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Three phase 2 trials were conducted to assess the efficacy and long-term safety of weight-based memantine extended release (ER) treatment in children with autism spectrum disorder. MEM-MD-91, a 50-week open-label trial, identified memantine extended-release treatment responders for enrollment into MEM-MD-68, a 12-week randomized, double-blind, placebo-controlled withdrawal trial. MEM-MD-69 was an open-label extension trial in which participants from MEM-MD-68, MEM-MD-91, and open-label trial MEM-MD-67 were treated ⩽48 weeks with memantine extended release. In MEM-MD-91, 517 (59.6%) participants were confirmed Social Responsiveness Scale responders at week 12; mean Social Responsiveness Scale total raw scores improved two to three times a minimal clinically important difference of 10 points. In MEM-MD-68, there was no difference between memantine and placebo on the primary efficacy parameter, the proportion of patients with a loss of therapeutic response (defined as ⩾10-point increase from baseline in Social Responsiveness Scale total raw score). MEM-MD-69 exploratory analyses revealed mean standard deviation improvement in Social Responsiveness Scale total raw score of 32.4 (26.4) from baseline of the first lead-in study. No new safety concerns were evident. While the a priori–defined efficacy results of the double-blind trial were not achieved, the considerable improvements in mean Social Responsiveness Scale scores from baseline in the open-label trials were presumed to be clinically important.

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.

To characterize milnacipran effects on systolic blood pressure (SBP), diastolic blood pressure (DBP), and heart rate (HR) in fibromyalgia patients using 24-hour ambulatory blood pressure monitoring (ABPM).This dose-escalation study included a 7-week double-blind treatment period and 2-week single-blind discontinuation period. Patients were randomized 2:1 to milnacipran (n = 210) or placebo (n = 111), with 50% of patients classified as 'hypertensive' at baseline (SBP ≥130 mmHg, DBP ≥85 mmHg, or current antihypertensive medication). Analyses were conducted at Weeks 4 and 7, after milnacipran dosages were escalated to 100 and 200 mg/day, respectively. Outcome measures included changes from baseline in mean ambulatory SBP, DBP, and heart rate for the 12-hour periods following the morning dose (post-AM dose) or evening dose (post-PM dose), and the entire 24-hour monitoring period. Primary outcome parameter was change from baseline in mean SBP for the 12-hour period post-AM dose. Safety analyses included adverse events and sitting vital sign readings taken at study visits.Milnacipran increased ABPM vital signs at Week 4 (100 mg/day) and Week 7 (200 mg/day). Increases in the 12-hour period post-AM dose were similar at Weeks 4 and 7 (both visits: SBP and DBP, 4 to 5 mmHg; HR, 13 to 14 bpm). Mean increases in ambulatory vital signs were generally comparable between hypertensive and normotensive patients over 24-hour periods. Normal patterns of diurnal variation in blood pressure and heart rate were maintained in patients receiving milnacipran. Sitting vital signs were consistent with ABPM findings. Nausea was the most common adverse event observed with milnacipran.Fibromyalgia patients receiving milnacipran in this ABPM study had mean increases in blood pressure and heart rate that were consistent with those observed in clinical efficacy trials. Diurnal variation was preserved and changes were not greater in hypertensive patients than in non-hypertensive patients. These findings cannot necessarily be generalized to other patient populations.This study was registered on clinicaltrials.gov (ID: NCT00618956).

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.

Lesley M Arnold,1 Robert H Palmer,2 Michael R Hufford,3 Wei Chen21Department of Psychiatry and Behavioral Neuroscience, University of Cincinnati College of Medicine, Cincinnati, OH, 2Medical Affairs, Forest Research Institute Inc, Jersey City, NJ, 3Clinical Development, Cypress Bioscience Inc, San Diego, CA, USABackground: The purpose of this study was to evaluate the effects of milnacipran on body weight in patients with fibromyalgia.Methods: Analyses were conducted in the following groups: patients from three double-blind, placebo-controlled milnacipran trials (3 months, n = 2096; 6 months, n = 1008); 354 patients receiving milnacipran in placebo-controlled trials and double-blind extension studies (total ≥ 12 months of treatment); and 1227 patients in a long-term (up to 3.25 years) open-label milnacipran study.Results: In placebo-controlled trials, 77% of patients were overweight or obese at baseline (body mass index ≥ 25 kg/m2). Mean weight loss was found with milnacipran at 3 months (100 mg/day, —1.14 kg; 200 mg/day, —0.97 kg; placebo, —0.06 kg; P > 0.001) and 6 months (100 mg/day, -1.01 kg; 200 mg/day, -0.71 kg; placebo, —0.04 kg; P > 0.05). Approximately twice as many milnacipran-treated patients had ≥5% weight loss from baseline compared with placebo (3 and 6 months, P > 0.01). In extension studies, mean weight loss in patients receiving ≥12 months of milnacipran was —1.06 kg. In patients receiving ≥3 years of treatment in the open-label study, mean changes at 12, 24, 30, and 36–38 months were —1.16, —0.76, —0.19, and +0.11 kg, respectively. Among milnacipran-treated patients, rates of nausea (the most common adverse event) were lower among patients who lost weight than among those who did not (3 months, P = 0.02).Conclusion: The majority of patients with fibromyalgia in the milnacipran studies were overweight or obese. Milnacipran was associated with mean weight loss at 3 and 6 months (P < 0.05 versus placebo) and at 12 and 24 months of treatment, with mean changes drifting back to baseline at 30 months (−0.19 kg) and 36–38 months (+0.11 kg, no placebo comparison).Keywords: fibromyalgia, milnacipran, body weight

Milnacipran has been shown to significantly improve the pain, global well-being, and physical function of fibromyalgia (FM), and is approved by the U.S. Food and Drug Administration for the management of this disorder. Post hoc analyses of data from two pivotal trials were conducted to further assess the clinical benefits of milnacipran, to determine the impact of baseline pain severity on treatment outcomes, and to confirm the safety and tolerability of this medication in patients with FM. Patients in these trials were randomized to placebo (n=624), milnacipran 100 mg/day (n=623), or milnacipran 200 mg/day (n=837). Two different composite responder analyses were used to evaluate efficacy: a 2-measure analysis, requiring ≥30% improvement from baseline visual analog scale 24-hour recall pain scores and a Patient Global Impression of Change (PGIC) score of "very much improved" or "much improved"; and a 3-measure analysis, requiring a ≥6-point improvement from baseline in SF-36 Physical Component Summary scores in addition to the pain and PGIC criteria. Additionally, a pooled analysis of mean changes from baseline pain scores was conducted in order to evaluate the efficacy of milnacipran over the entire course of treatment. At 3 months, composite responder rates were significantly higher in the milnacipran treatment groups than in the placebo group (2- and 3-measure composite responder analyses: P ≤ 0.001, both doses vs. placebo). These improvements were not dependent on baseline pain severity. Similar composite responder results were observed in patients who continued treatment for up to 6 months. Significant improvements in mean pain scores were seen with both doses of milnacipran vs. placebo as early as 1 week after treatment initiation and were sustained for up to 6 months of milnacipran treatment. The most common adverse events associated with milnacipran were nausea, headache, and constipation.

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.

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.

SUMMARY A theoretical basis for similar recurrence rates among H2-receptor antagonists exists based on recent concepts of ulcer recurrence, ulcer healing and suppression of nocturnal gastric acidity. In order to compare H2-receptor antagonists in the maintenance therapy of duodenal ulcer, a meta-analysis was carried out using 29 studies in the literature that met strict criteria. When the results of the placebo-controlled studies were expressed as odds ratios, a technique used to minimize differences in protocol design and patient populations among studies, cimetidine, ranitidine, famotidine and nizatidine were all found to be superior to placebo to approximately the same extent. Odds ratios (and 95% confidence limits) for the recurrences in the pooled studies were cimetidine 0.22 (0.18–0.28), ranitidine 0.23 (0.18–0.30), famotidine 0.28–0.31 and nizatidine 0.36. These reflected similar 1-year recurrence rates of 24.9% (n= 530) for 400 mg cimetidine nocte, 22.4 (n= 508) for 150 mg ranitidine nocte, 28.0% (n= 371) for 20 mg or 40 mg famotidine nocte, and 21.8% (n= 261) for 150 mg nizatidine nocte. In studies to compare cimetidine and ranitidine directly, the odds ratio (and 95% confidence limits) was 0.64 (0.48–0.86). However, for two studies done by a single protocol, the odds ratio of 0.51 (0.35–0.75) tended todiffer from the odds ratio of 0.85 (0.54-1.33) for six other studies (P = 0.09). These reflected recurrence rates for cimetidine and ranitidine of 28.3% and 16.8% (two studies) and 23.3% and 20.6% (six studies) respectively.

Background There are no approved medications for juvenile fibromyalgia (JFM), a disorder that is often under-diagnosed. The effects of milnacipran, a drug approved for the management of fibromyalgia (FM) in adults, was assessed in a clinical trial program for JFM. Methods Patients, ages 13–17 years who met the Yunus and Masi criteria for JFM and/or 1990 American College of Rheumatology criteria for FM, were enrolled in a responder-enriched, randomized withdrawal trial. After receiving open-label milnacipran (8 weeks), patients with ≥50 % improvement in pain underwent double-blind randomization (1:2) to either placebo or continuing treatment with milnacipran (8 weeks). All patients, including those who did not meet the randomization criteria for double-blind withdrawal, were allowed to enter an extension study with open-label milnacipran (up to 52 weeks). The primary endpoint was loss of therapeutic response (LTR) during the double-blind period. Additional outcome measures included the Patient Global Impression of Severity (PGIS), Pediatric Quality of Life Inventory (PedsQL: Generic Core Scales, Multidimensional Fatigue Scale), and Multidimensional Anxiety Scale for Children (MASC). Safety assessments included adverse events (AEs), vital signs, electrocardiograms, and laboratory tests. Results The milnacipran program was terminated early due to low enrollment. Because only 20 patients were randomized into the double-blind withdrawal period, statistical analyses were not conducted for the LTR endpoint. However, 116 patients entered the open-label period of the initial study and 57 participated in the open-label extension study. Their experience provides preliminary information about the use of milnacipran in JFM patients. During both open-label periods, there were mean improvements in pain severity, PGIC, PedsQL, and MASC scores. No unexpected safety issues were detected. The most commonly reported treatment-emergent AEs were nausea, headache, vomiting, and dizziness. Mean increases in heart rate and blood pressure were observed, and were consistent with the AE profile in adults with FM. Conclusions The open-label findings provide preliminary evidence that milnacipran may improve symptoms of JFM, with a safety and tolerability profile that is consistent with the experience in adult FM patients. Future trial designs for JFM should consider the relatively low recognition of this condition compared to adult FM and the difficulties with enrollment. Trial registration NCT01328002; NCT01331109 Electronic supplementary material The online version of this article (doi:10.1186/s12969-015-0025-9) contains supplementary material, which is available to authorized users.

BACKGROUND Fatigue is a core symptom in fibromyalgia that can negatively affect a patient's quality of life. OBJECTIVE The objective of this study was to analyze fatigue-related data from 3 randomized, placebo-controlled trials of milnacipran (n = 3109) in fibromyalgia patients. METHODS Fatigue was assessed with the Multidimensional Fatigue Inventory (MFI). Treatment effects were evaluated by changes in MFI total scores and identifying patients with improvement of 30% or greater from baseline. Path analyses were conducted to evaluate direct and indirect effects of treatment on fatigue. RESULTS Patients had high levels of baseline fatigue; mean MFI total score was 68.1 (of 100). After 3 months of stable-dose treatment, patients receiving milnacipran 100 and/or 200 mg/d had significant improvement in MFI total and subscale scores (P < 0.05 vs placebo). The largest treatment effect was found in patients with equal to or greater than 20% to 40% fatigue improvement. Significantly more patients met the threshold of 30% or greater with milnacipran (100 mg/d, 17.6%; 200 mg/d, 15.2%) than with placebo (9.9%); odds ratios for this responder status were 1.93 and 1.63, respectively (P < 0.05 for both doses). Path analyses indicated that up to 28% of fatigue improvement may be attributed to direct milnacipran effects (ie, not indirectly through effects on pain or other symptoms). CONCLUSIONS Fibromyalgia patients in the milnacipran studies had high levels of baseline fatigue. Patients receiving milnacipran had statistically significant and clinically meaningful reductions in fatigue that were not completely attributable to indirect treatment effects through pain reduction. Evaluating and managing fatigue are an important clinical concern when treating patients with fibromyalgia.

Objective: The objective of this study was to investigate the renal effects of celecoxib, a cyclooxygenase-2 (COX-2) specific nonsteroidal anti-inflammatory drug (NSAID). Subjects and treatment: Six volume-depleted, conscious, chronically instrumented dogs received four treatments using a cross-over design, with at least 13 days between treatments. An i.v. bolus dose (3, 10, and 30 μmol/kg) of vehicle, indomethacin, celecoxib, or 6-MNA, the active metabolite of nabumetone, were administered with an hour between doses. Methods: Renal function was assessed at baseline and 30 min after each dose. Results: Treatment with indomethacin or celecoxib resulted in a dose-dependent reduction in renal plasma flow (RPF), glomerular filtration rate (GFR), urine flow, sodium excretion, and fractional sodium excretion. GFR was reduced by 27% with 30 μmol/kg indomethacin (p < 0.05) and by 58% with 30 μmol/kg celecoxib (p < 0.5). Similarly, RPF was significantly (p < 0.05) reduced by 33% and 65% with 30 μmol/kg indomethacin and celecoxib, respectively. Reductions in renal function with celecoxib occurred at a therapeutic index (determined by comparison anti-edemic activities of the drugs in rat paw carrageenan assays) equal to or lower than indomethacin. In contrast, treatment with vehicle or 6-MNA resulted in no reductions in renal function. Conclusion: Administration of either celecoxib (specific COX-2 inhibitor) or indomethacin (selective COX-1 inhibitor) resulted in significant reductions in renal function. COX-2 specific inhibitors do not appear to lack the renal effects of NSAIDs.

The purpose of this study was to compare the tolerability and efficacy of nabumetone and naproxen in the treatment of patients with rheumatoid arthritis (RA). The occurrence of gastrointestinal (GI) adverse events was compared.Nonsteroidal anti-inflammatory drugs (NSAIDs) have similar efficacy at equipotent doses, but the therapeutic response to various NSAIDs often differs in individual patients.This was a 3-month, randomized, double-blind, multicenter, parallel-group study conducted in adult patients with RA. The study had 2 phases: a 3- to 14-day washout period and a 12-week treatment period. During the treatment phase, the tolerability and efficacy of nabumetone 2000 mg/d were compared with those of naproxen 1000 mg/d. The change from baseline in efficacy variables, including global assessments, number of tender or swollen joints, and pain, was evaluated. The study was sized to provide an 80% power to detect a 15% difference in the percentage improvement on the physician's global assessment (alpha = 0.05). GI safety was assessed by monitoring the occurrence of clinically important adverse GI events.A total of 346 RA patients at 31 US rheumatology centers were randomly assigned to treatment (173 patients per group). The study population was predominantly white (87.0%) and female (70.5%), with a mean age of 54 years. Both treatments improved the signs and symptoms of RA, with no statistically significant differences between groups for any efficacy variables. No serious GI adverse events occurred with either NSAID. The most frequent treatment-related adverse events in both groups were predominantly GI in origin, as were those that resulted in withdrawal from the study. Diarrhea with lower abdominal pain was the most common adverse event in the nabumetone group; upper abdominal pain was the most common adverse event in the naproxen group. The only significant difference between the 2 groups was a higher incidence of diarrhea (P0.01) in patients receiving nabumetone.Nabumetone 2000 mg/d was as effective as naproxen 1000 mg/d in relieving the signs and symptoms of RA. In this study, no serious GI adverse events were observed with either NSAID, but nabumetone was associated with a higher incidence of diarrhea.

Lucinda Bateman,1 Robert H Palmer,2 Joel M Trugman,2 Yuhua Lin2 1Fatigue Consultation Clinic, Salt Lake City, UT, 2Forest Research Institute, Jersey City, NJ, USA Background: The purpose of this study was to evaluate the safety, tolerability, and efficacy of milnacipran following a direct switch from duloxetine in fibromyalgia patients experiencing inadequate clinical response to duloxetine after receiving treatment for 6 weeks or longer. Methods: This exploratory study included 107 patients with fibromyalgia who had been treated with duloxetine 60 mg/day for at least 4 weeks prior to enrollment. Following a 2-week open-label period on duloxetine, patients who had visual analog scale pain scores ≥ 40 and were dissatisfied with current treatment were randomized 4:1 to milnacipran 100 mg/day (n = 86) or placebo (n = 21) for 10 weeks of double-blind treatment. The small placebo group was included solely to blind the study and minimize expectation bias among patients and investigators, and there was no preplanned statistical comparison between treatment groups. The primary efficacy parameter was the percentage of patients rating themselves as “much improved” or “very much improved” on the Patient Global Impression of Change (PGIC) at the final visit. Other efficacy parameters included changes in one-week recall visual analog scale pain, Fibromyalgia Impact Questionnaire Revised (FIQR), and Multiple Ability Self-Report Questionnaire (MASQ). Results: Of patients switched to milnacipran, 32.9% were classified as PGIC responders, and they also demonstrated improvement in visual analog scale pain, FIQR total, and MASQ total scores (mean changes from baseline were −12.3, −7.77, and −2.39, respectively). Nausea and dizziness were the most common treatment-emergent adverse events in patients switched to milnacipran, reported in 21% and 15%, respectively, of patients in this group. Conclusion: Results from this exploratory study suggest that switching from duloxetine to milnacipran may be beneficial in some patients with fibromyalgia who have an inadequate response to duloxetine. Further research investigating the efficacy and safety of switching fibromyalgia therapies is warranted. Keywords: fibromyalgia, milnacipran, duloxetine, switch

Milnacipran, a serotonin and norepinephrine reuptake inhibitor with preferential inhibition of norepinephrine reuptake over serotonin, is approved in the United States for the management of fibromyalgia. Owing to its effects on norepinephrine and serotonin, as well as its lack of activity at other receptor systems, it was hypothesized that milnacipran would provide improvements in pain and other fibromyalgia symptoms without some of the unpleasant side effects associated with other medications historically used for treating fibromyalgia. The clinical safety and efficacy of milnacipran 100 and 200 mg/day in individuals with fibromyalgia has been investigated in four large, randomized, double-blind, placebo-controlled studies and three long-term extension studies. The clinical studies used composite responder analyses to identify the proportion of individual patients reporting simultaneous and clinically significant improvements in pain, global status, and physical function, in addition to assessing improvement in various symptom domains such as fatigue and dyscognition. In the clinical studies, patients receiving milnacipran reported significant improvements in pain and other symptoms for up to 15 months of treatment. Most adverse events were mild to moderate in severity and were related to the intrinsic pharmacologic properties of the drug. Long-term exposure to milnacipran did not result in any new safety concerns. As with other serotonin and norepinephrine reuptake inhibitors, increases in heart rate and blood pressure have been observed in some patients with milnacipran treatment.

To examine the effects of abruptly withdrawing milnacipran during the 2-week discontinuation phase of a study in which FM patients had received 12 weeks of stable-dose treatment with milnacipran at 100 mg/day.The effects of withdrawing milnacipran were evaluated prospectively over a 2-week period (Weeks 12 to 14) using a randomized, placebo-controlled withdrawal design. Patients who had originally received milnacipran 100 mg/d for 12 weeks were re-randomized to continue milnacipran (n = 178) or switch directly to placebo (n = 178); patients originally receiving placebo continued placebo (n = 359).Clinicalstrials.gov (NCT00314249).Loss of efficacy was evaluated by mean changes in pain and functional measures and by percentage of composite responders, defined as patients with simultaneous improvements in pain, global status, and physical functioning. Newly emergent adverse events and changes in vital signs were also recorded.Within 2 weeks,patients switched from milnacipran to placebo had greater mean worsening in pain, functioning, and global status measures when compared with patients continuing treatment. In addition, significantly fewer composite responders were found in patients who discontinued active treatment than in patients who continued receiving milnacipran (22.0% vs 32.3%, p 0.05). Incidences of newly emergent adverse events were 16.3% and 18.0% in patients discontinuing and continuing treatment, respectively. Mean vital sign changes decreased or returned to baseline within 2 weeks of discontinuation.Patients discontinuing milnacipran experienced worsening in multiple efficacy parameters within 2 weeks. Vital sign changes observed with milnacipran during the 12-week stable-dose period decreased or returned to baseline values within 2 weeks after discontinuation of treatment. No new safety concerns were found during this discontinuation period with milnacipran.

Patients with fibromyalgia often experience depressive symptoms in addition to chronic pain and other characteristic symptoms associated with this disorder.To examine the relationships among pain, depressive symptoms, and global status in a clinical trial of milnacipran for fibromyalgia.Data from a randomized, double-blind study (milnacipran 100 mg/d, n = 516; placebo, n = 509) were analyzed. Treatment outcomes included quantitative changes in pain and Beck depression inventory (BDI) scores, mean Patient Global Impression of Change (PGIC) scores, and three responder endpoints: patients with ≥30% pain improvement, PGIC score ≤2, and patients meeting both pain and PGIC responder criteria (2-measure composite responders). Correlations and path analyses were conducted to evaluate relationships among improvements in depressive symptoms, pain, and PGIC.Patients receiving milnacipran had greater decreases in mean pain scores, lower mean PGIC endpoint scores, and higher responder rates regardless of baseline severity of depressive symptoms. The highest responder rates were found in patients with greater than four-point improvement in BDI scores (milnacipran vs. placebo: pain, 57.5% vs. 39.0%; PGIC, 60.1% vs. 38.2%; 2-measure composite, 49.0% vs. 27.9%; all p0.01), although significant differences between treatment groups were also found in patients with no improvement or worsening of depressive symptoms. Correlations between changes in BDI and changes in pain or PGIC were low (r ≤ 0.3). Path analyses indicated 87.2% of pain reduction to be a direct effect of milnacipran treatment.Symptom improvements with milnacipran were only weakly associated with baseline depressive symptoms and were largely independent of improvements in depressive symptomatology.

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.

Milnacipran has been shown to significantly improve the pain, global well-being, and physical function of fibromyalgia (FM), and is approved by the U.S. Food and Drug Administration for the management of this disorder. Post hoc analyses of data from two pivotal trials were conducted to further assess the clinical benefits of milnacipran, to determine the impact of baseline pain severity on treatment outcomes, and to confirm the safety and tolerability of this medication in patients with FM. Patients in these trials were randomized to placebo (n=624), milnacipran 100 mg/day (n=623), or milnacipran 200 mg/day (n=837). Two different composite responder analyses were used to evaluate efficacy: a 2-measure analysis, requiring ≥30% improvement from baseline visual analog scale 24-hour recall pain scores and a Patient Global Impression of Change (PGIC) score of "very much improved" or "much improved"; and a 3-measure analysis, requiring a ≥6-point improvement from baseline in SF-36 Physical Component Summary scores in addition to the pain and PGIC criteria. Additionally, a pooled analysis of mean changes from baseline pain scores was conducted in order to evaluate the efficacy of milnacipran over the entire course of treatment. At 3 months, composite responder rates were significantly higher in the milnacipran treatment groups than in the placebo group (2- and 3-measure composite responder analyses: P ≤ 0.001, both doses vs. placebo). These improvements were not dependent on baseline pain severity. Similar composite responder results were observed in patients who continued treatment for up to 6 months. Significant improvements in mean pain scores were seen with both doses of milnacipran vs. placebo as early as 1 week after treatment initiation and were sustained for up to 6 months of milnacipran treatment. The most common adverse events associated with milnacipran were nausea, headache, and constipation.

Milnacipran is approved for management of fibromyalgia in the United States. In this double-blind, placebo- and active drug-controlled study (N = 100), effects of supratherapeutic doses of milnacipran on cardiac repolarization were evaluated in healthy volunteers. The primary outcome was the largest mean difference between milnacipran and placebo in time-matched baseline-adjusted QT interval corrected for heart rate using an individual correction formula (QTcNi). In addition, data were analyzed using the Fridericia formula (QTcF) and a post hoc piecewise QTcNi analysis based on a dichotomous cut of RR interval data at 800 ms. Moxifloxacin (400 mg single dose) was used to establish assay sensitivity. Using the QTcNi method, the largest difference in baseline-adjusted QTcNi between milnacipran 300 mg bid and placebo was -4.7 ms (90% confidence interval [CI]: -9.4 to -0.1), indicating no QT prolongation. Analysis using the Fridericia formula (QTcF) showed a maximum adjusted mean change of +7.7 ms, but QTcF versus RR interval plots indicated overcorrection with this method. The piecewise QTcNi correction method demonstrated a more accurate correction for drug-induced heart rate increase; mean baseline-adjusted between-group difference was +0.9 ms (90% CI: -6.6 to 8.3). The results suggest that milnacipran would not significantly affect cardiac repolarization at clinically relevant therapeutic and supratherapeutic concentrations.

Objective. To evaluate the durability of improvement and long-term efficacy of milnacipran treatment in fibromyalgia, to assess efficacy in patients re-randomized from placebo to milnacipran, and to collect additional information on the tolerability and efficacy of long-term treatment with milnacipran. Design. A total of 449 patients who successfully completed a 6-month lead-in study enrolled in this 6-month extension study (87.7% of eligible subjects). Patients initially receiving milnacipran 200 mg/day during the lead-in study were maintained at 200 mg/day (n = 209); patients initially assigned to placebo or milnacipran 100 mg/day were re-randomized (1:4) to either 100 mg/day (n = 48) or 200 mg/day (n = 192) of milnacipran for an additional 6 months of treatment. Efficacy assessments included visual analog scale pain ratings, Fibromyalgia Impact Questionnaire (FIQ) total score, and Patient Global Impression of Change (PGIC). Results. Patients continuing on milnacipran demonstrated a sustained reduction in pain over the full 12-month period. Additional beneficial effects were also maintained, as indicated by the PGIC and FIQ. Patients initially assigned to either placebo or milnacipran 100 mg/day in the lead-in study and subsequently re-randomized to milnacipran 200 mg/day in the extension study experienced further improvements in their mean pain scores, FIQ total scores, and PGIC ratings at 1 year. Milnacipran treatment was generally well tolerated. The most commonly reported newly emergent adverse event was nausea. Conclusions. In addition to confirming that milnacipran safely and effectively improves the multiple symptoms of fibromyalgia, these data indicate that milnacipran provides 1-year durable efficacy in this patient population.

Objective.To evaluate the safety and efficacy of milnacipran, a dual norepinephrine and serotonin reuptake inhibitor, in the treatment of fibromyalgia (FM).Methods.A 27-week, randomized, double-blind, multicenter study compared milnacipran 100 and 200 mg/day with placebo in the treatment of 888 patients with FM. Two composite responder definitions were used to classify each patient’s individual response to therapy. “FM responders” concurrently satisfied response criteria for improvements in pain (visual analog scale 24-h morning recall), patient global impression of change (PGIC), and physical functioning (SF-36 Physical Component Summary); while “FM pain responders” concurrently satisfied response criteria for improvements in pain and PGIC.Results.At the primary endpoint, after 3-month stable dose treatment, a significantly higher percentage of milnacipran-treated patients met criteria as FM responders versus placebo (milnacipran 200 mg/day, p = 0.017; milnacipran 100 mg/day, p = 0.028). A significantly higher percentage of patients treated with milnacipran 200 mg/day also met criteria as FM pain responders versus placebo (p = 0.032). Significant pain reductions were observed after Week 1 with both milnacipran doses. At 15 weeks, milnacipran 200 mg/day led to significant improvements over placebo in pain (realtime, daily and weekly recall; all measures, p < 0.05), PGIC (p < 0.001), fatigue (p = 0.016), cognition (p = 0.025), and multiple SF-36 domains. Milnacipran was safe and well tolerated by the majority of patients during 27 weeks of treatment; nausea and headache were the most common adverse events.Conclusion.Milnacipran is safe and effective for the treatment of multiple symptoms of FM.

Background: Preclinical and clinical studies have suggested that milnacipran, a dual norepinephrine-serotonin reuptake inhibitor, may be efficacious in the treatment of fibromyalgia (FM). Objective: This study was conducted to evaluate the efficacy and tolerability of milnacipran in treating the multiple domains of FM. Methods: This was a multicenter, double-blind, placebo-controlled trial. Adult patients (age 18–70 years) who met 1990 American College of Rheumatology criteria for FM were randomized to receive milnacipran 100 mg/d, milnacipran 200 mg/d, or placebo for 15 weeks. Because this was a pivotal registration trial, the primary end points were chosen to investigate efficacy for 2 potential indications: the treatment of FM and the treatment of FM pain. Thus, the 2 primary efficacy end points were rates of FM composite responders and FM pain composite responders. FM composite responders were defined as patients concurrently experiencing clinically meaningful improvements in the following 3 domain criteria: pain (≥30% improvement, as recorded in an electronic diary); patients' global status (a rating of very much improved or much improved on the Patient Global Impression of Change [PGIC] scale); and physical function (a ≥6-point improvement on the 36-item Short-Form Health Survey [SF-36] Physical Component Summary score). FM pain composite responders were defined as those who met the pain and PGIC criteria. Adverse events reported by patients or observed by investigators were recorded throughout the trial. Results: Of 2270 patients screened, 1196 were randomized to receive milnacipran 100 mg/d (n = 399), milnacipran 200 mg/d (n = 396), or placebo (n = 401). The majority of patients were female (96.2%) and white (93.5%). The population had a mean age of 50.2 years, a mean baseline weight of 180.8 pounds, and a mean baseline body mass index of 30.6 kg/m 2 . Compared with placebo, significantly greater proportions of milnacipran-treated patients were FM composite responders (100 mg/d: P = 0.01; 200 mg/d: P = 0.02) and FM pain composite responders (100 mg/d: P = 0.03; 200 mg/d: P = 0.004). Milnacipran was associated with significant improvements in pain after 1 week of treatment (100 mg/d: P = 0.004; 200 mg/d: P = 0.04), as well as significant improvements in multiple secondary efficacy end points, including global status (PGIC: P P P = 0.02), and fatigue (Multidimensional Fatigue Inventory— 100 mg/d: P = 0.04). The most commonly reported adverse events with milnacipran were nausea (100 mg/d, 34.3%; 200 mg/d, 37.6%), headache (18.0% and 17.7%, respectively), and constipation (14.3% and 17.9%). Adverse events resulted in premature study discontinuation in 19.5% and 23.7% of those who received milnacipran 100 and 200 mg/d, respectively, compared with 9.5% of placebo recipients. Conclusion: In these adult patients with FM, both doses of milnacipran (100 and 200 mg/d) were associated with significant improvements in pain and other symptoms. Clinical Trials Identification Number: NCT00098124.

To compare the efficacy and tolerability of clarithromycin extended-release (ER) to amoxicillin/ clavulanate in patients diagnosed with acute bacterial sinusitis.In a controlled, multicenter, investigator-blinded study, 437 ambulatory patients at least 12 years old with signs/symptoms and radiographic findings of acute sinusitis were randomized to receive clarithromycin ER 1000 mg once daily or amoxicillin/ clavulanate 875 mg/l25 mg twice daily for 14 days.Clinical and bacteriological response rates were determined at a test-of-cure visit, which was conducted up to 10 days following the completion of treatment. Radiological response was assessed at a follow-up visit.The clinical cure rate in clinically evaluable patients was 98% (184/188) in the clarithromycin ER group and 97% (179/185) in the amoxicillin/clavulanate group (95% CI for the difference in rates [-2.4%, 4.7%]). Clinical cure was sustained at the follow-up visit (96% for each treatment group). The pathogen eradication rates were 94% (61/65) in the clarithromycin ER group and 98% (61/62) in the amoxicillin/clavulanate group (95% CI for difference in rates [-12.0%, 2.9%]). The radiological success rate was 94% (172/183) in both the clarithromycin ER and amoxicillin/clavulanate groups (95% CI for difference in rates [-4.9%, 4.9%]). Symptomatic improvement or relief was observed as early as 2 days-5 days after the initiation of study drug, with a statistically significantly higher resolution rate of sinus pressure (p = 0.027) and improvement/resolution rate of nasal congestion (p = 0.035) during treatment with clarithromycin ER. The resolution/improvement rate at the test-of-cure visit for each treatment group wasor = 94% for the primary acute sinusitis signs/symptoms, with a statistically significantly higher resolution/improvement rate of purulent nasal discharge with clarithromycin ER (p = 0.010). Both study drugs had a positive and rapid impact on quality of life. Patients reported a high level of satisfaction and probability of using either study antibiotic again, and health care resource use was low, with slightly fewer sinusitis-related physician and outpatient visits required by patients in the clarithromycin ER group (p = 0.055). The treatment groups were comparable with respect to incidence of drug-related adverse events.In this multinational population of patients with acute bacterial sinusitis, clarithromycin ER was comparable, and for selected measures superior, to amoxicillin/clavulanate based on clinical, bacteriological, and radiological responses as well as quality of life measures, satisfaction with antibiotic therapy, and health care resource utilization.

The objective of this study was to compare the efficacy, tolerability, and safety of two clarithromycin regimens, extended-release (ER) 1000 mg once daily for 5 days and immediate-release (IR) 500 mg twice daily for 7 days, in the treatment of acute bacterial exacerbation of chronic bronchitis (ABECB).This was a double-blind, randomized, parallel-group, multicenter study of ambulatory patients at least 40 years old with a presumptive diagnosis of ABECB, purulent sputum, and documented evidence of chronic obstructive pulmonary disease (COPD), including forced expiratory volume in one second (FEV(1))70% of predicted value. Clinical cure, bacteriological cure, and target pathogen eradication rates were determined at a test-of-cure visit (study days 14-40). Safety was assessed based on the incidence of study drug-related adverse events.A total of 485 patients were randomized (240 to ER and 245 to IR). Clinical cure rates were similar for evaluable patients treated with ER (84%, 157/187) and those treated with IR (84%, 172/204) (95% CI -7.9, 7.2). The bacteriological cure rates were 87% (82/94) and 89% (91/102), and the overall target pathogen eradication rates were 88% (107/122) and 89% (117/131) for the respective treatment groups. The incidence of adverse events was 13% (31/240) in the ER group and 18% (45/245) in the IR group. The rate of gastrointestinal adverse events was lower with ER (8%, 19/240) compared to IR (11%, 26/245). Clarithromycin ER-treated patients reported statistically significantly fewer adverse events due to abnormal taste than did clarithromycin IR-treated patients (3% and 8%, respectively, p = 0.012).Both once-daily, 5-day, short-course therapy with clarithromycin ER and 7-day, twice-daily therapy with clarithromycin IR were effective in resolving clinical signs/symptoms of ABECB and eradicating the causative pathogens, with no statistically significant difference in clinical cure rate between the treatment groups. Clarithromycin ER was better tolerated, causing fewer gastrointestinal adverse events and statistically significantly fewer reports of abnormal taste as compared with clarithromycin IR.

Philip J Mease,1 Daniel J Clauw,2 Joel M Trugman,3 Robert H Palmer,3 Yong Wang3 1Swedish Medical Center and University of Washington, Seattle, WA, USA; 2Chronic Pain and Fatigue Research Center, University of Michigan Health System, Ann Arbor, MI, USA; 3Forest Research Institute, Jersey City, NJ, USA Background: Fibromyalgia patients from a long-term, open-label study of milnacipran (50–200 mg/day) were eligible to participate in a 12-week, randomized, placebo-controlled withdrawal study. The withdrawal study evaluated loss of therapeutic response in patients who achieved ≥50% pain improvements after receiving up to 3.25 years of milnacipran. This post-hoc analysis investigated whether patients who met lower thresholds of pain improvement also experienced worsening of fibromyalgia symptoms upon treatment withdrawal. Method: Among patients who received milnacipran ≥100 mg/day during the long-term study, three subgroups were identified based on percentage of pain reduction at randomization: ≥50% (protocol-defined "responders"; n=150); ≥30% to

Goals: To evaluate the efficacy and gastrointestinal safety of nabumetone and diclofenac in the treatment of elderly patients with osteoarthritis, participating in a 3-month efficacy trial. Background: Elderly patients have an elevated risk for developing gastrointestinal complications with chronic use of nonsteroidal anti-inflammatory drugs. Study: This was a randomized, double-blind, parallel-group, multicenter study with a 3- to 14-day placebo washout period and a 12-week active treatment phase. Patients 65 years or older with moderate-to-severe osteoarthritis of the knee or hip were randomized to receive 1,000 to 2,000 mg/d of nabumetone or 100 to 150 mg/d of diclofenac. The primary efficacy parameters were the percent of patients improved using a Patients' and Physicians' Global Assessment at endpoint. Gastrointestinal safety was assessed by the incidence of gastrointestinal symptoms and adverse events. Results: Three hundred thirty-five patients (mean age = 72 years) with active osteoarthritis were enrolled. There were no statistically significant differences between the two treatment groups in any of the primary efficacy variables. However, differences between the groups were apparent in the frequency of adverse gastrointestinal events. Two patients in the diclofenac group had evidence of gastrointestinal bleeding and/or ulcer compared with none in the nabumetone group. In addition, significantly more (p < 0.05) patients (4%) receiving diclofenac had alanine transaminase values more than twice the upper limit of normal at endpoint compared with patients receiving nabumetone (0%). Conclusions: Nabumetone was as effective as diclofenac in the treatment of elderly patients with moderate-to-severe osteoarthritis. However, the gastrointestinal safety profile of nabumetone was superior to that of diclofenac with respect to elevation of liver enzymes.

Background: Clarithromycin has an established bacteriologic efficacy and safety profile in the treatment of respiratory tract infections. Objective: This study compares the efficacy and tolerability of extended-release and immediate-release formulations of clarithromycin in patients with acute maxillary sinusitis. Methods: Fourteen days' treatment with once-daily clarithromycin was compared with the immediate-release, twice-daily formulation in a phase III, randomized, double-blind, parallel-group, multicenter study. Patients aged ≥12 years with signs, symptoms, and a radiologically confirmed diagnosis of acute maxillary sinusitis were eligible. Patients were assessed before treatment, within 48 hours after treatment, on study days 16 to 18, and at the test-of-cure visit on study days 24 to 31. Patients who received ≥1 dose of study drug were included in the safety analysis. Results: Of 283 patients treated, 245 were included in the efficacy analysis (122 in the extended-release group, 123 in the immediate-release group). Treatment groups were well matched with respect to demographic characteristics and medical condition and history. At the test-of-cure visit, 85% of patients in the clarithromycin extended-release group and 79% in the immediate-release group were deemed clinical cures; 89% and 91% in the extended-release and immediate-release groups, respectively, demonstrated radiographic success. Overall incidences of study drug-related adverse events were similar in the 2 treatment groups (32% in the extended-release group and 28% in the immediate-release group); however, significantly fewer patients receiving extended-release clarithromycin (2142 [1%]), compared with those receiving the immediate-release formulation (10141 [7%]; P = 0.02) discontinued therapy because of drug-related gastrointestinal symptoms or abnormal taste. No clinically meaningful changes in laboratory values or vital signs were observed during the study. Conclusion: Although the efficacy of the 2 formulations was comparable, once-daily clarithromycin extended-release was better tolerated than the twice-daily immediate-release formulation by patients with acute maxillary sinusitis.

We assessed the effects of nabumetone, sulindac, and placebo on renal function and renal excretion of vasodilatory prostaglandins in older female patients (age >50 years) with osteoarthritis and normal renal function. Using a prospective, crossover design, we compared the effects of nabumetone 2000 mg/d and sulindac 400 mg/d with placebo on glomerular filtration rate (GFR), renal plasma flow (RPF), and urinary excretion of prostaglandin E 2 and 6-keto-prostaglandin F 1α in 12 patients. Urinary excretion of vasodilatory prostaglandins was not decreased after 14 days of treatment with either nabumetone or sulindac. Likewise, treatment with nabumetone or sulindac did not significantly alter renal function compared with placebo. There were no differences in mean changes in GFR or RPF from baseline after treatment with nabumetone or sulindac compared with placebo. The mean (± SD) changes in GFR from baseline were 0% ± 8% in patients receiving nabumetone, −8% ± 15% in patients receiving sulindac, and −7% 5% in patients receiving placebo. The results of this study demonstrate that treatment with nabumetone or sulindac caused no deterioration in renal function in older female patients with osteoarthritis and normal renal function.

Introduction 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. 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). Methods After 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

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.