Biology and therapy of fibromyalgia. Evidence-based biomarkers for fibromyalgia syndrome

  • Dina Dadabhoy1,

    Affiliated with

    • Leslie J Crofford2,

      Affiliated with

      • Michael Spaeth3,

        Affiliated with

        • I Jon Russell4 and

          Affiliated with

          • Daniel J Clauw5Email author

            Affiliated with

            Arthritis Research & Therapy200810:211

            DOI: 10.1186/ar2443

            Published: 8 August 2008

            Abstract

            Researchers studying fibromyalgia strive to identify objective, measurable biomarkers that may identify susceptible individuals, may facilitate diagnosis, or that parallel activity of the disease. Candidate objective measures range from sophisticated functional neuroimaging to office-ready measures of the pressure pain threshold. A systematic literature review was completed to assess highly investigated, objective measures used in fibromyalgia studies. To date, only experimental pain testing has been shown to coincide with improvements in clinical status in a longitudinal study. Concerted efforts to systematically evaluate additional objective measures in research trials will be vital for ongoing progress in outcome research and translation into clinical practice.

            Introduction

            Fibromyalgia (FM) is a chronic condition characterized by widespread pain and tenderness on examination, along with symptoms of nonrestorative sleep, fatigue, and cognitive difficulties. Recent familial studies have suggested an underlying genetic susceptibility on which environmental factors trigger the expression of symptoms [1, 2]. Despite the myalgias that patients experience, no abnormality in muscle has been reliably found [3]. Instead, aberrant pain and sensory processing probably caused by alterations in the central nervous system function are being consistently recognized in FM and related syndromes. Investigations into the autonomic nervous system and the hypothalamic–pituitary–adrenal axis also suggest a role of these stress-response systems in vulnerability to FM or in symptom expression in FM.

            Our improved understanding of FM has stimulated the search for biomarkers to be used to identify individuals susceptible to the syndrome, for the diagnosis of FM, for objective measures of disease activity, or as surrogate endpoints of clinical trials. Using an expert panel from the FM workshop of the Outcome Measures in Rheumatology (OMERACT), a list of potential objective measures was first developed. Studies evaluating the measures were then methodically compiled by systematic review of the literature using a search for FM and the specific objective measure of interest. The databases searched included MEDLINE (1966 to 2006), PubMed (1966 to 2006), CINAHL (1982 to 2006), EMBASE (1988 to 2006), Healthstar (1975 to 2000), Current Contents (2000 to 2006), Web of Science (1980 to 2006), PsychInfo (1887 to 2006), Science Citation Indexes (1996 to 2006), and/or Cochrane Collaboration Reviews (1993 to 2006). The resulting published studies were used as the basis for the review.

            Genetics

            Increasing evidence supports a genetic predisposition to FM. First-degree relatives of individuals with FM display an eightfold greater risk of developing the syndrome than those in the general population [1]. As such, a genetic study using multicase families has been completed that identified an HLA linkage not yet replicated [4].

            Polymorphisms in the serotonergic 5-hydroxy tryptamine 2A receptor (T/T phenotype), the serotonin transporter, the dopamine 4 receptor and the catecholamine o-methyl trans-ferase enzyme have also been evaluated in patients with FM [510]. Notably, these polymorphisms all affect the metabolism or transport of monoamines, compounds that have a critical role in both sensory processing and the human stress response. With the exception of the catecholamine o-methyl transferase finding and the dopamine-4-receptor gene polymorphism, however, which have not been replicated or refuted, the other findings initially noted were generally not found in subsequent studies [410]. In some cases, the findings in FM were found when all individuals with this disorder were studied, but not when individuals free of psychiatric comorbidities were studied, suggesting that some of the above findings may track more closely with psychiatric comorbidity than inherent features of FM. Other candidate genes evaluated but not shown to be associated with FM are presented in Table 1.
            Table 1

            Genetics in fibromyalgia

            Reference

            Year of study

            Number of subjects

            Number of control

            Objective measure

            Findings

            Bondy and colleagues [5]

            1999

            168 FMS

            115

            5-HT2A, T102C polymorphism

            Different from control, but not significant for specific allele

            Gürsoy and colleagues [6]

            2001

            58 FMS

            58

            5-HT2A, T102C polymorphism

            Not significant

            Gürsoy and colleagues [7]

            2003

            61 FMS

            61

            COMT haplotype

            Over-representation of LL variant (low activity). Similar to migraine and TMD

            Offenbaecher and colleagues [8]

            1999

            62 FMS

            110

            5-HTT

            One positive for over-representative SS genotype, one negative study. Suggestion that any association might be related to comorbid psychology

            Gürsoy [9]

            2002

            53 FMS

            60 mentally healthy

            5-HTT

             

            Yunus and colleagues [4]

            1999

            40 multicase families

             

            HLA

            Linkage to HLA

            Buskila and colleagues [10]

            2004

              

            Dopamine D4 receptor polymorphism

            Decrease in the frequency of the seven-repeat allele in exon III of the D4 receptor gene associated with fibromyalgia. Finding associated with low novelty-seeking personality

            COMT, catecholamine o-methyl transferase; FMS, fibromyalgia syndrome; 5-HT2A, serotonergic 5-hydroxytryptamine 2A receptor (T/T phenotype); 5-HTT, serotonin transporter; TMD, temporomandibular disorder.

            Evoked (experimental) pain measures

            Even before the establishment of the American College of Rheumatology criteria for FM in 1990, which require both widespread pain and tenderness, investigators have used psychophysical pain testing to learn more about the nature of this condition. In fact, the early findings that the tenderness in FM was detectable throughout the body, rather than just confined to areas of tender points or muscle, was a hallmark finding that led investigators to believe this was a central nervous system pain amplification syndrome [11]. These measures are only relatively objective since they require patient self-report, but tender points do clearly measure a phenomenon that is independent from spontaneous, clinical pain.

            Numerous experimental pain studies have evaluated methods of quantifying the sensory experience of pain. Various groups using an assortment of devices that produce several stimuli have assessed the pain threshold and have attempted to quantify the pain experience in FM. A review of the investigated modalities gives the greatest support for the use of the tender point intensity/index, pressure pain thresholds, or heat pain thresholds as objective measures of the degree of hyperalgesia (increased pain to normally painful stimuli) and allodynia (pain in response to normally nonpainful stimuli) of an individual. Another consistent finding has been an absence of descending endogenous analgesic activity in FM.

            Tender point count

            The American College of Rheumatology criteria for FM require that an individual has a certain degree of tenderness. A tender point count is performed by applying 4 kg pressure manually to 18 predefined tender points, and then asking the patient whether these areas are tender. A positive response is considered a tender point; if an individual has 11 tender points or more, this element of the case definition is satisfied.

            The apparent close link between tenderness and FM has been well studied in both clinical trials of new therapies and in mechanistic studies. In a number of longitudinal randomized, placebo-controlled trials, improvements in clinical pain have corresponded with a significant change in tender point counts or in the tender point index [1214]. In contrast, other studies did not show a correspondence between improvements in clinical pain and tender point counts [1520].

            The discrepancies between studies could either be because the therapies did not improve tenderness or because tender points are not a good measure of tenderness. Both factors are likely to play a role since, in certain studies where multiple measures of the pain threshold were used, tender point counts did not significantly improve whereas other measures did [21, 22]. Moreover, other studies have shown that tender points are not a pure measure of tenderness. For example, there is a strong correlation between tender point counts and measures of distress in population-based studies [23]. Tender points have also been demonstrated to be biased by cognitive and emotional aspects of pain perception, whereas other measures of tenderness are much less so (see below) [24]. Improvements in tender point counts in some previous FM trials therefore possibly occurred because of improvements in distress, rather than because of inherent improvements in pressure pain threshold. Finally, tender points are often not continuously distributed in samples; rather, most people have either very few or nearly 18 tender points. As such, many investigators do not feel that tender point counts are useful to assess tenderness, and have instead turned to psychophysically and statistically superior measures.

            Pressure pain thresholds

            Directly measuring pressure pain thresholds is an alternative method of documenting tenderness. Devices that measure pressure pain thresholds have been used to demonstrate a left-shift and lowered pressure pain thresholds in patients with FM compared with control individuals, and this finding is noted anywhere in the body, both at tender points and in areas previously considered control points (Table 2). These findings suggest to many investigators that the term control points should be abandoned, or replaced by a term such as high-threshold tender point, since FM patients are just as tender in these regions relative to healthy control individuals.
            Table 2

            Pressure pain thresholds in fibromyalgia

            Reference

            Year of study

            Number of FM patients

            Number of control individuals

            QST

            QST method

            Findings

            Staud and colleagues [102]

            2005

            11

            12

            PPT: affected and CP

            ASC

            Decreased PPT (opposite of HC) after exercise

            Sandberg and colleagues [103]

            2005

            19

            19 HC, 7 TM

            PPT: TP

            ASC

            FM, TM with decreased PPT

            Montoya and colleagues [104]

            2005

            12

            12

            PPT, ERP

            ASC

            No difference (trend toward FM with decreased PPT). HC with decreased PPTs with repeat stimuli in one session. Decreased PPT for left hand versus right hand. FM decreased PPT in second assessment period (after EEG)

            Laursen and colleagues [105]

            2005

            2005

            10 FM/whiplash, 10 RA, 10 CLBP, 10 endometriosis

            41

            PPT: TP and CP

            ASC

            FM/whiplash, RA, endometriosis, CLBP with decreased PPT. Correlation between pressure hyperalgesia at lowest PPT sites and physical function impairment and mental health found

            Landis and colleagues [51]

            2004

            37

            30

            PPT: TP and CP

            ASC

            FM women with decreased PPT. PPT correlated with sleep spindle incidence and duration

            Landis and colleagues [106]

            2004

            33

            37

            PPT: TP

            ASC

            FM women with decreased PPT

            Maquet and colleagues [107]

            2004

            20

            50 females, 50 males

            PPT: TP

            ASC

            HC with decreased intraindividual variation (FM w/24%). HC females with decreased PPT compared with HC males. FM with decreased PPT compared with HC females. No difference between dominant and nondominant hands. PPT reproducibility and discrimination optimal at gluteal and knee

            Geisser and colleagues [108]

            2003

            20

            20

            PPT: TP and CP

            ASC

            FM with decreased PPT (more statistically significant than HPT). Catastrophizing correlated with decreased PPT. Depression associated with increased PPT

            Yoldas and colleagues [47]

            2003

            11

            10

            PPT and ERP

            ASC

            FM reduced P300 amplitude, correlated well with PPT

            Ernberg and colleagues [109]

            2003

            18

            n/a

            PP: over masseter

            ASC

            No difference (trend toward decreased PPT after antagonist)

            Carli and colleagues [110]

            2002

            145 (FM, CFS, WP, MPTE, MP)

            22

            PPT: CP and TP, HPT, CPT, cold pressor test, ischemic tourniquet test

            ASC

            FM with decreased PPT (CFS, MPTE), HPT (CFS), cold pressor test (CFS), ischemic tourniquet test (CFS, MPTE, WP, MP) than HC

            Hedenberg-Magnusson and colleagues [111]

            2002

            18

            15 masseter myalgia

            PPT: over masseter

            ASC

            Decreased PPT after treatment in both groups. Correlated with symptoms

            Ernberg and colleagues [112]

            2000

            12

            12 HC, 12 RA

            PPT: masseter

            ASC

            FM with decreased PPT

            Graven-Nielsen and colleagues [113]

            2000

            15 FM ketamine Responders

            Placebo

            EPT, PPT: TA muscle, PPT and pain tolerance: 3 TPs

            ASC

            Increased PPT at TA muscle, pain pressure tolerance after ketamine compared with placebo. Noted improvement in symptoms

            Ernberg and colleagues [114]

            2000

            12

            12

            PPT

            ASC

            FM with no significant increase in pain or decrease in PPT. HC with increased pain and decrease in PPT after infusion

            Ernberg and colleagues [115]

            1999

            18

            10 HC, 17 local myalgia

            PPT, pain tolerance: Masseter

            ASC

            FM with decreased PPT associated with higher fraction of masseter to serum serotonin levels

            Kosek and Hansson [30]

            1997

            10

            10

            PPT

            ASC

            FM decreased PPT

            Kosek and colleagues [31]

            1996

            10

            10

            PPT

            ASC

            FM decreased PPT

            McDermid and colleagues [116]

            1996

            20

            20 HC, 20 RA

            PPT: TP and CP

            ASC

            FM decreased PT compared with RA, HC. RA decreased PT compared with HC

            Kosek and colleagues [117]

            1995

            16

            n/a

            PPT at cream site

            ASC

            No difference in PPT after EMLA cream

            Tunks and colleagues [118]

            1995 1995

            6

            6 myofascial 6 pain controls, 6 HC

            PPT: TP and CP

            ASC

            FM and myofascial pain was discriminated from HC by dolorimetry and palpation

            Wolfe and colleagues [119]

            1995

            391

            n/a

            TPC, dolorimetry

            ASC

            PPT and TPC correlate with symptoms, but TPC correlates better

            Gibson and colleagues [29]

            1994

            10

            10

            PPT: TP and CP

            ASC

            FM decreased PPT at CT and TP, but data not clearly shown

            Lautenbacher and colleagues [120]

            1994

            26

            26

            PPT: CP and TP

            ASC

            FM decreased PPT

            Granges and Littlejohn [121]

            1993

            60

            60

            PPT: TP and CP

            ASC

            FM decreased HPT, PPT, CPT in CP and TP

            Lautenschlager and colleagues [122]

            1991

            47

            n/a

            PPT: TP and CP

            ASC

            Body diagram correlated better with dolorimetric findings than visual analog scale

            ASC, ascending; CFS, chronic fatigue syndrome; CLBP, chronic low back pain; CP, control point; CPT, cold pain threshold; CT, cold perception threshold; EEG, electroencephalography; EMLA, local anesthetic cream; EPT, electrical pain threshold; ERP, event-related potential; FM, fibro-myalgia; HC, healthy control individuals; HPT, heat pain threshold; MP, diffuse multiregional pain; MPTE, multiregional pain associated with at least 11 tender points; n/a, not applicable; PPT, pain pressure thresholds; QST, quantitative sensory testing; RA, rheumatoid arthritis; TA, tibialis anterior; TM, temporal mandibular disorder; TP, tender point; TPC, tender point count; WP, widespread pain.

            Many of these studies initially used commercial devices or dolorimeters to deliver continuously increasing pressure via blunt probes. These measures were found to be sensitive to psychophysical and psychological biases, however, slightly similar to tender point counts using digital palpation (reviewed in [25]). For instance, the rate of increase of stimulus pressure, controlled by the operator, and patient distress were both shown to influence the pain threshold [24, 26]. To minimize the bias, more sophisticated paradigms using random delivery of pressures have been developed and investigated [27, 28] (Table 3). Random delivery may be less sensitive to certain influences, but it is not free of bias. For instance, in a study by Petzke and colleagues, FM patients reported higher pain during random delivery than during ascending – possibly due to a perceived lack of control [28].
            Table 3

            Pain pressure thresholds and fibromyalgia (FM): part 2

            Reference

            Year of Study

            Number of FM patients

            Number of control individuals

            QST

            QST method

            Findings

            Petzke and colleagues [123]

            2005

            43

            28

            PPT: CP

            ASC and random

            FM patients report greater pain intensity but less relative unpleasantness compared with HC

            Giesecke and colleagues [124]

            2004

            16

            11 HC, 11 CLBP

            PPT: CP

            ASC and random

            FM and CLBP with decreased PPT

            Giesecke and colleagues [125]

            2003

            97

            n/a

            PPT: CP

            ASC and random

            FM subgroups: high and low tenderness. High or low control over pain correlated with cognitive and mood factors

            Petzke and colleagues [28]

            2003

            43

            28

            PPT: CP, suprathreshold

            ASC and random

            FM decreased PPT, suprathresholds. Ratings from random method were consistently higher than those of the ASC method, possibly due to perceived lack of perceived control

            Petzke and colleagues [24]

            2003

            39 FM, 6 CWP, 3 regional

            28 no pain, 3 pain

            PPT: CP and TP

            ASC and random

            Random method independent of psychological state. ASC correlated more with psychological state

            Gracely and colleagues [126]

            2002

            16

            16

            PPT: CP

            ASC and random

            FM with decreased PPT

            Chang and colleagues [27]

            2000

            11 IBS + FM

            11 IBS, 10 HC

            PPT: TP and CP

            ASC and random

            In random method, IBS + FM with more decreased PPT than IBS, but not HC. IBS with higher PPT than HC. In ASC, IBS similar PPT to HC

            Bendtsen and colleagues [127]

            1997

            25

            25

            PPT: TP and CP, suprathreshold

            Random

            FM with left shift in response function for stimuli applied to tender point (trapezius m) only, no difference in CP compared with HC

            ASC, ascending; CLBP, chronic low back pain; CP, control point; CWP, chronic widespread pain; HC, healthy control individuals; IBS, irritable bowel syndrome; PPT, pain pressure thresholds; QST, quantitative sensory testing; TP, tender point.

            A recent longitudinal study compared the three different evoked measures – tender point counts, the dolorimeter (ascending pressure paradigm), and the multiple random staircase (random pressure paradigm) – with clinical reports of pain improvement [21]. Although both clinical pain measures improved during the course of the study involving acupuncture, only one of the evoked measures – the multiple random staircase measure, which presented stimuli to individuals in an unpredictable fashion – improved after treatment. These results suggest that, of the different methods, the random stimuli paradigm may be more likely to systematically change over time. Interpretation of the results is nonetheless limited and will need to be reproduced and examined using other treatment modalities.

            Heat, cold, and electrical stimuli

            In addition to the heightened sensitivity to pressure noted in FM, other types of painful stimuli also are judged more painful by these patients. A decreased heat pain threshold in FM patients as compared with control individuals has been shown by multiple groups [2830] (Table 4). A reduced cold pain threshold has been reported by one group in two different studies [30, 31]. Sensitivity to warmth and the ability to detect electrical stimuli do not appear to be discriminative measures at this time.
            Table 4

            Heat pain threshold, cold pain threshold, and electrical stimuli in fibromyalgia

            Reference

            Year of study

            Number of FM patients

            Number of control individuals

            QST

            QST method

            Findings

            Petzke and colleagues [28]

            2003

            43

            28

            HPT, suprathreshold

            ASC and RAN

            FM decreased HPT, suprathresholds. Pain ratings from RAN were consistently higher than ASC, possibly due to perceived lack of perceived control

            Gibson and colleagues [29]

            1994

            10

            10

            WT and HPT

            ASC and RAN

            FM decreased HPT, no difference in WT

            Staud and colleagues [102]

            2005

            11

            12

            Suprathreshold: affected and CP

            ASC

            Increased thermal pain ratings after exercise (opposite of HC)

            Geisser and colleagues [108]

            2003

            20

            20

            HPT, WT

            ASC

            FM with decreased HPT. Higher intensity and unpleasantness for non-noxious stimuli

            Kosek and Hansson [30]

            1997

            10

            10

            CT, WT, CPT, HPT

            ASC

            FM decreased CT in forearm. FM decreased CPT and HPT. No difference in WT

            Lautenbacher and Rollman [34]

            1997

            25

            26

            HPT

            ASC

            FM had decreased HPT

            Kosek and colleagues [31]

            1996

            10

            10

            CT, WT, CPT, HPT

            ASC

            FM decreased HPT, CPT. FM had decreased WT only at TP

            Lorenz and colleagues [128]

            1996

            10

            10

            HPT

            ASC

            FM decreased HPT

            Lautenbacher and colleagues [120]

            1994

            26

            26

            HPT

            ASC

            FM decreased HPT, no difference in WT

            Lautenbacher and Rollman [34]

            1997

            25

            26

            Electrical

            ASC

            No difference in electrical detection/PT

            Lautenbacher and colleagues [120]

            1994

            26

            26

            Electrical – CP and TP

            ASC

            FM decreased electrocutaneous only at TP, not control points

            Arroyo and Cohen [129]

            1993

            10

            10

            Electrical detection, suprathreshold

            ASC

            No difference in electrical detection, FM decreased electrical tolerance

            ASC, ascending; CP, control point; CPT, cold pain threshold; CT, cold perception threshold; FM, fibromyalgia; HC, healthy control individuals; HPT, heat pain threshold; PT, pain threshold; QST, quantitative sensory testing; RAN, random; TP, tender point; WT, warmth perception threshold.

            Diminished diffuse noxious inhibitory control

            In the process of understanding altered evoked pain sensitivity present in FM, evaluation of the intrinsic analgesic systems has uncovered another potential biomarker: diminished diffuse noxious inhibitory control (DNIC). DNIC testing in both animals and humans involves testing the pain threshold at baseline, and then administering an acutely painful stimulus that leads to a systemic analgesic effect, presumably by activating endogenous analgesic systems.

            Several studies by different groups, using different conditioning stimuli (the acute noxious stimulus) and test stimuli (the stimulus used to measure pain threshold at baseline and following the acute, noxious stimulus), have indicated a deficiency of DNIC in individuals with FM. Diminished DNIC was observed in four cross-sectional studies by different groups that used variable test and conditioning stimuli [3134] (Table 5). Diminished DNIC has also been noted in other types of chronic pain; that is, temporomandibular disorder and hip osteoarthritis [35, 36]. The normalization of DNIC after hip osteoarthritis surgery suggests it may be an objective measure of chronic pain that can change over time with treatment [36].
            Table 5

            Diffuse noxious inhibitory controls (DNIC) in fibromyalgia (FM)

            Reference

            Year of study

            Number of FM patients

            Number of control individuals

            Test stimuli (noxious stimuli)

            Heterotopic conditioning noxious stimuli

            Findings

            Julien and colleagues [32]

            2005

            30

            30 HC, 30 CLBP

            Water bath, cold, noxious

            Water bath, cold, noxious

            Diminished DNIC in FM patients, not CLBP

            Staud and colleagues [33]

            2003

            11

            22 females, 11 males

            Wind up

            Water bath, heat, noxious

            Diminished DNIC in female HC and female FM patients

            Kosek and Hansson [30]

            1997

            10

            10

            CT, WT, HPT, CPT

            Tourniquet

            Diminished DNIC in FM patients

            Lautenbacher and Rollman [34]

            1997

            25

            26

            Electrical pain threshold Electrical detection

            Thermode tonic cold thermal, noxious and non-noxious

            Diminished DNIC in FM patients No difference

            CLBP, chronic low back pain; CT, cold perception threshold; CPT, cold pain threshold; HC, healthy control individuals; HPT, heat pain threshold; WT, warmth perception threshold.

            Functional neural imaging

            Functional neural imaging enables investigators to visualize how the brain processes the sensory experience of pain. The primary modes of functional imaging that have been used in FM include functional magnetic resonance imaging (fMRI), single-photon emission computed tomography (SPECT), and positron emission tomography.

            fMRI studies evaluating pain processing have the strongest current evidence of the functional imaging studies, because they corroborate this left-shift in stimulus–response function (that is, hyperalgesia/allodynia) noted in FM. Specifically, several areas of the brain consistently show greater activation in FM patients than in control individuals given the same objective stimulus intensity – especially the secondary somatosensory cortex, insula and the anterior cingulate cortex. These findings have been noted in five cross-sectional studies by two different groups, using both pressure and heat stimuli [37, 38] (Table 6). In the study by Giesecke and colleagues, the clinical pain intensity corresponded with an increase in the evoked regional cerebral blood flow [37]. The resting regional cerebral blood flow was evaluated by a third group in a longitudinal study using fMRI, and showed change after drug treatment [39]. These studies have also been useful in identifying differences in pain processing in individuals with and without psychological comorbidities, showing for example that depression does not seem to be influencing the magnitude of neuronal activation in sensory pain regions such as the secondary somatosensory cortex, whereas cognitive factors such as catastrophizing did influence the sensory intensity of pain [37, 40].
            Table 6

            Neural imaging in fibromyalgia (FM)

            Reference

            Year of study

            Number of FM patients

            Number of Control individuals

            Neural imaging

            Description

            QST

            Findings

            Giesecke and colleagues [37]

            2005

            7

            7 MDD/FM, 7 HC

            fMRI

            QST evoked rCBF association to depression

            Pressure pain MRS

            Clinical pain intensity – associated with increased rCBF of insula bilaterally, contralateral ACC, prefrontal cortex. Symptoms of depression – not associated with increased rCBF of SI, SII; associated amygdala and contralateral anterior insula

            Gracely and colleagues [40]

            2004

            15 high catastrophizers

            14 low catastrophizers

            fMRI

            QST evoked rCBF association to catastrophizing

            Pressure pain MRS

            Both low and high with increased rCBF in contralateral insula, SI, SII, inferior parietal lobule and thalamus, ipsilateral S1, cerebellum, posterior cingulated gyrus, and superior and inferior frontal gyrus. High catastrophizers with unique activation in contralateral anterior ACC, contralateral ipsilateral lentiform

            Giesecke and colleagues [124]

            2004

            16

            11 HC, 11 CLBP

            fMRI

            QST evoked rCBF

            Pressure pain MRS

            In CLBP and FM patients, QST (equal pressure) increased rCBF of contralateral SI and SII, inferior parietal lobule, cerebellum, and ipsilateral SII. In HC, QST (equal pressure) activation of contralateral SII. Equal evoked equal pain associated with similar activation

            Koeppe and colleagues [39]

            2004

            ?

            None

            fMRI

            Injection of 5-HT-3 receptor antagonist (topisetron) rCBF

            n/a

            In FM patients, topisetron treatment reduced rCBF of SI, contralateral posterior insula, ACC

            Cook and colleagues [38]

            2004

            9

            9 HC

            fMRI

            QST evoked activation of rCBF

            Nonpainful and painful heat, 47°C

            In FM, nonpainful heat increased rCBF in prefrontal, supplemental motor, insular, and ACC as compared with HC. In FM patients, painful heat increased activity in contralateral insular cortex as compared with HC

            Gracely and colleagues [126]

            2002

            16

            16 HC

            fMRI

            QST evoked activation of rCBF

            Pressure pain MRS, neutral site

            Common areas of evoked equal pain increased rCBF including contralateral SI, inferior parietal lobule, SII, superior temporal gyrus (STG), insula, putamen, and ipsilateral cerebellum. Decreased rCBF in ipsilateral SI. In HC, QST (equal pressure) activated ipsilateral STG and precentral gyrus

            Yunus and colleagues [130]

            2004

            12

            7 HC

            PET

            Resting rCBF

            n/a

            No difference

            Chang and colleagues [131]

            2003

            10 IBS + FM

            10 IBS

            PET

            QST evoked activation of rCBF

            Noxious visceral and somatic pressure

            In IBS patients, noxious visceral stimuli evoked increased rCBF increase in middle subregion of the ACC. In IBS + FM patients, somatic stimuli evoked greater rCBF in middle subregion of the ACC extending to ACC and the thalamus

            Wik and colleagues [132]

            2006

            8

            None

            PET

            QST evoked activation of rCBF

            Acute pain

            In FM patients, frontal and parietal cortical activation during acute pain compared with rest (as expected). Reduced rCBF in retrosplenial cortex (evaluative processing)

            Wood and colleagues [41]

            2007

            11

            11 HC

            PET

            QST evoked binding of D2/D3 ligand

            Nonpainful and painful saline injection

            In FM patients, lack of dopamine release in basal ganglia compared with HC during painful stimuli. In HC, amount of dopamine release correlated with amount of perceived pain; in FM patients, no such correlation observed

            Adiguzel and colleagues [42]

            2004

            14

            None

            SPECT

            Amitriptyline (3 months) resting rCBF

            n/a

            Increased rCBF in bilateral hemithalami after amitriptyline. No correlation between symptoms and findings

            Gur and colleagues [45]

            2002

            19

            20 HC

            SPECT

            Resting rCBF

            n/a

            Increased rCBF in caudate nucleus. FM patients with less depression had increased uptake in pons

            Kwiatek and colleagues [43]

            2000

            17

            22 HC

            SPECT

            Resting rCBF

            n/a

            Reduced rCBF in right thalamus and potine tegmentum, no reduction in left thalamus, or caudate nucleus. No correlation between symptoms and findings

            Mountz and colleagues [44]

            1995

            10

            7 HC

            SPECT

            Resting rCBF

            n/a

            Reduced rCBF in bilateral hemithalami and caudate nucleus correlated with low pain threshold No correlation between symptoms and findings

            ACC, anterior cingulate cortex; CLBP, chronic low back pain; fMRI, functional magnetic resonance imaging; HC, healthy control individuals; 5-HT-3, 5-hydroxytryptamine 3; IBS, irritable bowel syndrome; MDD, major depression disorder; MRS, multiple random staircase; n/a, not applicable; PET, positron emission tomography; QST, quantitative sensory testing; rCBF, regional cerebral blood flow; SI, somatosensory cortex I; SII, somatosensory cortex II; SPECT, single-photon emission computed tomography.

            Positron emission tomography imaging in FM has been reported in only a few studies with inconclusive results. The only positive study is a recent one showing there may be altered dopaminergic activity in FM [41].

            SPECT imaging has been studied in four cross-sectional studies by different groups that consistently found reduced regional cerebral blood flow in the right thalamus of patients with FM (three of the four studies) [4245]. No correlation between symptoms and findings were noted in the SPECT studies.

            The consistent abnormalities seen in fMRI and SPECT studies suggest either of these methods might be useful to use as a biomarker, but longitudinal studies showing that improvements in symptoms coincide with normalization of functional imaging findings would be necessary to establish this role. The advantages of fMRI imaging over positron emission tomography and SPECT include the less invasive nature and the higher temporal and spatial resolutions of fMRI. Disadvantages of fMRI include the cost and practicability as well as the inability to perform receptor–ligand studies that are possible with positron emission tomography and SPECT.

            Event-related potentials

            Cerebral potentials evoked by noninvasive stimulation provide a unique opportunity to investigate the functional integrity and magnitude of brain processing pathways. Expressing the ability of the human brain to discriminate, classify, and memorize the significance of exogenous stimuli, event-related potentials (ERPs) have been used as a marker of cognitive function in patients with psychiatric and neurological disorders. The electrical waveforms generated can be divided into late and early components, and the waveforms are designated by their polarity (P-positive, N-negative) and latency (timing of peak) after stimulus onset. Additionally, the amplitude – the size of the voltage difference between the component peak and a prestimulus baseline – is also quantified. Auditory, somatosensory, and visual ERPs have been evaluated in patients with FM in a few studies.

            Among the ERPs evaluated to date, the P300 potential (most commonly generated by an auditory consciously attended stimuli) appears to be the most promising to differentiate FM patients from control individuals. The P300 wave is a late cortical neuropsychological event, the latency of which reflects the information processing speed and the amplitude of which expresses memory functions. A reduced P300 amplitude during an auditory discriminated-task paradigm has been significantly noted in FM patients as compared with control individuals in three cross-sectional studies by two different groups [4648] (Table 7). All three studies also evaluated the P300 latency, but only the largest study by Alanoglu and colleagues noted an increase in P300 latency, a finding that may have not been found in the prior studies due to lack of power [46]. In the one of these three studies by Ozgocmen and colleagues that performed ERPs before and after treatment, 8 weeks of sertraline treatment led to an increase in the P300 magnitude [48].
            Table 7

            Evoked potentials in fibromyalgia (FM)

            Reference

            Year of study

            Number of FM patients

            Number of Control individuals

            Evoked potential

            Paradigm

            EP evaluated

            Findings

            Alanoglu and colleagues [46]

            2005

            34

            22

            Auditory

            Auditory discriminated task paradigm

            P300 wave

            FM reduced P300 amplitude and prolonged latency. No correlation between EP findings, pain scores, and quality of life measurements

            Yoldas and colleagues [47]

            2003

            11

            10

            Auditory

            Auditory discriminated task paradigm

            P300 wave

            FM reduced P300 amplitude, but no difference in potential latency. P300 latency negatively correlated with total myalgic scores and the control point scores. P300 amplitude correlated with PPT and total myalgic scores. No correlation in amplitude or latency with depression or anxiety.

            Ozgocmen and colleagues [48]

            2003

            13

            10

            Auditory

            Auditory discriminated task paradigm ~before and after sertraline treatment (8 weeks)

            P300 wave

            no difference in potential latency at baseline. Sertraline treatment resulted in increase in potential amplitude by 8 weeks without change in latency. No correlation between EP findings, fatigue and pain scores, but correlated to total myalgic scores

            EP, evoked potential; PPT, pain pressure thresholds.

            These studies generally failed to show an association between the ERP findings and symptom severity, although there was an association noted with the total myalgic score. Although the change in the P300 potential after sertraline treatment was attractive, the authors agreed that – given the corresponding significant clinical improvement in pain, fatigue, or depression – the mechanism for the change remained unclear, and they acknowledged it may represent regression to the mean. Larger studies by different groups with an attention to standardizing methods are essential prior to mainstream use of this marker.

            In contrast to auditory potentials, there are few and varied studies evaluating somatosensory and visual ERPs. The assorted protocols used in the studies investigating somato-sensory and visual ERPs may have contributed to the lack of consistently demonstrated differences in FM and normal individuals. The lack of an established standardized methodology makes direct comparison difficult and may limit the evidence of reproducibility.

            Sleep and activity

            In addition to pain, other symptoms very commonly seen in FM include disturbed sleep and poor function. Sleep logs and polysomnography have consistently confirmed patient reports of hypersomnolence [49, 50]. Using polysomnography, investigators have correlated hypersomnolence with poor sleep quality by demonstration of fewer sleep spindles, an increase in the cyclic alternating pattern rate, or poor sleep efficiency [5153]. Sleep abnormalities are rarely shown to correlate with symptoms in FM, however, and many investigators anecdotally feel as though even identifying and treating specific sleep disorders often seen in FM patients (for example, obstructive sleep apnea, upper airway resistance, restless leg or periodic limb movement syndromes) does not necessarily lead to improvements in the core symptoms of FM.

            Actigraphy

            A method of motion assessment that infers sleep and wakefulness from the presence of limb movements, actigraphy is increasingly being used as a surrogate marker for both sleep and activity. The actigraph typically combines a movement detector and memory storage on a watch-like device. The device can be worn on the wrist or the ankle continuously for long periods of time. Sleep-pattern measures available via actigraphy analyses include sleep latency, the wake time after sleep onset, and the total sleep time; sleep architecture cannot be measured, as with polysomnography. Compared with polysomnography, however, actigraphy is less expensive, less invasive, and more conducive to repeated measures, resulting in extensive use in intervention studies [54].

            Actigraphy is being increasingly used in FM studies and appears promising, but has not yet proven adequately sensitive to stand alone in clinical evaluation or treatment trials [50, 55, 56]. As a measure of sleep quality there have been inconsistent actigraphy results, with one group noting increased levels of activity at night in FM (also noted in patients with major depression) [55] and another group noting no difference [50]. Edinger and colleagues used actigraphy as an outcome measure in an intervention trial comparing cognitive behavior therapy intervention with sleep hygiene and usual care in the treatment of insomnia [57]. Deriving an actigraphic improvement criterion, the investigators showed a greater number of patients receiving cognitive behavior therapy had clinically significant improvement in the total wake time compared with sleep hygiene therapy. No statistical difference between cognitive behavior therapy and usual care was able to be demonstrated, even though a statistical difference between the groups was shown using sleep log data in the same study.

            As an objective measure of functional status, actigraphy might hold more promise as a surrogate outcome measure, because it allows the direct recording of activity levels, rather than relying on patient self-report [58]. Kop and colleagues demonstrated that although patients with FM have 36-Item Short Form health survey scores nearly two standard deviations below the population average, they have the same average activity level as a group of sedentary control individuals [58]. The FM patients had much lower peak activity levels, however, suggesting that the problems in function that FM patients report might be more due to an inability to rise to the intermittent demands of day-to-day life than due to overall reduced function.

            Stress–response systems and sex hormones

            The theoretical link between stress–response systems and symptom expression is supported by studies demonstrating alterations of the hypothalamic–pituitary–adrenal axis and the autonomic nervous system in FM. Probing different aspects of the stress systems is underway to uncover objective ways to identify persons at risk or to identify reproducible abnormalities. One group clearly with increased susceptibility is women. Investigators hypothesize a potential effect of sex hormones on the stress response to partly explain the female predominance seen in FM, but this connection has not yet been specifically examined in FM patients [59].

            Hypothalamic–pituitary–adrenal axis

            In basal and diurnal cortisol studies, the most consistently found measure is a flattened diurnal plasma cortisol level with an elevated trough, found in three of four cross-sectional studies by two out of three groups [6062] (Table 8). Studies evaluating basal plasma cortisol levels, salivary basal and diurnal cortisol levels, and urinary cortisol levels have shown inconsistent results, but they generally demonstrate normal to reduced basal levels. Since atypical depression can show a reduced cortisol level, biopsychological factors that influence cortisol levels may be contributing to the inconsistent results currently found in the literature [63]. These factors need to be better elucidated and accounted for in future studies. Nonetheless, a flattened diurnal cortisol level is a promising objective measure.
            Table 8

            Basal and diurnal cortisol and fibromyalgia (FM)

            Reference

            Year of study

            Number of FM patients

            Number of control individuals

            Measured (plasma)

            Findings

            McCain and Tilbe [60]

            1989

            20

            20 RA

            Plasma cortisol

            Normal peak, elevated trough, flattened diurnal compared to RA

            Crofford and colleagues [133]

            1994

            7

            7

            Plasma cortisol

            Normal peak, elevated trough, flattened diurnal

            Crofford and colleagues [61]

            2004

            13

            12 FMS + CFS, 15 CFS

            Plasma cortisol

            Delay in rate of decline in FM, elevated cortisol in late period in FM, flattened diurnal, lower O/N cortisol in CFS

            Adler and colleagues [62]

            1999

            15

            13

            Plasma cortisol – total and free

            Normal, normal diurnal

            Korszun and colleagues [134]

            1999

            9

            9 HC, 8 CFS

            Plasma cortisol

            Normal

            Malt and colleagues [135]

            2002

            22

            13

            Plasma cortisol

            Normal

            Valkeinen and colleagues [136]

            2005

            13 (60 years old)

            13 (59 years old)

            Plasma cortisol

            Normal

            Griep and colleagues [64]

            1993

            10

            10

            Plasma cortisol

            Normal

            Gur and colleagues [137]

            2004

            63 (<35 years old)

            38 (<35 years old)

            Plasma cortisol

            Reduced

            Gur and colleagues [63]

            2004

            68

            46 HC, 62 CFS

            Plasma cortisol

            Reduced in FM with high BDI scores (>17), not in those with low BDI. Reduced in CFS

            Griep and colleagues [66]

            1998

            40

            14 HC, 28 CLBP

            Plasma cortisol

            Reduced

            Lentjes and colleagues [138]

            1997

            40

            14 HC, 28 CLBP

            Plasma cortisol – total and free

            Reduced total cortisol in FM only, Normal free cortisol in FM, CLBP

            Riedel and colleagues [65]

            1998

            16

            17

            Plasma cortisol

            Elevated

            Catley and colleagues [139]

            2000

            21

            22 HC, 18 RA

            Salivary cortisol 6 times/day

            Elevated, normal diurnal

            McClean and colleagues [140]

            2005

            20

            16

            Salivary cortisol 5 times/day

            Normal, normal diurnal strong relationship between current pain symptoms and cortisol levels at waking and 1 hour after waking. No relationship between fatigue and stress

            Weissbecker and colleagues [141]

            2006

            85

            n/a

            Salivary cortisol 6 times/day

            Flattened diurnal, greater cortisol responses to awakening in FM with history psychological, physical abuse

            Dedert and colleagues [142]

            2004

            91

            n/a

            Salivary cortisol 5 times/day

            Flattened diurnal on those with low religiosity

            Sephton and colleagues [143]

            2003

            50

            n/a

            Salivary cortisol 5 times/day

            Higher log-transformed mean salivary cortisols associated with better memory

            Adler and colleagues [62]

            1999

            15

            13

            24-hour urinary cortisol

            Normal

            Maes and colleagues [144]

            1998

            ?

            PTSD, depression

            24-hour urinary cortisol

            Normal

            Torpy and colleagues [145]

            2000

            13

            8

            24-hour urinary cortisol

            Normal (trend toward reduced)

            Crofford and colleagues [133]

            1994

            12

            10

            24-hour urinary cortisol

            Reduced (no difference between depressed and non depressed)

            Lentjes and colleagues [138]

            1997

            40

            14 HC, 28 CLBP

            24-hour urinary cortisol

            Reduced in FM and CLBP

            Griep and colleagues [66]

            1998

            40

            14 HC, 28 CLBP

            24-hour urinary cortisol

            Reduced

            BDI, Beck Depression Inventory; CFS, chronic fatigue syndrome; CLBP, chronic low back pain; FMS, fibromyalgia syndrome; HC, healthy control individuals; PTSD, post-traumatic stress disorder; RA, rheumatoid arthritis.

            Evaluation of other components of the hypothalamic–pituitary–adrenal axis has been relatively unrevealing. Basal and diurnal adrenocorticotropic hormone shows no difference in FM patients versus healthy control individuals [62, 64, 65] (Additional file 1). Provocative hypothalamic–pituitary–adrenal studies utilizing the cosyntropin test have shown inconsistent results [62, 6668] (Additional file 2).

            Results of the dexamethasone suppression test have been reported in a number of studies by different groups, and the results reveal normal to high levels of cortisol following infusion of the corticosteroid [60, 64, 66, 69, 70] (Additional file 3). Depression also typically follows a pattern of resistance to the dexamethasone test, and therefore is a confounding factor in a large number of these evaluations.

            Studies have also been completed to assess the cortisol response to exogenous corticotropin-releasing hormone or endogenous activators of corticotropin-releasing hormone (that is, hypoglycemia, IL-6) in FM. Investigators found normal to reduced cortisol levels in patients with FM after an increase in corticotropin-releasing hormone, but these results were not reproduced in other similar studies. Further investigation taking into account psychological factors as well as doses of different drugs will be prudent.

            Autonomic reactivity

            Tilt table testing and heart rate variability have been evaluated in patients with FM. The consistent and reproducible finding of lower heart rate variability in FM patients compared with control individuals (in three cross-sectional studies by two different groups) makes it a more useful measure than tilt table testing [7173]. An abnormal drop in blood pressure or an excessive rate of syncope during tilt table testing has been noted in two out of three cross-sectional studies completed by three different groups [7476]. One study noted no difference in normal individuals and control individuals using univariate analysis [76]. Moreover, recent findings also suggest that aberrations in heart rate variability may predispose to fibromyalgia symptoms [77, 78], possibly identifying patients at risk.

            Sex hormones

            FM syndrome is more prevalent in women than in men, suggesting a role of sex hormones in the pathophysiology of FM [79]. To date, two studies have failed to show an association between sex hormones and pain sensitivity [79, 80]. The reason for a female predominance in FM is complex and warrants further investigation.

            Serologic and biochemical abnormalities

            Physicians from multiple disciplines have used simple blood tests to diagnose and evaluate treatment for various diseases. Scientists have similarly evaluated a number of compounds in the serum and cerebrospinal fluid of patients with FM to find a comparable marker of disease or disease activity. Despite the effort to find easily accessible measures, no clinically suitable tests have yet been appropriately validated for FM.

            Autoantibodies

            The search for representative autoantibodies is a predictable step for a disease like FM, often evaluated by rheuma-tologists and coexisting with autoimmune diseases. Antiserotonin antibody, antiganglioside antibody, and antiphospholipid antibody have been shown to be different in FM patients and control individuals, but the applicability of these findings is not yet clear [81] (Table 9). Antiserotonin antibody has been shown to be increased in FM in three cross-sectional studies by two different groups [8183]. Antiganglioside antibody and antiphospholipid antibody have each been shown to be increased in FM in two cross-sectional studies by the same group [81, 82]. A different group evaluating antiganglioside antibody in a third cross-sectional study was unable to reproduce the results [83]. Antithromboplastin antibody [83], antipolymer antibody [84], and anti-68/48 kDa and anti-45 kDa [85] have each been evaluated in one cross-sectional study and have shown increased levels in FM. A review of the literature demonstrates that antinuclear antibodies, antithyroid antibodies, antisilicone antibodies, and antiglutamic acid decarboxylase are not informative in FM.
            Table 9

            Autoantibodies and fibromyalgia (FM)

            Reference

            Year of study

            Number of FM patients

            Number of control individuals

            Objective measure

            Findings

            Klein and colleagues [82]

            1992

            50

            ?HC

            Antiserotonin

            Increased in FMS

                

            Antiganglioside

            Increased in FMS

                

            Antiphospholipid

            Increased in FMS

            Klein and Berg [81]

            1995

            100

            42 CFS, ?HC

            Antiserotonin

            Increased in CFS and FMS

                

            Antigangliosides

            Increased in CFS and FMS

                

            Antiphospholipid

            Increased in CFS and FMS

            Werle and colleagues [83]

            2001

            203

            64

            Antiserotonin

            Increased

                

            Antithromboplastin

            Increased

                

            Antiganglioside

            No difference

                

            Gm1

            No difference

            Wilson and colleagues [84]

            1999

            47

            16 OA,12 RA, banked sera, 15 myositis, 30 RA, 30 SLE, 30 SSc

            Antipolymer antibody

            Increased in antipolymer antibodies, higher in severe versus mild

            Nishikai and colleagues [85]

            2001

            125

            114 CFS, ?psych, ?CTD

            Anti-68/48 kDa

            Increased in FMS and CFS

                

            Anti-45 kDa

            Increased in FMS and CFS

            CFS, chronic fatigue syndrome; CTD, connective tissue disease; FMS, fibromyalgia syndrome; HC, healthy control individuals; OA, osteoarthritis; RA, rheumatoid arthritis; SLE, systemic lupus erythmatosus; SSc, systemic sclerosis.

            The nonspecific increase in antibodies to a number of antigens may be a nonspecific finding that arises from a subtle shift in immune function in this spectrum of illness. In the closely related chronic fatigue syndrome, investigators have noted a shift from a T1 to a T2 immune response, which would be expected to lead to increased production of nonspecific antibodies. Any antibody or autoantibody proposed as either a diagnostic test for FM or a biomarker of FM must therefore be carefully tested using various control individuals to ensure its authenticity.

            Neuropeptides

            Substance P is a neuropeptide released in spinal fluid when axons are stimulated. Four different cross-sectional studies by various groups in FM patients noted an elevation of substance P in cerebrospinal fluid [8689]. In contrast, a normal substance P level has been noted in the cerebrospinal fluid of patients with chronic fatigue syndrome [90]. Although these results appear promising, elevated substance P is not specific for FM but rather has been shown to occur in other pain states such as chronic, daily headaches and chronic neck or shoulder pain associated with whiplash injury [91, 92]. A high level of substance P therefore seems to be a biological marker of the presence of chronic pain.

            Nerve growth factor and calcitonin gene-related peptide are additional neuropeptides that have been evaluated in FM. Nerve growth factor was shown in one study to have increased levels in FM and not in FM/rheumatoid arthritis overlap, therefore presenting inconclusive results [93]. Cerebrospinal fluid and serum calcitonin gene-related peptide have been studied and not found to be different in FM patients and control individuals [94, 95].

            Biochemicals and cytokines

            The amino acid tryptophan and the cytokine IL-8 have both been shown to be different in patients compared with control individuals in a couple of studies, but neither have been evaluated in longitudinal studies [9698]. A low tryptophan level has been found in two of three studies by three different groups [96, 99, 100]. IL-8 has been consistently demonstrated in three studies by two different groups [97, 98, 101]. Moreover, IL-8 has been shown to correlate with symptoms of FM and not to be associated with depressed FM [98]. Serum IL-6 was evaluated and found to be normal in FM patients [98, 101].

            Muscle abnormalities

            Despite the interest and investigation for objective peripheral muscle abnormalities, the results have remained variable and have not yet been reproduced by different groups. Additionally, there is great heterogeneity in the methods evaluating for objective muscle abnormalities that render a complete review of the data beyond the scope of the present study. To dissect out possible useful objective measures, further investigations are necessary, preferably utilizing non-invasive procedures.

            Conclusion

            Except for psychophysical pain testing, no objective measure has been appropriately evaluated and shown to improve with improvements in clinical status in a longitudinal study, and thus to qualify as a biomarker (see Table 10 for summary). These tests are not, however, entirely objective. Of the objective tests, those that hold the most promise as biomarkers are probably tests that directly assess elements of neural function, such as functional neuroimaging, ERPs, and DNIC. An effort by different groups to systematically evaluate these measures in research trials to obtain useful, comparable results will be vital for ongoing progress in outcome research. There will be an ongoing need to identify biomarkers for future studies that have reproducibility and predictive value, practicability, and biological and temporal relevance in FM.
            Table 10

            Summary of findings for objective markers

            Objective marker

            Findings

            Genetics

            Polymorphisms in catecholamine o-methyl transferase have been noted in some ethnic groups but not others; dopamine 4 receptor findings have not been replicated or refuted as compared with other polymorphisms

            Tender point counts or index

            Multiple studies suggesting utility. The tender point count and the tender point index may be influenced by cognitive and emotional aspects of pain, and therefore may be biased

            Pressure pain threshold

            Multiple studies suggesting utility. The pressure pain threshold may be influenced by cognitive and emotional aspects of pain, which may be minimized by utilizing a random pressure paradigm

            Heat and cold pain threshold

            Consistently different in patients versus control individuals but not shown to be correlated with changes in clinical pain

            Diminished diffuse noxious inhibitory controls

            Four cross-sectional studies by different groups suggest utility. Needs further exploration with standardized methods, longitudinal studies

            Functional neural imaging

            Multiple studies suggesting utility. May be influenced by cognitive aspects of pain. Longitudinal studies needed

            Event-related potentials

            Reduced P300 amplitude has been noted in three cross-sectional studies by two different groups. Larger studies with standardized methods are necessary. Longitudinal studies needed

            Sleep logs and polysomnography

            Confirm reports of hypersomnolence, but no changes are pathognomonic of or specific for fibromyalgia

            Actigraphy

            Inconsistent measure of sleep quality. Report suggesting utility in measuring functional status. Larger, longitudinal studies needed

            Hypothalamic–pituitary–adrenal axis

            Flattened diurnal cortisol noted in three of four cross-sectional studies by two of three groups. Need to explore influence of biopsychosocial factors. Longitudinal studies needed

            Autonomic reactivity

            Lower heart rate variability noted in three cross-sectional studies by two different groups. May predispose to condition. Longitudinal studies needed

            Autoantibodies

            Antiserotonin antibody noted to be increased in three cross-sectional studies by two different groups.

             

            Stringent controls necessary prior to determining utility. Longitudinal studies needed

            Neuropeptides

            Substance P noted to be increased in cerebrospinal fluid in four cross-sectional studies by various groups.

             

            Potential nonspecific marker of chronic pain

            Biochemical and cytokines

            Low tryptophan and elevated IL-8 noted. Longitudinal studies needed

            Muscle abnormalities

            No clear and reproducible abnormality. Additional studies with standardized methods needed

            Abbreviations

            DNIC: 

            diffuse noxious inhibitory control

            ERP: 

            event-related potential

            FM: 

            fibromyalgia

            fMRI: 

            functional magnetic resonance imaging

            IL: 

            interleukin

            SPECT: 

            single-photon emission computed tomography

            Declarations

            Authors’ Affiliations

            (1)
            Northwest Rheumatology Specialists
            (2)
            Department of Internal Medicine, University of Kentucky
            (3)
            Center for Clinical Rheumatology Research
            (4)
            Department of Medicine, The University of Texas Health Science Center at San Antonio
            (5)
            Department of Internal Medicine, University of Michigan Medical School

            References

            1. Arnold LM, Hudson JI, Hess EV, Ware AE, Fritz DA, Auchenbach MB, Stark LO, Keck PE Jr: Family study of fibromyalgia. Arthritis Rheum 2004, 50:944–952.PubMedView Article
            2. Buskila D, Sarzi-Puttini P, Ablin JN: The genetics of fibromyalgia syndrome. Pharmacogenomics 2007, 8:67–74.PubMedView Article
            3. Simms RW, Roy SH, Hrovat M, Anderson JJ, Skrinar G, LePoole SR, Zerbini CA, de Luca C, Jolesz F: Lack of association between fibromyalgia syndrome and abnormalities in muscle energy metabolism. Arthritis Rheum 1994, 37:794–800.PubMedView Article
            4. Yunus MB, Khan MA, Rawlings KK, Green JR, Olson JM, Shah S: Genetic linkage analysis of multicase families with fibromyalgia syndrome. J Rheumatol 1999, 26:408–412.PubMed
            5. Bondy B, Spaeth M, Offenbaecher M, Glatzeder K, Stratz T, Schwarz M, de Jonge S, Kruger M, Engel RR, Farber L, Pongratz DE, Ackenheil M: The T102C polymorphism of the 5-HT2A-receptor gene in fibromyalgia. Neurobiol Dis 1999, 6:433–439.PubMedView Article
            6. Gürsoy S, Erdal E, Herken H, Madenci E, Alasehirli B: Association of T102C polymorphism of the 5-HT2A receptor gene with psychiatric status in fibromyalgia syndrome. Rheumatol Int 2001, 21:58–61.PubMedView Article
            7. Gürsoy S, Erdal E, Herken H, Madenci E, Alasehirli B, Erdal N: Significance of catechol- O -methyltransferase gene polymorphism in fibromyalgia syndrome. Rheumatol Int 2003, 23:104–107.PubMed
            8. Offenbaecher M, Bondy B, de Jonge S, Glatzeder K, Kruger M, Schoeps P, Ackenheil M: Possible association of fibromyalgia with a polymorphism in the serotonin transporter gene regulatory region. Arthritis Rheum 1999, 42:2482–2488.PubMedView Article
            9. Gürsoy S: Absence of association of the serotonin transporter gene polymorphism with the mentally healthy subset of fibromyalgia patients. Clin Rheumatol 2002, 21:194–197.PubMedView Article
            10. Buskila D, Cohen H, Neumann L, Ebstein RP: An association between fibromyalgia and the dopamine D4 receptor exon III repeat polymorphism and relationship to novelty seeking personality traits. Mol Psychiatry 2004, 9:730–731.PubMedView Article
            11. Yunus MB: Towards a model of pathophysiology of fibromyalgia: aberrant central pain mechanisms with peripheral modulation. J Rheumatol 1992, 19:846–850.PubMed
            12. Bell IR, Lewis DA, Brooks AJ, Schwartz GE, Lewis SE, Walsh BT, Baldwin CM: Improved clinical status in fibromyalgia patients treated with individualized homeopathic remedies versus placebo. Rheumatology (Oxford) 2004, 43:577–582.View Article
            13. Scharf MB, Baumann M, Berkowitz DV: The effects of sodium oxybate on clinical symptoms and sleep patterns in patients with fibromyalgia. J Rheumatol 2003, 30:1070–1074.PubMed
            14. Farber L, Stratz TH, Bruckle W, Spath M, Pongratz D, Lautenschlager J, Kotter I, Zoller B, Peter HH, Neeck G, Welzel D, Muller W: Short-term treatment of primary fibromyalgia with the 5-HT3-receptor antagonist tropisetron. Results of a randomized, double-blind, placebo-controlled multicenter trial in 418 patients. Int J Clin Pharmacol Res 2001, 21:1–13.PubMed
            15. Arnold LM, Hess EV, Hudson JI, Welge JA, Berno SE, Keck PE Jr: A randomized, placebo-controlled, double-blind, flexible-dose study of fluoxetine in the treatment of women with fibromyalgia. Am J Med 2002, 112:191–197.PubMedView Article
            16. Goldenberg D, Mayskiy M, Mossey C, Ruthazer R, Schmid C: A randomized, double-blind crossover trial of fluoxetine and amitriptyline in the treatment of fibromyalgia. Arthritis Rheum 1996, 39:1852–1859.PubMedView Article
            17. Gowans SE, de Hueck A, Voss S, Silaj A, Abbey SE, Reynolds WJ: Effect of a randomized, controlled trial of exercise on mood and physical function in individuals with fibromyalgia. Arthritis Rheum 2001, 45:519–529.PubMedView Article
            18. Jacobsen S, Danneskiold-Samsoe B, Andersen RB: Oral S-adenosylmethionine in primary fibromyalgia. Double-blind clinical evaluation. Scand J Rheumatol 1991, 20:294–302.PubMedView Article
            19. Scudds RA, McCain GA, Rollman GB, Harth M: Improvements in pain responsiveness in patients with fibrositis after successful treatment with amitriptyline. J Rheumatol Suppl 1989, 19:98–103.PubMed
            20. Arnold LM, Keck PEJ, Welge JA: Antidepressant treatment of fibromyalgia. A meta-analysis and review. Psychosomatics 2000, 41:104–113.PubMedView Article
            21. Harris RE, Gracely RH, McLean SA, Williams DA, Giesecke T, Petzke F, Sen A, Clauw DJ: Comparison of clinical and evoked pain measures in fibromyalgia. J Pain 2006, 7:521–527.PubMedView Article
            22. Geisser ME, Gracely RH, Giesecke T, Petzke FW, Williams DA, Clauw DJ: The association between experimental and clinical pain measures among persons with fibromyalgia and chronic fatigue syndrome. Eur J Pain 2007, 11:202–207.PubMedView Article
            23. Wolfe F: The relation between tender points and fibromyalgia symptom variables: evidence that fibromyalgia is not a discrete disorder in the clinic. Annals Rheum Dis 1997, 56:268–271.View Article
            24. Petzke F, Gracely RH, Park KM, Ambrose K, Clauw DJ: What do tender points measure? Influence of distress on 4 measures of tenderness. J Rheumatol 2003, 30:567–574.PubMed
            25. Gracely RH, Grant MA, Giesecke T: Evoked pain measures in fibromyalgia. Best Pract Res Clin Rheumatol 2003, 17:593–609.PubMedView Article
            26. Jensen K, Andersen HO, Olesen J, Lindblom U: Pressure–pain threshold in human temporal region. Evaluation of a new pressure algometer. Pain 1986, 25:313–323.PubMedView Article
            27. Chang L, Mayer EA, Johnson T, FitzGerald LZ, Naliboff B: Differences in somatic perception in female patients with irritable bowel syndrome with and without fibromyalgia. Pain 2000, 84:297–307.PubMedView Article
            28. Petzke F, Clauw DJ, Ambrose K, Khine A, Gracely RH: Increased pain sensitivity in fibromyalgia: effects of stimulus type and mode of presentation. Pain 2003, 105:403–413.PubMedView Article
            29. Gibson SJ, Littlejohn GO, Gorman MM, Helme RD, Granges G: Altered heat pain thresholds and cerebral event-related potentials following painful CO 2 laser stimulation in subjects with fibromyalgia syndrome. Pain 1994, 58:185–193.PubMedView Article
            30. Kosek E, Hansson P: Modulatory influence on somatosensory perception from vibration and heterotopic noxious conditioning stimulation (HNCS) in fibromyalgia patients and healthy subjects. Pain 1997, 70:41–51.PubMedView Article
            31. Kosek E, Ekholm J, Hansson P: Sensory dysfunction in fibromyalgia patients with implications for pathogenic mechanisms. Pain 1996, 68:375–383.PubMedView Article
            32. Julien N, Goffaux P, Arsenault P, Marchand S: Widespread pain in fibromyalgia is related to a deficit of endogenous pain inhibition. Pain 2005, 114:295–302.PubMedView Article
            33. Staud R, Robinson ME, Vierck CJ Jr, Price DD: Diffuse noxious inhibitory controls (DNIC) attenuate temporal summation of second pain in normal males but not in normal females or fibromyalgia patients. Pain 2003, 101:167–174.PubMedView Article
            34. Lautenbacher S, Rollman GB: Possible deficiencies of pain modulation in fibromyalgia. Clin J Pain 1997, 13:189–196.PubMedView Article
            35. Maixner W, Fillingim R, Booker D, Sigurdsson A: Sensitivity of patients with painful temporomandibular disorders to experimentally evoked pain. Pain 1995, 63:341–351.PubMedView Article
            36. Kosek E, Ordeberg G: Lack of pressure pain modulation by heterotopic noxious conditioning stimulation in patients with painful osteoarthritis before, but not following, surgical pain relief. Pain 2000, 88:69–78.PubMedView Article
            37. Giesecke T, Gracely RH, Williams DA, Geisser M, Petzke F, Clauw DJ: The relationship between depression, clinical pain, and experimental pain in a chronic pain cohort. Arthritis Rheum 2005, 52:1577–1584.PubMedView Article
            38. Cook DB, Lange G, Ciccone DS, Liu WC, Steffener J, Natelson BH: Functional imaging of pain in patients with primary fibromyalgia. J Rheumatol 2004, 31:364–378.PubMed
            39. Koeppe C, Schneider C, Thieme K, Mense S, Stratz T, Muller W, Flor H: The influence of the 5-HT3 receptor antagonist tropisetron on pain in fibromyalgia: a functional magnetic resonance imaging pilot study. Scand J Rheumatol Suppl 2004, 119:24–27.PubMedView Article
            40. Gracely RH, Geisser ME, Giesecke T, Grant MA, Petzke F, Williams DA, Clauw DJ: Pain catastrophizing and neural responses to pain among persons with fibromyalgia. Brain 2004, 127:835–843.PubMedView Article
            41. Wood PB, Schweinhardt P, Jaeger E, Dagher A, Hakyemez H, Rabiner EA, Bushnell MC, Chizh BA: Fibromyalgia patients show an abnormal dopamine response to pain. Eur J Neurosci 2007, 25:3576–3582.PubMedView Article
            42. Adiguzel O, Kaptanoglu E, Turgut B, Nacitarhan V: The possible effect of clinical recovery on regional cerebral blood flow deficits in fibromyalgia: a prospective study with semiquantitative SPECT. South Med J 2004, 97:651–655.PubMedView Article
            43. Kwiatek R, Barnden L, Tedman R, Jarrett R, Chew J, Rowe C, Pile K: Regional cerebral blood flow in fibromyalgia: single-photon-emission computed tomography evidence of reduction in the pontine tegmentum and thalami. Arthritis Rheum 2000, 43:2823–2833.PubMedView Article
            44. Mountz JM, Bradley LA, Modell JG, Alexander RW, Triana-Alexander M, Aaron LA, Stewart KE, Alarcon GS, Mountz JD: Fibromyalgia in women. Abnormalities of regional cerebral blood flow in the thalamus and the caudate nucleus are associated with low pain threshold levels. Arthritis Rheum 1995, 38:926–938.PubMedView Article
            45. Gur A, Karakoc M, Erdogan S, Nas K, Cevik R, Sarac AJ: Regional cerebral blood flow and cytokines in young females with fibromyalgia. Clin Exp Rheumatol 2002, 20:753–760.PubMed
            46. Alanoglu E, Ulas UH, Ozdag F, Odabasi Z, Cakci A, Vural O: Auditory event-related brain potentials in fibromyalgia syndrome. Rheumatol Int 2005, 25:345–349.PubMedView Article
            47. Yoldas T, Ozgocmen S, Yildizhan H, Yigiter R, Ulvi H, Ardicoglu O: Auditory p300 event-related potentials in fibromyalgia patients. Yonsei Med J 2003, 44:89–93.PubMed
            48. Ozgocmen S, Yoldas T, Kamanli A, Yildizhan H, Yigiter R, Ardicoglu O: Auditory P300 event related potentials and serotonin reuptake inhibitor treatment in patients with fibromyalgia. Ann Rheum Dis 2003, 62:551–555.PubMedView Article
            49. Sergi M, Rizzi M, Braghiroli A, Puttini PS, Greco M, Cazzola M, Andreoli A: Periodic breathing during sleep in patients affected by fibromyalgia syndrome. Eur Respir J 1999, 14:203–208.PubMedView Article
            50. Landis CA, Frey CA, Lentz MJ, Rothermel J, Buchwald D, Shaver JL: Self-reported sleep quality and fatigue correlates with actigraphy in midlife women with fibromyalgia. Nurs Res 2003, 52:140–147.PubMedView Article
            51. Landis CA, Lentz MJ, Rothermel J, Buchwald D, Shaver JL: Decreased sleep spindles and spindle activity in midlife women with fibromyalgia and pain. Sleep 2004, 27:741–750.PubMed
            52. Gold AR, Dipalo F, Gold MS, Broderick J: Inspiratory airflow dynamics during sleep in women with fibromyalgia. Sleep 2004, 27:459–466.PubMed
            53. Rizzi M, Sarzi-Puttini P, Atzeni F, Capsoni F, Andreoli A, Pecis M, Colombo S, Carrabba M, Sergi M: Cyclic alternating pattern: a new marker of sleep alteration in patients with fibromyalgia? J Rheumatol 2004, 31:1193–1199.PubMed
            54. Sadeh A, Acebo C: The role of actigraphy in sleep medicine. Sleep Med Rev 2002, 6:113–124.PubMedView Article
            55. Korszun A, Young EA, Engleberg NC, Brucksch CB, Greden JF, Crofford LA: Use of actigraphy for monitoring sleep and activity levels in patients with fibromyalgia and depression. J Psychosom Res 2002, 52:439–443.PubMedView Article
            56. Long AC, Palermao TM, Manees AM: Brief report: using actigraphy to compare physical activity levels in adolescents with chronic pain and healthy adolescents. J Pediatr Psychol 2008, 33:660–665.PubMedView Article
            57. Edinger JD, Wohlgemuth WK, Krystal AD, Rice JR: Behavioral insomnia therapy for fibromyalgia patients: a randomized clinical trial. Arch Intern Med 2005, 165:2527–2535.PubMedView Article
            58. Kop WJ, Lyden A, Berlin AA, Ambrose K, Olsen C, Gracely RH, Williams DA, Clauw DJ: Ambulatory monitoring of physical activity and symptoms in fibromyalgia and chronic fatigue syndrome. Arthritis Rheum 2005, 52:296–303.PubMedView Article
            59. Kajantie E, Phillips DI: The effects of sex and hormonal status on the physiological response to acute psychosocial stress. Psychoneuronedocriology 2006, 31:151–178.View Article
            60. McCain GA, Tilbe KS: Diurnal hormone variation in fibromyalgia syndrome: a comparison with rheumatoid arthritis. J Rheumatol Suppl 1989, 19:154–157.PubMed
            61. Crofford LJ, Young EA, Engleberg NC, Korszun A, Brucksch CB, McClure LA, Brown MB, Demitrack MA: Basal circadian and pulsatile ACTH and cortisol secretion in patients with fibromyalgia and/or chronic fatigue syndrome. Brain Behav Immun 2004, 18:314–325.PubMedView Article
            62. Adler GK, Kinsley BT, Hurwitz S, Mossey CJ, Goldenberg DL: Reduced hypothalamicpituitary and sympathoadrenal responses to hypoglycemia in women with fibromyalgia syndrome. Am J Med 1999, 106:534–543.PubMedView Article
            63. Gur A, Cevik R, Nas K, Colpan L, Sarac S: Cortisol and hypothalamic–pituitary–gonadal axis hormones in follicularphase women with fibromyalgia and chronic fatigue syndrome and effect of depressive symptoms on these hormones. Arthritis Res Ther 2004, 6:R232-R238.PubMedView Article
            64. Griep EN, Boersma JW, de Kloet ER: Altered reactivity of the hypothalamic–pituitary–adrenal axis in the primary fibromyalgia syndrome [see comments]. J Rheumatol 1993, 20:469–474.PubMed
            65. Riedel W, Layka H, Neeck G: Secretory pattern of GH, TSH, thyroid hormones, ACTH, cortisol, FSH, and LH in patients with fibromyalgia syndrome following systemic injection of the relevant hypothalamic-releasing hormones. Zeitschr Rheumatol 1998,57(Suppl 2):81–87.View Article
            66. Griep EN, Boersma JW, Lentjes EG, Prins AP, Korst JK, de Kloet ER: Function of the hypothalamic–pituitary–adrenal axis in patients with fibromyalgia and low back pain. J Rheumatol 1998, 25:1374–1381.PubMed
            67. Kirnap M, Colak R, Eser C, Ozsoy O, Tutus A, Kelestimur F: A comparison between low-dose (1 μg), standard-dose (250 μg) ACTH stimulation tests and insulin tolerance test in the evaluation of hypothalamo-pituitary–adrenal axis in primary fibromyalgia syndrome. Clin Endocrinol (Oxford) 2001, 55:455–459.View Article
            68. Calis M, Gokce C, Ates F, Ulker S, Izgi HB, Demir H, Kirnap M, Sofuoglu S, Durak AC, Tutus A, Kelestimur F: Investigation of the hypothalamo-pituitary–adrenal axis (HPA) by 1 μg ACTH test and metyrapone test in patients with primary fibromyalgia syndrome. J Endocrinol Invest 2004, 27:42–46.PubMed
            69. Ferraccioli G, Cavalieri F, Salaffi F, Fontana S, Scita F, Nolli M, Maestri D: Neuroendocrinologic findings in primary fibromyalgia (soft tissue chronic pain syndrome) and in other chronic rheumatic conditions (rheumatoid arthritis, low back pain) [see comments]. J Rheumatol 1990, 17:869–873.PubMed
            70. Ataoglu S, Ozcetin A, Yildiz O, Ataoglu A: Evaluation of dexamethasone suppression test in fibromyalgia patients with or without depression. Swiss Med Wkly 2003, 133:241–244.PubMed
            71. Cohen H, Neumann L, Shore M, Amir M, Cassuto Y, Buskila D: Autonomic dysfunction in patients with fibromyalgia: application of power spectral analysis of heart rate variability [see comments]. Semin Arthritis Rheum 2000, 29:217–227.PubMedView Article
            72. Cohen H, Neumann L, Kotler M, Buskila D: Autonomic nervous system derangement in fibromyalgia syndrome and related disorders. Isr Med Assoc J 2001, 3:755–760.PubMed
            73. Martinez-Lavin M, Hermosillo AG, Rosas M, Soto ME: Circadian studies of autonomic nervous balance in patients with fibromyalgia: a heart rate variability analysis. Arthritis Rheum 1998, 41:1966–1971.PubMedView Article
            74. Bou-Holaigah I, Calkins H, Flynn JA, Tunin C, Chang HC, Kan JS, Rowe PC: Provocation of hypotension and pain during upright tilt table testing in adults with fibromyalgia. Clin Exp Rheumatol 1997, 15:239–246.PubMed
            75. Furlan R, Colombo S, Perego F, Atzeni F, Diana A, Barbic F, Porta A, Pace F, Malliani A, Sarzi-Puttini P: Abnormalities of cardiovascular neural control and reduced orthostatic tolerance in patients with primary fibromyalgia. J Rheumatol 2005, 32:1787–1793.PubMed
            76. Naschitz JE, Mussafia-Priselac R, Peck ER, Peck S, Naftali N, Storch S, Slobodin G, Elias N, Rosner I: Hyperventilation and amplified blood pressure response: is there a link? J Hum Hypertens 2005, 19:381–387.PubMedView Article
            77. McBeth J, Chiu YH, Silman AJ, Ray D, Morriss R, Dickens C, Gupta A, Macfarlane GJ: Hypothalamic–pituitary–adrenal stress axis function and the relationship with chronic widespread pain and its antecedents. Arthritis Res Ther 2005, 7:R992-R1000.PubMedView Article
            78. Glass JM, Lyden A, Petzke F, Clauw D: The effect of brief exercise cessation on pain, fatigue, and mood symptom development in healthy, fit individuals. J Psychosom Res 2004, 57:391–398.PubMed
            79. Okifuji A, Turk DC: Sex hormones and pain in regularly menstruating women with fibromyalgia syndrome. J Pain 2006, 7:851–859.PubMedView Article
            80. Macfarlane TV, Blinkhorn A, Worthington HV, Davies RM, Macfarlane GJ: Sex hormonal factors and chronic widespread pain: a population study among women. Rheumatology 2002, 41:454–457.PubMedView Article
            81. Klein R, Berg PA: High incidence of antibodies to 5-hydroxytryptamine, gangliosides and phospholipids in patients with chronic fatigue and fibromyalgia syndrome and their relatives: evidence for a clinical entity of both disorders. Eur J Med Res 1995, 1:21–26.PubMed
            82. Klein R, Bänsch M, Berg PA: Clinical relevance of antibodies against serotonin and gangliosides in patients with primary fibromyalgia syndrome. Psychoneuroendocrinology 1992, 17:593–598.PubMedView Article
            83. Werle E, Fischer HP, Müller A, Fiehn W, Eich W: Antibodies against serotonin have no diagnostic relevance in patients with fibromyalgia syndrome. J Rheumatol 2001, 28:595–600.PubMed
            84. Wilson RB, Gluck OS, Tesser JR, Rice JC, Meyer A, Bridges AJ: Antipolymer antibody reactivity in a subset of patients with fibromyalgia correlates with severity. J Rheumatol 1999, 26:402–407.PubMed
            85. Nishikai M, Tomomatsu S, Hankins RW, Takagi S, Miyachi K, Kosaka S, Akiya K: Autoantibodies to a 68/48 kDa protein in chronic fatigue syndrome and primary fibromyalgia: a possible marker for hypersomnia and cognitive disorders. Rheumatology 2001, 40:806–810.PubMedView Article
            86. Vaeroy H, Helle R, Forre O, Kass E, Terenius L: Elevated CSF levels of substance P and high incidence of Raynaud phenomenon in patients with fibromyalgia: new features for diagnosis. Pain 1988, 32:21–26.PubMedView Article
            87. Russell IJ, Orr MD, Littman B, Vipraio GA, Alboukrek D, Michalek JE, Lopez Y, MacKillip F: Elevated cerebrospinal fluid levels of substance P in patients with the fibromyalgia syndrome. Arthritis Rheum 1994, 37:1593–1601.PubMedView Article
            88. Bradley LA, Alberts KR, Alarcon GS, Alexander MT, Mountz JM, Wiegent DA, Lin HG, Blalock JE, Aaron LA, Alexander RW, San Pedro EC, Martin MY, Morell AC: Abnormal brain regional cerebral blood flow and cerebrospinal fluid levels of substance P in patients and non-patients with fibromyalgia [abstract]. Arthritis Rheum 1996, (Suppl 9):212.
            89. Liu Z, Welin M, Bragee B, Nyberg F: A high-recovery extraction procedure for quantitative analysis of substance P and opioid peptides in human cerebrospinal fluid. Peptides 2000, 21:853–860.PubMedView Article
            90. Evengard B, Nilsson CG, Lindh G, Lindquist L, Eneroth P, Fredrikson S, Terenius L, Henriksson KG: Chronic fatigue syndrome differs from fibromyalgia. No evidence for elevated substance P levels in cerebrospinal fluid of patients with chronic fatigue syndrome. Pain 1998, 78:153–155.PubMedView Article
            91. Sarchielli P, Alberti A, Floridi A, Gallai V: Levels of nerve growth factor in cerebrospinal fluid of chronic daily headache patients. Neurology 2001, 57:132–134.PubMed
            92. Alpar EK, Onuoha G, Killampalli VV, Waters R: Management of chronic pain in whiplash injury. J Bone Joint Surg Br 2002, 84:807–811.PubMedView Article
            93. Giovengo SL, Russell IJ, Larson AA: Increased concentrations of nerve growth factor in cerebrospinal fluid of patients with fibromyalgia. J Rheumatol 1999, 26:1564–1569.PubMed
            94. Vaeroy H, Sakurada T, Forre O, Kass E, Terenius L: Modulation of pain in fibromyalgia (fibrositis syndrome): cerebrospinal fluid (CSF) investigation of pain related neuropeptides with special reference to calcitonin gene related peptide (CGRP). J Rheumatol Suppl 1989, 19:94–97.PubMed
            95. Hocherl K, Farber L, Ladenburger S, Vosshage D, Stratz T, Muller W, Grobecker H: Effect of tropisetron on circulating catecholamines and other putative biochemical markers in serum of patients with fibromyalgia [in process citation]. Scand J Rheumatol Suppl 2000, 113:46–48.PubMed
            96. Russell IJ, Michalek JE, Vipraio GA, Fletcher EM, Wall K: Serum amino acids in fibrositis/fibromyalgia syndrome. J Rheumatol 1989, 19:158–163.
            97. Wallace D, Bowman RL, Wormsley SB, Peter JB: Cytokines and immune regulation in patients with fibrositis. Arthritis Rheum 1989, 32:1334–1335.PubMedView Article
            98. Gur A, Karakoc M, Nas K, Remzi, Cevik, Denli A, Sarac J: Cytokines and depression in cases with fibromyalgia. J Rheumatol 2002, 29:358–361.PubMed
            99. Yunus MB, Dailey JW, Aldag JC, Masi AT, Jobe PC: Plasma tryptophan and other amino acids in primary fibromyalgia: a controlled study. J Rheumatol 1992, 19:90–94.PubMed
            100. Larson AA, Giovengo SL, Russell IJ, Michalek JE: Changes in the concentrations of amino acids in the cerebrospinal fluid that correlate with pain in patients with fibromyalgia: implications for nitric oxide pathways. Pain 2000, 87:201–211.PubMedView Article
            101. Wallace DJ, Wallace JB: All about Fibromyalgia. New York: Oxford University Press; 2001.
            102. Staud R, Robinson ME, Price DD: Isometric exercise has opposite effects on central pain mechanisms in fibromyalgia patients compared to normal controls. Pain 2005, 118:176–184.PubMedView Article
            103. Sandberg M, Larsson B, Lindberg LG, Gerdle B: Different patterns of blood flow response in the trapezius muscle following needle stimulation (acupuncture) between healthy subjects and patients with fibromyalgia and work-related trapezius myalgia. Eur J Pain 2005, 9:497–510.PubMedView Article
            104. Montoya P, Pauli P, Batra A, Wiedemann G: Altered processing of pain-related information in patients with fibromyalgia. Eur J Pain 2005, 9:293–303.PubMedView Article
            105. Laursen BS, Bajaj P, Olesen AS, Delmar C, Arendt-Nielsen L: Health related quality of life and quantitative pain measurement in females with chronic non-malignant pain. Eur J Pain 2005, 9:267–275.PubMedView Article
            106. Landis CA, Lentz MJ, Tsuji J, Buchwald D, Shaver JL: Pain, psychological variables, sleep quality, and natural killer cell activity in midlife women with and without fibromyalgia. Brain Behav Immun 2004, 18:304–313.PubMedView Article
            107. Maquet D, Croisier JL, Demoulin C, Crielaard JM: Pressure pain thresholds of tender point sites in patients with fibromyalgia and in healthy controls. Eur J Pain 2004, 8:111–117.PubMedView Article
            108. Geisser ME, Casey KL, Brucksch CB, Ribbens CM, Appleton BB, Crofford LJ: Perception of noxious and innocuous heat stimulation among healthy women and women with fibromyalgia: association with mood, somatic focus, and catastrophizing. Pain 2003, 103:243–250.View Article
            109. Ernberg M, Lundeberg T, Kopp S: Effects on muscle pain by intramuscular injection of granisetron in patients with fibromyalgia. Pain 2003, 101:275–282.PubMedView Article
            110. Carli G, Suman AL, Biasi G, Marcolongo R: Reactivity to superficial and deep stimuli in pateints with chronic musculoskeletal pain. Pain 2002, 100:259–269.PubMedView Article
            111. Hedenberg-Magnusson B, Ernberg M, Alstergren P, Kopp S: Effect on prostaglandin E 2 and leukotriene B 4 levels by local administration of glucocorticoid in human masseter muscle myalgia. Acta Odontol Scand 2002, 60:29–36.PubMedView Article
            112. Ernberg M, Lundeberg T, Kopp S: Plasma and serotonin levels and their relationship to orofacial pain and anxiety in fibromyalgia. J Orofac Pain 2000, 14:37–46.PubMed
            113. Graven-Nielsen T, Aspergen Kendall S, Henriksson KG, Bengtsson M, Sorensen J, Johnson A, Gerdle B, Arendt-Nielsen L: Ketamine reduces muscle pain, temporal summation, and referred pain in fibromyalgia patients. Pain 2000, 85:483–4891.PubMedView Article
            114. Ernberg M, Lundeberg T, Kopp S: Pain and allodynia/hyperalgesia induced by intramuscular injection of serotonin in patients with fibromyalgia and healthy individuals. Pain 2000, 85:31–39.PubMedView Article
            115. Ernberg M, Hedenberg-Magnusson B, Alstergren P, Kopp S: The level of serotonin in the superficial masseter muscle in relation to local pain and allodynia. Life Sci 1999, 65:313–325.PubMedView Article
            116. McDermid AJ, Rollman GB, McCain GA: Generalized hypervigilance in fibromyalgia: evidence of perceptual amplification. Pain 1996, 66:133–144.PubMedView Article
            117. Kosek E, Ekholm J, Hansson P: Increased pressure pain sensibility in fibromyalgia patients is located deep to the skin but not restricted to muscle tissue. Pain 1995, 63:335–339.PubMedView Article
            118. Tunks E, McCain GA, Hart LE, Teasell RW, Goldsmith CH, Rollman GB, McDermid AJ, DeShane PJ: The reliability of examination for tenderness in patients with myofascial pain, chronic fibromyalgia and controls. J Rheumatol 1995, 22:944–952.PubMed
            119. Wolfe F, Ross K, Anderson J, Russell IJ: Aspects of fibromyalgia in the general population: sex, pain threshold, and fibromyagia symptoms. J Rheumatol 1995, 22:151–156.PubMed
            120. Lautenbacher S, Rollman GB, McCain GA: Multi-method assessment of experimental and clinical pain in patients with fibromyalgia. Pain 1994, 59:45–53.PubMedView Article
            121. Granges G, Littlejohn G: Pressure pain threshold in pain-free subjects, in patients with chronic regional pain syndromes, and in patients with fibromyalgia syndrome. Arthritis Rheum 1993, 36:642–646.PubMedView Article
            122. Lautenschlager J, Seglias J, Bruckle W, Muller W: Comparisons of spontaneous pain and tenderness in patients with primary fibromyalgia. Clin Rheumatol 1991, 10:168–173.PubMedView Article
            123. Petzke F, Harris RE, Williams DA, Clauw DJ, Gracely RH: Differences in unpleasantness induced by experimental pressure pain between patients with fibromyalgia and healthy controls. Eur J Pain 2005, 9:325–335.PubMedView Article
            124. Giesecke T, Gracely RH, Grant MA, Nachemson A, Petzke F, Williams DA, Clauw DJ: Evidence of augmented central pain processing in idiopathic chronic low back pain. Arthritis Rheum 2004, 50:613–623.PubMedView Article
            125. Giesecke T, Williams DA, Harris RE, Cupps TR, Tian X, Tian TX, Gracely RH, Clauw DJ: Subgrouping of fibromyalgia patients on the basis of pressure-pain thresholds and psychological factors. Arthritis Rheum 2003, 48:2916–2922.PubMedView Article
            126. Gracely RH, Petzke F, Wolf JM, Clauw DJ: Functional magnetic resonance imaging evidence of augmented pain processing in fibromyalgia. Arthritis Rheum 2002, 46:1333–1343.PubMedView Article
            127. Bendtsen L, Nørregaard J, Jensen R, Olesen J: Evidence of qualitatively altered nociception in patients with fibromyalgia. Arthritis Rheum 1997, 40:98–102.PubMedView Article
            128. Lorenz J, Grasedyck K, Bromm B: Middle and long latency somatosensory evoked potentials after painful laser stimulation in patients with fibromyalgia syndrome. Electroencephalogr Clin Neurophysiol 1996, 100:165–168.PubMedView Article
            129. Arroyo JF, Cohen ML: Abnormal responses to electrocutaneous stimulation in fibromyalgia. J Rheumatol 1993, 20:1925–1931.PubMed
            130. Yunus MB, Young CS, Saeed SA, Mountz JM, Aldag JC: Positron emission tomography in patients with fibromyalgia syndrome and healthy controls. Arthritis Rheum 2004, 51:513–518.PubMedView Article
            131. Chang L, Berman S, Mayer EA, Suyenobu B, Derbyshire S, Naliboff B, Vogt B, FitzGerald L, Mandelkern MA: Brain responses to visceral and somatic stimuli in patients with irritable bowel syndrome with and without fibromyalgia. Am J Gastroenterol 2003, 98:1354–1361.PubMedView Article
            132. Wik G, Fischer H, Finer B, Bragee B, Kristianson M, Fredrikson M: Retrospenial cortical deactivation during painful stimulation of fibromyalgic patients. Int J Neurosci 2006, 116:1–8.PubMedView Article
            133. Crofford LJ, Pillemer SR, Kalogeras KT, Cash JM, Michelson D, Kling MA, Sternberg EM, Gold PW, Chrousos GP, Wilder RL: Hypothalamic–pituitary–adrenal axis perturbations in patients with fibromyalgia. Arthritis Rheum 1994, 37:1583–1592.PubMedView Article
            134. Korszun A, Sackett-Lundeen L, Papadopoulos E, Brucksch C, Masterson L, Engelberg NC, Haus E, Demitrack MA, Crofford L: Melatonin levels in women with fibromyalgia and chronic fatigue syndrome. J Rheumatol 1999, 26:2675–2680.PubMed
            135. Malt EA, Olafsson S, Lund A, Ursin H: Factors explaining variance in perceived pain in women with fibromyalgia. BMC Musculoskelet Disord 2002, 3:12.PubMedView Article
            136. Valkeinen H, Häkkinen K, Pakarinen A, Hannonen P, Häkkinen A, Airaksinen O, Niemitukia L, Kraemer WJ, Alén M: Muscle hypertrophy, strength development, and serum hormones during strength training in elderly women with fibromyalgia. Scand J Rheumatol 2005, 34:309–314.PubMedView Article
            137. Gur A, Cevik R, Sarac AJ, Colpan L, Em S: Hypothalamic–pituitary–gonadal axis and cortisol in young women with primary fibromyalgia: the potential roles of depression, fatigue, and sleep disturbance in the occurrence of hypocortisolism. Ann Rheum Dis 2004, 63:1504–1506.PubMedView Article
            138. Lentjes EG, Griep EN, Boersma JW, Romijn FP, de Kloet ER: Glucocorticoid receptors, fibromyalgia and low back pain. Psychoneuroendocrinology 1997, 22:603–614.PubMedView Article
            139. Catley D, Kaell AT, Kirschbaum C, Stone AA: A naturalistic evaluation of cortisol secretion in persons with fibromyalgia and rheumatoid arthritis. Arthritis Care Res 2000, 13:51–61.PubMedView Article
            140. McLean SA, Williams DA, Harris RE, Kop WJ, Groner KH, Ambrose K, Lyden AK, Gracely RH, Crofford LJ, Geisser ME, Sen A, Biswas P, Clauw DJ: Momentary relationship between cortisol secretion and symptoms in patients with fibromyalgia. Arthritis Rheum 2005, 52:3660–3669.PubMedView Article
            141. Weissbecker I, Floyd A, Dedert E, Salmon P, Sephton S: Childhood trauma and diurnal cortisol disruption in fibromyalgia syndrome. Psychoneuroendocrinology 2006, 31:312–324.PubMedView Article
            142. Dedert EA, Studts JL, Weissbecker I, Salmon PG, Banis PL, Sephton SE: Religiosity may help preserve the cortisol rhythm in women with stress-related illness. Int J Psychiatry Med 2004, 34:61–77.PubMedView Article
            143. Sephton SE, Studts JL, Hoover K, Weissbecker I, Lynch G, Ho I, McGuffin S, Salmon P: Biological and psychological factors associated with memory function in fibromyalgia syndrome. Health Psychol 2003, 22:592–597.PubMedView Article
            144. Maes M, Lin A, Bonaccorso S, van Hunsel F, Van Gastel A, Delmeire L, Biondi M, Bosmans E, Kenis G, Scharpé S: Increased 24-hour urinary cortisol excretion in patients with post-traumatic stress disorder and patients with major depression, but not in patients with fibromyalgia. Acta Psychiatr Scand 1998, 98:328–335.PubMedView Article
            145. Torpy DJ, Papanicolaou DA, Lotsikas AJ, Wilder RL, Chrousos GP, Pillemer SR: Responses of the sympathetic nervous system and the hypothalamic–pituitary–adrenal axis to interleukin-6: a pilot study in fibromyalgia. Arthritis Rheum 2000, 43:872–880.PubMedView Article

            Copyright

            © BioMed Central Ltd 2008