Self-guided digital behavioural therapy versus active control for fibromyalgia (PROSPER-FM): a phase 3, multicentre, randomised controlled trial.

BACKGROUND: International guidelines have recommended cognitive behavioural therapy, including acceptance and commitment therapy (ACT), as it offers validated benefits for managing fibromyalgia; however, it is inaccessible to most patients. We aimed to evaluate the effect of a 12-week, self-guided, smartphone-delivered digital ACT programme on fibromyalgia management. METHODS: In the PROSPER-FM randomised clinical trial conducted at 25 US community sites, adult participants aged 22-75 years with fibromyalgia were recruited and randomly assigned (1:1) to the digital ACT group or an active control group that offered daily symptom tracking and monitoring and access to health-related and fibromyalgia-related educational materials. Randomisation was done with a web-based system in permuted blocks of four at the site level. We used a blind-to-hypothesis approach in which participants were informed they would be randomly assigned to one of two potentially effective therapies under evaluation. Research staff were not masked to group allocation, with the exception of a masked statistics group while preparing statistical programming for the interim analysis. The primary endpoint was patient global impression of change (PGIC) response rate at week 12. Analyses were by intention to treat. The trial was registered with ClinicalTrials.gov, NCT05243511 (now fully closed). FINDINGS: Between Feb 8, 2022, and Feb 2, 2023, 590 individuals were screened, of whom 275 (257 women and 18 men) were randomly assigned to the digital ACT group (n=140) and the active control group (n=135). At 12 weeks, 99 (71%) of 140 ACT participants reported improvement on PGIC versus 30 (22%) of 135 active control participants, corresponding to a difference in proportions of 48·4% (95% CI 37·9-58·9; p<0·0001). No device-related safety events were reported. INTERPRETATION: Digital ACT was safe and efficacious compared with digital symptom tracking in managing fibromyalgia in adult patients. FUNDING: Swing Therapeutics.

Self-guided digital acceptance and commitment therapy for fibromyalgia management: results of a randomized, active-controlled, phase II pilot clinical trial.

Although empirically validated for fibromyalgia (FM), cognitive and behavioral therapies, including Acceptance and Commitment Therapy (ACT), are inaccessible to many patients. A self-guided, smartphone-based ACT program would significantly improve accessibility. The SMART-FM study assessed the feasibility of conducting a predominantly virtual clinical trial in an FM population in addition to evaluating preliminary evidence for the safety and efficacy of a digital ACT program for FM (FM-ACT). Sixty-seven patients with FM were randomized to 12 weeks of FM-ACT (n = 39) or digital symptom tracking (FM-ST; n = 28). The study population was 98.5% female, with an average age of 53 years and an average baseline FM symptom severity score of 8 out of 11. Endpoints included the Fibromyalgia Impact Questionnaire-Revised (FIQ-R) and the Patient Global Impression of Change (PGIC). The between-arm effect size for the change from baseline to Week 12 in FIQ-R total scores was d = 0.44 (least-squares mean difference, - 5.7; SE, 3.16; 95% CI, - 11.9 to 0.6; P = .074). At Week 12, 73.0% of FM-ACT participants reported improvement on the PGIC versus 22.2% of FM-ST participants (P < .001). FM-ACT demonstrated improved outcomes compared to FM-ST, with high engagement and low attrition in both arms. Retrospectively registered at ClinicalTrials.gov (NCT05005351) on August 13, 2021.

Juvenile Fibromyalgia: Different from the Adult Chronic Pain Syndrome?

While a majority of research has focused on adult fibromyalgia (FM), recent evidence has provided insights into the presence and impact of FM in children and adolescents. Commonly referred as juvenile fibromyalgia (JFM), youths, particularly adolescent girls, present with persistent widespread pain and cardinal symptoms observed in adult FM. A majority of youth with JFM continue to experience symptoms into adulthood, which highlights the importance of early recognition and intervention. Some differences are observed between adult and juvenile-onset FM syndrome with regard to comorbidities (e.g., joint hypermobility is common in JFM). Psychological comorbidities are common but less severe in JFM. Compared to adult FM, approved pharmacological treatments for JFM are lacking, but non-pharmacologic approaches (e.g., cognitive-behavioral therapy and exercise) show promise. A number of conceptual issues still remain including (1) directly comparing similarities and differences in symptoms and (2) identifying shared and unique mechanisms underlying FM in adults and youths.

A randomized, placebo-controlled, double-blinded trial of duloxetine in the treatment of general fatigue in patients with chronic fatigue syndrome.

OBJECTIVE: To assess the efficacy and safety of duloxetine in patients with chronic fatigue syndrome. METHODS: A 12-week, randomized, double-blind study was designed to compare duloxetine 60-120 mg/d (n = 30) with placebo (n = 30) for efficacy and safety in the treatment of patients with chronic fatigue syndrome. The primary outcome measure was the Multidimensional Fatigue Inventory general fatigue subscale (range: 4-20, with higher scores indicating greater fatigue). Secondary measures were the remaining Multidimensional Fatigue Inventory subscales, Brief Pain Inventory, Medical Outcomes Study Short Form-36, Hospital Anxiety and Depression Scale, Centers for Disease Control and Prevention Symptom Inventory, Patient Global Impression of Improvement, and Clinical Global Impression of Severity. The primary analysis of efficacy for continuous variables was a longitudinal analysis of the intent-to-treat sample, with treatment-by-time interaction as the measure of effect. RESULTS: The improvement in the Multidimensional Fatigue Inventory general fatigue scores for the duloxetine group was not significantly greater than for the placebo group (P = 0.23; estimated difference between groups at week 12 = -1.0 [95% CI: -2.8, 0.7]). The duloxetine group was significantly superior to the placebo group on the Multidimensional Fatigue Inventory mental fatigue score, Brief Pain Inventory average pain severity and interference scores, Short Form-36 bodily pain domain, and Clinical Global Impression of Severity score. Duloxetine was generally well tolerated. CONCLUSION: The primary efficacy measure of general fatigue did not significantly improve with duloxetine when compared with placebo. Significant improvement in secondary measures of mental fatigue, pain, and global measure of severity suggests that duloxetine may be efficacious for some chronic fatigue syndrome symptom domains, but larger controlled trials are needed to confirm these results.

Time to improvement of pain and sleep quality in clinical trials of pregabalin for the treatment of fibromyalgia.

OBJECTIVE: To determine the time to immediate and sustained clinical improvement in pain and sleep quality with pregabalin in patients with fibromyalgia. DESIGN: A post hoc analysis of four 8- to 14-week phase 2-3, placebo-controlled trials of fixed-dose pregabalin (150-600 mg/day) for fibromyalgia, comprising 12 pregabalin and four placebo treatment arms. PATIENTS: A total of 2,747 patients with fibromyalgia, aged 18-82 years. METHODS: Pain and sleep quality scores, recorded daily on 11-point numeric rating scales (NRSs), were analyzed to determine time to immediate improvement with pregabalin, defined as the first of ≥2 consecutive days when the mean NRS score was significantly lower for pregabalin vs placebo in those treatment arms with a significant improvement at endpoint, and time to sustained clinical improvement with pregabalin, defined as a ≥1-point reduction of the baseline NRS score of patient responders who had a ≥30% improvement on the pain NRS, sleep NRS, or Fibromyalgia Impact Questionnaire (FIQ) from baseline to endpoint, or who reported "much improved" or "very much improved" on the Patient Global Impression of Change (PGIC) at endpoint. RESULTS: Significant improvements in pain and sleep quality scores at endpoint vs placebo were seen in 8/12 and 11/12 pregabalin treatment arms, respectively (P < 0.05). In these arms, time to immediate improvements in pain or sleep occurred by day 1 or 2. Time to sustained clinical improvement occurred significantly earlier in pain, sleep, PGIC, and FIQ responders (P < 0.02) with pregabalin vs placebo. CONCLUSIONS: Both immediate and sustained clinical improvements in pain and sleep quality occurred faster with pregabalin vs placebo.

The fibromyalgia family study: a genome-wide linkage scan study.

OBJECTIVE: Familial aggregation of fibromyalgia has been increasingly recognized. The goal of this study was to conduct a genome-wide linkage scan to identify susceptibility loci for fibromyalgia. METHODS: We genotyped members of 116 families from the Fibromyalgia Family Study and performed a model-free genome-wide linkage analysis of fibromyalgia with 341 microsatellite markers, using the Haseman-Elston regression approach. RESULTS: The estimated sibling recurrence risk ratio (λs ) for fibromyalgia was 13.6 (95% confidence interval 10.0-18.5), based on a reported population prevalence of 2%. Genome-wide suggestive evidence of linkage was observed at markers D17S2196 (empirical P [Pe ]=0.00030) and D17S1294 (Pe=0.00035) on chromosome 17p11.2-q11.2. CONCLUSION: The estimated sibling recurrence risk ratio (λs ) observed in this study suggests a strong genetic component of fibromyalgia. This is the first report of genome-wide suggestive linkage of fibromyalgia to the chromosome 17p11.2-q11.2 region. Further investigation of these multicase families from the Fibromyalgia Family Study is warranted to identify potential causal risk variants for fibromyalgia.

Assessment of sleep in patients with fibromyalgia: qualitative development of the fibromyalgia sleep diary.

OBJECTIVES: Sleep disturbance is a common experience in fibromyalgia (FM). The field lacks a sleep specific patient reported outcome (PRO) measure developed and validated in a FM population. The study objective is to gain an in-depth understanding of sleep in FM and to develop a PRO measure of it. METHODS: Research involved the following stages: 1) A literature review conducted to identify key concepts associated with FM patient experience of sleep and PRO measures that have been used to assess this; 2) Qualitative interviews with therapeutic area experts; 3) Focus groups with FM patients who experienced sleep disturbance; 4) Development of a conceptual framework and the Fibromyalgia Sleep Diary (FMSD); and 5) Cognitive interviews with patients to explore content validity of the FMSD. RESULTS: The literature review and expert interviews supported sleep disturbance being an important aspect of the FM patient experience, and underscored the need for a new FM specific sleep PRO measure. Results from the focus groups demonstrated that FM patients experience sleep disturbances that they attribute to their FM symptoms, such as pain and stiffness, confirming the importance of understanding more about sleep changes. Aspects of sleep raised by FM patients included poor sleep quality and insufficient quantity including difficulty with falling asleep, getting comfortable, and staying asleep; restlessness; light sleep; not feeling rested upon awakening; and difficulty starting the day. Cognitive interview results showed that the 8-item FMSD, developed to reflect the concepts identified above, was relevant to FM patients with content that was interpreted as intended. CONCLUSIONS: The FMSD was developed in line with the recommendations of the FDA PRO guidance and ISPOR PRO Task Force. The qualitative evidence generated thus far strongly supports the content validity of the FMSD as a PRO measure of sleep disturbance in FM populations. Psychometric evaluation of the FMSD to demonstrate reliability, validity and sensitivity to change is recommended as a next step.

Safety and efficacy of esreboxetine in patients with fibromyalgia: a fourteen-week, randomized, double-blind, placebo-controlled, multicenter clinical trial.

OBJECTIVE: To evaluate the efficacy, tolerability, and safety of multiple fixed dosages of esreboxetine for the treatment of fibromyalgia. METHODS: Patients meeting the American College of Rheumatology criteria for fibromyalgia were randomized to receive esreboxetine at dosages of 4 mg/day (n=277), 8 mg/day (n=284), or 10 mg/day (n=283) or matching placebo (n=278) for 14 weeks. The primary efficacy outcomes were the weekly mean pain score and the Fibromyalgia Impact Questionnaire (FIQ) total score at week 14. Secondary efficacy measures included scores for the Patient's Global Impression of Change (PGIC) scale, the Global Fatigue Index (GFI), and the 36-item Short-Form health survey (SF-36; physical function scale only) at week 14. The safety profile of esreboxetine was evaluated based on adverse events and other safety measures. RESULTS: Patients receiving all dosages of esreboxetine demonstrated statistically significant improvements in the pain score (P≤0.025), the FIQ score (P≤0.023), and the PGIC score (P≤0.007) compared with patients in the placebo group. Additionally, patients receiving esreboxetine at dosages of 4 mg/day and 8 mg/day showed statistically significant improvements in the GFI score compared with those receiving placebo (P=0.001). No significant differences in SF-36 physical function scores were observed between patients receiving esreboxetine (any dosage) and those receiving placebo. Adverse events were mostly mild to moderate in severity; insomnia, constipation, dry mouth, nausea, dizziness, hot flush, headache, hyperhidrosis, and palpitations were reported most frequently. CONCLUSION: Esreboxetine was generally well tolerated and was associated with significant improvements in pain, FIQ, PGIC, and fatigue scores compared with placebo. The lack of a dose-response relationship in both the efficacy and safety analyses suggests that esreboxetine at a dosage of 4 mg/day would offer clinical benefit with the least risk of drug exposure.

Development of responder definitions for fibromyalgia clinical trials.

OBJECTIVE: To develop responder definitions for fibromyalgia (FM) clinical trials using key symptom and function domains. METHODS: Twenty-four candidate responder definitions were developed by expert consensus and were evaluated in 12 randomized, placebo-controlled trials of 4 medications for the treatment of FM. For each definition, the treatment effects of the medication compared with placebo were analyzed using Cochran-Mantel-Haenszel tests or chi-square tests. A meta-analysis of the pooled results for the 4 medications established risk ratios to determine the definitions that best favored medication over placebo. RESULTS: Two definitions performed best in the analyses. Both definitions included ≥30% reduction in pain and ≥10% improvement in physical function. The definitions differed in that one (≥30% improvement in FM [FM30] short version) included ≥30% improvement in sleep or fatigue, and the other (FM30 long version) required ≥30% improvement in 2 of the following symptoms: sleep, fatigue, depression, anxiety, or cognition. In the analysis of both versions, the response rate was ≥15% for each medication and was significantly greater compared with placebo. The risk ratio favoring drug over placebo in the pooled analysis for FM30 version 3 (short version) was 1.50 (95% confidence interval [95% CI] 1.24-1.82; P ≤ 0.0001); the risk ratio for FM30 version 6 (long version) was 1.60 (95% CI 1.31-1.96; P ≤ 0.00001). CONCLUSION: Among the 24 responder definitions tested, 2 were identified as most sensitive in identifying response to treatment. The identification of responder definitions for FM clinical trials that include assessments of key symptom and function domains may improve the sensitivity of clinical trials to identify meaningful improvements, leading to improved management of FM.

Cognitive behavioral therapy for the treatment of juvenile fibromyalgia: a multisite, single-blind, randomized, controlled clinical trial.

OBJECTIVE: Juvenile fibromyalgia syndrome (FMS) is a chronic musculoskeletal pain disorder in children and adolescents for which there are no evidence-based treatments. The objective of this multisite, single-blind, randomized clinical trial was to test whether cognitive-behavioral therapy (CBT) was superior to fibromyalgia (FM) education in reducing functional disability, pain, and symptoms of depression in juvenile FMS. METHODS: Participants were 114 adolescents (ages 11-18 years) with juvenile FMS. After receiving stable medications for 8 weeks, patients were randomized to either CBT or FM education and received 8 weekly individual sessions with a therapist and 2 booster sessions. Assessments were conducted at baseline, immediately following the 8-week treatment phase, and at 6-month followup. RESULTS: The majority of patients (87.7%) completed the trial per protocol. Intent-to-treat analyses showed that patients in both groups had significant reductions in functional disability, pain, and symptoms of depression at the end of the study, and CBT was significantly superior to FM education in reducing the primary outcome of functional disability (mean baseline to end-of-treatment difference between groups 5.39 [95% confidence interval 1.57, 9.22]). Reduction in symptoms of depression was clinically significant for both groups, with mean scores in the range of normal/nondepressed by the end of the study. Reduction in pain was not clinically significant for either group (<30% decrease in pain). There were no study-related adverse events. CONCLUSION: In this controlled trial, CBT was found to be a safe and effective treatment for reducing functional disability and symptoms of depression in adolescents with juvenile FMS.

Efficacy and Safety of Sublingual Cyclobenzaprine for the Treatment of Fibromyalgia: Results From a Randomized, Double-Blind, Placebo-Controlled Trial.

OBJECTIVE: To evaluate the efficacy and safety of TNX-102 SL, a once-nightly sublingual formulation of cyclobenzaprine, in reducing pain in patients with fibromyalgia (FM). METHODS: RELIEF was a double-blind, randomized, placebo-controlled trial. Overall, 503 patients received TNX-102 SL 2.8 mg for 2 weeks, followed by 5.6 mg for 12 weeks (248 patients), or matching placebo (255 patients). The primary end point was change from baseline at week 14 in the weekly average of daily pain scores. Secondary end points included Patient Global Impression of Change (PGIC) scores, Fibromyalgia Impact Questionnaire Revised (FIQR) scores, Patient-Reported Outcomes Measurement Information System (PROMIS) Sleep Disturbance and Fatigue scores, and daily sleep quality. Safety was assessed by adverse event (AE) reporting. RESULTS: Reduction in daily pain from baseline at week 14 was significantly greater with TNX-102 SL (least squares [LS] mean change -1.9 [95% confidence interval (95% CI) -2.1, -1.7]) versus placebo (LS mean change -1.5 [95% CI -1.7, -1.3]; P = 0.01). TNX-102 SL was not associated with significant improvement in PGIC at week 14 but was associated with improvements in FIQR scores, PROMIS scores, and daily sleep quality. Overall, 59.7% of patients receiving TNX-102 SL and 46.3% receiving placebo reported treatment-emergent AEs; the most common were oral hypoesthesia (17.3% with TNX-102 SL versus 0.4% with placebo), oral paresthesia (5.6% versus 0.4%, respectively), and product taste abnormal (4.4% versus 0.4%, respectively). CONCLUSION: In this phase III, randomized, controlled trial of patients with FM, treatment with TNX-102 SL was associated with significant reductions in daily pain and was safe and well tolerated.

The effect of duloxetine treatment on cognition in patients with fibromyalgia.

OBJECTIVES: To determine the effect of duloxetine treatment on cognition in patients with fibromyalgia. METHODS: Cognitive testing was conducted in a subset of adult patients in a randomized, double-blind, placebo-controlled trial of duloxetine. Patients met the American College of Rheumatology criteria for fibromyalgia and had a score of 4 or higher on the Brief Pain Inventory 24-hour average pain severity item. Patients who consented to cognitive testing were randomized to duloxetine (n = 80) or placebo (n = 76). The primary end point was at Week 12. Speed of processing on tasks requiring visual attention, working memory, and executive function was assessed with a Symbol Digit Substitution Test and Trail-Making Test A and B. Episodic memory was tested using the Verbal Learning and Recall Test. The change from baseline to end point (last-observation-carried-forward analysis) was analyzed by an analysis of covariance model, which included baseline, treatment, investigator, and treatment-by-investigator interaction. RESULTS: Most of the patients were white (89%) women (92%), ranging in age from 21 to 88 years. Mean scores on the cognitive tests were within 2 SD of published scores for similar-aged participants in the general population, indicating no substantial impairment. Baseline-to-end point changes in cognitive scores did not differ significantly between duloxetine and placebo treatment groups. CONCLUSIONS: Although scores differed somewhat from norms for age, substantial cognitive impairment was not evident in patients with fibromyalgia as assessed by the Symbol Digit Substitution Test, Trail-Making Test, and Verbal Learning and Recall Test. Overall, duloxetine treatment had neither positive nor negative effects on cognition. TRIAL REGISTRATION: Clintrials.gov NCT00673452.

Relationships among pain, depressed mood, and global status in fibromyalgia patients: post hoc analyses of a randomized, placebo-controlled trial of milnacipran.

BACKGROUND: Patients with fibromyalgia often experience depressive symptoms in addition to chronic pain and other characteristic symptoms associated with this disorder. OBJECTIVE: To examine the relationships among pain, depressive symptoms, and global status in a clinical trial of milnacipran for fibromyalgia. METHODS: Data from a randomized, double-blind study (milnacipran 100 mg/d, n = 516; placebo, n = 509) were analyzed. Treatment outcomes included quantitative changes in pain and Beck depression inventory (BDI) scores, mean Patient Global Impression of Change (PGIC) scores, and three responder endpoints: patients with ≥30% pain improvement, PGIC score ≤2, and patients meeting both pain and PGIC responder criteria (2-measure composite responders). Correlations and path analyses were conducted to evaluate relationships among improvements in depressive symptoms, pain, and PGIC. RESULTS: Patients receiving milnacipran had greater decreases in mean pain scores, lower mean PGIC endpoint scores, and higher responder rates regardless of baseline severity of depressive symptoms. The highest responder rates were found in patients with greater than four-point improvement in BDI scores (milnacipran vs. placebo: pain, 57.5% vs. 39.0%; PGIC, 60.1% vs. 38.2%; 2-measure composite, 49.0% vs. 27.9%; all p < 0.01), although significant differences between treatment groups were also found in patients with no improvement or worsening of depressive symptoms. Correlations between changes in BDI and changes in pain or PGIC were low (r ≤ 0.3). Path analyses indicated 87.2% of pain reduction to be a direct effect of milnacipran treatment. CONCLUSION: Symptom improvements with milnacipran were only weakly associated with baseline depressive symptoms and were largely independent of improvements in depressive symptomatology.

Sphygmomanometry-evoked allodynia in chronic pain patients with and without fibromyalgia.

BACKGROUND: Fibromyalgia is a chronic pain syndrome that affects about 2% of the U.S. general population, with greater prevalence among women (3.5%) than men (0.5%). Previous research results suggest that the experience of pain (allodynia) upon sphygmomanometry may indicate the presence of fibromyalgia. OBJECTIVE: The aim of this study was to confirm these findings in patients with fibromyalgia and other chronic pain conditions and evaluate the use of sphygmomanometry as a potential screening tool for the identification of patients with fibromyalgia. METHODS: A total of 150 people participated in this multicenter, cross-sectional observational study. The study included a physician-conducted evaluation to determine if the participant met the American College of Rheumatology (ACR) 1990 diagnostic criteria for fibromyalgia. The presence of sphygmomanometry-evoked allodynia was assessed during a seated cuff pressure inflation that was repeated three times on each arm. Each site was provided a sphygmomanometer to ensure standardization, and the pressure of the cuff at the moment of pain initiation was recorded. If the patient did not indicate pain prior to 180 mmHg, then the inflation was stopped, a notation of no pain was made, and a cuff pressure of 180 mmHg was recorded. The mean of the six cuff pressure measurements was used for the analyses. Logistic regression was performed to analyze the relationship between sphygmomanometry-evoked allodynia and fibromyalgia. RESULTS: The evaluable sample was 148 (one participant had too large an arm circumference for the sphygmomanometer and another did not receive the clinician evaluation of ACR-determined fibromyalgia diagnosis). Over half of the participants were determined to have an ACR diagnosis of fibromyalgia. Of these, 71 (91%) were women and had an average age of 54 years. Of the 70 participants with no fibromyalgia diagnosis, 42 (60%) were women and also had an average age of 54 years. Sixty-one (78%) of the fibromyalgia participants, compared with 25 (36%) of those with no fibromyalgia diagnosis, reported sphygmomanometry-evoked allodynia. The participants with fibromyalgia reported pain ata lower cuff pressure compared with those without fibromyalgia (132 mmHg vs. 166 mmHg, p < .01). The logistic regression showed that sphygmomanometry-evoked allodynia predicted an ACR-determined FM diagnosis (χ(2) = 19.4, p < .01). DISCUSSION: These findings support previous research suggesting that patients who report pain upon sphygmomanometry may warrant further evaluation for the presence of fibromyalgia.

The prevalence of comorbid chronic pain conditions among patients with temporomandibular disorders: A systematic review.

BACKGROUND: This systematic review was designed to evaluate the presence of comorbid conditions among patients with temporomandibular disorders (TMDs). TYPES OF STUDIES REVIEWED: The authors reviewed studies that reported the prevalence or incidence of chronic pain conditions or psychiatric disorders (anxiety, mood, personality disorders) among patients with any type of TMD. The authors calculated sample size-weighted prevalence estimates when data were reported in 2 or more studies for the same comorbid condition. RESULTS: A total of 9 prevalence studies and no incidence studies were eligible for review; 8 of the studies examined chronic pain comorbidities. Weighted estimates showed high prevalence of pain comorbidities across studies, including current chronic back pain (66%), myofascial syndrome (50%), chronic stomach pain (50%), chronic migraine headache (40%), irritable bowel syndrome (19%), and fibromyalgia (14%). A single study examined psychiatric disorders and found that current depression was the most prevalent disorder identified (17.5%). CONCLUSIONS AND PRACTICAL IMPLICATIONS: There is a high prevalence of comorbid chronic pain conditions among patients with TMDs, with more than 50% of patients reporting chronic back pain, myofascial syndrome, and chronic stomach pain. Psychiatric disorders among patients with different types of TMDs were studied less commonly in this pain population. Knowledge of the distribution of these and other comorbid disease conditions among patients with different types of TMDs can help dentists and other health care providers to identify personalized treatment strategies, including the coordination of care across medical specialties.

Efficacy and safety of milnacipran 100 mg/day in patients with fibromyalgia: results of a randomized, double-blind, placebo-controlled trial.

OBJECTIVE: To assess the efficacy and safety of milnacipran at a dosage of 100 mg/day (50 mg twice daily) for monotherapy treatment of fibromyalgia. METHODS: A double-blind, placebo-controlled trial was performed to assess 1,025 patients with fibromyalgia who were randomized to receive milnacipran 100 mg/day (n = 516) or placebo (n = 509). Patients underwent 4-6 weeks of flexible dose escalation followed by 12 weeks of stable-dose treatment. Two composite responder definitions were used as primary end points to classify the response to treatment. The 2-measure composite response required achievement of ≥30% improvement from baseline in the pain score and a rating of "very much improved" or "much improved" on the Patient's Global Impression of Change (PGIC) scale. The 3-measure composite response required satisfaction of these same 2 improvement criteria for pain and global status as well as improvement in physical function on the Short Form 36 (SF-36) physical component summary (PCS) score. RESULTS: After 12 weeks of stable-dose treatment, a significantly greater proportion of milnacipran-treated patients compared with placebo-treated patients showed clinically meaningful improvements, as evidenced by the proportion of patients meeting the 2-measure composite responder criteria (P < 0.001 in the baseline observation carried forward [BOCF] analysis) and 3-measure composite responder criteria (P < 0.001 in the BOCF). Milnacipran-treated patients also demonstrated significantly greater improvements from baseline on multiple secondary outcomes, including 24-hour and weekly recall pain score, PGIC score, SF-36 PCS and mental component summary scores, average pain severity score on the Brief Pain Inventory, Fibromyalgia Impact Questionnaire total score (all P < 0.001 versus placebo), and Multidimensional Fatigue Inventory total score (P = 0.036 versus placebo). Milnacipran was well tolerated by most patients, with nausea being the most commonly reported adverse event (placebo-adjusted rate of 15.8%). CONCLUSION: Milnacipran administered at a dosage of 100 mg/day improved pain, global status, fatigue, and physical and mental function in patients with fibromyalgia.

Correlations between fibromyalgia symptom and function domains and patient global impression of change: a pooled analysis of three randomized, placebo-controlled trials of pregabalin.

OBJECTIVE: The objective of the study was to conduct an analysis of pooled data from pregabalin fibromyalgia clinical trials to determine which fibromyalgia symptom and function domains drive patient perception of improvement. DESIGN: Data from three double-blind, placebo-controlled trials of pregabalin in fibromyalgia patients were pooled for this analysis. Changes in independent variables, including the Medical Outcomes Study 36-item Short-Form Health Survey, Medical Outcomes Study-Sleep Scale, sleep quality score from the daily sleep diary, pain score from the daily pain diary, Fibromyalgia Impact Questionnaire, and Multidimensional Assessment of Fatigue were analyzed as predictors of outcome on the dependent variable, Patient Global Impression of Change (PGIC). Correlation analysis assessed relationships between the independent variables and PGIC. Cluster analysis identified dependencies among variables, and a shrinkage and selection method and stepwise logistic regression determined rank order of variables. RESULTS: Improvement in PGIC at endpoint showed highest correlation with pain improvement, fatigue, sleep, and work and physical function (0.4 < r < 0.6). Cluster analysis identified three main clusters of symptoms at endpoint: mood (anxiety and depression), pain and sleep, and function and fatigue. Pain was ranked as the most important outcome explaining variability in PGIC, followed by fatigue and sleep. CONCLUSIONS: Pain, fatigue, and sleep associate most strongly with improvement in PGIC. Physical- and work-related function also correlated with patients' overall assessment of improvement. These domains and their respective outcome measures can be used to improve assessment of patients' response to treatment.

The Prevalence of Psychiatric and Chronic Pain Comorbidities in Fibromyalgia: an ACTTION systematic review.

Fibromyalgia (FM) is a chronic widespread pain condition that overlaps with multiple comorbid health conditions and contributes to considerable patient distress. The aim of this review was to provide a systematic overview of psychiatric and chronic pain comorbidities among patients diagnosed with FM and to inform the development of recommendations for the design of clinical trials. Thirty-one, cross-sectional, clinical epidemiology studies that evaluated patients diagnosed with FM were included for review. None of the reviewed studies reported on the incidence of these comorbidities. Sample size-weighted prevalence estimates were calculated when prevalence data were reported in 2 or more studies for the same comorbid condition. The most prevalent comorbidity across all studies reviewed was depression/major depressive disorder (MDD) with over half of the patients included having this diagnosis in their lifetime (weighted prevalence up to 63%). In addition, nearly one-third of FM patients examined had current or lifetime bipolar disorder, panic disorder, or post-traumatic stress disorder. Less common psychiatric disorders reported included generalized anxiety disorder, obsessive compulsive disorder, and specific phobias (agoraphobia, social phobia). There were fewer studies that examined chronic pain comorbidities among FM patients, but when evaluated, prevalence was also high ranging from 39% to 76% (i.e., chronic tension-type or migraine headache, irritable bowel syndrome, myofascial pain syndrome, and temporomandibular disorders). The results of the review suggest that depression and chronic pain conditions involving head/jaw pain and IBS were elevated among FM patients compared to other conditions in the clinic-based studies. In contrast, anxiety-related disorders were much less common. Addressing the presence of these comorbid health conditions in clinical trials of treatments for FM would increase the generalizability and real-world applicability of FM research.

Relationships among pain and depressive and anxiety symptoms in clinical trials of pregabalin in fibromyalgia.

BACKGROUND: Fibromyalgia, as defined by the American College of Rheumatology, is characterized by widespread pain lasting for at least 3 months, with pain in at least 11 out of 18 tender points when palpated with digital pressure. OBJECTIVE: The authors investigated the relationship between changes in pain and symptoms of anxiety and depression, using data from pregabalin clinical trials. METHOD: Results from three double-blind, placebo-controlled trials of pregabalin monotherapy in fibromyalgia (8-14 weeks) were pooled, and baseline to end-point changes in pain and Hospital Anxiety and Depression Scale (HADS) scores were analyzed. Path-analysis evaluated the association between improvements in anxiety and depression and pain relief. RESULTS: Baseline HADS scores indicated moderate-to-severe anxiety in 38% of patients and moderate-to-severe depressive symptoms in 27%. The improvement in pain was not related to baseline levels of anxiety or depression. The correlation between changes in pain and depressive or anxiety symptoms was low-to-moderate. Path-analysis showed that most of the pain relief observed with pregabalin treatment was a direct analgesic effect and was not explained by improvement in mood. CONCLUSION: Response to treatment of pain in the pregabalin trials did not depend on baseline levels of anxiety or depressive symptoms, and pregabalin improved pain in fibromyalgia patients with or without depressive or anxiety symptoms. Changes in the level of anxiety or depression had a low-to-moderate impact on pain reduction. Pain reduction with pregabalin treatment appeared to result mostly from a direct treatment effect, rather than an indirect effect mediated through improvement in anxiety or depressive symptoms.

Relationship between school absenteeism and depressive symptoms among adolescents with juvenile fibromyalgia.

OBJECTIVE: To describe school absences in adolescents with Juvenile Primary Fibromyalgia Syndrome (JPFS) and examine the relationship between school absenteeism, pain, psychiatric symptoms, and maternal pain history. METHODS: Adolescents with JPFS (N = 102; mean age 14.96 years) completed measures of pain and depressive symptoms, and completed a psychiatric interview. Parents provided information about the adolescents' school absences, type of schooling, and parental pain history. School attendance reports were obtained directly from schools. RESULTS: Over 12% of adolescents with JPFS were homeschooled. Those enrolled in regular school missed 2.9 days per month on average, with one-third of participants missing more than 3 days per month. Pain and maternal pain history were not related to school absenteeism. However, depressive symptoms were significantly associated with school absences. CONCLUSION: Many adolescents with JPFS experience difficulties with regular school attendance. Long-term risks associated with school absenteeism and the importance of addressing psychological factors are discussed.