thyroid autoimmunityand fibromyalgic disease severity. ClinRheumatol 2007; 26: 2115-20.15. Sarzi-Puttini P, Atzeni F, Turiel M, Furlan R, VulpioL, Carrabba M, Pace F. The Italian version of the FibrofatigueScale, a reliable tool for the evaluation of fibromyalgiasympoms. J Psychosom Res 2004; 56: 213-16.16. Sarzi-Puttini P, Atzeni F, Fiorini T, Panni B, RandisiG, Turiel M, et al. Validation of an Italia version of theFibromyalgia Impact Questionnaire (FIQ-1) Clin ExpRheumatol 2003; 21: 459-64.17. Sarzi-Puttini P, Buskila D, Carrabba M, Doria A,Atzeni F. Treatment strategy in Fibromylgia Sindrome:where are we now? Semin. Arthritis Rheum 2008; 37:353-65.18. Cazzola M, Sarzi-Puttini P, Buskila D, Atzeni F. Pharmacologicaltreatment of fibromyalgia. Reumatismo2007; 59: 280-91.19. McCain GA. A cost-effective approach to the diagnosisand treatment of fibromyalgia. Rheum Dis ClinNorth Am 1996; 22; 323-49.20. Goossens ME, Rutten-van Molken MP, Vlaeyn JW,van der Linden SM. The cost diary: a method to measuredirect and indirect costs in cost-effectiveness research.J Clin Epidemiol 2000; 53: 688-95.21. Walen HR, Cronan PA, Bibatti SM. Factors associatedwith healthcare costs in women with fibromyalgia. AmJ Manag Care 2001; 25: 39-47.22. Oliver K,Cronan TA, Walen HR Tomita M. Effects ofsocial support and education on health care costs for patientswith fibromyalgia J Rheumatol 2001; 28: 2711-9.23. Pfeiffer A, Thompson JM, Nelson A, Tuker S, LuedkteC, Finnie S, et al. Effects of a 1.5 day multidisciplinaryoutpatient treatment program for fibromyalgia: apilot study Am J Phys Med. Rehabil 2003; 82: 186-91.24. Buesing AR A conservative, cost-effective approach tofibromyalgia JAAPA 2005; 18: 32-7.25. Ribinson RL, Jones ML. In search of pharmacoeconomicevaluations fof fibromyalgia treatments: a reviewExpert Opin Pharmacother 2006; 7: 1027-39.26. Lind BK, Lafferty WE, Tyree PT, Diehr PK, GrembowskiDE. Use of complementary and alternativemedicine providers by fibromyalgia patients under insurancecoverage Arthritis Rheum 2007; 57: 71-6.27. Zijlstra TR Braakman-Jansen LM, Taal E, Rasker JJ,van der Laar MA. Cost-effectiveness of Spa treatmentfor fibromyalgia: general health improvement is not forfree Rheumatology 2007; 46: 1454-59.28. Wolfe F, Anderson J, Harkness D, Bennett RM, CaroXJ, Goldenberg DL, et al. A prospective, longitudinal,multicentric study on service utilization and costs in fibromyalgia.Arthritis Rheum 1997; 40: 1560-70.29. With KP, Speechley M, Harth M,Ostbye T. The LondonFibromyalgia Epidemiology Study: direct healthcare costs of fibromyalgia syndrome in London,CanadaJ Rheumatol 1999; 26: 885-9.30. Robinson RL, Bimbaum HG, Morley MA, Sisitsky T,Greenberg PE, Claxton AJ. Economic cost and epidemiologicalcharacteristics of patients with fibromyalgiaclaims J Rheumatol 2003; 30: 1318-25.31. Penrod JR, Bernatsky S, Adam V, Baron M, Dayan N,Dobkin PL. Healh services costs and their detrminatsin women with fibromyalgia J Rheumatol 2004; 31:1391-8.32. Boonen A, van den Heuvel L, van Tubergen A,Goosens M, Severens Jl, van der Heijde D, et al. Largedifferences in cost of illness and well being betweenpatients with fibromyalgia, chronic low back pain orankylosing spondylitis Ann Rheum Dis 2005; 64: 396-402.33. Robinson RL, Bimbauem HG, Morley MA, Sisitsky T,Greeberg PE, Wolfe F. Depression and fibromyalgia:treatment and cost when diagnosed separately or concurrently.J Rheumatol 2004; 31: 1621-9.34. Berger A, Dukes E, Martin S, Edelsberg J, Oster G.Characteristics and healthcare costs of patients withfibromyalgia syndrome Int J Clin Pract 2007; 61: 1498-508.35. With LA, Bimbaum HG, Kaltenboeck A, Tang J, MallettD, Robinson RL. Employees with fibromyalgia;medical comorbidity, healthcare costs and work loss.Occup Environ Med 2008; 50: 13-24.36. www.istat.it37. www.inps.it38. www.inail.it39. www.disabilitaincifre.it40. Burkhardt C, Clark SR, Bennet RM. The FibromyalgiaImpact Questionnaire: development and validation.J Rheumatol 1991;18: 728-33.41. Marsico A. Malattie reumatiche : impatto nel mondodel lavoro del 2000. atti del III Congresso Nazionaledei Reumatologi Ospedalieri Terme di Telese (BN) 9-11 dicembre 1999; 73-8.42. Gerloni V, Ghirardini M, Fantini F. Assessmnt of nonarticular tenderness and prevalence of primary fibromyalgiasyndrome in healthy Italian schoolchildren.Arthritis Rheum 1998; 41: 1405.43. Baffigi A, Granata A, Sarzi-Puttini P, et al. Quality oflife and mood disturbances in fibromyalgia and irritablebowel syndrome Ann Rheum Dis 2002: 61 (suppl1); 151.44. Mannerkorpi K. Exercise in fibromyalgia Curr OpinRheumatol 2005; 17: 190-4.45. Rooks DS, Silvermann CB, Kantrowitz FG. The effectof progressive strength training and aerobic exercise onmuscle strength and cardiovascular fitness in womenwith fibromyalgia: a pilot study. Arthritis Rheum 2002;47: 22-8.46. www.it.geocities.com/fibroamici2004/47. www.rheumatology.org/public/factscheets/fibromya -new.asp?aud=pat48. www.afsafund.org49. www.fmaware.org/site/PageServer50. www.fmpartnership.org51. www.sindromefibromiagica.it52. www.weiss.de