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Topiramate for neuropathic pain and fibromyalgia in adults

  1. Philip J Wiffen1,
  2. Sheena Derry1,*,
  3. Michael PT Lunn2,
  4. R Andrew Moore1

Editorial Group: Cochrane Neuromuscular Group

Published Online: 30 AUG 2013

Assessed as up-to-date: 8 MAY 2013

DOI: 10.1002/14651858.CD008314.pub3


How to Cite

Wiffen PJ, Derry S, Lunn MPT, Moore RA. Topiramate for neuropathic pain and fibromyalgia in adults. Cochrane Database of Systematic Reviews 2013, Issue 8. Art. No.: CD008314. DOI: 10.1002/14651858.CD008314.pub3.

Author Information

  1. 1

    University of Oxford, Pain Research and Nuffield Department of Clinical Neurosciences (Nuffield Division of Anaesthetics), Oxford, Oxfordshire, UK

  2. 2

    National Hospital for Neurology and Neurosurgery, Department of Neurology and MRC Centre for Neuromuscular Diseases, London, UK

*Sheena Derry, Pain Research and Nuffield Department of Clinical Neurosciences (Nuffield Division of Anaesthetics), University of Oxford, Pain Research Unit, Churchill Hospital, Oxford, Oxfordshire, OX3 7LE, UK. sheena.derry@ndcn.ox.ac.uk.

Publication History

  1. Publication Status: Stable (no update expected for reasons given in 'What's new')
  2. Published Online: 30 AUG 2013

SEARCH

 
Characteristics of included studies [ordered by study ID]
Khoromi 2005

MethodsSingle-centre, randomised, double-blind, active, placebo (diphenhydramine)-controlled
Two-period cross-over study: 4-week titration, 2-week maintenance, 2-week washout with dose taper, then cross-over


ParticipantsLumbar radiculopathy ≥ 3 months
Average pain ≥ 4/10 in past month
Mean age ˜58 years (28 to 74)
M 23, F 20
N = 41 (1 participant ineligible, 1 participant dropped out prior to randomisation)


InterventionsTopiramate to maximum 400 mg/day

Placebo

Titration to maximum tolerated dose over 4 weeks: topiramate starting at 50 mg in the evening, increasing by 50 mg increments, or diphenhydramine starting at 6.25 mg, increasing to maximum 25 mg twice daily


Outcomes1. Mean score for average leg pain during maintenance, based on daily pain records (0 to 10)
2. PGIC (leg and back) pain (worse, none, slight, moderate, a lot, complete). ≥ moderate = responder
3. Oswestry Low Back Pain Disability Questionnaire
4. Beck Depression Inventory
5. Short Form-36 Health Survey

Imputation not mentioned


NotesOxford Quality Score: R1, DB1, W1. Total = 3/5


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Unclear riskMethod not described

Allocation concealment (selection bias)Low risk"independent (NIH) pharmacist"

Blinding of participants and personnel (performance bias)
All outcomes
Unclear riskNo details given. "Patients and research staff were blinded to the randomization order"

Blinding of outcome assessment (detection bias)
All outcomes
Unclear riskNo details given. "Patients and research staff were blinded to the randomization order"

Incomplete outcome data (attrition bias)
All outcomes
High risk> 10% withdrawals with active treatment. Imputation not mentioned

SizeHigh risk< 50 participants per treatment arm

NCT00231673

MethodsMulticentre, randomised, double-blind, placebo-controlled, parallel group study

Duration 18 weeks, consisting of 6-week titration and 12-week maintenance periods


ParticipantsDiabetic peripheral polyneuropathy

Current pain at least mild

Age 18 to 75 years

Duration of condition 6 months or longer


InterventionsTopiramate 200 mg/day or placebo


Outcomes1. Pain intensity - VAS and categorical scales

2. Adverse events


NotesMain focus of study was nerve conduction


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Unclear riskNot described

Allocation concealment (selection bias)Unclear riskNot described

Blinding of participants and personnel (performance bias)
All outcomes
Unclear riskNot described

Blinding of outcome assessment (detection bias)
All outcomes
Unclear riskNot described

Incomplete outcome data (attrition bias)
All outcomes
Unclear riskNot described

SizeHigh riskFewer than 50 participants in treatment arm

Raskin 2004

MethodsMulticentre, randomised, double-blind, placebo-controlled
Parallel groups: up to 28-day washout, 8-week dose titration, 4-week maintenance dose


ParticipantsSymmetric diabetic peripheral neuropathy > 3 months, < 10 years
Diabetic control stable ≥ 3 months, with HbA1c ≤ 11%
Baseline pain ≥ 4/10 after washout

Exclude: history of failure of topiramate for a painful condition

Mean age 59 (± 10) years
M 157, F 160

N = 317


InterventionsTopiramate to maximum 400 mg/day, n = 208

Placebo, n = 109

Titration to maximum tolerated dose: topiramate 25 mg in evening increasing by 25 mg/day in weeks 2 to 4, 50 mg in weeks 5 and 6, and 100 mg in weeks 7 and 8
Dose tapered if participant left study

Rescue medication (500 mg paracetamol or similar) available for first 6 weeks only and not within 24 hours of any study visit
Mean daily dose (maintenance) of topiramate: 320 mg


Outcomes1. Pain intensity on 100 mm VAS. Mean and responder = > 30% and > 50% reduction in score
2. Current pain on 5-point categorical scale (none, mild, moderate, severe, extreme)
3. Worst pain in last week on 5-point categorical scale
4. SF-36
5. Sleep disruption on 0 to 10-point scale
6. PGIC on 5-point scale (poor, fair, good, very good, excellent)

Imputation - primary efficacy used LOCF, then compared with analysis using weighting by inverse of probability of completing (for completers)


NotesOxford Quality Score: R2, DB2, W1. Total = 5/5


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Low riskComputer-generated, balanced blocks

Allocation concealment (selection bias)Unclear riskNot described. Investigators assigned treatment sequentially

Blinding of participants and personnel (performance bias)
All outcomes
Low risk"identically appearing placebo tablets"

Blinding of outcome assessment (detection bias)
All outcomes
Low risk"identically appearing placebo tablets"

Incomplete outcome data (attrition bias)
All outcomes
High risk> 10% withdrawals. Imputation - primary efficacy analysis used LOCF

SizeUnclear risk208 (topiramate) and 109 (placebo) participants

Thienel 2004

MethodsMulticentre, randomised, double-blind, placebo-controlled
Parallel groups: up to 28-day baseline/washout, 6- to 10-week titration (depending on target dose), 12-week maintenance dose

Three studies combined and published in one report


ParticipantsBilateral diabetic peripheral neuropathy ≥ 6 months
Diabetic control stable ≥ 3 months, with HbA1c ≤ 11%
Baseline pain ≥ moderate after washout (scale 0 to 4: none, mild, moderate, severe, extreme)

Mean age 58 (± 10) years (21 to 81)
M 733, F 536

N = 1269 (ITT= 1259)


InterventionsTopiramate to maximum 100 mg/day, n = 253

Topiramate to maximum 200 mg/day, n = 372

Topiramate to maximum 400 mg/day, n = 260

Placebo, n = 384

Titration: topiramate 25 mg/day in evening, increasing in 25 mg increments to 100 mg/day, then in weekly 50 mg increments to target dose or maximum tolerated dose

Short-acting immediate-release analgesics permitted as rescue medication during double-blind treatment


Outcomes1. Pain intensity on 100 mm VAS (mean and median reported for each trial. Change from baseline to final visit reported)
2. Current pain on 5-point categorical scale (none, mild, moderate, severe, extreme)
3. Worst pain in last week on 5-point categorical scale
4. Sleep disruption on 0 to 10-point scale
5. SF-36

Pain evaluations used LOCF for early withdrawal


NotesOxford Quality Score: R2, DB2, W1. Total = 5/5


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Low riskComputer-generated by study sponsor, balanced, stratified by centre

Allocation concealment (selection bias)Low riskNot described, but judged likely to be remote allocation because of central generation of randomised sequence

Blinding of participants and personnel (performance bias)
All outcomes
Low risk"Study medications were identical in appearance and packaged in identical containers"

Blinding of outcome assessment (detection bias)
All outcomes
Low risk"Study medications were identical in appearance and packaged in identical containers"

Incomplete outcome data (attrition bias)
All outcomes
High risk> 10% withdrawals. Imputation for pain evaluations - LOCF for early withdrawal

SizeLow risk> 200 participants per treatment arm

 
Characteristics of excluded studies [ordered by study ID]

StudyReason for exclusion

Edwards 1998Abstract

Edwards 2000Abstract

Muehlbacher 2006Not specifically neuropathic pain

Vinik 2003Abstract

 
Characteristics of studies awaiting assessment [ordered by study ID]
NCT00001725

MethodsPossibly randomised cross-over study of topiramate and dextromethorphan (estimated 100 participants)

ParticipantsOrofacial pain and trigeminal pain

InterventionsTopiramate, dextromethorphan

OutcomesNot known

NotesReported as completed, but without study results

Wang 2011

MethodsMeta-analysis of randomised trials (six trials, 354 participants)

ParticipantsTrigeminal neuralgia

InterventionsTopiramate, carbamazepine

OutcomesNot known, undefined efficacy

NotesChinese-language studies described as of poor quality

 
Comparison 1. Topiramate versus placebo

Outcome or subgroup titleNo. of studiesNo. of participantsStatistical methodEffect size

 1 Any adverse event2398Risk Ratio (M-H, Fixed, 95% CI)1.17 [1.04, 1.31]

 2 Serious adverse events21586Risk Ratio (M-H, Fixed, 95% CI)0.87 [0.59, 1.27]

 3 Adverse event withdrawals31038Risk Ratio (M-H, Fixed, 95% CI)3.35 [2.41, 4.64]

 4 Lack of efficacy withdrawals31038Risk Ratio (M-H, Fixed, 95% CI)0.68 [0.50, 0.93]

 
Summary of findings for the main comparison. Topiramate 200 to 400 mg versus placebo for neuropathic pain

Intervention: topiramate 200 to 400 mg compared with placebo

Patient or population: neuropathic pain (two studies found in painful diabetic neuropathy, and one in lumbar radiculopathy)

Settings: community

Intervention: oral topiramate 200 to 400 mg daily

Comparison: oral placebo

OutcomeProbable outcome with interventionProbable outcome with comparatorNNTB or NNTH and/or relative effect (95% CI)Number of participantsQuality of the evidence
(GRADE)
Comments

At least 50% reduction in pain or equivalentNo adequate dataNo adequate dataNo adequate data317 participants

(1 study)
Diabetic peripheral neuropathy

LOCF imputation makes any estimate an overestimation, and bulk of data in studies report no difference between topiramate and placebo
Low numbers

"Moderate" benefit

At least 30% reduction in pain
No adequate dataNo adequate dataNo adequate data317 participants

(1 study)
Diabetic peripheral neuropathy

LOCF imputation makes any estimate an overestimation, and bulk of data in studies report no difference between topiramate and placebo
Low numbers

Proportion below 30/100 mm on VASNo data

Patient Global Impression of Change much or very much improvedNo adequate dataNo adequate dataNo adequate data399 participants

(2 studies)
Variously reported, and inadequate numbers for satisfactory analysis

Adverse event withdrawals270 in 100081 in 1000NNTH 5.4 (4.3 to 7.1)

RR 3.4 (2.4 to 4.7)
1038 participants

178 events
Moderate qualityLow number of events

Serious adverse events66 in 100075 in 1000NNTH not calculated

RR 0.9 (0.6 to 1.3)
1586 participants

110 events
Moderate qualityLow number of events

DeathThere were no deaths related to treatment

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.

 LOCF: last observation carried forward; VAS: visual analogue scale; NNTB: number needed to treat for an additional beneficial effect: NNTH: number needed to treat for an additional harmful effect; RR: risk ratio.