Milnacipran combined with pregabalin in fibromyalgia: a randomized, open-label study evaluating the safety and efficacy of adding milnacipran in patients with incomplete response to pregabalin

Abstract

Objective: To evaluate the safety, tolerability, and efficacy of adding milnacipran to pregabalin in patients with fibromyalgia who have experienced an incomplete response to pregabalin. Methods: In this randomized, multicenter, open-label study, patients received pregabalin 300 or 450 mg/day during a 4-to 12-week run-in period. Patients with weekly recall visual analog scale (VAS) pain score of at least 40 and up to 90, Patient Global Impression of Severity score of at least 4, and Patient Global Impression of Change (PGIC) score of at least 3 were classified as incomplete responders and randomized to continue pregabalin alone (n = 180) or receive milnacipran 100 mg/day added to pregabalin (n = 184). The primary efficacy parameter was responder status based on PGIC score of up to 2. The secondary efficacy parameter was change from randomization in weekly recall VAS pain score. Safety parameters included adverse events (AEs), vital signs, and clinical laboratory tests. Results: The percentage of PGIC responders was significantly higher with milnacipran added to pregabalin (46.4%) than with pregabalin alone (20.8%; p < 0.001). Mean improvement from randomization in weekly recall VAS pain scores was greater in patients receiving milnacipran added to pregabalin (−20.77) than in patients receiving pregabalin alone (−6.43; p < 0.001). During the run-in period, the most common treatment-emergent AEs with pregabalin were dizziness (22.8%), somnolence (17.3%), and fatigue (9.1%). During the randomized period, the most common treatment-emergent AEs with milnacipran added to pregabalin were nausea (12.5%), fatigue (10.3%), and constipation (9.8%). Conclusions: In this exploratory, open-label study, adding milnacipran to pregabalin improved global status, pain, and other symptoms in patients with fibromyalgia with an incomplete response to pregabalin treatment.

Serotonin and noradrenaline reuptake inhibitors (SNRIs) for fibromyalgia

“…Nearly all studies selected statistical methods (last observation carried forward) that bias results towards exaggerating the efficacy of drugs (Moore 2012). …”

“…Last observation carried forward can lead to overestimation of efficacy, particularly in situations where adverse event withdrawal rates differ between active and control groups. At this time it is unclear what strategy can actually be used to deal with missing data inside studies (Moore 2012). We examined and reported imputation strategies clearly.…”

An evidence-based review of pregabalin for the treatment of fibromyalgia

“…A total of seven combination studies involving pregabalin were identified (summarized in Table 1; see also Table 3 of the Supplemental Online Material for more details of each individual study) [69][70][71][72][73][74][75]. The placebo-controlled clinical study in which pregabalin was added on top of an antidepressant [51] because has been discussed in detail above as the antidepressant was being administered for the treatment of depression alone and not FM.…”

“…Based on withdrawals due to AEs, the tolerability of pregabalin in combination with another treatment was no worse when compared with placebo or either treatment when administered alone. It is worth noting that the majority of studies discussed here were conducted in relatively small patient populations, with some exceptions [71,73]. Nonetheless, these studies provide a platform for future large-scale, randomized, placebo-or comparator-controlled, double-blind trials of pregabalin in combination with other treatments.…”

Treatment of fibromyalgia

“…3,24 The effect sizes for nonpharmacological approaches tend to be larger than those for drugs, but combinations of drugs have only recently started to be tested. There have been some positive results, [25][26][27] emphasising the potential utility of a multimodal approach.…”