OBJECTIVE:Fibromyalgia is the prototypic nociplastic chronic pain syndrome, characterized by widespread pain, nonrestorative sleep, and fatigue. We evaluated efficacy and safety of bedtime TNX-102 SL (sublingual cyclobenzaprine) 5.6 mg for treatment of fibromyalgia. METHODS:This phase 3, double-blind, multicenter, placebo-controlled trial randomized patients 1:1 to once-nightly TNX-102 SL 2.8 mg for 2 weeks, followed by 5.6 mg for 12 weeks, or to matching placebo (NCT05273749). The primary endpoint was change from baseline at week 14 in weekly average of daily diary pain intensity scores. Secondary endpoints included Patient Global Impression of Change, Fibromyalgia Impact Questionnaire (Revised) Symptoms and Function domains, Patient-Reported Outcomes Measurement Information System instruments for Sleep Disturbance and Fatigue, and daily diary sleep quality scores. RESULTS:Overall, 81.0% (n = 187/231) and 79.6% (n = 179/225) of patients receiving TNX-102 SL and placebo completed the trial, respectively. Treatment with TNX-102 SL vs placebo was associated with significantly greater reductions in the primary pain endpoint (P < .001; mean [SE], -1.8 [0.12] vs -1.2 [0.12]) and in each of the 6 secondary endpoints (P ≤ .001; all). The most common systemic treatment-emergent adverse events (TEAEs) with TNX-102 SL and placebo were COVID-19 (4.3% vs 3.1%, respectively), headache (3.0% vs 1.8%), and somnolence (3.0% vs 1.3%); the most common TEAEs overall were local administration-site reactions including oral hypoesthesia (23.4% vs 0.4%), product taste abnormal (11.3% vs 0.9%), and oral paresthesia (6.9% vs 0.9%), which were transient and self-limited. CONCLUSION:Bedtime TNX-102 SL treatment was associated with significant improvements in fibromyalgia symptoms and function and was well tolerated. CLINICAL TRIAL REGISTRATION:ClinicalTrials.gov/study/NCT05273749, first patient screened March 21, 2022.

Behavioral therapies, such as Acceptance and Commitment Therapy (ACT), have been empirically supported for treating fibromyalgia (FM). However, clinical adoption is challenging due to limited access to qualified providers. A smartphone-based, FDA cleared prescription digital therapy (FM-ACT) addresses this barrier by providing self-guided ACT for treatment of FM symptoms. We report the effectiveness of FM-ACT from PROSPER-FM (NCT05243511), a pivotal randomized controlled trial (RCT). The trial randomized 275 participants with FM to receive 12 weeks of FM-ACT or an active comparator (Symptom Tracker (ST), designed as a daily symptom tracker/monitor with access to patient education materials). The primary endpoint was Patient Global Impression of Change (PGIC) at Week 12. Secondary endpoints (collected weekly) included the Revised Fibromyalgia Impact Questionnaire (FIQ-R), Pain Intensity, Pain Interference, and Sleep Interference. At week 12, 70.6% of the FM-ACT participants improved on PGIC (vs 22.2% in the ST control, p < 0.001). The FM-ACT arm improved significantly more on FIQ-R total score than the ST control (p < 0.001, Effect Size = 0.65). Superiority of FM-ACT emerged early (between Weeks 2 and 7) on FIQ-R total and domain scores, Pain Intensity, and Pain Interference. FM-ACT was superior to ST control on virtually all endpoints at Week 12. No treatment related adverse events were observed. Results from the pivotal RCT demonstrated that FM-ACT offers clinical benefits in improving wellbeing, lowering FM severity, and reducing common FM symptoms. Clinical benefits started to display a few weeks into the therapy.

Currently, there are only three FDA-approved medications for the treatment of fibromyalgia. Real-world studies demonstrate that these medications are frequently discontinued within 6 to 12 months of initiation, often due to tolerability concerns. This leaves patients with limited treatment options for this debilitating condition. Esreboxetine is a novel, extended-release, potent and highly-selective norepinephrine reuptake inhibitor under investigation for the treatment of fibromyalgia in adults. Esreboxetine has demonstrated efficacy and safety in randomized, placebo-controlled trials for the treatment of fibromyalgia (Arnold, 2010; Arnold, 2012). Here we present the long-term safety of flexibly dosed esreboxetine (4-10 mg) in patients with fibromyalgia who enrolled in an open-label extension study after completing a 14-week, Phase 3, randomized, double-blind, placebo-controlled, multicenter clinical trial (NCT00612170). A total of 386 participants (93% female) were included in the safety population. The median treatment duration was 101 days (range 1-297) and 64 participants were treated for over six months. A total of 287 (74.4%) participants reported adverse events (AEs) and 47 (12.2%) discontinued due to AEs (all causality). The most common AEs (>10%) were dry mouth (15.0%), constipation (14.2%), nausea (12.2%), and insomnia (10.9%). Most AEs were mild to moderate in severity and consistent with the pharmacology of esreboxetine. Only 6 participants (1.6%) discontinued due to insufficient clinical response. These data provide additional support for the overall safety, tolerability, and continued clinical development of esreboxetine for the treatment of fibromyalgia, a patient population with significant unmet medical need.

Several unmet needs exist for fibromyalgia treatment including long-term efficacy. Esreboxetine is an extended-release, potent and highly-selective norepinephrine reuptake inhibitor under investigation for fibromyalgia. Esreboxetine has demonstrated efficacy and safety in placebo-controlled fibromyalgia trials ranging in duration from 8-14 weeks (Arnold, 2010; Arnold, 2012). This open-label study evaluated long-term treatment of flexibly dosed esreboxetine (4-10 mg) in adult patients with fibromyalgia. At baseline, all participants (N=572; 91% female) had a score ≥40 on the 100-mm pain visual analogue scale (VAS) and met the 1990 American College of Rheumatology fibromyalgia criteria. The median duration of treatment was 140 days; 265 participants received treatment for more than 6 months and 77 were treated for more than 1 year. Discontinuations due to adverse events (AEs) occurred in 35.3% of participants (all causality) and mainly occurred early in treatment. AEs were mostly mild-to-moderate in severity, and the most common (>10%) AEs were dry mouth, constipation, insomnia, headache, hyperhidrosis, nausea, and dizziness. Pain was improved at all timepoints. At Week 2, the mean VAS decrease was –10.2 (baseline score=70.4). Further improvements were noted with continued treatment: -15.8 (Week 4;n=447), -23.2 (Week 8;n=370), -28.6 (Week 32;n=242), -31.2 (Week 44;n=143). Similar improvement trends were reported on the Fibromyalgia Impact Questionnaire (FIQ): mean FIQ decrease was -18.27 at Week 32. These results demonstrate the efficacy and safety of esreboxetine for the treatment of fibromyalgia and support the continued development of esreboxetine as a promising treatment for fibromyalgia. This study was supported by Axsome Therapeutics and Pfizer.

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 fibromyalgiarelated 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 484% (95% CI 379-589; p<00001). 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. Copyright (c) 2024 Elsevier Ltd. All rights reserved, including those for text and data mining, AI training, and similar technologies.

In this phase 3, randomized, controlled trial of patients with fibromyalgia, treatment with TNX-102 SL was associated with significant reductions in daily pain and was safe and well tolerated.

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.

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.

Post-traumatic stress disorder (PTSD) is a complex and difficult-to-treat psychiatric condition with high unmet need. NYX-783 is a small molecule that modulates the N-methyl-D-aspartate receptor.

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.

Juvenile-onset fibromyalgia (JFM) is typically diagnosed in adolescence and characterized by widespread pain and marked functional impairment. The long-term impact of JFM into adulthood is poorly understood. The objectives of this study were to describe physical and psychosocial outcomes of youth diagnosed with JFM in early adulthood (∼8-year follow-up), examine longitudinal trajectories of pain and depressive symptoms from adolescence to young adulthood, and examine the impact of pain and depressive symptoms on physical functioning over time. Participants were 97 youth with JFM enrolled in a prospective longitudinal study in which pain symptoms, and physical and psychosocial functioning were assessed at 4 time points over approximately 8 years. At the time 4 follow-up (Mage = 24.2 years), the majority continued to suffer from pain and impairment in physical, social, and psychological domains. However, trajectories of pain and emotional symptoms showed varying patterns. Longitudinal analysis using growth mixture modeling revealed 2 pain trajectories (Steady Improvement and Rapid Rebounding Improvement), whereas depressive symptoms followed 3 distinct trajectories (Low-Stable, Improving, and Worsening). Membership in the Worsening Depressive symptoms group was associated with poorer physical functioning over time (P < 0.001) compared with the Low-Stable and Improving groups. This study offers evidence that although JFM symptoms persist for most individuals, pain severity tends to decrease over time. However, depressive symptoms follow distinct trajectories that indicate subgroups of JFM. In particular, JFM patients with worsening depressive symptoms showed decreasing physical functioning and may require more intensive and consistent intervention to prevent long-term disability.

Objective: To investigate the efficacy and safety of mirogabalin, a preferentially selective alpha(2)delta ligand, in patients with fibromyalgia (FM). Methods: In three 13-week, multicenter, double-blind, phase 3 studies (studies A, B, and C), patients with FM (n = 1293, 1270, and 1301, respectively) were randomized (1:1:1:1) to placebo, pregabalin 150 mg twice daily, mirogabalin 15 mg once daily or mirogabalin 15 mg twice daily. The primary endpoint was the change in weekly average daily worst pain score (ADPS) at week 13. Key secondary endpoints included Patient Global Impression of Change and change in the Fibromyalgia Impact Questionnaire total score. Long-term safety of mirogabalin was assessed in a 52-week extension study. Results: Neither mirogabalin dose demonstrated a significant ADPS reduction from baseline vs. placebo at week 13 in any of the three studies. Pregabalin significantly reduced ADPS from baseline vs. placebo in studies B and C (p = .0008 and .0001, respectively). The effect of mirogabalin compared with placebo on key secondary endpoints was variable across the studies. Mirogabalin was well tolerated by most patients in the phase 3 studies; no unexpected adverse events occurring during the 52-week extension study. Conclusion: While both mirogabalin doses were well tolerated by most patients and showed potential for reducing pain associated with FM, the primary endpoint of significant pain reduction in patients on mirogabalin compared with placebo was not achieved in any of the three randomized controlled studies.

Currently, there are no medications approved for the treatment of juvenile fibromyalgia (JFM). We evaluated the safety and efficacy of duloxetine 30/60 mg once daily (QD) versus placebo in adolescents with JFM. In this Phase 3b, multisite (US, Argentina, Puerto Rico, and India) trial, patients aged 13–17 years with JFM and a score of ≥4 on the Brief Pain Inventory-Modified Short Form: Adolescent Version (BPI) 24-h average pain severity score were randomized to duloxetine or placebo for the 13-week double-blind period. The starting duloxetine dose was 30 mg, with a target dose of 60 mg QD, as tolerated. The primary endpoint was the mean change in 24-h average pain severity of the Brief Pain Inventory (BPI) from baseline to Week 13, analyzed using mixed-model repeated measures (MMRM) technique. Secondary measures were BPI severity and interference scores; treatment response (≥30%, ≥50% reductions on BPI average pain severity); Pediatric Pain Questionnaire; Clinical Global Impression of Severity: Overall and Mental Illness scales; Functional Disability Inventory: child and parent versions; Children’s Depression Inventory; Multidimensional Anxiety Scale for Children; and safety and tolerability. Continuous secondary efficacy measures were analyzed using analysis of covariance or MMRM, and categorical data using Cochran-Mantel-Haenszel test and Fisher’s exact test, where appropriate. A total of 184 patients with JFM received duloxetine (N = 91) or placebo (N = 93), of which 149 patients (81.0%) completed the 13-week double-blind treatment period. Baseline characteristics were comparable between groups; majority of the patients were Caucasian (77.17%) and females (75.0%), with a mean age of 15.53 years. For the primary measure, BPI average pain severity, the mean change was not statistically different between duloxetine and placebo (− 1.62 vs. -0.97, respectively; p = .052). For secondary efficacy outcomes, statistically significantly more duloxetine- versus placebo-treated patients had a treatment response (≥30% and ≥50% reductions on BPI average pain severity) and improvement of the general activity and relationships items on the BPI interference subscale. The percentage of patients reporting at least 1 treatment-emergent adverse event was higher in the duloxetine versus placebo groups (82.42% vs. 62.37%, respectively; p = .003). The overall safety profile of duloxetine in this study was similar to that reported previously in duloxetine pediatric trials of other indications. The primary study outcome, mean change in 24-h BPI average pain severity rating from baseline to Week 13, did not significantly improve with duloxetine compared to placebo in patients with JFM. However, significantly more patients on duloxetine compared to placebo had a ≥30% and ≥50% reduction in pain severity. There were no new safety concerns related to duloxetine in the study population. ClinicalTrials.gov Identifier: NCT01237587 . Registered 08 November, /2010.