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Carbamazepine for chronic neuropathic pain and fibromyalgia in adults

  1. Philip J Wiffen1,*,
  2. Sheena Derry1,
  3. R Andrew Moore1,
  4. Eija A Kalso2,3

Editorial Group: Cochrane Pain, Palliative and Supportive Care Group

Published Online: 10 APR 2014

Assessed as up-to-date: 7 FEB 2014

DOI: 10.1002/14651858.CD005451.pub3


How to Cite

Wiffen PJ, Derry S, Moore RA, Kalso EA. Carbamazepine for chronic neuropathic pain and fibromyalgia in adults. Cochrane Database of Systematic Reviews 2014, Issue 4. Art. No.: CD005451. DOI: 10.1002/14651858.CD005451.pub3.

Author Information

  1. 1

    University of Oxford, Pain Research and Nuffield Department of Clinical Neurosciences, Oxford, Oxfordshire, UK

  2. 2

    Helsinki University Central Hospital, Department of Anaesthesia, Intensive Care Medicine, Emergency Medicine and Pain Medicine, Helsinki, Finland

  3. 3

    University of Helsinki, Institute of Clinical Medicine, Helsinki, Finland

*Philip J Wiffen, Pain Research and Nuffield Department of Clinical Neurosciences, University of Oxford, Pain Research Unit, Churchill Hospital, Oxford, Oxfordshire, OX3 7LE, UK. phil.wiffen@ndcn.ox.ac.uk.

Publication History

  1. Publication Status: Stable (no update expected for reasons given in 'What's new')
  2. Published Online: 10 APR 2014

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Characteristics of included studies [ordered by study ID]
Campbell 1966

MethodsMulticentre, randomised, double blind, placebo controlled, cross-over. Not enriched. Duration 8 weeks (4 two-week periods)


ParticipantsTrigeminal neuralgia

N = 77 (but 7 excluded, 6 for logistic problems, one for a rash)

36 started on carbamazepine, 34 (report says 35 in one place) started on placebo

Age range 20 to 84 (mean 59) years. Male 34%


InterventionsCBZ 100 mg 4 x daily to 200 mg 3 x daily (1 centre), or 200 mg 4 x daily (2 centres)

Placebo

Order of treatment CBZ, P, CBZ, P or P, CBZ, P, CBZ


OutcomesPain intensity: 4 point scale to determine "upgrading"

Frequency of paroxysms and triggers

Adverse events

Withdrawals


NotesOxford Quality Score: R = 2, DB = 2, W = 1, Total = 5

Geigy supplied tablets


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Low risk'random number lists'

Allocation concealment (selection bias)Unclear risk'neither patient nor doctor knowing the order of therapy given'

Blinding (performance bias and detection bias)
Active and controlled appeared similar
Low risk'placebo indistinguishable in appearance from active drugs'

DurationHigh risk2 week treatment period

OutcomeHigh riskUpgrading not level of change

Incomple outcome assessmentUnclear riskNot stated

SizeHigh riskGroup size below 50

Gomez-Perez 1996

MethodsRandomised, double blind, double dummy, active controlled, cross-over (washout and phase 2 only). Duration: two 30-day treatment periods plus washout. Not obviously enriched


ParticipantsAdult patients with diabetic neuropathy - severe pain

N = 16

Age and sex not stated


InterventionsCBZ 300 mg to 600 mg daily

Nortriptyline 10 mg plus fluphenazine 0.5 mg combination (3 to 6 tablets daily)

Dose increment over 3 days then stable to day 15 then double dose for next 15 days. 2 to 4 weeks washout then cross-over


OutcomesSymptom intensity for pain and paraesthesia: Vertical VAS, 0 to 100

Withdrawals

Adverse events


NotesOxford Quality Score: R = 1, DB = 2, W = 1, Total = 4

Geigy supplied the drugs


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Unclear risk'randomly assigned'

Allocation concealment (selection bias)Unclear riskNo statement

Blinding (performance bias and detection bias)
Active and controlled appeared similar
Low risk'an identical placebo tablet of the comparing drug was given simultaneously with the active drug'. Double dummy design

DurationUnclear risk4 week treatment periods

OutcomeLow riskAt least 50% decrease of pain

Incomple outcome assessmentUnclear riskNot stated

SizeHigh riskGroup size below 50

Jia 2006

MethodsRandomised, double blind, double dummy, active control, parallel group. Not obviously enriched

Duration 14 days


ParticipantsPainful peripheral diabetic neuropathy

N = 132 (66 in each treatment group)

Age and sex not reported


InterventionsCBZ 100 mg twice daily

Venlafaxine 25 mg twice daily


OutcomesNumerical pain intensity scores using 11 point Likert scale

Assessment of ADL, sleep and mood

Withdrawals

Adverse events


NotesOxford Quality Score: R = 2, DB = 2, W = 1, Total = 5


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Low risk'random sequence generated by computer'

Allocation concealment (selection bias)Low risk'sealed opaque envelopes'

Blinding (performance bias and detection bias)
Active and controlled appeared similar
Low riskDouble dummy design. 'each patient took venlafaxine 25mg plus one dummy carbamazepine' or vice versa

DurationHigh risk14 days

OutcomeHigh riskMean data only, no responder analysis

Incomple outcome assessmentUnclear riskNot stated

SizeUnclear risk66 in each treatment group

Killian 1968

MethodsRandomised, double blind, placebo controlled, partial cross-over. Duration 10 days (two 5-day periods). Not obviously enriched

Open follow-up, range 2 weeks to 36 months


ParticipantsTrigeminal neuralgia N = 30, postherpetic neuralgia N = 6, other chronic neuralgia N = 6

36 of 42 participants studied double blind (24 of 30 with trigeminal neuralgia)

Age range 36 to 83 (mean 52) years, Female 66%


InterventionsCarbamazepine dose titration 400 mg to 1 g daily
Placebo


OutcomesComplete or very good pain response

Withdrawals

Adverse events


NotesOxford Quality Score: R = 1, DB = 2, W = 1, Total = 4

Geigy sponsored


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Unclear risk'which were randomised'

Allocation concealment (selection bias)Unclear riskNo statement

Blinding (performance bias and detection bias)
Active and controlled appeared similar
Low risk' a double bind technique . . .consisted of identical tablets'

DurationHigh risk5-day treatment period

OutcomeLow riskComplete or very good pain response is equivalent to ≥ 50% pain relief

Incomple outcome assessmentUnclear riskNot stated

SizeHigh riskGroups size below 50

Lechin 1989

MethodsMulticentre (4), randomised, double blind, active control, cross-over. Duration 24 weeks (4 week run-in, then two 8-week periods with 4-week washout). Not enriched

Open follow-up on pimozide


ParticipantsTrigeminal neuralgia. Duration of illness 8 to 17 (median 13) years

N = 59 randomised. Only 48 evaluated due to protocol violation and dropout

Age 48 to 64 (mean 59) years. Male 24, Female 24


InterventionsCBZ 300 mg to 1200 mg daily in 2 divided doses

Pimozide 4 mg to 12 mg daily in 2 divided doses

Step titration with daily doses as follows: CBZ and pimozide, days 1 to 4 300 mg and 4 mg respectively; days 5 to 9 600 mg and 6 mg respectively; days 10 to 14, 900 mg and 8 mg respectively; day 15 to end of treatment, 1200 mg and 12 mg respectively


OutcomesTrigeminal neuralgia symptom score

Adverse events


NotesOxford Quality Score: R = 1, DB = 2, W = 1, Total = 4

Grant from Foundation of the Institute for Experimental Medicine


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Unclear risk'patients were randomly distributed in two groups'

Allocation concealment (selection bias)Unclear riskNot stated

Blinding (performance bias and detection bias)
Active and controlled appeared similar
Low risk'all medications were administered in identical dark capsules'

DurationLow risk8 weeks treatment

OutcomeHigh riskAverage pain score

Incomple outcome assessmentUnclear riskNot stated

SizeHigh riskGroup size below 50

Leijon 1989

MethodsRandomised, double blind, double dummy, active control, cross-over. Duration 14 weeks (three 4-week periods with two 1-week washouts). No follow up. Partially enriched


ParticipantsCentral post stroke pain

N = 15

Age not reported, Male 12, Female 3


InterventionsStepped increase to final dose of CBZ 800 mg daily starting at 100 mg twice daily on day 1 then increasing on days 2, 6, 15, 18

Stepped increase to final daily dose of amitriptyline of 25 mg in the morning and 50 mg at night, starting at 12.5 mg twice daily on day 1 then increasing on days 2, 6, 15, 18


OutcomesDaily pain intensity (10 step verbal scale), post treatment global rating

Withdrawals


NotesOxford Quality Score: R = 1, DB = 2, W = 1, Total = 4

Sponsorship - Swedish public funds


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Unclear risk'treatment given in randomised order'

Allocation concealment (selection bias)Unclear riskNot stated

Blinding (performance bias and detection bias)
Active and controlled appeared similar
Low risk'identical capsules containing active drug or lactulose(!) were given in double dummy technique'

DurationUnclear risk4 week treatment periods

OutcomeLow riskIndividual pain response levels shown

Incomple outcome assessmentUnclear riskNot stated

SizeHigh riskGroup size below 50

Lindstrom 1987

MethodsRandomised, double blind, active control, cross-over (two 2-week periods - washout?). No follow up. Not enriched


ParticipantsTrigeminal neuralgia

N = 12

Age 41 to 78 years. Male 5, Female 7


InterventionsCBZ to maximum tolerated dose

Tocainide 20 mg/kg in 3 divided daily doses. Actual doses not reported


OutcomesTN pain score (summary of intensity, frequency and duration of attacks), 0 to 10 scale


NotesOxford Quality Score: R = 1, DB = 1, W = 0, Total = 2

Sponsored by Folsam Research Foundaton, Vivian L Smith Foundation


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Unclear risk'randomised double blind technique'

Allocation concealment (selection bias)Unclear riskNot stated

Blinding (performance bias and detection bias)
Active and controlled appeared similar
Unclear riskStated as double blind but no further information

DurationHigh risk2 week treatment

OutcomeLow riskProbable that TN pain score ≤ 3/10 equivalent to no worse than mild pain

Incomple outcome assessmentUnclear riskNot stated

SizeHigh riskGroup size below 50

Nicol 1969

MethodsRandomised, double blind, placebo controlled, partial cross-over (successful first treatment period stayed on same treatment). Duration of treatment 2 to 42 months. Not obviously enriched.

Follow up 46 months.


ParticipantsFacial pain

N = 64, 54 with trigeminal neuralgia

Results presented on 44 TN only, due to insufficient follow up

Age not given. Male 21, Female 23


InterventionsCBZ dose titration 100 mg to 2.4 g daily

Placebo

Participants started on one treatment and increased dose to 8 tablets daily. At two weeks, if no satisfactory results, the second treatment was substituted

20 had carbamazepine only, 7 had placebo only; 17 had placebo then carbamazepine


OutcomesWithdrawals


NotesOxford Quality Score: R = 1, DB = 1, W = 1, Total = 3

Geighy supplied the tablets


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Unclear risk'randomised investigation'

Allocation concealment (selection bias)Unclear riskNot stated

Blinding (performance bias and detection bias)
Active and controlled appeared similar
Unclear riskStated as double blind but no further information

DurationLow risklong duration ≥12 weeks

OutcomeUnclear riskProbable that response was equivalent to ≥ 30% pain relief

Incomple outcome assessmentUnclear riskNot stated

SizeHigh riskPartial crossover means that groups size was below 50

Rull 1969

MethodsRandomised, double blind, placebo-controlled, cross-over. Duration 6 weeks (three 2-week periods), no follow-up. Not obviously enriched


ParticipantsDiabetic neuropathy

N = 30

Mean age 54 (21 to 81) years. Male 21, Female 30


InterventionsCBZ 200 mg to 600 mg daily

Placebo

Sequence CBZ, P, CBZ or P, CBZ, P


OutcomesParticipant reported change in symptoms (-5 to +5), reported as 5 categories

Adverse events


NotesOxford Quality Score: R = 1, DB = 2, W = 1, Total = 4


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Unclear risk'on a random basis, individuals were assigned'

Allocation concealment (selection bias)Unclear riskNot stated

Blinding (performance bias and detection bias)
Active and controlled appeared similar
Low risk'both drug and placebo were identical'

DurationHigh risk2 week treatment period

OutcomeLow riskImprovement by +3 to +5 points probably equivalent to ≥ 30% pain relief

Incomple outcome assessmentUnclear riskNot stated

SizeHigh riskGroup size below 50

Wilton 1974

MethodsRandomised, double blind, placebo controlled, cross-over. Duration 4 weeks: 2-week washout then 7 days on each treatment period. No washout between treatments


ParticipantsDiabetic neuropathy of at least 3 months

N = 40

Mean age 56 (range 28 to 70) years. Female 75%


InterventionsCarbamazepine 200 mg 3 x daily

Placebo


OutcomesPatient reported pain: 10 cm VAS scale

Reported numbness, agitation, ability to sleep, depression and anxiety


NotesOxford Quality Score: R = 1, DB = 1, W = 0, Total = 2

Geighy gave assistance


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Unclear risk'according to a pre-randomised balanced sequence'

Allocation concealment (selection bias)Unclear riskNot stated

Blinding (performance bias and detection bias)
Active and controlled appeared similar
Low risk'tegretol and an identical placebo dosage'

DurationHigh risk7 days treatment period

OutcomeHigh riskMean pain scores

Incomple outcome assessmentUnclear riskNot stated

SizeHigh riskGroup size below 50

 
Characteristics of excluded studies [ordered by study ID]

StudyReason for exclusion

Crill 1973Review

Erzurumlu 1995Not RCT

Gerson 1977Open label

Harke 2001RCT but required pretreatment with spinal cord stimulation. 8 days treatment.

Keczkes 1980Acute condition. Pre-emptive treatment to reduce incidence of postherpetic neuralgia. Probably not blinded

Kudoh 1998Not RCT

Lloyd-Smith 1969Not randomised. Some patients crossed to placebo without consent

Rasmussen 1970Single blind

Rockliff 1966Fewer than 10 participants per treatment arm

Salinas 2012Pre-emptive treatment to reduce incidence or intensity of neuropathic pain

Shaikh 2011Not randomised or double blind

Swerdlow 1981Case series

Swerdlow 1984Review

Vilming 1986Fewer than 10 participants per treatment arm

 
Characteristics of studies awaiting assessment [ordered by study ID]
Badran 1975

Methods

Participants

Interventions

Outcomes

NotesUnable to locate paper

Liebel 2001

Methods

Participants

Interventions

Outcomes

NotesUnable to locate paper

 
Comparison 1. Carbamazepine in neuropathic pain

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

 1 Any pain improvement4188Risk Ratio (M-H, Fixed, 95% CI)6.46 [3.43, 12.17]

    1.1 Trigeminal neuralgia
298Risk Ratio (M-H, Fixed, 95% CI)6.02 [2.82, 12.85]

    1.2 Painful diabetic neuropathy
160Risk Ratio (M-H, Fixed, 95% CI)8.5 [2.15, 33.62]

    1.3 Central post stroke pain
130Risk Ratio (M-H, Fixed, 95% CI)5.0 [0.66, 37.85]

 2 At least 1 adverse event4346Risk Ratio (M-H, Fixed, 95% CI)2.40 [1.85, 3.12]

 
Summary of findings for the main comparison.

Carbamazepine compared with placebo for chronic neuropathic pain

Patient or population: adults with neuropathic pain (Trigeminal neuralgia, painful diabetic neuropathy, chronic post stroke pain)

Settings: community

Intervention: oral carbamazepine (100 mg to 2400 mg daily)

Comparison: placebo

OutcomesProbable outcome with placeboProbable outcome with interventionNNT or NNH and/or relative effect (95% CI)No of participants
and studies
Quality of the evidence
(GRADE)
Comments

"Substantial" benefit

At least 50% reduction in pain or equivalent
94 in 1000608 in 1000RR 6.5 (3.4 to 12)

NNT 1.9 (1.6 to 2.5)
188 participants,

4 studies
LowMixed conditions and doses, small studies of short duration, imputation not reported

"Moderate" benefit

At least 30% reduction in pain
No dataVery lowNo data




Proportion below 30/100 mm on VASNo dataVery lowNo data




Patient Global Impression of Change much or very much improvedNo dataVery lowNo data




Any adverse event270 in 1000660 in 1000RR 2.4 (1.9 to 3.2)

NNH 2.6 (2.1 to 3.5)
346 participants,

4 studies
LowCross-over studies

Denominator = all potentially exposed

Adverse event withdrawals0 in 100030 in 1000not calculated523 participants,

8 studies
Very lowCross-over studies

Denominator = all potentially exposed

Serious adverse eventsnot reported3not calculated46 participants,

2 studies
Very lowDenominator = all potentially exposed

Deathnot reported4not calculated44 participants

1 study
Very lowDenominator = all potentially exposed

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.

 NNT: number needed to treat for an additional beneficial effect: NNH: number needed to treat for an additional harmful effect; RR: risk ratio; VAS: visual analogue scale.