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Serotonin and noradrenaline reuptake inhibitors (SNRIs) for
fibromyalgia syndrome (Review)
Häuser W, Urrútia G, Tort S, Üçeyler N, Walitt B
This is a reprint of a Cochrane review, prepared and maintained by The Cochrane Collaboration and published in The Cochrane Library
2013, Issue 4
http://www.thecochranelibrary.com
Serotonin and noradrenaline reuptake inhibitors (SNRIs) for fibromyalgia syndrome (Review)
Copyright © 2013 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
TABLE OF CONTENTS
HEADER . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
ABSTRACT . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
PLAIN LANGUAGE SUMMARY . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
SUMMARY OF FINDINGS FOR THE MAIN COMPARISON . . . . . . . . . . . . . . . . . . .
BACKGROUND . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
OBJECTIVES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
METHODS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
RESULTS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Figure 1.
. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Figure 2.
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Figure 3.
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Figure 4.
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Figure 5.
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Figure 6.
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DISCUSSION . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
AUTHORS’ CONCLUSIONS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
ACKNOWLEDGEMENTS
. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
REFERENCES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
CHARACTERISTICS OF STUDIES . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
DATA AND ANALYSES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Analysis 1.1. Comparison 1 SNRI versus placebo final treatment, Outcome 1 Pain. . . . . . . . . . . . .
Analysis 1.2. Comparison 1 SNRI versus placebo final treatment, Outcome 2 30% pain reduction. . . . . . .
Analysis 1.3. Comparison 1 SNRI versus placebo final treatment, Outcome 3 50% pain reduction. . . . . . .
Analysis 1.4. Comparison 1 SNRI versus placebo final treatment, Outcome 4 Fatigue. . . . . . . . . . . .
Analysis 1.5. Comparison 1 SNRI versus placebo final treatment, Outcome 5 Sleep problems. . . . . . . . .
Analysis 1.6. Comparison 1 SNRI versus placebo final treatment, Outcome 6 Depression. . . . . . . . . . .
Analysis 1.7. Comparison 1 SNRI versus placebo final treatment, Outcome 7 Anxiety. . . . . . . . . . . .
Analysis 1.8. Comparison 1 SNRI versus placebo final treatment, Outcome 8 Disease-related quality of life. . . .
Analysis 1.9. Comparison 1 SNRI versus placebo final treatment, Outcome 9 Disability. . . . . . . . . . .
Analysis 1.10. Comparison 1 SNRI versus placebo final treatment, Outcome 10 Cognitive disturbances. . . . . .
Analysis 1.11. Comparison 1 SNRI versus placebo final treatment, Outcome 11 Participant-perceived improvement.
Analysis 1.12. Comparison 1 SNRI versus placebo final treatment, Outcome 12 Tenderness. . . . . . . . . .
Analysis 1.13. Comparison 1 SNRI versus placebo final treatment, Outcome 13 Withdrawal due to adverse events. .
Analysis 1.14. Comparison 1 SNRI versus placebo final treatment, Outcome 14 Serious adverse events. . . . . .
Analysis 2.1. Comparison 2 Active drug baseline and final treatment, Outcome 1 Pain. . . . . . . . . . . .
Analysis 2.2. Comparison 2 Active drug baseline and final treatment, Outcome 2 Quality of life. . . . . . . .
Analysis 3.1. Comparison 3 Placebo baseline and final treatment, Outcome 1 Pain. . . . . . . . . . . . .
Analysis 3.2. Comparison 3 Placebo baseline and final treatment, Outcome 2 Quality of life. . . . . . . . . .
ADDITIONAL TABLES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
APPENDICES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
WHAT’S NEW . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
CONTRIBUTIONS OF AUTHORS . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
DECLARATIONS OF INTEREST . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
SOURCES OF SUPPORT . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
DIFFERENCES BETWEEN PROTOCOL AND REVIEW . . . . . . . . . . . . . . . . . . . . .
INDEX TERMS
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[Intervention Review]
Serotonin and noradrenaline reuptake inhibitors (SNRIs) for
fibromyalgia syndrome
Winfried Häuser1 , Gerard Urrútia2 , Sera Tort3 , Nurcan Üçeyler4, Brian Walitt5
1 Department of Psychosomatic Medicine and Psychotherapy, Technische Universität München, München, Germany. 2 Iberoamerican
Cochrane Centre - IIB Sant Pau, CIBER Epidemiología y Salud Pública (CIBERESP), Spain, Barcelona, Spain. 3 Iberoamerican
Cochrane Centre, Institute of Biomedical Research (IIB Sant Pau), Barcelona, Spain. 4 Department of Neurology, University of
Würzburg, Würzburg, Germany. 5 Georgetown University Medical Center, Washington Hospital Center, Washington, DC, USA
Contact address: Winfried Häuser, Department of Psychosomatic Medicine and Psychotherapy, Technische Universität München,
Langerstr. 3, München, D-81675, Germany. [email protected].
Editorial group: Cochrane Musculoskeletal Group.
Publication status and date: Edited (no change to conclusions), published in Issue 4, 2013.
Review content assessed as up-to-date: 27 December 2012.
Citation: Häuser W, Urrútia G, Tort S, Üçeyler N, Walitt B. Serotonin and noradrenaline reuptake inhibitors (SNRIs) for fibromyalgia
syndrome. Cochrane Database of Systematic Reviews 2013, Issue 1. Art. No.: CD010292. DOI: 10.1002/14651858.CD010292.
Copyright © 2013 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
ABSTRACT
Background
Fibromyalgia syndrome (FMS) is a clinically well-defined chronic condition of unknown etiology characterized by chronic widespread
pain that often co-exists with sleep disturbances, cognitive dysfunction and fatigue. Patients often report high disability levels and poor
quality of life (QOL). Drug therapy focuses on reducing key symptoms and improving quality of life.
Objectives
To assess the benefits and harms of serotonin and noradrenaline reuptake inhibitors (SNRIs) compared with placebo for treating FMS
symptoms in adults.
Search methods
We searched the Cochrane Central Register of Controlled Trials (CENTRAL), (The Cochrane Library 2012, Issue 9), MEDLINE
(1966 to September 2012), EMBASE (1980 to September 2012), www.clinicalstudyresults.org (U.S.-marketed pharmaceuticals) (to
September 2012) and www.clinicaltrials.gov (to September 2012) for published and ongoing trials and examined the reference lists of
reviewed articles.
Selection criteria
We selected randomized, controlled trials of any formulation of SNRIs against placebo for the treatment of FMS in adults.
Data collection and analysis
Two review authors independently extracted the data from the included studies, and assessed the risks of bias of the studies. Discrepancies
were resolved by discussion.
Serotonin and noradrenaline reuptake inhibitors (SNRIs) for fibromyalgia syndrome (Review)
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Main results
Ten studies were included with a total of 6038 participants. Five studies investigated duloxetine against placebo, and five investigated
milnacipran against placebo. A total of 3611 participants were included into duloxetine or milnacipran groups and 2427 participants
into placebo groups. The studies had a low risk of bias in general. Duloxetine and milnacipran had a small incremental effect over
placebo in reducing pain (standardized mean difference (SMD) -0.23; 95% confidence interval (CI) -0.29 to -0.18; 6.1% relative
improvement). One-hundred and ninety-two participants per 1000 on placebo reported an at least 50% pain reduction compared to
280 per 1000 on SNRIs (Risk ratio (RR) 1.49, 95% CI 1.35 to 1.64; number needed to treat to benefit (NNTB) 11, 95% CI 9 to 15).
Duloxetine and milnacipran did not reduce fatigue substantially (SMD -0.14; 95% CI -0.19 to -0.08; 2.5% relative improvement;
NNTB 17, 95% CI 12 to 29), and did not improve QOL substantially (SMD -0.20; 95% CI -0.25 to -0.14; 4.6% relative improvement;
NNTB 12, 95% CI 9 to 17) compared to placebo. There were no statistically significant differences between either duloxetine or
milnacipran and placebo in reducing sleep problems (SMD -0.07; 95% CI -0.16 to 0.03; 2.5% relative improvement). One-hundred
and seven participants per 1000 on placebo dropped out due to adverse events compared to 196 per 1000 on SNRIs. The dropout rate
due to adverse events in the duloxetine and milnacipran groups was statistically significantly higher than in placebo groups (RR 1.83,
95% CI 1.53 to 2.18; number needed to treat to harm (NNTH) 11, 95% CI 9 to 13). There was no statistically significant difference
in serious adverse events between either duloxetine or milnacipran and placebo (RR 0.78, 95% CI 0.55 to 1.12).
Authors’ conclusions
The SNRIs duloxetine and milnacipran provided a small incremental benefit over placebo in reducing pain. The superiority of duloxetine
and milnacipran over placebo in reducing fatigue and limitations of QOL was not substantial. Duloxetine and milnacipran were not
superior to placebo in reducing sleep problems. The dropout rates due to adverse events were higher for duloxetine and milnacipran
than for placebo. The most frequently reported symptoms leading to stopping medication were nausea, dry mouth, constipation,
headache, somnolence/dizziness and insomnia. Rare complications of both drugs may include suicidality, liver damage, abnormal
bleeding, elevated blood pressure and urinary hesitation.
PLAIN LANGUAGE SUMMARY
Serotonin and noradrenaline reuptake inhibitors for fibromyalgia
Researchers in the Cochrane Collaboration conducted a review of research about the effects of serotonin and noradrenaline reuptake
inhibitors (SNRIs) on fibromyalgia syndrome (FMS). After searching for all relevant studies, they found 10 studies with up to 6038
people. Their findings are summarized below.
Adults with FMS, who took the SNRIs duloxetine or milnacipran rather than a fake medication (placebo), were likely to have :
- reduced pain,
- slightly improved quality of life and reduced fatigue,
- no improvement for sleep problems,
- more drug-induced side effects and a greater likelihood of stopping medication.
Serious side effects such as liver damage and suicidality were very rare. There was no difference between the SNRIs duloxetine or
milnacipran and fake medication for these serious side effects.
What is fibromyalgia syndrome and what are serotonin and noradrenaline reuptake inhibitors?
People with FMS suffer from chronic widespread pain, sleep problems and fatigue. There is no cure for FMS at present, so the treatments
aim to relieve the symptoms and to improve quality of life.
Serotonin and noradrenaline are chemicals which are produced by the human body, involved in the regulation of pain, sleep and mood.
Low concentrations of serotonin have been reported in people with FMS. SNRIs are antidepressants that increase the concentration of
serotonin and noradrenaline in the brain.
The SNRIs duloxetine and milnacipran had been approved by the US Food and Drug Administration but not by the European
Medicines Agency for the management of FMS. The US and European Regulatory Authorities differed in their judgment of the efficacy
Serotonin and noradrenaline reuptake inhibitors (SNRIs) for fibromyalgia syndrome (Review)
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and safety of both drugs. Therefore it is important to know for people with FMS and healthcare providers on the effects of SNRIs on
FMS.
Best estimate of what happens to people with FMS when they take duloxetine or milnacipran after an average of 18 weeks
Pain:
Pain was reduced by 50% in:
- 29 out of 100 people taking duloxetine or milnacipran
- 19 out of 100 people taking placebo.
- Therefore, 10 more people in every 100 benefited from duloxetine or milnacipran than benefited from placebo (10% absolute
improvement).
Sleep problems and fatigue:
People taking duloxetine or milnacipran reported a slight reduction in fatigue and the same amount of sleep problems as people taking
placebo.
Disease-related quality of life (QOL):
- People taking duloxetine or milnacipran scored their quality of life as 14 (on a scale of 0 to100),
- People taking placebo scored theirs as 10.
- This means that people taking duloxetine or milnacipran rated their quality of life four points higher than people taking placebo.
Stopping treatment due to the side effects:
- 20 people out of 100 taking duloxetine or milnacipran stopped medication due to side effects.
- 11 people out of 100 taking fake medication stopped medication due to side effects.
- This means that 9 more people out of 100 stopped taking duloxetin or milnacipran than stopped taking fake medication because of
side effects.
Serious adverse events:
There were no differences between duloxetine or milnacipran and fake medication in the number of serious adverse events.
We often do not have precise information about side effects and complications. This is particularly true for rare but serious side
effects. Possible side effects may include nausea, dry mouth, headache, constipation and hyperhidrosis. Rare complications may include
suicidality, liver damage, abnormal bleeding, elevated blood pressure and urinary hesitation.
Serotonin and noradrenaline reuptake inhibitors (SNRIs) for fibromyalgia syndrome (Review)
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Serotonin and noradrenaline reuptake inhibitors (SNRIs) for fibromyalgia syndrome (Review)
Copyright © 2013 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
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286 per 1000
(261 to 317)
Fatigue
Baseline mean 69.4 (SD The mean fatigue in the
(20-100 scale)
12.3)2
intervention groups was
0.14 standard deviations
Higher scores indicate
lower
higher fatigue levels
(0.19 to 0.08 lower)
192 per 1000
Moderate risk population
5656
(9 studies)
5994
(10 studies)
RR 1.49
(1.35 to 1.64)
No of Participants
(studies)
50% pain reduction
SNRI versus placebo
Control
Relative effect
(95% CI)
6038
(10 studies)
Corresponding risk
Assumed risk
Illustrative comparative risks* (95% CI)
Pain (0-100 scale)
Baseline mean 64.4 (SD The mean pain in the inHigher scores indicate 17.0)1
tervention groups was
0.23 standard deviations
higher pain levels
lower
(0.29 to 0.18 lower)
Outcomes
Patient or population: Participants with FMS
Settings: Study centres in North America and Europe
Intervention: SNRI versus placebo
SNRI versus placebo final treatment FMS
S U M M A R Y O F F I N D I N G S F O R T H E M A I N C O M P A R I S O N [Explanation]
⊕⊕⊕⊕
high
⊕⊕⊕⊕
high
⊕⊕⊕⊕
high
Quality of the evidence
(GRADE)
SMD -0.14 (-0.19 to -0.
08)
Absolute improvement 1.
7%
Absolute risk difference
10%
(95% CI 7 to 13)
Relative per cent change
50%
(95% CI 37 to 66)
NNTB 11 (95% CI 9 to 15)
SMD -0.23 (95% CI -0,29
to -0.18)
3.9 % (95% CI 3.1 to 4,
9%) fewer points on the
scale (absolute improvement)
6.1 % (95% CI 4.8 to 7.
7%) relative improvement
NNTB 11 (95% CI 9 to 15)
Comments
Serotonin and noradrenaline reuptake inhibitors (SNRIs) for fibromyalgia syndrome (Review)
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Serious adverse events
Moderate risk population
196 per 1000
(166 to 230)
RR 0.78
(0.55 to 1.12)
5845
(9 studies)
6179
(10 studies)
Withdrawal due to ad- Moderate risk population
verse events
107 per 1000
5987
(10 studies)
Disease-related quality Baseline mean 57.9 (SD The mean health-related
of life
14.1)7
quality of life in the inter(0-100 scale)
vention groups was
Higher scores indicate
0.19 standard deviations
higher burden of disease
lower
(lower quality of life)
(0.24 to 0.14 lower)
RR 1.83
(1.53 to 2.18)
4081
(6 studies)
Sleep problems
Baseline mean 68.0 (23. The mean sleep in the in(0-100 scale)
8)3
tervention groups was
Higher scores indicate
0.07 standard deviations
higher sleep problem
lower
levels
(0.16 lower to 0.03
higher)
⊕⊕⊕
moderate8
⊕⊕⊕⊕
high
⊕⊕⊕⊕
high
⊕⊕
low4,5,6
Absolute risk difference
0%
(95% CI -1 to 0)
Relative percent change
22 %
Absolute risk difference
9%
(95% CI 6 to 12)
Relative percent change
83 %
(95% CI 53 to 118)
NNTH 11 (95% CI 9 to 13)
SMD -0.20 (95% CI -0.25
to -0.14)
Absolute improvement 2.
7%
(95% CI 2.0% to 3.4%)
fewer points on the scale
Relative improvement 4.
6%
(95% CI 1.0 % to 5.8%)
NNTB 12 (95% CI 9 to 17)
(95% CI 1.0% to 2.3%)
fewer points on the scale
Relative improvement 2.
5%
SMD -0.07 (95% CI -0.16
(95% CI 1.4% to 3.4%)
to 0.03)
NNTB 17 (95% 12 to 29)
Absolute improvement 1.
7% (95% CI 0.7% to 3.
8%) fewer points on the
scale
Relative improvement 2.
5%
(95% CI 1.1% to 5.6%)
Serotonin and noradrenaline reuptake inhibitors (SNRIs) for fibromyalgia syndrome (Review)
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19 per 1000
(13 to 27)
2
Arnold 2010b N = 509 participants; Patient Electronic Diary 24 hour pain (0-100)
Clauw 2008: N = 401 participants; MFI NRS 20-100 scale
3 Mease 2009a: N = 223 participants; MOS Sleep problem index NRS 0-100 scale
4,5 Not all studies reported the sleep outcomes
6 95% CI included no effect
7 Arnold 2010b; N = 509 participants; FIQ VAS 0-100 scale
8
Serious adverse events not reported by one study
Abbreviations
FIQ = Fibromyalgia Impact Questionnaire
MFI = Multidimensional Fatigue Inventory
MOS-Sleep problem index = Medical Outcome Study - Sleep problem index
NRS = Numerical rating scale
VAS = Visual analogue scale
1
GRADE Working Group grades of evidence
High quality: further research is very unlikely to change our confidence in the estimate of effect.
Moderate quality: further research is likely to have an important impact on our confidence in the estimate of effect and may change the estimate.
Low quality: further research is very likely to have an important impact on our confidence in the estimate of effect and is likely to change the estimate.
Very low quality: we are very uncertain about the estimate.
*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).
Abbreviations
CI = Confidence interval
FMS = fibromyalgia syndrome
GRADE = Grading of Recommendations, Assessment, Development and Evaluation in clinical guidelines
NNTH = Number Needed to Treat for an additional Harmful outcome
NNTB = Number Needed to Treat for an additional Beneficial outcome
RR = risk ratio
SMD = standardized mean difference
SNRI = serotonin and noradrenaline reuptake inhibitors
24 per 1000
(95% CI 45% improvement to 12% worsening)
BACKGROUND
nervous system. Serotonin and noradrenaline are implicated in the
mediation of endogenous pain inhibitory mechanisms.
Description of the condition
The key symptoms of fibromyalgia syndrome (FMS) are chronic,
widespread pain associated with cognitive dysfunction, sleep disturbances and physical fatigue (Häuser 2008; Wolfe 2010). Correspondingly, patients often report high disability levels and poor
quality of life, along with extensive use of medical care (Hawley
1991; Sauer 2011; Winkelmann 2011; Wolfe 1997). Lacking a
specific laboratory test, diagnosis is established by a history of the
key symptoms and the exclusion of somatic diseases that could
explain the key symptoms (Häuser 2009; Wolfe 2010). For the
clinical diagnosis the American College of Rheumatology (ACR)
1990 classification (Wolfe 1990), the ACR 2010 preliminary diagnostic criteria (Wolfe 2010), and the modified ACR 2010 preliminary diagnostic criteria (survey criteria) can be used (Häuser
2012; Wolfe 2011a). Previously other standardized criteria were
used to diagnose FMS (Smythe 1981; Yunus 1981; Yunus 1982;
Yunus 1984).
The prevalence of FMS in adults in the USA was estimated to
be five million (Lawrence 2008). The estimated overall prevalence
of FMS was 2.9% in the general population of five European
countries (Branco 2010b).
The definite etiology (cause) of this syndrome remains unknown.
A systematic review of studies of candidate genes demonstrated
that 5-HT2A receptor 102T/C polymorphism (multiple forms)
conferred susceptibility to FMS (Lee 2010), while a systematic
review of case-control studies found an association between physical and sexual abuse and FMS (Häuser 2010a). For patients with
rheumatoid arthritis (RA), social disadvantage, psychological distress and RA severity predicted future development of FMS (Wolfe
2011). Several factors are associated with the pathophysiology of
FMS, but the causal relationship is unclear. This includes alterations of central pain pathways, hyporeactivity (low activity) of
the hypothalamus-pituitary-adrenal axis, increased systemic proinflammatory and reduced anti-inflammatory cytokine profiles,
and disturbances in the dopaminergic and serotonergic systems
(Sommer 2012). There is evidence that cardinal pain symptoms of
fibromyalgia may be due to alterations in central processing of sensory input, along with aberrations in the endogenous inhibition
of pain. Exposure to physical or psychosocial stressors as outlined
above may contribute to dysfunctional pain processing (Bradley
2009).
Since specific treatment aimed at altering the pathogenesis is not
possible, drug therapy that focuses on symptom reduction is ubiquitously employed.
How the intervention might work
Dysfunction of serotonin and noradrenaline transmission, which
mediates endogenous analgesic mechanisms via the descending
inhibitory pain pathways in the central nervous system, may play
a key role in the pathophysiology of FMS. Researchers found that
levels of metabolites of biogenic amines key to descending inhibition were lower than normal in at least three FMS body fluid
compartments (Legangneux 2001; Russell 1992). Imbalance or
deficiency in serotonin and noradrenaline is also associated with
other key symptoms of FMS such as fatigue and cognitive deficits
(Bradley 2009). Treatment with SNRI increases transmission of
these neurotransmitters and may improve disease states associated
with serotonin and noradrenaline deficiencies such as pain, fatigue
and cognitive deficits.
Why it is important to do this review
There is a transatlantic difference in the approval of SNRIs as a
treatment for FMS by drug agencies (Briley 2010). The SNRIs duloxetine and milnacipran have been approved by the US Food and
Drug Administration (FDA), but not by the European Medical
Agencies (EMA), for the management of FMS. The FDA stated
that the sponsors of the two drugs had provided adequate evidence of their benefits and harms to support their indication for
the management of FMS (Food and Drug Administration 2009a;
Food and Drug Administration 2009b).The EMA, however, denied clinically relevant effects for both drugs, on the basis of a lack
of robust evidence of efficacy, and because the adverse effects profile was considered to outweigh the benefits (European Medicines
Agency 2008; European Medicines Agency 2010). Meanwhile
new randomized controlled trials with duloxetine (Arnold 2010a),
and milnacipran (Arnold 2010b), were published that had not
been evaluated by the FDA and EMA. With new data available,
and in the light of the divergent appraisals of duloxetine and milnacipran by the FDA and EMA, we saw the need to evaluate
the efficacy and safety of SNRIs according to recently established
methodological standards of pain medicine (Moore 2010a), in order to assist FMS-patients and doctors in shared decision making
on pharmacological treatment options.
OBJECTIVES
Description of the intervention
Serotonin and noradrenaline (norepinephrine) reuptake inhibitors
(SNRIs) act on noradrenergic and serotonergic neurons in the
To assess the benefits and harms of serotonin and noradrenaline
reuptake inhibitors (SNRIs) compared with placebo or other active drug(s) in the treatment of FMS. The outcomes of efficacy
Serotonin and noradrenaline reuptake inhibitors (SNRIs) for fibromyalgia syndrome (Review)
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(benefits) were derived from the key domains as defined by a consensus among experts and people with FMS (Mease 2009a). Safety
(harms) was defined by the frequency of study withdrawals due to
adverse events and of serious adverse events.
METHODS
Criteria for considering studies for this review
(MFI), Fatigue Severity Scale (FSS), or other validated scales) over
single item scales (e.g. Fibromyalgia Impact Questionnaire (FIQ)
fatigue VAS, or other single item scales).
3. Self-reported sleep problems: we used the following preference:
validated combined scale (e.g. Medical Outcomes Study (MOS)
sleep scale, or other validated scales), over single item assessment
(e.g. FIQ sleep VAS, or other single item scales).
4. Self-reported disease-related quality of life (QOL) measured by
the total score of the Fibromyalgia Impact Questionnaire (FIQ).
5. Safety.
5.1 Withdrawals due to side effects.
5.2 Serious adverse events.
Types of studies
We selected all relevant double-blind randomized controlled trials
(RCTs), with SNRIs and with a study duration of more than four
weeks.
Types of participants
Adults (over 18 years) having a clinical diagnosis of FMS by any
published, recognized and standardized criteria (Smythe 1981;
Wolfe 1990; Wolfe 2010; Wolfe 2011a, Yunus 1981; Yunus 1982;
Yunus 1984).
Types of interventions
We included trials comparing SNRIs with placebo or another active drug with proven efficacy to reduce FMS-symptoms.
We allowed co-interventions, such as physical therapy or other
drugs different from those being assessed in the trial.
We considered the following SNRIs in this review: desvenlaxafine,
duloxetine, milnacipran, venlaxafine
Types of outcome measures
We followed some suggestions of the OMERACT Fibromyalgia
Working Group (Mease 2009b), the Initiative of Methods, Measurement and Pain Assessment in Clinical Trials (IMMPACT)
(Dworkin 2009), and of best practice in the reporting of systematic reviews in chronic pain (Moore 2010a), for selecting outcome
measures.
Minor outcomes
1. Self-reported 30% pain reduction.
2. Self-reported depression: we used the following preference: validated combined scale (Beck Depression Inventory (BDI), or other
validated scales), over single-item assessment (e.g. FIQ subscale
for depression, or other single item scales).
3. Self-reported anxiety: we used the following preference: validated combined scale (Beck Anxiety Inventory (BAI), State Trait
Anxiety Inventory (STAI), or other validated scales), over single
item scale (FIQ anxiety VAS, or other single item scales).
4.Self-reported disability (impairment of physical function): we
used the following preference: validated combined scale (Brief Pain
Inventory (BPI) interference from pain, Short-Form Health Survey (SF-36) physical summary score, or other validated scales),
over single item scale (FIQ physical impairment VAS, or other
single item scales).
5. Self-reported sexual function: we used the following preference: validated combined scale (Arizona Sexual Experience Scale,
or other validated scale), over single item scale.
6. Patient perceived global improvement (Patient Global Impression of Change (PGIC), or Clinical Global Impression (CGI) of
severity).
7. Self-reported cognitive disturbances: validated combined scale
(Multiple Ability Self-report Questionnaire (MASQ), or any other
validated scale), over single item scale.
8. Tenderness: measurement of tender point pain threshold.
Major outcomes
Search methods for identification of studies
1. Self-reported pain: we used the following preference: a) electronic diaries over paper; b) 24-hour recall pain, weekly recall pain
with visual analogue scale (VAS); c) paper VAS, paper numeric 11point ordinal scale (Numeric Rating Scale NRS), combined pain
measures, pain drawings.
1.1 Self-reported pain.
1.2 Self-reported 50% pain reduction.
2. Self-reported fatigue: we used the following preference: validated combined scale (e.g. Multidimensional Fatigue Inventory
We ran an electronic search in the Cochrane Central Register of
Controlled Trials (CENTRAL) (The Cochrane Library 2012, Issue
9), MEDLINE accessed through PubMed (1966 to September
2012), and EMBASE accessed through OVID (1980 to September
2012). Furthermore we searched www.clinicalstudyresults.org (
U.S.-marketed pharmaceuticals) and www.clinicaltrials.gov (website of the US National Institute of Health) to 12 September 2012
for ongoing trials (See Appendix 1). We searched bibliographies
from reviewed articles and we retrieved relevant articles. Our search
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included all languages. We analyzed the reports of the approval of
duloxetine and milnacipran for FMS of the FDA center for drug
evaluation and research (Food and Drug Administration 2009a;
Food and Drug Administration 2009b). We contacted content
experts for unpublished and further possible studies.
Data collection and analysis
Selection of studies
Two review authors (GU,ST) independently scrutinized all the
titles and abstracts revealed by the searches and determined which
fulfilled the selection criteria. A third review author (WH) verified
that the selection had been properly realized.
Data extraction and management
Two review authors (NÜ, WH) extracted data independently onto
a specially designed data extraction form. We would have resolved any disagreements by discussion with the third review author (GU), but this was not necessary. One author (WH) entered
data into Review Manager (RevMan) and a second author (NÜ)
checked them. Discrepancies were resolved by discussion.
Assessment of risk of bias in included studies
Two review authors (NÜ,WH) independently assessed the risk of
bias of each included trial. We resolved disagreements by consensus and, if needed, referral to a third review author (ST). For each
included study, we assessed risk of bias against key criteria: random sequence generation (selection bias); allocation concealment
(selection bias); incomplete outcome data (attrition bias); selective outcome reporting (reporting bias); blinding of participants
and personnel (performance bias); blinding of outcome assessment (detection bias) in accordance with methods recommended
by The Cochrane Collaboration (Higgins 2011). Each of these criteria was explicitly judged as being of: low risk of bias, high risk of
bias or unclear risk of bias (i.e. lack of information or uncertainty
over the potential for bias). The quality of evidence was rated by
the GRADE approach with GRADEprofiler (Guyatt 2011).
large effect size (Cohen 1988). We considered values of g less than
0.2 to equate to a “not substantial” effect size.
Differences in mean reductions of symptoms between active drug
and placebo groups do not adequately describe the potential benefit of a drug treatment. The differences between treatment and
placebo group reflect the incremental benefit of active treatment
that contribute to treatment effect after subtracting out placebo,
natural history and regression to the mean (Dworkin 2009). The
differences between treatment and placebo group in FMS are limited by the magnitude of the response in the placebo group that
accounts for approximately 50% of the treatment response in the
active drug groups in FMS trials (Häuser 2011a). Therefore, we
calculated the MD of the pain and QOL outcomes at baseline and
at final treatment for active drug and placebo groups to give an
impression of the potential of true drug and placebo. Pain outcomes were converted to a 0 to 10 scale. QOL outcomes (FIQ
total score) were converted to a 0 to 100 scale. We calculated the
mean baseline pain and QOL scores in the placebo group by using
the generic inverse method. We used the following benchmarks:
a) pain reduction: i) 20% to 30% decrease classed as minimally
important; ii) 30% to 50% decrease classed as moderately important; iii) 50% or more decrease classed as substantial (Dworkin
2008); b) Health-Related Quality of Life (HRQOL) (FIQ total
score): minimal clinically important difference defined as at least
a 14% reduction (Bennett 2009).
The numbers needed to treat for an additional beneficial outcome (NNTBs) for continuous variables (fatigue, sleep problems,
HRQOL) were calculated using the Wells calculator software available at the Cochrane Musculoskeletal Group editorial office, which
estimates, from the SMDs, the proportion of participants who will
benefit from treatment. The estimation of responders is nearly independent of the minimally important difference (MIT) (Norman
2001). We used a MIT of 0.5 for calculation.
Unit of analysis issues
In trials where multiple SNRI-dosage arms were compared with
one placebo group, for continuous outcomes we adjusted the number of participants in the placebo group according to the number
of participants in the different SNRI-dosage arms. For dichotomous variables we pooled the different SNRI dosage arms and
compared the pooled results with the placebo arm.
Measures of treatment effect
Dealing with missing data
The effect measures of choice were risk ratio (RR) for dichotomous
data and mean difference (MD) or standardized mean difference
(SMD) (when different scales were used to measure outcomes) for
continuous data. Uncertainty was expressed with 95% confidence
intervals (CIs). We used Cohen’s categories to evaluate the magnitude of the effect size, calculated by SMD, with values for Hedges’
g as follows: 0.2 to 0.5 equating to a small effect size, 0.5 to 0.8
equating to a medium effect size, and more than 0.8 equating to a
We used intention-to-treat (ITT) analysis data. The ITT population consisted of participants who were randomized, took the
assigned study medication, and provided at least one post-baseline
assessment. Wherever possible, we assigned zero improvement to
missing participants. However, most studies in chronic pain report
results, including responder results, using last observation carried
forward. This has been questioned as being potentially biased, as
withdrawal is an important outcome that makes last observation
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carried forward unreliable. Last observation carried forward can
lead to overestimation of efficacy, particularly in situations where
adverse event withdrawal rates differ between active and control
groups. At this time it is unclear what strategy can actually be
used to deal with missing data inside studies (Moore 2012). We
examined and reported imputation strategies clearly.
Where means or SDs were missing, attempts were made to obtain
these data through contacting trial authors. Where SDs were not
available from trial authors, they were calculated from t-values,
CIs or standard errors, where reported in articles (Higgins 2011).
Where 30% and 50% pain reduction rates were not reported and
not provided on request, they were calculated from means and
SDs by a validated imputation method (Furukawa 2005).
Assessment of heterogeneity
We used the I2 statistic for heterogeneity. I2 statisitic values less
than 25% indicate low heterogeneity; values of 25% to 50% indicate moderate heterogeneity, and values of 50% or over indicate
substantial heterogeneity (Higgins 2011).
A more detailed analysis of European versus non-European participants was not possible because the studies with mixed continent
samples did not report how many participants were recruited from
each continent. We decided to restrict the comparisons on the key
domains of FMS (pain, fatigue, sleep) and adverse events in order
not to inflate the number of comparisons. To test the hypotheses
of a subgroup effect, a test of interaction with a predetermined
two-tailed α value of 0.05 was used for subgroup analysis of studies with and without European participants (Altman 2003). The
intended subgroup analyses with gender and pain were not conducted because individual patient data were not available.
Sensitivity analysis
The intended sensitivity analyses (different statistical models applied, presence of temporal differences, diagnostic criteria used
in the trial, according to the presence/absence of any mental or
psychiatric disorder, and according to the presence/absence of any
concomitant systemic disease) were not conducted, because the
studies did not differ in these characteristics.
Assessment of reporting biases
Publication bias was addressed by visual inspection of funnel plots
and tests for funnel plot asymmetry (Begg 1994; Egger 1997),
when there were at least 10 studies included in the meta-analysis
(Higgins 2011).
Outcome reporting bias was addressed by checking whether the
means and SDs of all primary and secondary outcomes outlined
in the methods section of the published studies had been reported,
or provided on request.
Data synthesis
We undertook each meta-analysis using a random-effects model
in RevMan.
Subgroup analysis and investigation of heterogeneity
We performed a subgroup analysis of duloxetine, and milnacipran,
studies to test for potential differences in benefits and harms of
these two drugs. We performed a subgroup analysis of studies with
and without European participants to test for potential transatlantic differences between the efficacy and adverse events of SNRIs.
RESULTS
Description of studies
See: Characteristics of included studies; Characteristics of excluded
studies.
We initially identified 3755 studies. We excluded 3735 references
as they did not fulfill inclusion criteria related to the interventions evaluated in this review. We did not find head-to-head comparisons of SNRIs or of SNRIs with other drugs used for FMStreatment. We identified 20 studies potentially related to SNRIs,
and the full text was obtained for each of them. We excluded 10
studies (Branco 2011; Chappell 2009; Dwight 1998; Gendreau
2005; Goldenberg 2010; Hsiao 2007; Mease 2010; Sayard 2003;
Saxe 2012; Wyeth 2008). See the Characteristics of excluded
studies table for further details about reasons for exclusion and
Figure 1 for studies’ flow. Finally, we included 10 studies. See the
Characteristics of included studies table for a full description of
the studies.
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Figure 1. Study flow diagram.
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Included studies
We included five studies comparing placebo with duloxetine (
Arnold 2004; Arnold 2005; Arnold 2010a; Chappell 2008; Russell
2008), and five studies comparing placebo with milnacipran (
Arnold 2010b; Branco 2010; Clauw 2008; Mease 2009a; Vitton
2004), in the analysis.
mg/day, and in milnacipran trials was hydrocodone up to 60 mg/
day.
Major outcomes
Pain
Study characteristics
All studies were conducted in research centers. Five studies were
conducted in the USA (Arnold 2004; Arnold 2005; Clauw 2008;
Mease 2009a; Vitton 2004), two studies in the USA and Puerto
Rico (Arnold 2010a; Russell 2008), one study each in the USA
and Western Europe (Chappell 2008), in the USA and Canada
(Arnold 2010b), and in Europe (Branco 2010). All studies had a
parallel design. The median of the therapy phase of the studies was
17.5 weeks (range 12 to 27 weeks). A total of 3611 participants
were included into true drug groups, and 2427 participants into
placebo groups. The mean of participants in all true drug group
arms was 366 (range 97 to 605), and in placebo groups was 241
(range 28 to 509).
All studies used different measures for pain. We selected the predefined primary outcome variables of the studies for analysis.
Pain was assessed in duloxetine studies by the Brief Pain Inventory
(BPI) 24 average pain score, and in milnacipran trials by the patient
electronic diary 24-hour recall pain.
Fatigue
Fatigue was assessed either by the single item of the FIQ (Arnold
2004; Arnold 2005; Vitton 2004), or by the Multidimensional
Fatigue Inventory (MFI) in the other studies. The fatigue score of
the FIQ was not reported by one study (Arnold 2005).
Sleep disturbances
Participant characteristics
Participants were recruited in duloxetine trials by referral and advertisement in media, and in milnacipran trials by referral. All
studies included participants over 18 years old. All studies excluded participants with somatic diseases including inflammatory
rheumatic diseases. All duloxetine studies included participants
with mental disorders, except for major depression (all studies)
and general anxiety disorder (all but one study (Arnold 2010a)).
All milnacipran studies excluded participants with severe mental
disorders including major depression. One study did not report
the number of participants screened (Chappell 2008). In nine
studies 5740 of the 10,589 screened participants (54.2%) were
randomized. Middle-aged white women prevailed in all studies:
the median of the mean age was 49 years (range 47 to 51 years).
The median of the percentage of women was 95% (range 92% to
100%). The median of the percentage of whites was 89.5% (range
77.5% to 97.5%).
Sleep disturbances were assessed by the BPI sleep interference scale
in the duloxetine studies, and by Medical Outcomes Study (MOS)
in three milnacipran studies (Branco 2010; Clauw 2008; Mease
2009a). The Vitton 2004 study used the Jenkins Sleep Scale. Three
duloxetine studies did not report the sleep outcomes (Arnold 2004;
Arnold 2010a; Chappell 2008). One milnacipran study did not
report on the assessment of sleep outcomes (Arnold 2010b).
Quality of life
All studies except one reported the FIQ-total score as a measure of disease-specific health-related quality of life (HRQOL)
(Arnold 2010a). Cognitive disturbances (“fibro fog”) were assessed
in three duloxetine studies by the mental fatigue subscale of the
MFI (Arnold 2010a; Chappell 2008; Russell 2008), and in four
milnacipran studies by the Multiple Ability Self-report Questionnaire (MASQ) (Arnold 2010b; Branco 2010; Clauw 2008; Mease
2009a).
Interventions
All studies, except for three (Arnold 2010a; Arnold 2010b; Vitton
2004), had fixed dosages. In five studies two dosages of SNRIs
(duloxetine 60 and 120 mg/day and milnacipran 100 and 200
mg/day) were tested against placebo (Arnold 2005; Clauw 2008;
Mease 2009a; Russell 2008; Vitton 2004). The other studies had
a single SNRI-arm. The rescue medication in duloxetine trials was
acetaminophen (paracetamol) up to 2 g/day and aspirin up to 325
Adverse events
All studies used physical examination, electrocardiograms, and laboratory analysis for the assessment of adverse events. Four studies did not report details about how subjective adverse symptoms
were assessed (Arnold 2004; Arnold 2005; Arnold 2010a; Arnold
2010b). Three studies reported the recording of spontaneously-reported adverse events (Chappell 2008; Russell 2008; Vitton 2004),
Serotonin and noradrenaline reuptake inhibitors (SNRIs) for fibromyalgia syndrome (Review)
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another two studies reported spontaneously-reported and investigator-observed adverse events (Clauw 2008; Mease 2009a), and
one study reported both spontaneously-reported and observerassessed (use of non-leading questions) adverse events (Branco
2010).
Minor outcomes
Depression and anxiety
Depression was assessed in all studies by the Beck Depression
Inventory (BDI), except for the Arnold 2005 study that used the
Hamilton Depression Rating Scale (HDRS), and Vitton 2004 that
used the FIQ single item depression scale. Anxiety was assessed
by the Beck Anxiety Inventory (BAI) in three studies (Arnold
2004; Arnold 2010a; Arnold 2010b), by the Stait-Trait Anxiety
Inventory (STAI) in one study (Branco 2010), and by the FIQ
single item scale in one study (Vitton 2004). The remaining studies
did not assess anxiety.
Disability
We used the BPI average interference scale as a measure of disability
for seven studies. The remaining three studies used three different
measures for disability/physical function, namely subscale data of:
Multidimensional Health Assessment Questionnaire (MDHAQ)
(Clauw 2008); the Short Form Health Survey (SF-36) (Mease
2009a); and the FIQ (Vitton 2004).
Sexual function
Only two studies reported on the assessment of sexual function,
however, one study did not report the data (Clauw 2008), and the
other did not report the SDs (Mease 2009a).
Patient perceived global improvement
All studies but one (Vitton 2004) assessed global improvement
using the patient global impression of change scale (PGIC). The
data presented in one study (Branco 2010) were not suited for
analysis.
Cognitive disturbances
Three studies used the cognitive function subscale of the Multiple
Ability Self-report Questionnaire (MASQ) (Arnold 2010b; Clauw
2008; Mease 2009a), four studies used the mental fatigue subscale
of the Multidimensional Fatigue Inventory (MFI) (Arnold 2010a;
Branco 2010; Chappell 2008; Russell 2008) and three studies
did not assess cognitive disturbances (Arnold 2004; Arnold 2005;
Vitton 2004).
Tender point pain threshold
Tender point pain threshold measurements were only conducted
in four duloxetine studies (Arnold 2004; Arnold 2005; Chappell
2008; Russell 2008).
Risk of bias in included studies
In general, the risk of bias of included studies was low (See Figure
2 and Figure 3 for risk of bias summary and graph). Detailed
information regarding risk of bias assessments of every study are
given in the Characteristics of included studies table.
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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Allocation
Blinding
anxiety outcomes. Clauw 2008 did not report 50% pain reduction rates and anxiety outcomes. Mease 2009a did not report the
standard deviations of sexual dysfunction outcome. Most notably,
the missing outcomes were not provided on request, therefore, a
reporting bias for some outcomes (pain, anxiety, sleep problems,
sexual dysfunction) in some studies cannot be excluded.
Blinding of participants, personnel and outcome assessors were
adequate in all studies.
Effects of interventions
Random sequence generation and allocation concealment were
adequate in all studies.
Incomplete outcome data
All studies used ITT analysis. All studies except Vitton 2004 imputed missing data by baseline or last observation carried forward
method. Most outcomes of the study of Vitton 2004 were based
on observed cases analysis that were provided on request.
See: Summary of findings for the main comparison Serotonin
and noradrenaline reuptake inhibitors (SNRI) versus placebo for
fibromyalgia syndrome (FMS) - results at final treatment
All SNRIs versus placebo
Pain
Selective reporting
Viusal inspection of funnel plots was not indicative for a publication bias. In Egger’s test the intercept of the effect size on pain was
-1.16 (95% CI -0.08 to -2.23) with t equal to 2.30 (two-tailed P
value 0.04). In Begg’s test Kendall’s tau without continuity correction was -0.40 and Z equalled 2.12 (two-tailed P value 0.03).
Both tests were indicative for a publication bias. All studies with
duloxetine and milnacipran had been registered for the application of an approval for FMS-management by regulatory agencies.
We searched these databases, therefore, we do not assume a nonpublication of RCTs with both drugs in FMS.
All studies except Vitton 2004 did not report completely on all
outcomes assessed. Arnold 2004 did not report 30% pain reduction rates, sleep outcomes and serious adverse events. Arnold 2005
did not report anxiety outcomes. Arnold 2010a did not report
sleep problem outcomes. Arnold 2010b did not report sleep problem and anxiety outcomes. Branco 2010 did not report 50% pain
reduction rates. Chappell 2008 did not report sleep problem and
Mean pain reduction
All 10 studies, with 6038 participants, were entered into an analysis
of the effects of SNRIs on pain reduction. The overall effect on
pain was significant (P value < 0.001). The SMD was -0.23 (95%
CI -0.29 to -0.18). According to Cohen’s categories the effect on
pain of SNRIs compared to placebo was small.
50% pain reduction
All 10 studies, with 5994 participants, were entered into an analysis
of the RR of a 50% pain reduction. The response rates for two
studies had to be calculated by an imputation method because
the data had not been reported and were not provided on request
(Branco 2010; Clauw 2008). The RR of a 50% pain reduction by
SNRI versus placebo was significant (P value < 0.0001): the RR
was 1.49 (95% CI 1.35 to 1.64) (see Figure 4).
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Figure 4. Forest plot of comparison: 1 SNRI versus placebo final treatment, outcome: 1.3 50% pain
reduction.
Fatigue
Nine studies, with 5656 participants, were entered into an analysis
of the effects of SNRIs on fatigue reduction. The overall effect on
fatigue was significant (P value < 0.001). SMD was -0.14 (95% CI
-0.19 to -0.08). Based on Cohen’s categories, the effect on fatigue
of SNRIs versus placebo was not substantial.
Sleep problems
Six studies, with 4081 participants, were entered into an analysis
of the effects of SNRIs on reduction of sleep disturbances. The
overall effect on sleep disturbances was not significant (P value =
0.15).
Disease-related quality of life (QOL)
Nine studies, with 5457 participants, were entered into an analysis
of the effects of SNRIs on the total score of the FIQ. The overall
effect on QOL was significant (P value < 0.001). SMD was -0.20 (0.25 to -0.14). Based on Cohen’s categories the effect on disability
of SNRIs versus placebo was not substantial (see Figure 5).
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Figure 5. Forest plot of comparison: 1 SNRI versus placebo final treatment, outcome: 1.8 Disease-related
quality of life.
Withdrawal due to adverse events
All 10 studies, with 6179 participants, were entered into an analysis
of withdrawals due to adverse events. 743 out of 3607 participants
(20.6%) dropped out due to adverse events in true drug groups
and 262 out of 2412 (10.9%) dropped out in placebo groups.
The RR of dropping out due to adverse events was significant (P
value < 0.001). The RR was 1.83 (95% CI 1.55 to 2.15). The
number of participants needed to achieve an incremental harm by
true drug was 11 (96% CI 9 to 13) (see Figure 6).
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Figure 6. Forest plot of comparison: 1 SNRI versus placebo final treatment, outcome: 1.13 Withdrawal due
to adverse events.
Serious adverse events
Nine studies, with 5845 participants, were entered into an analysis
of withdrawals due to serious adverse events. The RR of dropping
out due to serious adverse events was not significant (P value 0.15).
The RR was 0.78 (95% CI 0.55 to 1.12).
30% pain reduction
All 10 studies, with 6004 participants, were entered into an analysis
of the risk ratio (RR) of a 30% pain reduction. The RR of a 30%
pain reduction by SNRI versus placebo was significant (P value <
0.0001): the RR was 1.36 (95% CI 1.26 to 1.46).
Anxiety
Five studies, with 2713 participants, were entered into an analysis
of the effects of SNRIs on anxiety reduction. The overall effect on
anxiety was not significant (P value = 0.54).
Disability
Ten studies, with 5995 participants, were entered into an analysis
of the effects of SNRIs on disability reduction. The overall effect
on disability was significant (P value < 0.001). SMD was -0.22
(95% CI -0.28 to -0.16). Based on Cohen’s categories the effect
on disability of SNRIs versus placebo was small.
Depression
Nine studies, with 5656 participants, were entered into an analysis of the effects of SNRIs on depression reduction. One study
reported only the outcomes of one of three dosage groups (Russell
2008).The overall effect on depression was significant (P value <
0.001). SMD was -0.15 (95% CI -0.21 to -0.10). Based on Cohen’s categories, the effect on depression of SNRIs versus placebo
was not substantial.
Sexual function
Two studies reported on the assessment of sexual function. A quantitative synthesis was not possible due to a lack of data reporting
(Clauw 2008). In one study both milnacipran arms did not differ significantly from placebo in reducing sexual problems (Mease
2009a).
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Patient perceived global improvement
Placebo baseline and final treatment
Eight studies, with 4551 participants, were entered into an analysis
of the effects of SNRIs on patient perceived global improvement.
The overall effect on patient perceived global improvement was
significant (P value < 0.001). SMD was -0.27 (95% CI -0.33 to 0.21). Based on Cohen’s categories the effect on patient perceived
global improvement of SNRIs versus placebo was small.
Pain reduction number needed to treat for an additional
beneficial outcome
Cognitive disturbances
Seven studies, with 5344 participants, were entered into an analysis
of the effects of SNRIs on cognitive disturbances. The overall
effect on “fibro fog” was significant (P value < 0.001). SMD was
-0.15 (95% CI -0.21 to -0.10). Based on Cohen’s categories, the
effect on cognitive disturbances of SNRIs versus placebo was not
substantial.
Tenderness
Four studies, with 1364 participants, performed tender point pain
threshold measurement. SNRIs were superior to placebo in raising
the tender point pain threshold (P value < 0.001), suggesting less
tenderness. SMD was -0.23 (95% CI -0.35 to -0.12). Based on
Cohen’s categories the effect on tenderness of SNRIs versus placebo
was small.
SNRIs baseline and final treatment
Pain reduction
The outcomes were converted into a 0 to 10 scale, if necessary.
Ten studies, with 6038 participants, were entered into an analysis
of the mean difference of pain at final treatment and at baseline
in true drug groups. The pooled mean pain score was 6.53 (95%
CI 6.42 to 6.63). The mean difference (MD) was 2.04 (95% CI
1.86 to 2.21) of a 0 to 10 numeric scale. Based on benchmarks
for interpreting changes in chronic pain trials (Dworkin 2008),
SNRIs led to a moderately important (31.2%) pain reduction:
1423 out of 3617 participants (39.3%) reported an at least 30%
pain reduction, and 1118 out of 3566 (31.4%) reported an at least
50% pain reduction.
QOL
The outcomes were converted into a 0 to 100 scale, if necessary.
Nine studies, with 5457 participants, were entered into an analysis
of the mean difference of QOL measured by the FIQ total score
at final treatment and at baseline in true drug groups. The pooled
mean QOL score was 58.42 (95% CI 45.70 to 64.45). The MD
was 14.28 (95% CI 12.84 to 15.72). Based on a benchmark (
Bennett 2009), SNRIs led to a minimal clinically relevant (24.4%)
change in the FIQ total score.
The outcomes were converted into a 0-10 scale, if necessary. Ten
studies, with 4716 participants, were entered into an analysis of
the mean difference of pain at final treatment and at baseline in
placebo groups. The pooled mean pain score was 6.55 ( 95% CI
6.49 to 6.60). The MD was 1.22 (95% CI 1.11 to 1.33) of a 010 numeric scale.
Based on benchmarks for interpreting changes in chronic pain
trials (Dworkin 2008), placebo led to a minimally important
(18.6%) pain reduction: 717 out of 2387 participants (30.0%)
reported an at least 30% pain reduction, and 475 out of 2382
(19.90%) reported an at least 50% pain reduction.
The number needed to treat for an additional beneficial outcome
(NNTB) to achieve an at least 30% pain reduction by true drug
was 11 participants (95% CI 8 to 14). The NNTB to achieve an
at least 50% pain reduction by true drug was nine participants
(95% CI 7 to 11).
QOL
The outcomes were converted into a 0 to 100 scale, if necessary.
Nine studies with 4262 participants were entered into an analysis
of the mean difference of QOL measured by the FIQ total score
at final treatment and at baseline in placebo drug groups. The
pooled mean QOL score was 55.08 (95% CI 45.70 to 64.45).
The MD was 10.06 (95% CI 8.32 to 11.79). Based on a benchmark (Bennett 2009), placebo led to a minimal clinically relevant
(18.6%) change in the FIQ total score.
Subgroup analysis
We restricted the subgroup analyses to the main outcomes.
Duloxetine and milnacipran
Duloxetine was superior to milnacipran in reducing mean pain
and mean sleep problems. The SMD for mean pain reduction
in duloxetine groups was -0.32 (95% CI -0.41 to -0.22) and in
milnacipran groups -0.20 (95% CI -0.26 to -0.13) (Chi² 4.3; P
value 0.04) (see Analysis 1.1). The SMD for mean sleep problem
reduction in duloxetine groups was -0.24 (95% CI -0.37 to 0.12), and in milnacipran groups was 0.02 (95% CI -0.05 to 0.10) (Chi² 12.8; P value 0.0003) (see Analysis 1.5).There were
no significant differences between the two drugs in the other main
outcomes (50% pain reduction, fatigue, QOL, withdrawal due
to adverse events (see Analysis 1.3., Analysis 1.4, Analysis 1.8,
Analysis 1.13)).
Serotonin and noradrenaline reuptake inhibitors (SNRIs) for fibromyalgia syndrome (Review)
Copyright © 2013 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
19
Studies with and without European participants
The RR of a 50% pain reduction was higher in studies without
European participants than with European participants (Z = 2.04;
P value 0.05). There were no significant differences in the other
outcomes (pain, fatigue, QOL, withdrawal due to adverse events)
(see Additional Table 1).
DISCUSSION
Summary of main results
The SNRIs duloxetine and milnacipran had a small incremental
effect compared to the effect placebo had in reducing pain, disability and tenderness, and increasing patient-perceived global improvement. The incremental effect of duloxetine and milnacipran
compared to the effect placebo had in reducing fatigue, depression, limitations of QOL and cognitive disturbances was not substantial. There were no significant differences between duloxetine
or milnacipran and placebo in reducing sleep problems and anxiety. The drop out rate due to adverse events with duloxetine or
milnacipran was significantly higher than with a placebo. There
were no significant differences in the frequency of serious adverse
events between duloxetine or milnacipran and placebo.
Duloxetine and milnacipran led to a moderately important pain
reduction, while placebo led to a minimally important pain reduction. Duloxetine was superior to milnacipran in reducing pain.
Both SNRIs and placebo led to a clinically relevant improvement
of a disease-specific quality of life score.
Overall completeness and applicability of
evidence
We are sure that we did not miss to include a study with the
SNRIs duloxetine and milnacipran, because all trials with these
drugs had been registered within the application of an approval
for FMS-management by regulatory agencies. We cannot rule out
the possibility that negative study results with other SNRIs have
not been published or have been missed by our search strategy. All
statements regarding the efficacy and safety of SNRIs should be
restricted to duloxetine and milnacipran only. We identified one
study investigating desvenlaxafine was terminated prior to completion. The limited data available did not suggest any therapeutic
effect, therefore, it would be inappropriate to suggest a class effect
of SNRIs on FMS-symptoms.
The applicability (external validity) of evidence is strongly limited
for the following reasons:
1. The studies were performed in research centers and not in routine clinical care. It is known that the efficacy of drug therapies
is higher in the context of RCTs than in routine clinical care
(Routman 2010).
2. The exclusion criteria were strict. Participants were not allowed to take some defined concomitant medications for their
FMS symptoms. This excluded a large number of participants
who were unwilling, or unable, to come off medications, such
as other antidepressants and anticonvulsants. For this reason, patient selection in the RCTs was biased towards recruiting participants with less severe symptoms than are seen in the community
(Fuller-Thomson 2012). Participants with other medical disorders, such as inflammatory rheumatic diseases, were also excluded.
The study results cannot be applied to patients with FMS complicated by other medical disorders. Also, the SNRI studies excluded
most participants with psychiatric diagnoses. All except one of the
studies with milnacipran excluded all potential participants with
major mental disorders, while the studies with duloxetine excluded
all participants with major mental disorders except for those with
major depression and general anxiety disorder. The study results
cannot be applied to patients with FMS and concomitant psychiatric disease, except for the duloxetine studies that suggest efficacy
in FMS with major depression and general anxiety disorder.
3. The majority of the participants were middle-aged women.
The authors of the duloxetine-studies provided a pooled subgroup
analysis that demonstrated the efficacy of duloxetine in male participants (Russell 2008). A similar analysis was not available for
milnacipran. Both pharmaceutical companies (Eli-Lilly and Pierre
Fabre/Forest Laboratories) did not present a subgroup analysis of
participants over 65 years of age. The results of these drugs cannot
be applied to children and adolescents with FMS, because they
were excluded from the trials.
The substantial placebo effect seen across all of the SNRI trials is
worth noting here. The improvement seen with placebo is considered to be a clinically significant amount. If a similar improvement
in pain were seen with a new drug that was tested against placebo,
the results would be used to justify its use in FMS. Furthermore,
the high degree of placebo effect seen with SNRIs was observed in
all FMS drug trials (Häuser 2011a).
Quality of the evidence
All of the reviewed studies had been sponsored by pharmaceutical companies. Although the original data of half of the studies
analyzed in this review had been presented to the EMA and the
FDA, a meta-analysis of all studies conducted by an independent
statistical unit had not been performed until now. The quality
of evidence of this review is based on the data presented in peer
reviewed journals and some additional details that were provided
on request by the pharmaceutical companies or principal investigators. However, not all data requested were provided. A selective
non-reporting of some negative study results on pain, sleep and
anxiety, as well as non-reporting of serious adverse events is possible. Despite these limitations, the overall quality of evidence was
high for most primary outcomes in the majority of studies (see
Summary of findings for the main comparison).
Serotonin and noradrenaline reuptake inhibitors (SNRIs) for fibromyalgia syndrome (Review)
Copyright © 2013 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
20
Potential biases in the review process
We searched for unpublished studies with SNRIs other than duloxetine and milnacipran for FMS, but we are not certain that we
identified all other studies that might have been performed but not
published. We did identify one study that tested desvenlaxafine
but it was terminated prior to completion.
Efficacy outcomes were analyzed using last observation carried
forward to impute missing data. This procedure may lead to an
overestimation of efficacy (Moore 2012). The use of the baseline
observation carried forward method has been recommended for
analysis (Moore 2010a). In addition, the 50% pain reduction rates
of two studies with milnacipran were not reported, or provided, on
request (Branco 2010; Clauw 2008). We calculated these values
by an established imputation method (Furukawa 2005).
The influence of allowed co-interventions (e.g. rescue medication)
on positive effects and adverse events was unclear because type and
dosage of co-interventions were not clearly reported or controlled
for.
Agreements and disagreements with other
studies or reviews
We cannot share the conclusion of some reviews that the efficacy
of duloxetine and milnacipran in the management of FMS has
been proven (Arnold 2010c; Kyle 2010; Ormseth 2010; Ursini
2010). Neither drug has a benefit on all key symptoms of FMS.
We confirm the results of a previous analysis, that duloxetine and
milnacipran are superior to placebo in the reduction of pain and
limitations of QOL (Häuser 2011b), but not in the reduction of
fatigue and sleep disturbances. Our results do confirm the conclusions of the aforementioned reviews, that tolerability and safety of both drugs is limited, because a substantial number of participants dropped out of trials due to adverse events. The most
frequent adverse events in both drugs were nausea, dry mouth,
headache, constipation and hyperhidrosis (increased perspiration)
(Häuser 2010b). The lack of difference in serious adverse events
between true drug and placebo demonstrated that both drugs are
rather safe. The subgroup analyses demonstrated that duloxetine
is superior to milnacipran in mean pain reduction, confirming the
conclusions of previous analyses performed with adjusted indirect comparisons that did not include all studies available (Häuser
2010b; Häuser 2011b). This review could not confirm the results
of a previous analysis (Häuser 2011b), that milnacipran is superior
to duloxetine in reducing fatigue, and that duloxetine is superior
to milnacipran in reducing sleep disturbances and limitations of
QOL.
In the light of current regulatory differences regarding the use
of SNRIs in FMS in the USA and Europe, it seems relevant to
comment on whether the data support either of these positions.
It is our view that the trial data show that the benefits of SNRIs
(NNTB = 9 for an incremental 50% pain reduction) are nearly
counterbalanced by the risk of side effects (number needed to
treat for an additional harmful outcome (NNTH) = 11 for an
incremental drop out rate due to adverse events). The data do not
provide clear support for either of the regulatory positions over
the other.
If duloxetine or milnacipran are being considered for the treatment of FMS, a frank discussion between the physician and patient
about the potential benefits and harms of both drugs should occur.
The contraindications (concomitant use of monoaminooxydase
inhibitors, uncontrolled narrow-angle glaucoma, substantial alcohol use or evidence of chronic liver damage) and warnings (suicidality, hepatotoxicity, serotonin syndrome, abnormal bleeding,
discontinuation syndrome, elevated blood pressure, urinary hesitation and retention) should also be kept in mind (Häuser 2010b).
The recommended dosages are duloxetine 60 mg/day, and milnacipran 100 mg/day. Häuser 2010b observed that higher dosages
are not more efficacious, but are associated with more adverse
events.
Monotherapy of FMS with duloxetine and milnacipran should be
discouraged. Current best practices in FMS guidelines recommend
using a combination of pharmacological therapy with aerobic exercise and psychological therapies. Although the combination of
SNRIs with non-pharmacological treatment options has not been
tested in randomized controlled trials, this dearth of data should
not be used as a reason to avoid combination therapy. This is especially true for symptoms where duloxetine and milnacipran are
ineffective, but other therapies are effective, e.g. aerobic exercise
for fatigue (Häuser 2010c), and cognitive-behavioral therapies for
depression (Bernardy 2010).
AUTHORS’ CONCLUSIONS
Implications for practice
Of the SNRIs currently available, only duloxetine and milnacipran
have been sufficiently studied for the management of FMS.The
potential benefit of duloxetine and milnacipran to reduce pain
is counterbalanced by their potential harms: 22% of participants
reported a substantial (at least 50%) pain reduction at post-treatment; 21% discontinued medication due to adverse events. Both
drugs did not reduce sleep problems. Their incremental benefit
over placebo to reduce fatigue was not substantial.
Both drugs have been approved for treatment of FMS in USA, but
not in Europe. Duloxetine is approved in most European countries
for major depression. Its efficacy in pain reduction has been shown
for FMS-patients with and without major depression (Arnold
2005; Russell 2008). In contrast, there are no data available to
show whether milnacipran is effective in FMS-patients with major
depression. Therefore, duloxetine can be regarded to be the first
drug option for FMS-patients with major depression.
Serotonin and noradrenaline reuptake inhibitors (SNRIs) for fibromyalgia syndrome (Review)
Copyright © 2013 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
21
Lastly, it should be noted that the positive effects of duloxetine
and milnacipran on FMS-symptoms has been proven for only six
months in placebo-controlled trials, therefore, a trial of omission
can be considered with responders after these time intervals.
Implications for research
The main research directions that would help in the future include:
Available studies with SNRIs in FMS
Analysis of all studies investigating duloxetine and milnacipran
in FMS at the level of individual patient data could provide important information, e.g. whether or not a clinically important
pain response delivers large functional and quality of life benefits
(Moore 2010b). Moreover, a re-analysis of the data using baseline
observation carried forward, and responder analysis where discontinuation is classified as non-response, would allow a determination of the true efficacy of duloxetine and milnacipran in FMS.
These analyses should be performed by a research team not affiliated with the manufacturers of the drugs.
Future studies with SNRIs in FMS
1. Duloxetine and milnacipran are effective in a minority of patients. Clinical effectiveness trials with SNRIs are necessary; they
should provide information on the proportion of patients with a
moderate or substantial response, with tolerable adverse events,
and with willingness to continue therapy (Moore 2010c).
2. The significance of the two SNRIs duloxetine and milnacipran compared to established therapies such as aerobic exercise, amitriptyline and cognitive-behavioral therapies in the management of FMS still needs to be determined.
3. Clinical studies in FMS should be conducted with patient samples representative of clinical practice including participants with
comorbid anxiety, affective disorders and inflammatory rheumatic
diseases. Moreover, studies should include participants with different durations of disease and levels of severity all over the world.
Subgroup analyses for male participants and seniors should also
be conducted.
4. The assessment strategies of adverse events in RCTs should
be standardized by regulatory agencies. Potential effects of cointerventions on outcomes should be controlled for.
5. The definition of subgroups (e.g. FMS with and without major
depression) and the development of more tailored therapies are
major tasks of future research.
ACKNOWLEDGEMENTS
None.
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Moore 2010c
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173–6.
Moore 2012
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Wiffen P, et al.Estimate at your peril: imputation methods
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Nishishinya 2006
Nishishinya MB, Walitt B, Urrútia G, Mease PJ, Rodríguez
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Ormseth 2010
Ormseth MJ, Eyler AE, Hammonds CL, Boomershine CS.
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Serotonin and noradrenaline reuptake inhibitors (SNRIs) for fibromyalgia syndrome (Review)
Copyright © 2013 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
25
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∗
Indicates the major publication for the study
Serotonin and noradrenaline reuptake inhibitors (SNRIs) for fibromyalgia syndrome (Review)
Copyright © 2013 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
26
CHARACTERISTICS OF STUDIES
Characteristics of included studies [ordered by study ID]
Arnold 2004
Methods
Study setting: multicenter study with 18 outpatient research centres in USA
Study design: parallel
Duration therapy: 12 weeks
Follow-up: not described
Analysis: ITT; LOCF; mixed-effects model: the model included the fixed, categorical
effects of treatment, investigator, visit, and interaction of treatment with visit, as well as
the continuous, fixed covariates of baseline and interaction of baseline with visit
Participants
Participants: 207 (89% female, 87% white, mean age 49 years)
Inclusion criteria: ACR 1990 criteria; score ≥ 4 on the pain intensity item of the FIQ;
age ≥ 18 years; with and without major depressive disorder (MDD)
Exclusion criteria: pain from traumatic injury or structural or regional rheumatic disease; rheumatoid arthritis, inflammatory arthritis, or autoimmune disease; unstable medical or psychiatric illness; current dysthymia, which is more resistant to treatment than
major depression, or primary psychiatric disorder other than MDD; substance abuse
in the last year; history of psychosis; pregnancy or breast feeding; unacceptable contraception in those of childbearing potential; involvement in disability reviews that might
compromise treatment response; use of an investigational drug within 30 days; prior
participation in a study of duloxetine; severe allergic reactions to multiple medications;
intolerance to 3 psychoactive drugs or 1 SSRI; and failure to respond to 2 adequate
regimens of 2 different classes of antidepressants for depression or fibromyalgia. Concomitant medication exclusions included use of medications or herbal agents with CNS
activity (antidepressants required a 7-day washout prior to visit 2 except for monoamine
oxidase inhibitors, which required a 14-day washout, and fluoxetine, which required a
30-day washout); regular use of analgesics with the exception of acetaminophen up to 2
g/day and aspirin up to 325 mg/day; chronic use of sedatives, antiemetics, or antispasmodics; episodic use of anticoagulants; 3 months stable therapy with antihypertensives,
hormones, antiarrhythmics, antidiarrheals, antihistamines, cough/cold preparations (excluding dextromethorphan), or laxatives; and initiation of or change in unconventional
or alternative therapies
Interventions
Active drug: DLX 120 mg (n = 104) for 12 weeks. Titration from 20 mg/day to 60 mg
twice a day during first 2 weeks of the therapy phase, as follows: 20 mg every day for 5
days, 20 mg twice a day for at least 3 days, 40 mg twice a day for at least 2 days, and 60
mg twice a day for the remainder of the study
Placebo (n = 103) for 12 weeks
Rescue and/or allowed medication: acetaminophen (paracetamol) up to 2 g/day and
aspirin up to 325 mg/day
Outcomes
Pain: Brief Pain Inventory (BPI) average pain severity (NRS 0-10)
Fatigue: FIQ single item (VAS 0-10)
Sleep: BPI (NRS 0-10): not reported
Depression: BDI -II total score (NRS 0-63)
Anxiety: Beck Anxiety Inventory total score (NRS 0-63)
Serotonin and noradrenaline reuptake inhibitors (SNRIs) for fibromyalgia syndrome (Review)
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27
Arnold 2004
(Continued)
Disability: BPI interference from pain (NRS 0-10)
Sexual function: not assessed
Quality of life: FIQ total score (0-80)
Cognitive disturbances: not assessed
Global perceived improvement: Patient Global Impression of Change PGIC (1-7)
Tenderness: mean tender point threshold (kg/cm²)
Adverse events (AEs): physical examination, electrocardiograms (EKGs ,ECGs), and
laboratory analysis. Details of assessment of adverse symptoms not reported
Notes
Safety: 90.4% of the DLX and 74.8% of the placebo group reported at least 1 adverse
event (AE) (P < 0.01). DLX-treated subjects reported insomnia, dry mouth, and constipation significantly more frequently than did placebo-treated subjects. Most treatmentemergent AEs were of mild or moderate severity. There were no significant treatment
group differences in the percentage of severe treatment-emergent AEs (details not reported). No deaths were reported
These mean differences in laboratory test were within normal reference ranges and were
not considered clinically relevant. No subject experienced elevated corrected QT intervals
during the study
Risk of bias
Bias
Authors’ judgement
Support for judgement
Random sequence generation (selection Low risk
bias)
Computer-generated random sequence using an interactive response system
Allocation concealment (selection bias)
Low risk
Central independent unit (details reported
on request)
Incomplete outcome data (attrition bias)
All outcomes
Low risk
Imputation using last observation carried
forward for efficacy data. ITT analysis
Selective reporting (reporting bias)
High risk
Outcomes: sleep problems, 30% pain reduction and serious AEs not reported
Blinding of participants and personnel Low risk
(performance bias)
All outcomes
Double blind (number and appearance of
placebo capsules similar, details reported on
request)
Blinding of outcome assessment (detection Low risk
bias)
All outcomes
Independent data imputation and statistical analysis (details reported on request)
Serotonin and noradrenaline reuptake inhibitors (SNRIs) for fibromyalgia syndrome (Review)
Copyright © 2013 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
28
Arnold 2005
Methods
Study setting: multicenter study with 21 outpatient research centres in USA
Study design: parallel
Duration therapy: 12 weeks
Follow-up: not described
Analysis: ITT; LOCF; primary analysis: changes from baseline to endpoint on the BPI
average pain severity score, other efficacy measures were analysed by an analysis of covariance (ANCOVA) model with the terms of treatment, investigator, and baseline score.
Secondary analysis: longitudinal changes from baseline on continuous efficacy measures
analysed with a mixed-effects model for analysis of repeated measures. The model included the fixed, categorical effects of treatment, investigator, visit, and treatment-byvisit interaction, as well as the continuous, fixed covariates of baseline and baseline-byvisit interaction
Participants
Participants: 354 (100% females, 90% white, mean age 49.6 years)
Inclusion criteria: ACR 1990 criteria; score ≥ 4 on the pain intensity item of the FIQ;
age ≥ 18 years; with and without MDD
Exclusion criteria: pain from traumatic injury or structural or regional rheumatic disease; rheumatoid arthritis, inflammatory arthritis, or autoimmune disease; unstable medical or psychiatric illness; current primary psychiatric diagnosis other than MDD, a primary anxiety disorder within the past year (specific phobias allowed); substance abuse
within the past year; serious suicide risk; pregnancy or breast-feeding; women who, in the
opinion of the investigator, were treatment refractory or may have had an involvement in
disability reviews that might compromise treatment response; severe allergic reactions to
multiple medications; or prior participation in a study of DLX. Concomitant medication
exclusions included use of medications or herbal agents with CNS activity; regular use
of analgesics with the exception of acetaminophen up to 2 g/day and aspirin for cardiac
prophylaxis up to 325 mg/day; chronic use of sedatives, antiemetics, or antispasmodics;
and initiation of or change in unconventional or alternative therapies
Interventions
Active drugs
DLX 60 mg/day (118) participants
DLX 120 mg/day (116 participants): forced titration from 60 mg/d to 120 mg/d within
3 days
Placebo (120 participants)
Rescue and or allowed medication: acetaminophen up to 2 g/day and aspirin up to
325 mg/day
Outcomes
Pain: (BPI average pain severity (NRS 0-10)
Fatigue: FIQ (VAS 0-10): not reported
Sleep: BPI sleep interference (NRS 0-10)
Depression: Hamilton Depression Rating Scale HDRS (NRS 0-52)
Anxiety: FIQ (VAS 0-10): not reported
Disability: BPI interference from pain (NRS 0-10)
Sexual function: not assessed
Quality of life: FIQ total score (0-80)
Cognitive disturbances: not assessed
Global perceived improvement: PGIC (1-7)
Tenderness: mean tender point threshold (kg/cm²)
AEs: physical examination, electrocardiograms (EKGs/ECGs), and laboratory analysis.
Details of assessment of adverse symptoms not reported
Serotonin and noradrenaline reuptake inhibitors (SNRIs) for fibromyalgia syndrome (Review)
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29
Arnold 2005
(Continued)
Notes
Safety: 92.4% of the participants in the DLX 60 mg group and 90.5% of the participants
in the DLX 120 mg group reported at least 1 AE compared to placebo group (79.2%).
Participants in the DLX 60 mg and 120 mg groups reported nausea, dry mouth, constipation, decreased appetite and anorexia significantly more frequently than did placebotreated participants. Diarrhea and nasopharyngitis were reported more frequently by
participants treated with DLX 60 mg than did placebo treated participants. Somnolence,
increased sweating, feeling jittery, and nervousness were reported significantly more frequently by participants on DLX 120 mg compared with placebo-treated participants.
There were no significant treatment group differences in the percentage of serious treatment-emergent AEs (1 blood creatine phosphokinase and 1 hepatic enzyme increase
each in DLX groups). No deaths were reported
Mean increases of alkaline phosphatase and a mean decrease in chloride, mean increase
of weight, systolic and diastolic heart pressure in both DLX-groups over placebo were
significant, but not considered clinically relevant
Risk of bias
Bias
Authors’ judgement
Support for judgement
Random sequence generation (selection Low risk
bias)
Computer-generated random sequence using an interactive response system (details
reported on request)
Allocation concealment (selection bias)
Low risk
Central independent unit (details reported
on request)
Incomplete outcome data (attrition bias)
All outcomes
Low risk
Imputation using last observation carried
forward for efficacy data. ITT analysis
Selective reporting (reporting bias)
Unclear risk
Outcome of anxiety not reported
Blinding of participants and personnel Low risk
(performance bias)
All outcomes
Double blind (number and appearance of
placebo capsules similar, details reported on
request)
Blinding of outcome assessment (detection Low risk
bias)
All outcomes
Independent data imputation and statistical analysis (details reported on request)
Serotonin and noradrenaline reuptake inhibitors (SNRIs) for fibromyalgia syndrome (Review)
Copyright © 2013 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
30
Arnold 2010a
Methods
Study setting: multicenter study with 48 outpatient research centres in USA and Puerto
Rico
Study design: parallel
Duration therapy: 24 weeks
Follow-up: not described
Analysis: ITT; LOCF; a restricted maximum likelihood-based MMRM analysis utilized
on longitudinal changes from baseline for continuous efficacy measures.The model included the fixed categorical effects of treatment, investigator, visit, and treatment-byvisit interaction, as well as the continuous, fixed covariates of baseline score and baseline score-by-visit interaction. LOCF changes from baseline to endpoint were analyzed
using an analysis of covariance (ANCOVA) model with the terms of treatment, investigator, and baseline scores. Continuous baseline measures were evaluated using fixedeffects (treatment, investigator) analysis of variance (ANOVA), and categorical baseline
measures were evaluated using Fisher’s exact test. Continuous safety measures were analyzed using MMRM, ANOVA, or ANCOVA as described above, and categorical safety
measures were analyzed using Fisher’s exact test. Rank-transformed laboratory analytes
were analyzed using the ANOVA model to assess treatment differences.
Participants
Participants: 530 (93% female, 77% white, mean age 50 years)
Inclusion criteria: ACR 1990 criteria; score ≥ 4 on the pain intensity item of the FIQ;
age ≥ 18 years; with and without MDD/generalized anxiety disorder (GAD)
Exclusion criteria: current or diagnosed within the past year with any primary psychiatric disorder other than MDD or GAD defined by DSM-IV; clinically judged to be at
serious risk of suicide; had any unstable medical illness likely to require intervention or
hospitalization; pain symptoms unrelated to FM that could interfere with interpretation
of outcome measures; regional pain syndromes; multiple surgeries or failed back syndrome; a confirmed current or previous diagnosis of rheumatoid arthritis, inflammatory
arthritis, or other autoimmune disease; severe liver disease; pregnant or breast-feeding;
or history of substance abuse within the past year. Participants were also excluded if they
had been treated with an adequate trial of DLX and did not respond or could not tolerate
DLX; were judged by the opinion of the investigator to be treatment-refractory in FM;
or whose treatment response might be compromised by disability compensation issues
Interventions
Active drug:DLX flexible 60-120 mg/day (263 participants): DLX was initiated at 30
mg and escalated to 60 mg after 1 week. At week 4 and week 8 visits, DLX dose was
automatically escalated via IVRS by 30 mg daily for those participants who had < 50%
reduction from baseline in their BPI 24-hour pain score and the investigator had endorsed
a dose increase. If the patient could not tolerate the dose increase, it was reduced to the
pre-escalation dose via IVRS
Placebo (267 participants)
Rescue and/or allowed medication: acetaminophen up to 2 g/day and aspirin up to
325mg/day
Outcomes
Pain: BPI 24-h average pain severity (NRS 0-10)
Fatigue: MFI general fatigue (NRS 4-20)
Sleep: bothered by sleep difficulties (NRS 0-10): data extracted from figure
Depression: BDI total score (NRS 0-63)
Anxiety: BAI total score (NRS 0-63)
Disability: BPI pain interference pain (NRS 0-10)
Sexual function: not assessed
Serotonin and noradrenaline reuptake inhibitors (SNRIs) for fibromyalgia syndrome (Review)
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31
Arnold 2010a
(Continued)
Quality of life: FIQ not used
Cognitive disturbances: MFI mental fatigue (NRS 4-20)
Global perceived improvement: PGIC (NRS 1-7)
Tenderness: not assessed
AEs: physical examination, EKGs, and laboratory analysis. Details of assessment of
adverse symptoms not reported
Notes
Safety: significantly more participants in the DLX group than in the placebo group reported at least 1 AE (82.9% vs 71.5%). Participants in the DLX group reported significantly more nausea, headache, constipation,dry mouth, dizziness, diarrhea, hyperhidrosis, hot flush, vomiting, feeling jittery and middle insomnia. Occurrence of constipation
and hyperhydrosis were severe and significantly greater with DLX treatment. There were
no significant treatment group differences in the rate of serious AEs (SAEs) (1 suicidal
ideation in placebo group)
Mean increases in some laboratory tests, mean increase of weight, systolic and diastolic
heart pressure in DLX group over placebo were significant, but not considered clinically
relevant
Risk of bias
Bias
Authors’ judgement
Support for judgement
Random sequence generation (selection Low risk
bias)
Computer-generated random sequence using an interactive response system
Allocation concealment (selection bias)
Low risk
Central independent unit (details reported
on request)
Incomplete outcome data (attrition bias)
All outcomes
Low risk
Imputation using last observation carried
forward for efficacy data. ITT analysis
Selective reporting (reporting bias)
Unclear risk
Outcome of sleep not reported
Blinding of participants and personnel Low risk
(performance bias)
All outcomes
Double blind (number and appearance of
placebo capsules similar-details reported on
request)
Blinding of outcome assessment (detection Low risk
bias)
All outcomes
Independent data imputation and statistical analysis (details reported on request)
Serotonin and noradrenaline reuptake inhibitors (SNRIs) for fibromyalgia syndrome (Review)
Copyright © 2013 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
32
Arnold 2010b
Methods
Study setting: multicenter study with 68 outpatient research centres in USA and Canada
Study design: parallel
Duration therapy: 18-20 weeks
Follow-up: not described
Statistical analysis: ITT, BOCF and LOCF (LOCF data reported);data were analyzed at
each post-baseline visit using an analysis of covariance (ANCOVA) model, with treatment
group and study center as factors and the baseline value as a covariate, except for PGIC,
which were analyzed using analysis of variance (ANOVA)
Participants
Participants: 1025 participants (95% women, 91% white, mean age 49 years)
Inclusion criteria: 1990 ACR criteria, 18-70 years, raw score of ≥ 4 on the FIQ
Exclusion criteria: previous exposure to milnacipran (MLN); treatment with an investigational drug within 30 days of screening; BDI score > 25 at screening or randomization; current major depressive episode as determined by MINI; significant risk of suicide
according to investigator’s judgment or results of the MINI or BDI; lifetime history of
psychosis, hypomania, or mania; substance abuse; other severe psychiatric illness as determined by investigator judgment; history of behavior that would, in the investigator’s
judgment, prohibit compliance for the duration of the study; active or pending disability
claim, workman’s compensation claim, or litigation; pregnancy or breastfeeding; unacceptable contraception; active or unstable medical illness; prostate enlargement or other
genitourinary disorder
Interventions
Active drug: MLN flexible up to 100 mg/day (516 participants): MLN 12.5 mg on days
1-3; MLN 25 mg (12.5 mg twice daily) for 4 days; MLN 50 mg (25 mg twice daily) for
7 days; MLN 75 mg (37.5 mg twice daily) for 7 days; and MLN 100 mg (50 mg twice
daily) for 7 days. If side effects developed, the dose of milnacipran could be temporarily
reduced
Placebo (509 participants)
Rescue and allowed medication: tramadol or hydrocodone between randomisation and
week 4 (end of dose escalation). Permitted analgesic medications were acetaminophen,
aspirin, and NSAIDs
Outcomes
Pain: PED 24-h recall pain score (VAS 0-100)
Fatigue: MFI total (NRS 20-100)
Sleep: BPI sleep interference: not reported
Depression: BDI total score (NRS 0-63)
Anxiety: BAI total score (NRS 0-63)
Disability: BPI pain interference pain (NRS 0-10)
Sexual function: not assessed
Quality of life: FIQ total score (VAS 0-100)
Cognitive disturbances: MASQ cognitive function (NRS 38-190)
Global perceived improvement: PGIC (NRS 1-7)
Tenderness: not assessed
AEs: physical examination, EKGs, and laboratory analysis. Details of assessment of
adverse symptoms not reported
Notes
Safety: AEs reported in 75.0% in the placebo group and 84.1% in MLN group (P < 0.
001). Nausea, constipation, hot flush, dizziness, hyperhidrosis, palpitations, tachycardia
and hypertension more frequent in MLN than in placebo. Proportion of participants
Serotonin and noradrenaline reuptake inhibitors (SNRIs) for fibromyalgia syndrome (Review)
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33
Arnold 2010b
(Continued)
experiencing SAEs was comparable across treatment groups. No deaths reported during
study
Mean increases in some laboratory tests, mean increase of weight, systolic and diastolic
heart pressure in DLX group over placebo were significant, but not considered clinically
relevant
Risk of bias
Bias
Authors’ judgement
Support for judgement
Random sequence generation (selection Low risk
bias)
Computer-generated random sequence using an interactive response system
Allocation concealment (selection bias)
Low risk
Central independent unit
Incomplete outcome data (attrition bias)
All outcomes
Low risk
Imputation using last observation carried
forward for efficacy data. ITT analysis
Selective reporting (reporting bias)
Unclear risk
Outcomes of sleep and anxiety not reported
Blinding of participants and personnel Low risk
(performance bias)
All outcomes
Double blind (number and appearance of
placebo capsules similar, details reported on
request)
Blinding of outcome assessment (detection Low risk
bias)
All outcomes
Independent data imputation and statistical analysis (details reported on request)
Branco 2010
Methods
Study setting: multicenter study with 89 outpatient research centres in 13 European
countries
Study design: parallel
Duration therapy: 17 weeks
Follow-up: not described
Analysis: ITT; LOCF; change from baseline in FIQ score was analyzed using a covariance
analysis (ANCOVA) model with baseline FIQ score as a covariate and country and
treatment as fixed factors. Changes from baseline in other secondary efficacy assessments
were similarly analyzed using ANCOVA
Participants
Participants: 884 (94% female, % white not reported and not provided on request,
mean age 49 years)
Inclusion criteria: 1990 ACR criteria; raw score ≥ 3 on physical function component
of FIQ; baseline VAS pain intensity rating between 40-90 (0-100 scale)
Exclusion criteria: severe psychiatric illness including generalized anxiety disorder or
current major depressive episode (assessed by MINI, BDI27 score > 25), alcohol/substance abuse; significant cardiovascular, respiratory, rheumatoid, rheumatic, hepatic, renal, or other medical condition; systemic infection; epilepsy; active cancer; severe sleep
Serotonin and noradrenaline reuptake inhibitors (SNRIs) for fibromyalgia syndrome (Review)
Copyright © 2013 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
34
Branco 2010
(Continued)
apnea; unstable endocrine disease; active peptic ulcer or inflammatory bowel disease;
prostatic enlargement or other genitourinary disorders (in male participants); pregnancy
or breastfeeding; and history or behavior that would prohibit compliance for the duration of the study
Interventions
Active drug: MLN 200 mg/day (430 participants): 25 mg once daily (evening dose,
days 1 and 2); 25 mg twice daily (days 3-7); 50 mg (days 8-14); 50 mg (morning dose)
and 100 mg (evening dose, days 15-21); and 100 mg (days 22-28). Participants then
entered the 12-week stable-dose treatment period, followed by a 9-day down-titration
phase and a 2-week follow-up phase without treatment
Placebo (446 participants)
Rescue or allowed medication: not reported
Outcomes
Pain: PED 24-h recall pain score (VAS 0-100); 50% response rates not reported and not
provided on request; calculated by imputation method
Fatigue: MFI total (NRS 20-100)
Sleep: MOS-Sleep Index II (NRS 0-100)
Depression: BDI total score (NRS 0-63)
Anxiety: State-Trait Anxiety Inventory (NRS 20-80)
Disability: BPI pain interference pain (NRS 0-10)
Sexual function: not assessed
Quality of life: FIQ total score (VAS 0-100)
Cognitive disturbances: MASQ cognitive function (NRS 38-190)
Global perceived improvement: PGIC: details insufficiently reported
Tenderness: not assessed
AEs: physical examination, EKGs, and laboratory analysis. AEs were assessed throughout
the study based on spontaneous reporting by participants, investigators’ use of nonleading questions, and clinical evaluation
Notes
Safety: a total of 331 (74.2%) placebo-treated participants and 363 (84.2%) milnacipran-treated participants experienced at least 1 treatment-emergent AE (P < 0.01)
. Nausea, hyperhidrosis, constipation, palpitations, hot flush and tachycardia occurred
significantly more frequent in MLN group than in placebo group. Potentially clinically
significant increases in supine systolic BP (≥ 180 mmHg with ≥ 20 mmHg increase
from baseline), diastolic BP (≥ 105 mmHg with ≥ 15 mmHg increase from baseline),
and heart rate (≥ 120 bpm with ≥ 15 bpm increase from baseline) observed in 0.9%,
3.5%, and 1.4%, respectively, of participants treated with milnacipran, compared with
1.1%, 2.0%, and 0.2%, respectively, for placebo-treated participants. No deaths were
reported during the study
Risk of bias
Bias
Authors’ judgement
Random sequence generation (selection Low risk
bias)
Serotonin and noradrenaline reuptake inhibitors (SNRIs) for fibromyalgia syndrome (Review)
Copyright © 2013 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
Support for judgement
Computer-generated random sequence using an interactive response system (details
provided on request)
35
Branco 2010
(Continued)
Allocation concealment (selection bias)
Low risk
Central independent unit (details provided
on request)
Incomplete outcome data (attrition bias)
All outcomes
Low risk
Imputation using last observation carried
forward for efficacy data. ITT analysis
Selective reporting (reporting bias)
High risk
50% pain reduction not reported and not
provided on request; The FDA report on
MLN stated that a female participant committed suicide and that this death was possibly related to MLN
Blinding of participants and personnel Low risk
(performance bias)
All outcomes
Double blind (number and appearance of
placebo capsules similar-details reported on
request)
Blinding of outcome assessment (detection Low risk
bias)
All outcomes
Independent data imputation and statistical analysis (details reported on request)
Chappell 2008
Methods
Study setting: multicenter study with 36 outpatient research centres in Western Europe
(Germany, Spain, Sweden, UK) and USA
Study design: parallel
Duration therapy: 27 weeks
Follow-up: not described
Analysis: ITT; LOCF; an analysis-of-covariance (ANCOVA) model was the primary
analytic method used to analyzed continuous efficacy variables, overall and within subgroups, where the model contained the main effects of treatment and investigator, with
the baseline score as a covariate. The treatment-by-investigator interaction was tested
using a separate ANCOVA. Some efficacy variables measured repeatedly over time were
analyzed using a likelihood-based MMRM approach, to better understand the time profile of response. The model included the fixed categorical effects of treatment, investigator, visit, and treatment-by-visit interaction, as well as the continuous fixed covariates
of baseline score and baseline score-by-visit interaction
Participants
Participants: 330 (93% women, 91% white, mean age 50 years)
Inclusion criteria: ACR 1990 criteria; age ≥ 18 years; with and without MDD
Exclusion criteria: current or previous treatment with DLX; any current primary Axis
I diagnosis other than MDD; pain symptoms related to traumatic injury, structural
rheumatic disease, or regional rheumatic disease (such as osteoarthritis, bursitis, tendonitis); regional pain syndrome; multiple surgeries or failed back syndrome; confirmed
current or previous diagnosis of rheumatoid arthritis, inflammatory arthritis, infectious
arthritis, or an autoimmune disease; and serious medical illness
Serotonin and noradrenaline reuptake inhibitors (SNRIs) for fibromyalgia syndrome (Review)
Copyright © 2013 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
36
Chappell 2008
(Continued)
Interventions
Active drug: DLX 60 mg/day or 120 mg/day (162 participants): participants randomly
assigned to the DLX 60 mg treatment group underwent a titration in which they received
DLX 30 mg for 1 week before receiving DLX 60 mg for 12 weeks. At visit 8 (week 13)
participants who did not have 50% reduction in the BPI-Modified Short Form average
pain scorewere blindly escalated to 120 mg. Those that could not tolerate this dose were
allowed to return to the 60 mg dose. Participants were allowed to increase their dose to
120 mg at any time between visits 8 and 10 (weeks 13 and 23), based upon whether
they had 50% reduction in their BPI average pain score. If at any time between visits 9
and 11 (weeks 18 and 27) participants had tolerability issues with the higher dose (120
mg), they were allowed to go back to the lower dose (60 mg)
Placebo (168 participants)
Rescue or allowed medication: not reported
Outcomes
Pain: BPI 24-h average pain severity (NRS 0-10)
Fatigue: MFI general fatigue (NRS 4-20)
Sleep: BPI sleep interference (NRS 0-10): not reported
Depression: BDI-II total score (NRS 0-63)
Anxiety: FIQ anxiety (VAS 0-10): not reported
Disability: BPI pain interference (NRS 0-10)
Sexual function: not assessed
Quality of life: FIQ total score (VAS 0-80)
Cognitive disturbances: MFI mental fatigue (NRS 4-20)
Global perceived improvement: PGIC (NRS 1-7)
Tenderness: mean tender point threshold (kg/cm²)
AEs: physical examination, EKGs, and laboratory analysis. AEs were assessed throughout
the study based on spontaneous reporting by participants
Notes
Safety: Significantly more participants with DLX reported at least 1 AE compared to
placebo (89.5% vs 81.5%; P 0.04). AEs that occurred in 5% of DLX-treated and twice
the rate of placebo-treated participants included nausea, headache, dry mouth, diarrhoea,
constipation, hyperhidrosis, arthralgia, somnolence, dyspepsia, sleep disorder. No significant difference between treatment groups was observed in the percentage of participants
with at least 1 SAE. There were no deaths
Mean increases of alkaline phosphatase, alanine transaminase and a mean decrease in
chloride, mean increase of weight, systolic and diastolic heart pressure in both DLXgroups over placebo were significant, but not considered clinically relevant
Risk of bias
Bias
Authors’ judgement
Support for judgement
Random sequence generation (selection Low risk
bias)
Computer-generated random sequence
stratified by major depression status within
each study centre
Allocation concealment (selection bias)
Central independent unit (details reported
on request)
Low risk
Serotonin and noradrenaline reuptake inhibitors (SNRIs) for fibromyalgia syndrome (Review)
Copyright © 2013 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
37
Chappell 2008
(Continued)
Incomplete outcome data (attrition bias)
All outcomes
Low risk
Imputation using last observation carried
forward for efficacy data. ITT analysis
Selective reporting (reporting bias)
Unclear risk
Outcomes of sleep and anxiety not reported
Blinding of participants and personnel Low risk
(performance bias)
All outcomes
Double blind (number and appearance of
placebo capsules similar, details reported on
request)
Blinding of outcome assessment (detection Low risk
bias)
All outcomes
Independent data imputation and statistical analysis (details reported on request)
Clauw 2008
Methods
Study setting: multicenter study with 86 outpatient research centres in USA
Study design: parallel
Duration therapy: 15 weeks
Follow-up: not described
Analysis: ITT; BOCF for primary endpoints, LOCF for secondary endpoints; ANCOVA
with baseline values as covariates
Participants
Participants: 1196 (96% female, 93% white, mean age 50 years)
Inclusion criteria: 1990 ACR criteria; raw score ≥ 4 on the physical function component
of the FIQ; baseline VAS pain intensity rating between ≥ 40 (0 to 100 scale)
Exclusion criteria: severe psychiatric illness including generalized anxiety disorder or
current major depressive episode (assessed by MINI), BDI27 score > 25; alcohol/substance abuse; significant cardiovascular, respiratory, rheumatoid, rheumatic, hepatic, renal, or other medical condition; systemic infection; epilepsy; active cancer; severe sleep
apnea; unstable endocrine disease; active peptic ulcer or inflammatory bowel disease;
prostatic enlargement or other genitourinary disorders (in male participants); pregnancy
or breastfeeding; and history or behavior that would prohibit compliance for the duration of the study
Interventions
Active drugs
MLN 100 mg/day (399 participants): dose escalation within 3 weeks
MLN 200 mg/day (396 participants): dose escalation within 3 weeks
Placebo (401 participants)
Rescue medication: hydrocodone up to 60 mg/day
Outcomes
Pain: PED 24-h recall pain score (VAS 0-100); 50% response rates not reported and not
provided on request; calculated by imputation method
Fatigue: MFI total (NRS 20-100)
Sleep: MOS-Sleep Index II (NRS 0-100)
Depression: BDI total score (NRS 0-63)
Anxiety: FIQ anxiety (VAS 0-10): not reported
Disability: MDHAQ disability subscale score
Sexual function: Arizona sexual experience scale: not reported
Serotonin and noradrenaline reuptake inhibitors (SNRIs) for fibromyalgia syndrome (Review)
Copyright © 2013 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
38
Clauw 2008
(Continued)
Quality of life: FIQ total score (VAS 0-100)
Cognitive disturbances: MASQ cognitive function (NRS 38-190)
Global perceived improvement: PGIC (NRS 1-7)
Tenderness: not assessed
AEs: physical examination, EKGs, and laboratory analysis. AEs were
assessed throughout the study based on spontaneous reporting by participants and investigators’ observation
Notes
Safety: 89.7% of the participants in the MLN 100 mg group, 87.4% in the MLN 20 mg
group and 79.1% in the placebo group reported at least 1 AE (P < 0.001). AEs occurring
in ≥ 5% in either MLN group and with an incidence ≥ 2 times as high as in placebo
group were constipation, hot flush, dizziness, palpitations, hyperhidrosis, hypertension,
vomiting, increased heart rate and migraine. No significant differences in potentially
clinically relevant increase in supine heart rate or systolic blood pressure were found
between MLN and placebo groups
Risk of bias
Bias
Authors’ judgement
Support for judgement
Random sequence generation (selection Low risk
bias)
Computer-generated random sequence using an interactive response system (details
provided on request)
Allocation concealment (selection bias)
Low risk
Central independent unit (details provided
on request)
Incomplete outcome data (attrition bias)
All outcomes
Low risk
Imputation using baseline and last observation carried forward for efficacy data. ITT
analysis
Selective reporting (reporting bias)
High risk
Anxiety scores and number of 50% pain
reduction not reported and not provided
on request
Blinding of participants and personnel Low risk
(performance bias)
All outcomes
Double blind (number and appearance of
placebo capsules similar, details reported on
request)
Blinding of outcome assessment (detection Low risk
bias)
All outcomes
Independent data imputation and statistical analysis (details reported on request)
Serotonin and noradrenaline reuptake inhibitors (SNRIs) for fibromyalgia syndrome (Review)
Copyright © 2013 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
39
Mease 2009a
Methods
Study setting: multicenter study with 59 outpatient research centres in USA
Study design: parallel
Duration therapy: 27 weeks
Follow-up: not described
Analysis: ITT; BOCF for primary endpoints, LOCF for secondary endpoints; changes
from baseline in paper-based VAS assessments of pain, as well as other secondary efficacy
assessments, were summarized by treatment group and visit. These data were analyzed
at each post-baseline visit using an ANCOVA model, with treatment group and study
centre as factors and the baseline value as a covariate
Participants
Participants: 888 (95% female, 94% white, mean age 49 years)
Inclusion criteria: 1990 ACR criteria; baseline VAS pain intensity rating between ≥ 50
(0 to 100 scale)
Exclusion criteria: severe psychiatric illness; current major depressive episode (as assessed
by MINI); significant risk of suicide
according to the investigator’s judgment; alcohol or other drug abuse; a history of significant cardiovascular, respiratory, endocrine, genitourinary, liver, or kidney disease; autoimmune disease; systemic infection; cancer or current chemotherapy; significant sleep
apnea; active peptic ulcer or inflammatory bowel disease
Interventions
Active drugs
MLN 100 mg/day (224 participants): dose-escalation period lasted 3 weeks
MLN 200 mg/day (441 participants):dose-escalation period lasted 3 weeks
Placebo (223 participants)
Rescue medication: hydrocodone up to 60 mg/day
Outcomes
Pain: PED 24-h recall pain score (VAS 0-100); missing means and SDs provided on
request
Fatigue: MFI total (NRS 20-100); missing SDs reported on request
Sleep: MOS-Sleep Index I (NRS 0-100); missing SDs provided on request
Depression: BDI total score (NRS 0-63): missing means and SDs provided on request
Anxiety: FIQ (VAS 0-10): not reported
Disability: SF-36 physical function (0-50): missing means and SDs provided on request
Sexual function: Arizona sexual experience scale (NRS 5-30); missing means and SDs
provided on request
Quality of life: FIQ total score (VAS 0-100): missing SDs provided on request
Cognitive disturbances: MASQ cognitive function (NRS 38-190)
Global perceived improvement: PGIC (NRS 1-7): only OC cases reported and analyzed
Tenderness: not assessed
AEs: physical examination, EKGs, and laboratory analysis. AEs were
assessed throughout the study based on spontaneous reporting by participants and investigators’ observation
Notes
Safety: the incidence of treatment-emergent AEs was 85.2% among placebo participants
and 90.7% and 83.9% among participants on MLN 200 mg/day and 100 mg/day,
respectively. AEs occurred in at least 5% of participants in either MLN treatment group,
and at an incidence of 2 times that of placebo participants, and included: constipation,
hyperhidrosis, hot flush, vomiting, increased heart rate, dry mouth, palpitations, and
hypertension
3 participants had SAEs that were judged to be possibly or probably related to study
Serotonin and noradrenaline reuptake inhibitors (SNRIs) for fibromyalgia syndrome (Review)
Copyright © 2013 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
40
Mease 2009a
(Continued)
medication, including 1 case each of chest discomfort, exercise-induced intermittent
rapid heart rate and chest pain, and nausea. Cardiac assessments in the first 2 cases
revealed no evidence of coronary ischemia and neither patient experienced long-term
sequelae. The frequency of potentially clinically significant changes in supine systolic (≥
180 mmHg with an increase of ≥ 20 mmHg from baseline) or diastolic blood pressure
(≥ 110 mmHg with an increase of ≥ 15 mmHg from baseline) was comparable among
MLN-treated and placebo-treated participants
Risk of bias
Bias
Authors’ judgement
Support for judgement
Random sequence generation (selection Low risk
bias)
Computer-generated random sequence using an interactive response system (details
provided on request)
Allocation concealment (selection bias)
Low risk
Central independent unit (details provided
on request)
Incomplete outcome data (attrition bias)
All outcomes
Low risk
Imputation using last observation carried
forward for efficacy data. ITT analysis
Selective reporting (reporting bias)
Unclear risk
Standard deviations of outcome “sexual
dysfunction” not reported and not provided on request
Blinding of participants and personnel Low risk
(performance bias)
All outcomes
Double blind (number and appearance of
placebo capsules similar-details reported on
request)
Blinding of outcome assessment (detection Low risk
bias)
All outcomes
Independent data imputation and statistical analysis (details reported on request)
Serotonin and noradrenaline reuptake inhibitors (SNRIs) for fibromyalgia syndrome (Review)
Copyright © 2013 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
41
Russell 2008
Methods
Study setting: multicenter study with 38 outpatient research centres in USA and Puerto
Rico
Study design: parallel
Duration: 26 weeks
Follow up: not described
Analysis: ITT; LOCF; for continuous efficacy variables, with the exception of the PGI-I
scores, treatment group differences in change from baseline to endpoint were examined
using an analysis of covariance (ANCOVA) model with treatment and investigator as
main effects and the baseline score as the covariate. To assess the robustness of the coprimary endpoints, a
similar ANCOVA analysis in which the baseline observation was carried forward (BOCF)
for all participants who discontinued early was implemented post hoc for the BPI average
pain score. Similarly, for the PGI-I, mean scores at endpoint were reassessed with all
discontinued participants assigned an endpoint PGI-I score of 4, corresponding to “no
change”
Participants
Participants: 520 (95% women, 84% white, mean age 51 years)
Inclusion criteria: ACR 1990 criteria; score ≥ 4 on the pain intensity item of the FIQ;
age ≥ 18 years; with and without MDD
Exclusion criteria: any current primary psychiatric diagnosis other than MDD; pain
symptoms unrelated to fibromyalgia that could interfere with interpretation of outcome
measures; regional pain syndromes; multiple surgeries or failed back syndrome; a confirmed current or previous diagnosis of rheumatoid arthritis, inflammatory arthritis, or
other autoimmune disease; unstable medical or psychiatric disorders; severe liver disease;
current pregnancy or breast-feeding; or a history of substance abuse within the past year.
Participants who were judged by the investigator to be treatment-refractory or whose
response might be compromised by disability compensation issues in the opinion of the
investigator were also excluded
Interventions
Active drugs
DLX 20/60 mg/day (79 participants): blindly increased to 60 mg/day after 3 months
on study drug when participants entered the second half of the 6-month trial
DLX 60 mg/day (150 participants): started at 30 mg/day for 1 week, then titrated to 60
mg/day
DLX 120 mg/day (147 participants): started at 30 mg/day for 1 week, then titrated to
60 mg/day for 1 week, and then to 120 mg/day
Placebo (144 participants)
Rescue and/or allowed medication: acetaminophen up to 2 g/day and aspirin up to
325 mg/day
Outcomes
Pain: BPI average pain severity (NRS 0-10)
Fatigue: MFI general fatigue (NRS 4-20)
Sleep: BPI sleep interference (NRS 0-10): not reported
Depression: BDI-II total score (NRS 0-63): incompletety reported
Anxiety: FIQ anxiety (VAS 0-10): not reported
Disability: BPI pain interference pain (NRS 0-10)
Sexual function: not assessed
Quality of life: FIQ score (VAS 0-80)
Cognitive disturbances: MFI mental fatigue (NRS 4-20)
Serotonin and noradrenaline reuptake inhibitors (SNRIs) for fibromyalgia syndrome (Review)
Copyright © 2013 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
42
Russell 2008
(Continued)
Global perceived improvement: PGIC (NRS 1-7)
Tenderness: mean tender point threshold (kg/cm²)
AEs: physical examination, EKGs, and laboratory analysis. AEs were assessed throughout
the study based on spontaneous reporting by participants
Notes
Safety: the rates of participants in DLX and placebo groups experiencing at least 1 AE
were not reported. 15 treatment-emergent AEs occurred in at least 1 of the DLX groups
at a frequency greater than 5% and twice the rate of the placebo group. There were no
statistically significant differences in SAEs between treatment groups. In the opinion
of the investigator, the serious adverse event of suicidal ideation was possibly causally
related to the study drug, but not to the protocol procedures
Risk of bias
Bias
Authors’ judgement
Support for judgement
Random sequence generation (selection Low risk
bias)
Randomisation: computer-generated random sequence using an interactive response
system
Allocation concealment (selection bias)
Low risk
Central independent unit (details reported
on request)
Incomplete outcome data (attrition bias)
All outcomes
Low risk
Imputation using last observation carried
forward for efficacy data. ITT analysis
Selective reporting (reporting bias)
High risk
Outcomes of sleep, anxiety and depression
not reported; depression scores only reported in ClinicalStudyResults.org for 20/
60 mg DLX
Blinding of participants and personnel Low risk
(performance bias)
All outcomes
Double blind (number and appearance of
placebo capsules similar, details reported on
request)
Blinding of outcome assessment (detection Low risk
bias)
All outcomes
Independent data imputation and statistical analysis (details reported on request)
Serotonin and noradrenaline reuptake inhibitors (SNRIs) for fibromyalgia syndrome (Review)
Copyright © 2013 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
43
Vitton 2004
Methods
Study setting: multicenter study with 12 outpatient research centres in USA
Study design: parallel
Duration therapy: 12 weeks
Follow-up: not described
Analysis: ITT; LOCF; ANOVA
Participants
Participants: 125 (97% female, 84% white, mean age 47 years)
Inclusion criteria: 1990 ACR criteria; 18-70 years
Exclusion criteria: severe psychiatric illness excluding depression; significant risk of
suicide according to the investigator’s judgement; alcohol or other drug abuse; a history
of significant cardiovascular, respiratory, endocrine, genitourinary, liver or kidney disease;
autoimmune disease; systemic infection; cancer or current chemotherapy; significant
sleep apnea; life expectancy < 1 year; active peptic ulcer or inflammatory bowel disease
Interventions
Active drugs
MLN flexible dosage up to 200 mg/day, dose escalation within 3 weeks
46 participants: once a day
51 participants: twice a day
Placebo (28 participants)
The study used a flexible dosing titration design, where participants on active treatment
initially received 25 mg of MLN in 1 dose of 25 mg or 2 doses of 12.5 mg a day during
week 1. Participants who tolerated this dose were stepped up to a daily dose of 50 mg
for week 2, 100 mg for week 3 and 200 mg for week 4, or matching placebo
Rescue medication: hydrocodone up to 60 mg/day
Outcomes
Pain: PED 24-h recall pain score (VAS 0-100)
Fatigue: FIQ VAS 0-10. Data provided on request. OC analysis
Sleep: Jenkins Sleep Survey total score (NRS). Data provided on request.OC analysis
Depression: FIQ VAS 0-10. Data provided on request. OC analysis
Anxiety: FIQ VAS 0-10. Data provided on request. OC analysis
Disability: FIQ VAS 0-10. Data provided on request. OC analysis
Sexual function: Not assessed
Quality of life: FIQ total score (VAS 0-80). Data provided on request. OC-Analysis
Cognitive disturbances: not assessed
Global perceived improvement: not assessed
Tenderness: not assessed
AEs: physical examination, EKGs, and laboratory analysis. AEs were assessed throughout
the study based on spontaneous reporting by participants
Notes
Safety: no data on at least 1 AE in MLN and placebo group reported. No SAE or death
reported. Headache, nausea, constipation and dizziness more frequent in MLN than in
placebo
Risk of bias
Bias
Authors’ judgement
Random sequence generation (selection Low risk
bias)
Serotonin and noradrenaline reuptake inhibitors (SNRIs) for fibromyalgia syndrome (Review)
Copyright © 2013 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
Support for judgement
Computer-generated random sequence
(details provided on request)
44
Vitton 2004
(Continued)
Allocation concealment (selection bias)
Low risk
Central independent unit (details provided
on request)
Incomplete outcome data (attrition bias)
All outcomes
High risk
OC analysis
Selective reporting (reporting bias)
Low risk
All outcomes reported or provided on request
Blinding of participants and personnel Low risk
(performance bias)
All outcomes
Double blind (number and appearance of
placebo capsules similar, details reported on
request)
Blinding of outcome assessment (detection Low risk
bias)
All outcomes
Independent data imputation and statistical analysis (details reported on request)
Abbreviations
≥ = greater than or equal to
< = less than
ACR = American College of Rheumatology
AE = adverse event
BAI = Beck Anxiety Inventory
BDI = Beck Depression Inventory
BOCF = basis observation carried forward (statistical method)
BP = blood pressure
BPI = Brief Pain Inventory
bpm = beats per minute
CNS = central nervous system
DLX = duloxetine
DSM-IV = Diagnostic and Statistical Manual of Mental Disorders, 4th edition
ECG = EKG = electrocardiogram
EKG = ECG = electrocardiogram
FIQ = Fibromyalgia Impact Questionnaire
FM = fibromyalgia
GAD = generalized anxiety disorder
HDRS = Hamilton Depression Rating Scale
IVRS = Interactive Voice Respone System
ITT = intention-to-treat analysis
LOCF = last observation carried forward (statistical method)
MASQ = Multiple Ability Self-report Questionnaire
MDD = major depressive disorder
MDHAQ = Multi-Dimensional Health Assessment Questionnaire
MFI = Multidimensional Fatigue Inventory
MINI = Mini International Neuropsychiatric Interview
MLN = milnacipran
MMRM = mixed-effects model repeated measures
MOS = Medical Outcomes Study
Serotonin and noradrenaline reuptake inhibitors (SNRIs) for fibromyalgia syndrome (Review)
Copyright © 2013 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
45
NRS = Numerical rating scale
NSAID = non-steroidal anti-inflammatory drug
OC = observed cases
PED = patient electronic diary
PGIC = Patient Global Impression of Change Inventory
QT = The Q-T interval represents the time for both ventricular depolarization and repolarization to occur, and therefore roughly
estimates the duration of an average ventricular action potential in the ECG.
SAE = serious adverse effect
SSR = Society of Skeletal Radiology
VAS = visual analogue scale
Characteristics of excluded studies [ordered by study ID]
Study
Reason for exclusion
Branco 2011
1-year extension study, double-blind, randomized, not placebo controlled, of 3 doses of MLN (468 participants)
Chappell 2009
8-week open-label period followed by a 52-week, double-blind, that were not placebo-controlled, randomized
to 1 or 2 doses of DLX (350 participants)
Dwight 1998
8-week open trial with venlaxafine in 15 FMS-participants
Gendreau 2005
Double publication (see Vitton 2004)
Goldenberg 2010
6-month extension study, double-blind, randomized, not placebo-controlled, of 2 doses of MLN (449 participants)
Hsiao 2007
Case report of 1 patient with FM comorbid with premenstrual dysphoric disorder with a low dose of venlafaxine
Mease 2010
6-month extension phases without placebo-control of 2 randomized controlled trials with DLX (492 participants)
Saxe 2012
2-week randomized, placebo-controlled withdrawal design. Participants who had originally received MLN
100mg/day for 12 weeks were re-randomized to continue MLN (n=178) or switch directly to placebo (n=178);
participants originally receiving placebo continued with placebo (n=359)
Sayard 2003
12-week open trial with venlaxafine in 15 FMS-patients
Wyeth 2008
Randomized placebo-controlled trial with 696 FMS-patients on 4 fixed oral doses of desvenlaxafine sustained
release (DVS SR) (50 mg, 100 mg, 150 mg and 200 mg). Interim data analysis indicated that none of the 4
DVS SR treatment groups showed separation from placebo, and that there was a high placebo response rate.
Consequently, the study was discontinued because of the failure of DVS to meet the predefined efficacy criteria
(pain reduction, health-related quality of life (FIQ-total score) and PGIC score). Discontinuation rates because
of side effects were twice as high in desvenlaxafine 100 mg,150 mg and 200 mg groups than in placebo. Details
(Means, SDs, absolute numbers) not reported
Abbreviations
DLX = duloxetine
Serotonin and noradrenaline reuptake inhibitors (SNRIs) for fibromyalgia syndrome (Review)
Copyright © 2013 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
46
FM = fibromyalgia
FMS = fibromyalgia syndrome
MLN = milnacipran
PGIC = Patient Global Impression of Change Inventory
SD = standard deviation
Serotonin and noradrenaline reuptake inhibitors (SNRIs) for fibromyalgia syndrome (Review)
Copyright © 2013 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
47
DATA AND ANALYSES
Comparison 1. SNRI versus placebo final treatment
Outcome or subgroup title
1 Pain
1.1 Duloxetine
1.2 MIlncipran
2 30% pain reduction
2.1 Duloxetine
2.2 Milnacipran
3 50% pain reduction
3.1 Duloxetine
3.2 Milnacipran
4 Fatigue
4.1 Duloxetine
4.2 Milnacpran
5 Sleep problems
5.1 Duloxetine
5.2 Milnacipran
6 Depression
6.1 Duloxetine
6.2 Milnacipran
7 Anxiety
7.1 Duloxetine
7.2 Milnacipran
8 Disease-related quality of life
8.1 Duloxetine
8.2 Milnacipran
9 Disability
9.1 Duloxetine
9.2 Milnacipran
10 Cognitive disturbances
10.1 Duloxetine
10.2 Milnacipran
11 Participant-perceived
improvement
11.1 Duloxetine
11.2 Milnacipran
12 Tenderness
12.1 Duloxetine
12.2 Milnacipran
13 Withdrawal due to adverse
events
13.1 Duloxetine
13.2 Milnacipran
14 Serious adverse events
14.1 Duloxetine
No. of
studies
No. of
participants
Statistical method
Effect size
10
5
5
10
5
5
10
5
5
9
4
5
6
2
4
10
5
5
5
2
3
9
4
5
10
5
5
7
3
4
8
6012
1925
4087
6004
1894
4110
5994
1884
4110
5656
1568
4088
4081
996
3085
5658
1570
4088
2713
709
2004
5457
1380
4077
5995
1908
4087
5344
1360
3984
4551
Std. Mean Difference (IV, Random, 95% CI)
Std. Mean Difference (IV, Random, 95% CI)
Std. Mean Difference (IV, Random, 95% CI)
Risk Ratio (IV, Random, 95% CI)
Risk Ratio (IV, Random, 95% CI)
Risk Ratio (IV, Random, 95% CI)
Risk Ratio (IV, Random, 95% CI)
Risk Ratio (IV, Random, 95% CI)
Risk Ratio (IV, Random, 95% CI)
Std. Mean Difference (IV, Random, 95% CI)
Std. Mean Difference (IV, Random, 95% CI)
Std. Mean Difference (IV, Random, 95% CI)
Std. Mean Difference (IV, Random, 95% CI)
Std. Mean Difference (IV, Random, 95% CI)
Std. Mean Difference (IV, Random, 95% CI)
Std. Mean Difference (IV, Random, 95% CI)
Std. Mean Difference (IV, Random, 95% CI)
Std. Mean Difference (IV, Random, 95% CI)
Std. Mean Difference (IV, Random, 95% CI)
Std. Mean Difference (IV, Random, 95% CI)
Std. Mean Difference (IV, Random, 95% CI)
Std. Mean Difference (IV, Random, 95% CI)
Std. Mean Difference (IV, Random, 95% CI)
Std. Mean Difference (IV, Random, 95% CI)
Std. Mean Difference (IV, Random, 95% CI)
Std. Mean Difference (IV, Random, 95% CI)
Std. Mean Difference (IV, Random, 95% CI)
Std. Mean Difference (IV, Random, 95% CI)
Std. Mean Difference (IV, Random, 95% CI)
Std. Mean Difference (IV, Random, 95% CI)
Std. Mean Difference (IV, Random, 95% CI)
-0.23 [-0.29, -0.18]
-0.32 [-0.41, -0.22]
-0.20 [-0.26, -0.13]
1.36 [1.26, 1.46]
1.33 [1.18, 1.51]
1.38 [1.25, 1.51]
1.49 [1.35, 1.64]
1.59 [1.35, 1.88]
1.44 [1.28, 1.62]
-0.14 [-0.19, -0.08]
-0.12 [-0.23, -0.02]
-0.14 [-0.21, -0.08]
-0.07 [-0.16, 0.03]
-0.24 [-0.37, -0.12]
0.02 [-0.05, 0.10]
-0.15 [-0.21, -0.10]
-0.26 [-0.37, -0.16]
-0.11 [-0.17, -0.04]
-0.03 [-0.15, 0.08]
-0.05 [-0.22, 0.13]
-0.04 [-0.23, 0.14]
-0.20 [-0.25, -0.14]
-0.27 [-0.39, -0.15]
-0.18 [-0.24, -0.11]
-0.22 [-0.28, -0.16]
-0.33 [-0.43, -0.24]
-0.16 [-0.23, -0.10]
-0.15 [-0.21, -0.10]
-0.27 [-0.38, -0.16]
-0.11 [-0.18, -0.05]
-0.27 [-0.33, -0.21]
5
3
4
4
0
10
1903
2648
1364
1364
0
6059
Std. Mean Difference (IV, Random, 95% CI)
Std. Mean Difference (IV, Random, 95% CI)
Std. Mean Difference (IV, Random, 95% CI)
Std. Mean Difference (IV, Random, 95% CI)
Std. Mean Difference (IV, Random, 95% CI)
Risk Ratio (IV, Random, 95% CI)
-0.29 [-0.39, -0.20]
-0.25 [-0.33, -0.17]
-0.23 [-0.35, -0.12]
-0.23 [-0.35, -0.12]
0.0 [0.0, 0.0]
1.83 [1.53, 2.18]
5
5
9
4
1941
4118
5845
1734
Risk Ratio (IV, Random, 95% CI)
Risk Ratio (IV, Random, 95% CI)
Risk Ratio (IV, Random, 95% CI)
Risk Ratio (IV, Random, 95% CI)
1.65 [1.30, 2.09]
2.00 [1.47, 2.73]
0.78 [0.55, 1.12]
0.63 [0.34, 1.16]
Serotonin and noradrenaline reuptake inhibitors (SNRIs) for fibromyalgia syndrome (Review)
Copyright © 2013 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
48
14.2 Milnacipran
5
4111
Risk Ratio (IV, Random, 95% CI)
0.88 [0.57, 1.37]
Comparison 2. Active drug baseline and final treatment
Outcome or subgroup title
1 Pain
2 Quality of life
No. of
studies
No. of
participants
10
9
6908
6699
Statistical method
Mean Difference (IV, Random, 95% CI)
Mean Difference (IV, Random, 95% CI)
Effect size
2.04 [1.86, 2.21]
15.89 [14.45, 17.34]
Comparison 3. Placebo baseline and final treatment
Outcome or subgroup title
1 Pain
2 Quality of life
No. of
studies
No. of
participants
10
9
4716
4262
Statistical method
Mean Difference (IV, Random, 95% CI)
Mean Difference (IV, Random, 95% CI)
Serotonin and noradrenaline reuptake inhibitors (SNRIs) for fibromyalgia syndrome (Review)
Copyright © 2013 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
Effect size
1.22 [1.11, 1.33]
11.41 [10.31, 12.51]
49
Analysis 1.1. Comparison 1 SNRI versus placebo final treatment, Outcome 1 Pain.
Review:
Serotonin and noradrenaline reuptake inhibitors (SNRIs) for fibromyalgia syndrome
Comparison: 1 SNRI versus placebo final treatment
Outcome: 1 Pain
Study or subgroup
Favours SNRIs
Std.
Mean
Difference
Favours Placebo
Weight
IV,Random,95% CI
Std.
Mean
Difference
N
Mean(SD)
N
Mean(SD)
IV,Random,95% CI
Arnold 2004
100
-1.83 (2.4)
102
-0.94 (2.3)
3.6 %
-0.38 [ -0.66, -0.10 ]
Arnold 2005
116
-2.39 (2.4)
59
-1.16 (2.3)
2.8 %
-0.52 [ -0.84, -0.20 ]
Arnold 2005
114
-2.4 (2.4)
59
-1.16 (2.3)
2.8 %
-0.52 [ -0.84, -0.20 ]
Arnold 2010a
263
-2.3 (2.7)
267
-1.5 (2.8)
9.6 %
-0.29 [ -0.46, -0.12 ]
Chappell 2008
158
-1.62 (2.5)
167
-1.13 (2.5)
5.9 %
-0.20 [ -0.41, 0.02 ]
Russell 2008
79
-2 (2.5)
30
-1.43 (2.5)
1.6 %
-0.23 [ -0.65, 0.20 ]
Russell 2008
150
-1.98 (2.6)
58
-1.43 (2.5)
3.1 %
-0.21 [ -0.52, 0.09 ]
Russell 2008
147
-2.26 (2.5)
56
-1.43 (2.5)
2.9 %
-0.33 [ -0.64, -0.02 ]
1 Duloxetine
Subtotal (95% CI)
1127
32.3 % -0.32 [ -0.41, -0.22 ]
798
Heterogeneity: Tau2 = 0.0; Chi2 = 5.20, df = 7 (P = 0.64); I2 =0.0%
Test for overall effect: Z = 6.62 (P < 0.00001)
2 MIlncipran
Arnold 2010b
516
-17.7 (27.9)
509 -10.76 (29.3)
18.7 %
-0.24 [ -0.37, -0.12 ]
Branco 2010
430
-16.5 (24.5)
446 -11.97 (24.1)
16.0 %
-0.19 [ -0.32, -0.05 ]
Clauw 2008
396
-17.4 (21.9)
200
-13 (20)
9.7 %
-0.21 [ -0.38, -0.04 ]
Clauw 2008
399
-15.7 (22)
201
-13 (20)
9.8 %
-0.13 [ -0.30, 0.04 ]
Mease 2009a
223
53.2 (24.6)
75
56.2 (23.9)
4.1 %
-0.12 [ -0.38, 0.14 ]
Mease 2009a
441
52.2 (24.4)
148
56.2 (23.9)
8.1 %
-0.16 [ -0.35, 0.02 ]
Vitton 2004
42
-2.3 (2.7)
13
-0.8 (2.7)
0.7 %
-0.55 [ -1.18, 0.08 ]
Vitton 2004
37
-1.9 (2.9)
11
-0.8 (2.7)
0.6 %
-0.38 [ -1.06, 0.30 ]
Subtotal (95% CI)
2484
1603
67.7 % -0.20 [ -0.26, -0.13 ]
2401
100.0 % -0.23 [ -0.29, -0.18 ]
Heterogeneity: Tau2 = 0.0; Chi2 = 3.12, df = 7 (P = 0.87); I2 =0.0%
Test for overall effect: Z = 5.92 (P < 0.00001)
Total (95% CI)
3611
Heterogeneity: Tau2 = 0.0; Chi2 = 12.63, df = 15 (P = 0.63); I2 =0.0%
Test for overall effect: Z = 8.64 (P < 0.00001)
Test for subgroup differences: Chi2 = 4.32, df = 1 (P = 0.04), I2 =77%
-2
-1
0
Favours SNRIs
Serotonin and noradrenaline reuptake inhibitors (SNRIs) for fibromyalgia syndrome (Review)
Copyright © 2013 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
1
2
Favours Placebo
50
Analysis 1.2. Comparison 1 SNRI versus placebo final treatment, Outcome 2 30% pain reduction.
Review:
Serotonin and noradrenaline reuptake inhibitors (SNRIs) for fibromyalgia syndrome
Comparison: 1 SNRI versus placebo final treatment
Outcome: 2 30% pain reduction
Study or subgroup
SNRIs
Placebo
n/N
n/N
Risk Ratio
Weight
Arnold 2004
34/101
32/103
3.5 %
1.08 [ 0.73, 1.61 ]
Arnold 2005
125/230
39/118
6.9 %
1.64 [ 1.24, 2.18 ]
Arnold 2010a
119/249
85/248
11.8 %
1.39 [ 1.12, 1.73 ]
Chappell 2008
60/158
55/167
6.4 %
1.15 [ 0.86, 1.55 ]
183/376
54/144
10.0 %
1.30 [ 1.03, 1.64 ]
1114
780
38.6 %
1.33 [ 1.18, 1.51 ]
IV,Random,95% CI
Risk Ratio
IV,Random,95% CI
1 Duloxetine
Russell 2008
Subtotal (95% CI)
Total events: 521 (SNRIs), 265 (Placebo)
Heterogeneity: Tau2 = 0.00; Chi2 = 4.31, df = 4 (P = 0.37); I2 =7%
Test for overall effect: Z = 4.52 (P < 0.00001)
2 Milnacipran
Arnold 2010b
230/516
156/509
20.9 %
1.45 [ 1.24, 1.71 ]
Branco 2010
166/430
134/446
16.1 %
1.28 [ 1.07, 1.55 ]
Clauw 2008
307/795
115/401
17.5 %
1.35 [ 1.13, 1.61 ]
Mease 2009a
171/665
41/223
5.9 %
1.40 [ 1.03, 1.90 ]
36/97
6/28
1.0 %
1.73 [ 0.81, 3.69 ]
2503
1607
61.4 %
1.38 [ 1.25, 1.51 ]
100.0 %
1.36 [ 1.26, 1.46 ]
Vitton 2004
Subtotal (95% CI)
Total events: 910 (SNRIs), 452 (Placebo)
Heterogeneity: Tau2 = 0.0; Chi2 = 1.40, df = 4 (P = 0.84); I2 =0.0%
Test for overall effect: Z = 6.60 (P < 0.00001)
Total (95% CI)
3617
2387
Total events: 1431 (SNRIs), 717 (Placebo)
Heterogeneity: Tau2 = 0.0; Chi2 = 5.86, df = 9 (P = 0.75); I2 =0.0%
Test for overall effect: Z = 8.12 (P < 0.00001)
Test for subgroup differences: Chi2 = 0.15, df = 1 (P = 0.70), I2 =0.0%
0.01
0.1
Favours placebo
1
10
100
Favours SNRIs
Serotonin and noradrenaline reuptake inhibitors (SNRIs) for fibromyalgia syndrome (Review)
Copyright © 2013 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
51
Analysis 1.3. Comparison 1 SNRI versus placebo final treatment, Outcome 3 50% pain reduction.
Review:
Serotonin and noradrenaline reuptake inhibitors (SNRIs) for fibromyalgia syndrome
Comparison: 1 SNRI versus placebo final treatment
Outcome: 3 50% pain reduction
Study or subgroup
SNRIs
Placebo
n/N
n/N
Risk Ratio
Weight
Arnold 2004
29/104
17/103
3.3 %
1.69 [ 0.99, 2.88 ]
Arnold 2005
95/230
27/118
6.9 %
1.81 [ 1.25, 2.60 ]
Arnold 2010a
83/249
52/248
10.4 %
1.59 [ 1.18, 2.14 ]
Chappell 2008
37/158
30/167
5.0 %
1.30 [ 0.85, 2.00 ]
126/368
30/139
7.7 %
1.59 [ 1.12, 2.24 ]
1109
775
33.2 %
1.59 [ 1.35, 1.88 ]
IV,Random,95% CI
Risk Ratio
IV,Random,95% CI
1 Duloxetine
Russell 2008
Subtotal (95% CI)
Total events: 370 (SNRIs), 156 (Placebo)
Heterogeneity: Tau2 = 0.0; Chi2 = 1.33, df = 4 (P = 0.86); I2 =0.0%
Test for overall effect: Z = 5.47 (P < 0.00001)
2 Milnacipran
Arnold 2010b
143/516
92/509
17.2 %
1.53 [ 1.22, 1.93 ]
Branco 2010
112/430
88/446
15.3 %
1.32 [ 1.03, 1.69 ]
Clauw 2008
224/795
75/401
17.1 %
1.51 [ 1.19, 1.90 ]
Mease 2009a
241/665
58/223
15.6 %
1.39 [ 1.09, 1.78 ]
27/97
6/28
1.5 %
1.30 [ 0.60, 2.83 ]
2503
1607
66.8 %
1.44 [ 1.28, 1.62 ]
100.0 %
1.49 [ 1.35, 1.64 ]
Vitton 2004
Subtotal (95% CI)
Total events: 747 (SNRIs), 319 (Placebo)
Heterogeneity: Tau2 = 0.0; Chi2 = 1.04, df = 4 (P = 0.90); I2 =0.0%
Test for overall effect: Z = 6.04 (P < 0.00001)
Total (95% CI)
3612
2382
Total events: 1117 (SNRIs), 475 (Placebo)
Heterogeneity: Tau2 = 0.0; Chi2 = 3.36, df = 9 (P = 0.95); I2 =0.0%
Test for overall effect: Z = 8.09 (P < 0.00001)
Test for subgroup differences: Chi2 = 0.98, df = 1 (P = 0.32), I2 =0.0%
0.5
0.7
Favours placebo
1
1.5
2
Favours SNRIs
Serotonin and noradrenaline reuptake inhibitors (SNRIs) for fibromyalgia syndrome (Review)
Copyright © 2013 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
52
Analysis 1.4. Comparison 1 SNRI versus placebo final treatment, Outcome 4 Fatigue.
Review:
Serotonin and noradrenaline reuptake inhibitors (SNRIs) for fibromyalgia syndrome
Comparison: 1 SNRI versus placebo final treatment
Outcome: 4 Fatigue
Study or subgroup
SNRIs
Std.
Mean
Difference
Placebo
Weight
IV,Random,95% CI
Std.
Mean
Difference
N
Mean(SD)
N
Mean(SD)
IV,Random,95% CI
Arnold 2004
101
-1.3 (2.9)
103
-0.88 (2.9)
3.9 %
-0.14 [ -0.42, 0.13 ]
Arnold 2010a
263
-2.2 (3.2)
267
-1.4 (3.3)
10.2 %
-0.25 [ -0.42, -0.07 ]
Chappell 2008
152
-0.33 (3.7)
162
-0.37 (3.7)
6.1 %
0.01 [ -0.21, 0.23 ]
Russell 2008
147
-2.12 (4)
56
-1.69 (4.1)
3.1 %
-0.11 [ -0.41, 0.20 ]
Russell 2008
79
-1.79 (3.9)
30
-1.69 (4.1)
1.7 %
-0.03 [ -0.45, 0.40 ]
Russell 2008
150
-1.83 (4)
58
-1.69 (4.1)
3.2 %
-0.03 [ -0.34, 0.27 ]
28.3 %
-0.12 [ -0.23, -0.02 ]
1 Duloxetine
Subtotal (95% CI)
892
676
Heterogeneity: Tau2 = 0.0; Chi2 = 3.95, df = 5 (P = 0.56); I2 =0.0%
Test for overall effect: Z = 2.36 (P = 0.018)
2 Milnacpran
Arnold 2010b
516
-4.31 (17.5)
509
-2.61 (17.4)
19.8 %
-0.10 [ -0.22, 0.03 ]
Branco 2010
430
-5.94 (15.1)
446
-3.53 (14.8)
16.9 %
-0.16 [ -0.29, -0.03 ]
Clauw 2008
399
-5.4 (11.9)
201
-3.8 (12)
10.3 %
-0.13 [ -0.30, 0.04 ]
Clauw 2008
396
-5.4 (11.9)
200
-3.8 (12)
10.3 %
-0.13 [ -0.30, 0.04 ]
Mease 2009a
224
-5 (12.8)
75
-3.4 (12.1)
4.4 %
-0.13 [ -0.39, 0.14 ]
Mease 2009a
441
-5.8 (14)
148
-3.4 (12.1)
8.6 %
-0.18 [ -0.36, 0.01 ]
Vitton 2004
42
-2 (2.6)
13
-0.7 (2.8)
0.8 %
-0.48 [ -1.11, 0.14 ]
Vitton 2004
37
-2.4 (2.6)
11
-0.7 (2.8)
0.6 %
-0.63 [ -1.32, 0.05 ]
71.7 %
-0.14 [ -0.21, -0.08 ]
100.0 %
-0.14 [ -0.19, -0.08 ]
Subtotal (95% CI)
2485
1603
Heterogeneity: Tau2 = 0.0; Chi2 = 3.85, df = 7 (P = 0.80); I2 =0.0%
Test for overall effect: Z = 4.35 (P = 0.000014)
Total (95% CI)
3377
2279
Heterogeneity: Tau2 = 0.0; Chi2 = 7.91, df = 13 (P = 0.85); I2 =0.0%
Test for overall effect: Z = 4.94 (P < 0.00001)
Test for subgroup differences: Chi2 = 0.10, df = 1 (P = 0.75), I2 =0.0%
-2
-1
Favours SNRIs
0
1
2
Favours placebo
Serotonin and noradrenaline reuptake inhibitors (SNRIs) for fibromyalgia syndrome (Review)
Copyright © 2013 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
53
Analysis 1.5. Comparison 1 SNRI versus placebo final treatment, Outcome 5 Sleep problems.
Review:
Serotonin and noradrenaline reuptake inhibitors (SNRIs) for fibromyalgia syndrome
Comparison: 1 SNRI versus placebo final treatment
Outcome: 5 Sleep problems
Study or subgroup
SNRIs
Std.
Mean
Difference
Placebo
Weight
IV,Random,95% CI
Std.
Mean
Difference
N
Mean(SD)
N
Mean(SD)
IV,Random,95% CI
Arnold 2005
114
-2.69 (3.1)
118
-1.71 (2.7)
8.7 %
-0.34 [ -0.60, -0.08 ]
Arnold 2005
116
-2.67 (3.1)
118
-1.71 (3)
8.7 %
-0.31 [ -0.57, -0.06 ]
Arnold 2010a
263
-2 (2.9)
267
-1.5 (2.9)
13.6 %
-0.17 [ -0.34, 0.00 ]
31.0 %
-0.24 [ -0.37, -0.12 ]
1 Duloxetine
Subtotal (95% CI)
493
503
Heterogeneity: Tau2 = 0.0; Chi2 = 1.45, df = 2 (P = 0.48); I2 =0.0%
Test for overall effect: Z = 3.82 (P = 0.00013)
2 Milnacipran
Branco 2010
430
-6.9 (20.1)
446
-7.4 (19.6)
16.5 %
0.03 [ -0.11, 0.16 ]
Clauw 2008
396
-2.3 (23.1)
200
-3 (22)
13.7 %
0.03 [ -0.14, 0.20 ]
Clauw 2008
399
-1.7 (21.9)
201
-3 (22)
13.7 %
0.06 [ -0.11, 0.23 ]
Mease 2009a
224
-0.1 (20.2)
148
0.1 (20.6)
11.2 %
-0.01 [ -0.22, 0.20 ]
Mease 2009a
441
1.7 (22.2)
75
0.1 (20.6)
9.3 %
0.07 [ -0.17, 0.32 ]
Vitton 2004
51
-1.3 (2.6)
15
-0.5 (2.9)
2.4 %
-0.30 [ -0.87, 0.28 ]
Vitton 2004
46
-1.3 (3.6)
13
-0.5 (2.9)
2.2 %
-0.23 [ -0.84, 0.39 ]
69.0 %
0.02 [ -0.05, 0.10 ]
100.0 %
-0.07 [ -0.16, 0.03 ]
Subtotal (95% CI)
1987
1098
Heterogeneity: Tau2 = 0.0; Chi2 = 2.24, df = 6 (P = 0.90); I2 =0.0%
Test for overall effect: Z = 0.61 (P = 0.54)
Total (95% CI)
2480
1601
Heterogeneity: Tau2 = 0.01; Chi2 = 16.50, df = 9 (P = 0.06); I2 =45%
Test for overall effect: Z = 1.44 (P = 0.15)
Test for subgroup differences: Chi2 = 12.80, df = 1 (P = 0.00), I2 =92%
-2
-1
Favours SNRIs
0
1
2
Favours placebo
Serotonin and noradrenaline reuptake inhibitors (SNRIs) for fibromyalgia syndrome (Review)
Copyright © 2013 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
54
Analysis 1.6. Comparison 1 SNRI versus placebo final treatment, Outcome 6 Depression.
Review:
Serotonin and noradrenaline reuptake inhibitors (SNRIs) for fibromyalgia syndrome
Comparison: 1 SNRI versus placebo final treatment
Outcome: 6 Depression
Study or subgroup
SNRIs
Std.
Mean
Difference
Placebo
Weight
IV,Random,95% CI
Std.
Mean
Difference
N
Mean(SD)
N
Mean(SD)
IV,Random,95% CI
Arnold 2004
88
-3.32 (8)
89
-1.02 (7.7)
3.4 %
-0.29 [ -0.59, 0.00 ]
Arnold 2005
110
-2.79 (4.7)
54
-2.24 (4.7)
2.8 %
-0.12 [ -0.44, 0.21 ]
Arnold 2005
111
-3.79 (4.6)
55
-2.24 (4.7)
2.8 %
-0.33 [ -0.66, -0.01 ]
Arnold 2010a
263
-5.5 (8.1)
267
-3.6 (8.2)
10.1 %
-0.23 [ -0.40, -0.06 ]
Chappell 2008
154
-3.42 (7.7)
164
-1.45 (7.8)
6.1 %
-0.25 [ -0.47, -0.03 ]
76
-7.26 (7)
139
-3.91 (8.9)
3.7 %
-0.40 [ -0.69, -0.12 ]
28.8 %
-0.26 [ -0.37, -0.16 ]
1 Duloxetine
Russell 2008
Subtotal (95% CI)
802
768
Heterogeneity: Tau2 = 0.0; Chi2 = 2.06, df = 5 (P = 0.84); I2 =0.0%
Test for overall effect: Z = 5.12 (P < 0.00001)
2 Milnacipran
Arnold 2010b
516
-2.12 (7)
509
-1.24 (7)
19.7 %
-0.13 [ -0.25, 0.00 ]
Branco 2010
430
-0.74 (7.5)
446
-0.29 (7.2)
16.8 %
-0.06 [ -0.19, 0.07 ]
Clauw 2008
399
-3 (8)
201
-2.3 (8)
10.3 %
-0.09 [ -0.26, 0.08 ]
Clauw 2008
396
-3.6 (8)
200
-2.3 (8)
10.2 %
-0.16 [ -0.33, 0.01 ]
Mease 2009a
224
-2.8 (7.8)
75
-2.3 (8.3)
4.3 %
-0.06 [ -0.32, 0.20 ]
Mease 2009a
441
-3 (8.9)
148
-2.3 (8.3)
8.5 %
-0.08 [ -0.27, 0.11 ]
Vitton 2004
37
-1.7 (2.9)
11
-0.6 (2.7)
0.6 %
-0.38 [ -1.06, 0.30 ]
Vitton 2004
42
-1.5 (2.9)
13
-0.6 (2.7)
0.8 %
-0.31 [ -0.94, 0.31 ]
71.2 %
-0.11 [ -0.17, -0.04 ]
100.0 %
-0.15 [ -0.21, -0.10 ]
Subtotal (95% CI)
2485
1603
Heterogeneity: Tau2 = 0.0; Chi2 = 2.22, df = 7 (P = 0.95); I2 =0.0%
Test for overall effect: Z = 3.20 (P = 0.0014)
Total (95% CI)
3287
2371
Heterogeneity: Tau2 = 0.0; Chi2 = 11.05, df = 13 (P = 0.61); I2 =0.0%
Test for overall effect: Z = 5.45 (P < 0.00001)
Test for subgroup differences: Chi2 = 6.77, df = 1 (P = 0.01), I2 =85%
-4
-2
Favours SNRIs
0
2
4
Favours placebo
Serotonin and noradrenaline reuptake inhibitors (SNRIs) for fibromyalgia syndrome (Review)
Copyright © 2013 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
55
Analysis 1.7. Comparison 1 SNRI versus placebo final treatment, Outcome 7 Anxiety.
Review:
Serotonin and noradrenaline reuptake inhibitors (SNRIs) for fibromyalgia syndrome
Comparison: 1 SNRI versus placebo final treatment
Outcome: 7 Anxiety
Study or subgroup
SNRIs
Std.
Mean
Difference
Placebo
Weight
IV,Random,95% CI
Std.
Mean
Difference
N
Mean(SD)
N
Mean(SD)
IV,Random,95% CI
Arnold 2004
93
-2.6 (6.7)
86
-1.39 (6.4)
12.0 %
-0.18 [ -0.48, 0.11 ]
Arnold 2010a
263
-3.1 (8.1)
267
-3.2 (8.2)
23.2 %
0.01 [ -0.16, 0.18 ]
35.2 %
-0.05 [ -0.22, 0.13 ]
1 Duloxetine
Subtotal (95% CI)
356
353
Heterogeneity: Tau2 = 0.00; Chi2 = 1.28, df = 1 (P = 0.26); I2 =22%
Test for overall effect: Z = 0.53 (P = 0.60)
2 Milnacipran
Arnold 2010b
516
-0.7 (9)
509
-1.7 (9)
30.1 %
0.11 [ -0.01, 0.23 ]
Branco 2010
430
-0.96 (11.2)
446
0.01 (11)
28.5 %
-0.09 [ -0.22, 0.05 ]
Vitton 2004
42
-1.6 (3.1)
13
-0.5 (3.4)
3.4 %
-0.34 [ -0.97, 0.28 ]
Vitton 2004
37
-1.8 (2.9)
11
-0.5 (3.4)
2.9 %
-0.42 [ -1.10, 0.25 ]
64.8 %
-0.04 [ -0.23, 0.14 ]
100.0 %
-0.03 [ -0.15, 0.08 ]
Subtotal (95% CI)
1025
979
Heterogeneity: Tau2 = 0.02; Chi2 = 7.46, df = 3 (P = 0.06); I2 =60%
Test for overall effect: Z = 0.45 (P = 0.65)
Total (95% CI)
1381
1332
Heterogeneity: Tau2 = 0.01; Chi2 = 8.96, df = 5 (P = 0.11); I2 =44%
Test for overall effect: Z = 0.57 (P = 0.57)
Test for subgroup differences: Chi2 = 0.00, df = 1 (P = 0.97), I2 =0.0%
-4
-2
Favours SNRIs
0
2
4
Favours placebo
Serotonin and noradrenaline reuptake inhibitors (SNRIs) for fibromyalgia syndrome (Review)
Copyright © 2013 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
56
Analysis 1.8. Comparison 1 SNRI versus placebo final treatment, Outcome 8 Disease-related quality of life.
Review:
Serotonin and noradrenaline reuptake inhibitors (SNRIs) for fibromyalgia syndrome
Comparison: 1 SNRI versus placebo final treatment
Outcome: 8 Disease-related quality of life
Study or subgroup
Favours SNRIs
Std.
Mean
Difference
Favours Placebo
N
Weight
IV,Random,95% CI
Std.
Mean
Difference
Mean(SD)
N
Mean(SD)
IV,Random,95% CI
Arnold 2004
101 -13.46 (18.3)
102
-7.93 (17.5)
4.1 %
-0.31 [ -0.58, -0.03 ]
Arnold 2005
114 -16.72 (16.6)
58
-8.35 (16.4)
3.1 %
-0.50 [ -0.82, -0.18 ]
Arnold 2005
112 -16.81 (16.6)
57
-8.35 (16.4)
3.0 %
-0.51 [ -0.83, -0.19 ]
Chappell 2008
153
-7.96 (17)
163
-5.81 (16.5)
6.5 %
-0.13 [ -0.35, 0.09 ]
Russell 2008
147
-13.86 (17)
56 -10.42 (17.5)
3.3 %
-0.20 [ -0.51, 0.11 ]
Russell 2008
150 -12.28 (17.6)
58 -10.42 (17.5)
3.4 %
-0.11 [ -0.41, 0.20 ]
Russell 2008
79 -14.77 (16.7)
30 -10.42 (17.5)
1.8 %
-0.26 [ -0.68, 0.17 ]
1 Duloxetine
Subtotal (95% CI)
856
524
25.2 % -0.27 [ -0.39, -0.15 ]
Heterogeneity: Tau2 = 0.00; Chi2 = 7.13, df = 6 (P = 0.31); I2 =16%
Test for overall effect: Z = 4.28 (P = 0.000019)
2 Milnacipran
Arnold 2010b
516 -12.34 (24.8)
509
-7.12 (24.4)
21.0 %
-0.21 [ -0.33, -0.09 ]
Branco 2010
430 -14.18 (21.4)
446 -11.18 (20.9)
18.0 %
-0.14 [ -0.27, -0.01 ]
Clauw 2008
396
-15.4 (19.9)
200
-12 (20)
10.9 %
-0.17 [ -0.34, 0.00 ]
Clauw 2008
399
-16.6 (20)
201
-12 (20)
10.9 %
-0.23 [ -0.40, -0.06 ]
Mease 2009a
441
-16.7 (21.6)
75
-15 (20.5)
5.3 %
-0.08 [ -0.32, 0.17 ]
Mease 2009a
224
-17.7 (22.5)
148
-15 (20.5)
7.3 %
-0.12 [ -0.33, 0.08 ]
Vitton 2004
37
-10.5 (14.5)
11
-5.4 (13.4)
0.7 %
-0.35 [ -1.03, 0.33 ]
Vitton 2004
33
-10.3 (14.1)
11
-5.4 (13.4)
0.7 %
-0.35 [ -1.03, 0.34 ]
Subtotal (95% CI)
2476
1601
74.8 % -0.18 [ -0.24, -0.11 ]
2125
100.0 % -0.20 [ -0.25, -0.14 ]
Heterogeneity: Tau2 = 0.0; Chi2 = 2.31, df = 7 (P = 0.94); I2 =0.0%
Test for overall effect: Z = 5.31 (P < 0.00001)
Total (95% CI)
3332
Heterogeneity: Tau2 = 0.0; Chi2 = 11.22, df = 14 (P = 0.67); I2 =0.0%
Test for overall effect: Z = 6.91 (P < 0.00001)
Test for subgroup differences: Chi2 = 1.72, df = 1 (P = 0.19), I2 =42%
-2
-1
0
Favours SNRIs
Serotonin and noradrenaline reuptake inhibitors (SNRIs) for fibromyalgia syndrome (Review)
Copyright © 2013 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
1
2
Favours Placebo
57
Analysis 1.9. Comparison 1 SNRI versus placebo final treatment, Outcome 9 Disability.
Review:
Serotonin and noradrenaline reuptake inhibitors (SNRIs) for fibromyalgia syndrome
Comparison: 1 SNRI versus placebo final treatment
Outcome: 9 Disability
Study or subgroup
SNRIs
Std.
Mean
Difference
Placebo
Weight
IV,Random,95% CI
Std.
Mean
Difference
N
Mean(SD)
N
Mean(SD)
IV,Random,95% CI
Arnold 2004
101
-2.01 (2.6)
102
-0.95 (2.7)
3.9 %
-0.40 [ -0.68, -0.12 ]
Arnold 2005
116
-2.57 (2.4)
59
-1.43 (2.3)
3.0 %
-0.48 [ -0.80, -0.16 ]
Arnold 2005
114
-2.58 (2.3)
59
-1.43 (2.3)
3.0 %
-0.50 [ -0.82, -0.18 ]
Arnold 2010a
263
-2.6 (3.2)
267
-1.7 (3.3)
9.7 %
-0.28 [ -0.45, -0.11 ]
Chappell 2008
158
-1.69 (2.5)
167
-1.03 (2.5)
6.1 %
-0.26 [ -0.48, -0.04 ]
Russell 2008
77
-2.34 (2.4)
29
-1.37 (2.4)
1.6 %
-0.40 [ -0.83, 0.03 ]
Russell 2008
144
-1.98 (2.6)
56
-1.37 (2.4)
3.1 %
-0.24 [ -0.55, 0.07 ]
Russell 2008
142
-2.27 (2.5)
54
-1.37 (2.4)
3.0 %
-0.36 [ -0.68, -0.05 ]
33.5 %
-0.33 [ -0.43, -0.24 ]
1 Duloxetine
Subtotal (95% CI)
1115
793
Heterogeneity: Tau2 = 0.0; Chi2 = 3.35, df = 7 (P = 0.85); I2 =0.0%
Test for overall effect: Z = 7.00 (P < 0.00001)
2 Milnacipran
Arnold 2010b
516
-1.49 (3.2)
509
-0.91 (2.9)
17.5 %
-0.19 [ -0.31, -0.07 ]
Branco 2010
430
-1.26 (2.3)
446
-0.93 (2.3)
15.3 %
-0.14 [ -0.28, -0.01 ]
Clauw 2008
396
-2.6 (6)
200
-1.5 (6)
9.8 %
-0.18 [ -0.35, -0.01 ]
Clauw 2008
399
-2.4 (6)
201
-1.5 (6)
9.8 %
-0.15 [ -0.32, 0.02 ]
Mease 2009a
223
-2.99 (8.46)
74
-2.43 (7.74)
4.3 %
-0.07 [ -0.33, 0.20 ]
Mease 2009a
441
-3.34 (8.42)
148
-2.43 (7.74)
8.3 %
-0.11 [ -0.30, 0.08 ]
Vitton 2004
43
-3.2 (6.2)
13
0.1 (7.5)
0.8 %
-0.50 [ -1.13, 0.13 ]
Vitton 2004
37
-3.5 (5.9)
11
0.1 (7.5)
0.7 %
-0.56 [ -1.25, 0.12 ]
66.5 %
-0.16 [ -0.23, -0.10 ]
100.0 %
-0.22 [ -0.28, -0.16 ]
Subtotal (95% CI)
2485
1602
Heterogeneity: Tau2 = 0.0; Chi2 = 3.59, df = 7 (P = 0.83); I2 =0.0%
Test for overall effect: Z = 4.92 (P < 0.00001)
Total (95% CI)
3600
2395
Heterogeneity: Tau2 = 0.00; Chi2 = 15.82, df = 15 (P = 0.39); I2 =5%
Test for overall effect: Z = 7.76 (P < 0.00001)
Test for subgroup differences: Chi2 = 8.89, df = 1 (P = 0.00), I2 =89%
-4
-2
Favours SNRIs
0
2
4
Favours placebo
Serotonin and noradrenaline reuptake inhibitors (SNRIs) for fibromyalgia syndrome (Review)
Copyright © 2013 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
58
Analysis 1.10. Comparison 1 SNRI versus placebo final treatment, Outcome 10 Cognitive disturbances.
Review:
Serotonin and noradrenaline reuptake inhibitors (SNRIs) for fibromyalgia syndrome
Comparison: 1 SNRI versus placebo final treatment
Outcome: 10 Cognitive disturbances
Study or subgroup
SNRIs
Std.
Mean
Difference
Placebo
Weight
IV,Random,95% CI
Std.
Mean
Difference
N
Mean(SD)
N
Mean(SD)
IV,Random,95% CI
Arnold 2010a
263
-2 (3.2)
263
-1.1 (3.3)
10.7 %
-0.28 [ -0.45, -0.10 ]
Chappell 2008
153
-0.99 (4.1)
161
-0.03 (3.9)
6.4 %
-0.24 [ -0.46, -0.02 ]
Russell 2008
79
-2.37 (3.9)
30
-1.14 (4.1)
1.8 %
-0.31 [ -0.73, 0.11 ]
Russell 2008
147
-2.37 (4)
56
-1.14 (4.1)
3.3 %
-0.30 [ -0.61, 0.00 ]
Russell 2008
150
-2.29 (4.2)
58
-1.14 (4.1)
3.4 %
-0.27 [ -0.58, 0.03 ]
25.6 %
-0.27 [ -0.38, -0.16 ]
1 Duloxetine
Subtotal (95% CI)
792
568
Heterogeneity: Tau2 = 0.0; Chi2 = 0.16, df = 4 (P = 1.00); I2 =0.0%
Test for overall effect: Z = 4.81 (P < 0.00001)
2 Milnacipran
Arnold 2010b
516
-3.89 (17.5)
509
-2.36 (17.4)
21.0 %
-0.09 [ -0.21, 0.03 ]
Branco 2010
430
-5.88 (20.8)
446
-3.53 (20.3)
17.9 %
-0.11 [ -0.25, 0.02 ]
Clauw 2008
399
-3.3 (12)
201
-2.5 (12)
11.0 %
-0.07 [ -0.24, 0.10 ]
Clauw 2008
395
-3.8 (11.9)
200
-2.5 (12)
10.9 %
-0.11 [ -0.28, 0.06 ]
Mease 2009a
224
-1.56 (11.5)
75
0.16 (12.93)
4.6 %
-0.14 [ -0.41, 0.12 ]
Mease 2009a
441
-2.68 (13.5)
148
0.16 (12.93)
9.1 %
-0.21 [ -0.40, -0.03 ]
74.4 %
-0.11 [ -0.18, -0.05 ]
100.0 %
-0.15 [ -0.21, -0.10 ]
Subtotal (95% CI)
2405
1579
Heterogeneity: Tau2 = 0.0; Chi2 = 1.60, df = 5 (P = 0.90); I2 =0.0%
Test for overall effect: Z = 3.40 (P = 0.00069)
Total (95% CI)
3197
2147
Heterogeneity: Tau2 = 0.0; Chi2 = 7.70, df = 10 (P = 0.66); I2 =0.0%
Test for overall effect: Z = 5.36 (P < 0.00001)
Test for subgroup differences: Chi2 = 5.94, df = 1 (P = 0.01), I2 =83%
-4
-2
Favours SNRIs
0
2
4
Favours placebo
Serotonin and noradrenaline reuptake inhibitors (SNRIs) for fibromyalgia syndrome (Review)
Copyright © 2013 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
59
Analysis 1.11. Comparison 1 SNRI versus placebo final treatment, Outcome 11 Participant-perceived
improvement.
Review:
Serotonin and noradrenaline reuptake inhibitors (SNRIs) for fibromyalgia syndrome
Comparison: 1 SNRI versus placebo final treatment
Outcome: 11 Participant-perceived improvement
Study or subgroup
SNRIs
Std.
Mean
Difference
Placebo
Weight
IV,Random,95% CI
Std.
Mean
Difference
N
Mean(SD)
N
Mean(SD)
IV,Random,95% CI
Arnold 2004
95
3.02 (1.7)
99
3.53 (1.7)
4.6 %
-0.30 [ -0.58, -0.02 ]
Arnold 2005
111
3.06 (1.8)
55
3.71 (1.6)
3.5 %
-0.37 [ -0.70, -0.05 ]
Arnold 2005
114
3.11 (1.9)
56
3.71 (1.6)
3.6 %
-0.33 [ -0.65, -0.01 ]
Arnold 2010a
263
2.8 (1.8)
267
3.4 (1.6)
12.5 %
-0.35 [ -0.52, -0.18 ]
Chappell 2008
158
3.4 (1.6)
165
3.7 (1.5)
7.7 %
-0.19 [ -0.41, 0.03 ]
Russell 2008
150
3.08 (1.6)
58
3.37 (1.6)
4.0 %
-0.18 [ -0.48, 0.12 ]
Russell 2008
147
2.93 (1.6)
56
3.37 (1.6)
3.9 %
-0.27 [ -0.58, 0.03 ]
Russell 2008
79
2.79 (1.5)
30
3.37 (1.6)
2.1 %
-0.38 [ -0.80, 0.05 ]
41.8 %
-0.29 [ -0.39, -0.20 ]
1 Duloxetine
Subtotal (95% CI)
1117
786
Heterogeneity: Tau2 = 0.0; Chi2 = 2.23, df = 7 (P = 0.95); I2 =0.0%
Test for overall effect: Z = 6.14 (P < 0.00001)
2 Milnacipran
Arnold 2010b
516
3.06 (1.8)
509
3.53 (1.8)
24.4 %
-0.26 [ -0.38, -0.14 ]
Clauw 2008
393
3.1 (2)
199
3.5 (2)
12.6 %
-0.20 [ -0.37, -0.03 ]
Clauw 2008
386
3 (2)
198
3.5 (2)
12.5 %
-0.25 [ -0.42, -0.08 ]
Mease 2009a
115
2.78 (1.8)
43
3.07 (1.6)
3.0 %
-0.17 [ -0.52, 0.19 ]
Mease 2009a
204
2.52 (1.7)
85
3.07 (1.6)
5.7 %
-0.33 [ -0.58, -0.07 ]
58.2 %
-0.25 [ -0.33, -0.17 ]
100.0 %
-0.27 [ -0.33, -0.21 ]
Subtotal (95% CI)
1614
1034
Heterogeneity: Tau2 = 0.0; Chi2 = 0.94, df = 4 (P = 0.92); I2 =0.0%
Test for overall effect: Z = 6.08 (P < 0.00001)
Total (95% CI)
2731
1820
Heterogeneity: Tau2 = 0.0; Chi2 = 3.74, df = 12 (P = 0.99); I2 =0.0%
Test for overall effect: Z = 8.61 (P < 0.00001)
Test for subgroup differences: Chi2 = 0.57, df = 1 (P = 0.45), I2 =0.0%
-4
-2
Favours SNRIs
0
2
4
Favours Placebo
Serotonin and noradrenaline reuptake inhibitors (SNRIs) for fibromyalgia syndrome (Review)
Copyright © 2013 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
60
Analysis 1.12. Comparison 1 SNRI versus placebo final treatment, Outcome 12 Tenderness.
Review:
Serotonin and noradrenaline reuptake inhibitors (SNRIs) for fibromyalgia syndrome
Comparison: 1 SNRI versus placebo final treatment
Outcome: 12 Tenderness
Study or subgroup
SNRIs
Std.
Mean
Difference
Placebo
Weight
IV,Random,95% CI
Std.
Mean
Difference
N
Mean(SD)
N
Mean(SD)
IV,Random,95% CI
Arnold 2004
104
-0.29 (0.7)
103
0.04 (0.7)
16.6 %
-0.47 [ -0.75, -0.19 ]
Arnold 2005
111
-0.22 (0.8)
55
-0.06 (0.8)
12.1 %
-0.20 [ -0.52, 0.12 ]
Arnold 2005
110
-0.39 (0.8)
54
-0.06 (0.8)
11.7 %
-0.41 [ -0.74, -0.08 ]
Chappell 2008
148
-0.4 (1.1)
159
-0.2 (1)
25.2 %
-0.19 [ -0.41, 0.03 ]
Russell 2008
150
-0.52 (1.1)
58
-0.42 (1.1)
13.8 %
-0.09 [ -0.39, 0.21 ]
Russell 2008
79
-0.54 (1.1)
30
-0.42 (1.1)
7.2 %
-0.11 [ -0.53, 0.31 ]
Russell 2008
147
-0.54 (1.1)
56
-0.42 (1.1)
13.4 %
-0.11 [ -0.42, 0.20 ]
100.0 %
-0.23 [ -0.35, -0.12 ]
0
0.0 %
0.0 [ 0.0, 0.0 ]
515
100.0 %
-0.23 [ -0.35, -0.12 ]
1 Duloxetine
Subtotal (95% CI)
849
515
Heterogeneity: Tau2 = 0.0; Chi2 = 5.93, df = 6 (P = 0.43); I2 =0.0%
Test for overall effect: Z = 4.06 (P = 0.000050)
2 Milnacipran
Subtotal (95% CI)
0
Heterogeneity: not applicable
Test for overall effect: not applicable
Total (95% CI)
849
Heterogeneity: Tau2 = 0.0; Chi2 = 5.93, df = 6 (P = 0.43); I2 =0.0%
Test for overall effect: Z = 4.06 (P = 0.000050)
Test for subgroup differences: Not applicable
-100
-50
SNRIs
0
50
100
Placebo
Serotonin and noradrenaline reuptake inhibitors (SNRIs) for fibromyalgia syndrome (Review)
Copyright © 2013 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
61
Analysis 1.13. Comparison 1 SNRI versus placebo final treatment, Outcome 13 Withdrawal due to adverse
events.
Review:
Serotonin and noradrenaline reuptake inhibitors (SNRIs) for fibromyalgia syndrome
Comparison: 1 SNRI versus placebo final treatment
Outcome: 13 Withdrawal due to adverse events
Study or subgroup
SNRIs
Placebo
n/N
n/N
Risk Ratio
Weight
Arnold 2004
18/104
11/103
5.3 %
1.62 [ 0.81, 3.26 ]
Arnold 2005
52/234
14/120
7.8 %
1.90 [ 1.10, 3.29 ]
Arnold 2010a
41/263
24/267
9.6 %
1.73 [ 1.08, 2.79 ]
Chappell 2008
30/162
19/168
8.1 %
1.64 [ 0.96, 2.79 ]
Russell 2008
62/376
17/144
8.9 %
1.40 [ 0.85, 2.31 ]
1139
802
39.7 %
1.65 [ 1.30, 2.09 ]
IV,Random,95% CI
Risk Ratio
IV,Random,95% CI
1 Duloxetine
Subtotal (95% CI)
Total events: 203 (SNRIs), 85 (Placebo)
Heterogeneity: Tau2 = 0.0; Chi2 = 0.73, df = 4 (P = 0.95); I2 =0.0%
Test for overall effect: Z = 4.07 (P = 0.000046)
2 Milnacipran
Arnold 2010b
92/516
71/509
17.6 %
1.28 [ 0.96, 1.70 ]
Branco 2010
96/435
44/449
15.1 %
2.25 [ 1.62, 3.14 ]
Clauw 2008
172/795
38/401
15.1 %
2.28 [ 1.64, 3.18 ]
Mease 2009a
163/665
23/223
11.7 %
2.38 [ 1.58, 3.58 ]
17/97
1/28
0.8 %
4.91 [ 0.68, 35.28 ]
2508
1610
60.3 %
2.00 [ 1.47, 2.73 ]
100.0 %
1.83 [ 1.53, 2.18 ]
Vitton 2004
Subtotal (95% CI)
Total events: 540 (SNRIs), 177 (Placebo)
Heterogeneity: Tau2 = 0.07; Chi2 = 11.70, df = 4 (P = 0.02); I2 =66%
Test for overall effect: Z = 4.37 (P = 0.000013)
Total (95% CI)
3647
2412
Total events: 743 (SNRIs), 262 (Placebo)
Heterogeneity: Tau2 = 0.02; Chi2 = 13.32, df = 9 (P = 0.15); I2 =32%
Test for overall effect: Z = 6.75 (P < 0.00001)
Test for subgroup differences: Chi2 = 0.94, df = 1 (P = 0.33), I2 =0.0%
0.05
0.2
Favours SNRIs
1
5
20
Favours Placebo
Serotonin and noradrenaline reuptake inhibitors (SNRIs) for fibromyalgia syndrome (Review)
Copyright © 2013 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
62
Analysis 1.14. Comparison 1 SNRI versus placebo final treatment, Outcome 14 Serious adverse events.
Review:
Serotonin and noradrenaline reuptake inhibitors (SNRIs) for fibromyalgia syndrome
Comparison: 1 SNRI versus placebo final treatment
Outcome: 14 Serious adverse events
Study or subgroup
SNRIs
Placebo
n/N
n/N
Risk Ratio
Weight
Arnold 2005
2/234
0/120
1.4 %
2.57 [ 0.12, 53.20 ]
Arnold 2010a
1/267
6/263
2.9 %
0.16 [ 0.02, 1.35 ]
Chappell 2008
4/162
4/168
6.8 %
1.04 [ 0.26, 4.08 ]
17/376
11/144
23.7 %
0.59 [ 0.28, 1.23 ]
1039
695
34.7 %
0.63 [ 0.34, 1.16 ]
IV,Random,95% CI
Risk Ratio
IV,Random,95% CI
1 Duloxetine
Russell 2008
Subtotal (95% CI)
Total events: 24 (SNRIs), 21 (Placebo)
Heterogeneity: Tau2 = 0.0; Chi2 = 2.93, df = 3 (P = 0.40); I2 =0.0%
Test for overall effect: Z = 1.49 (P = 0.14)
2 Milnacipran
Arnold 2010b
8/516
6/509
11.5 %
1.32 [ 0.46, 3.76 ]
Branco 2010
14/431
16/446
25.6 %
0.91 [ 0.45, 1.83 ]
Clauw 2008
9/795
6/401
12.1 %
0.76 [ 0.27, 2.11 ]
Mease 2009a
14/665
6/223
14.3 %
0.78 [ 0.30, 2.01 ]
1/97
1/28
1.7 %
0.29 [ 0.02, 4.47 ]
2504
1607
65.3 %
0.88 [ 0.57, 1.37 ]
100.0 %
0.78 [ 0.55, 1.12 ]
Vitton 2004
Subtotal (95% CI)
Total events: 46 (SNRIs), 35 (Placebo)
Heterogeneity: Tau2 = 0.0; Chi2 = 1.35, df = 4 (P = 0.85); I2 =0.0%
Test for overall effect: Z = 0.57 (P = 0.57)
Total (95% CI)
3543
2302
Total events: 70 (SNRIs), 56 (Placebo)
Heterogeneity: Tau2 = 0.0; Chi2 = 5.03, df = 8 (P = 0.75); I2 =0.0%
Test for overall effect: Z = 1.34 (P = 0.18)
Test for subgroup differences: Chi2 = 0.76, df = 1 (P = 0.38), I2 =0.0%
0.5
0.7
Favours SNRIs
1
1.5
2
Favours Placebo
Serotonin and noradrenaline reuptake inhibitors (SNRIs) for fibromyalgia syndrome (Review)
Copyright © 2013 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
63
Analysis 2.1. Comparison 2 Active drug baseline and final treatment, Outcome 1 Pain.
Review:
Serotonin and noradrenaline reuptake inhibitors (SNRIs) for fibromyalgia syndrome
Comparison: 2 Active drug baseline and final treatment
Outcome: 1 Pain
Study or subgroup
Baseline
Mean
Difference
Final treatment
Weight
N
Mean(SD)
N
Mean(SD)
Arnold 2004
103
6.1 (1.7)
103
4.3 (2.4)
5.2 %
1.80 [ 1.23, 2.37 ]
Arnold 2005
118
6.4 (1.4)
116
4 (2.4)
5.9 %
2.40 [ 1.90, 2.90 ]
Arnold 2005
116
6.4 (1.6)
114
4 (2.4)
5.6 %
2.40 [ 1.87, 2.93 ]
Arnold 2010a
263
6.5 (1.6)
263
4.2 (2.7)
7.5 %
2.30 [ 1.92, 2.68 ]
Arnold 2010b
516
6.3 (1.3)
516
4.5 (2.8)
9.1 %
1.80 [ 1.53, 2.07 ]
Branco 2010
430
6.6 (1.3)
430
4.9 (2.5)
9.1 %
1.70 [ 1.43, 1.97 ]
Chappell 2008
162
6.6 (1.5)
158
5 (2.5)
6.5 %
1.60 [ 1.15, 2.05 ]
Clauw 2008
399
6.5 (1.4)
399
4.9 (2)
9.5 %
1.60 [ 1.36, 1.84 ]
Clauw 2008
396
6.5 (1.4)
396
4.7 (2.2)
9.3 %
1.80 [ 1.54, 2.06 ]
Mease 2009a
224
6.6 (1.2)
115
4.3 (3.3)
4.7 %
2.30 [ 1.68, 2.92 ]
Mease 2009a
441
6.8 (1.2)
204
4.3 (3.7)
5.7 %
2.50 [ 1.98, 3.02 ]
Russell 2008
150
6.5 (1.4)
150
4 (2.6)
6.3 %
2.50 [ 2.03, 2.97 ]
Russell 2008
79
6.8 (1.6)
79
4.6 (2.5)
4.4 %
2.20 [ 1.55, 2.85 ]
Russell 2008
147
6.4 (1.6)
147
4.1 (2.5)
6.2 %
2.30 [ 1.82, 2.78 ]
Vitton 2004
49
6.9 (1.9)
42
4.6 (2.7)
2.5 %
2.30 [ 1.33, 3.27 ]
Vitton 2004
46
7 (1.7)
37
5.1 (2.9)
2.2 %
1.90 [ 0.84, 2.96 ]
100.0 %
2.04 [ 1.86, 2.21 ]
Total (95% CI)
3639
IV,Random,95% CI
Mean
Difference
IV,Random,95% CI
3269
Heterogeneity: Tau2 = 0.07; Chi2 = 39.37, df = 15 (P = 0.00056); I2 =62%
Test for overall effect: Z = 22.77 (P < 0.00001)
Test for subgroup differences: Not applicable
-2
-1
0
Baseline
Serotonin and noradrenaline reuptake inhibitors (SNRIs) for fibromyalgia syndrome (Review)
Copyright © 2013 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
1
2
Final treatment
64
Analysis 2.2. Comparison 2 Active drug baseline and final treatment, Outcome 2 Quality of life.
Review:
Serotonin and noradrenaline reuptake inhibitors (SNRIs) for fibromyalgia syndrome
Comparison: 2 Active drug baseline and final treatment
Outcome: 2 Quality of life
Study or subgroup
Baseline
Mean
Difference
Final treatment
Weight
N
Mean(SD)
N
Mean(SD)
Arnold 2004
104
60.9 (18.8)
102
44 (22.9)
4.3 %
16.90 [ 11.17, 22.63 ]
Arnold 2005
118
64.3 (15.3)
114
43.4 (23.6)
5.0 %
20.90 [ 15.76, 26.04 ]
Arnold 2005
116
65.6 (15.9)
112
44.6 (20.8)
5.4 %
21.00 [ 16.18, 25.82 ]
Arnold 2010b
516
56.7 (12.7)
516
44.4 (24.8)
9.7 %
12.30 [ 9.90, 14.70 ]
Branco 2010
430
56.7 (11.9)
430
42.5 (21.3)
9.9 %
14.20 [ 11.89, 16.51 ]
Chappell 2008
162
62 (14.1)
153
52 (21.3)
6.5 %
10.00 [ 5.99, 14.01 ]
Clauw 2008
396
64.5 (13.8)
396
47.1 (22)
9.4 %
17.40 [ 14.84, 19.96 ]
Clauw 2008
399
64.6 (13.5)
399
48.8 (22)
9.4 %
15.80 [ 13.27, 18.33 ]
Mease 2009a
441
64.3 (14.4)
441
47.6 (22.6)
9.5 %
16.70 [ 14.20, 19.20 ]
Mease 2009a
223
65.1 (13.7)
223
47.4 (22.2)
7.6 %
17.70 [ 14.28, 21.12 ]
Russell 2008
79
67.5 (14.3)
79
49 (20.9)
4.4 %
18.50 [ 12.92, 24.08 ]
Russell 2008
150
64.6 (14.8)
150
49.3 (22)
6.2 %
15.30 [ 11.06, 19.54 ]
Russell 2008
147
64.6 (17.6)
147
47.3 (17.3)
6.6 %
17.30 [ 13.31, 21.29 ]
Vitton 2004
42
49.9 (13)
33
37 (17.6)
3.1 %
12.90 [ 5.72, 20.08 ]
Vitton 2004
44
50.6 (14.3)
37
37.5 (18.1)
3.1 %
13.10 [ 5.90, 20.30 ]
100.0 %
15.89 [ 14.45, 17.34 ]
Total (95% CI)
3367
IV,Random,95% CI
Mean
Difference
IV,Random,95% CI
3332
Heterogeneity: Tau2 = 4.10; Chi2 = 32.12, df = 14 (P = 0.004); I2 =56%
Test for overall effect: Z = 21.57 (P < 0.00001)
Test for subgroup differences: Not applicable
-20
-10
Baseline
0
10
20
Final treatment
Serotonin and noradrenaline reuptake inhibitors (SNRIs) for fibromyalgia syndrome (Review)
Copyright © 2013 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
65
Analysis 3.1. Comparison 3 Placebo baseline and final treatment, Outcome 1 Pain.
Review:
Serotonin and noradrenaline reuptake inhibitors (SNRIs) for fibromyalgia syndrome
Comparison: 3 Placebo baseline and final treatment
Outcome: 1 Pain
Study or subgroup
Baseline
Mean
Difference
Final treatment
Weight
N
Mean(SD)
N
Mean(SD)
Arnold 2004
104
6.1 (1.8)
102
5.2 (2.3)
4.0 %
0.90 [ 0.34, 1.46 ]
Arnold 2005
120
6.5 (1.5)
118
5.3 (2.3)
5.3 %
1.20 [ 0.71, 1.69 ]
Arnold 2010a
267
6.5 (1.6)
267
5 (2.8)
8.6 %
1.50 [ 1.11, 1.89 ]
Arnold 2010b
509
6.4 (1.3)
509
5.3 (2.9)
16.9 %
1.10 [ 0.82, 1.38 ]
Branco 2010
446
6.6 (1.3)
446
5.3 (2.4)
20.0 %
1.30 [ 1.05, 1.55 ]
Chappell 2008
168
6.4 (1.5)
167
5.3 (2.5)
6.6 %
1.10 [ 0.66, 1.54 ]
Clauw 2008
401
6.6 (1.3)
401
5.3 (2)
23.6 %
1.30 [ 1.07, 1.53 ]
Mease 2009a
223
6.8 (1.2)
128
5.9 (2.1)
8.2 %
0.90 [ 0.50, 1.30 ]
Russell 2008
144
6.6 (1.7)
144
5.2 (2.2)
6.2 %
1.40 [ 0.95, 1.85 ]
Vitton 2004
28
6.7 (2.2)
24
5.9 (2.7)
0.7 %
0.80 [ -0.55, 2.15 ]
100.0 %
1.22 [ 1.11, 1.33 ]
Total (95% CI)
2410
IV,Random,95% CI
Mean
Difference
IV,Random,95% CI
2306
Heterogeneity: Tau2 = 0.0; Chi2 = 8.57, df = 9 (P = 0.48); I2 =0.0%
Test for overall effect: Z = 21.08 (P < 0.00001)
Test for subgroup differences: Not applicable
-4
-2
0
Baseline
Serotonin and noradrenaline reuptake inhibitors (SNRIs) for fibromyalgia syndrome (Review)
Copyright © 2013 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
2
4
Final treatment
66
Analysis 3.2. Comparison 3 Placebo baseline and final treatment, Outcome 2 Quality of life.
Review:
Serotonin and noradrenaline reuptake inhibitors (SNRIs) for fibromyalgia syndrome
Comparison: 3 Placebo baseline and final treatment
Outcome: 2 Quality of life
Study or subgroup
Baseline
Mean
Difference
Final treatment
Mean
Difference
Weight
N
Mean(SD)
N
Mean(SD)
Arnold 2004
101
62.8 (16.6)
101
52.9 (21.9)
4.2 %
9.90 [ 4.54, 15.26 ]
Arnold 2005
120
66.4 (15.5)
115
55.9 (20.5)
5.5 %
10.50 [ 5.84, 15.16 ]
Arnold 2010b
509
57.9 (12.7)
509
45.6 (24.8)
19.8 %
12.30 [ 9.88, 14.72 ]
Branco 2010
446
57 (11.8)
446
45.8 (20.9)
23.2 %
11.20 [ 8.97, 13.43 ]
Chappell 2008
168
63.3 (15.6)
163
56 (20.6)
7.7 %
7.30 [ 3.35, 11.25 ]
Clauw 2008
401
62.5 (14.1)
401
50.5 (14.1)
29.7 %
12.00 [ 10.05, 13.95 ]
Mease 2009a
223
64.7 (13.4)
223
48.8 (59.8)
1.9 %
15.90 [ 7.86, 23.94 ]
Russell 2008
144
66.3 (14)
144
53.3 (21.9)
6.6 %
13.00 [ 8.75, 17.25 ]
Vitton 2004
26
51.6 (16)
22
44.8 (16.8)
1.4 %
6.80 [ -2.53, 16.13 ]
100.0 %
11.41 [ 10.31, 12.51 ]
Total (95% CI)
2138
IV,Random,95% CI
IV,Random,95% CI
2124
Heterogeneity: Tau2 = 0.07; Chi2 = 8.20, df = 8 (P = 0.41); I2 =2%
Test for overall effect: Z = 20.27 (P < 0.00001)
Test for subgroup differences: Not applicable
-20
-10
Baseline
0
10
20
Final treatment
ADDITIONAL TABLES
Table 1. Subgroup analysis: Efficacy and safety of SNRIs in studies with and without European participants
Outcome title
Number
of
participants
Effect size
Test for
SMD (95% CI) or overall
RR (95% CI)
effect
P value
Heterogeneity
I²(%);
Pain
Test of interaction:
effect estimate and
P value
Z = 1.0; P = 0.32
Without European 4837
participants
-0.25 (-0.31 to -0. < 0.001
19)
0
With European par- 1201
ticipants
-0.19 (-0-30 to -0. < 0.001
08)
0
Serotonin and noradrenaline reuptake inhibitors (SNRIs) for fibromyalgia syndrome (Review)
Copyright © 2013 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
67
Table 1. Subgroup analysis: Efficacy and safety of SNRIs in studies with and without European participants
Fatigue
(Continued)
Z = 0.57; P = 0.57
Without European 4466
participants
-0.14 (-0.21 to -0. < 0.001
08)
0
With European par- 1190
ticipants
-0.10 (-0.2 to -0.06) < 0.001
41
Disease-related
quality of life
Z = 1.0; P = 0.32
Without European 4795
participants
-0.21 (-0.27 to -0. < 0.001
15)
0
With European par- 1192
ticipants
-0.14 (-0.25 to -0. < 0.001
02)
0
RR 50% pain reduction
Z = 2.0; P = 0.045
Without European 4774
participants
1.56 (1.40 to 1.74)
< 0.001
0
With European par- 1201
ticipants
1.32 (1.06 to 1.63)
< 0.001
0
Withdrawal due to
adverse events
Z = 0.82; P = 0.41
Without European 4965
participants
1.78 (1.47 to 2.17)
< 0.001
0
With European par- 1214
ticipants
2.06 (1.55 to 2.73)
< 0.001
0
Abbreviations
CI= confidence interval
RR = risk ratio
SMD: standardized mean difference
Serotonin and noradrenaline reuptake inhibitors (SNRIs) for fibromyalgia syndrome (Review)
Copyright © 2013 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
68
APPENDICES
Appendix 1. Search strategies and hits retrieved
RCTs in FMS (updated search September 11, 2012)
DATABASE (ACCESS) and date of search
Search Strategy and hits retrieved
MEDLINE
(PubMed)
11 September 2012
#1“Fibromyalgia”[MeSH] OR fibromyalgi*[ti] OR fibrositis[ti] 6070
#2 (randomized controlled trial[pt] OR controlled clinical trial[pt] OR randomized[tiab] OR placebo[tiab] OR drug therapy[sh] OR randomly[tiab] OR
trial[tiab] OR groups[tiab]) NOT (animals[mh] NOT (humans[mh] AND animals[mh])) 2600091
#3 Search cymbalta OR savella OR ixel OR pristiq OR effexor OR desvenlafaxine OR duloxetine OR milnacipran OR venlafaxine 4353
#4 Search ((#1) AND #2) AND #3 Filters: Publication date from 2010/10/01
to 2012/09/10 42
CENTRAL
(The Cochrane Library)
2012, Issue 9
#1MeSH descriptor Fibromyalgia explode all trees 510
#2 (fibromyalgi$):ti,ab,kw or (fibrositis):ti,ab,kw 62
#3 (#1 OR #2), from 2010 to 2012 107
#4 (cymbalta):ti,ab,kw or (savella):ti,ab,kw or (ixel):ti,ab,kw or (pristiq):ti,ab,
kw or (effexor):ti,ab,kw 17
#5 (desvenlaxafine):ti,ab,kw or (duloxetine):ti,ab,kw or (milnacipran):ti,ab,kw
or (venlaxafine):ti,ab,kw 454
#6 (#4 OR #5), from 2010 to 2012 77
#7 (#3 AND #6) 17
EMBASE via SCOPUS
11 September 2012
1 (TITLE-ABS-KEY(random) OR TITLE-ABS-KEY(placebo) OR TITLEABS-KEY(double-blind)) AND DOCTYPE(ar) AND PUBYEAR > 2009
97115
2 (TITLE-ABS-KEY(expfibromyalgia/) OR TITLE-ABS-KEY(fibrositis) OR
TITLE-ABS-KEY(fibromyalgia)) AND DOCTYPE(ar) AND PUBYEAR >
2009 1265
3 (TITLE-ABS-KEY(cymbalta) OR TITLE-ABS-KEY(savella) OR TITLEABS-KEY(ixel) OR TITLE-ABS-KEY(pristiq) OR TITLE-ABS-KEY(effexor)
OR TITLE-ABS-KEY(desvenlaxafine) OR TITLE-ABS-KEY(duloxetine) OR
TITLE-ABS-KEY(venlaxafine) OR TITLE-ABS-KEY(milnacipran)) AND
DOCTYPE(ar) AND PUBYEAR > 2009 1051
4 ((TITLE-ABS-KEY(expfibromyalgia/) OR TITLE-ABS-KEY(fibrositis) OR
TITLE-ABS-KEY(fibromyalgia)) AND DOCTYPE(ar) AND PUBYEAR >
2009) AND ((TITLE-ABS-KEY(random) OR TITLE-ABS-KEY(placebo) OR
TITLE-ABS-KEY(double-blind)) AND DOCTYPE(ar) AND PUBYEAR >
2009) AND ((TITLE-ABS-KEY(cymbalta) OR TITLE-ABS-KEY(savella) OR
TITLE-ABS-KEY(ixel) OR TITLE-ABS-KEY(pristiq) OR TITLE-ABS-KEY
(effexor) OR TITLE-ABS-KEY(desvenlaxafine) OR TITLE-ABS-KEY(duloxetine) OR TITLE-ABS-KEY(venlaxafine) OR TITLE-ABS-KEY(milnacipran)
) AND DOCTYPE(ar) AND PUBYEAR > 2009) 50
Serotonin and noradrenaline reuptake inhibitors (SNRIs) for fibromyalgia syndrome (Review)
Copyright © 2013 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
69
(Continued)
ClinicalTrials.gov
11 September 2012
1 fibromyalgia 401
2 fibromyalgia and desvenlaxafine 4
3 fibromyalgia and duloxetine 25
4 fibromyalgia and milnacipran 27
5 fibromyalgia and venlaxafine 0
RCTs in FMS (updated search November 2010)
DATABASE (ACCESS) and date of search
Search Strategy and hits retrieved
MEDLINE
(PubMed)
4 November.2010
#1“Fibromyalgia”[MeSH] OR fibromyalgi*[ti] OR fibrositis[ti] 5248
#2 (randomized controlled trial[pt] OR controlled clinical trial[pt] OR randomized[tiab] OR placebo[tiab] OR drug therapy[sh] OR randomly[tiab] OR
trial[tiab] OR groups[tiab]) NOT (animals[mh] NOT (humans[mh] AND
animals[mh])) 2309479
#3 #1 AND #2 1682
#4 (#2) AND #1 Limits: Publication Date from 2009 312
CENTRAL
(The Cochrane Library)
2010, Issue 10
#1MeSH descriptor Fibromyalgia explode all trees 449
#2 fibromyalgi* 755
#3 fibrositis 50
#4 #1 OR #2 OR #3 774
#5 (#1 OR #2 OR #3), from 2009 to 2010 137 (69 in clinical trials)
EMBASE
(Ovid)
4 November.2010
1 exp Fibromyalgia/ 8833
2 fibromyalgia.ti,ab. 6702
3 exp Fibromyalgia/ 8833
4 fibrositis.ti. 271
5 1 or 2 or 3 or 4 9482
6 random:.tw. or placebo:.mp. or double-blind:.mp. 776985
7 5 and 6 1417
8 limit 7 to yr=“2009 -Current” 405
ClinicalStudyResults.org
31 December 2010
1 fibromyalgia 19
2 fibromyalgia and cymbalta 4
3 fibromyalgia and savella or ixel: no search possible
4 fibromyalgia and pristiq 4
5 fibromyalgia and effexor 0
ClinicalTrials.gov
31 December 2010
1 fibromyalgia 326
2 fibromyalgia and desvenlaxafine 4
3 fibromyalgia and duloxetine 20
4 fibromyalgia and milnacipran 20
5 fibromyalgia and venlaxafine 0
RCTs in FMS (initial search February 2009)
Serotonin and noradrenaline reuptake inhibitors (SNRIs) for fibromyalgia syndrome (Review)
Copyright © 2013 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
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DATABASE (ACCESS) and date of search
Search Strategy and hits retrieved
MEDLINE
(PubMed)
9 February 2009
#1“Fibromyalgia”[MeSH] OR fibromyalgi*[ti] OR fibrositis[ti] 4433
#2 (randomized controlled trial[pt] OR controlled clinical trial[pt] OR randomized[tiab] OR placebo[tiab] OR drug therapy[sh] OR randomly[tiab] OR
trial[tiab] OR groups[tiab]) AND humans [mh] 1912816
#3 #1 AND #2 1316
CENTRAL
(The Cochrane Library)
2009, Issue 1
#1MeSH descriptor Fibromyalgia explode all trees 315
#2 fibromyalgi* 512
#3 fibrositis 36
#4 #1 OR #2 OR #3 526
EMBASE
(Ovid)
9 February 2009
1 exp Fibromyalgia/ 5537
2 fibromyalgia.ti,ab. 4304
3 exp Fibromyalgia/ 354
4 fibrositis.ti. 122
5 1 or 2 or 3 or 4 6046
6 random:.tw. or placebo:.mp. or double-blind:.mp. 514373
7 5 and 6 886
WHAT’S NEW
Last assessed as up-to-date: 27 December 2012.
Date
Event
Description
21 March 2013
Amended
Minor edits in summary of findings table
14 January 2013
Amended
Revisions to risk of bias tables
23 October 2012
Amended
The protocol ’Antidepressants and centrally active agents for fibromyalgia syndrome’ published
in 2006 (Nishishinya 2006) has been split into several systematic reviews that will be/have been
published as:
- Anticonvulsants for fibromyalgia syndrome
- Monoamine oxidase inhibitors (MAOIs) for fobromyalgia syndrome
- Non-steroidal anti-inflammatory drugs (NSAIDs), analgesics and opioid agents for fibromyalgia
syndrome
- Sedatives and hypnotic agents for fibromyalgia syndrome
- Selective serotonin reuptake inhibitors (SNRIs) for fibromyalgia syndrome
- Serotonin and noradrenaline reuptake inhibitors (SNRIs) for fibromyalgia syndrome
- Tricyclic agents for fibromyalgia syndrome
Serotonin and noradrenaline reuptake inhibitors (SNRIs) for fibromyalgia syndrome (Review)
Copyright © 2013 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
71
CONTRIBUTIONS OF AUTHORS
WH: topic conception and methodological aspects; protocol revision; systematic review study selection, data extraction, data analysis,
interpretation of findings and author of review.
NÜ: systematic review study selection, data extraction, data analysis, data extraction, interpretation of findings; review final proof.
ST:topic conception and methodological aspects; protocol review and revision; search of literature; systematic review dispute resolution
for methodological quality; review final proof.
GU: topic conception and methodological aspects; protocol review and revision; search of literature; review final proof.
BW: protocol review and revision; interpretation of findings; review final proof.
DECLARATIONS OF INTEREST
WH received one consulting fee from Daiichi Sankyo. NÜ received consultancy honoraria by Grünenthal GmbH and travel grants
by Pfizer, Astellas, Grünenthal GmbH, and CSL Behring. BW received a consulting fee from Jazz Pharmaceuticals and was a site
investigator for a milnacipran trial. ST and GU have no conflicts of interest to declare.
SOURCES OF SUPPORT
Internal sources
• New Source of support, Not specified.
None
External sources
• New Source of support, Not specified.
None
DIFFERENCES BETWEEN PROTOCOL AND REVIEW
The protocol ’Antidepressants and centrally active agents for fibromyalgia syndrome’ has been split into several systematic reviews
(Nishishinya 2006). We have added an additional comparison, namely cognitive disturbances, and the calculation of intra-group effect
sizes (baseline and final treatment) of true drug and placebo on pain and QOL. A random-effects model was used for all analysis
irrespective of the amount of heterogeneity. The GRADE approach was used for the grading of evidence.
INDEX TERMS
Serotonin and noradrenaline reuptake inhibitors (SNRIs) for fibromyalgia syndrome (Review)
Copyright © 2013 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
72
Medical Subject Headings (MeSH)
Adrenergic Uptake Inhibitors [∗ therapeutic use]; Cyclopropanes [∗ therapeutic use]; Fibromyalgia [∗ drug therapy]; Norepinephrine
[∗ metabolism]; Quality of Life; Serotonin Uptake Inhibitors [∗ therapeutic use]; Syndrome; Thiophenes [∗ therapeutic use]
MeSH check words
Adult; Humans
Serotonin and noradrenaline reuptake inhibitors (SNRIs) for fibromyalgia syndrome (Review)
Copyright © 2013 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
73