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Objectives To evaluate the effects of long-term milnacipran treatment in fibromyalgia patients. Methods Patients completing a previous milnacipran study were eligible to participate in this long-term (up to 3.25 y), open-label study. After washout, dose escalation, and 8 weeks of stable-dose treatment (100 mg/d), patients received flexible doses of milnacipran (50 to 200 mg/d) for the remainder of the study. Safety evaluations included adverse events and vital signs. Clinical measures included weekly recall pain (visual analog scale [VAS]), Patient Global Disease Status (PGDS), and the Short Form-36 Health Survey (SF-36, including the Physical Component Summary [PCS] and Mental Component Summary scores). Cohort analyses were conducted to assess the effects of milnacipran over varying periods of time. Results Of 1227 patients entering the study, 585 (47.7%) were classified as completers, including 379 (30.9%) patients who were currently enrolled when the study was administratively terminated. Mean duration of treatment was 19 months, with 206 patients reaching the final visit and receiving 36 to 38 months of study treatment. The percentage of patients with ≥1 treatment-emergent adverse event was 88.3%, with nausea (25.9%) and headache (13.4%) being the most common events. Discontinuations due to adverse events occurred in 20.9% of patients. Potentially clinically significant increases in blood pressure or heart rate occurred in ≤1.1% of patients. Mean improvement from baseline in weekly recall VAS pain was 17.6; improvements in global status (PGDS) and physical functioning (SF-36 PCS) were also observed. In all patient cohorts, these improvements were observed by month 3 and remained relatively constant over time. At final study visit in the 3-year cohort, 70.3% of patients rated their overall fibromyalgia as "much improved" or "very much improved." Discussion No new safety concerns were identified in this long-term study. Sustained symptom improvements were found in fibromyalgia patients who received up to 3.25 years of milnacipran treatment.

Clinical trials on the treatment of pain syndromes have adopted Patient Global Impression of Change (PGIC) as a primary outcome. However, little is known about how change in clinical status influences these ratings. The present study examined relationships between changes in pain, depressed mood, physical functioning, vitality, sleep disturbance, cognitive complaints, and PGIC ratings among 1260 participants with fibromyalgia (FM) who completed one of two trials examining the safety and efficacy of milnacipran. Many of the relationships between change in clinical status and PGIC ratings were stronger among persons who rated themselves as improved (responders) versus those reporting no change or a worsening of their condition (non-responders). Among non-responders, simultaneous regression analysis revealed that greater degrees of depressed mood and pain, and poorer physical function were significantly associated with worse PGIC ratings. Among responders, improvements in pain were significantly associated with better PGIC ratings, along with improvements in vitality, sleep, physical function, and cognitive complaints. These findings underscore the complexity of global ratings in FM patients, and suggest the association between clinical status and PGIC ratings varies as a function of perceived treatment response. Several domains were associated with PGIC ratings, highlighting the need to assess multiple outcomes in clinical trials of treatments for FM.

The effect of H2-receptor antagonists on alcohol absorption appears to vary, depending on testing conditions and subject population. In this crossover study of cimetidine (400 mg b.i.d.) and ranitidine (150 mg b.i.d.), we evaluate alcohol pharmacokinetics in 10 subjects after ingestion of moderate doses (0.5 g/kg) of ethanol under four challenge conditions: (a) a single dose of placebo prior to alcohol ingestion in the morning, (b) a single dose of H2-antagonist prior to alcohol ingestion in the morning, (c) 14-day chronic dosing with H2-antagonist prior to alcohol ingestion in the evening, and (d) 28-day chronic dosing with H2-antagonist prior to alcohol ingestion in the morning. No significant increases were observed for alcohol in the area under the curve (AUC) or Cmax. Significant decreases in AUC (16 and 13%) were observed following administration of single- and multiple-dose cimetidine, and a significant decrease in Cmax (14%) was observed following a single dose of ranitidine--all given prior to alcohol ingestion in the morning. These results do not support any clinically meaningful effect of H2-antagonists on alcohol absorption following ingestion of a moderate dose of ethanol.

Objective: To evaluate the safety, tolerability, and efficacy of milnacipran following a direct switch from duloxetine in fibromyalgia (FM) patients with inadequate response to duloxetine. Background Milnacipran and duloxetine are approved for the management of FM. As individual patient responses to analgesic medications differ, switching therapies to achieve greater benefit or avoid certain side effects is common. Design/Methods: Patients receiving duloxetine 60 mg/day for ≥4 weeks at screening were eligible. After 2 weeks of open-label duloxetine 60 mg/day, patients with VAS pain scores ≥40 (range, 0-100 mm) and dissatisfied with duloxetine were randomized 4:1 to milnacipran 100 mg/day (n=86) or placebo (n=21) for 10 weeks. The primary efficacy parameter was responder status based on Patient Global Impression of Change (PGIC), with responders defined as patients rating themselves “much improved” or “very much improved”. The secondary efficacy parameter was change from baseline in 1-week recall VAS pain score. Statistical analyses were descriptive and used LOCF to impute missing data. Results: In patients switched from duloxetine to milnacipran, 32.9% were PGIC responders and the mean decrease from baseline in VAS pain was 12.3 mm at the Week 10 visit (23.8% of placebo-treated patients were PGIC responders and the mean decrease in VAS pain was 1.3 mm). In a post hoc analysis, 34.2%, 29.1%, and 25.3% of patients switched to milnacipran had ≥30%, ≥40%, and ≥50% improvement in VAS pain scores, respectively. The most common (TEAEs) in patients switched to milnacipran were nausea (21%) and dizziness (15%); nausea and dizziness occurred in 29% and 5% of patients switched to placebo, respectively. Conclusions: These results suggest that FM patients with an inadequate response to duloxetine treatment may benefit from a switch to milnacipran for management of their symptoms. Additionally, a direct switch from duloxetine to milnacipran was safe and well tolerated in this study. Supported by: Forest Laboratories, Inc. Disclosure: Dr. Bateman has received personal compensation for activities with Forest Laboratories consultations and The Speakers Bureau as a consultant and/or speaker. Dr. Spera has received personal compensation for activities with Forest Research Institute as an employee. Dr. Palmer has received personal compensation for activities with Forest Laboratories, Inc. as an employee. Dr. Trugman has received personal compensation for activities with Forest Laboratories as an employee. Dr. Thacker has received personal compensation for activities with Forest Laboratories, Inc. as and employee. Dr. Lin has received personal compensation for activities with Forest Research Institute as an employee.