Anticonvulsivos y Fibromialgia

Anticonvulsants for fibromyalgia (Review)
Üçeyler N, Sommer C, Walitt B, Häuser W
This is a reprint of a Cochrane review, prepared and maintained by The Cochrane Collaboration and published in The Cochrane Library
2013, Issue 10
http://www.thecochranelibrary.com

Copyright © 2013 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
TABLE OF CONTENTS
HEADER . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1
ABSTRACT . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1
PLAIN LANGUAGE SUMMARY . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2
SUMMARY OF FINDINGS FOR THE MAIN COMPARISON . . . . . . . . . . . . . . . . . . . 4
BACKGROUND . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 7
OBJECTIVES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 8
METHODS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 8
RESULTS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 10
Figure 1. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 12
Figure 2. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 14
Figure 3. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 15
Figure 4. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 18
Figure 5. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 20
Figure 6. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 21
DISCUSSION . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 22
AUTHORS’ CONCLUSIONS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 24
ACKNOWLEDGEMENTS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 25
REFERENCES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 25
CHARACTERISTICS OF STUDIES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 29
DATA AND ANALYSES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 45
Analysis 1.1. Comparison 1 Gabapentin flexible 1200 to 2400 mg/day versus placebo at end of treatment, Outcome 1
Pain. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 48
Analysis 1.2. Comparison 1 Gabapentin flexible 1200 to 2400 mg/day versus placebo at end of treatment, Outcome 2 50%
pain reduction. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 49
Sleep problems. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 49
Health-related quality of life. . . . . . . . . . . . . . . . . . . . . . . . . . . . . 50
Withdrawal due to adverse events. . . . . . . . . . . . . . . . . . . . . . . . . . . . 50
Dizziness. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 51
Analysis 1.7. Comparison 1 Gabapentin flexible 1200 to 2400 mg/day versus placebo at end of treatment, Outcome 7 30%
pain reduction. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 51
Depression. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 52
Disability. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 52
Analysis 2.1. Comparison 2 Lacosamide 400 mg/day versus placebo at end of treatment, Outcome 1 Pain. . . . . 53
Analysis 2.2. Comparison 2 Lacosamide 400 mg/day versus placebo at end of treatment, Outcome 2 Fatigue. . . . 53
Analysis 2.3. Comparison 2 Lacosamide 400 mg/day versus placebo at end of treatment, Outcome 3 Sleep problems. 54
Analysis 2.4. Comparison 2 Lacosamide 400 mg/day versus placebo at end of treatment, Outcome 4 Health-related quality
of life. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 54
Analysis 2.5. Comparison 2 Lacosamide 400 mg/day versus placebo at end of treatment, Outcome 5 Serious adverse
events. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 55
Analysis 2.6. Comparison 2 Lacosamide 400 mg/day versus placebo at end of treatment, Outcome 6 Dizziness. . . 55
Analysis 2.7. Comparison 2 Lacosamide 400 mg/day versus placebo at end of treatment, Outcome 7 Anxiety. . . . 56
Analysis 2.8. Comparison 2 Lacosamide 400 mg/day versus placebo at end of treatment, Outcome 8 Depression. . . 56
Analysis 2.9. Comparison 2 Lacosamide 400 mg/day versus placebo at end of treatment, Outcome 9 Disability. . . 57
Analysis 2.10. Comparison 2 Lacosamide 400 mg/day versus placebo at end of treatment, Outcome 10 Patient Global
Impression of Change ’much’ or ’very much’ improved. . . . . . . . . . . . . . . . . . . . 57
Anticonvulsants for fibromyalgia (Review) i
Analysis 3.1. Comparison 3 Levetiracetam up to 3000 mg/day versus placebo at end of treatment, Outcome 1 Pain. . 58
Analysis 3.2. Comparison 3 Levetiracetam up to 3000 mg/day versus placebo at end of treatment, Outcome 2 50% pain
reduction. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 58
Analysis 3.3. Comparison 3 Levetiracetam up to 3000 mg/day versus placebo at end of treatment, Outcome 3 Sleep
problems. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 59
Analysis 3.4. Comparison 3 Levetiracetam up to 3000 mg/day versus placebo at end of treatment, Outcome 4 Health-
related quality of life. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 59
Analysis 3.5. Comparison 3 Levetiracetam up to 3000 mg/day versus placebo at end of treatment, Outcome 5 Withdrawal
due to adverse events. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 60
Analysis 3.6. Comparison 3 Levetiracetam up to 3000 mg/day versus placebo at end of treatment, Outcome 6 Dizziness. 60
Analysis 3.7. Comparison 3 Levetiracetam up to 3000 mg/day versus placebo at end of treatment, Outcome 7 30% pain
reduction. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 61
Analysis 4.1. Comparison 4 Pregabalin versus placebo at end of treatment, Outcome 1 Pain. . . . . . . . . . 62
Analysis 4.2. Comparison 4 Pregabalin versus placebo at end of treatment, Outcome 2 50% pain reduction. . . . 63
Analysis 4.3. Comparison 4 Pregabalin versus placebo at end of treatment, Outcome 3 Fatigue. . . . . . . . . 65
Analysis 4.4. Comparison 4 Pregabalin versus placebo at end of treatment, Outcome 4 Sleep problems. . . . . . 66
Analysis 4.5. Comparison 4 Pregabalin versus placebo at end of treatment, Outcome 5 Health-related quality of life. 68
Analysis 4.6. Comparison 4 Pregabalin versus placebo at end of treatment, Outcome 6 Withdrawal due to adverse events. 69
Analysis 4.7. Comparison 4 Pregabalin versus placebo at end of treatment, Outcome 7 Serious adverse events. . . . 71
Analysis 4.8. Comparison 4 Pregabalin versus placebo at end of treatment, Outcome 8 Dizziness. . . . . . . . 72
Analysis 4.9. Comparison 4 Pregabalin versus placebo at end of treatment, Outcome 9 30% pain reduction. . . . 74
Analysis 4.10. Comparison 4 Pregabalin versus placebo at end of treatment, Outcome 10 Anxiety. . . . . . . . 76
Analysis 4.11. Comparison 4 Pregabalin versus placebo at end of treatment, Outcome 11 Depression. . . . . . 77
Analysis 4.12. Comparison 4 Pregabalin versus placebo at end of treatment, Outcome 12 Disability. . . . . . . 79
Analysis 4.13. Comparison 4 Pregabalin versus placebo at end of treatment, Outcome 13 Patient Global Impression of
Change ’much’ or ’very much’ improved. . . . . . . . . . . . . . . . . . . . . . . . . 80
APPENDICES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 81
WHAT’S NEW . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 93
CONTRIBUTIONS OF AUTHORS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 93
DECLARATIONS OF INTEREST . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 94
DIFFERENCES BETWEEN PROTOCOL AND REVIEW . . . . . . . . . . . . . . . . . . . . . 94
INDEX TERMS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 94
Anticonvulsants for fibromyalgia (Review) ii

[Intervention Review]
Anticonvulsants for fibromyalgia
Nurcan Üçeyler1 , Claudia Sommer1 , Brian Walitt2 , Winfried Häuser3

1 Department of Neurology, University of Würzburg, Würzburg,
Germany. 2 Georgetown University Medical Center, Washington Hos-
pital Center, Washington, DC, USA. 3 Department of Psychosomatic Medicine and Psychotherapy, Technische Universität München,
München, Germany
Contact address: Winfried Häuser, Department of Psychosomatic Medicine and Psychotherapy, Technische Universität München,
Langerstr. 3, München, D-81675, Germany. whaeuser@klinikum-saarbruecken.de.
Editorial group: Cochrane Musculoskeletal Group.

Publication status and date: New, published in Issue 10, 2013.
Review content assessed as up-to-date: 30 August 2013.
Citation: Üçeyler N, Sommer C, Walitt B, Häuser W. Anticonvulsants for fibromyalgia. Cochrane Database of Systematic Reviews 2013,
Issue 10. Art. No.: CD010782. DOI: 10.1002/14651858.CD010782.
ABSTRACT
Background
Fibromyalgia (FM) is a clinically well-defined chronic condition of unknown aetiology characterised by chronic widespread pain that
often co-exists with sleep problems and fatigue. People often report high disability levels and poor health-related quality of life (HRQoL).
Drug therapy focuses on reducing key symptoms and disability, and improving HRQoL. Anticonvulsants (antiepileptic drugs) are
drugs frequently used for the treatment of chronic pain syndromes.
Objectives
To assess the benefits and harms of anticonvulsants for treating FM symptoms.
Search methods
We searched the Cochrane Central Register of Controlled Trials (CENTRAL) (Issue 8, 2013), MEDLINE (1966 to August 2013),
PsycINFO (1966 to August 2013), SCOPUS (1980 to August 2013) and the reference lists of reviewed articles for published studies
and www.clinicaltrials.gov (to August 2013) for unpublished trials.
Selection criteria
We selected randomised controlled trials of any formulation of anticonvulsants used for the treatment of people with FM of any age.
Data collection and analysis
Two review authors independently extracted the data of all included studies and assessed the risks of bias of the studies. We resolved
discrepancies by discussion.
Main results
We included eight studies: five with pregabalin and one study each with gabapentin, lacosamide and levetiracetam. A total of 2480
people were included into anticonvulsants groups and 1099 people in placebo groups. The median therapy phase of the studies was
13 weeks. The amount and quality of evidence were insufficient to draw definite conclusions on the efficacy and safety of gabapentin,
lacosamide and levetiracetam in FM. The amount and quality of evidence was sufficient to draw definite conclusions on the efficacy
and safety of pregabalin in FM. Therefore, we focused on our interpretation of the evidence for pregabalin due to our greater certainty
about its effects and its greater relevance to clinical practice. All pregabalin studies had a low risk of bias. Reporting a 50% or greater
Anticonvulsants for fibromyalgia (Review) 1
reduction in pain was more frequent with pregabalin use than with a placebo (risk ratio (RR) 1.59; 95% confidence interval (CI) 1.33
to 1.90; number needed to treat for an additional beneficial outcome (NNTB) 12; 95% CI 9 to 21). The number of people who
reported being ’much’ or ’very much’ improved was higher with pregabalin than with placebo (RR 1.38; 95% CI 1.23 to 1.55; NNTB
9; 95% CI 7 to 15). Pregabalin did not substantially reduce fatigue (SMD -0.17; 95% CI -0.25 to -0.09; 2.7% absolute improvement
on a 1 to 50 scale) compared with placebo. Pregabalin had a small benefit over placebo in reducing sleep problems by 6.2% fewer
points on a scale of 0 to 100 (standardised mean difference (SMD) -0.35; 95% CI -0.43 to -0.27). The dropout rate due to adverse
events was higher with pregabalin use than with placebo use (RR 1.68; 95% CI 1.36 to 2.07; number needed to treat for an additional
harmful outcome (NNTH) 13; 95% CI 9 to 23). There was no significant difference in serious adverse events between pregabalin and
placebo use (RR 1.03; 95% CI 0.71 to 1.49). Dizziness was reported as an adverse event more frequently with pregabalin use than with
placebo use (RR 3.77; 95% CI 3.06 to 4.63; NNTH 4; 95% CI 3 to 5).
Authors’ conclusions
The anticonvulsant, pregabalin, demonstrated a small benefit over placebo in reducing pain and sleep problems. Pregabalin use was
shown not to substantially reduce fatigue compared with placebo. Study dropout rates due to adverse events were higher with pregabalin
use compared with placebo. Dizziness was a particularly frequent adverse event seen with pregabalin use. At the time of writing this
review, pregabalin is the only anticonvulsant drug approved for treating FM in the US and in 25 other non-European countries.
However, pregabalin has not been approved for treating FM in Europe. The amount and quality of evidence were insufficient to draw
definite conclusions on the efficacy and safety of gabapentin, lacosamide and levetiracetam in FM.
PLAIN LANGUAGE SUMMARY
Anticonvulsants for fibromyalgia
Researchers in The Cochrane Collaboration conducted a review of research about the effects of anticonvulsants (antiepileptic drugs)
on fibromyalgia (FM). After searching for all relevant studies, they found eight studies with up to 3579 people. The anticonvulsants
that they studied were gabapentin, lacosamide, levetiracetam and pregabalin. They found reliable conclusions for pregabalin only.
Key results: pregabalin compared with fake medication after an average of 13 weeks
- Pregabalin slightly reduces pain and sleep problems.
- Pregabalin slightly reduces fatigue.
- Pregabalin increases medication side effects, in particular dizziness.
- Pregabalin does not differ from fake medication in serious side effects.
Possible side effects may include drowsiness, weight gain, swelling in the legs, blurred vision and co-ordination problems. Rare
complications may include angio-oedema (swelling that happens just below the surface of the skin, most often around the lips and eyes),
allergies and diseases of the immune system, worsening of heart failure, impairment of a person’s ability to drive or operate machinery,
and abuse or dependency on pregabalin. Serious side effects, such as suicidal thoughts, are very rare.
What is FM and what are anticonvulsants?
People with FM suffer from chronic widespread pain, sleep problems and fatigue. There is no cure for FM at present. Treatments aim
at relieving the symptoms and improving quality of life.
Anticonvulsants are medications which help people with epileptic seizures. Neurons are cells that send messages to the brain. For
example some neurons send messages about light, sound or touch to the brain. If something goes wrong and the neurons send too
many messages quickly, then people may feel pain more strongly. Anticonvulsants can help slow the neurons down in the spinal cord
and the brain. Some anticonvulsants can reduce pain and sleep problems in chronic pain due to nerve damage and can stabilize mood
in people with anxiety and depressive disorders. People with fibromyalgia can have more brain activity and stronger reactions to the
stimulus from their senses, so anticonvulsants might help with that. Pregabalin is approved for use in FM patients in most countries of
North and South America and Asia, but not in Europe.
Best estimate of what happens to people with FM when they take pregabalin
Pain:
- 9 more people out of 100 who took pregabalin reached 50% or greater pain reduction than people who took fake medication (9%
absolute improvement).
- 23 out of 100 people had their pain reduced by 50% or greater when they took pregabalin compared with 14 out of 100 people when
they took a fake medication.
Global improvement:
- 11 more people out of 100 who took pregabalin improved ’much’ and ’very much’ globally than people who took fake medication
(12% absolute improvement).
- 39 out of 100 people improved ’much’ and ’very much’ globally when they took pregabalin compared with 28 out of 100 people when
they took a fake medication.
Fatigue (measured on a 1 to 50 scale):
- People who took pregabalin reported a slight reduction of fatigue (2.7% absolute improvement) than people who took a fake
medication.
- People who took pregabalin rated their fatigue as 34.6 compared with 35.6 in people who took a fake medication.
Sleep problems (measured on a 0 to 100 scale):
- People who took pregabalin reported a reduction of sleep problems (6.2% absolute improvement) than people who took a fake
medication.
- People who took pregabalin rated their sleep problems to be 54.9 compared with 58.6 in people who took fake medication
Stopping medication due to side effects:
- 7 more people out of 100 stopped pregabalin compared with fake medication because of side effects (8% absolute deterioration).
- 18 people out of 100 who took anticonvulsants stopped medication due to side effects compared with 11 people out of 100 who took
a fake medication.
Serious side effects:
- There were no differences between pregabalin (5.2%) and fake medication (4.1%) in the number of serious adverse events.
Dizziness:
- 24 more people out of 100 reported dizziness as a side effect of pregabalin (28% absolute deterioration).
- 35 people out of 100 who took pregabalin reported dizziness as a side effect compared with 11 people out of 100 who took a fake
medication.

Anticonvulsants for fibromyalgia (Review) 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]
Pregabalin versus placebo at final treatment for fibromyalgia
Patient or population: People with fibromyalgia

Settings: Research centres
Intervention: Pregabalin versus placebo at final treatment
Outcomes Illustrative comparative risks* (95% CI) Relative effect No of participants Quality of the evidence Comments
(95% CI) (studies) (GRADE)
Assumed risk Corresponding risk
Control Anticonvulsants versus

placebo at final treat-
ment
50% pain reduction 137 per 1000 217 per 1000 RR 1.59 3256 ⊕⊕⊕⊕ Absolute risk difference
(182 to 260) (1.33 to 1.90) (5 studies) high (fewer pain) 8% (95% CI
6% to 11%)
Relative per cent im-
provement 59% (95% CI
33% to 90%)
NNTB 12 (95% CI 9 to 21)
Patient Global Impres- 279 per 1000 385 per 1000 RR 1.38 3183 ⊕⊕⊕⊕ Absolute risk difference
sion of Change of ’much’ (344 to 432) (1.23 to 1.55) (5 studies) high (more global impression
or ’very much’ improved of ’much’ and ’very much’
improved) 12% (95% CI
4% to 20%)
Relative per cent im-
provement 38% (95% CI
23% to 55%)
NNTB 9 (95% CI 7 to 15)
4
Fatigue (1-50 scale) MAF baseline fatigue The mean fatigue in the 3195 ⊕⊕⊕⊕ SMD -0.17 (-0.25 to -0.
Higher scores indicate score control group intervention groups was (5 studies) high 09)
higher fatigue levels 35.6 (standard deviation 0.17 standard deviations 2.7% (95% CI 1.4% to
8.0) ** lower 4.0%) fewer points on
(0.25 to 0.09 lower) the fatigue scale (abso-
lute improvement)
3.8% (95% CI 2.0% to 5.
6%) relative improvement
NNTB 13 (95% CI 9 to 25)
Sleep problems (0-100 MOS baseline overall The mean sleep problems 3139 ⊕⊕⊕⊕ SMD -0.35 (-0.43 to -0.
scale). Higher scores in- sleep problem index con- in the intervention groups (5 studies) high 27)
dicate more sleep prob- trol group was 6.2% (95% CI 4.8%
lems 58.5 (17.8) *** 0.35 standard deviations to 7.7%) fewer points on
lower the sleep problem scale
(0.43 to 0.27 lower) (absolute improvement)
10.6% (95% CI 82.% to
13.1%) relative improve-
ment
NNTB 7 (95% CI 5 to 8)
Withdrawal due to ad- 110 per 1000 185 per 1000 RR 1.68 3259 ⊕⊕⊕⊕ Absolute risk difference
verse events (150 to 229) (1.36 to 2.07) (5 studies) high (more withdrawal due to
adverse events) 8% (95%
CI 5% to 12%)
Relative per cent worsen-
ing 68% (95% CI 36% to
107%)
NNTH 13 (95% CI 9 to 23)
Serious adverse events 41 per 1000 42 per 1000 RR 1.03 2729 ⊕⊕⊕ Absolute risk difference 0
(29 to 61) (0.71 to 1.49) (4 studies) moderate 1 (95% CI -1 to 1)
Relative per cent change
0 (95% CI -1 to 1)
Not statistically signifi-
cant
5
Dizziness reported to be 93 per 1000 350 per 1000 RR 3.77 3257 ⊕⊕⊕⊕ Absolute risk difference
an adverse event (284 to 429) (3.06 to 4.63) (5 studies) high (more dizziness) 28%
(95% CI 24% to 32%)
Relative per cent worsen-
ing 277% (95% CI 206%
to 363%)
NNTH 4 (95% CI 3 to 5)
*The basis for the assumed risk (e.g. the median control group risk across studies) is provided in footnotes. The corresponding risk (and its 95% confidence interval) is based on the
assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI).
CI: confidence interval; MAF: Multidimensional Assessment of Fatigue; MOS: Medical Outcomes Study; NNTB: number needed to treat for an additional beneficial outcome; NNTH: number
needed to treat for an additional harmful outcome; NRS: numeric rating scale; RR: risk ratio; SMD: standardised mean difference.
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.
1Frequency of serious adverse events not reported by one study.
** Arnold 2008: n = 190 participants; MAF (NRS 1-50).
*** Arnold 2008: n = 190 participants; MOS Overall Sleep Problems Index (NRS 0-100).
6
BACKGROUND Since specific treatment aimed at altering the pathogenesis is not
possible, drug therapy focusing on symptom reduction is widely
Fibromyalgia (FM) is a common disorder occurring in all pop- employed.
ulations across the world. It has been estimated that five million
adults have FM in the US (Lawrence 2008). The estimated overall
prevalence of FM in the general population in European countries
ranges from 2.1% (Wolfe 2013a) to 2.9% (Branco 2010). Peo- Description of the intervention
ple often report high disability levels and poor quality of life, and Central pain conditions, in which persistent pain occurs in the ab-
make extensive use of medical care (Marschall 2011; Winkelmann sence of objective anatomic abnormality, are presumed to respond
2011; Wolfe 1997). People with FM use a wide range of different best to centrally active neuromodulating agents such as antide-
types of drugs and non-pharmacological therapies (Bennett 2007; pressants and anticonvulsants (Phillips 2011). Anticonvulsants re-
Bernardy 2013; Birse 2012; Corrigan 2012; Deare 2013; Derry duce the release of several neurotransmitters and peptides includ-
2012; Eccleston 2012; Häuser 2012a; Häuser 2013; Hearn 2012; ing glutamate, noradrenaline (norepinephrine) and substance P
Moore 2012a; Seidel 2013; Tort 2012; Wiffen 2013a; Wiffen (Dooley 2007). The reduced neurotransmitter release is presumed
2013b). to account for the analgesic, anticonvulsant and anxiolytic effects
of anticonvulsants.
Description of the condition

The key symptoms of FM are chronic widespread pain associated How the intervention might work
with sleep problems, cognitive dysfunction and physical fatigue Augmented central nervous system processing of stimuli might
(Häuser 2008; Wolfe 2010). Lacking a specific laboratory test, di- be one pathophysiological mechanism underlying FM (Gracely
agnosis is established by the patient’s report of the key symptoms 2011). Pregabalin and gabapentin are structural analogues of the
and a physician’s exclusion of other illnesses that would account neurotransmitter gamma-aminobutyric acid (GABA). These sec-
for the key symptoms (Eich 2012a; Wolfe 2010). For clinical diag- ond-generation anticonvulsants are alpha-2-delta ligands that bind
nosis, the American College of Rheumatology (ACR) 1990 clas- to, and modulate, voltage-gated calcium channels. By reducing cal-
sification criteria (Wolfe 1990), the ACR 2010 preliminary diag- cium influx at nerve terminals, both drugs diminish the release of
nostic criteria (Wolfe 2010), and the Fibromyalgia Survey Diag- several neurotransmitters, including glutamate, noradrenaline and
nostic Criteria (Wolfe 2011a), can be used. substance P. This mechanism is assumed to be the basis for the anal-
A biopsychosocial model of factors predisposing, triggering and gesic, anticonvulsant and anxiolytic actions of the drugs (Dooley
perpetuating FM symptoms has been suggested (Sommer 2012). 2007). Both drugs differ in their pharmacokinetic and pharma-
Polymorphisms of genes in the serotoninergic, dopaminergic and codynamic characteristics (Bockbrader 2010). Lacosamide, an-
catecholaminergic systems (Buskila 2009), and physical and sexual other anticonvulsant, is described as a functionalised amino acid
abuse in childhood and adolescence (Häuser 2011a), predispose molecule that selectively enhances the slow inactivation of voltage-
to FM. Social disadvantage, psychological and physical stress, and gated sodium channels and interacts with the collapsin-response
somatic diseases such as rheumatoid arthritis trigger the develop- mediator protein-2. Voltage-gated sodium channels play an im-
ment of FM symptoms (Buskila 2009; Wolfe 2011). A small fi- portant role in the excitability of nociceptors (Beydoun 2009).
bre pathology was detected in people with FM (Üçeyler 2013). The mode of action of the anticonvulsant, levetiracetam, is not
Depressive disorders have a negative impact on the clinical out- fully elucidated, but it has been found to target high-voltage, N-
come of FM (Lange 2010). Several factors, such as alterations of type calcium channels, as well as the synaptic vesicle protein 2A
central pain pathways, hyporeactivity of the hypothalamus-pitu- (Ulloa 2009).
itary-adrenal axis, increased systemic pro-inflammatory and re-
duced anti-inflammatory cytokine profiles, and disturbances in
the dopaminergic and serotonergic systems have been associated
with FM pathophysiology. However, none of these factors has been
Why it is important to do this review
demonstrated to have a causal relationship to FM or to be spe- Previous Cochrane reviews have studied the efficacy and safety
cific for FM (Sommer 2012). The current pathophysiology con- of gabapentin (Moore 2011), pregabalin (Moore 2009) and la-
cept views FM as the result of alterations in central processing of cosamide (Hearn 2012) in chronic neuropathic pain and FM in
sensory input and its cognitive-emotional appraisal, along with adults. These reviews did not report on outcomes relevant for FM
aberrations in the endogenous inhibition of pain (Buskila 2009). such as fatigue, sleep problems and psychological symptoms. The
Exposure to physical or psychosocial stressors as outlined above approach of combining different neuropathic pain syndromes and
may contribute to dysfunctional pain processing (Bradley 2009; FM is continued in the protocol on antiepileptic drugs for neuro-
Sommer 2012). pathic pain and FM (Wiffen 2013a).

There is a transatlantic difference in the approval of the anticon- Types of interventions
vulsant pregabalin as a treatment of FM by regulatory authorities We included trials with anticonvulsants at any dose, administered
(Briley 2010). Pregabalin has been approved by the US Food and by any route to reduce FM symptoms compared with placebo or
Drug Administration (FDA) and by the Japanese Pharmaceuti- another active drug administered by any route.
cal and Medical Devices Agency but not by the European Medi- We allowed co-interventions, such as physical therapy or other
cal Agency (EMA) for the management of FM. The FDA stated drugs different from those being assessed in the trial.
that the sponsors of pregabalin had provided adequate evidence We considered the following anticonvulsants used in pain therapy
of the benefits to support the indication for the management of for this review (Attal 2010): carbamazepine, clonazepam, felba-
FM (FDA 2007). The EMA denied clinically relevant effects for mate, gabapentin, hydantoin, levetiracetam, lacosamide, lamot-
pregabalin in European patients. The adverse effects profile was rigine, oxcarbazepine, pregabalin, tiagabine, topiramate, valproic
considered to outweigh the benefits, given the lack of robust evi- acid and vigabatrin.
dence of efficacy (European Medicines Agency 2009). Because of
the divergent appraisals of pregabalin by the FDA and EMA, we
saw the need to evaluate the benefits and harms of anticonvulsants Types of outcome measures
according to more recently established methodological standards
We followed some suggestions of the OMERACT (Outcome Mea-
of pain medicine (Moore 2010b), to assist people with FM and
sures in Rheumatology) Fibromyalgia Working Group on the key
doctors to share decision making on pharmacological treatment
domains of FM (Mease 2009); the Initiative of Methods, Mea-
options.
surement and Pain Assessment in Clinical trials (IMMPACT)
(Dworkin 2009); and of best practice in the reporting of system-
atic reviews in chronic pain (Moore 2010a), for selecting out-
come measures. Furthermore, we selected a specific adverse event,
namely self reported dizziness, as a measure of tolerability: dizzi-
OBJECTIVES ness had been reported to be the most frequent side effect of pre-
To assess the benefits and harms of anticonvulsant use in the treat- gabalin (Straube 2010), and to be a major symptom of ’fibro fog’
ment of FM. (Centers for Disease Control and Prevention 2011).
We derived the outcomes of efficacy (benefits) from the key do-
mains as defined by a consensus among experts and people with
FM (Mease 2009). We assessed harms by the safety and tolerability
METHODS of anticonvulsants. We defined safety as the frequency of serious
adverse events independent of any determination of study-related-
ness by the investigators. We defined tolerability by the frequency
of study withdrawals due to adverse event and by the frequency of
Criteria for considering studies for this review dizziness reported as adverse event.
Major outcomes
Types of studies
1. Self reported 50% or greater pain reduction: we used the
We included randomised controlled trials (RCTs), double-blind,
following preference a. electronic diaries, paper diaries; b. 24-
with anticonvulsants and with a study duration of eight weeks and
hour recall pain, weekly recall pain (visual analogue scale (VAS));
longer. We required a parallel design. We excluded RCTs with a
c. paper VAS, paper numeric 11-point ordinal numeric rating
cross-over or an enriched enrolment withdrawal design. We re-
scale (NRS); d. combined pain measures.
quired full journal publication, with the exception of online clin-
2. Patient-perceived improvement (Patient Global Impression
ical trial result summaries of otherwise unpublished clinical trials
of Change (PGIC)): number of participants who reported to be
and abstracts with data for analysis. We excluded studies that were
’much’ or ’very much’ improved.
non-randomised, studies of experimental pain, case reports or se-
3. Self reported fatigue: we used the following preference:
ries and clinical observations.
validated combined scales (e.g. Multidimensional Fatigue
Inventory (MFI), Fatigue Severity Scale (FSS), other validated
scales (single-item scales (e.g. Fibromyalgia Impact
Types of participants Questionnaire (FIQ) fatigue VAS).
Participants of any age having a clinical diagnosis of FM by any 4. Self reported sleep problems: we used the following
published standardised criteria (Häuser 2010a; Wolfe 1990; Wolfe preference: validated combined scales (e.g. Medical Outcomes
2010; Wolfe 2011a). Study (MOS) Sleep Problem Index, other validated combined

scales), single-item assessment (e.g. FIQ sleep VAS, other single- Two review authors (WH, NÜ) independently scrutinised all the
item scales). titles and abstracts revealed by the searches and determined which
5. Safety: serious adverse events. fulfilled the selection criteria. A third review author (CS) verified
6. Tolerability: that the selection had been properly realised.
i) withdrawals due to adverse event;
ii) specific adverse event: dizziness.
Data extraction and management
Two review authors (NÜ, WH) extracted data independently into
Minor outcomes a specially designed data extraction form. We resolved disagree-
1. Self reported pain intensity. ments by discussion if necessary with the third review author (CS).
2. Self reported 30% or greater pain reduction. One review author (WH) entered data into Review Manager 5
3. Self reported health-related quality of life (HRQoL) (RevMan 2012), and a second author (NÜ) checked them. We
measured by the total score of the FIQ. resolved discrepancies by discussion.
4. Self reported depression: we used the following preference:
validated combined scales (Hospital Anxiety and Depression
Assessment of risk of bias in included studies
Scale (HADS), Beck Depression Inventory (BDI), other
validated scales), single-item assessment (e.g. FIQ subscale for Two review authors (NÜ, WH) independently extracted the fol-
depression, other single-item scales). lowing information from reports of included studies into stan-
5. Self reported anxiety: we used the following preference: dardised forms: methods (setting, design, duration, follow-up and
validated combined scales (HADS, BAI Beck Anxiety Inventory, statistical analysis of study), participants (mean age, gender, race,
State Trait Anxiety Inventory (STAI), other validated scales), inclusion and exclusion criteria), intervention (dosages of anti-
single-item scale (FIQ anxiety VAS, other single-item scales). convulsants, rescue and co-medication allowed), type of outcome
6. Self reported disability (impairment of physical function): measures, type of safety assessment and sponsoring. Two review
we used the following preference: validated combined scale authors (NÜ, WH) independently assessed the risk of bias of each
(Short-Form Health Survey (SF-36) Physical Functioning, FIQ included trial. We resolved disagreements by consensus and, if
physical impairment, Brief Pain Inventory (BPI) interference needed, referral to a third review author (CS). For each included
from pain, other validated combined scales), single-item scale. study, we assessed risk of bias against key criteria: random se-
quence generation (selection bias); allocation concealment (selec-
tion bias); incomplete outcome data (attrition bias); selective out-
come reporting (reporting bias); blinding of participants and per-
Search methods for identification of studies
sonnel (performance bias); blinding of outcome assessment (de-
tection bias) in accordance with methods recommended by The
Electronic searches Cochrane Collaboration (Higgins 2011). We judged each of these
criteria explicitly using: ’low risk’ of bias, ’high risk’ of bias and
We performed an electronic search in the Cochrane Central Regis-
’unclear risk’ of bias (either lack of information or uncertainty over
ter of Controlled Trials (CENTRAL) (Issue 8, 2013), MEDLINE
the potential for bias).
accessed through PubMed (1966 to August 2013) and SCOPUS
accessed through Ovid (1980 to August 2013). The search strat-
egy used for MEDLINE is detailed in Appendix 1. Furthermore, Measures of treatment effect
we searched www.clinicaltrials.gov (website of the US National The effect measures of choice were risk ratio (RR) for dichotomous
Institute of Health) to August 2013 for unpublished trials. Our data and standardised mean difference (SMD) (when different
search included all languages. scales were used to measure the same outcomes) for continuous
data. We expressed uncertainty using 95% confidence intervals
Searching other resources (CIs). We used Cohen’s categories to evaluate the magnitude of
the effect size, calculated by SMD, with Hedges’ g of 0.2 = small,
We searched bibliographies from reviewed articles and we retrieved
0.5 = medium and 0.8 = large (Cohen 1988). We labelled g < 0.2
relevant articles. We contacted content experts to assist in locating
to be a ’not substantial’ effect size.
other relevant or unpublished studies.
Unit of analysis issues

Data collection and analysis In the case of multiple anticonvulsant dosage arms compared with
one placebo group, we adjusted the number of participants in
the placebo group according to the number of participants in the
Selection of studies different anticonvulsant-dosage arms for continuous outcomes.

Dealing with missing data Subgroup analysis and investigation of heterogeneity
If both intention-to-treat (ITT) and per protocol data were re- We performed subgroup comparisons of different dosages of pre-
ported, we used ITT data for analysis. The ITT population con- gabalin since differences in the efficacy and adverse events of dif-
sisted of participants who were randomised, took the assigned ferent dosages of pregabalin had been reported (Straube 2010). We
study medication and provided at least one post-baseline assess- performed subgroup comparisons of different types of anticon-
ment (modified ITT). Wherever possible, we assigned zero im- vulsants. We post-hoc decided not to perform the planned sub-
provement to missing participants. However, most studies in group analysis of studies with American, European, and Japanese
chronic pain report results, including responder results, using last participants to test for potential transatlantic differences between
observation carried forward. This has been questioned as being the efficacy and adverse events of anticonvulsants for the follow-
potentially biased with outcomes of withdrawal being important ing reasons. There was no study with only European participants
outcomes that make last observation carried forward unreliable. available. We decided to report the results of the comparisons of
Last observation carried forward can lead to overestimation of ef- European and Non-European participants as presented in the pub-
ficacy, particularly in situations where adverse event withdrawal lication and provided on request (Pauer 2011), and by the EMA
rates differ between active and control groups. At this time, it is report (European Medicines Agency 2009). The comparison of
unclear what strategy can actually be used to deal with missing American and Japanese participants would have been biased by
data inside studies (Moore 2012b). We examined and clearly re- the different dosage regimens in the studies with fixed dosages in
ported imputation strategies. the US studies and flexible dosage in the Japanese study (Ohta
Where means or standard deviations (SD) were missing, we at- 2012).
tempted to obtain these data through contacting trial authors.
Where SDs were not available from trial authors, we calculated
them from t-values, CIs or standard errors, where reported in arti- Sensitivity analysis
cles (Higgins 2011). Where missing SDs could not be calculated The protocol “Antidepressants and centrally active agents for fi-
from t values, CIs or standard errors, we calculated them from SDs bromyalgia syndrome” intended to perform sensitivity analyses
of studies with the same drug and the same outcome scale by a (different statistical models applied, presence of temporal differ-
validated imputation method (Furukawa 2006). Where 30% and ences, diagnostic criteria used in the trial, according to the pres-
50% pain reduction rates were not reported and not provided on ence/absence of any mental disorder, according to the presence/
request, we calculated them from means and SDs by a validated absence of any concomitant systemic disease) (Nishishinya 2006).
imputation method (Furukawa 2005).
’Summary of findings’ table

Assessment of heterogeneity The quality of evidence was rated by the GRADE approach with
GRADEprofiler (Guyatt 2011).
We used the I2 statistic for heterogeneity. I2
statistic values less than
The numbers needed to treat for an additional beneficial (NNTB)
25% indicated low, 25% to 50% indicated moderate and 50% or
or harmful (NNTH) outcome for continuous variables (fatigue,
greater indicated substantial heterogeneity (Higgins 2003).
sleep problems) in the ’Summary of findings’ table were calculated
using the Wells calculator software available at the Cochrane Mus-
culoskeletal Group editorial office, which estimates the propor-
Assessment of reporting biases tion of participants who will benefit from treatment from SMDs.
We addressed publication bias by visual inspection of funnel plots The estimation of responders is nearly independent from the min-
and tests for funnel plot asymmetry (Begg 1994; Egger 1997), imally important difference (MID) (Norman 2001). We used a
when there were at least 10 studies included in the meta-analysis minimal clinically important difference of 15% for calculation.
(Higgins 2011).
We addressed outcome reporting bias by checking if the means
and SDs of all primary and secondary outcomes as outlined in the
methods section of the studies published had been reported or had
been provided on request. RESULTS
Data synthesis Description of studies

We undertook each meta-analysis using a random-effects model See Characteristics of excluded studies and Characteristics of
in Review Manager 5 (RevMan 2012). included studies tables for full description of studies.

Results of the search
We identified 710 studies. We excluded 700 references, as they
did not meet inclusion criteria related with the interventions eval-
uated in this review. We did not find head-to-head comparisons
of anticonvulsants or of anticonvulsants with other drugs used for
FM treatment. We identified 10 studies potentially related with
anticonvulsants and obtained the full text for each of them. We
excluded two studies after full-text review (Crofford 2008; Roth
2012) (see Figure 1).

Figure 1. Study flow diagram.

Interventions
Included studies
Four pregabalin studies tested three fixed dosage arms against
We included five studies with pregabalin (Arnold 2008; Crofford
placebo. Three studies tested 300, 450, and 600 mg/day against
2005; Mease 2008; Ohta 2012; Pauer 2011), and one study each
placebo (Arnold 2008; Mease 2008; Pauer 2011), and one study
with gabapentin (Arnold 2007), lacosamide (UCB 2006), and
tested 150, 300, and 450 mg/day against placebo (Crofford 2005).
levetiracetam (Rowbotham 2012) into analysis.
One study each used a flexible dosage of pregabalin (300 or
450 mg/day) (Ohta 2012), of gabapentin (between 1200 and
Study characteristics 2400 mg/day) (Arnold 2007), and of levetiracetam (up to 3000
Two studies were initiated by investigators and were financially mg/day) (Rowbotham 2012), according to efficacy and tolerabil-
supported by grants from the National Institute of Health (Arnold ity. The study with lacosamide used a fixed dosage of 400 mg/
2007; Rowbotham 2012). The gabapentin study also received sup- day (UCB 2006). The rescue medication was paracetamol (ac-
port from the manufacturer (Arnold 2007). The remaining stud- etaminophen) or over-the-counter non-steroidal anti-inflamma-
ies were initiated and financed by the manufacturer of pregabalin tory drugs (dosage not reported) in two trials (Arnold 2007; Ohta
(Arnold 2008; Crofford 2005; Mease 2008; Ohta 2012; Pauer 2012), paracetamol less than 4 g/day and aspirin less than 325 mg/
2011) and lacosamide (UCB 2006). Conflicts of interest of the day in two trials (Arnold 2008; Crofford 2005), and paracetamol
study investigators were reported by all except three studies (Pauer up to 4 g/day (Mease 2008). Three studies did not report details of
2011; Rowbotham 2012; UCB 2006). All studies were conducted rescue medication (Pauer 2011; Rowbotham 2012; UCB 2006).
in research centres. The median number of study centres was 44
(range 1 to 84). One study did not report the number of study cen-
Outcomes
tres (UCB 2006). Of the five studies with pregabalin, three studies
were conducted in the US (Arnold 2008; Crofford 2005; Mease Pain was assessed in one study by the BPI 24 mean pain score
2008), one study in Japan (Ohta 2012), and one study included (Arnold 2007), in one study by the pain score of the McGill Pain
countries all over the world except for the US (Europe, Middle Questionnaire (Crofford 2005), and in the other studies by a 0 to
America, Australia, Canada, India and Korea) (Pauer 2011). The 10 or 0 to 100 NRS daily pain scale. Fatigue was assessed by the sum
studies with gabapentin (Arnold 2007), lacosamide (UCB 2006), score of Multidimensional Assessment of Fatigue Questionnaire
and levetiracetam (Rowbotham 2012), were conducted in the US. (MAF) in three studies (Arnold 2008; Crofford 2005; Mease
All studies had a parallel design. The median therapy phase of the 2008), in the remaining studies by the single-item fatigue score
studies was 13 (range 8 to 15) weeks. of the FIQ. Sleep disturbances were assessed by a single-item sleep
interference scale in three studies (Arnold 2007; Rowbotham
2012; UCB 2006), and by the MOS Sleep Problems Index in the
Participant characteristics remaining studies.Depression and anxiety were assessed in all studies
The lacosamide study did not report details of inclusion and ex- by the HADS except for one study that used the Montgomery
clusion criteria and participant characteristics except for age and Depression Rating Scale (MDRS) for depression and the FIQ
gender (UCB 2006). Race was not reported by the levetiracetam single-item scale for anxiety (Arnold 2007), and one study that
study (Rowbotham 2012). All studies included people over 18 used the FIQ single-item scales (Rowbotham 2012). Disability
years old. All studies excluded people with somatic diseases includ- was assessed by the BPI mean interference scale in two studies
ing inflammatory rheumatic diseases. All studies excluded people (Arnold 2007; UCB 2006), by the FIQ disability scale in one
with unstable or severe mental disorders or psychological condi- study (Rowbotham 2012), and by the physical functioning scale
tions. Details regarding the exclusion of people with moderate and of the SF-36 in the remaining studies. HRQoL was assessed in all
severe depressive or anxiety disorders were not reported by any studies by the FIQ total score. No study assessed sexual function or
study. All studies excluded people taking centrally acting drugs cognitive disturbances. Tender point pain threshold measurements
such as antidepressants. The median of screened participants who were only conducted in one study with gabapentin (Arnold 2007).
were randomised was 64 (range 56 to 76). A total of 2480 partic-
ipants were included into true drug and of 1099 participants in
placebo groups. Middle-aged white women prevailed in all stud- Excluded studies
ies: the median of the mean age was 49 (range 47 to 50) years. We excluded one study with three dosage arms of pregabalin (300,
The median of the percentage of women was 93% (range 89% to 450 and 600 mg/day), 1051 participants and 26 weeks’ double-
96%). The median of the percentage of white women was 91% blind duration and an enriched enrolment withdrawal design (pri-
(range 0% to 97%). mary endpoint: loss of therapeutic response, defined as < 30% pain

reduction) from meta-analysis because the outcomes were differ-
ent from the ones of the studies with a parallel design (Crofford
2008). We excluded one study with cross-over design and flexible
dosages of pregabalin (300 or 450 mg/day) and 115 participants
because of short (four weeks) study duration and because of cross-
over design (Roth 2012).
Risk of bias in included studies

We compiled a ’Risk of bias’ table (See Figure 2 and Figure 3 for
’Risk of bias’ summary and graph). Most risks of bias were low.
The only criteria indicating high risk of bias were incomplete out-
come data and selective non-reporting by some studies. 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.

Figure 3. Risk of bias summary: review authors’ judgements about each risk of bias item for each included
study.

Allocation
Gabapentin versus placebo
Random sequence generation and allocation concealment were
50% or greater pain reduction: one study with 150 participants
adequate in all studies except for one that did not report details
was entered into an analysis of a 50% or greater pain reduction.
(UCB 2006).
A total of 32 of 75 (42.7%) participants with gabapentin and
20 of 75 (26.7%) participants with placebo reported a 50% or
Blinding greater pain reduction. The RR of a 50% or greater pain reduction
by anticonvulsants versus placebo was statistically significant (RR
Blinding of participants, personnel and outcome assessors were
1.60; 95% CI 1.01 to 2.53; P value = 0.04) (Analysis 1.2).
adequate in all studies.
Sleep problems: one study with 119 participants was entered into
an analysis of the effects of gabapentin on reduction of sleep prob-
Incomplete outcome data lems. The overall effect on sleep problems was statistically signifi-
cant (SMD -0.71; 95% CI -1.08 to -0.24; P value < 0.001). Based
Three studies reported observed cases analyses (Arnold 2007;
on Cohen’s categories, the effect of gabapentin versus placebo on
Rowbotham 2012; UCB 2006). All other studies used ITT analy-
fatigue was small (Analysis 1.3).
sis. These studies imputed missing data by last observation carried
Withdrawal due to adverse events: one study with 150 participants
forward method.
was entered into an analysis of withdrawals due to adverse events.
A total of 12 of 75 (16.0%) participants dropped out due to ad-
Selective reporting verse events with gabapentin and 7 of 75 (9.3%) participants with
Visual inspection of funnel plots was not indicative for a publi- placebo. The RR of dropping out due to adverse events was not
cation bias. The studies with pregabalin had been registered for statistically significant (RR 1.71; 95% CI 0.71 to 4.11; P value =
the application of an approval for FM management by regulatory 0.23) (Analysis 1.5).
agencies. We had searched these databases. Therefore, we do not Dizziness: one study with 150 participants was entered into
assume a non-publication of RCTs with pregabalin in FM. an analysis of dizziness attributed to be an adverse event of
Arnold 2007 did not report anxiety and fatigue outcomes. gabapentin. A total of 38 of 75 (50.7%) participants with
Crofford 2005 did not report HRQoL outcomes and serious ad- gabapentin and 23 of 75 (30.7%) participants with placebo re-
verse events. Mease 2008 did not report the details of disability ported dizziness that was attributed to therapy. The RR of dizzi-
outcomes. Rowbotham 2012 did not report fatigue, anxiety, de- ness attributed to gabapentin versus placebo was statistically sig-
pression and disability outcomes. UCB 2006 did not report details nificant (RR 2.71; 95% CI 1.21 to 6.07; P value = 0.02) (Analysis
of adverse events. 1.6).
Pain: one study with 119 participants was entered into an analysis
of the effects of gabapentin on pain reduction. The overall effect
Other potential sources of bias on pain was statistically significant (SMD -0.49; 95% CI -0.86 to
All studies excluded people with unstable mental disorders or psy- -0.13; P value = 0.008) (Analysis 1.1).
chological conditions. The external validity of the pregabalin stud- 30% or greater pain reduction: one study with 150 participants
ies is difficult to assess, because the exclusion criteria for men- were entered into an analysis of a 30% or greater pain reduction. A
tal disorders were not well defined and a standardised psychiatric total of 38 of 75 (50.7%) participants with gabapentin and 23 of
interview was not conducted by any of the studies reviewed. A 75 (30.7%) participants with placebo reported a 30% or greater
pooled analysis of three studies with pregabalin (Arnold 2008; pain reduction. The RR of a 30% or greater pain reduction by
Crofford 2005; Mease 2008), reported that baseline HADS scores gabapentin versus placebo was statistically significant (RR 1.65;
indicated moderate-to-severe anxiety in 38% of participants and 95% CI 1.10 to 2.48; P value = 0.02) (Analysis 1.7).
moderate-to-severe depressive symptoms in 27% of participants Health-related quality of life (HRQoL): one study with 119 partic-
(Arnold 2010a). These HADS scores indicate that some partici- ipants was entered into an analysis of the effects of gabapentin on
pants with anxiety or depressive disorders, or both, were included the total score of the FIQ. The overall effect on HRQoL was sta-
in the trials. tistically significant (SMD -0.66; 95% CI -1.03 to -0.29; P value
< 0.001). Based on Cohen’s categories, the effect of gabapentin
versus placebo on HRQoL was not substantial (Analysis 1.4).
Effects of interventions Depression: one study with 119 participants was entered into an
See: Summary of findings for the main comparison Pregabalin analysis of the antidepressive effects of gabapentin. The overall
versus placebo at end of treatment for fibromyalgia effect on depression was statistically significant (SMD -0.52; 95%

CI -0.89 to -0.16; P value = 0.0005). Based on Cohen’s categories, 95% CI 1.08 to 5.06; P value = 0.03) (Analysis 2.6).
the effect of gabapentin versus placebo on depression was moderate
(Analysis 1.8).
Disability: one study with 119 participants was entered into an Levetiracetam versus placebo
analysis of the effects of gabapentin on disability reduction. The One study was analysed. The number of participants with reported
overall effect on disability was statistically significant (SMD -0.94; or analysable results ranged from 50 to 66. The pain response rates
95% CI -1.32 to -0.56; P value < 0.0001). Based on Cohen’s had to be calculated by an imputation method because the data
categories, the effect of gabapentin versus placebo on depression had not been reported and were not provided on request. There
was large (Analysis 1.9). was no significant difference on effect sizes or RRs of mean pain
reduction (SMD -0.21; 95% CI -0.77 to 0.36) (Analysis 3.1),
50% pain reduction (RR 1.52; 95% CI 0.43 to 5.34) (Analysis
3.2), reduction of sleep problems (SMD -0.16; 95% CI -0.72 to
Lacosamide versus placebo
0.40) (Analysis 3.3), withdrawals due to adverse events (RR 0.87;
One study was analysed. The number of participants with re- 95% CI 0.21 to 3.56) (Analysis 3.5), and 30% pain reduction
ported or analysable results ranged from 121 to 159. The impu- (RR 1.23; 95% CI 0.65 to 2.33) (Analysis 3.7). However, the
tation method could not be applied because baseline values were RR of dizziness attributed to levetiracetam versus placebo was
not reported. There was no significant difference on effect sizes statistically significant (RR 1.30; (95% CI 1.02 to 1.66; P value =
and RRs for pain reduction (SMD -0.25; 95% CI -0.56 to 0.07) 0.04) (Analysis 3.6).
(Analysis 2.1), fatigue reduction (SMD -0.07; 95% CI -0.43 to
0.28) (Analysis 2.2), sleep problems (SMD -0.19; 95% CI -0.51 to
0.12) (Analysis 2.3), reductions of limitations of HRQoL (SMD - Pregabalin versus placebo
0.15; 95% CI -0.47 to 0.16) (Analysis 2.4), serious adverse events 50% or greater pain reduction: five studies with 3256 participants
(RR 0.15; 95% CI 0.01 to 2.82) (Analysis 2.5), anxiety (SMD were entered into an analysis of a 50% or greater pain reduction.
0.00; 95% CI -0.34 to 0.34) (Analysis 2.7), depression reduc- A total of 514 of 2319 (22.2%) participants with pregabalin and
tion (SMD 0.11; 95% CI -0.23 to 0.45) (Analysis 2.8), disability 128 of 937 (13.7%) participants with placebo reported a 50% or
reduction (RR -0.19; 95% CI -0.51 to 0.12) (Analysis 2.9), or greater pain reduction. The RR of a 50% or greater pain reduction
PGIC ’much’ or ’very much’ improved (RR 1.32; 95% CI 0.85 to by anticonvulsants versus placebo was significant (RR 1.59; 95%
2.04) (Analysis 2.10). However, the RR of dizziness attributed to CI 1.33 to 1.90; P value < 0.0001). The NNTB by drug over
lacosamide versus placebo was statistically significant (RR 2.34; placebo was 12 (95% CI 9 to 21) (Figure 4).

Figure 4. Forest plot of comparison: 4 Pregabalin versus placebo at end of treatment, outcome: 4.2 50%
pain reduction.

Patient global impression of change (PGIC): five studies with 3183
participants were entered into an analysis of the effects of anti-
convulsants on PGIC ’much’ or ’very much’ improved. A total
of 892 of 2265 (39.4%) participants with pregabalin and 256 of
918 (27.9%) participants with placebo reported to be ’much’ or
’very much’ improved. The RR of a PGIC ’much’ or ’very much’
improved by pregabalin versus placebo was statistically significant
(RR 1.38; 95% CI 1.23 to 1.55; P value < 0.0001). The NNTB
to achieve a benefit by pregabalin over placebo was 9 (95% CI 7
to 13) (see Analysis 4.13).
Fatigue: five studies with 3195 participants were entered into an
analysis of the effects of pregabalin on fatigue reduction. The over-
all effect on fatigue was statistically significant (SMD -0.17; 95%
CI -0.25 to -0.09; P value < 0.001). Based on Cohen’s categories,
the effect of pregabalin versus placebo on fatigue was not substan-
tial (see Figure 5).

Figure 5. Forest plot of comparison: 4 Pregabalin versus placebo at end of treatment, outcome: 4.3 Fatigue.
Sleep problems: five studies with 3193 participants were entered

into an analysis of the effects of pregabalin on reduction of sleep
problems. The overall effect on sleep problems was statistically
significant (SMD -0.35; 95% CI -0.43 to -0.27; P value < 0.001).
Based on Cohen’s categories, the effect of anticonvulsants versus
placebo on fatigue was small (see Figure 6).

Figure 6. Forest plot of comparison: 4 Pregabalin versus placebo at end of treatment, outcome: 4.4 Sleep
problems.
Withdrawal due to adverse events: five studies with 3259 partici-

pants were entered into an analysis of withdrawals due to adverse value = 0.99) (Analysis 4.7).
events. A total of 449 of 2317 (19.4%) participants dropped out Dizziness: five studies with 3257 participants were entered into
due to adverse events with pregabalin and 104 of 942 (11.0%) an analysis of dizziness attributed to be an adverse event of drug
participants with placebo. The RR of dropping out due to adverse therapy. A total of 883 of 2319 (38.1%) participants with pre-
events was statistically significant (RR 1.68; 95% CI 1.36 to 2.07; gabalin and 87 of 938 (9.3%) participants with placebo reported
P value < 0.001). The NNTH by pregabalin over placebo was 12 dizziness that was attributed to drug therapy. The RR of dizziness
(95% CI 9 to 17) (see Analysis 4.6). attributed to pregabalin versus placebo was statistically significant
Serious adverse events: four studies with 2729 participants were en- (RR 3.77; 95% CI 3.06 to 4.63; P value < 0.001). The NNTH
tered into an analysis of withdrawals due to serious adverse events. by pregabalin over placebo was 4 (95% CI 3 to 5) (see Analysis
In 100 of 1921 (5.2%) participants with pregabalin and in 33 of 4.8).
808 (4.1%) participants with placebo a serious adverse event was Mean pain reduction: five studies with 3252 participants were en-
recorded. The RR of dropping out due to serious adverse events tered into an analysis of the effects of pregabalin on pain reduction.
was not statistically significant (RR 1.03; 95% CI 0.71 to 1.49; P The overall effect on pain was statistically significant (SMD -0.28;

95% CI -0.35 to -0.20; P value < 0.001). According to Cohen’s statistically significant but not substantial.
categories, the effect of pregabalin compared with placebo on pain Studies with and without European participants: Pauer 2011 re-
was small (Analysis 4.1). ported that the placebo-adjusted results demonstrated greater im-
30% or greater pain reduction: five studies with 3259 participants provement in PGIC and sleep endpoints in European participants
were entered into an analysis of a 30% or greater pain reduction. (n = 379) and greater improvement in pain and FIQ total score in
A total of 928 of 2319 (40.0%) participants with pregabalin and non-European participants (n = 357). Discontinuation rates due
274 of 940 (29.1%) participants with placebo reported a 30% or to adverse events were more frequent in European participants
greater pain reduction. The RR of a 30% or greater pain reduction (23.0%) than in non-European participants (16.0%). The EMA
by pregabalin versus placebo was significant (RR 1.37; 95% CI presented in its refusal assessment report for pregabalin the effect
1.22 to 1.53; P value < 0.0001). The NNTB by pregabalin over sizes of pregabalin 300, 450 and 600 mg/day on pain in European
placebo was 9 (96% CI 7 to 13) (Analysis 4.9). participants (European Medicines Agency 2009). The 95% CIs
Health-related quality of life (HRQoL): four studies with 2724 of all three dosages included zero indicating a non-significant su-
participants were entered into an analysis of the effects of prega- periority of pregabalin over placebo.
balin on the total score of the FIQ. The overall effect on HRQoL We did not conduct the intended subgroup analyses with gender
was statistically significant (SMD -0.17; 95% CI -0.26 to -0.09; and pain because individual participant data were not available.
P value < 0.001). Based on Cohen’s categories, the effect of pre-
gabalin versus placebo on HRQoL was not substantial (Analysis
4.5). Sensitivity analyses
Depression: five studies with 3212 participants were entered into The intended sensitivity analyses (different statistical models ap-
an analysis of the antidepressive effects of pregabalin. The overall plied, presence of temporal differences, diagnostic criteria used in
effect on depression was statistically significant (SMD -0.09; 95% the trial, according to the presence/absence of any mental disorder,
CI -0.16 to -0.01; P value < 0.001). Based on Cohen’s categories, according to the presence or absence of any concomitant systemic
the effect of pregabalin versus placebo on depression was not sub- disease) were not conducted, because the studies did not differ in
stantial (Analysis 4.11). these characteristics.
Anxiety: five studies with 3214 participants were entered into an
analysis of the effects of pregabalin on anxiety reduction. The over-
all effect on anxiety was statistically significant (SMD -0.12; 95%
CI -0.20 to -0.04; P value < 0.001). Based on Cohen’s categories, DISCUSSION
the effect of pregabalin versus placebo on anxiety was not substan-
tial (Analysis 4.10).
Summary of main results
Disability: five studies with 3145 participants were entered into
an analysis of the effects of pregabalin on disability reduction. The There is high-quality evidence that pregabalin has a small bene-
overall effect on disability was not statistically significant (SMD - fit compared with placebo in reducing pain and sleep problems.
0.01; 95% CI -0.11 to 0.09; P value = 0.82) (Analysis 4.12). There is high-quality evidence that the effects of pregabalin com-
pared with placebo in reducing fatigue, depression, anxiety and
Subgroup analysis limitations of HRQoL are not substantial. There is high-quality
evidence that there is no significant difference between pregabalin
Different dosages of pregabalin: there were no statistically signif- and placebo in the reduction of disability. There is high-quality ev-
icant overall subgroup differences in the reduction of mean pain idence that the dropout rate due to adverse events with pregabalin
(P value = 0.64), 30% or greater pain reduction (P value = 0.79), is significantly higher than with placebo. There is moderate-qual-
50% or greater pain reduction (P value = 0.59), fatigue (P value ity evidence that the frequency of serious adverse events is similar
= 0.49), sleep problems (P value = 0.29), limitations of disease- between pregabalin and placebo. The amount and quality of evi-
related HRQoL (P value = 0.75), anxiety (P value = 0.65), de- dence are insufficient to draw definite conclusions on the efficacy
pression (P value = 0.96), PGIC (P value = 0.84), dropout due and safety of gabapentin, lacosamide and levetiracetam in FM. It
to adverse events (P value = 0.10), and serious adverse events (P would be inappropriate to suggest a class effect of anticonvulsants
value = 0.83). There was a statistically significant overall subgroup on FM symptoms.
difference in the dropout rate due to adverse events (P value =
0.04), which was highest in the 600 mg/day arm. There was a sta-
tistically significant overall subgroup difference in the reduction
of disability (P value = 0.03). The effect size of pregabalin flexible
Overall completeness and applicability of
(SMD -0.29; 95% CI -0.47 to -0.12) on disability was statistically
evidence
significant and small, the one for pregabalin 600 mg/day arm in- We are confident that we have identified all available evidence
cluded zero and the ones for other pregabalin dosages arms were on pregabalin because all of the trials had been registered as part

of the application for regulatory approval for FM management. observation carried forward method has been recommended for
We cannot rule out the possibility that negative study results with analysis (Moore 2010b).
other anticonvulsants had not been published or have been missed In addition, the 30% and 50% pain reduction rates of one study
by our search strategy. were not reported and not provided on request (Rowbotham
The applicability (external validity) of evidence is strongly limited 2012). We calculated these values using an established imputation
for the following reasons: method (Furukawa 2005).
1. The studies were performed in research centres and not in rou- The influence of allowed co-interventions (e.g. rescue medication)
tine clinical care. It is known that the efficacy of drug therapies on positive effects and adverse events was unclear because type and
is higher in the context of RCTs than in routine clinical care dosage of co-interventions were not clearly reported or controlled
(Routman 2010). for.
2. The exclusion criteria were strict. Participants were not allowed
to take some defined concomitant medications for their FM symp-
toms. This excluded a large number of people who were unwill- Agreements and disagreements with other
ing or unable to come off medications such as other antidepres- studies or reviews
sants and anticonvulsants. For this reason, participant selection in
Our results on the efficacy, tolerability and safety of pregabalin are
the RCTs was biased towards recruiting participants better able to
in line with those of one systematic review (Straube 2010), with
manage their symptoms without medication than seen in the com-
individual participant data of four studies that we included in our
munity. Participants with other medical disorders, such as inflam-
review (Arnold 2008; Crofford 2005; Mease 2008; Pauer 2011).
matory rheumatic diseases, were also excluded. The study results
Significant benefit of pregabalin over placebo was seen for mean
also cannot be applied to people with FM complicated by other
pain and sleep scores and the proportion of participants achiev-
medical disorders. The study results cannot be applied to people
ing at least 50% pain relief. A minority of participants had sub-
with FM and concomitant mental disease, because no subgroup
stantial benefit with pregabalin, and more had moderate benefit.
analysis of people with depressive or anxiety disorders had been
Many participants had only marginal or no benefit (Moore 2009;
presented by the manufacturer.
Straube 2010). Straube 2010 reported a benefit of pregabalin over
3. The majority of the participants were middle-aged women,
placebo on most of the individual domains of the SF-36. How-
making it difficult to apply the results to the general population.
ever, the authors found no significant effect on disability (physical
The manufacturer did not perform subgroup analyses of partic-
role limitation) or any positive effect on physical functioning. In
ipants over 65 years of age or of male participants. The results
line with Tzellos 2010 and Straube 2010, we found no significant
of anticonvulsants cannot be applied to children and adolescents
differences in the efficacy of pregabalin 300, 450, and 600 mg/
with FM because they had also been excluded.
day. The proportions of participants with somnolence, dizziness
and more than 7% weight gain were significantly greater with
pregabalin than with placebo (Straube 2010). The tolerability of
Quality of the evidence pregabalin by people with FM was limited, because 18% of par-
All of the reviewed studies except for one (Rowbotham 2012) had ticipants with anticonvulsants dropped out due to adverse events.
been sponsored by pharmaceutical companies. The quality of evi- In accordance with Straube 2010, we found a dose-response re-
dence of this review is based on the data presented in peer reviewed lationship of adverse events (dizziness, dropout rate). There was
journals and some additional details which were provided on re- no difference with regard to serious adverse events between pre-
quest by the pharmaceutical companies or principal investigators. gabalin and placebo (Straube 2010). However, it should be noted
However, not all data requested were provided. We had no access that rare serious adverse events with pregabalin, such as heart fail-
to individual participant data. A selective non-reporting of seri- ure exacerbation (Page 2008), psychosis (Olaizola 2006), suicidal
ous adverse events by one study is possible (Crofford 2005). De- tendencies (Mutschler 2011), and abuse and dependency (Gahr
spite these limitations, the overall quality of evidence was high for 2013), had been reported outside the context of RCTs.
most primary outcomes in the majority of studies (see Summary The EERW (Enriched Enrollment Randomized Withdrawal) trial
of findings for the main comparison). of Crofford 2008, which could not be combined with the studies
with a parallel design for meta-analysis, confirmed the efficacy of
pregabalin in people with FM. The trial used a six-week open titra-
tion to allow participants to obtain a substantial benefit (at least
Potential biases in the review process 50% pain relief and ’much’ or ’very much’ improved on PGIC)
Absence of a publication bias can never be confirmed. and have tolerable adverse events. Participants who achieved this
Efficacy outcomes were analysed using last observation carried outcome then entered a randomised, double-blind, 26-week with-
forward to impute for missing data. This procedure may lead to an drawal phase in which either the established dose or placebo was
overestimation of efficacy (Moore 2012b). The use of the baseline used. During the open-label phase, 54% had at least 50% pain

relief on a VAS over baseline and a PGIC of ’much’ or ’very much’ FM treated with open-label pregabalin (75 to 300 mg twice daily)
improved and so were able to enter the randomised double-blind for up to one year were stable and were consistent with those
phase. For pregabalin, 90 of 279 (32%) participants experienced of RCTs. 12.4% of the participants discontinued pregabalin be-
loss of therapeutic response over 26 weeks, compared with 174 cause of adverse events within one year. The most commonly re-
of 287 (61%) participants with placebo. The NNTH to prevent ported treatment-emergent adverse events with open-label prega-
one person experiencing a loss of treatment response for FM was balin treatment were dizziness, somnolence, headache, peripheral
4 (95% CI 3 to 5). A total of 37 of 279 (13.3%) participants oedema, and increased weight (Arnold 2012). The data of RCTs
dropped out due to adverse events with pregabalin and 20 of 287 and of extension studies do not answer the question for how long
(7.0%) participants with placebo (NNTH 16; 95% CI 9 to 75). pregabalin - if effective and tolerated - should be taken by the
Our results on gabapentin are in line with a Cochrane review on patient. Longitudinal studies demonstrated that FM symptoms
gabapentin in neuropathic pain syndromes that included one study persisted in nearly all participants over more than 10 years (Eich
in FM (Arnold 2007). The amount of evidence for gabapentin 2012a). No data are available on the long-term (> one year) effec-
in FM was low, excluding any confidence on its efficacy (Moore tiveness, tolerability and safety of pregabalin in FM.
2011). Our results that lacosamide is not effective in FM is in If pregabalin is considered for the treatment of FM, potential ben-
line with a Cochrane review on lacosamide in neuropathic pain efits and harms should be frankly discussed between the physician
syndromes (Hearn 2012), which included one study in FM (UCB and the patient. The warnings (angio-oedema, hypersensitivity re-
2006). We found no other studies or reviews on levetiracetam in actions, impairment of a person’s ability to drive or operate ma-
FM. Of note, gabapentin, lacosamide and levetiracetam were not chinery) should be discussed (Häuser 2010a). A marked increase
licensed by any regulatory agency for FM or mental disorders. of reports on abuse and dependence of pregabalin has been noted
Considering the current differences in regulatory approval re- (Gahr 2013). Pregabalin should be individually tapered according
garding the use of pregabalin in FM in the US and Japan ver- to effectiveness and tolerability. The recommended dose is 150
sus Europe, it seems relevant to comment if our data support ei- mg/day twice daily. Pregabalin should be started with 25 to 50
ther of these positions. According to EMA analysis, pregabalin mg at night and at the weekend because of potential neuropsychi-
did not significantly reduce mean pain in European participants atric side effects. Titration in weekly increments of 25 to 50 mg
(European Medicines Agency 2009). Moreover, European partic- based on tolerability and therapeutic response is recommended
ipants dropped out more frequently due to adverse events (23%) (Boomershine 2010).
than US (16%) (European Medicines Agency 2009) and Japanese Therapy of FM with drugs only, such as pregabalin alone, should
participants (14%) (Ohta 2012). Individual participant data were be discouraged since current best practices in FM guidelines
provided by Pfizer to EMA, but not to us. Therefore, EMA, but recommend using the combination of pharmacological therapy
not us, could perform analysis of European and American partic- with aerobic exercise and psychological therapies (Eich 2012b;
ipants. Therefore, our review cannot provide support for any of Fitzcharles 2013). Although the combination of pregabalin with
these regulatory positions. non-pharmacological treatment options had not been tested in
The data on the efficacy of anticonvulsants were gathered in the RCTs, combination therapy should be considered. This is espe-
context of RCTs in which people with FM received more frequent cially true for such symptoms that are only marginally responsive
and detailed attention by the number of study visits and control to pregabalin, but can be effectively treated with other therapies
examinations than they receive in routine clinical care. The context such as aerobic exercise for fatigue (Häuser 2010b), and cognitive
of an RCT might explain the remarkable number of participants behavioural therapies for depression (Bernardy 2010).
that reported a substantial pain reduction (15%) and an overall
’much’ or ’very much’ improvement in PGIC (28%) with placebo.
We found comparable placebo response rates in studies with du-
loxetine, milnacipran and sodium oxybate (Häuser 2012b). The AUTHORS’ CONCLUSIONS
effectiveness of drugs in clinical practice can be lower. Of 3123
adults with FM who participated in an 11-year longitudinal study Implications for practice
of the National Data Bank of Rheumatic Diseases, up to 39%
Of all the anticonvulsants considered in this review, the amount
were treated with centrally acting agents (duloxetine, gabapentin,
and quality of evidence is only sufficient to draw definite conclu-
milnacipran and pregabalin). For participants treated with these
sions on the efficacy and safety of pregabalin in FM. The poten-
drugs, pain scores were reduced significantly following the start of
tial benefit of pregabalin to reduce pain is counterbalanced by its
these drugs. The mean pain score decreased from 6.2 to 6.0 (rel-
potential harms: 217 of 1000 participants reported a substantial
ative improvement of 2.8%). There was no significant improve-
(at least 50%) pain reduction at end of treatment with pregabalin
ment in fatigue or functional status (Wolfe 2013b).
(137 per 1000 with placebo). A total of 185 per 1000 discontin-
The pooled data from three extension studies for up to one year
ued medication due to adverse events with pregabalin (110 per
suggested that the adverse event and safety profile of patients with
1000 with placebo). The mean improvement of sleep problems by

pregabalin compared with placebo was 10.6%. The incremental information on the proportion of participants with a moderate or
benefit over placebo to reduce fatigue, limitations of quality of life, substantial response, with tolerable adverse events and with will-
depression and anxiety was not substantial from a statistical point ingness to continue therapy (Moore 2010b).
of view. Pregabalin did not reduce disability.
2. The significance of pregabalin compared with established ther-
Of all the anticonvulsants considered in this review, only prega- apies, such as aerobic exercise, amitriptyline and cognitive be-
balin is approved for FM. However, its approval is not universal, havioural therapies, in the management of FM still needs to be
with pregabalin being approved for use in most countries of Amer- determined.
ica and Asia, but not in Europe. Pregabalin is approved for the
3. Clinical studies in FM should be conducted with patient sam-
treatment of general anxiety disorder in some European countries.
ples representative for clinical practice including participants with
Lastly, it should be noted that the positive effects of pregabalin on co-morbid anxiety and depressive disorders and inflammatory
FM symptoms has been proven only for six months in placebo- rheumatic diseases. Moreover, studies should include participants
controlled trials (Crofford 2008). It is reasonable to consider a trial with different disease durations and different severity levels all over
of omission with responders after six months. Pregabalin should the world. Subgroup analyses for males and elderly people should
be discontinued gradually. be conducted.
4. The assessment strategies of adverse events in randomised con-
Implications for research trolled trials should be standardised by regulatory agencies. Poten-
The main research directions that would help: tial effects of co-interventions on outcomes should be controlled
for.
Available studies with anticonvulsants in FM:
5. The definition of subgroups (e.g. FM with and without general
1. A re-analysis of the data using baseline observation carried for- anxiety disorder) and the development of more tailored therapies
ward and responder analysis where discontinuation is classified as are major tasks of future research.
non-response would allow a determination of the true efficacy of
pregabalin in FM. These analyses should be performed by a re-
search team not affiliated with the manufacturers of pregabalin.
Future studies with anticonvulsants in FM: ACKNOWLEDGEMENTS
1. Pregabalin provides a substantial benefit along with mild or no We thank Dr. Petra Klose, Internal Medicine V (Integrative
side effects only to a minority of participants. Clinical effective- Medicine), Kliniken Essen-Mitte, Essen, Germany, for her assis-
ness trials with anticonvulsants are necessary; they should provide tance in the search of literature.
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CHARACTERISTICS OF STUDIES
Characteristics of included studies [ordered by study ID]
Arnold 2007
Methods Study setting: Multicentre study with 3 outpatient research centres in the USA
Study design: Parallel
Duration therapy: 12 weeks
Follow-up: Not performed
Analysis: ITT; LOCF; for the primary analysis of continuous variables collected at more
than 2 time points, a longitudinal analysis that compared the rate of change of the
outcome during the treatment period between groups was used. The difference in rate of
change was estimated by random regression methods, as described elsewhere. A model
for the mean of the outcome variable that included terms for treatment, time, treatment-
by-time interaction and centre was used. Time was modelled as a continuous variable.
To account for the correlation of observations among participants, the SAS procedure
MIXED (SAS Institute, Cary, NC) with the best fitting of the following covariance
structures was used: unstructured, first-order heterogeneous autoregressive and first-
order autoregressive. The longitudinal analyses used all available observations from all
time points from all participants who completed a baseline evaluation. As a secondary
analysis, changes from baseline to end point (the LOCF method) were analysed using
an analysis of variance model, with a term for centre
Participants Participants: 150 (90% women, 97% white, mean age 48 years)
Inclusion criteria: ACR 1990 criteria; age ≥ 18 years; participants were required to
score 4 on the mean pain severity item of the BPI
Exclusion criteria: Pain from traumatic injury or structural or regional rheumatic dis-
ease; rheumatoid arthritis, inflammatory arthritis or autoimmune disease; unstable med-
ical or psychiatric illness; lifetime history of psychosis, hypomania or mania, epilepsy
or dementia; substance abuse in the last 6 months; serious risk of suicide; pregnancy or
breastfeeding; unacceptable contraception in those of childbearing potential; participants
who, in the opinion of the investigator, were treatment refractory; prior treatment with
gabapentin or pregabalin; and treatment with an investigational drug within 30 days of
screening. Concomitant medication exclusions consisted of medications or herbal agents
with CNS effects, with the exception of episodic use of sedating antihistamines (antide-
pressants required a 14-day washout period prior to beginning study medication except
for fluoxetine, which required a 30-day washout period); analgesics, with the exception
of paracetamol (acetaminophen) or over-the-counter NSAIDs; and unconventional or
alternative therapies
Interventions Active drug: Gabapentin flexible 1200-2400 mg/d (75 participants): 300 mg once a
day at bedtime for 1 week, 300 mg twice a day for 1 week, 300 mg twice a day and 600
mg once a day at bedtime for 2 weeks, 600 mg 3 times a day for 2 weeks, and 600 mg
twice a day and 1200 mg once a day at bedtime (2400 mg/d) for the remainder of the
study beginning at week 6. If a participant could not tolerate 2400 mg/d, the dosage was
reduced to a minimum of 1200 mg/d, administered 3 times a day. The study medication
dose was stable for at least the last 4 weeks of the therapy phase. During the tapering
phase, the dosage was decreased by 300 mg/d until discontinuation
Placebo: 75 participants

Arnold 2007 (Continued)
Rescue or allowed medication, or both: Paracetamol (acetaminophen) or over-the-

counter NSAIDs (dosage not reported)
Outcomes Pain: BPI mean pain severity (NRS 0-10). LOCF analysis reported; 50% pain reduction
rates not reported and calculated by imputation method
Fatigue: FIQ (VAS 0-10): Not reported
Sleep: BPI sleep interference (NRS 0-10). Observed cases reported
Depression: Montgomery Asberg Depression Rating Scale score (NRS 0-60). Observed
cases reported
Anxiety: FIQ (VAS 0-10): Not reported
Disability: BPI interference from pain (NRS 0-10). Observed cases reported
Quality of life: FIQ total score (0-80). Observed cases reported
Patient-perceived improvement: PGIC: Data extracted from figure
AEs: At the randomisation visit, and at each subsequent visit until the end of the therapy
phase, AEs were reviewed (no details reported)
Notes Safety: Gabapentin-treated participants reported dizziness, sedation, lightheadedness

and weight gain significantly more frequently than did placebo-treated participants. Most
treatment-emergent AEs were mild to moderate in severity. There were no clinically
important findings in the laboratory results, physical examinations, or ECGs
Funding sources and any declaration of interest of primary investigators: Supported
by NIH grant N01-AR-2-2264 from the National Institute of Arthritis and Muscu-
loskeletal and Skin Diseases (Dr. Arnold, principal investigator). Dr. Arnold received
consulting fees from Eli Lilly (more than USD10,000) and from Pfizer, Cypress Bio-
science, Wyeth Pharmaceuticals, Sanofi-Aventis, Böehringer Ingelheim, Sepracor, Forest
Laboratories, Allergan, and Vivus (< USD10,000 each). She also has received research
support from Eli Lilly, Pfizer, Cypress Bioscience, Wyeth Pharmaceuticals, Sanofi-Aven-
tis and Böehringer Ingelheim. Dr. Keck received consulting fees (< USD10,000) from,
or is a member of the scientific advisory boards of, Abbott, AstraZeneca Pharmaceuticals,
Bristol-Myers Squibb, GlaxoSmithKline, Eli Lilly and Pfizer. He is a principal or co-
investigator on research studies sponsored by Abbott, the American Diabetes Associa-
tion, AstraZeneca Pharmaceuticals, Bristol-Myers Squibb, GlaxoSmithKline, Eli Lilly,
Janssen Pharmaceutica, the National Institute of Mental Health, the National Institute
of Drug Abuse, Pfizer, the Stanley Medical Research Institute and UCB
Risk of bias
Bias Authors’ judgement Support for judgement
Random sequence generation (selection Low risk Computer-generated random sequence

bias) stratified by major depression status (details
provided on request)
Allocation concealment (selection bias) Low risk Central independent unit (details reported
on request)
Blinding of participants and personnel Low risk Double blind (number and appearance of
(performance bias) placebo capsules similar)
All outcomes

Blinding of outcome assessment (detection Low risk Independent data imputation and statisti-
bias) cal analysis (details reported on request)
All outcomes
Incomplete outcome data (attrition bias) High risk Observed cases analysis
All outcomes
Selective reporting (reporting bias) High risk Outcomes anxiety and fatigue not reported
Arnold 2008
Analysis: ITT; LOCF; analysis of covariance with treatment centre and baseline scores
as covariates
Inclusion criteria: ACR 1990 criteria; age ≥ 18 years; pain score of at least 40 on a 100
VAS
Exclusion criteria: Inflammatory rheumatic diseases; active infections; untreated en-
docrine disorder; severe painful disorder (e.g. painful diabetic peripheral neuropathy,
postherpetic pain) that might confound the assessment of pain due to FM; unstable
medical or psychiatric disorder (e.g. serious hepatic, respiratory, neurological, haema-
tological or immunological illness, unstable cardiovascular disease; or any other severe
acute or chronic medical or psychiatric condition or laboratory abnormalities, including
creatinine clearance < 50 mL/min; history of illicit alcohol or drug abuse within the past
2 years; pending workers’s compensation, current receipt of disability; past or pending
litigation for monetary compensation related to FM; other concomitant medication for
FM (antidepressants, anticonvulsants) as well as agents used to treat pain or insomnia
Interventions Active drug: Pregabalin 300 mg/d (183 participants), pregabalin 450 mg/d (190 par-
ticipants), pregabalin 600 mg/d (188 participants) twice/d, 2 weeks’ dose escalation
Rescue or allowed medication: Paracetamol (acetaminophen) < 4 g/d, aspirin < 325
mg/d
Outcomes Pain: Daily diary mean pain (NRS 0-10)

Fatigue: MAF (NRS 1-50)
Sleep: MOS Sleep Problems Index (NRS 0-100)
Depression: HADS (NRS 0-21)
Anxiety: HADS (NRS 0-21)
Disability: SF-36, physical functioning (NRS 50-0)
Quality of life: FIQ total score (0-80)
Patient-perceived improvement: PGIC (1-7)
AEs: Observed or spontaneously reported AEs; laboratory results, physical examinations,
ECG

Notes Safety: Of the 745 participants who received study medication, 614 (82%) had at least
1 AE and 473 (53%) had at least 1 AE that was judged to be related with treatment.
The incidence of all-causality AEs was higher with pregabalin (72%) than with placebo
(38%). The severity of the majority of treatment-related AEs was mild to moderate (89%
pregabalin vs. 98% placebo)
Dizziness and somnolence were the most common AEs in pregabalin groups leading
to discontinuation of treatment. There were no clinically important findings in the
laboratory results, physical examinations or ECGs
Funding sources and any declaration of interest of primary investigators: Dr. Arnold
received consulting fees from Eli Lilly, Pfizer, Cypress Biosciences, Wyeth Pharmaceu-
ticals, Sanofi-Aventis, Böehringer Ingelheim, Allergan, Forest Laboratories and Vivus.
Dr. Arnold received research grant support from Eli Lilly, Pfizer, Cypress Biosciences,
Wyeth Pharmaceuticals, Sanofi-Aventis, Böehringer Ingelheim, Allergan and Forest Lab-
oratories. Dr. Arnold is on the Speakers Bureau for Eli Lilly and Pfizer. Dr. Russell has
consulted for conducted research studies for Pfizer, Autoimmune Technologies, LLC,
LKB World, Jazz Pharmaceuticals, Gruenethal and Allergan. He is on speaker’s panel for
Merck, Ortho-McNeil and Pfizer. Erdal Diri received research grants from Hoffmann-
LaRoche, Pfizer, Pain Therapeutics, Proctor & Gamble Pharmaceutics and Corona. He
is a speaker and consultant for Pfizer, Amgen, Centecor and Abbott. Rachel Duan, James
Youg, Susan Martin, Jeannette Barreite and George Haig are employees of Pfizer and own
Pfizer stocks. Uma Sharma is a consultant for Pfizer, Wyeth, Eisal, Analgesic Research
and Amgen. Editorial support was provided by Yilmarie Yanchik, an employee of Pfizer.
Statistical support was provided by Ed Whalen, an employee of Pfizer
Risk of bias

on request)
All outcomes
All outcomes
Incomplete outcome data (attrition bias) Low risk Imputation using LOCF and ITT analysis
All outcomes for efficacy data
Selective reporting (reporting bias) Low risk All outcomes reported

Crofford 2005
Analysis: ITT; LOCF; analysis of covariance, with treatment and centre as the main
effects and the baseline value as the covariate
Inclusion criteria: ACR 1990 criteria; age ≥ 18 years; score of 40 mm on the 100-mm
VAS of the SF-MPQ
Exclusion criteria:
Inflammatory rheumatic disease or other severe painful disorders that might confound
assessment of FM pain. People were also excluded if they had clinically significant or
unstable medical or psychological conditions that, in the opinion of the investigator,
would compromise participation in the study. Participants with a calculated creatinine
clearance rate of 60 mL/min (Cockroft-Gault equation) were specifically excluded. Those
who had failed to respond to previous treatment with gabapentin at dosages of 1200 mg/d
for pain associated with FM were excluded. Women who were not postmenopausal were
tested to confirm that they were not pregnant or breastfeeding during the study, and all
women of childbearing potential were advised to use contraception reliably. Participants
who were receiving disability, applying for disability, or engaged in litigation related to
FM were excluded
ticipants), pregabalin 450 mg/d (132 participants) 3 times/d
Rescue or allowed medication: Paracetamol (acetaminophen) < 4 g/d, aspirin < 325
mg/d
Outcomes Pain: SF-MPQ (VAS 0-100)

Depression: HADS (NRS 0-21): details provided on request
Anxiety: HADS (NRS 0-21); details provided on request
Quality of life: Not assessed
Patient-perceived improvement: PGIC: not reported
AEs: All spontaneously reported or observed treatment-emergent AEs were recorded at
each clinic visit, along with the dates on which they began and ended. The sponsor
classified AEs using Coding Symbols for a Thesaurus of Adverse Reaction Terms, 4th
Edition (COSTART IV) . A 12-lead ECG was recorded at screening and end point,
and clinical laboratory tests (haematology, urinalysis and chemistry) were performed at
screening, week 3, and end point. Serious AE not reported
Notes Safety: Most AEs were mild or moderate. Dizziness and somnolence were the 2 most fre-
quently reported AEs and tended to be dose-related across pregabalin groups. Non-CNS
AEs that were more frequent in the pregabalin groups included weight gain and periph-
eral oedema. There were no clinically important findings in the analyses of haematology,
blood chemistry or urinalysis. Similarly, there were no clinically significant findings in
the visual function, physical, or neurological examinations or on the ECGs

Crofford 2005 (Continued)

by Pfizer Global Research and Development, Ann
Arbor, Michigan. Dr. Crofford has received consulting fees of < USD10,000 from Cy-
press Bioscience, Eli Lilly & Co, Orphan Pharmaceuticals, Pfizer and Wyeth. Dr. Row-
botham has received consulting fees of < USD10,000 from Eli Lilly & Co and Xeno-
port, owns stock in Xenoport and Neuromolecular and was a co-investigator on a study
of gabapentin funded by Pfizer. Dr. Mease has received consulting fees of < USD10,
000 from Pfizer, Cypress Bioscience, Eli Lilly & Co and Pierre Fabre and owns stock in
Cypress Bioscience. Dr. Dworkin has served on the advisory board or as a consultant for
fees of < USD10,000 for Abbott Laboratories, Alpharma, AstraZeneca Pharmaceuticals,
Bristol-Myers Squibb, Elan Pharmaceuticals, Eli Lilly & Co, GlaxoSmithKline, Johnson
& Johnson, Merck KGaA, NeurogesX Inc., Ortho-McNeil Pharmaceutical and UCB
Pharma; has received consulting fees of > USD10,000 from Pfizer, Allergan, Novartis,
Epicept and Endo; and owns stock in NeurogesX, Inc. Ms Corbin, Mr. Young, Ms LaM-
oreaux, Ms Martin and Dr. Sharma own stock in Pfizer
Risk of bias

on request)
(performance bias) placebo capsules similar, details reported on
All outcomes request)
All outcomes
Selective reporting (reporting bias) High risk Quality of life scores and SAEs not reported
and not provided on request

Mease 2008
Analysis: ITT; LOCF; analysis of covariance with treatment centre and baseline scores
as covariates
Inclusion criteria: ACR 1990 criteria; age ≥ 18 years; pain score of at least 4 on a 0-10
NRS
Exclusion criteria: Inflammatory or rheumatological disease; other severe pain disorders;
clinically significant or unstable medical or psychological conditions; creatinine clearance
< 60 mL/min, severe depression, receiving or applying for disability benefits
Interventions Active drug: pregabalin 300 mg/d (185 participants), pregabalin 450 mg/d (183 par-
Rescue or allowed medication: paracetamol (acetaminophen) < 4 g/d
Outcomes Pain: Daily diary mean pain (NRS 0-10); 50% pain reduction rates provided on request
Fatigue: MAF (NRS 1-50), details provided on request
Depression: HADS (NRS 0-21): details provided on request
Anxiety: HADS (NRS 0-21): details provided on request
Disability: SF-36, physical functioning (NRS 50-0): data provided on request
Quality of life: FIQ total score (0-100); standard deviations provided on request
AEs: Volunteered by participants or observed by the clinician at every visit, laboratory
results, physical examinations, ECG
Notes Safety: At least 1 AE was reported by 89.2% of participants with pregabalin 300 mg/d,
91.8% of participants with pregabalin 450 mg/d, 93.7% of participants with pregabalin
600 mg/d and by 76.3% of participants with placebo
Dizziness, somnolence and weight gain were more common in pregabalin groups com-
pared with placebo. There were no clinically important findings in the laboratory results,
physical examinations, or ECGs
by Pfizer Global Research and Development, Ann
Arbor, Michigan. Dr. Mease has received research grant support from Pfizer, Cypress
Bioscience, Forest Laboratories, Eli Lilly, Allergan, Wyeth Pharmaceuticals, Jazz Pharma-
ceuticals and Fralex Therapeutics. Dr. Russell has received research grant support from
Pfizer, Eli Lilly, Allergan, Böehringer Ingelheim, Cypress Bioscience, Jazz Pharmaceuti-
cals, Grünenthal and Pierre Fabre. Dr. Arnold has received research grant support from
Eli Lilly, Pfizer, Cypress Biosciences, Wyeth Pharmaceuticals, Sanofi-Aventis, Böehringer
Ingelheim, Allergan and Forest Laboratories. Dr. Florian, Mr. Young and Ms Mareen
are employees of Pfizer and own stock of Pfizer. Dr Sharma was an employee of Pfizer
when the study was conducted and owns stocks of Pfizer
Risk of bias

Mease 2008 (Continued)

bias) (details provided on request)
on request)
All outcomes
All outcomes
Selective reporting (reporting bias) High risk Disability not reported
Ohta 2012
Methods Study setting: Multicentre study with 44 outpatient research centres in Japan
Analysis: ITT; LOCF; a mixed-effect model taking baseline value as covariate was used
for the analysis, which included participants as the random effect and dose groups, points
at time of evaluation, and interaction between a dose group and its point at time of
evaluation as the fixed effects
Participants Participants: 501 (89% women, 10% Japanese, mean age 47 years)
Inclusion criteria: ACR 1990 criteria; age ≥ 18 years; pain score of ≥ 40 mm on the
100-mm VAS at visit 2, and had assessed and documented their pain score on at least 4
of the past 7 days prior to visit 2 while recording a mean pain score of ≥ 4 on the 11-
point NRS
Exclusion criteria: Decrease of ≥ 30% on their pain VAS during the placebo run-in
period (at visit 2 compared with visit 1), in order to remove potential placebo-responders.
Participants were also excluded if they were being treated for depression or if they were
at risk of suicide or self harm in the opinion of the study investigator; inflammatory
or rheumatological disease; other severe pain disorders; clinical significant or unstable
medical or psychological conditions; history of malignancy; creatinine clearance < 60
mL/min, severe depression, receiving or applying for disability benefits
Interventions Active drug: Pregabalin (251 participants): treatment was started at 150 mg/d, escalated
to 300 mg/d 1 week later, and to 450 mg/d after another week. The dose was adjusted
(increased or decreased) until visit 5 of the study, after which the maintenance dose was

Ohta 2012 (Continued)
either 300 or 450 mg/d

Rescue or allowed medication: Paracetamol (acetaminophen) or NSAIDs for additional
pain relief, although for NSAIDs, the participant must have already been on a stable
regimen for longer than 30 days

Fatigue: FIQ Fatigue single scale (VAS 0-10)
AEs: volunteered by participants or observed by the clinician at every visit, laboratory
results, physical examinations, ECG
Notes Safety: The incidence of all-causality AEs was higher with pregabalin (occurring in
225 of 250 participants, 90.0%) than with placebo (175 of 248 participants, 70.6%)
. Similarly, the incidence of treatment-related AEs was higher with pregabalin (206 of
250 participants, 82.4%) than with placebo (128 of 248 participants, 51.6%). The most
common AEs in this study were somnolence, dizziness, nasopharyngitis, increased weight
and constipation with pregabalin treatment, and somnolence and nasopharyngitis with
placebo
A laboratory test result of increased creatine kinase was more frequent with pregabalin (7
of 250 participants, 2.8%) than with placebo (1 of 248 participants, 0.4%), although all
cases were of mild severity. Increased weight was reported more frequently with pregabalin
(39 of 250 participants, 15.6% (38 mild, 1 moderate)) than with placebo (9 of 248
participants, 3.6% (8 mild, 1 moderate)). There were no clinically significant changes
in blood pressure or pulse rate in the pregabalin and placebo group.
There were 4 serious AEs in 4 (0.8%) participants who had received ≥ 1 dose of treatment;
1 participant was from the placebo group (abnormal liver function test result) and 3
were from the pregabalin group (breast cancer, viral gastroenteritis and musculoskeletal
stiffness). Severe AEs were observed in 2 participants from the pregabalin group (breast
cancer and loss of consciousness, each in 1 participant) and all other AEs were mild or
moderate. As assessed by the study investigators, there was no causal relationship to the
study drug for any serious or severe AEs.
Suicidal ideation (mild), as rated by C-SSRS, was noted in 2 participants in the pregabalin
group. The investigator (a physician specialising in psychosomatic medicine) had noted
suicidal ideation in each of these people prior to the start of the study. In each case,
incidence was attributable to family environment and was judged to have no causal
relationship to the study drug. The suicidal ideation in these cases was not judged by the
study investigator to be a real desire, and treatment with the study drug was continued
Funding sources and any declaration of interest of primary investigators: The study
was funded by Pfizer Japan Inc. Medical writing support was provided by Joshua Fink
PhD, of UBC Scientific Solutions, and funded by Pfizer Inc. HOhta, MO and MS are
employees of Pfizer Japan, Inc. KN and HOka received a consultancy fee from Pfizer
Japan, Inc. for their participation in this study. CU declares no competing interests. KN,
HOka and CU were not compensated for their work on the manuscript

Ohta 2012 (Continued)
Risk of bias

on request)
All outcomes
All outcomes
Selective reporting (reporting bias) Low risk All outcomes reported on request
Pauer 2011
Methods Study setting: Multicentre study with 73 outpatient research centres in the USA, Middle
America, South America, Western Europe, Asia, Australia and India
Analysis: ITT; LOCF; analysis of covariance with treatment centre, week, treatment by
week interaction and baseline scores as covariates
Inclusion criteria: ACR 1990 criteria; age ≥ 18 years; pain score of at least 40 on a 100
VAS
Exclusion criteria: Participants who demonstrated a high placebo response (≥ 30%
decrease on the VAS following the 1-week run-in period compared with screening). Pro-
vided on request: other severe pain conditions; any widespread inflammatory muscu-
loskeletal disorder, active infections or untreated endocrine disorders; previous participa-
tion in a clinical trial with pregabalin, previous exposure to pregabalin or currently prega-
balin for any condition; severe depression according to the judgement of the investigator;
serious internal diseases or any other acute or chronic medical or psychiatric condition
or laboratory abnormality that may increase the risk associated with trial participation;
intake of any experimental drug within 30 days prior to screening; use of prohibited
pain/sleep medication (including antidepressants, sedatives, hypnotics, NSAIDs, opi-
oids, muscle relaxants) in the absence of appropriate washout period; pending disability
claims or currently receiving monetary compensation pertinent to the patient’s FM or

Pauer 2011 (Continued)
co-morbid diseases
Rescue or allowed medication: No details reported

Depression: HADS (NRS 0-21): data available on clinicaltrials.gov/ct2/show/
NCT00333866
Anxiety: HADS (NRS 0-21): data available on clinicaltrials.gov/ct2/show/
NCT00333866
Disability: SF-36, physical functioning (NRS 50-0): data available on clinicaltrials.gov/
ct2/show/NCT00333866
AEs: AE were recorded at each visit. Investigators rated the severity of each AE and
its relationship to study drug. Clinical laboratory evaluations, physical examinations,
abbreviated neurological examinations, and 12-lead ECGs were performed at regular
intervals
Notes Safety: Of the 736 participants receiving study medication, 626 (85%) experienced at
least 1 AE. The occurrence of AE increased with dosage (73%, 85%, 90% and 92% for
placebo, 300, 450 and 600 mg/d pregabalin-treated participants, respectively).The AEs
most frequently reported by pregabalin-treated participants were dizziness, somnolence,
weight gain, headache, peripheral oedema, fatigue and dry mouth. Most AE were rated
by investigators as mild or moderate. 18 participants experienced SAE, 4 participants
treated with placebo and 14 pregabalin. Only 1 SAE, an incidence of chest pain in
1 person in the 450 mg/d pregabalin group, was considered by the investigator to be
related to treatment and the person was withdrawn from the study. 8 other participants
experienced an SAE that led to withdrawal from the study and 1 participant experienced
an SAE that led to a dose reduction
There were no clinically relevant differences in clinical laboratory evaluations, vital signs,
physical examination or ECG findings
by Pfizer. No declaration of interest of primary investigators included
Risk of bias

on request)

Pauer 2011 (Continued)
All outcomes
All outcomes
Selective reporting (reporting bias) Low risk All outcomes reported
Rowbotham 2012
Methods Study setting: Single-centre study in the USA, investigator-initiated

Analysis: Completer analysis by mixed effect regressions
Participants Participants: 60 participants (93% female, 79% white, mean age 49 years)
Inclusion criteria: ACR 1990 criteria; age ≥ 18 years; McGill Pain Questionnaire VAS
of at least 40mm on 100-mm scale at screening and mean daily diary pain at least 4 out
of 10 during the 7 days prior to study drug initiation
Exclusion criteria: Pregnant or lactating women, hypersensitivity to levetiracetam or
prior treatment with it; clinically significant liver, kidney or haematological disorders,
a Westergen erythrocyte sedimentation rate exceeding 40 mm/min, abnormal elevated
antinuclear antibody (1:160) or rheumatoid factor (> 80 IU/mL) levels, another expla-
nation for their pain, illicit drug or alcohol abuse within the last year, involvement in
unsettled litigation pertaining to their FM (such as automobile accident, civil lawsuit or
worker’s compensation), and ongoing monetary compensation as a result of litigation
or disability claims with the exception of US social security disability benefits; subjects
who are considered unreliable as to medication compliance or adherence to scheduled
appointments as determined by the investigators; subjects who have serious or unstable
medical or psychological conditions that in the opinion of the investigator(s), would
compromise the subject’s participation in the study
Interventions Active drug: 40 participants were titrated to a maximum 3000 mg/d over a 6-week
period and tapered off study medication after 8 weeks of treatment
Rescue or allowed medication: Continuation of stable doses of antidepressants and
opiates allowed
Outcomes Pain: Diary pain (NRS 0-10); 30% and 50% pain reduction not reported and calculated
by imputation method
Fatigue: FIQ Fatigue single scale not reported
Sleep: Diary sleep interference (NRS 0-10)

Rowbotham 2012 (Continued)
Depression: FIQ Depression not reported

Anxiety: FIQ Anxiety not reported
Disability: FIQ Disability not reported
AEs: Subject-reported AEs were classified into 1 of 39 categories and a subject was
considered positive even if they reported an AE at only 1 visit after beginning treatment
Notes Safety: There were no SAEs in either group. AEs such as thinking abnormal, restlessness,
itching and movement disorder were significantly more frequent in the levetiracetam
group
by an investigator-initiated grant from UCB Pharma and NIH grant K24 NS02164. No
declaration of interest of primary investigator included
Risk of bias

on request)
All outcomes
All outcomes
Incomplete outcome data (attrition bias) High risk Only observed cases data available
All outcomes
Selective reporting (reporting bias) High risk Outcomes FIQ subscales fatigue, anxiety,
depression, disability not reported

UCB 2006
Methods Study setting: Multicentre study, number of outpatient research centres in the USA not
reported
Analysis: ITT; LOCF; analysis of covariance with treatment centre, week, treatment by
week interaction and baseline scores as covariates
Participants Participants: 159 (93% women, race not reported, mean age 50 years)
Inclusion criteria: Not reported
Exclusion criteria: Not reported
Interventions Active drug: Lacosamide 400 mg (81 participants), 4-week titration from 100 mg/d to
400 mg/d, increasing by 100 mg/d at weekly intervals; 8-week maintenance
Rescue or allowed medication: No details reported

Fatigue: Fatigue score of FIQ (VAS 0-10)
Sleep: Mean daily interference with sleep (NRS 0-10)
Disability: Mean daily interference with activity (NRS 0-10)
AEs: No details reported
Notes Safety: No deaths in either group. No further details reported

by UCB. No declaration of interest of primary investigators included
Risk of bias
Random sequence generation (selection Unclear risk Not reported

bias)
Allocation concealment (selection bias) Unclear risk Not reported
All outcomes
Blinding of outcome assessment (detection Low risk Participant reported and participant
bias) blinded
All outcomes

UCB 2006 (Continued)
Incomplete outcome data (attrition bias) High risk Imputation using LOCF for continuous
All outcomes data reported, but not used. ITT for PGIC,
AEs and withdrawals
Selective reporting (reporting bias) High risk No details of AEs reported
ACR: American College of Rheumatology; AE: adverse event; BPI: Brief Pain Inventory; C-SSRS: Columbia Suicide Severity Rating
Scale; CNS: central nervous system; ECG: electrocardiogram; FIQ: Fibromyalgia Impact Questionnaire; FM: fibromyalgia; HADS:
Hospital Anxiety and Depression Scale; ITT: intention to treat; LOCF: last observation carried forward; MAF: Multidimensional
Assessment of Fatigue; MOS: Medical Outcomes Study; NIH: National Institutes of Health; NRS: numeric rating scale; NSAID:
non-steroidal anti-inflammatory drug; PGIC: Patient Global Impression of Change; SAE: serious adverse events; SF-36: Short-Form
Health Survey - 36 items; SF-MPQ: Short-Form McGill Pain Questionnaire; VAS: visual analogue scale.
Characteristics of excluded studies [ordered by study ID]
Study Reason for exclusion
Crofford 2008 Pregabalin: Study design (enriched enrolment randomised withdrawal design) over 26 weeks cannot be combined
with parallel or cross-over designs for meta-analysis
Roth 2012 Pregabalin: Pregabalin and placebo treatment 4 weeks each within a cross-over design

DATA AND ANALYSES
Comparison 1. Gabapentin flexible 1200 to 2400 mg/day versus placebo at end of treatment
No. of No. of
Outcome or subgroup title studies participants Statistical method Effect size
1 Pain 1 119 Std. Mean Difference (IV, Random, 95% CI) -0.49 [-0.86, -0.13]
2 50% pain reduction 1 150 Risk Ratio (IV, Random, 95% CI) 1.6 [1.01, 2.53]
3 Sleep problems 1 119 Std. Mean Difference (IV, Random, 95% CI) -0.71 [-1.08, -0.34]
4 Health-related quality of life 1 119 Std. Mean Difference (IV, Random, 95% CI) -0.66 [-1.03, -0.29]
5 Withdrawal due to adverse 1 150 Risk Ratio (IV, Random, 95% CI) 1.71 [0.71, 4.11]
events
6 Dizziness 1 150 Risk Ratio (IV, Random, 95% CI) 2.71 [1.21, 6.07]
7 30% pain reduction 1 150 Risk Ratio (M-H, Random, 95% CI) 1.65 [1.10, 2.48]
8 Depression 1 119 Std. Mean Difference (IV, Random, 95% CI) -0.52 [-0.89, -0.16]
9 Disability 1 119 Std. Mean Difference (IV, Random, 95% CI) -0.94 [-1.32, -0.56]
Comparison 2. Lacosamide 400 mg/day versus placebo at end of treatment
No. of No. of
1 Pain 1 158 Std. Mean Difference (IV, Random, 95% CI) -0.25 [-0.56, 0.07]
2 Fatigue 1 121 Std. Mean Difference (IV, Random, 95% CI) -0.07 [-0.43, 0.28]
3 Sleep problems 1 158 Std. Mean Difference (IV, Random, 95% CI) -0.19 [-0.51, 0.12]
4 Health-related quality of life 1 157 Std. Mean Difference (IV, Random, 95% CI) -0.15 [-0.47, 0.16]
5 Serious adverse events 1 159 Risk Ratio (IV, Random, 95% CI) 0.15 [0.01, 2.82]
7 Anxiety 1 133 Std. Mean Difference (IV, Random, 95% CI) 0.0 [-0.34, 0.34]
8 Depression 1 134 Std. Mean Difference (IV, Random, 95% CI) 0.11 [-0.23, 0.45]
9 Disability 1 158 Std. Mean Difference (IV, Random, 95% CI) -0.19 [-0.51, 0.12]
10 Patient Global Impression of 1 134 Risk Ratio (IV, Random, 95% CI) 1.32 [0.85, 2.04]
Change ’much’ or ’very much’
improved

Comparison 3. Levetiracetam up to 3000 mg/day versus placebo at end of treatment
No. of No. of
1 Pain 1 50 Std. Mean Difference (IV, Random, 95% CI) -0.21 [-0.77, 0.36]
3 Sleep problems 1 50 Std. Mean Difference (IV, Random, 95% CI) -0.16 [-0.72, 0.40]
4 Health-related quality of life 1 50 Std. Mean Difference (IV, Random, 95% CI) 0.14 [-0.42, 0.70]
events
Comparison 4. Pregabalin versus placebo at end of treatment
No. of No. of
1 Pain 5 3252 Std. Mean Difference (IV, Random, 95% CI) -0.28 [-0.35, -0.20]
1.1 Pregabalin 150 mg/d 1 175 Std. Mean Difference (IV, Random, 95% CI) -0.10 [-0.45, 0.24]
1.2 Pregabalin 300 mg/d 4 913 Std. Mean Difference (IV, Random, 95% CI) -0.24 [-0.39, -0.09]
1.5 Pregabalin flexible 300 or 1 498 Std. Mean Difference (IV, Random, 95% CI) -0.24 [-0.41, -0.06]
450 mg/d
2.1 Pregabalin 150 mg/d 1 175 Risk Ratio (IV, Random, 95% CI) 0.92 [0.39, 2.19]
2.5 Pregabalin flexible 300 1 498 Risk Ratio (IV, Random, 95% CI) 1.88 [1.26, 2.83]
mg/d or 450 mg/d
3 Fatigue 5 3195 Std. Mean Difference (IV, Random, 95% CI) -0.17 [-0.25, -0.09]
450 mg/d
4 Sleep problems 5 3193 Std. Mean Difference (IV, Random, 95% CI) -0.35 [-0.43, -0.27]
450 mg/d
5 Health-related quality of life 4 2724 Std. Mean Difference (IV, Random, 95% CI) -0.17 [-0.26, -0.09]
5.4 Pregabalin flexible 300 1 498 Std. Mean Difference (IV, Random, 95% CI) -0.20 [-0.37, -0.02]
mg/d or 450 mg/d
events
mg/d or 450 mg/d
7 Serious adverse events 4 2729 Risk Ratio (IV, Random, 95% CI) 1.03 [0.71, 1.49]
mg/d or 450 mg/d
mg/d or 450 mg/d
mg/d or 450 mg/d
10 Anxiety 5 3214 Std. Mean Difference (IV, Random, 95% CI) -0.12 [-0.20, -0.04]
10.1 Pregabalin 150 mg/d 1 166 Std. Mean Difference (IV, Random, 95% CI) 0.07 [-0.28, 0.42]
10.5 Pregabalin flexible 300 1 496 Std. Mean Difference (IV, Random, 95% CI) -0.17 [-0.35, 0.01]
mg/d or 450 mg/d
11 Depression 5 3212 Std. Mean Difference (IV, Random, 95% CI) -0.09 [-0.16, -0.01]
11.5 Pregabalin flexible 300 1 496 Std. Mean Difference (IV, Random, 95% CI) -0.09 [-0.27, 0.08]
mg/d or 450 mg/d
12 Disability 5 3145 Std. Mean Difference (IV, Random, 95% CI) -0.01 [-0.11, 0.09]

12.5 Pregabalin flexible 300 1 498 Std. Mean Difference (IV, Random, 95% CI) -0.29 [-0.47, -0.12]
mg/d or 450 mg/d
13 Patient Global Impression of 5 3183 Risk Ratio (IV, Random, 95% CI) 1.38 [1.23, 1.55]
Change ’much’ or ’very much’
improved
mg/d or 450 mg/d
Analysis 1.1. Comparison 1 Gabapentin flexible 1200 to 2400 mg/day versus placebo at end of treatment,
Outcome 1 Pain.
Review: Anticonvulsants for fibromyalgia
Comparison: 1 Gabapentin flexible 1200 to 2400 mg/day versus placebo at end of treatment
Outcome: 1 Pain
Std. Std.
Mean Mean
Study or subgroup Gabapentin Placebo Difference Weight Difference
N Mean(SD) N Mean(SD) IV,Random,95% CI IV,Random,95% CI
Arnold 2007 57 3.8 (2.2) 62 5 (2.6) 100.0 % -0.49 [ -0.86, -0.13 ]
Total (95% CI) 57 62 100.0 % -0.49 [ -0.86, -0.13 ]

Heterogeneity: not applicable
Test for overall effect: Z = 2.65 (P = 0.0081)
Test for subgroup differences: Not applicable
-4 -2 0 2 4
Favours gabapentin Favours placebo

Outcome 2 50% pain reduction.
Outcome: 2 50% pain reduction
Study or subgroup Gabapentin Placebo Risk Ratio Weight Risk Ratio

n/N n/N IV,Random,95% CI IV,Random,95% CI
Arnold 2007 32/75 20/75 100.0 % 1.60 [ 1.01, 2.53 ]
Total (95% CI) 75 75 100.0 % 1.60 [ 1.01, 2.53 ]

Total events: 32 (Gabapentin), 20 (Placebo)
0.01 0.1 1 10 100

Favours placebo Favours gabapentin
Outcome 3 Sleep problems.
Outcome: 3 Sleep problems
Std. Std.
Mean Mean
Arnold 2007 57 33.4 (19.5) 62 47.8 (20.9) 100.0 % -0.71 [ -1.08, -0.34 ]
Total (95% CI) 57 62 100.0 % -0.71 [ -1.08, -0.34 ]

-2 -1 0 1 2

Outcome 4 Health-related quality of life.
Outcome: 4 Health-related quality of life
Std. Std.
Mean Mean
Arnold 2007 57 26.2 (15.1) 62 37.3 (18.1) 100.0 % -0.66 [ -1.03, -0.29 ]
Total (95% CI) 57 62 100.0 % -0.66 [ -1.03, -0.29 ]

-4 -2 0 2 4
Outcome 5 Withdrawal due to adverse events.
Outcome: 5 Withdrawal due to adverse events

Arnold 2007 12/75 7/75 100.0 % 1.71 [ 0.71, 4.11 ]
Total (95% CI) 75 75 100.0 % 1.71 [ 0.71, 4.11 ]

0.05 0.2 1 5 20

Outcome 6 Dizziness.
Outcome: 6 Dizziness

Arnold 2007 19/75 7/75 100.0 % 2.71 [ 1.21, 6.07 ]
Total (95% CI) 75 75 100.0 % 2.71 [ 1.21, 6.07 ]

0.01 0.1 1 10 100

Outcome 7 30% pain reduction.

M- M-
H,Random,95% H,Random,95%
n/N n/N CI CI
Arnold 2007 38/75 23/75 100.0 % 1.65 [ 1.10, 2.48 ]
Total (95% CI) 75 75 100.0 % 1.65 [ 1.10, 2.48 ]

0.01 0.1 1 10 100


Outcome 8 Depression.
Outcome: 8 Depression
Std. Std.
Mean Mean
Arnold 2007 57 9.1 (9.4) 62 13.9 (8.9) 100.0 % -0.52 [ -0.89, -0.16 ]
Total (95% CI) 57 62 100.0 % -0.52 [ -0.89, -0.16 ]

-4 -2 0 2 4
Outcome 9 Disability.
Outcome: 9 Disability
Std. Std.
Mean Mean
Arnold 2007 57 2.2 (2.2) 62 4.6 (2.8) 100.0 % -0.94 [ -1.32, -0.56 ]
Total (95% CI) 57 62 100.0 % -0.94 [ -1.32, -0.56 ]

Test for overall effect: Z = 4.86 (P < 0.00001)
-4 -2 0 2 4

Analysis 2.1. Comparison 2 Lacosamide 400 mg/day versus placebo at end of treatment, Outcome 1 Pain.
Comparison: 2 Lacosamide 400 mg/day versus placebo at end of treatment
Outcome: 1 Pain
Std. Std.
Mean Mean
Study or subgroup Lacosamide Placebo Difference Weight Difference
UCB 2006 78 -1.8 (2.13) 80 -1.3 (1.92) 100.0 % -0.25 [ -0.56, 0.07 ]
Total (95% CI) 78 80 100.0 % -0.25 [ -0.56, 0.07 ]

-2 -1 0 1 2
Favours lacosamide Favours placebo
Analysis 2.2. Comparison 2 Lacosamide 400 mg/day versus placebo at end of treatment, Outcome 2
Fatigue.
Outcome: 2 Fatigue
Std. Std.
Mean Mean
UCB 2006 60 -1.9 (2.9) 61 -1.7 (2.4) 100.0 % -0.07 [ -0.43, 0.28 ]
Total (95% CI) 60 61 100.0 % -0.07 [ -0.43, 0.28 ]

-2 -1 0 1 2

Analysis 2.3. Comparison 2 Lacosamide 400 mg/day versus placebo at end of treatment, Outcome 3 Sleep
problems.
Std. Std.
Mean Mean
UCB 2006 78 -1.64 (2.16) 80 -1.24 (1.94) 100.0 % -0.19 [ -0.51, 0.12 ]
Total (95% CI) 78 80 100.0 % -0.19 [ -0.51, 0.12 ]

-2 -1 0 1 2
Health-related quality of life.
Std. Std.
Mean Mean
UCB 2006 78 -17.5 (19.3) 79 -14.7 (16.9) 100.0 % -0.15 [ -0.47, 0.16 ]
Total (95% CI) 78 79 100.0 % -0.15 [ -0.47, 0.16 ]

-4 -2 0 2 4

Serious adverse events.
Outcome: 5 Serious adverse events
Study or subgroup Lacosamide Placebo Risk Ratio Weight Risk Ratio

UCB 2006 0/78 3/81 100.0 % 0.15 [ 0.01, 2.82 ]
Total (95% CI) 78 81 100.0 % 0.15 [ 0.01, 2.82 ]

Total events: 0 (Lacosamide), 3 (Placebo)
0.005 0.1 1 10 200

Favours placebo Favours lacosamide
Dizziness.

UCB 2006 18/78 8/81 100.0 % 2.34 [ 1.08, 5.06 ]
Total (95% CI) 78 81 100.0 % 2.34 [ 1.08, 5.06 ]

0.005 0.1 1 10 200


Anxiety.
Outcome: 7 Anxiety
Std. Std.
Mean Mean
UCB 2006 66 -1.2 (3.2) 67 -1.2 (3.2) 100.0 % 0.0 [ -0.34, 0.34 ]
Total (95% CI) 66 67 100.0 % 0.0 [ -0.34, 0.34 ]

-2 -1 0 1 2
Depression.
Std. Std.
Mean Mean
UCB 2006 67 -0.8 (2.8) 67 -1.1 (2.8) 100.0 % 0.11 [ -0.23, 0.45 ]
Total (95% CI) 67 67 100.0 % 0.11 [ -0.23, 0.45 ]

-2 -1 0 1 2

Disability.
Std. Std.
Mean Mean
UCB 2006 78 -1.64 (2.16) 80 -1.24 (1.94) 100.0 % -0.19 [ -0.51, 0.12 ]
Total (95% CI) 78 80 100.0 % -0.19 [ -0.51, 0.12 ]

-2 -1 0 1 2
Patient Global Impression of Change ’much’ or ’very much’ improved.
Outcome: 10 Patient Global Impression of Change ’much’ or ’very much’ improved

UCB 2006 29/67 22/67 100.0 % 1.32 [ 0.85, 2.04 ]
Total (95% CI) 67 67 100.0 % 1.32 [ 0.85, 2.04 ]

0.2 0.5 1 2 5

Analysis 3.1. Comparison 3 Levetiracetam up to 3000 mg/day versus placebo at end of treatment, Outcome
1 Pain.
Comparison: 3 Levetiracetam up to 3000 mg/day versus placebo at end of treatment
Outcome: 1 Pain
Std. Std.
Mean Mean
Study or subgroup Levetiracetam Placebo Difference Weight Difference
Rowbotham 2012 29 4.6 (2.2) 21 5 (1.4) 100.0 % -0.21 [ -0.77, 0.36 ]
Total (95% CI) 29 21 100.0 % -0.21 [ -0.77, 0.36 ]

-4 -2 0 2 4
Favours levetiracetam Favours placebo
2 50% pain reduction.
Study or subgroup Levetiracetam Placebo Risk Ratio Weight Risk Ratio

Rowbotham 2012 7/40 3/26 100.0 % 1.52 [ 0.43, 5.34 ]
Total (95% CI) 40 26 100.0 % 1.52 [ 0.43, 5.34 ]

Total events: 7 (Levetiracetam), 3 (Placebo)
0.2 0.5 1 2 5
Favours placebo Favours levetiracetam

3 Sleep problems.
Std. Std.
Mean Mean
Rowbotham 2012 29 3.6 (2.7) 21 4 (2.1) 100.0 % -0.16 [ -0.72, 0.40 ]
Total (95% CI) 29 21 100.0 % -0.16 [ -0.72, 0.40 ]

-4 -2 0 2 4
4 Health-related quality of life.
Std. Std.
Mean Mean
Rowbotham 2012 29 47.4 (23.1) 21 44.3 (20) 100.0 % 0.14 [ -0.42, 0.70 ]
Total (95% CI) 29 21 100.0 % 0.14 [ -0.42, 0.70 ]

-2 -1 0 1 2

5 Withdrawal due to adverse events.

Rowbotham 2012 4/40 3/26 100.0 % 0.87 [ 0.21, 3.56 ]
Total (95% CI) 40 26 100.0 % 0.87 [ 0.21, 3.56 ]

0.02 0.1 1 10 50
6 Dizziness.

Rowbotham 2012 38/40 19/26 100.0 % 1.30 [ 1.02, 1.66 ]
Total (95% CI) 40 26 100.0 % 1.30 [ 1.02, 1.66 ]

0.1 0.2 0.5 1 2 5 10


7 30% pain reduction.

Rowbotham 2012 17/40 9/26 100.0 % 1.23 [ 0.65, 2.33 ]
Total (95% CI) 40 26 100.0 % 1.23 [ 0.65, 2.33 ]

0.1 0.2 0.5 1 2 5 10


Analysis 4.1. Comparison 4 Pregabalin versus placebo at end of treatment, Outcome 1 Pain.
Comparison: 4 Pregabalin versus placebo at end of treatment
Outcome: 1 Pain
Std. Std.
Mean Mean
Study or subgroup Pregabalin Placebo Difference Weight Difference
1 Pregabalin 150 mg/d

Crofford 2005 132 -1.3 (2) 43 -1.1 (1.9) 5.1 % -0.10 [ -0.45, 0.24 ]
Subtotal (95% CI) 132 43 5.1 % -0.10 [ -0.45, 0.24 ]

Arnold 2008 183 -1.75 (2.16) 61 -1.04 (2.03) 7.1 % -0.33 [ -0.62, -0.04 ]
Crofford 2005 132 -1.7 (2.4) 43 -1.1 (1.9) 5.1 % -0.26 [ -0.61, 0.08 ]
Mease 2008 185 -1.84 (2.17) 64 -1.4 (2.2) 7.5 % -0.20 [ -0.49, 0.08 ]
Pauer 2011 184 -1.06 (1.9) 61 -0.73 (1.9) 7.2 % -0.17 [ -0.46, 0.12 ]
Subtotal (95% CI) 684 229 26.9 % -0.24 [ -0.39, -0.09 ]

Heterogeneity: Tau2 = 0.0; Chi2 = 0.68, df = 3 (P = 0.88); I2 =0.0%
Arnold 2008 190 -2.03 (2.07) 62 -1.04 (2.03) 7.2 % -0.48 [ -0.77, -0.19 ]
Crofford 2005 132 -2.1 (2.2) 43 -1.1 (1.9) 5.0 % -0.47 [ -0.81, -0.12 ]
Mease 2008 183 -1.87 (2.16) 63 -1.4 (2.2) 7.3 % -0.22 [ -0.50, 0.07 ]
Pauer 2011 181 -1.29 (1.88) 61 -0.73 (1.9) 7.1 % -0.30 [ -0.59, 0.00 ]
Subtotal (95% CI) 686 229 26.7 % -0.36 [ -0.51, -0.20 ]

Arnold 2008 188 -2.05 (2.06) 61 -1.04 (2.03) 7.1 % -0.49 [ -0.78, -0.20 ]
Mease 2008 190 -2.06 (2.2) 64 -1.4 (2.2) 7.5 % -0.30 [ -0.58, -0.01 ]
Pauer 2011 186 -0.96 (1.9) 62 -0.73 (1.9) 7.3 % -0.12 [ -0.41, 0.17 ]
Subtotal (95% CI) 564 187 21.9 % -0.30 [ -0.51, -0.09 ]

Heterogeneity: Tau2 = 0.01; Chi2 = 3.13, df = 2 (P = 0.21); I2 =36%
5 Pregabalin flexible 300 or 450 mg/d
Ohta 2012 250 -1.48 (1.9) 248 -1.03 (1.89) 19.5 % -0.24 [ -0.41, -0.06 ]
-2 -1 0 1 2
Pregabalin Placebo
(Continued . . . )

(. . .Continued)
Std. Std.
Mean Mean
Subtotal (95% CI) 250 248 19.5 % -0.24 [ -0.41, -0.06 ]
Total (95% CI) 2316 936 100.0 % -0.28 [ -0.35, -0.20 ]
Test for subgroup differences: Chi2 = 2.54, df = 4 (P = 0.64), I2 =0.0%
-2 -1 0 1 2
Pregabalin Placebo
Analysis 4.2. Comparison 4 Pregabalin versus placebo at end of treatment, Outcome 2 50% pain reduction.
Study or subgroup Pregabalin Placebo Risk Ratio Weight Risk Ratio


Crofford 2005 17/132 6/43 4.3 % 0.92 [ 0.39, 2.19 ]
Subtotal (95% CI) 132 43 4.3 % 0.92 [ 0.39, 2.19 ]

Total events: 17 (Pregabalin), 6 (Placebo)
Arnold 2008 44/183 9/61 7.5 % 1.63 [ 0.85, 3.14 ]
Crofford 2005 25/134 6/43 4.8 % 1.34 [ 0.59, 3.04 ]
Mease 2008 43/185 12/64 9.8 % 1.24 [ 0.70, 2.20 ]
Pauer 2011 33/184 6/61 4.8 % 1.82 [ 0.80, 4.14 ]
Subtotal (95% CI) 686 229 26.9 % 1.45 [ 1.03, 2.05 ]
0.01 0.1 1 10 100

Placebo Pregabalin
(Continued . . . )

(. . . Continued)
Arnold 2008 52/190 9/62 7.7 % 1.89 [ 0.99, 3.60 ]
Crofford 2005 38/132 6/43 5.2 % 2.06 [ 0.94, 4.54 ]
Mease 2008 43/183 11/63 9.0 % 1.35 [ 0.74, 2.45 ]
Pauer 2011 33/182 5/61 4.0 % 2.21 [ 0.90, 5.41 ]
Subtotal (95% CI) 687 229 26.0 % 1.75 [ 1.23, 2.49 ]

Arnold 2008 57/188 10/62 8.7 % 1.88 [ 1.02, 3.45 ]
Mease 2008 44/190 12/64 9.9 % 1.24 [ 0.70, 2.19 ]
Pauer 2011 28/186 6/62 4.6 % 1.56 [ 0.68, 3.58 ]
Subtotal (95% CI) 564 188 23.2 % 1.51 [ 1.04, 2.20 ]

5 Pregabalin flexible 300 mg/d or 450 mg/d
Ohta 2012 57/250 30/248 19.6 % 1.88 [ 1.26, 2.83 ]
Subtotal (95% CI) 250 248 19.6 % 1.88 [ 1.26, 2.83 ]

Total (95% CI) 2319 937 100.0 % 1.59 [ 1.33, 1.90 ]
0.01 0.1 1 10 100

Placebo Pregabalin

Analysis 4.3. Comparison 4 Pregabalin versus placebo at end of treatment, Outcome 3 Fatigue.
Outcome: 3 Fatigue
Std. Std.
Mean Mean

Crofford 2005 125 30.67 (10.6) 40 32.85 (10.6) 4.8 % -0.20 [ -0.56, 0.15 ]
Subtotal (95% CI) 125 40 4.8 % -0.20 [ -0.56, 0.15 ]

Arnold 2008 181 -4.25 (9.55) 60 -3.33 (9.55) 7.2 % -0.10 [ -0.39, 0.20 ]
Crofford 2005 126 29.37 (10.5) 41 32.85 (10.6) 4.9 % -0.33 [ -0.68, 0.03 ]
Mease 2008 185 -8.9 (11.8) 63 -7.1 (9.6) 7.5 % -0.16 [ -0.45, 0.13 ]
Pauer 2011 175 -2.83 (8.33) 61 -1.9 (8.39) 7.2 % -0.11 [ -0.40, 0.18 ]
Subtotal (95% CI) 667 225 26.7 % -0.16 [ -0.31, -0.01 ]

Arnold 2008 188 -4.74 (9.6) 61 -3.33 (9.55) 7.3 % -0.15 [ -0.44, 0.14 ]
Crofford 2005 125 29.41 (10.6) 41 32.85 (10.6) 4.9 % -0.32 [ -0.68, 0.03 ]
Mease 2008 183 -7.2 (11.3) 63 -7.1 (9.6) 7.5 % -0.01 [ -0.30, 0.28 ]
Pauer 2011 175 -3.32 (8.47) 61 -1.9 (8.39) 7.2 % -0.17 [ -0.46, 0.12 ]
Subtotal (95% CI) 671 226 26.8 % -0.15 [ -0.30, 0.01 ]

Arnold 2008 187 -4.83 (9.57) 60 -3.33 (9.55) 7.2 % -0.16 [ -0.45, 0.13 ]
Mease 2008 190 -7.6 (10.7) 64 -7.1 (9.6) 7.6 % -0.05 [ -0.33, 0.24 ]
Pauer 2011 181 -2.2 (8.34) 61 -1.9 (8.39) 7.3 % -0.04 [ -0.33, 0.25 ]
Subtotal (95% CI) 558 185 22.1 % -0.08 [ -0.25, 0.09 ]

Ohta 2012 250 -1.43 (2.21) 248 -0.94 (0.14) 19.6 % -0.31 [ -0.49, -0.14 ]
-1 -0.5 0 0.5 1
Pregabalin Placebo
(Continued . . . )

(. . .Continued)
Std. Std.
Mean Mean
Subtotal (95% CI) 250 248 19.6 % -0.31 [ -0.49, -0.14 ]
Total (95% CI) 2271 924 100.0 % -0.17 [ -0.25, -0.09 ]
-1 -0.5 0 0.5 1
Pregabalin Placebo
Analysis 4.4. Comparison 4 Pregabalin versus placebo at end of treatment, Outcome 4 Sleep problems.
Std. Std.
Mean Mean

Crofford 2005 123 45.66 (19.3) 40 54.16 (19.3) 4.9 % -0.44 [ -0.80, -0.08 ]
Subtotal (95% CI) 123 40 4.9 % -0.44 [ -0.80, -0.08 ]

Arnold 2008 183 -11.39 (18.8) 60 -6.65 (18.78) 7.3 % -0.25 [ -0.54, 0.04 ]
Crofford 2005 123 45.26 (19.2) 41 54 (19.3) 5.0 % -0.45 [ -0.81, -0.10 ]
Mease 2008 184 -19.14 (20.07) 62 -14.32 (26.1) 7.5 % -0.22 [ -0.51, 0.07 ]
Pauer 2011 183 -13.18 (24.1) 61 -5.99 (24.2) 7.4 % -0.30 [ -0.59, -0.01 ]
Subtotal (95% CI) 673 224 27.3 % -0.29 [ -0.44, -0.14 ]
-4 -2 0 2 4
Pregabalin Placebo
(Continued . . . )

(. . .Continued)
Std. Std.
Mean Mean
Arnold 2008 188 -12.85 (18.03) 60 -6.65 (18.78) 7.4 % -0.34 [ -0.63, -0.05 ]
Crofford 2005 122 40.44 (19.2) 40 54.16 (19.3) 4.8 % -0.71 [ -1.08, -0.34 ]
Mease 2008 183 -20.45 (20.16) 62 -14.32 (26.1) 7.5 % -0.28 [ -0.57, 0.01 ]
Pauer 2011 177 -19.26 (24.5) 61 -5.99 (24.2) 7.2 % -0.54 [ -0.84, -0.25 ]
Subtotal (95% CI) 670 223 26.9 % -0.45 [ -0.63, -0.27 ]

Arnold 2008 188 -15.09 (18.92) 60 -6.65 (18.78) 7.3 % -0.45 [ -0.74, -0.15 ]
Mease 2008 187 -19.52 (20.23) 63 -14.32 (26.1) 7.6 % -0.24 [ -0.52, 0.05 ]
Pauer 2011 185 -18.7 (24.2) 61 -5.99 (24.2) 7.3 % -0.52 [ -0.82, -0.23 ]
Subtotal (95% CI) 560 184 22.3 % -0.40 [ -0.57, -0.23 ]

Ohta 2012 249 -10.06 (15) 247 -7.07 (15.1) 18.6 % -0.20 [ -0.37, -0.02 ]
Subtotal (95% CI) 249 247 18.6 % -0.20 [ -0.37, -0.02 ]

Total (95% CI) 2275 918 100.0 % -0.35 [ -0.43, -0.27 ]
Test for subgroup differences: Chi2 = 4.99, df = 4 (P = 0.29), I2 =20%
-4 -2 0 2 4
Pregabalin Placebo

Analysis 4.5. Comparison 4 Pregabalin versus placebo at end of treatment, Outcome 5 Health-related
quality of life.
Std. Std.
Mean Mean

Arnold 2008 183 -10.7 (18.1) 61 -7.74 (18.1) 8.4 % -0.16 [ -0.45, 0.13 ]
Mease 2008 185 -16.15 (19.9) 64 -13.66 (19.8) 8.8 % -0.12 [ -0.41, 0.16 ]
Pauer 2011 184 -8.11 (17.6) 61 -6.94 (17.6) 8.5 % -0.07 [ -0.36, 0.22 ]
Subtotal (95% CI) 552 186 25.7 % -0.12 [ -0.28, 0.05 ]

Arnold 2008 190 -12.98 (18.1) 61 -7.74 (18.1) 8.5 % -0.29 [ -0.58, 0.00 ]
Mease 2008 183 -15.71 (19.9) 63 -13.66 (19.8) 8.7 % -0.10 [ -0.39, 0.18 ]
Pauer 2011 179 -12.79 (17.7) 61 -6.94 (17.6) 8.3 % -0.33 [ -0.62, -0.04 ]
Subtotal (95% CI) 552 185 25.5 % -0.24 [ -0.41, -0.07 ]

Arnold 2008 188 -13.08 (18.2) 61 -7.74 (18.1) 8.5 % -0.29 [ -0.58, 0.00 ]
Mease 2008 190 -14.88 (20) 64 -13.66 (19.8) 8.9 % -0.06 [ -0.34, 0.22 ]
Pauer 2011 186 -8.38 (17.6) 62 -6.94 (17.6) 8.6 % -0.08 [ -0.37, 0.21 ]
Subtotal (95% CI) 564 187 25.9 % -0.14 [ -0.31, 0.02 ]

Ohta 2012 250 -10.59 (16.92) 248 -7.26 (17) 22.9 % -0.20 [ -0.37, -0.02 ]
Subtotal (95% CI) 250 248 22.9 % -0.20 [ -0.37, -0.02 ]

Total (95% CI) 1918 806 100.0 % -0.17 [ -0.26, -0.09 ]
-1 -0.5 0 0.5 1
Pregabalin Placebo

Analysis 4.6. Comparison 4 Pregabalin versus placebo at end of treatment, Outcome 6 Withdrawal due to
adverse events.


Crofford 2005 11/132 3/43 2.9 % 1.19 [ 0.35, 4.08 ]
Subtotal (95% CI) 132 43 2.9 % 1.19 [ 0.35, 4.08 ]

Arnold 2008 31/183 6/61 6.5 % 1.72 [ 0.75, 3.93 ]
Crofford 2005 10/134 4/44 3.6 % 0.82 [ 0.27, 2.49 ]
Mease 2008 35/185 7/64 7.6 % 1.73 [ 0.81, 3.70 ]
Pauer 2011 35/184 7/62 7.7 % 1.68 [ 0.79, 3.60 ]
Subtotal (95% CI) 686 231 25.4 % 1.54 [ 1.02, 2.34 ]

Arnold 2008 43/190 7/62 7.9 % 2.00 [ 0.95, 4.22 ]
Crofford 2005 17/132 3/44 3.2 % 1.89 [ 0.58, 6.14 ]
Mease 2008 37/183 6/63 6.7 % 2.12 [ 0.94, 4.79 ]
Pauer 2011 36/182 6/61 6.7 % 2.01 [ 0.89, 4.54 ]
Subtotal (95% CI) 687 230 24.5 % 2.02 [ 1.32, 3.09 ]

Arnold 2008 50/188 7/62 8.1 % 2.36 [ 1.13, 4.92 ]
Mease 2008 62/190 7/64 8.3 % 2.98 [ 1.44, 6.18 ]
0.05 0.2 1 5 20
Placebo Pregabalin
(Continued . . . )

(. . . Continued)
Pauer 2011 48/186 7/62 8.1 % 2.29 [ 1.09, 4.79 ]
Subtotal (95% CI) 564 188 24.6 % 2.53 [ 1.65, 3.86 ]

Ohta 2012 34/248 34/250 22.6 % 1.01 [ 0.65, 1.57 ]
Subtotal (95% CI) 248 250 22.6 % 1.01 [ 0.65, 1.57 ]

Total (95% CI) 2317 942 100.0 % 1.68 [ 1.36, 2.07 ]
0.05 0.2 1 5 20
Placebo Pregabalin

Analysis 4.7. Comparison 4 Pregabalin versus placebo at end of treatment, Outcome 7 Serious adverse
events.
Outcome: 7 Serious adverse events


Arnold 2008 2/183 0/61 1.5 % 1.68 [ 0.08, 34.62 ]
Mease 2008 25/185 9/64 27.5 % 0.96 [ 0.47, 1.95 ]
Pauer 2011 2/184 1/61 2.4 % 0.66 [ 0.06, 7.19 ]
Subtotal (95% CI) 552 186 31.4 % 0.96 [ 0.50, 1.86 ]

Arnold 2008 2/190 1/62 2.4 % 0.65 [ 0.06, 7.07 ]
Mease 2008 22/183 8/63 24.0 % 0.95 [ 0.44, 2.02 ]
Pauer 2011 8/182 1/61 3.2 % 2.68 [ 0.34, 21.01 ]
Subtotal (95% CI) 555 186 29.6 % 1.03 [ 0.52, 2.03 ]

Arnold 2008 2/188 1/62 2.4 % 0.66 [ 0.06, 7.15 ]
Mease 2008 30/190 9/64 28.9 % 1.12 [ 0.56, 2.24 ]
Pauer 2011 4/186 2/62 4.9 % 0.67 [ 0.13, 3.55 ]
Subtotal (95% CI) 564 188 36.3 % 1.01 [ 0.55, 1.87 ]

Ohta 2012 3/250 1/248 2.7 % 2.98 [ 0.31, 28.42 ]
Subtotal (95% CI) 250 248 2.7 % 2.98 [ 0.31, 28.42 ]

Total (95% CI) 1921 808 100.0 % 1.03 [ 0.71, 1.49 ]
0.01 0.1 1 10 100

Placebo Pregabalin
(Continued . . . )

(. . . Continued)
0.01 0.1 1 10 100

Placebo Pregabalin
Analysis 4.8. Comparison 4 Pregabalin versus placebo at end of treatment, Outcome 8 Dizziness.


Crofford 2005 30/132 4/43 4.4 % 2.44 [ 0.91, 6.54 ]
Subtotal (95% CI) 132 43 4.4 % 2.44 [ 0.91, 6.54 ]

Arnold 2008 51/183 4/61 4.5 % 4.25 [ 1.60, 11.27 ]
Crofford 2005 42/134 5/44 5.7 % 2.76 [ 1.16, 6.53 ]
Mease 2008 60/185 5/64 5.7 % 4.15 [ 1.74, 9.88 ]
Pauer 2011 68/184 9/61 10.7 % 2.50 [ 1.33, 4.71 ]
Subtotal (95% CI) 686 230 26.5 % 3.11 [ 2.09, 4.65 ]

Arnold 2008 71/190 5/62 5.8 % 4.63 [ 1.96, 10.95 ]
0.01 0.1 1 10 100

Placebo Pregabalin
(Continued . . . )

(. . . Continued)
Crofford 2005 65/132 5/44 6.0 % 4.33 [ 1.86, 10.07 ]
Mease 2008 83/183 5/63 5.8 % 5.71 [ 2.43, 13.45 ]
Pauer 2011 76/182 9/61 10.8 % 2.83 [ 1.51, 5.30 ]
Subtotal (95% CI) 687 230 28.4 % 3.95 [ 2.68, 5.82 ]

Arnold 2008 79/188 5/61 5.8 % 5.13 [ 2.18, 12.07 ]
Mease 2008 91/190 6/64 7.1 % 5.11 [ 2.35, 11.10 ]
Pauer 2011 93/186 10/62 12.4 % 3.10 [ 1.73, 5.57 ]
Subtotal (95% CI) 564 187 25.3 % 4.00 [ 2.65, 6.03 ]

Ohta 2012 74/250 15/248 15.4 % 4.89 [ 2.89, 8.28 ]
Subtotal (95% CI) 250 248 15.4 % 4.89 [ 2.89, 8.28 ]

Total (95% CI) 2319 938 100.0 % 3.77 [ 3.06, 4.63 ]
0.01 0.1 1 10 100

Placebo Pregabalin

Analysis 4.9. Comparison 4 Pregabalin versus placebo at end of treatment, Outcome 9 30% pain reduction.


Crofford 2005 41/132 13/44 4.7 % 1.05 [ 0.62, 1.77 ]
Subtotal (95% CI) 132 44 4.7 % 1.05 [ 0.62, 1.77 ]

Arnold 2008 76/183 18/61 7.1 % 1.41 [ 0.92, 2.15 ]
Crofford 2005 51/134 14/44 5.4 % 1.20 [ 0.74, 1.94 ]
Mease 2008 80/185 22/64 9.0 % 1.26 [ 0.86, 1.83 ]
Pauer 2011 61/184 12/61 4.3 % 1.69 [ 0.98, 2.91 ]
Subtotal (95% CI) 686 230 25.8 % 1.35 [ 1.08, 1.68 ]

Arnold 2008 94/190 19/62 7.9 % 1.61 [ 1.08, 2.41 ]
Crofford 2005 64/132 14/44 5.8 % 1.52 [ 0.96, 2.43 ]
Mease 2008 79/183 22/63 9.0 % 1.24 [ 0.85, 1.80 ]
Pauer 2011 62/182 11/61 3.9 % 1.89 [ 1.07, 3.35 ]
Subtotal (95% CI) 687 230 26.7 % 1.49 [ 1.20, 1.85 ]

Arnold 2008 88/188 19/62 7.8 % 1.53 [ 1.02, 2.29 ]
Mease 2008 83/190 22/64 9.1 % 1.27 [ 0.87, 1.85 ]
Pauer 2011 48/186 12/62 4.0 % 1.33 [ 0.76, 2.34 ]
Subtotal (95% CI) 564 188 20.9 % 1.37 [ 1.07, 1.76 ]

0.05 0.2 1 5 20
Placebo Pregabalin
(Continued . . . )

(. . . Continued)
Ohta 2012 101/250 76/248 22.1 % 1.32 [ 1.04, 1.68 ]
Subtotal (95% CI) 250 248 22.1 % 1.32 [ 1.04, 1.68 ]

Total (95% CI) 2319 940 100.0 % 1.37 [ 1.22, 1.53 ]
0.05 0.2 1 5 20
Placebo Pregabalin

Analysis 4.10. Comparison 4 Pregabalin versus placebo at end of treatment, Outcome 10 Anxiety.
Outcome: 10 Anxiety
Std. Std.
Mean Mean

Crofford 2005 125 8.3 (4.4) 41 8 (4.3) 4.9 % 0.07 [ -0.28, 0.42 ]
Subtotal (95% CI) 125 41 4.9 % 0.07 [ -0.28, 0.42 ]

Arnold 2008 183 -1.03 (3.17) 61 -0.41 (3.24) 7.2 % -0.19 [ -0.48, 0.10 ]
Crofford 2005 127 8.6 (4.6) 42 8 (4.3) 5.0 % 0.13 [ -0.22, 0.48 ]
Mease 2008 185 -1.9 (3.7) 64 -1.7 (3.6) 7.5 % -0.05 [ -0.34, 0.23 ]
Pauer 2011 180 -0.44 (3.25) 61 -0.3 (3.37) 7.2 % -0.04 [ -0.33, 0.25 ]
Subtotal (95% CI) 675 228 26.9 % -0.05 [ -0.20, 0.10 ]

Arnold 2008 189 -0.91 (3.16) 61 -0.41 (3.24) 7.3 % -0.16 [ -0.45, 0.13 ]
Crofford 2005 126 7.5 (4.3) 42 8 (4.3) 5.0 % -0.12 [ -0.47, 0.23 ]
Mease 2008 183 -2.3 (3.7) 63 -1.7 (3.6) 7.4 % -0.16 [ -0.45, 0.12 ]
Pauer 2011 176 -0.81 (3.45) 60 -0.3 (3.37) 7.1 % -0.15 [ -0.44, 0.15 ]
Subtotal (95% CI) 674 226 26.7 % -0.15 [ -0.30, 0.00 ]

Arnold 2008 188 -1.19 (3.15) 61 -0.41 (3.24) 7.2 % -0.25 [ -0.53, 0.04 ]
Mease 2008 190 -1.9 (3.3) 64 -1.7 (3.6) 7.6 % -0.06 [ -0.34, 0.22 ]
Pauer 2011 185 -0.9 (3.4) 61 -0.3 (3.37) 7.2 % -0.18 [ -0.47, 0.11 ]
Subtotal (95% CI) 563 186 22.0 % -0.16 [ -0.32, 0.01 ]

Ohta 2012 249 -0.57 (2.84) 247 -0.09 (2.82) 19.5 % -0.17 [ -0.35, 0.01 ]
-2 -1 0 1 2
Pregabalin Placebo
(Continued . . . )

(. . .Continued)
Std. Std.
Mean Mean
Subtotal (95% CI) 249 247 19.5 % -0.17 [ -0.35, 0.01 ]
Total (95% CI) 2286 928 100.0 % -0.12 [ -0.20, -0.04 ]
-2 -1 0 1 2
Pregabalin Placebo
Analysis 4.11. Comparison 4 Pregabalin versus placebo at end of treatment, Outcome 11 Depression.
Std. Std.
Mean Mean

Crofford 2005 124 6.8 (3.8) 41 7.2 (4.4) 4.9 % -0.10 [ -0.45, 0.25 ]
Subtotal (95% CI) 124 41 4.9 % -0.10 [ -0.45, 0.25 ]

Arnold 2008 183 -0.39 (3.24) 61 -0.53 (3.24) 7.2 % 0.04 [ -0.25, 0.33 ]
Crofford 2005 126 7.5 (4.9) 42 7.2 (4.4) 5.0 % 0.06 [ -0.29, 0.41 ]
Mease 2008 185 -1.8 (3.8) 64 -1 (3.6) 7.5 % -0.21 [ -0.50, 0.07 ]
Pauer 2011 180 -0.34 (3.34) 61 -0.11 (3.24) 7.2 % -0.07 [ -0.36, 0.22 ]
Subtotal (95% CI) 674 228 26.9 % -0.05 [ -0.20, 0.10 ]
-2 -1 0 1 2
Pregabalin Placebo
(Continued . . . )

(. . .Continued)
Std. Std.
Mean Mean
Arnold 2008 189 -0.85 (3.3) 61 -0.53 (3.24) 7.3 % -0.10 [ -0.39, 0.19 ]
Crofford 2005 126 6.8 (4.3) 42 7.2 (4.4) 5.0 % -0.09 [ -0.44, 0.26 ]
Mease 2008 183 -1.6 (4.1) 63 -1 (3.6) 7.4 % -0.15 [ -0.44, 0.14 ]
Pauer 2011 176 -0.7 (3.31) 60 -0.11 (3.24) 7.0 % -0.18 [ -0.47, 0.11 ]
Subtotal (95% CI) 674 226 26.7 % -0.13 [ -0.28, 0.02 ]

Arnold 2008 188 -0.81 (3.3) 61 -0.53 (3.24) 7.3 % -0.08 [ -0.37, 0.20 ]
Mease 2008 190 -1.5 (3.5) 64 -1 (3.6) 7.5 % -0.14 [ -0.42, 0.14 ]
Pauer 2011 185 0.04 (3.26) 61 -0.11 (3.24) 7.2 % 0.05 [ -0.24, 0.34 ]
Subtotal (95% CI) 563 186 22.1 % -0.06 [ -0.23, 0.10 ]

Ohta 2012 249 -0.29 (3.16) 247 0 (3.14) 19.6 % -0.09 [ -0.27, 0.08 ]
Subtotal (95% CI) 249 247 19.6 % -0.09 [ -0.27, 0.08 ]

Total (95% CI) 2284 928 100.0 % -0.09 [ -0.16, -0.01 ]
-2 -1 0 1 2
Pregabalin Placebo

Analysis 4.12. Comparison 4 Pregabalin versus placebo at end of treatment, Outcome 12 Disability.
Std. Std.
Mean Mean

Crofford 2005 125 48.21 (18.23) 41 46.14 (18.22) 5.8 % 0.11 [ -0.24, 0.47 ]
Subtotal (95% CI) 125 41 5.8 % 0.11 [ -0.24, 0.47 ]

Arnold 2008 183 -5.79 (17.99) 61 -6.51 (17.94) 7.7 % 0.04 [ -0.25, 0.33 ]
Crofford 2005 126 48.66 (18.18) 42 46.14 (18.22) 5.9 % 0.14 [ -0.21, 0.49 ]
Mease 2008 185 54.1 (25.7) 64 52.6 (25.7) 7.9 % 0.06 [ -0.23, 0.34 ]
Pauer 2011 162 -5.3 (16.67) 56 -4.64 (17.16) 7.2 % -0.04 [ -0.34, 0.26 ]
Subtotal (95% CI) 656 223 28.8 % 0.04 [ -0.11, 0.20 ]

Arnold 2008 190 -9.2 (17.92) 61 -6.51 (18.94) 7.8 % -0.15 [ -0.44, 0.14 ]
Crofford 2005 127 51.22 (18.26) 42 46.14 (18.22) 5.9 % 0.28 [ -0.07, 0.63 ]
Mease 2008 183 54.2 (25) 63 52.6 (25.7) 7.9 % 0.06 [ -0.22, 0.35 ]
Pauer 2011 165 -6.63 (17.34) 57 -4.64 (17.16) 7.3 % -0.11 [ -0.42, 0.19 ]
Subtotal (95% CI) 665 223 28.8 % 0.00 [ -0.17, 0.18 ]

Arnold 2008 188 -8.69 (18.09) 61 -6.51 (18.94) 7.8 % -0.12 [ -0.41, 0.17 ]
Mease 2008 190 57.3 (25.5) 64 52.6 (25.7) 8.0 % 0.18 [ -0.10, 0.47 ]
Pauer 2011 155 -4.14 (16.31) 56 -4.64 (17.16) 7.2 % 0.03 [ -0.28, 0.34 ]
Subtotal (95% CI) 533 181 22.9 % 0.03 [ -0.14, 0.21 ]

Ohta 2012 250 -9.01 (14.7) 248 -4.72 (14.64) 13.6 % -0.29 [ -0.47, -0.12 ]
-4 -2 0 2 4
Pregabalin Placebo
(Continued . . . )

(. . .Continued)
Std. Std.
Mean Mean
Subtotal (95% CI) 250 248 13.6 % -0.29 [ -0.47, -0.12 ]
Total (95% CI) 2229 916 100.0 % -0.01 [ -0.11, 0.09 ]
-4 -2 0 2 4
Pregabalin Placebo
Analysis 4.13. Comparison 4 Pregabalin versus placebo at end of treatment, Outcome 13 Patient Global
Impression of Change ’much’ or ’very much’ improved.
Outcome: 13 Patient Global Impression of Change ’much’ or ’very much’ improved


Crofford 2005 44/132 11/43 4.4 % 1.30 [ 0.74, 2.29 ]
Subtotal (95% CI) 132 43 4.4 % 1.30 [ 0.74, 2.29 ]

Arnold 2008 51/160 13/55 5.0 % 1.35 [ 0.80, 2.28 ]
Crofford 2005 55/134 11/44 4.6 % 1.64 [ 0.95, 2.85 ]
Mease 2008 76/185 21/63 9.1 % 1.23 [ 0.83, 1.82 ]
Pauer 2011 58/184 19/61 7.5 % 1.01 [ 0.66, 1.56 ]
0.01 0.1 1 10 100

Placebo Pregabalin
(Continued . . . )

(. . . Continued)
Subtotal (95% CI) 663 223 26.3 % 1.25 [ 0.99, 1.57 ]
Arnold 2008 80/171 13/56 5.5 % 2.02 [ 1.22, 3.33 ]
Crofford 2005 70/132 11/44 4.8 % 2.12 [ 1.24, 3.63 ]
Mease 2008 71/183 20/63 8.5 % 1.22 [ 0.81, 1.83 ]
Pauer 2011 66/182 18/61 7.4 % 1.23 [ 0.80, 1.89 ]
Subtotal (95% CI) 668 224 26.2 % 1.54 [ 1.15, 2.06 ]

Arnold 2008 78/177 13/55 5.5 % 1.86 [ 1.13, 3.08 ]
Mease 2008 81/190 21/64 9.2 % 1.30 [ 0.88, 1.91 ]
Pauer 2011 66/186 19/62 7.8 % 1.16 [ 0.76, 1.77 ]
Subtotal (95% CI) 553 181 22.5 % 1.37 [ 1.06, 1.76 ]

Ohta 2012 96/249 66/247 20.6 % 1.44 [ 1.11, 1.87 ]
Subtotal (95% CI) 249 247 20.6 % 1.44 [ 1.11, 1.87 ]

Total (95% CI) 2265 918 100.0 % 1.38 [ 1.23, 1.55 ]
0.01 0.1 1 10 100

Placebo Pregabalin

APPENDICES
Appendix 1. MEDLINE search strategy
Search Query Items found
#1 Search anticonvulsants 128,656
#2 Search anticonvulsant*[tiab] OR anti convulsant*[tiab] 34,452

OR anti-convulsant*[tiab] OR antiepileptic*[tiab] OR
anti epileptic*[tiab] OR anti-epileptic*[tiab]
#3 Search carbamazepine 13,816
#4 Search Carbamazepine[tiab] 11,543

or Amizepin[tiab] or Amizepine[tiab] or Atretol[tiab] or
Biston[tiab] or Calepsin[tiab] or Carbamazepin[tiab] or
Carbategral[tiab] or Carbatrol[tiab] or Convuline[tiab]
or Epimax[tiab] or Epitol[tiab] or Equetro[tiab] or Fin-
lepsin[tiab] or Lexin[tiab] or Mazepine[tiab] or Neu-
rotol[tiab] or Neurotop[tiab] or Servimazepin[tiab] or
Sirtal[tiab] or Tegral[tiab] or Tegretal[tiab] or Tegretol
[tiab]or Tegrital[tiab] or Telesmin[tiab] or Teril[tiab] or
Timonil[tiab]
#5 Search Oxcarbazepine[tiab] or Apydan[tiab] or Oxocarba- 1297

mazepine[tiab] or Oxocarbazepine[tiab] or Timox[tiab]
or Trileptal[tiab]
#6 Search Felbamat[tiab] or Felbatol[tiab] or Taloxa[tiab] 15
#7 Search Gabapentin[tiab] or Neurontin[tiab] or Neuro- 3835

tonin[tiab]
#8 Search Levetiracetam[tiab] or Keppra[tiab] 1845
#9 Search Pregabalin[tiab] or Lyrica[tiab] 1502
#10 Search phenytoin 16,173
#11 Search Phenytoin[tiab] or Alepsin[tiab] or Aleviatin[tiab] 10,425

or Antilepsin[tiab] or Antisacer[tiab] or Cansoin[tiab] or
Citrullamon[tiab] or Comital[tiab] or Danten[tiab] or
Dantoin[tiab] or Denyl[tiab] or Difetoin[tiab] or Differ-
enin[tiab] or Difhydan[tiab] or Di Hydan[tiab] or Di-
hydan[tiab] or Dilantin[tiab] or Dintoin[tiab] or Din-
toina[tiab] or Diphantoin[tiab] or Diphantoine[tiab] or
Diphantoin[tiab] or Diphedal[tiab] or Diphedan[tiab] or
Diphenin[tiab] or Diphenine[tiab] or Diphentoin[tiab]

(Continued)
or Diphenylan[tiab] or Diphenytoin[tiab] or Ekko[tiab]

or Epanutin[tiab] or Epelin[tiab] or Epilantin[tiab] or
Eptal[tiab] or Eptoin[tiab] or Fenantoin[tiab] or Feni-
toin[tiab] or Fenytoin[tiab] or Fenytoine[tiab] or Hidan-
tal[tiab] or Hydantin[tiab] or Hydantinal [tiab]or Hydan-
toinal[tiab] or Idantoin[tiab] or Lepitoin[tiab] or Mine-
toin[tiab] or Neosidantoina[tiab] or Phenhydan[tiab] or
Phenhydane[tiab] or Phenybin[tiab] or Phenydan[tiab]
or Phenydantin[tiab] or Phenytoine[tiab] or Pheny-
toin[tiab] or Phenytoinum[tiab] or Phenytonium[tiab]
or Sanepil[tiab] or Sodantoin[tiab] or Sodanton[tiab] or
Solantoin[tiab] or Solantyl[tiab] or Tacosal[tiab] or Zen-
tropil[tiab]
#12 Search lacosamide[tiab] or erlosamide[tiab] or vim- 308

pat[tiab]
#13 Search Lamotrigine[tiab] or Labileno[tiab] or Lamic- 3651

tal[tiab]
#14 Search valproic acid 11,669
#15 Search Sodium[tiab] valproate[tiab] or Alpha Propy- 7647

lvalerate[tiab] or Alpha Propylvaleric Acid[tiab] or
Apilepsin[tiab] or Convulex[tiab] or Depacon[tiab] or
Depakene[tiab] or Depakin[tiab] or Depakine[tiab] or
Deprakine[tiab] or Dipropylacetate[tiab] or Dipropy-
lacetatic Acid[tiab] or Dipropyl Acetic Acid[tiab]
or Dipropylacetic Acid[tiab] or Diprosin[tiab] or
Epilim[tiab] or Ergenyl[tiab] or Everiden[tiab] or
Goilim[tiab] or Labazene[tiab] or Leptilan[tiab] or Lep-
tilanil[tiab] or Mylproin[tiab] or Myproic Acid[tiab]
or Orfiril[tiab] or Orlept[tiab] or Propymal[tiab] or
Valerin[tiab] or Valparin[tiab] or Valpro[tiab] or Val-
proate[tiab] or Valproate Sodium[tiab] or Vupral[tiab]
#16 Search Tiagabin[tiab] or Gabitril[tiab] 29
#17 Search Topiramate[tiab] or Epitomax[tiab] or Topa- 3056

max[tiab] or Topimax[tiab]
#18 Search 2933

Clonazepam[tiab] or Clonex[tiab] or Klonopin[tiab] or
Paxam[tiab] or Kriadex[tiab] or Ravotril[tiab] or Riva-
tril[tiab] or Rivotril[tiab]
#19 Search ((((((((((((((((((#2) OR #3) OR #4) OR #5) OR # 144,982

6) OR #7) OR #8) OR #9) OR #10) OR #11) OR #12)
OR #13) OR #14) OR #15) OR #16) OR #17) OR #18)

(Continued)
OR #1)
#20 Search Fibromialgia OR Fibrositis OR FMS 12,163
#21 Search fibromyalgi* 7538
#22 Search (#20 or #21) 12,180
#23 Search randomized controlled trial[pt] OR controlled 3,215,866

clinical trial[pt] OR randomized[tiab] OR placebo[tiab]
OR drug therapy[sh] OR randomly[tiab] OR trial[tiab]
OR groups[tiab]
#24 Search animals[mh] NOT humans[mh] 3,811,701
#25 Search (#23 not #24) 2,759,538
#26 Search (#19 AND #22 AND #25) 224
Appendix 2. CENTRAL search strategy
ID Search Hits
#1 (anticonvulsants):ti,ab,kw or (Anti convulsant$ or anticonvul- 3563

sant$ or anti-convulsant$ or anti epileptic$ or antiepileptic$
or anti-epileptic$):ti,ab,kw or (Carbamazepine or Amizepin or
Amizepine or Atretol or Biston or Calepsin or Carbamazepin
or Carbategral or Carbatrol or Convuline):ti,ab,kw or (Epi-
max or Epitol or Equetro or Finlepsin or Lexin or Mazepine
or Neurotol or Neurotop or Servimazepin or Sirtal or Tegral
or Tegretal or Tegretol or Tegrital or Telesmin or Teril or Ti-
monil):ti,ab,kw in Trials
#2 MeSH descriptor Anticonvulsants explode all trees 1919
#3 MeSH descriptor Carbamazepine explode all trees 699
#4 (Oxcarbazepine or Apydan or Oxocarbamazepine or Oxocar- 1323

bazepine or Timox or Trileptal):ti,ab,kw or (Clonazepam or
Clonex or Klonopin or Paxam or Kriadex or Ravotril or Riva-
tril or Rivotril):ti,ab,kw or (Felbamat or Felbatol or Taloxa):ti,
ab,kw or (Gabapentin or Neurontin or Neurotonin):ti,ab,kw
or (Levetiracetam or Keppra):ti,ab,kw in Trials

(Continued)
#5 (Pregabalin or Lyrica):ti,ab,kw or (Phenytoin or Alepsin or 1258

Aleviatin or Antilepsin or Antisacer):ti,ab,kw or (Cansoin or
Citrullamon or Comital or Danten or Dantoin or Denyl or
Difetoin or Differenin or Difhydan ):ti,ab,kw or (Di Hydan or
Dihydan or Dilantin or Dintoin or Dintoina or Diphantoin
or Diphantoine or Diphantoin or Diphedal or Diphedan or
Diphenin or Diphenine or Diphentoin):ti,ab,kw or (Dipheny-
lan or Diphenytoin or Ekko or Epanutin or Epelin or Epi-
lantin or Eptal or Eptoin or Fenantoin or Fenitoin or Fenytoin
or Fenytoine):ti,ab,kw in Trials
#6 (Hidantal or Hydantin or Hydantinal or Hydantoinal or Idan- 1477

toin or Lepitoin or Minetoin or Neosidantoina ):ti,ab,kw
or (Phenhydan or Phenhydane or Phenybin or Phenydan or
Phenydantin or Phenytoine or Phenytoin ):ti,ab,kw or (Pheny-
toinum or Phenytonium or Sanepil or Sodantoin or Sodanton
or Solantoin or Solantyl or Tacosal or Zentropil):ti,ab,kw or
(lacosamide or erlosamide or vimpat):ti,ab,kw or (Lamotrigine
or Labileno or Lamictal):ti,ab,kw in Trials
#7 MeSH descriptor Phenytoin explode all trees 500
#8 (Valproic acid):ti,ab,kw or (Sodium valproate or Alpha Propy- 1154

lvalerate or Alpha Propylvaleric Acid or Apilepsin or Con-
vulex or Depacon or Depakene or Depakin or Depakine
or Deprakine ):ti,ab,kw or (Dipropylacetate or Dipropylac-
etatic Acid or Dipropyl Acetic Acid or Dipropylacetic Acid
or Diprosin or Epilim or Ergenyl or Everiden ):ti,ab,kw or
(Goilim or Labazene or Leptilan or Leptilanil or Mylproin or
Myproic Acid or Orfiril or Orlept ):ti,ab,kw or (Propymal or
Valerin or Valparin or Valpro or Valproate or Valproate Sodium
or Vupral):ti,ab,kw in Trials
#9 MeSH descriptor Valproic Acid explode all trees 648
#10 (Tiagabin or Gabitril):ti,ab,kw or (Topiramate or Epitomax or 780

Topamax or Topimax):ti,ab,kw or (Vigabatrin or Sabril):ti,ab,
kw in Trials
#11 (fibromyalgia):ti,ab,kw or (fibromyalgi$):ti,ab,kw or (fibrosi- 987

tis):ti,ab,kw or (fms):ti,ab,kw in Trials
#12 MeSH descriptor Fibromyalgia explode all trees 565
#13 (randomized controlled trial):pt or (controlled tiral):pt or (ran- 381,667

dom allocation):ti,ab,kw or (double blind):ti,ab,kw or (single
blind):ti,ab,kw in Trials

(Continued)
#14 (clinical trial):pt and (pacebo$):ti,ab,kw and (random):ti,ab, 1

kw and (clinical trial):ti,ab,kw and (randomized controlled
trial or controlled trial):ti,ab,kw in Trials
#15 (placebo$):ti,ab,kw or (random$):ti,ab,kw or (clinical trial):ti, 455,068

ab,kw or (clinical trial):pt or (randomized controlled trial or
controlled trial):ti,ab,kw
#16 (animal):ti,ab,kw in Trials 12,551
#17 (human):ti,ab,kw in Trials 462,550
#18 (#1 OR #2 OR #3 OR #4 OR #5 OR #6 OR #7 OR #8 OR 6177

#9 OR #10)
#19 (#11 OR #12) 987
#20 (#13 OR #14 OR #15) 517,597
#21 (#17 AND NOT #16) 450,301
#22 (#18 AND #19 AND #20 AND #21) 32
Appendix 3. PsycInfo search strategy
Searches Results
1 (Anti convulsant$ or anticonvulsant$ or anti-convulsant$ or 7859

anti epileptic$ or antiepileptic$ or anti-epileptic$).ab. or (Anti
convulsant$ or anticonvulsant$ or anti-convulsant$ or anti
epileptic$ or antiepileptic$ or anti-epileptic$).ti. or (Anti con-
vulsant$ or anticonvulsant$ or anti-convulsant$ or anti epilep-
tic$ or antiepileptic$ or anti-epileptic$).id. or anticonvulsants.
ab. or anticonvulsants.ti. or anticonvulsants.id. or anticonvul-
sants.sh. or (Anti convulsant$ or anticonvulsant$ or anti-con-
vulsant$ or anti epileptic$ or antiepileptic$ or anti-epileptic$)
.sh
2 anticonvulsants.ab. or anticonvulsants.ti. or anticonvulsants. 1603

id. or anticonvulsants.sh
3 (Carbamazepine or Amizepin or Amizepine or Atretol or Bis- 2925

ton or Calepsin or Carbamazepin or Carbategral or Carba-
trol or Convuline or Epimax or Epitol or Equetro or Finlepsin
or Lexin or Mazepine).ab. or (Carbamazepine or Amizepin or
Amizepine or Atretol or Biston or Calepsin or Carbamazepin

(Continued)
or Carbategral or Carbatrol or Convuline or Epimax or Epitol

or Equetro or Finlepsin or Lexin or Mazepine).ti. or (Carba-
mazepine or Amizepin or Amizepine or Atretol or Biston or
Calepsin or Carbamazepin or Carbategral or Carbatrol or Con-
vuline or Epimax or Epitol or Equetro or Finlepsin or Lexin or
Mazepine).id. or (Carbamazepine or Amizepin or Amizepine
or Atretol or Biston or Calepsin or Carbamazepin or Carbate-
gral or Carbatrol or Convuline or Epimax or Epitol or Equetro
or Finlepsin or Lexin or Mazepine).sh
4 (Neurotol or Neurotop or Servimazepin or Sirtal or Tegral or 51

Tegretal or Tegretol or Tegrital or Telesmin or Teril or Timonil)
.ab. or (Neurotol or Neurotop or Servimazepin or Sirtal or
Tegral or Tegretal or Tegretol or Tegrital or Telesmin or Teril or
Timonil).ti. or (Neurotol or Neurotop or Servimazepin or Sirtal
or Tegral or Tegretal or Tegretol or Tegrital or Telesmin or Teril
or Timonil).id. or (Neurotol or Neurotop or Servimazepin or
Sirtal or Tegral or Tegretal or Tegretol or Tegrital or Telesmin
or Teril or Timonil).sh
5 (Clonazepam or Clonex or Klonopin or Paxam or Kriadex or 914

Ravotril or Rivatril or Rivotril).ab. or (Clonazepam or Clonex
or Klonopin or Paxam or Kriadex or Ravotril or Rivatril or Riv-
otril).ti. or (Clonazepam or Clonex or Klonopin or Paxam or
Kriadex or Ravotril or Rivatril or Rivotril).id. or (Clonazepam
or Clonex or Klonopin or Paxam or Kriadex or Ravotril or Ri-
vatril or Rivotril).sh
6 (Oxcarbazepine or Apydan or Oxocarbamazepine or Oxo- 436

carbazepine or Timox or Trileptal).ab. or (Oxcarbazepine or
Apydan or Oxocarbamazepine or Oxocarbazepine or Timox
or Trileptal).ti. or (Oxcarbazepine or Apydan or Oxocarba-
mazepine or Oxocarbazepine or Timox or Trileptal).id. or
(Oxcarbazepine or Apydan or Oxocarbamazepine or Oxocar-
bazepine or Timox or Trileptal).sh
7 (Felbamat or Felbatol or Taloxa).ab. or (Felbamat or Felbatol or 2

Taloxa).ti. or (Felbamat or Felbatol or Taloxa).id. or (Felbamat
or Felbatol or Taloxa).sh
8 (Gabapentin or Neurontin or Neurotonin).ab. or (Gabapentin 996

or Neurontin or Neurotonin).ti. or (Gabapentin or Neuron-
tin or Neurotonin).id. or (Gabapentin or Neurontin or Neu-
rotonin).sh
9 (Levetiracetam or Keppra).ab. or (Levetiracetam or Keppra).ti. 642

or (Levetiracetam or Keppra).id. or (Levetiracetam or Keppra)
.sh

(Continued)
10 (Pregabalin or Lyrica).ab. or (Pregabalin or Lyrica).ti. or (Pre- 459

gabalin or Lyrica).id. or (Pregabalin or Lyrica).sh
11 (Phenytoin or Alepsin or Aleviatin or Antilepsin or Antisacer 882

or Cansoin or Citrullamon or Comital or Danten or Dan-
toin or Denyl or Difetoin or Differenin or Difhydan).ab. or
(Phenytoin or Alepsin or Aleviatin or Antilepsin or Antisacer or
Cansoin or Citrullamon or Comital or Danten or Dantoin or
Denyl or Difetoin or Differenin or Difhydan).ti. or (Phenytoin
or Alepsin or Aleviatin or Antilepsin or Antisacer or Cansoin
or Citrullamon or Comital or Danten or Dantoin or Denyl
or Difetoin or Differenin or Difhydan).id. or (Phenytoin or
Alepsin or Aleviatin or Antilepsin or Antisacer or Cansoin or
Citrullamon or Comital or Danten or Dantoin or Denyl or
Difetoin or Differenin or Difhydan).sh
12 (Di Hydan or Dihydan or Dilantin or Dintoin or Dintoina 82

or Diphantoin or Diphantoine or Diphantoin or Diphedal or
Diphedan or Diphenin or Diphenine or Diphentoin).ab. or
(Di Hydan or Dihydan or Dilantin or Dintoin or Dintoina
Diphedan or Diphenin or Diphenine or Diphentoin).ti. or
Diphedan or Diphenin or Diphenine or Diphentoin).id. or
Diphedan or Diphenin or Diphenine or Diphentoin).sh
13 (Diphenylan or Diphenytoin or Ekko or Epanutin or Epelin or 1

Epilantin or Eptal or Eptoin or Fenantoin or Fenitoin or Feny-
toin or Fenytoine).ab. or (Diphenylan or Diphenytoin or Ekko
or Epanutin or Epelin or Epilantin or Eptal or Eptoin or Fenan-
toin or Fenitoin or Fenytoin or Fenytoine).ti. or (Diphenylan
or Diphenytoin or Ekko or Epanutin or Epelin or Epilantin or
Eptal or Eptoin or Fenantoin or Fenitoin or Fenytoin or Feny-
toine).id. or (Diphenylan or Diphenytoin or Ekko or Epanutin
or Epelin or Epilantin or Eptal or Eptoin or Fenantoin or Fen-
itoin or Fenytoin or Fenytoine).sh
14 (Hidantal or Hydantin or Hydantinal or Hydantoinal or Idan- 0

toin or Lepitoin or Minetoin or Neosidantoina).ab. or (Hi-
dantal or Hydantin or Hydantinal or Hydantoinal or Idantoin
or Lepitoin or Minetoin or Neosidantoina).ti. or (Hidantal or
Hydantin or Hydantinal or Hydantoinal or Idantoin or Lep-
itoin or Minetoin or Neosidantoina).id. or (Hidantal or Hy-
dantin or Hydantinal or Hydantoinal or Idantoin or Lepitoin
or Minetoin or Neosidantoina).sh

(Continued)
15 (Phenhydan or Phenhydane or Phenybin or Phenydan or 883

Phenydantin or Phenytoine or Phenytoin).ab. or (Phenhydan
or Phenhydane or Phenybin or Phenydan or Phenydantin or
Phenytoine or Phenytoin).ti. or (Phenhydan or Phenhydane
or Phenybin or Phenydan or Phenydantin or Phenytoine or
Phenytoin).id. or (Phenhydan or Phenhydane or Phenybin or
Phenydan or Phenydantin or Phenytoine or Phenytoin).sh
16 (Phenytoinum or Phenytonium or Sanepil or Sodantoin or 1

Sodanton or Solantoin or Solantyl or Tacosal or Zentropil).ab.
or (Phenytoinum or Phenytonium or Sanepil or Sodantoin or
Sodanton or Solantoin or Solantyl or Tacosal or Zentropil).ti.
Sodanton or Solantoin or Solantyl or Tacosal or Zentropil).id.
Sodanton or Solantoin or Solantyl or Tacosal or Zentropil).sh
17 (lacosamide or erlosamide or vimpat).ab. or (lacosamide or er- 88

losamide or vimpat).ti. or (lacosamide or erlosamide or vimpat)
.id. or (lacosamide or erlosamide or vimpat).sh
18 (Lamotrigine or Labileno or Lamictal).ab. or (Lamotrigine or 1472

Labileno or Lamictal).ti. or (Lamotrigine or Labileno or Lam-
ictal).id. or (Lamotrigine or Labileno or Lamictal).sh
19 Valproic acid.ab. or Valproic acid.ti. or Valproic acid.id. or Val- 1856

proic acid.sh
20 (Sodium valproate or Alpha Propylvalerate or Alpha Propylva- 523

leric Acid or Apilepsin or Convulex or Depacon or Depakene
or Depakin or Depakine or Deprakine).ab. or (Sodium val-
proate or Alpha Propylvalerate or Alpha Propylvaleric Acid or
Apilepsin or Convulex or Depacon or Depakene or Depakin
or Depakine or Deprakine).ti. or (Sodium valproate or Alpha
Propylvalerate or Alpha Propylvaleric Acid or Apilepsin or Con-
vulex or Depacon or Depakene or Depakin or Depakine or
Deprakine).id. or (Sodium valproate or Alpha Propylvalerate
or Alpha Propylvaleric Acid or Apilepsin or Convulex or De-
pacon or Depakene or Depakin or Depakine or Deprakine).sh
21 (Dipropylacetate or Dipropylacetatic Acid or Dipropyl Acetic 34

Acid or Dipropylacetic Acid or Diprosin or Epilim or Ergenyl
or Everiden).ab. or (Dipropylacetate or Dipropylacetatic Acid
or Dipropyl Acetic Acid or Dipropylacetic Acid or Diprosin
or Epilim or Ergenyl or Everiden).ti. or (Dipropylacetate or
Dipropylacetatic Acid or Dipropyl Acetic Acid or Dipropy-
lacetic Acid or Diprosin or Epilim or Ergenyl or Everiden).
id. or (Dipropylacetate or Dipropylacetatic Acid or Dipropyl

(Continued)
Acetic Acid or Dipropylacetic Acid or Diprosin or Epilim or

Ergenyl or Everiden).sh
22 (Goilim or Labazene or Leptilan or Leptilanil or Mylproin or 0

Myproic Acid or Orfiril or Orlept).ab. or (Goilim or Labazene
or Leptilan or Leptilanil or Mylproin or Myproic Acid or Orfiril
or Orlept).ti. or (Goilim or Labazene or Leptilan or Leptilanil or
Mylproin or Myproic Acid or Orfiril or Orlept).id. or (Goilim
or Labazene or Leptilan or Leptilanil or Mylproin or Myproic
Acid or Orfiril or Orlept).sh
23 (Propymal or Valerin or Valparin or Valpro or Valproate or 2326

Valproate Sodium or Vupral).ab. or (Propymal or Valerin or
Valparin or Valpro or Valproate or Valproate Sodium or Vupral)
.ti. or (Propymal or Valerin or Valparin or Valpro or Valproate
or Valproate Sodium or Vupral).id. or (Propymal or Valerin or
Valparin or Valpro or Valproate or Valproate Sodium or Vupral)
.sh
24 (Tiagabin or Gabitril).ab. or (Tiagabin or Gabitril).ti. or 4

(Tiagabin or Gabitril).id. or (Tiagabin or Gabitril).sh
25 (Topiramate or Epitomax or Topamax or Topimax).ab. or (Top- 1216

iramate or Epitomax or Topamax or Topimax).ti. or (Topira-
mate or Epitomax or Topamax or Topimax).id. or (Topiramate
or Epitomax or Topamax or Topimax).sh
26 (Vigabatrin or Sabril).ab. or (Vigabatrin or Sabril).ti. or (Viga- 245

batrin or Sabril).id. or (Vigabatrin or Sabril).sh
27 fibromyalgia.ab. or fibromyalgia.ti. or fibromyalgia.id. or fi- 2097

bromyalgia.sh
28 fibrositis.ab. or fibrositis.ti. or fibrositis.id. or fibrositis.sh 39
29 fms.ab. or fms.ti. or fms.id. or fms.sh. 599
30 randomized controlled trial.ab. or randomized controlled trial. 7360

ti. or randomized controlled trial.id. or randomized controlled
trial.pt
31 controlled clinical trial.ab. or controlled clinical trial.ti. or con- 909

trolled clinical trial.id. or controlled clinical trial.pt
32 double blind.ab. or double blind.ti. or single blind.ab. or single 18,096

blind.ti
33 placebo.ab. or placebo.ti. or random$.ab. or random$.ti. 139,111

(Continued)
34 1 or 2 or 3 or 4 or 5 or 6 or 7 or 8 or 9 or 10 or 11 or 12 or 13 14,709
or 14 or 15 or 16 or 17 or 18 or 19 or 20 or 21 or 22 or 23 or
24 or 25 or 26
35 27 or 28 or 29 2366
36 30 or 31 or 32 or 33 142,181
37 34 and 35 and 36 26
Appendix 4. Scopus search strategy

1
(TITLE-ABS-KEY(anticonvulsants/) OR TITLE-ABS-KEY(anti convulsant$ OR anticonvulsant$ OR anti-convulsant$ OR anti
epileptic$ OR antiepileptic$ OR anti-epileptic$))
59.068
2
(TITLE-ABS-KEY(anticonvulsants) OR TITLE-ABS-KEY(anti convulsant$ OR anticonvulsant$ OR anti-convulsant$ OR anti epilep-
tic$ OR antiepileptic$ OR anti-epileptic$))
59.068
3
(TITLE-ABS-KEY(carbamazepine) OR TITLE-ABS-KEY(carbamazepine OR amizepin OR amizepine OR atretol OR biston OR
calepsin OR carbamazepin OR carbategral OR carbatrol OR convuline OR epimax) OR TITLE-ABS-KEY(epitol OR equetro OR
finlepsin OR lexin OR mazepine OR neurotol OR neurotop OR servimazepin OR sirtal OR tegral OR tegretal OR tegretol OR tegrital
OR telesmin OR teril OR timonil))
51.288
4
(TITLE-ABS-KEY(oxcarbazepine OR apydan OR oxocarbamazepine OR oxocarbazepine OR timox OR trileptal) OR TITLE-ABS-
KEY(clonazepam OR clonex OR klonopin OR paxam OR kriadex OR ravotril OR rivatril OR rivotril))
24.960
5
(TITLE-ABS-KEY(felbamat OR felbatol OR taloxa) OR TITLE-ABS-KEY(gabapentin OR neurontin OR neurotonin) OR TITLE-
ABS-KEY(levetiracetam OR keppra) OR TITLE-ABS-KEY(pregabalin OR lyrica))
23.281
6
(TITLE-ABS-KEY(phenytoin OR alepsin OR aleviatin OR antilepsin OR antisacer OR cansoin OR citrullamon OR comital OR
danten OR dantoin OR denyl OR difetoin OR differenin OR difhydan OR di hydan OR dihydan OR dilantin OR dintoin OR
dintoina OR diphantoin OR diphantoine) OR TITLE-ABS-KEY(fenantoin OR fenitoin OR fenytoin OR fenytoine OR hidantal OR
hydantin OR hydantinal OR hydantoinal OR idantoin OR lepitoin OR minetoin OR neosidantoina OR phenhydan OR phenhydane
OR phenybin OR phenydan OR phenydantin OR phenytoine OR phenytoin OR phenyto))
54.875
7
(TITLE-ABS-KEY(lacosamide OR erlosamide OR vimpat) OR TITLE-ABS-KEY(lamotrigine OR labileno OR lamictal))
16.366
8
(TITLE-ABS-KEY(valproic acid) OR TITLE-ABS-KEY(sodium valproate OR alpha propylvalerate OR alpha propylvaleric acid OR
apilepsin OR convulex OR depacon OR depakene OR depakin OR depakine OR deprakine OR dipropylacetate OR dipropylacetatic
acid OR dipropyl acetic acid OR dipropylacetic acid OR diprosin) OR TITLE-ABS-KEY(epilim OR ergenyl OR everiden OR goilim
OR labazene OR leptilan OR leptilanil OR mylproin OR myproic acid OR orfiril OR orlept OR propymal OR valerin OR valparin
OR valpro OR valproate OR valproate sodium OR vupral))
43.266
9
(TITLE-ABS-KEY(tiagabin OR gabitril) OR TITLE-ABS-KEY(topiramate OR epitomax OR topamax OR topimax) OR TITLE-
ABS-KEY(vigabatrin OR sabril))
17.274
10
(TITLE-ABS-KEY(fibromyalgia) OR TITLE-ABS-KEY(fibrositis) OR TITLE-ABS-KEY(fms))
22.441
11
(TITLE-ABS-KEY(randomized controlled trial) OR TITLE-ABS-KEY(controlled trial) OR TITLE-ABS-KEY(placebo) OR TITLE-
ABS-KEY(single blind) OR TITLE-ABS-KEY(double blind))
901.308
12
#1 OR #2 OR #3 OR #4 OR #5 OR #6 OR #7 OR #8 OR #9
((TITLE-ABS-KEY(anticonvulsants/) OR TITLE-ABS-KEY(anti convulsant$ OR anticonvulsant$ OR anti-convulsant$ OR anti
epileptic$ OR antiepileptic$ OR anti-epileptic$))) OR ((TITLE-ABS-KEY(anticonvulsants) OR TITLE-ABS-KEY(anti convul-
sant$ OR anticonvulsant$ OR anti-convulsant$ OR anti epileptic$ OR antiepileptic$ OR anti-epileptic$))) OR ((TITLE-ABS-
KEY(carbamazepine) OR TITLE-ABS-KEY(carbamazepine OR amizepin OR amizepine OR atretol OR biston OR calepsin OR car-
bamazepin OR carbategral OR carbatrol OR convuline OR epimax) OR TITLE-ABS-KEY(epitol OR equetro OR finlepsin OR lexin
OR mazepine OR neurotol OR neurotop OR servimazepin OR sirtal OR tegral OR tegretal OR tegretol OR tegrital OR telesmin
OR teril OR timonil))) OR ((TITLE-ABS-KEY(oxcarbazepine OR apydan OR oxocarbamazepine OR oxocarbazepine OR timox
OR trileptal) OR TITLE-ABS-KEY(clonazepam OR clonex OR klonopin OR paxam OR kriadex OR ravotril OR rivatril OR riv-
otril))) OR ((TITLE-ABS-KEY(felbamat OR felbatol OR taloxa) OR TITLE-ABS-KEY(gabapentin OR neurontin OR neurotonin)
OR TITLE-ABS-KEY(levetiracetam OR keppra) OR TITLE-ABS-KEY(pregabalin OR lyrica))) OR ((TITLE-ABS-KEY(phenytoin
OR alepsin OR aleviatin OR antilepsin OR antisacer OR cansoin OR citrullamon OR comital OR danten OR dantoin OR denyl
OR difetoin OR differenin OR difhydan OR di hydan OR dihydan OR dilantin OR dintoin OR dintoina OR diphantoin OR
diphantoine) OR TITLE-ABS-KEY(fenantoin OR fenitoin OR fenytoin OR fenytoine OR hidantal OR hydantin OR hydantinal OR
hydantoinal OR idantoin OR lepitoin OR minetoin OR neosidantoina OR phenhydan OR phenhydane OR phenybin OR phenydan
OR phenydantin OR phenytoine OR phenytoin OR phenyto))) OR ((TITLE-ABS-KEY(lacosamide OR erlosamide OR vimpat)
OR TITLE-ABS-KEY(lamotrigine OR labileno OR lamictal))) OR ((TITLE-ABS-KEY(valproic acid) OR TITLE-ABS-KEY(sodium
valproate OR alpha propylvalerate OR alpha propylvaleric acid OR apilepsin OR convulex OR depacon OR depakene OR depakin OR
depakine OR deprakine OR dipropylacetate OR dipropylacetatic acid OR dipropyl acetic acid OR dipropylacetic acid OR diprosin)
OR TITLE-ABS-KEY(epilim OR ergenyl OR everiden OR goilim OR labazene OR leptilan OR leptilanil OR mylproin OR myproic
acid OR orfiril OR orlept OR propymal OR valerin OR valparin OR valpro OR valproate OR valproate sodium OR vupral))) OR
((TITLE-ABS-KEY(tiagabin OR gabitril) OR TITLE-ABS-KEY(topiramate OR epitomax OR topamax OR topimax) OR TITLE-
ABS-KEY(vigabatrin OR sabril)))
164.432
13
(#1 OR #2 OR #3 OR #4 OR #5 OR #6 OR #7 OR #8 OR #9) AND #10 AND #11
((TITLE-ABS-
KEY(fibromyalgia) OR TITLE-ABS-KEY(fibrositis) OR TITLE-ABS-KEY(fms))) AND ((TITLE-ABS-KEY(randomized controlled
trial) OR TITLE-ABS-KEY(controlled trial) OR TITLE-ABS-KEY(placebo) OR TITLE-ABS-KEY(single blind) OR TITLE-ABS-
KEY(double blind))) AND (((TITLE-ABS-KEY(anticonvulsants/) OR TITLE-ABS-KEY(anti convulsant$ OR anticonvulsant$ OR
anti-convulsant$ OR anti epileptic$ OR antiepileptic$ OR anti-epileptic$))) OR ((TITLE-ABS-KEY(anticonvulsants) OR TITLE-
ABS-KEY(anti convulsant$ OR anticonvulsant$ OR anti-convulsant$ OR anti epileptic$ OR antiepileptic$ OR anti-epileptic$)))
OR ((TITLE-ABS-KEY(carbamazepine) OR TITLE-ABS-KEY(carbamazepine OR amizepin OR amizepine OR atretol OR biston
OR calepsin OR carbamazepin OR carbategral OR carbatrol OR convuline OR epimax) OR TITLE-ABS-KEY(epitol OR equetro
OR finlepsin OR lexin OR mazepine OR neurotol OR neurotop OR servimazepin OR sirtal OR tegral OR tegretal OR tegretol OR
tegrital OR telesmin OR teril OR timonil))) OR ((TITLE-ABS-KEY(oxcarbazepine OR apydan OR oxocarbamazepine OR oxocar-
bazepine OR timox OR trileptal) OR TITLE-ABS-KEY(clonazepam OR clonex OR klonopin OR paxam OR kriadex OR ravotril
OR rivatril OR rivotril))) OR ((TITLE-ABS-KEY(felbamat OR felbatol OR taloxa) OR TITLE-ABS-KEY(gabapentin OR neuron-
tin OR neurotonin) OR TITLE-ABS-KEY(levetiracetam OR keppra) OR TITLE-ABS-KEY(pregabalin OR lyrica))) OR ((TITLE-
ABS-KEY(phenytoin OR alepsin OR aleviatin OR antilepsin OR antisacer OR cansoin OR citrullamon OR comital OR danten OR
dantoin OR denyl OR difetoin OR differenin OR difhydan OR di hydan OR dihydan OR dilantin OR dintoin OR dintoina OR
diphantoin OR diphantoine) OR TITLE-ABS-KEY(fenantoin OR fenitoin OR fenytoin OR fenytoine OR hidantal OR hydantin OR
hydantinal OR hydantoinal OR idantoin OR lepitoin OR minetoin OR neosidantoina OR phenhydan OR phenhydane OR phenybin
OR phenydan OR phenydantin OR phenytoine OR phenytoin OR phenyto))) OR ((TITLE-ABS-KEY(lacosamide OR erlosamide
OR vimpat) OR TITLE-ABS-KEY(lamotrigine OR labileno OR lamictal))) OR ((TITLE-ABS-KEY(valproic acid) OR TITLE-ABS-
KEY(sodium valproate OR alpha propylvalerate OR alpha propylvaleric acid OR apilepsin OR convulex OR depacon OR depakene
OR depakin OR depakine OR deprakine OR dipropylacetate OR dipropylacetatic acid OR dipropyl acetic acid OR dipropylacetic acid
OR diprosin) OR TITLE-ABS-KEY(epilim OR ergenyl OR everiden OR goilim OR labazene OR leptilan OR leptilanil OR mylproin
OR myproic acid OR orfiril OR orlept OR propymal OR valerin OR valparin OR valpro OR valproate OR valproate sodium OR
vupral))) OR ((TITLE-ABS-KEY(tiagabin OR gabitril) OR TITLE-ABS-KEY(topiramate OR epitomax OR topamax OR topimax)
OR TITLE-ABS-KEY(vigabatrin OR sabril))))
375
Appendix 5. clinicaltrials.gov search strategy
anticonvulsant and fibromyalgia: 33

fibromyalgia and antiepileptic drugs: 33
WHAT’S NEW
Last assessed as up-to-date: 30 August 2013.
Date Event Description
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
- Monoamine oxidase inhibitors (MAOIs) for fibromyalgia syndrome
- Non-steroidal anti-inflammatory drugs (NSAIDs), analgesics and opioid agents for fibromyalgia
- Sedatives and hypnotic agents for fibromyalgia
- Selective serotonin reuptake inhibitors (SSRIs) for fibromyalgia
- Serotonin and noradrenaline reuptake inhibitors (SNRIs) for fibromyalgia syndrome
- Tricyclic agents for fibromyalgia

CONTRIBUTIONS OF AUTHORS
NÜ: systematic review study selection, data extraction, data analysis, interpretation of findings; review final proof.
CS: data extraction, data analysis, interpretation of findings; review final proof.
BW: protocol review and revision; interpretation of findings; review final proof.
WH: topic conception and methodological aspects; protocol revision; systematic review study selection, data extraction, data analysis,
interpretation of findings and author of review.
DECLARATIONS OF INTEREST
NÜ received consultancy honoraria from Grünenthal GmbH and travel grants from Pfizer, Astellas, Grünenthal GmbH and CSL
Behring. CS received honoraria for educational lectures from Eli-Lilly and Pfizer. BW received a consulting fee from Jazz Pharmaceuticals
and was a site investigator for a milnacipran trial in FM. WH received honoraria for educational lectures from Eli-Lilly, Janssen-Cilag,
Mundipharma and Pfizer and a travel grant from Eli-Lilly. He serves on the advisory board of Daiichi Sankyo.
DIFFERENCES BETWEEN PROTOCOL AND REVIEW

The protocol ’Antidepressants and centrally active agents for fibromyalgia syndrome’ (Nishishinya 2006), has been split into several
systematic reviews. A random-effects model was used for all analyses irrespective of the amount of heterogeneity. The intended subgroup
analyses with gender and pain were not conducted because individual participant data were not available. 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 disorder, according to the presence/absence of any concomitant systemic disease) were not conducted
because the studies did not differ in these characteristics. The GRADE approach was used for the grading of evidence.
INDEX TERMS
Medical Subject Headings (MeSH)
Acetamides [therapeutic use]; Amines [therapeutic use]; Anticonvulsants [∗ therapeutic use]; Cyclohexanecarboxylic Acids [therapeutic
use]; Fibromyalgia [∗ drug therapy]; Piracetam [analogs & derivatives; therapeutic use]; gamma-Aminobutyric Acid [analogs & deriva-
tives; therapeutic use]
MeSH check words

Humans


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Anticonvulsants for fibromyalgia (Review)

Üçeyler N, Sommer C, Walitt B, Häuser W

Anticonvulsants for fibromyalgia (Review)

Anticonvulsants for fibromyalgia (Review) ii

Anticonvulsants for fibromyalgia

Nurcan Üçeyler1 , Claudia Sommer1 , Brian Walitt2 , Winfried Häuser3

Editorial group: Cochrane Musculoskeletal Group.

PLAIN LANGUAGE SUMMARY

Anticonvulsants for fibromyalgia

- Pregabalin slightly reduces pain and sleep problems.

- Pregabalin slightly reduces fatigue.

- Pregabalin increases medication side effects, in particular dizziness.

What is FM and what are anticonvulsants?

Anticonvulsants for fibromyalgia (Review) 3

Pregabalin versus placebo at final treatment for fibromyalgia

Patient or population: People with fibromyalgia

Assumed risk Corresponding risk

Control Anticonvulsants versus

GRADE Working Group grades of evidence

Description of the condition

Anticonvulsants for fibromyalgia (Review) 7

Anticonvulsants for fibromyalgia (Review) 8

Unit of analysis issues

Anticonvulsants for fibromyalgia (Review) 9

’Summary of findings’ table

Data synthesis Description of studies

Anticonvulsants for fibromyalgia (Review) 10

Anticonvulsants for fibromyalgia (Review) 11

Anticonvulsants for fibromyalgia (Review) 12

Anticonvulsants for fibromyalgia (Review) 13

Risk of bias in included studies

Anticonvulsants for fibromyalgia (Review) 14

Anticonvulsants for fibromyalgia (Review) 15

Anticonvulsants for fibromyalgia (Review) 16

Anticonvulsants for fibromyalgia (Review) 17

Anticonvulsants for fibromyalgia (Review) 18

Anticonvulsants for fibromyalgia (Review) 19

Sleep problems: five studies with 3193 participants were entered

Anticonvulsants for fibromyalgia (Review) 20

Withdrawal due to adverse events: five studies with 3259 partici-

Anticonvulsants for fibromyalgia (Review) 21

Anticonvulsants for fibromyalgia (Review) 22

Anticonvulsants for fibromyalgia (Review) 23

Anticonvulsants for fibromyalgia (Review) 24

Häuser 2012a Moore 2011

Anticonvulsants for fibromyalgia (Review) 29

Characteristics of included studies [ordered by study ID]

Anticonvulsants for fibromyalgia (Review) 30

Rescue or allowed medication, or both: Paracetamol (acetaminophen) or over-the-

Notes Safety: Gabapentin-treated participants reported dizziness, sedation, lightheadedness

Bias Authors’ judgement Support for judgement

Random sequence generation (selection Low risk Computer-generated random sequence

Anticonvulsants for fibromyalgia (Review) 31

Outcomes Pain: Daily diary mean pain (NRS 0-10)

Anticonvulsants for fibromyalgia (Review) 32

Bias Authors’ judgement Support for judgement

Random sequence generation (selection Low risk Computer-generated random sequence

Selective reporting (reporting bias) Low risk All outcomes reported