Abstract
IntroductionPrevious studies of long-term treatment response in fibromyalgia and other chronic pain states have generally been limited to approximately one year, leaving questions about the longer-term durability of response. The purpose of this study was to demonstrate continuing efficacy of milnacipran by characterizing changes in pain and other fibromyalgia symptoms after discontinuing long-term treatment. The mean length of milnacipran treatment at the time of randomized withdrawal was 36.1 months from initial exposure to milnacipran (range, 17.9 to 54.4 months).MethodsAfter completing a long-term, open-label, lead-in study of milnacipran (which followed varying periods of exposure in previous studies), adult patients with fibromyalgia entered the four-week open-label period of the current study for evaluation of ongoing treatment response. After the four-week period to confirm new baseline status, 151 patients taking milnacipran ≥100 mg/day and reporting ≥50% improvement from pre-milnacipran exposure in Visual Analogue Scale (VAS) pain scores were classified as responders. These responders entered the 12-week, double-blind withdrawal period in which they were randomized 2:1 to continue milnacipran or switched to placebo. The prespecified primary parameter was loss of therapeutic response (LTR), defined as increase in VAS pain score to <30% reduction from pre-milnacipran exposure or worsening of fibromyalgia requiring alternative treatment. Adverse events and vital signs were also monitored.ResultsTime to LTR was shorter in patients randomized to placebo than in patients continuing milnacipran (P < 0.001). Median time to LTR was 56 days with placebo and was not calculable for milnacipran, because less than half of the latter group of patients lost therapeutic response by study end. Additionally, 81% of patients continuing on milnacipran maintained clinically meaningful pain response (≥30% improvement from pre-milnacipran exposure), compared with 58% of patients switched to placebo (sensitivity analysis II; P < 0.001). The incidences of treatment-emergent adverse events were 58% and 47% for placebo and milnacipran, respectively. Mean decreases in blood pressure and heart rate were found in both groups, with greater decreases for patients switched to placebo.ConclusionsContinuing efficacy of milnacipran was demonstrated by the loss of effect following withdrawal of treatment in patients who received an average of three years of milnacipran treatment.Trial registrationClinicalTrials.gov: NCT01014585
Highlights
Previous studies of long-term treatment response in fibromyalgia and other chronic pain states have generally been limited to approximately one year, leaving questions about the longer-term durability of response
On the basis of the 1990 American College of Rheumatology (ACR) classification criteria, which focus on pain and tenderness [4], it has been estimated that fibromyalgia affects 2% to 4% of the general population [5,6]
Most discontinuations during the double-blind period were due to worsening of fibromyalgia requiring alternative treatment, which was one of the loss of therapeutic response (LTR) definitions used in this study
Summary
Previous studies of long-term treatment response in fibromyalgia and other chronic pain states have generally been limited to approximately one year, leaving questions about the longer-term durability of response. Because ongoing therapy is often required to manage the chronic symptoms of fibromyalgia, demonstration of a medicine’s long-term efficacy is of great interest to both clinicians and patients. Acting analgesics, such as the tricyclic compounds, were investigated once it became clear that the diffuse pain and other symptoms of fibromyalgia were likely due to aberrations in the central nervous system. Preliminary studies with amitriptyline and cyclobenzaprine showed efficacy in patients receiving one to three months of treatment [9,10] These initially promising results were not replicated in subsequent longer-term studies, and tolerability is always an issue when using tricyclic compounds. Another centrally acting analgesic that likely acts by largely augmenting serotonergic and noradrenergic activity (along with some weak μ-opioid effects) has been shown to have shortterm efficacy in patients with fibromyalgia [11,12,13]
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