Milnacipran for neuropathic pain and fibromyalgia in adults

Sheena Derry; Dipender Gill; Tudor Phillips; R Andrew Moore

doi:10.1002/14651858.CD008244.pub2

Milnacipran for neuropathic pain and fibromyalgia in adults

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References

References to studies included in this review

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excluded studies
ongoing studies
additional references

Arnold LM, Gendreau RM, Palmer RH, Gendreau JF, Wang Y. Efficacy and safety of milnacipran 100mg/day in patients with fibromyalgia. Arthritis and Rheumatism 2010;62(9):2745‐56.

Branco JC, Zachrisson O, Perrot S, Mainguy Y. A European multicenter randomized double‐blind placebo‐controlled monotherapy clinical trial of milnacipran in treatment of fibromyalgia. Journal of Rheumatology 2010;37(4):851‐9.

Clauw DJ, Mease P, Palmer RH, Gendreau RM, Wang Y. Milnacipran for the treatment of fibromyalgia in adults: a 15‐week, multicenter, randomized, double‐blind, placebo‐controlled, multiple‐dose clinical trial. Clinical Therapeutics 2008;30(11):1988‐2004.

Mease PJ, Clauw DJ, Gendreau RM, Rao SG, Kranzler J, Chen W, et al. The efficacy and safety or milnacipran for treatment of fibromyalgia. A randomized, double‐blind, placebo‐controlled trial. Journal of Rheumatology 2009;36(2):398‐409.

Gendreau RM, Thorn MD, Gendreau JF, Kranzler JD, Ribeiro S, Gracely RH, et al. Efficacy of milnacipran in patients with fibromyalgia. Journal of Rheumatology 2005;32:1975‐85.

Vitton O, Gendreau M, Gendreau J, Kranzler J, Rao SG. A double‐blind placebo‐controlled trial of milnacipran in the treatment of fibromyalgia. Human Psychopharmacology 2004;19:S27‐S35.

References to studies excluded from this review

Jump to:

included studies
ongoing studies
additional references

Branco JC, Cherin P, Montagne A, Bouroubi A, on behalf of the Multinational Coordinator Study Group. Longterm therapeutic response to milnacipran treatment for fibromyalgia. A European 1‐year extension study following a 3‐month study. Journal of Rheumatology 2011;38(7):1403‐12. [DOI: 10.3899/jrheum.101025]

Goldenberg DL, Clauw DJ, Palmer RH, Mease P, Chen W, Gendreau RM. Durability of therapeutic response to milnacipran treatment for fibromyalgia. Results of a randomized, double‐blind, monotherapy 6‐month extension study. Pain Medicine 2010;11(2):180‐94.

A multicenter, randomized, open‐label, controlled study to evaluate the safety, tolerability, and efficacy of milnacipran when added to pregabalin in the treatment of fibromyalgia. http://clinicaltrials.gov/ct2/show/NCT00797797?term=milnacipran&rank=18 2011 (accessed 12 August 2011).

References to ongoing studies

Jump to:

included studies
excluded studies
additional references

An exploratory randomized placebo controlled trial of milnacipran in patients with chronic neuropathic low back pain. http://clinicaltrials.gov/ct2/show/NCT01225068?term=milnacipran&rank=24 (accessed 12 August 2011).

A placebo controlled, randomized, double blind trial of milnacipran for the treatment of idiopathic neuropathy pain. http://clinicaltrials.gov/ct2/show/NCT00797797?term=milnacipran&rank=18 (accessed 12 August 2011).

Additional references

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included studies
excluded studies
ongoing studies

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Characteristics of studies

Characteristics of included studies [ordered by study ID]

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excluded studies
ongoing studies

Arnold 2010

Methods	Prospective, multicentre, randomised, double‐blinded, placebo‐controlled trial with parallel groups. Participants recruited from outpatient clinical/research centres in US and Canada. 1 to 4‐week screening and washout (all FM therapy stopped), 4 to 6‐week flexible dose titration, 12‐week stable dose of 100 mg/day milnacipran (50 mg twice daily). Participants unable to tolerate 100 mg daily were discontinued from study Data collected using electronic patient experience diary (PED); pain improvement based on time weighted average of mean weekly 24 h recall pain scores
Participants	Inclusion: age 18 to 70 years, ACR criteria for FM; physical function (FIQ) ≥ 4, and BDI > 25 at screening, mean PI ≥ 40 and ≤ 90/100 mm over 14‐day baseline period Excluded patients with various medical and psychiatric conditions/risk factors, and previous exposure to milnacipran; female participants not using adequate contraception N = 1025: mean age ˜49 years, M:F 48:977, 91% white, mean duration of symptoms ˜10.8 years, baseline pain > 60/100 mm
Interventions	Milnacipran 100 mg/day, n = 516 Placebo, n = 509 Permitted analgesics: paracetamol, aspirin, NSAIDs Short‐term rescue medication up to week 4: tramadol, hydrocodone
Outcomes	Pain intensity using 100 mm VAS: 30% and 50% improvement from baseline PGIC using 7‐point scale: much or very much improved Composite pain scores: 2‐measure BOCF composite responder criteria: 24 h and weekly recall pain scores using 100 mm VAS ≥ 30% and PGIC score 'much' or 'very much' improved on 7‐point scale 3‐measure BOCF composite responder criteria: 24 h and weekly recall pain scores using 100 mm VAS ≥ 30%, PGIC score 'much' or 'very much' improved on 7‐point scale, and SF‐36 PCS ≥ 6‐point improvement Adverse events Withdrawals
Notes	Oxford Quality Score: R = 1, DB = 2, W = 1. Total = 4
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Unclear risk	"Randomization assignments generated in blocks of four"
Allocation concealment (selection bias)	Low risk	"Assignments to treatment groups was conducted centrally (i.e. at the study level) using an interactive voice response system"
Blinding of participants and personnel (performance bias) All outcomes	Low risk	"identical‐appearing capsules were used by all patients during all phases of the study"
Blinding of outcome assessment (detection bias) All outcomes	Low risk	"Clinical staff, investigators, patients, and the study sponsor were blinded to treatment allocation"
Incomplete outcome data (attrition bias) All outcomes	High risk	Last observation carried forward in analysis of individual outcomes, but baseline observation carried forward in analysis of composite outcomes
Selective reporting (reporting bias)	Low risk	All relevant outcomes in methods were reported in some way, although not necessarily as our preferred outcome
Size	Low risk	Both groups > 200 participants

Branco 2010

Methods	Prospective, multicentre, randomised, double‐blinded, placebo‐controlled trial with parallel groups. Participants recruited from outpatient centres in Europe. 1 to 4‐week screening and washout (all FM therapy stopped), 4‐week dose escalation, 12‐week stable dose with target 200 mg/day milnacipran (100 mg twice daily), 9‐day down‐titration, 2‐week follow‐up Data collected using electronic patient experience diary (PED): daily pain intensity averaged for 2 weeks immediately preceding visit day Adverse event data collected by spontaneous reporting, non‐leading questions and clinical evaluation
Participants	Inclusion: age 18 to 70 years, met ACR criteria for FM; physical function (FIQ) ≥ 3, BDI > 25 at screening; mean PI ≥ 40 and ≥ 90 over 14‐day baseline period Exclusion: patients with various medical and psychiatric conditions/risk factors, considered unlikely to comply with treatment; female participants not using adequate contraception or pregnant N = 884: mean age ˜49 years, M:F 58:826, mean duration of symptoms ˜9.5 years
Interventions	Milnacipran 200 mg/day, n = 435 Placebo, n = 449
Outcomes	Pain intensity using 100 mm VAS: 30% improvement from baseline PGIC using 7‐point scale: much or very much improved Composite pain score: 2‐measure BOCF composite responder criteria: 24 h morning recall pain scores ≥ 30% using 100 mm VAS, PGIC score of 'very much' or 'much' improved Adverse events Withdrawals
Notes	Oxford Quality Score: R = 1, DB = 2, W = 1. Total = 4
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Unclear risk	Not described
Allocation concealment (selection bias)	Unclear risk	Not described
Blinding of participants and personnel (performance bias) All outcomes	Low risk	"In patients receiving placebo, twice‐daily sham dosing was used to maintain blinding"
Blinding of outcome assessment (detection bias) All outcomes	Unclear risk	Not described
Incomplete outcome data (attrition bias) All outcomes	High risk	Last observation carried forward in analysis of individual outcomes, but baseline observation carried forward in analysis of composite outcomes
Selective reporting (reporting bias)	Low risk	All relevant outcomes in methods were reported in some way, although not necessarily as our preferred outcome
Size	Low risk	Both groups > 200 participants

Clauw 2008

Methods	Prospective, multicentre, randomised, double‐blinded, placebo‐controlled trial with parallel groups. Participants recruited from outpatient centres in United States. 1 to 4‐week washout (all FM therapy stopped), 3‐week dose escalation, 12‐week stable dose with 100 mg/day (50 mg twice daily) or 200 mg/day (100 mg twice daily) milnacipran Data collected using electronic patient experience diary (PED): daily pain intensity averaged for 2 weeks immediately preceding visit day Adverse event data collected by spontaneous reporting and clinical evaluation
Participants	Inclusion: age 18 to 70 years, met ACR criteria for FM, physical function (FIQ) ≥ 4 and BDI > 25 at screening, baseline PI ≥ 40/100 Excluded: various medical and psychiatric conditions/risk factors, interfering medication over the last 30 days, female participants not using adequate contraception or pregnant N = 1151: mean age ˜50 years, M:F 45:1151, ˜93% white, mean duration of symptoms ˜10 years, baseline pain > 60/100 mm
Interventions	Milnacipran 100 mg/day, n = 401 (396 for analysis) Milnacipran 200 mg/day, n = 410 (399 for analyses) Placebo, n = 405 (401 for analysis)
Outcomes	Pain intensity using 100 mm VAS: 30% improvement from baseline PGIC using 7‐point scale: much or very much improved Composite pain scores: 2‐measure BOCF composite responder criteria: 24 h and weekly recall pain scores using 100 mm VAS ≥ 30% and PGIC score 'much' or 'very much' improved on 7‐point scale 3‐measure BOCF composite responder criteria: 24 h and weekly recall pain scores using 100 mm VAS ≥ 30%, PGIC score 'much' or 'very much' improved on 7‐point scale, and SF‐36 PCS ≥ 6‐point improvement Adverse events Withdrawals
Notes	Oxford Quality Score: R = 2, DB = 2, W = 1, Total = 5/5
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	"Randomization lists for each site were generated by a computer program"
Allocation concealment (selection bias)	Low risk	"randomization assignments were made via an interactive voice response system"
Blinding of participants and personnel (performance bias) All outcomes	Low risk	"Milnacipran and placebo capsules were visually identical."
Blinding of outcome assessment (detection bias) All outcomes	Low risk	"Clinical staff, investigators, patients, and the study sponsor were blinded to treatment allocation."
Incomplete outcome data (attrition bias) All outcomes	High risk	Last observation carried forward in analysis of individual outcomes, but baseline observation carried forward in analysis of composite outcomes
Selective reporting (reporting bias)	Low risk	All relevant outcomes in methods were reported in some way, although not necessarily as our preferred outcome
Size	Low risk	All groups > 200 participants

Mease 2009

Methods	Prospective, multicentre, randomised, double‐blinded, placebo‐controlled trial with parallel groups. Participants recruited from 59 outpatient clinical/research centres in the United States Electronic patient experience diary (PED) used to collect data; 1 to 4‐week screening and washout (all FM therapy stopped), 3‐week baseline measurement and PED training, 24‐week stable dose with placebo or 100 mg/day milnacipran (50 mg twice daily) or 200 mg/day (100 mg twice daily) milnacipran (ratio 1:1:2 respectively) Adverse events collected from spontaneous reports, clinical observation and clinical evaluation
Participants	Inclusion: age 18 to 70 years, met ACR criteria for FM, physical function (FIQ) ≥ 4, BDI > 25, and PI > 50/100 mm Exclusion: patients with various medical and psychiatric conditions/risk factors; female participants not using adequate contraception N = 888: mean age ˜49 years, M:F 39:849, ˜93% white, mean duration of symptoms ˜5.5 years, baseline PI > 60/100 at screening Analgesics prohibited, except for acetaminophen, aspirin, stable doses of NSAIDs, and hydrocortisone
Interventions	Milnacipran 100 mg/day, n = 224 Milnacipran 200 mg/day, n = 441 Placebo, n = 223
Outcomes	Composite pain scores: 2‐measure BOCF composite responder criteria: 24 h and 2‐week average recall pain scores using 100 mm VAS ≥ 30% and PGIC score 'much' or 'very much' improved on 7‐point scale 3‐measure BOCF composite responder criteria: 24 h and weekly recall pain scores using 100 mm VAS ≥ 30%, PGIC score 'much' or 'very much' improved on 7‐point scale, and SF‐36 PCS ≥ 6‐point improvement Adverse events Withdrawals
Notes	Oxford Quality Score: R = 1, DB = 1, W = 1. Total = 3/5
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Unclear risk	No described
Allocation concealment (selection bias)	Unclear risk	Not described
Blinding of participants and personnel (performance bias) All outcomes	Unclear risk	Not described
Blinding of outcome assessment (detection bias) All outcomes	Unclear risk	Not described
Incomplete outcome data (attrition bias) All outcomes	High risk	Last observation carried forward in individual outcome analysis
Selective reporting (reporting bias)	Low risk	All relevant outcomes in methods were reported in some way, although not necessarily as our preferred outcome
Size	Low risk	All groups > 200 participants

Vitton 2004

Methods	Prospective, multicentre, randomised, double‐blinded, placebo‐controlled trial with parallel groups. Participants recruited from outpatient centres in US with experience in treating fibromyalgia. Electronic patient experience diary (PED) used to collect data; 1 to 4‐week screening and washout (all FM therapy stopped), 2 week baseline measurement and PED training, 4‐week dose titration, 8‐week stable dose with 200 mg/day milnacipran (once daily), 200 mg/day milnacipran (100 mg twice daily), or placebo (ratio 3:3:2 respectively) Adverse events collected from spontaneous reports, clinical observation and clinical evaluation
Participants	Inclusion: age 18 to 70 years, met ACR criteria for FM; baseline PI ≥ 10/20 (Gracely log‐scale) Exclusion: patients with various medical and psychiatric conditions/risk factors, female participants not using adequate contraception N = 125 participants; mean age 46 to 48 years, 96% to 98% female, 79% to 89% Caucasian, mean duration of symptoms 3.8 to 4.3 years Analgesics prohibited, except for stable doses of acetaminophen, aspirin, and NSAIDs
Interventions	Milnacipran 200 mg/day (once daily), n = 46 Milnacipran 200 mg/day (twice daily), n = 51 Placebo comparator, n = 28
Outcomes	Pain (Short‐form McGill Pain Questionnaire, visual analogue scale, Gracely and Kwilosz anchored logarithmic scale) PGIC at end of study (completers analysis only) Adverse events Withdrawals
Notes	Oxford Quality Score: R = 2 (from Gendreau 2005), DB = 2 (from Gendreau 2005), W = 1. Total = 5/5
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	"Randomization was performed by an independent contract research organization that generated randomisation assignments" (from Gendreau 2005)
Allocation concealment (selection bias)	Unclear risk	Not described
Blinding of participants and personnel (performance bias) All outcomes	Low risk	"Blinding was rigorously maintained, as all patients took capsules morning and evening that were visually identical" (from Gendreau 2005)
Blinding of outcome assessment (detection bias) All outcomes	Low risk	"Patients and investigators remained blinded to patients' treatment allocation" (from Gendreau 2005)
Incomplete outcome data (attrition bias) All outcomes	High risk	Last observation carried forward for all analyses
Selective reporting (reporting bias)	Low risk	All relevant outcomes in methods were reported in some way, although not necessarily as our preferred outcome
Size	High risk	All groups ≤ 51

ACR: American College of Rheumatology; BDI: Beck Depression Inventory, BOCF: baseline observation carried forward; DB: double‐blinding; FIQ: fibromyalgia impact questionnaire; FM: fibromyalgia; h: hour; NSAIDS: non‐steroidal anti‐inflammatory drugs; PCS: physical component summary; PED: patient experience diary; PGIC: patient global impression of change; PI: pain intensity; R: randomisation; VAS: visual analogue scale; W: withdrawals

Characteristics of excluded studies [ordered by study ID]

Jump to:

included studies
ongoing studies

Study	Reason for exclusion
Branco 2011	Participants from Branco 2010 re‐randomised for extension study
Goldenberg 2010	No placebo control (trial followed a 6‐month lead‐in study, where placebo controls were re‐randomised to treatment with milnacipran)
NCT00797797	Open‐label study

Characteristics of ongoing studies [ordered by study ID]

Jump to:

included studies
excluded studies

NCT01225068

Trial name or title	An exploratory randomized placebo controlled trial of milnacipran in patients with chronic neuropathic low back pain
Methods	Randomised, double blind, placebo‐controlled, parallel‐group, 6 weeks
Participants	History of low back pain for a minimum of 6 months with radiation to leg or buttocks VAS pain > 50/100 Age 18 to 70 years
Interventions	Titration to 2 x 50 mg milnacipran daily, or placebo Option to increase to 2 x 100 mg daily after 2 weeks
Outcomes	Effect size of pain outcome measures (several pain outcome measures in the form of surveys will be used) Visual analogue pain scale, Brief Pain Index, McGill Pain Questionnaire, physical activity measurement, adverse events
Starting date	October 2010
Contact information	Danielle Barkema (d‐[email protected])
Notes	Recruiting (March 2011)

NCT01288937

Trial name or title	A placebo controlled, randomized, double blind trial of milnacipran for the treatment of idiopathic neuropathy pain
Methods	Randomised, double‐blind, placebo‐controlled, parallel‐group, 11 weeks
Participants	Patients with signs and symptoms of a peripheral neuropathy, with either abnormal nerve conductions or abnormal epidermal nerve fibre density with neuropathic pain Age 18 to 80 years Pain ≥ 6 months
Interventions	Titration to 2 x 50 mg milnacipran daily, or placebo
Outcomes	Change in average 11‐point Likert pain scale (0 to 10) Change in Rand‐36 Item Quality of Life Scale
Starting date	November 2010
Contact information	Thomas H Brannagan, MD
Notes	Recruiting (August 2011)

VAS: visual analogue scale

Data and analyses

Open in table viewer

Comparison 1. Milnacipran 100 mg/day versus placebo

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1 At least 30% pain relief Show forest plot	2	1825	Risk Ratio (M‐H, Fixed, 95% CI)	1.39 [1.23, 1.58]
Open in figure viewer Analysis 1.1 Comparison 1 Milnacipran 100 mg/day versus placebo, Outcome 1 At least 30% pain relief.
2 PGIC 'much improved' or 'very much improved' Show forest plot	2	1825	Risk Ratio (M‐H, Fixed, 95% CI)	1.52 [1.32, 1.74]
Open in figure viewer Analysis 1.2 Comparison 1 Milnacipran 100 mg/day versus placebo, Outcome 2 PGIC 'much improved' or 'very much improved'.
3 Composite 1 Show forest plot	3	2272	Risk Ratio (M‐H, Fixed, 95% CI)	1.46 [1.25, 1.71]
Open in figure viewer Analysis 1.3 Comparison 1 Milnacipran 100 mg/day versus placebo, Outcome 3 Composite 1.
4 Composite 2 Show forest plot	3	2272	Risk Ratio (M‐H, Fixed, 95% CI)	1.73 [1.41, 2.14]
Open in figure viewer Analysis 1.4 Comparison 1 Milnacipran 100 mg/day versus placebo, Outcome 4 Composite 2.
5 At least one adverse event Show forest plot	3	2272	Risk Ratio (M‐H, Fixed, 95% CI)	1.10 [1.06, 1.14]
Open in figure viewer Analysis 1.5 Comparison 1 Milnacipran 100 mg/day versus placebo, Outcome 5 At least one adverse event.
6 Serious adverse events Show forest plot	3	2272	Risk Ratio (M‐H, Fixed, 95% CI)	0.88 [0.45, 1.73]
Open in figure viewer Analysis 1.6 Comparison 1 Milnacipran 100 mg/day versus placebo, Outcome 6 Serious adverse events.
7 Individual adverse events Show forest plot	3		Risk Ratio (M‐H, Fixed, 95% CI)	Subtotals only
Open in figure viewer Analysis 1.7 Comparison 1 Milnacipran 100 mg/day versus placebo, Outcome 7 Individual adverse events.
7.1 Nausea	3	2272	Risk Ratio (M‐H, Fixed, 95% CI)	1.73 [1.50, 1.98]
7.2 Headache	3	2272	Risk Ratio (M‐H, Fixed, 95% CI)	1.21 [1.00, 1.46]
7.3 Constipation	3	2272	Risk Ratio (M‐H, Fixed, 95% CI)	4.12 [2.97, 5.71]
7.4 Hot flush	3	2272	Risk Ratio (M‐H, Fixed, 95% CI)	4.25 [2.86, 6.31]
7.5 Dizziness	3	2272	Risk Ratio (M‐H, Fixed, 95% CI)	2.02 [1.49, 2.74]
7.6 Palpitations	3	2272	Risk Ratio (M‐H, Fixed, 95% CI)	3.02 [1.97, 4.63]
7.7 Insomnia	3	2272	Risk Ratio (M‐H, Fixed, 95% CI)	1.19 [0.92, 1.53]
7.8 Increased heart rate/tachycardia	3	2272	Risk Ratio (M‐H, Fixed, 95% CI)	5.42 [2.87, 10.25]
7.9 Hyperhidrosis	3	2272	Risk Ratio (M‐H, Fixed, 95% CI)	5.09 [3.05, 8.50]
7.10 Diarrhoea	3	2272	Risk Ratio (M‐H, Fixed, 95% CI)	0.83 [0.59, 1.18]
7.11 Vomiting	2	1247	Risk Ratio (M‐H, Fixed, 95% CI)	2.70 [1.44, 5.05]
7.12 Sinusitis	2	1247	Risk Ratio (M‐H, Fixed, 95% CI)	0.92 [0.58, 1.45]
7.13 Hypertension	2	1825	Risk Ratio (M‐H, Fixed, 95% CI)	4.71 [2.47, 8.96]
7.14 Fatigue	2	1825	Risk Ratio (M‐H, Fixed, 95% CI)	1.27 [0.86, 1.86]
7.15 URTI	2	1472	Risk Ratio (M‐H, Fixed, 95% CI)	0.90 [0.59, 1.37]
8 All‐cause withdrawals Show forest plot	3	2272	Risk Ratio (M‐H, Fixed, 95% CI)	1.14 [1.02, 1.29]
Open in figure viewer Analysis 1.8 Comparison 1 Milnacipran 100 mg/day versus placebo, Outcome 8 All‐cause withdrawals.
9 Lack of efficacy withdrawals Show forest plot	3	2272	Risk Ratio (M‐H, Fixed, 95% CI)	0.75 [0.57, 1.00]
Open in figure viewer Analysis 1.9 Comparison 1 Milnacipran 100 mg/day versus placebo, Outcome 9 Lack of efficacy withdrawals.
10 Adverse event withdrawals Show forest plot	3	2272	Risk Ratio (M‐H, Fixed, 95% CI)	1.61 [1.32, 1.97]
Open in figure viewer Analysis 1.10 Comparison 1 Milnacipran 100 mg/day versus placebo, Outcome 10 Adverse event withdrawals.

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Comparison 2. Milnacipran 200 mg/day versus placebo

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1 At least 30% pain relief Show forest plot	3	1798	Risk Ratio (M‐H, Fixed, 95% CI)	1.35 [1.18, 1.54]
Open in figure viewer Analysis 2.1 Comparison 2 Milnacipran 200 mg/day versus placebo, Outcome 1 At least 30% pain relief.
2 PGIC 'much improved' or 'very much improved' Show forest plot	2	1673	Risk Ratio (M‐H, Fixed, 95% CI)	1.57 [1.34, 1.83]
Open in figure viewer Analysis 2.2 Comparison 2 Milnacipran 200 mg/day versus placebo, Outcome 2 PGIC 'much improved' or 'very much improved'.
3 Composite 1 Show forest plot	3	2337	Risk Ratio (M‐H, Fixed, 95% CI)	1.91 [1.59, 2.29]
Open in figure viewer Analysis 2.3 Comparison 2 Milnacipran 200 mg/day versus placebo, Outcome 3 Composite 1.
4 Composite 2 Show forest plot	2	1461	Risk Ratio (M‐H, Fixed, 95% CI)	1.61 [1.21, 2.13]
Open in figure viewer Analysis 2.4 Comparison 2 Milnacipran 200 mg/day versus placebo, Outcome 4 Composite 2.
5 At least one adverse event Show forest plot	3	2338	Risk Ratio (M‐H, Fixed, 95% CI)	1.10 [1.06, 1.15]
Open in figure viewer Analysis 2.5 Comparison 2 Milnacipran 200 mg/day versus placebo, Outcome 5 At least one adverse event.
6 Serious adverse events Show forest plot	4	2463	Risk Ratio (M‐H, Fixed, 95% CI)	0.91 [0.52, 1.60]
Open in figure viewer Analysis 2.6 Comparison 2 Milnacipran 200 mg/day versus placebo, Outcome 6 Serious adverse events.
7 Individual adverse events Show forest plot	3		Risk Ratio (M‐H, Fixed, 95% CI)	Subtotals only
Open in figure viewer Analysis 2.7 Comparison 2 Milnacipran 200 mg/day versus placebo, Outcome 7 Individual adverse events.
7.1 Nausea	3	2338	Risk Ratio (M‐H, Fixed, 95% CI)	2.37 [2.00, 2.80]
7.2 Headache	3	2338	Risk Ratio (M‐H, Fixed, 95% CI)	1.35 [1.10, 1.64]
7.3 Constipation	3	2338	Risk Ratio (M‐H, Fixed, 95% CI)	5.01 [3.46, 7.24]
7.4 Hot flush	3	2338	Risk Ratio (M‐H, Fixed, 95% CI)	6.71 [4.06, 11.09]
7.5 Dizziness	3	2338	Risk Ratio (M‐H, Fixed, 95% CI)	1.63 [1.22, 2.18]
7.6 Palpitations	3	2288	Risk Ratio (M‐H, Fixed, 95% CI)	3.38 [2.17, 5.29]
7.7 Insomnia	3	2338	Risk Ratio (M‐H, Fixed, 95% CI)	1.45 [1.11, 1.89]
7.8 Increased heart rate/tachycardia	3	2338	Risk Ratio (M‐H, Fixed, 95% CI)	6.81 [3.54, 13.13]
7.9 Hyperhidrosis	2	1461	Risk Ratio (M‐H, Fixed, 95% CI)	5.18 [2.67, 10.02]
7.10 Diarrhoea	2	1461	Risk Ratio (M‐H, Fixed, 95% CI)	0.63 [0.40, 0.99]
7.11 Vomiting	3	2338	Risk Ratio (M‐H, Fixed, 95% CI)	2.30 [1.48, 3.58]
7.12 Sinusitis	2	1461	Risk Ratio (M‐H, Fixed, 95% CI)	1.14 [0.76, 1.70]
8 All‐cause withdrawals Show forest plot	4	2416	Risk Ratio (M‐H, Fixed, 95% CI)	1.38 [1.22, 1.57]
Open in figure viewer Analysis 2.8 Comparison 2 Milnacipran 200 mg/day versus placebo, Outcome 8 All‐cause withdrawals.
9 Lack of efficacy withdrawals Show forest plot	4	2462	Risk Ratio (M‐H, Fixed, 95% CI)	0.66 [0.51, 0.87]
Open in figure viewer Analysis 2.9 Comparison 2 Milnacipran 200 mg/day versus placebo, Outcome 9 Lack of efficacy withdrawals.
10 Adverse event withdrawals Show forest plot	4	2470	Risk Ratio (M‐H, Fixed, 95% CI)	2.51 [2.03, 3.09]
Open in figure viewer Analysis 2.10 Comparison 2 Milnacipran 200 mg/day versus placebo, Outcome 10 Adverse event withdrawals.

Figure 1

'Risk of bias' graph: review authors' judgements about each risk of bias item presented as percentages across all included studies.

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Figure 2

'Risk of bias' summary: review authors' judgements about each risk of bias item for each included study.

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Figure 3

Forest plot of comparison: 1 Milnacipran 100 mg/day versus placebo, outcome: 1.1 At least 30% pain relief.

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Figure 4

Forest plot of comparison: 1 Milnacipran 100 mg/day versus placebo, outcome: 1.7 Individual adverse events.

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Analysis 1.1

Comparison 1 Milnacipran 100 mg/day versus placebo, Outcome 1 At least 30% pain relief.

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Analysis 1.2

Comparison 1 Milnacipran 100 mg/day versus placebo, Outcome 2 PGIC 'much improved' or 'very much improved'.

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Analysis 1.3

Comparison 1 Milnacipran 100 mg/day versus placebo, Outcome 3 Composite 1.

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Analysis 1.4

Comparison 1 Milnacipran 100 mg/day versus placebo, Outcome 4 Composite 2.

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Analysis 1.5

Comparison 1 Milnacipran 100 mg/day versus placebo, Outcome 5 At least one adverse event.

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Analysis 1.6

Comparison 1 Milnacipran 100 mg/day versus placebo, Outcome 6 Serious adverse events.

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Analysis 1.7

Comparison 1 Milnacipran 100 mg/day versus placebo, Outcome 7 Individual adverse events.

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Analysis 1.8

Comparison 1 Milnacipran 100 mg/day versus placebo, Outcome 8 All‐cause withdrawals.

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Analysis 1.9

Comparison 1 Milnacipran 100 mg/day versus placebo, Outcome 9 Lack of efficacy withdrawals.

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Analysis 1.10

Comparison 1 Milnacipran 100 mg/day versus placebo, Outcome 10 Adverse event withdrawals.

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Analysis 2.1

Comparison 2 Milnacipran 200 mg/day versus placebo, Outcome 1 At least 30% pain relief.

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Analysis 2.2

Comparison 2 Milnacipran 200 mg/day versus placebo, Outcome 2 PGIC 'much improved' or 'very much improved'.

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Analysis 2.3

Comparison 2 Milnacipran 200 mg/day versus placebo, Outcome 3 Composite 1.

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Analysis 2.4

Comparison 2 Milnacipran 200 mg/day versus placebo, Outcome 4 Composite 2.

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Analysis 2.5

Comparison 2 Milnacipran 200 mg/day versus placebo, Outcome 5 At least one adverse event.

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Analysis 2.6

Comparison 2 Milnacipran 200 mg/day versus placebo, Outcome 6 Serious adverse events.

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Analysis 2.7

Comparison 2 Milnacipran 200 mg/day versus placebo, Outcome 7 Individual adverse events.

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Analysis 2.8

Comparison 2 Milnacipran 200 mg/day versus placebo, Outcome 8 All‐cause withdrawals.

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Analysis 2.9

Comparison 2 Milnacipran 200 mg/day versus placebo, Outcome 9 Lack of efficacy withdrawals.

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Analysis 2.10

Comparison 2 Milnacipran 200 mg/day versus placebo, Outcome 10 Adverse event withdrawals.

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Comparison 1. Milnacipran 100 mg/day versus placebo

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1 At least 30% pain relief Show forest plot	2	1825	Risk Ratio (M‐H, Fixed, 95% CI)	1.39 [1.23, 1.58]

2 PGIC 'much improved' or 'very much improved' Show forest plot	2	1825	Risk Ratio (M‐H, Fixed, 95% CI)	1.52 [1.32, 1.74]

3 Composite 1 Show forest plot	3	2272	Risk Ratio (M‐H, Fixed, 95% CI)	1.46 [1.25, 1.71]

4 Composite 2 Show forest plot	3	2272	Risk Ratio (M‐H, Fixed, 95% CI)	1.73 [1.41, 2.14]

5 At least one adverse event Show forest plot	3	2272	Risk Ratio (M‐H, Fixed, 95% CI)	1.10 [1.06, 1.14]

6 Serious adverse events Show forest plot	3	2272	Risk Ratio (M‐H, Fixed, 95% CI)	0.88 [0.45, 1.73]

7 Individual adverse events Show forest plot	3		Risk Ratio (M‐H, Fixed, 95% CI)	Subtotals only

7.1 Nausea	3	2272	Risk Ratio (M‐H, Fixed, 95% CI)	1.73 [1.50, 1.98]
7.2 Headache	3	2272	Risk Ratio (M‐H, Fixed, 95% CI)	1.21 [1.00, 1.46]
7.3 Constipation	3	2272	Risk Ratio (M‐H, Fixed, 95% CI)	4.12 [2.97, 5.71]
7.4 Hot flush	3	2272	Risk Ratio (M‐H, Fixed, 95% CI)	4.25 [2.86, 6.31]
7.5 Dizziness	3	2272	Risk Ratio (M‐H, Fixed, 95% CI)	2.02 [1.49, 2.74]
7.6 Palpitations	3	2272	Risk Ratio (M‐H, Fixed, 95% CI)	3.02 [1.97, 4.63]
7.7 Insomnia	3	2272	Risk Ratio (M‐H, Fixed, 95% CI)	1.19 [0.92, 1.53]
7.8 Increased heart rate/tachycardia	3	2272	Risk Ratio (M‐H, Fixed, 95% CI)	5.42 [2.87, 10.25]
7.9 Hyperhidrosis	3	2272	Risk Ratio (M‐H, Fixed, 95% CI)	5.09 [3.05, 8.50]
7.10 Diarrhoea	3	2272	Risk Ratio (M‐H, Fixed, 95% CI)	0.83 [0.59, 1.18]
7.11 Vomiting	2	1247	Risk Ratio (M‐H, Fixed, 95% CI)	2.70 [1.44, 5.05]
7.12 Sinusitis	2	1247	Risk Ratio (M‐H, Fixed, 95% CI)	0.92 [0.58, 1.45]
7.13 Hypertension	2	1825	Risk Ratio (M‐H, Fixed, 95% CI)	4.71 [2.47, 8.96]
7.14 Fatigue	2	1825	Risk Ratio (M‐H, Fixed, 95% CI)	1.27 [0.86, 1.86]
7.15 URTI	2	1472	Risk Ratio (M‐H, Fixed, 95% CI)	0.90 [0.59, 1.37]
8 All‐cause withdrawals Show forest plot	3	2272	Risk Ratio (M‐H, Fixed, 95% CI)	1.14 [1.02, 1.29]

9 Lack of efficacy withdrawals Show forest plot	3	2272	Risk Ratio (M‐H, Fixed, 95% CI)	0.75 [0.57, 1.00]

10 Adverse event withdrawals Show forest plot	3	2272	Risk Ratio (M‐H, Fixed, 95% CI)	1.61 [1.32, 1.97]

Comparison 1. Milnacipran 100 mg/day versus placebo

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Comparison 2. Milnacipran 200 mg/day versus placebo

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1 At least 30% pain relief Show forest plot	3	1798	Risk Ratio (M‐H, Fixed, 95% CI)	1.35 [1.18, 1.54]

2 PGIC 'much improved' or 'very much improved' Show forest plot	2	1673	Risk Ratio (M‐H, Fixed, 95% CI)	1.57 [1.34, 1.83]

3 Composite 1 Show forest plot	3	2337	Risk Ratio (M‐H, Fixed, 95% CI)	1.91 [1.59, 2.29]

4 Composite 2 Show forest plot	2	1461	Risk Ratio (M‐H, Fixed, 95% CI)	1.61 [1.21, 2.13]

5 At least one adverse event Show forest plot	3	2338	Risk Ratio (M‐H, Fixed, 95% CI)	1.10 [1.06, 1.15]

6 Serious adverse events Show forest plot	4	2463	Risk Ratio (M‐H, Fixed, 95% CI)	0.91 [0.52, 1.60]

7 Individual adverse events Show forest plot	3		Risk Ratio (M‐H, Fixed, 95% CI)	Subtotals only

7.1 Nausea	3	2338	Risk Ratio (M‐H, Fixed, 95% CI)	2.37 [2.00, 2.80]
7.2 Headache	3	2338	Risk Ratio (M‐H, Fixed, 95% CI)	1.35 [1.10, 1.64]
7.3 Constipation	3	2338	Risk Ratio (M‐H, Fixed, 95% CI)	5.01 [3.46, 7.24]
7.4 Hot flush	3	2338	Risk Ratio (M‐H, Fixed, 95% CI)	6.71 [4.06, 11.09]
7.5 Dizziness	3	2338	Risk Ratio (M‐H, Fixed, 95% CI)	1.63 [1.22, 2.18]
7.6 Palpitations	3	2288	Risk Ratio (M‐H, Fixed, 95% CI)	3.38 [2.17, 5.29]
7.7 Insomnia	3	2338	Risk Ratio (M‐H, Fixed, 95% CI)	1.45 [1.11, 1.89]
7.8 Increased heart rate/tachycardia	3	2338	Risk Ratio (M‐H, Fixed, 95% CI)	6.81 [3.54, 13.13]
7.9 Hyperhidrosis	2	1461	Risk Ratio (M‐H, Fixed, 95% CI)	5.18 [2.67, 10.02]
7.10 Diarrhoea	2	1461	Risk Ratio (M‐H, Fixed, 95% CI)	0.63 [0.40, 0.99]
7.11 Vomiting	3	2338	Risk Ratio (M‐H, Fixed, 95% CI)	2.30 [1.48, 3.58]
7.12 Sinusitis	2	1461	Risk Ratio (M‐H, Fixed, 95% CI)	1.14 [0.76, 1.70]
8 All‐cause withdrawals Show forest plot	4	2416	Risk Ratio (M‐H, Fixed, 95% CI)	1.38 [1.22, 1.57]

9 Lack of efficacy withdrawals Show forest plot	4	2462	Risk Ratio (M‐H, Fixed, 95% CI)	0.66 [0.51, 0.87]

10 Adverse event withdrawals Show forest plot	4	2470	Risk Ratio (M‐H, Fixed, 95% CI)	2.51 [2.03, 3.09]

Comparison 2. Milnacipran 200 mg/day versus placebo

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References

References to studies included in this review

Arnold 2010 {published data only}

Branco 2010 {published data only}

Clauw 2008 {published data only}

Mease 2009 {published data only}

Vitton 2004 {published data only}

References to studies excluded from this review

Branco 2011 {published data only}

Goldenberg 2010 {published data only}

NCT00797797 {unpublished data only}

References to ongoing studies

NCT01225068 {published data only}

NCT01288937 {published data only}

Additional references

Dworkin 2008

Gustorff 2008

Hall 2006

Hauser 2010

Hauser 2011

Hoffman 2010

Jensen 2011

Kjaergard 2001

Kyle 2010

L'Abbé 1987

Lee 2010

McQuay 1998

McQuay 2007

Moore 1998

Moore 2005

Moore 2008

Moore 2009

Moore 2010a

Moore 2010b

Moore 2010c

Moore 2011

Nuesch 2010

Ormseth 2010

Recla 2010

RevMan 2011 [Computer program]

Roskell 2011

Saarto 2007

Straube 2008

Straube 2011

Sultan 2008

Suzuki 2004

Wolfe 1990

Wolfe 2010

Characteristics of studies

Characteristics of included studies [ordered by study ID]

Characteristics of excluded studies [ordered by study ID]

Characteristics of ongoing studies [ordered by study ID]

Data and analyses

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