Fibromyalgia syndrome is a systemic disorder of widespread pain which is thought to result from abnormal pain processing within the central nervous system. There are no currently approved treatments for this indication. Antidepressants appear, however, to be effective, especially those with an action on noradrenergic neurotransmission. The objective of the present study was to test the efficacy of the dual action noradrenaline and serotonin reuptake inhibitor antidepressant, milnacipran, in the treatment of fibromyalgia. The 125 patients, who were enrolled in a double-blind, placebo-controlled, flexible dose escalation trial, were randomized to receive placebo or milnacipran for 4 weeks of dose escalation (up to 200 mg/day), followed by 8 weeks at a constant dose. The study evaluated the efficacy and safety of milnacipran for the treatment of pain and associated symptoms such as fatigue, depressed mood and sleep. 75% of milnacipran-treated patients reported overall improvement, compared with 38% in the placebo group (p < 0.01). Furthermore, 37% of twice daily milnacipran-treated patients reported at least 50% reduction in pain intensity, compared with 14% of placebo-treated patients (p < 0.05). 84% of all milnacipran patients escalated to the highest dose (200 mg/day) with no tolerability issues. Most adverse events were mild to moderate in intensity, and transient in duration. These results suggest that milnacipran may have the potential to relieve not only pain but several of the other symptoms associated with fibromyalgia.
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.
ObjectiveInfections and other stressors have been implicated in the development of fibromyalgia. We hypothesized that these stressors could result in recurrent reactivations of latent herpes virus infections, which could lead to the development of fibromyalgia. This study evaluated a famciclovir + celecoxib drug combination (IMC-1), active against suspected herpes virus reactivation and infection, for the treatment of fibromyalgia.MethodsA total of 143 fibromyalgia patients were enrolled at 12 sites in a 16-week, double-blinded, placebo-controlled proof-of-concept trial. Randomized patients received either IMC-1 or placebo in a 1:1 ratio. Outcome measures included a 24-hour recall pain Numerical Rating Scale, the Revised Fibromyalgia Impact Questionnaire (FIQ-R), the Patient’s Global Impression of Change (PGIC) questionnaire, the Multidimensional Fatigue Inventory, the NIH Patient-Reported Outcomes Measurement Information System (PROMIS), and the Beck Depression Inventory-II conducted at baseline and weeks 6, 12, and 16 of the study.ResultsA significant decrease in fibromyalgia-related pain was observed for patients on IMC-1 treatment versus placebo. PGIC response rates were significantly improved with IMC-1 treatment. Overall, patient self-reported functioning, as measured by the FIQ-R, was significantly improved. Fatigue was also significantly improved as measured by the PROMIS fatigue inventory. The safety profile was encouraging. Despite the celecoxib component of IMC-1, gastrointestinal and nervous system treatment emergent adverse events were reported less frequently in the IMC-1 group, and study completion rates favored IMC-1 treatment.ConclusionIMC-1 was efficacious and safe in treating symptoms of fibromyalgia, supporting the hypothesis that herpes virus infections may contribute to this syndrome. Improved retention rates, decreased adverse event rates, and evidence of efficacy on a broad spectrum of outcome measures are suggestive that IMC-1 may represent an effective, novel treatment for fibromyalgia.
BackgroundThe importance of nonrestorative sleep in the pathophysiology of fibromyalgia (FM) suggests that treatments that improve sleep quality may improve FM globally by a mechanism distinct from that of centrally acting analgesics. TNX-102 SL is a sublingual formulation of cyclobenzaprine (2.8 mg) designed for rapid absorption and bedtime use. The current study was designed to evaluate the safety and efficacy of TNX-102 SL in the treatment of FM.ObjectivesThe BESTFIT study was designed to evaluate whether the sleep quality improvement associated with TNX-102 SL treatment would lead to improvement in the pain and other symptoms of FM.MethodsBESTFIT was a 12-week, randomized, double-blind, placebo-controlled trial conducted at 17 investigational US sites. Under a US Investigational New Drug Application, 205 participants were randomized 1:1 to receive TNX-102 SL (N=103) or matching placebo (N=102). Outcome measures included daily diary assessment of pain and sleep (0-10 NRS), the Fibromyalgia Impact Questionnaire (FIQ-R), Patient Global Impression of Change (PGIC), PROMIS Sleep Disturbance scale (PROMIS), and mood (Beck Depression Inventory, BDI). Data were analyzed by mean change from baseline using Mixed Effects Model Repeated Measures (MMRM) unless otherwise noted.ResultsTNX-102 SL treatment improved multiple domains of FM. Treatment improved the FIQ-R total score by -17.2 compared to -9.1 for placebo, p=0.015. PGIC response rate was improved vs. placebo (30.1% vs. 16.7%, p=0.025 by logistic regression). Several measures of sleep quality improved, including the PROMIS with a -9.5 improvement on active compared to -6.1 on placebo, p=0.004. Sleep as measured by daily diary (change from baseline to endpoint) was improved by -1.9 compared to -1.0 on placebo; p<0.001. TNX-102 improved sleep quality on FIQ-R by -2.9 compared to -1.2 on placebo; p<0.0001. Treatment decreased pain by -1.6 compared to -1.1 for placebo on the daily diary; p=0.086. The same week 12 pain data analyzed for 30% improvement from baseline (responder analysis) was significant with a 34% response rate compared to 20% for placebo; p=0.03. Pain reported at clinic visits (7 day recall NRS) was also significantly improved (p=0.014) as was the pain item on FIQ-R (7 day recall), p=0.004. The most common local adverse event was transient tongue or mouth numbness occurring in 42% of treated patients. Systemic adverse events were very infrequent, none of which occurred at a 5% or greater rate in the treated population. This excellent AE profile is consistent with the decision to use very low doses of cyclobenzaprine to optimize the risk-benefit ratio of this therapeutic approach.ConclusionsBedtime TNX-102 SL improved sleep quality by multiple measures. Nonrestorative sleep has been linked to central sensitization, which is a process in which regional chronic pain leads to changes in central pain processing and interpretation. The improvement in sleep quality resulting from bedtime treatment with TNX-102 SL was associated with improvements in multiple oth...
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