The efficacy and safety of milnacipran for treatment of fibromyalgia. a randomized, double-blind, placebo-controlled trial. Efficacy and safety of milnacipran 100 mg/day in patients with fibromyalgia: results of a randomized, double-blind, placebo-controlled trial. Milnacipran for the treatment of fibromyalgia in adults: a 15-week, multicenter, randomized, double-blind, placebo-controlled, multiple-dose clinical trial. A double-blind placebo-controlled trial of milnacipran in the treatment of fibromyalgia. A European multicenter randomized double-blind placebo-controlled monotherapy clinical trial of milnacipran in treatment of fibromyalgia. Controlled comparison of two doses of milnacipran (F 2207) and amitriptyline in major depressive inpatients. Interest of a loading dose of milnacipran in endogenous depressive inpatients. Comparison with the standard regimen and with fluvoxamine. A randomised, double-blind comparison of milnacipran and imipramine in the treatment of depression. Long-term efficacy and safety of milnacipran compared to clomipramine in patients with major depression.
To evaluate the safety and efficacy of milnacipran, a dual norepinephrine and serotonin reuptake inhibitor, in the treatment of fibromyalgia (FM).
                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.
                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.
                Milnacipran is safe and effective for the treatment of multiple symptoms of FM. To assess the efficacy and safety of milnacipran at a dosage of 100 mg/day (50 mg twice daily) for monotherapy treatment of fibromyalgia.
                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.
                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%).
                Milnacipran administered at a dosage of 100 mg/day improved pain, global status, fatigue, and physical and mental function in patients with fibromyalgia. Preclinical and clinical studies have suggested that milnacipran, a dual norepinephrine-serotonin reuptake inhibitor, may be efficacious in the treatment of fibromyalgia (FM).
                This study was conducted to evaluate the efficacy and tolerability of milnacipran in treating the multiple domains of FM.
                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 (> or = 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 > or = 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.
                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<0.001 for both doses), physical function (SF-36 physical functioning domain-100 mg/d: P < 0.001; 200 mg/d: 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.
                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. 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.
                2004 John Wiley & Sons, Ltd. This randomized, double-blind, placebo-controlled, multicenter study investigated the efficacy and safety of milnacipran in the treatment of fibromyalgia (FM) in a European population.
                Outpatients diagnosed with FM according to 1990 American College of Rheumatology criteria (N = 884) were randomized to placebo (n = 449) or milnacipran 200 mg/day (n = 435) for 17 weeks (4-week dose escalation, 12-week stable dose, 9-day down-titration), followed by a 2-week posttreatment period. The primary efficacy criterion was a 2-measure composite responder analysis requiring patients to achieve simultaneous improvements in pain (>or= 30% improvement from baseline in visual analog scale, 24-hour morning recall) and a rating of "very much" or "much" improved on the Patient Global Impression of Change scale. If responder analysis was positive, Fibromyalgia Impact Questionnaire (FIQ) was included as an additional key primary efficacy measure.
                At the end of the stable dose period (Week 16), milnacipran 200 mg/day showed significant improvements from baseline relative to placebo in the 2-measure composite responder criteria (p = 0.0003) and FIQ total score (p = 0.015). Significant improvements were also observed in multiple secondary efficacy endpoints, including Short-Form 36 Health Survey (SF-36) Physical Component Summary (p = 0.025), SF-36 Mental Component Summary (p = 0.007), Multidimensional Fatigue Inventory (p = 0.006), and Multiple Ability Self-Report Questionnaire (p = 0.041). Milnacipran was safe and well tolerated; nausea, hyperhidrosis, and headache were the most common adverse events.
                Milnacipran is an effective and safe treatment for pain and other predominant symptoms of FM. Registered as trial no. NCT00436033. A multicenter study compared the antidepressant efficacy and the tolerance of two doses of milnacipran (50 mg and 100 mg/day) and amitriptyline (150 mg/day) in three parallel groups of 45 major depressive inpatients defined by Research Diagnostic Criteria. After a wash-out period of 4-7 days on placebo with lorazepam and/or nitrazepam if necessary, patients were randomly assigned to a daily dose of milnacipran 50 mg, milnacipran 100 mg or amitriptyline 150 mg reached on the 5th day and then stable over a 4-week period, with weekly assessments by means of the Montgomery and Asberg depression scale, the Hamilton depression scale, the Clinical Global Impressions (CGI) and the Target Emergent Signs and Symptoms. Results showed significant superiority of both milnacipran 100 mg/day and amitriptyline over milnacipran 50 mg/day at the end of the treatment period. However, amitriptyline induced a nonsignificant trend toward more rapid improvement after 2 weeks of treatment, mainly based on items related to insomnia, supporting more sedative properties of amitriptyline as compared to milnacipran. Anticholinergic side-effects were significantly lower with milnacipran than with amitriptyline, explaining why milnacipran 100 mg exhibited at the end of the treatment period, a nonsignificantly better efficacy index on the CGI. Moreover, in contrast to milnacipran, amitriptyline was responsible for a significant decrease in blood pressure and a significant weight gain. A multicenter controlled study was designed to test the hypothesis that a loading dose of an antidepressant could shorten the latency of its clinical efficacy. Three parallel groups of about 40 endogenous depressive inpatients received either a loading dose of milnacipran (300 mg daily for 2 weeks and 150 mg daily during the 2 following weeks), the standard regimen of milnacipran in severe depression (200 mg daily for 4 weeks), or fluvoxamine (200 mg daily for 4 weeks). The duration of the study was 4 weeks, with assessments at baseline and after 4, 9, 14, 21, and 28 days of therapy by means of Montgomery and Asberg depression scale (MADS), the Hamilton depression scale, the Clinical Global Impressions (CGI), and a checklist of symptoms and side-effects. Results showed very similar evolution in the 3 treatment groups. In addition, the level of side-effects did not exhibit significant differences among the treatment groups, except for excitement-nervousness and akathisia which were more frequently reported with fluvoxamine. These results do not support the usefulness of a loading dose of an antidepressant such as milnacipran. They demonstrate however that milnacipran can be given at a 300 mg daily dose from the very first day of treatment with an excellent tolerance. This multicentre, double-blind, randomised trial in 109 patients compared the efficacy and tolerance of the novel selective serotonin and noradrenaline reuptake inhibitor (SNRI) antidepressant milnacipran (50 mg twice daily, n=53) with the established tricyclic agent imipramine (75 mg twice daily, n=56) over a period of 6 weeks, in patients with major depression (Montgomery-Asberg depression rating score (MADRS) > or =25). Initiation of antidepressant medication was conducted during a 2-week period of hospitalisation, after a 3- to 7-day washout period. Concomitant psychiatric medication was limited to lorazepam, cyamemazine, chloral hydrate and long-term uncomplicated lithium therapy. Assessment for efficacy using the MADRS and Hamilton rating scales of depression, a visual analogue scale and global evaluation revealed both agents to be highly effective (P=0.0001) in this group of patients. Milnacipran was found to be of similar efficacy to imipramine. Tolerance, assessed by physiological and biochemical examinations with routine inventory and spontaneous report of adverse events, revealed a clear advantage for milnacipran. The incidence of anticholinergic events with milnacipran was about half that with imipramine and the overall incidence of adverse events by either reporting method was markedly lower with milnacipran than with imipramine. Furthermore, the patient drop-out rate with imipramine was double that experienced with milnacipran. Milnacipran appears to possess equal antidepressant efficacy to imipramine but with markedly superior tolerance. Therefore, milnacipran constitutes an important new treatment option in major depression. Milnacipran is a new antidepressive drug, a combined noradrenaline/serotonin (NA/5-HT) reuptake inhibitor, which has been suggested to be as effective as and better tolerated than tricyclic antidepressants. Since long-term studies are lacking, we compared the efficacy, safety and tolerability of milnacipran and clomipramine in a double-blind, randomized, parallel-group study setting during 26 weeks of treatment in patients with major depression. A total of 107 patients were treated with either milnacipran (n=52) or clomipramine (n=55). Due to active treatment of duration less than 12 days in four patients and protocol deviation in one patient, in total 47 milnacipran-treated patients were eligible for efficacy analysis. Nine patients in the clomipramine group continued on active treatment for less than 12 days. Thus 46 clomipramine-treated patients were finally included in the efficacy analysis. After 1 week of dose escalation, there was a fixed dosage regimen of either milnacipran (200 mg daily) or clomipramine (150 mg daily) during weeks 2 to 10, followed by flexible dosing of milnacipran (100, 150 or 200 mg daily) or clomipramine (75, 100 or 150 mg daily) during weeks 11 to 26. A total of 53 patients (49%) completed the 26-week study period; 21% (11/52) of the patients in the milnacipran group and 38% (21/55) of the patients in the clomipramine group discontinued their medication prematurely due to adverse events, whereas 19% (10/52) of those on milnacipran and 7% (4/55) of those on clomipramine treatment withdrew due to either lack of efficacy or clinical deterioration. The mean change (+/-SD) in the Hamilton Depression Rating Scale (HAMD) score between the baseline and the last rating ranged from 23.7+/-3.1 to 12.0+/-9.5 in the milnacipran-treated patients and from 23.1+/-3.5 to 8.0+/-8.5 in the clomipramine-treated patients, revealing a significant difference in favour of clomipramine. In total 58% of the milnacipran-treated patients vs. 72% of the clomipramine-treated patients showed a > or = 50% reduction in their baseline HAMD scores and 45% vs. 63% had an HAMD score of < or = 7 at the last rating, respectively. Moreover, the time to the onset of the antidepressant action (defined as > or = 50% reduction of the baseline HAMD score) showed a significant difference in favour of clomipramine. In addition, clomipramine was significantly more efficacious in patients with a baseline HAMD score of > or = 24 as evidenced by the analysis of the HAMD score at week 6 and at the last rating. The Montgomery Asberg Depression Rating Scale (MADRS) and the Clinical Global Impression (CGI) scale did not show significant differences between the treatment groups. The safety analysis did not reveal any differences of clinical significance in cardiovascular variables between the study drugs. Dry mouth was significantly less frequently reported by the milnacipran-treated patients during the early and later phases (weeks 6 to 26) of the study, while insomnia was more common in the milnacipran group during weeks 1 to 6. In conclusion, milnacipran appeared to be less effective than clomipramine in the long-term treatment of depression. The side-effects of the drugs differed to a certain extent, and milnacipran tended to be somewhat better tolerated than clomipramine.
The evidence available indicates that milnacipran 100 mg or 200 mg is effective for a minority in the treatment of pain due to fibromyalgia, providing moderate levels of pain relief (at least 30%) to about 40% of participants, compared with about 30% with placebo. There were insufficient data to assess substantial levels of pain relief (at least 50%), and the use of last observation carried forward imputation may overestimate drug efficacy. Milnacipran is associated with increased adverse events and adverse event withdrawals, which were significantly greater for the higher dose. There were no data for the use of milnacipran for other chronic neuropathic pain conditions.