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'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 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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'Risk of bias' summary: review authors' judgements about each risk of bias item for each included study.
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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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Forest plot of comparison: 1 Milnacipran 100 mg/day versus placebo, outcome: 1.1 At least 30% pain relief.
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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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Forest plot of comparison: 1 Milnacipran 100 mg/day versus placebo, outcome: 1.7 Individual adverse events.
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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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Comparison 1 Milnacipran 100 mg/day versus placebo, Outcome 1 At least 30% pain relief.
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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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Comparison 1 Milnacipran 100 mg/day versus placebo, Outcome 2 PGIC 'much improved' or 'very much improved'.
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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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Comparison 1 Milnacipran 100 mg/day versus placebo, Outcome 3 Composite 1.
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Analysis 1.3

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

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Comparison 1 Milnacipran 100 mg/day versus placebo, Outcome 4 Composite 2.
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Analysis 1.4

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

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Comparison 1 Milnacipran 100 mg/day versus placebo, Outcome 5 At least one adverse event.
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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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Comparison 1 Milnacipran 100 mg/day versus placebo, Outcome 6 Serious adverse events.
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Analysis 1.6

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

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Comparison 1 Milnacipran 100 mg/day versus placebo, Outcome 7 Individual 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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Comparison 1 Milnacipran 100 mg/day versus placebo, Outcome 8 All‐cause withdrawals.
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Analysis 1.8

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

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Comparison 1 Milnacipran 100 mg/day versus placebo, Outcome 9 Lack of efficacy 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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Comparison 1 Milnacipran 100 mg/day versus placebo, Outcome 10 Adverse event 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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Comparison 2 Milnacipran 200 mg/day versus placebo, Outcome 1 At least 30% pain relief.
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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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Comparison 2 Milnacipran 200 mg/day versus placebo, Outcome 2 PGIC 'much improved' or 'very much improved'.
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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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Comparison 2 Milnacipran 200 mg/day versus placebo, Outcome 3 Composite 1.
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Analysis 2.3

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

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Comparison 2 Milnacipran 200 mg/day versus placebo, Outcome 4 Composite 2.
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Analysis 2.4

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

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Comparison 2 Milnacipran 200 mg/day versus placebo, Outcome 5 At least one adverse event.
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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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Comparison 2 Milnacipran 200 mg/day versus placebo, Outcome 6 Serious adverse events.
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Analysis 2.6

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

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Comparison 2 Milnacipran 200 mg/day versus placebo, Outcome 7 Individual 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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Comparison 2 Milnacipran 200 mg/day versus placebo, Outcome 8 All‐cause withdrawals.
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Analysis 2.8

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

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Comparison 2 Milnacipran 200 mg/day versus placebo, Outcome 9 Lack of efficacy 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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Comparison 2 Milnacipran 200 mg/day versus placebo, Outcome 10 Adverse event 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]
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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]
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Comparison 2. Milnacipran 200 mg/day versus placebo
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