Serotonin and noradrenaline reuptake inhibitors (SNRIs) for fibromyalgia

Patrick Welsch; Nurcan Üçeyler; Petra Klose; Brian Walitt; Winfried Häuser

doi:10.1002/14651858.CD010292.pub2

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Figure 1

Study flow diagram

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Figure 2

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 3

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

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Analysis 1.1

Comparison 1: SNRIs versus placebo in parallel and cross‐over design trials, Outcome 1: Self‐reported pain relief of 50% or greater

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Analysis 1.2

Comparison 1: SNRIs versus placebo in parallel and cross‐over design trials, Outcome 2: PGIC much or very much improved

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Analysis 1.3

Comparison 1: SNRIs versus placebo in parallel and cross‐over design trials, Outcome 3: Withdrawal due to adverse events

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Analysis 1.4

Comparison 1: SNRIs versus placebo in parallel and cross‐over design trials, Outcome 4: Serious adverse events

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Analysis 1.5

Comparison 1: SNRIs versus placebo in parallel and cross‐over design trials, Outcome 5: Self‐reported fatigue

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Analysis 1.6

Comparison 1: SNRIs versus placebo in parallel and cross‐over design trials, Outcome 6: Self‐reported sleep problems

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Analysis 1.7

Comparison 1: SNRIs versus placebo in parallel and cross‐over design trials, Outcome 7: Self‐reported health‐related quality of life

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Analysis 1.8

Comparison 1: SNRIs versus placebo in parallel and cross‐over design trials, Outcome 8: Self‐reported pain relief of 30% or greater

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Analysis 1.9

Comparison 1: SNRIs versus placebo in parallel and cross‐over design trials, Outcome 9: Self‐reported mean pain intensity

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Analysis 1.10

Comparison 1: SNRIs versus placebo in parallel and cross‐over design trials, Outcome 10: Self‐reported depression

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Analysis 1.11

Comparison 1: SNRIs versus placebo in parallel and cross‐over design trials, Outcome 11: Self‐reported anxiety

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Analysis 1.12

Comparison 1: SNRIs versus placebo in parallel and cross‐over design trials, Outcome 12: Self‐reported disability

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Analysis 1.13

Comparison 1: SNRIs versus placebo in parallel and cross‐over design trials, Outcome 13: Self‐reported cognitive disturbances

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Analysis 1.14

Comparison 1: SNRIs versus placebo in parallel and cross‐over design trials, Outcome 14: Tenderness

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Analysis 1.15

Comparison 1: SNRIs versus placebo in parallel and cross‐over design trials, Outcome 15: Withdrawal due to lack of efficacy

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Analysis 1.16

Comparison 1: SNRIs versus placebo in parallel and cross‐over design trials, Outcome 16: Nausea

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Analysis 1.17

Comparison 1: SNRIs versus placebo in parallel and cross‐over design trials, Outcome 17: Somnolence

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Analysis 1.18

Comparison 1: SNRIs versus placebo in parallel and cross‐over design trials, Outcome 18: Insomnia

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Summary of findings 1. Serotonin noradrenaline reuptake inhibitors compared with placebo for fibromyalgia ‐ studies with parallel design

Outcomes	Probable outcome with intervention (95% CI)	Probable outcome with placebo	Relative effect SMD or risk difference (95% CI)	No of participants (studies)	Quality of the evidence (GRADE)	Comments
Serotonin noradrenaline reuptake inhibitors compared with placebo for fibromyalgia ‐ studies with parallel design
Patient or population: people with fibromyalgia Settings: study centers in North, Central and South America, Asia and Europe Intervention: serotonin noradrenaline reuptake inhibitors (duloxetine, milnacipran) Comparison: placebo
Self‐reported pain relief of 50% or greater	309 per 1000 (282 to 344)	210 per 1000	RD 0.09 (0.07 to 0.11)	6918 (15 studies)	⊕⊕⊝⊝ low^1,2	NNTB 11 (95% CI 9 to 14)
Patient Global Impression to be much or very much improved (PGIC)	519 per 1000 (459 to 573)	293 per 1000	RD 0.19 (0.12 to 0.26)	2918 (6 studies)	⊕⊕⊝⊝ low^1,2	NNTB 5 (95% CI 4 to 8)
Self‐reported fatigue (20‐100 scale) Higher scores indicate higher fatigue problem levels	Mean fatigue score was 2.6 points lower (1.0 to 5.0 points lower) based on a 20‐100 scale	Baseline mean score 69.4 (SD 12.3)³	SMD ‐0.13 (‐0.18 to ‐0.08)	6168 (12 studies)	⊕⊕⊝⊝ low^1,2	NNTB 18 (95% CI 12 to 29)
Self‐reported sleep problems (0‐100 scale) Higher scores indicate higher sleep problem levels	Mean sleep problems score was 1.2 points lower (0.2 higher to 5.5 points lower) based on a 0‐100 scale	Baseline mean score 68.0 (23.8)⁴	SMD ‐0.07 (‐0.15 to 0.01)	4547 (8 studies)	⊕⊕⊝⊝ low^1,2	NNTB not calculated due to lack of statistically significant difference
Self‐reported health‐related quality of life (0‐100 scale) Higher scores indicate higher burden of disease (lower quality of life)	Mean health‐related quality of life problems score was 3.9 points lower (2.3 to 5.3 points lower) based on a 0‐100 scale	Baseline mean score 57.9 (SD 14.1)⁵	SMD ‐0.20 (‐0.25 to ‐0.15)	6861 (14 studies)	⊕⊕⊝⊝ low^1,2	NNTB 11 (95% CI 8 to 14)
Tolerability (withdrawal due to adverse events)	191 per 1000 (172 to 210)	102 per 1000	RD 0.07 (0.04 to 0.10)	7029 (15 studies)	⊕⊕⊝⊝ low^1,2	NNTH 14 (95% CI 10 to 25)
Safety (serious adverse events)	18 per 1000 (16 to 20)	21 per 1000	RD ‐0.00 (‐0.01 to 0.00)	6732 (13 studies)	⊕⊝⊝⊝ Verylow^1,2,6	NNTH not calculated due to lack of statistically significant difference
The basis for the assumed risk* (e.g. the median control group risk across studies) is provided in footnotes. The corresponding risk (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI). CI: Confidence interval; FIQ: Fibromyalgia Impact Questionnaire; MFI: Multidimensional Fatigue Inventory; MOS‐Sleep problem index: Medical Outcome Study ‐ sleep problem index; NNTB: number needed to treat for an additional beneficial outcome; NNTH: number needed to treat for an additional harm; NRS: numerical rating scale; RD: risk difference; SMD: standardized mean difference; VAS: visual analog scale
GRADE Working Group grades of evidence High quality: we are very confident that the true effect lies close to that of the estimate of the effect. Moderate quality: we are moderately confident in the effect estimate; the true effect is likely to be close to the estimate of effect, but there is a possibility that it is substantially different. Low quality: our confidence in the effect estimate is limited; the true effect may be substantially different from the estimate of the effect. Very low quality: we have very little confidence in the effect estimate; the true effect is likely to be substantially different from the estimate of effect.
¹Downgraded once: indirectness: participants with major medical diseases and mental disorders except major depression excluded in > 50% of studies ²Downgraded once: publication bias ³Clauw 2008: N = 401 participants; MFI NRS 20‐100 scale ⁴Mease 2009b: N = 223 participants; MOS Sleep problem index NRS 0‐100 scale ⁵Arnold 2010b; N = 509 participants; FIQ VAS 0‐80 scale ⁶Downgraded once: imprecision due to low event rate

Summary of findings 1. Serotonin noradrenaline reuptake inhibitors compared with placebo for fibromyalgia ‐ studies with parallel design

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Table 1. Subgroup analysis. Efficacy and safety of SNRIs in studies with North American and European participants

Outcome	Number of participants (studies)	Effect size RD (95% CI)	Test for overall effect P value	Heterogeneity I² (%)	Test of interaction: effect estimate and P value
Self‐reported pain relief 50% or greater					Z = 0.78; P = 0.43
Only North American participants	3935 (8)	0.10 (0.08 to 0.13)	< 0.001	0
Only European participants	960 (2)	0.06 (0.01 to 0.12)	0.02	0
Withdrawal due to adverse events					Z = 1.14; P = 0.25
Only North American participants	3935 (8)	0.08 (0.04 to 0.13)	< 0.0002	71
Only European participants	960 (2)	0.12 (0.08 to 0.17)	< 0.0001	0
CI: confidence interval; RD: risk difference; SNRIs: serotonin and noradrenaline reuptake inhibitors

Table 1. Subgroup analysis. Efficacy and safety of SNRIs in studies with North American and European participants

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Comparison 1. SNRIs versus placebo in parallel and cross‐over design trials

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1.1 Self‐reported pain relief of 50% or greater Show forest plot	15	6918	Risk Difference (IV, Random, 95% CI)	0.09 [0.07, 0.11]

1.1.1 Duloxetine	7	2582	Risk Difference (IV, Random, 95% CI)	0.10 [0.06, 0.14]
1.1.2 Milnacipran	8	4336	Risk Difference (IV, Random, 95% CI)	0.09 [0.06, 0.11]
1.2 PGIC much or very much improved Show forest plot	6	2918	Risk Difference (M‐H, Random, 95% CI)	0.19 [0.12, 0.26]

1.2.1 Duloxetine	1	530	Risk Difference (M‐H, Random, 95% CI)	0.35 [0.27, 0.42]
1.2.2 Milnacipran	5	2388	Risk Difference (M‐H, Random, 95% CI)	0.15 [0.11, 0.19]
1.3 Withdrawal due to adverse events Show forest plot	15	7029	Risk Difference (IV, Random, 95% CI)	0.07 [0.04, 0.10]

1.3.1 Desvenlafaxine	1	82	Risk Difference (IV, Random, 95% CI)	‐0.03 [‐0.09, 0.04]
1.3.2 Duloxetine	7	2642	Risk Difference (IV, Random, 95% CI)	0.05 [0.02, 0.07]
1.3.3 Milnacipran	7	4305	Risk Difference (IV, Random, 95% CI)	0.11 [0.07, 0.14]
1.4 Serious adverse events Show forest plot	13	6732	Risk Difference (IV, Random, 95% CI)	‐0.00 [‐0.01, 0.00]

1.4.1 Desvenlafaxine	1	82	Risk Difference (IV, Random, 95% CI)	0.00 [‐0.05, 0.05]
1.4.2 Duloxetine	6	2432	Risk Difference (IV, Random, 95% CI)	‐0.00 [‐0.01, 0.01]
1.4.3 Milnacipran	6	4218	Risk Difference (IV, Random, 95% CI)	‐0.00 [‐0.01, 0.01]
1.5 Self‐reported fatigue Show forest plot	12	6168	Std. Mean Difference (IV, Random, 95% CI)	‐0.13 [‐0.18, ‐0.08]

1.5.1 Duloxetine	5	1954	Std. Mean Difference (IV, Random, 95% CI)	‐0.12 [‐0.21, ‐0.03]
1.5.2 Milnacpran	7	4214	Std. Mean Difference (IV, Random, 95% CI)	‐0.14 [‐0.21, ‐0.07]
1.6 Self‐reported sleep problems Show forest plot	8	4547	Std. Mean Difference (IV, Random, 95% CI)	‐0.07 [‐0.15, 0.01]

1.6.1 Duloxetine	3	1382	Std. Mean Difference (IV, Random, 95% CI)	‐0.20 [‐0.31, ‐0.10]
1.6.2 Milnacipran	5	3165	Std. Mean Difference (IV, Random, 95% CI)	0.02 [‐0.05, 0.10]
1.7 Self‐reported health‐related quality of life Show forest plot	14	6861	Std. Mean Difference (IV, Random, 95% CI)	‐0.20 [‐0.25, ‐0.15]

1.7.1 Duloxetine	7	2604	Std. Mean Difference (IV, Random, 95% CI)	‐0.22 [‐0.30, ‐0.13]
1.7.2 Milnacipran	7	4257	Std. Mean Difference (IV, Random, 95% CI)	‐0.19 [‐0.25, ‐0.12]
1.8 Self‐reported pain relief of 30% or greater Show forest plot	15	6924	Risk Difference (IV, Random, 95% CI)	0.10 [0.08, 0.12]

1.8.1 Duloxetine	7	2588	Risk Difference (IV, Random, 95% CI)	0.11 [0.07, 0.15]
1.8.2 Milnacipran	8	4336	Risk Difference (IV, Random, 95% CI)	0.10 [0.07, 0.13]
1.9 Self‐reported mean pain intensity Show forest plot	16	7014	Std. Mean Difference (IV, Random, 95% CI)	‐0.22 [‐0.27, ‐0.17]

1.9.1 Desvenlafaxine	1	82	Std. Mean Difference (IV, Random, 95% CI)	0.16 [‐0.27, 0.59]
1.9.2 Duloxetine	7	2619	Std. Mean Difference (IV, Random, 95% CI)	‐0.26 [‐0.35, ‐0.18]
1.9.3 Milncipran	8	4313	Std. Mean Difference (IV, Random, 95% CI)	‐0.20 [‐0.26, ‐0.13]
1.10 Self‐reported depression Show forest plot	14	6478	Std. Mean Difference (IV, Random, 95% CI)	‐0.16 [‐0.21, ‐0.11]

1.10.1 Duloxetine	7	2264	Std. Mean Difference (IV, Random, 95% CI)	‐0.25 [‐0.34, ‐0.17]
1.10.2 Milnacipran	7	4214	Std. Mean Difference (IV, Random, 95% CI)	‐0.11 [‐0.17, ‐0.05]
1.11 Self‐reported anxiety Show forest plot	9	3533	Std. Mean Difference (IV, Random, 95% CI)	‐0.08 [‐0.21, 0.05]

1.11.1 Duloxetine	4	1403	Std. Mean Difference (IV, Random, 95% CI)	‐0.07 [‐0.17, 0.04]
1.11.2 Milnacipran	5	2130	Std. Mean Difference (IV, Random, 95% CI)	‐0.11 [‐0.36, 0.13]
1.12 Self‐reported disability Show forest plot	13	6789	Std. Mean Difference (IV, Random, 95% CI)	‐0.21 [‐0.26, ‐0.16]

1.12.1 Duloxetine	7	2602	Std. Mean Difference (IV, Random, 95% CI)	‐0.29 [‐0.37, ‐0.21]
1.12.2 Milnacipran	6	4187	Std. Mean Difference (IV, Random, 95% CI)	‐0.16 [‐0.22, ‐0.10]
1.13 Self‐reported cognitive disturbances Show forest plot	8	5444	Std. Mean Difference (IV, Random, 95% CI)	‐0.16 [‐0.21, ‐0.10]

1.13.1 Duloxetine	3	1360	Std. Mean Difference (IV, Random, 95% CI)	‐0.27 [‐0.38, ‐0.16]
1.13.2 Milnacipran	5	4084	Std. Mean Difference (IV, Random, 95% CI)	‐0.12 [‐0.18, ‐0.05]
1.14 Tenderness Show forest plot	5	1444	Std. Mean Difference (IV, Random, 95% CI)	‐0.21 [‐0.33, ‐0.09]

1.14.1 Duloxetine	4	1364	Std. Mean Difference (IV, Random, 95% CI)	‐0.23 [‐0.35, ‐0.12]
1.14.2 Milnacipran	1	80	Std. Mean Difference (IV, Random, 95% CI)	0.12 [‐0.31, 0.56]
1.15 Withdrawal due to lack of efficacy Show forest plot	14	6924	Risk Difference (IV, Random, 95% CI)	‐0.03 [‐0.04, ‐0.02]

1.15.1 Desvenlafaxine	1	82	Risk Difference (IV, Random, 95% CI)	0.07 [‐0.02, 0.16]
1.15.2 Duloxetine	7	2642	Risk Difference (IV, Random, 95% CI)	‐0.04 [‐0.06, ‐0.02]
1.15.3 Milnacipran	6	4200	Risk Difference (IV, Random, 95% CI)	‐0.02 [‐0.04, ‐0.01]
1.16 Nausea Show forest plot	12	6606	Risk Difference (IV, Random, 95% CI)	0.16 [0.14, 0.19]

1.16.1 Desvenlafaxine	1	82	Risk Difference (IV, Random, 95% CI)	0.04 [‐0.10, 0.18]
1.16.2 Duloxetine	6	2432	Risk Difference (IV, Random, 95% CI)	0.19 [0.15, 0.22]
1.16.3 Milnacipran	5	4092	Risk Difference (IV, Random, 95% CI)	0.15 [0.12, 0.18]
1.17 Somnolence Show forest plot	7	2514	Risk Difference (IV, Random, 95% CI)	0.05 [0.02, 0.08]

1.17.1 Desvenlafaxine	1	82	Risk Difference (IV, Random, 95% CI)	‐0.05 [‐0.17, 0.06]
1.17.2 Duloxetine	6	2432	Risk Difference (IV, Random, 95% CI)	0.06 [0.03, 0.09]
1.18 Insomnia Show forest plot	9	5387	Risk Difference (M‐H, Random, 95% CI)	0.03 [0.01, 0.04]

1.18.1 Desvenlafaxine	1	82	Risk Difference (M‐H, Random, 95% CI)	‐0.08 [‐0.18, 0.03]
1.18.2 Duloxetine	4	1684	Risk Difference (M‐H, Random, 95% CI)	0.04 [0.01, 0.07]
1.18.3 Milnacipran	4	3621	Risk Difference (M‐H, Random, 95% CI)	0.03 [0.01, 0.04]

Comparison 1. SNRIs versus placebo in parallel and cross‐over design trials

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