Central sensitivity syndromes: mounting pathophysiologic evidence to link fibromyalgia with other common chronic pain disorders

The aim of this study was to review emerging data from the fields of nursing, rheumatology, dentistry, gastroenterology, gynecology, neurology, and orthopedics that support or dispute pathophysiologic similarities in pain syndromes studied by each specialty. A literature search was performed through PubMed and Ovid using the terms fibromyalgia, temporomandibular joint disorder, irritable bowel syndrome, irritable bladder/interstitial cystitis, headache, chronic low back pain, chronic neck pain, functional syndromes, and somatization. Each term was linked with pathophysiology and/or central sensitization. This paper presents a review of relevant articles with a specific goal of identifying pathophysiologic findings related to nociceptive processing. The extant literature presents considerable overlap in the pathophysiology of these diagnoses. Given the psychosomatic lens through which many of these disorders are viewed, demonstration of evidence-based links supporting shared pathophysiology between these disorders could provide direction to clinicians and researchers working to treat these diagnoses. "Central sensitivity syndromes" denotes an emerging nomenclature that could be embraced by researchers investigating each of these disorders. Moreover, a shared paradigm would be useful in promoting cross-fertilization between researchers. Scientists and clinicians could most effectively forward the understanding and treatment of fibromyalgia and other common chronic pain disorders through an appreciation of their shared pathophysiology.

Pain Manag Nurs. 2011 Mar;12(1):15-24. Epub 2009 Dec 2

Mease PJ, Spaeth M, Clauw DJ, Arnold LM, Bradley LA, Jon Russell I, Kajdasz DK, Walker DJ, Chappell AS

Estimation of minimum clinically important difference for pain in fibromyalgia

OBJECTIVE: To estimate the minimum clinically important difference (MCID) for several pain measures obtained from the Brief Pain Inventory (BPI) for patients with fibromyalgia. METHODS: Data were pooled across 12-week treatment periods from 4 randomized, double-blind, placebo-controlled studies designed to evaluate the safety and efficacy of duloxetine for the treatment of fibromyalgia. Each study enrolled subjects with American College of Rheumatology-defined fibromyalgia who presented with moderate to severe pain. The MCIDs for the BPI average pain item score and the BPI severity score (the mean of the BPI pain scale values: right now, average, least, and worst), were estimated by anchoring against the Patient Global Impression of Improvement (PGI-I) scale. RESULTS: The anchor-based MCIDs for the BPI average pain item and severity scores were 2.1 and 2.2 points, respectively. These MCIDs correspond to 32.3% and 34.2% reductions from baseline in scores. CONCLUSION: In these analyses, the MCIDs for several pain measures obtained from the BPI were similar, approximately 2 points and corresponded to a 30%-35% improvement from baseline at endpoint. These findings may be beneficial for use in designing clinical trials in which the BPI is used to evaluate improvements in pain severity.

Arthritis Care Res (Hoboken). 2011 Feb 10. doi: 10.1002/acr.20449

Attentional deficits in fibromyalgia and its relationships with pain, emotional distress and sleep dysfunction complaints

Cognitive complaints are common among subjects with fibromyalgia (FM). Yet, few studies have been able to document these deficits with cognitive tasks. A main limitation of existing studies is that attention has been broadly defined and the tasks used to measure attention are not designed to cover all the main components of the attentional system. Research on attention has identified three primary functions of attention, known as alerting, orienting and executive functioning. This study used the attentional network test-interactions task to explore whether and which of the three attentional networks are altered in FM. Results showed that FM patients have impaired executive control (greater interference), reduced vigilance (slower overall reaction time) and greater alertness (higher reduction in errors after a warning cue). Vigilance and alertness showed several relations with depression, anxiety and sleep quality. Sleep dysfunction was a significant predictor for alertness, whereas there were no significant predictors for vigilance. These findings highlight that the treatment of sleep difficulties in FM patients may help with some of their cognitive complaints.

Psychol Health. 2011 Mar 3:1–16. [Epub ahead of print]

Chronic widespread musculoskeletal pain, fatigue, depression and disordered sleep in chronic post-SARS syndrome; a case-controlled study

BACKGROUND: The long term adverse effects of Severe Acute Respiratory Syndrome (SARS), a viral disease, are poorly understood. METHODS: Sleep physiology, somatic and mood symptoms of 22 Toronto subjects, 21 of whom were healthcare workers, (19 females, 3 males, mean age 46.29 yrs.+/- 11.02) who remained unable to return to their former occupation (mean 19.8 months, range: 13 to 36 months following SARS) were compared to 7 healthy female subjects. Because of their clinical similarities to patients with fibromyalgia syndrome (FMS) these post-SARS subjects were similarly compared to 21 drug free female patients, (mean age 42.4 +/- 11.8 yrs.) who fulfilled criteria for fibromyalgia. RESULTS: Chronic post-SARS is characterized by persistent fatigue, diffuse myalgia, weakness, depression, and nonrestorative sleep with associated REM-related apneas/hypopneas, an elevated sleep EEG cyclical alternating pattern, and alpha EEG sleep anomaly. Post-SARS patients had symptoms of pre- and post-sleep fatigue and post-sleep sleepiness that were similar to the symptoms of patients with FMS, and similar to symptoms of patients with chronic fatigue syndrome. Both post-SARS and FMS groups had sleep instability as indicated by the high sleep EEG cyclical alternating pattern rate. The post-SARS group had a lower rating of the alpha EEG sleep anomaly as compared to the FMS patients. The post-SARS group also reported less pre-sleep and post-sleep musculoskeletal pain symptoms. CONCLUSIONS: The clinical and sleep features of chronic post-SARS form a syndrome of chronic fatigue, pain, weakness, depression and sleep disturbance, which overlaps with the clinical and sleep features of FMS and chronic fatigue syndrome.

BMC Neurol. 2011 Mar 24; 11(1):37 [Epub ahead of print]

A deficit in peripheral serotonin levels in major depressive disorder but not in chronic widespread pain

OBJECTIVES: It has been proposed that serotonin dysfunctions underlie the pathophysiology of various mood disorders (including major depressive disorder, MDD) and chronic pain conditions characterized by deficient pain inhibition, such as fibromyalgia (FM). There is reliable data showing that serotonin disturbances are involved in the pathophysiology of MDD. However, in the case of FM, results published so far are less consistent. Therefore, the current cross-sectional study sought to measure plasma serotonin levels in FM patients, MDD patients, and healthy controls (HC). METHODS: Twenty-nine FM patients, 17 MDD patients, and 57 HC were recruited who did not differ in terms of age, sex, and the presence or absence of a regular menstrual cycle. Plasma samples were analysed with mass spectrometry. RESULTS: Serotonin levels were decreased in MDD patients, relative to FM patients and HC. Post hoc analyses showed that serotonin levels were decreased in FM patients taking antidepressants, relative to HC, but not in drug-free FM patients. Moreover, serotonin levels were negatively correlated with mood symptoms across groups. DISCUSSION: Our results further confirm that MDD is associated with decreased serotonin levels, but that serotonin levels are not altered in FM per se, and suggest that 5-Hydroxytryptamine is related to mood symptoms in these patient groups. Our results also suggest that the taking of antidepressants is a major confound to consider when studying serotonin functioning in FM. The long-term use of antidepressants in FM may lead to serotonin depletion. Conversely, serotonin depletion may be before the taking of antidepressants in FM.

Clin J Pain. 2011 Mar 16. [Epub ahead of print]

Validation of new symptom-based fibromyalgia criteria for irritable bowel syndrome co-morbidity studies

BACKGROUND/AIMS: There is significant co-morbidity between irritable bowel syndrome (IBS) and fibromyalgia syndrome (FMS). However, FMS is diagnosed by physical examination, which limits the conduct of co-morbidity studies in a large population-based study. The purpose of this study was to determine the diagnostic validity of a new symptom-based criteria in patients with FMS and/or IBS using the American College of Rheumatology (ACR) criteria as a gold standard. METHODS: The study participants consisted of women with FMS (n = 30), IBS (n = 27) and controls (n = 28). A new symptom-based diagnostic criteria for FMS comprised a regional pain scale and a visual analogue scale for fatigue. All subjects underwent a physical examination for FMS (ACR criteria) and structured questionnaires of regional pain scale and visual analogue scale for fatigue. A fibromyalgia intensity score was calculated and thresholds of tenderness were determined by a dolorimeter. RESULTS: The number of participants diagnosed with FMS in the entire study population (n = 85) was 31 by the new criteria. Compared to the ACR, the sensitivity of the new criteria was 82.9%, specificity 96.0%, positive predictive value 93.5% and negative predictive value 88.9%. In addition, new criteria were useful for the diagnosis of FMS among the subjects with IBS. A fibromyalgia intensity score was significantly correlated with the threshold of tenderness (r = -0.62, P < 0.001). CONCLUSIONS: The new symptom-based diagnostic criteria for the diagnosis of FMS can be used in large-scale clinical and epidemiological co-morbidity studies, in which physical examination is unfeasible. Gastroenterologists investigating the effects of co-morbid FMS in IBS patients can use these new criteria with confidence.

J Neurogastroenterol Motil. 2011 Jan; 17(1):67–72. Epub 2011 Jan 26

Impact of fibromyalgia severity on health economic costs: results from a European cross-sectional study

BACKGROUND: Fibromyalgia (FM) is a chronic disorder characterized by persistent and widespread pain, often accompanied with fatigue, sleep disturbance and other symptoms. FM affects a population mostly of a productive age and is thus associated with significant lost productivity and disability, in addition to healthcare costs for medications and physician office visits. While other studies have examined FM costs in Europe, few, if any, have examined cost by FM severity level. OBJECTIVE: The objective of this study was to examine health resource utilization (HRU) and costs associated with FM in routine clinical practice in France and Germany across disease severity levels. METHODS: A total of 299 patients with FM, previously diagnosed by a rheumatologist, were recruited from physician offices in France and Germany during routine visits. Subjects completed questions about their pain, health-related quality of life, treatment satisfaction, productivity and FM-related out-of-pocket expenses; site staff recorded clinical, treatment and HRU information for the previous 3 months based on a review of medical records. FM severity was defined using subjects' Fibromyalgia Impact Questionnaire (FIQ) total scores. Annual costs from a societal perspective were calculated in €, year 2008 values, and included direct costs (e.g. physician office visits, medications, out-of-pocket expenses) and indirect costs (e.g. missed days of work and lost productivity). The mean annual costs were calculated based on 3-month data. RESULTS: Subjects were reported to have a mean (SD) of 2.9 (1.9) physician office visits in France and 4.9 (3.2) visits in Germany over the past 3 months, corresponding to an average of 11.6 and 19.6 visits a year, respectively. A total of 91% of subjects were receiving prescription medication for their FM. French subjects reported a lower use of anti-inflammatories (39% of subjects) and a higher use of other analgesics (59% of subjects) than German subjects (67% and 34%, respectively). Subjects in full- or part-time employment reported missing a mean (SD) of 2.7 (6.0) days of work due to FM in France and 2.1 (3.8) days in Germany over the last 4 weeks (corresponding to 32.4 and 25.2 days of work missed due to FM per year in France and Germany, respectively). In France, total costs were €7900 (direct €910, indirect €6990). In Germany, total costs were €7256 (direct €1765, indirect €5491). A trend of higher total costs was seen as FM severity increased; however, the results were significant (p = 0.003) only for Germany. CONCLUSIONS: FM imposes a significant economic burden on society. Consistent with other studies, FM subjects were found to have substantial costs, over 75% of which were driven by indirect costs from lost productivity. These costs increased as FM severity increased, resulting in a more than 200% difference in cost between mild and severe FM. Overall FM costs were similar between France and Germany; although lost productivity accounted for a higher proportion of costs in France.

Appl Health Econ Health Policy. 2011 Mar 1; 9(2):125–36

Fibromyalgia criteria and severity scales for clinical and epidemiological studies: A modification of the ACR preliminary diagnostic criteria for fibromyalgia

OBJECTIVE: To develop a fibromyalgia (FM) survey questionnaire for epidemiologic and clinical studies using a modification of the 2010 American College of Rheumatology Preliminary Diagnostic Criteria for Fibromyalgia (ACR 2010). We also created a new FM symptom scale to further characterize FM severity. METHODS: The ACR 2010 consists of 2 scales, the Widespread Pain Index (WPI) and the Symptom Severity (SS) scale. We modified these ACR 2010 criteria by eliminating the physician's estimate of the extent of somatic symptoms and substituting the sum of 3 specific self-reported symptoms. We also created a 0–31 FM Symptom scale (FS) by adding the WPI to the modified SS scale. We administered the questionnaire to 729 patients previously diagnosed with FM, 845 with osteoarthritis (OA) or with other noninflammatory rheumatic conditions, 439 with systemic lupus erythematosus (SLE), and 5210 with rheumatoid arthritis (RA). RESULTS: The modified ACR 2010 criteria were satisfied by 60% with a prior diagnosis of FM, 21.1% with RA, 16.8% with OA, and 36.7% with SLE. The criteria properly identified diagnostic groups based on FM severity variables. An FS score ≥ 13 best separated criteria+ and criteria- patients, classifying 93.0% correctly, with a sensitivity of 96.6% and a specificity of 91.8% in the study population. CONCLUSION: A modification to the ACR 2010 criteria will allow their use in epidemiologic and clinical studies without the requirement for an examiner. The criteria are simple to use and administer, but they are not to be used for self-diagnosis. The FS may have wide utility beyond the bounds of FM, including substitution for widespread pain in epidemiological studies.

J Rheumatol. 2011 Feb 1. [Epub ahead of print]

Mortality in fibromyalgia: a study of 8,186 patients over thirty-five years

OBJECTIVE: To determine if mortality is increased among patients diagnosed as having fibromyalgia. METHODS: We studied 8,186 fibromyalgia patients seen between 1974 and 2009 in 3 settings: all fibromyalgia patients in a clinical practice, patients participating in the US National Data Bank for Rheumatic Diseases (NDB), and patients invited to participate in the NDB who refused participation. Internal controls included 10,087 patients with osteoarthritis. Deaths were determined by multiple source communication, and all patients were also screened in the US National Death Index (NDI). We calculated standardized mortality ratios (SMRs) based on age- and sex-stratified US population data, after adjustment for NDI nonresponse. RESULTS: There were 539 deaths, and the overall SMR was 0.90 (95% confidence interval [95% CI] 0.61–1.26). Among 1,665 clinic patients, the SMR was 0.92 (95% CI 0.81–1.05). Sensitivity analyses varying the rate of NDI nonidentification did not alter the nonassociation. Adjusted for age and sex, the hazard ratio for fibromyalgia compared with osteoarthritis was 1.05 (95% CI 0.94–1.17). The standardized mortality odds ratio (OR) compared with the US general population was increased for suicide (OR 3.31, 95% CI 2.15–5.11) and for accidental deaths (OR 1.45, 95% CI 1.02–2.06), but not for malignancy. CONCLUSION: Mortality does not appear to be increased in patients diagnosed with fibromyalgia, but the risk of death from suicide and accidents was increased.

Arthritis Care Res (Hoboken). 2011 Jan; 63(1):94–101. doi: 10.1002/acr.20301 Epub 2010 Jul 26