Study	Maximum daily dose of milnacipran Titration/fixed	Adverse events (general)	Adverse events (specific)	Withdrawals
Arnold 2010	1‐ to 4‐week screening and washout 4‐ to 6‐week flexible dose titration 12‐week stable dose 2‐week randomised discontinuation (not considered here) Target dose 100 mg/day (2 x 50 mg) Treatment duration Max 18 weeks Stable 12 weeks	Participants with ≥ 1 Miln = 434/516 Plac = 382/509 Most mild to moderate SAE: Miln = 8/516 Plac = 6/509 No deaths	In ≥ 5% Nausea: Miln 189/516, Plac 106/509 Headache: Miln 92/516, Plac 80/509 Constipation: Miln 76/516, Plac 20/509 Hot flush: Miln 56/516, Plac 18/509 Dizziness: Miln 54/516, Plac 26/509 Insomnia: Miln 51/516, Plac 41/509 Hyperhidrosis: Miln 40/516, Plac 7/509 Palpitations: Miln 38/516, Plac 15/509 Fatigue: Miln 31/516, Plac 22/509	Miln All‐cause = 159 AE = 92 LoE = 24 Pt consent = 27 Plac All‐cause = 150 AE = 71 LoE = 33 Participant consent = 21
Bateman 2013	4 weeks' duloxetine 60 mg/day for ≥ 4 weeks before enrolment 2 weeks' duloxetine 60 mg 10 weeks' randomised miln (direct switch) 100 mg/day with possibility to escalate to 200 mg/day or de‐escalate to 50‐75 mg/day or 10 weeks' placebo (first week blinded duloxetine 30 mg) 1 week down‐taper period	Participants with ≥ 1 Miln = 63/85 Plac = 16/21 Most mild to moderate SAE: Miln = 2/85 Plac = 0/21 No deaths	Nausea: Miln 18/85, Plac 6/21 Diarrhoea: Miln 4/85, Plac 3/21 Irritability: Miln 6/85, Plac 1/21 Fatigue: Miln 3/85, Plac 2/21 Nasopharyngitis: Miln 6/85, Plac 0/21 Blood pressure increased: Miln 5/85, Plac 0/21 Muscle spasms: Miln 0/85, Plac 2/21 Dizziness: Miln 13/85, Plac 1/21 Headache: Miln 10/85, Plac 2/21 Migraine: Miln 1/85, Plac 2/21 Paraesthesia: Miln 1/85, Plac 2/21 Insomnia: Miln 9/85, Plac 2/21 Anxiety: Miln 5/85, Plac 0/21 Hyperhidrosis: Miln 5/85, Plac 0/21 Hot flush: Miln 7/85, Plac 1/21	Miln All‐cause = 35/86 AE = 15 LoE = 8 Participant consent = 6 5 lost to follow‐up, 1 did not take any drug Plac All‐cause = 10/21 AE = 2 LoE = 6 Participant consent = 0 2 lost to follow‐up
Branco 2010	1‐ to 4‐week washout 2‐week training and randomisation 4‐week dose escalation 12‐week stable dose 9‐day down‐titration 2‐week follow‐up Target dose 200 mg/day (2 x 100 mg) Treatment duration Max 16 weeks Stable 12 weeks	Participants with ≥ 1 Miln: 363/431 Plac: 331/446 Most mild to moderate, and in titration period SAE Miln: 11/431 (14 events) Plac: 11/446 (16 events) No deaths	In ≥ 5% Nausea: Miln 112/431, Plac 50/446 Hyperhidrosis: Miln 102/431, Plac 13/446 Headache: Miln 73/431, Plac 55/446 Constipation: Miln 54/431, Plac 10/446 Dizziness: Miln 44/431, Plac 34/446 Palpitations: Miln 34/431, Plac 13/446 Insomnia: Miln 33/431, Plac 24/446 Nasopharyngitis: Miln 33/431, Plac 33/446 Hot flush: Miln 30/431, Plac 5/446 Tachycardia: Miln 29/431, Plac 3/446 Vomiting: 22/431, Plac 15/446	Miln All‐cause = 119 AE = 95 LoE = 24 Participant consent = 7 Plac All‐cause = 72 AE = 42 LoE = 31 Pt consent = 7 5 participants with Miln and 3 with Plac did not have evaluable data: problem with 1 study centre (4), did not receive medication (3), missing baseline data (1)
Clauw 2008	1‐ to 4‐week washout, 2‐week training, randomisation 3‐week dose escalation 12‐week stable dose Target dose 100 mg/day (2 x 50 mg) or 200 mg/day (2 x 100 mg) Treatment duration Max 15 weeks Stable 12 weeks	Participants with ≥ 1 Miln 100 = 358/399 Miln 200 = 346/396 Plac = 317/401 Most mild to moderate SAE Miln 100 = 5/399 Miln 200 = 4/396 Plac = 6/401 No deaths	In ≥ 5% active group: Nausea: Miln 100 137/399, Miln 200 149/396, Plac 77/401 Headache: Miln 100 72/399, Miln 200 70/396, Plac 58/401 Constipation: Miln 100 57/399, Miln 200 71/396, Plac 16/401 Insomnia: Miln 100 42/399, Miln 200 62/396, Plac 42/401 Hot flush: Miln 100 46/399, Miln 200 58/396, Plac 5/401 Dizziness: Miln 100 38/399, Miln 200 36/396, Plac 17/401 Palpitations: Miln 100 26/399, Miln 200 30/396, Plac 10/401 Fatigue: Miln 100 25/399, Miln 200 28/396, Plac 22/401 Sinusitis: Miln 100 22/399, Miln 200 26/396, Plac 18/401 Hyperhidrosis: Miln 100 25/399, Miln 200 23/396, Plac 5/401 Hypertension: Miln 100 25/399, Miln 200 15/396, Plac 6/401 Vomiting: Miln 100 24/399, Miln 200 20/396, Plac 9/401 Diarrhoea: Miln 100 22/399, Miln 200 13/396, Plac 24/401 Increased heart rate: Miln 100 20/399, Miln 200 21/396, Plac 1/401 Migraine: Miln 100 20/399, Miln 200 20/396, Plac 9/401 Depression: Miln 100 14/399, Miln 200 12/396, Plac 24/401	Miln 100 All‐cause = 135 AE = 78 LoE = 28 Participant consent = 14 Miln 200 All‐cause = 139 AE = 94 LoE = 19 Participant consent = 15 Placebo All‐cause = 111 AE = 38 LoE = 36 Participant consent = 20 2 participants with Miln 100, 5 with Miln 200, and 4 with Plac excluded from all analyses: problem with 1 study centre (9), did not receive medication (1), enrolled at 2 centres (1)
Mease 2009	1‐4 weeks' screening and washout 2‐week baseline and training, randomisation 3‐week dose escalation 24 weeks' stable dose All medication given as divided doses, 2 x daily Treatment duration Max 27 weeks Stable 24 weeks	Participants with ≥ 1: Miln 100 = 188/224 Miln 200 = 400/441 Plac = 190/223 Most mild or moderate SAE: Miln 100 = 3/224 Miln 200 = 11/441 Plac = 6/223	In ≥ 5%: Nausea: Miln 100 73/224, Miln 200 177/441, Plac 47/223 Headache: Miln 100 35/224, Miln 200 78/441, Plac 26/223 Constipation: Miln 100 41/224, Miln 200 63/441, Plac 6/223 Hyperhidrosis: Miln 100 22/224, Miln 200 55/441, Plac 5/223 Dizziness: Miln 100 26/224, Miln 200 50/441, Plac 15/223 Hot flush: Miln 100 22/224, Miln 200 46/441, Plac 6/223 Insomnia: Miln 100 24/224, Miln 200 41/441, Plac 15/223 Vomiting: Miln 100 11/224, Miln 200 36/441, Plac 4/223 Sinusitis: Miln 100 11/224, Miln 200 32/441, Plac 18/223 Increased heart rate: Miln 100 12/224, Miln 200 32/441, Plac 5/223 Dry mouth: Miln 100 13/224, Miln 200 31/441, Plac 6/223 URTI: Miln 100 20/224, Miln 200 30/441, Plac 16/223 Palpitations: Miln 100 18/224, Miln 200 25/441, Plac 2/223 Diarrhoea: Miln 100 10/224, Miln 200 23/441, Plac 16/223	Miln 100 All‐cause = 96/224 AE = 44/224 LoE = 26/224 Miln 200 All‐cause = 202/441 AE = 119/441 LoE = 49/441 Plac All‐cause = 78/223 AE = 23/223 LoE = 34/223
Vitton 2004	1‐4 weeks‐ screening and washout 2‐week baseline/training, randomisation 4‐week dose titration 8‐week stable dose Miln given as single or divided dose Treatment duration Max 12 weeks Stable 8 weeks	No data for participants with ≥ 1 AE No SAE Most AE of mild or moderate intensity	No data	Miln 2 x 100 All‐cause = 14/51 AE = 7/51 LoE = 3/51 Miln 1 x 200 All‐cause = 14/46 AE = 10/46 LoE = 3/46 Plac All‐cause = 7/28 AE = 1/28 LoE = 5/28
AE: adverse event; LoE: lack of efficacy; max: maximum; Miln: milnacipran; Plac: placebo; SAE: serious adverse event; URTI: upper respiratory tract infection