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Lamotrigine for chronic neuropathic pain and fibromyalgia in adults

  1. Philip J Wiffen*,
  2. Sheena Derry,
  3. R Andrew Moore

Editorial Group: Cochrane Pain, Palliative and Supportive Care Group

Published Online: 3 DEC 2013

Assessed as up-to-date: 26 NOV 2013

DOI: 10.1002/14651858.CD006044.pub4


How to Cite

Wiffen PJ, Derry S, Moore RA. Lamotrigine for chronic neuropathic pain and fibromyalgia in adults. Cochrane Database of Systematic Reviews 2013, Issue 12. Art. No.: CD006044. DOI: 10.1002/14651858.CD006044.pub4.

Author Information

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

*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: New search for studies and content updated (no change to conclusions)
  2. Published Online: 3 DEC 2013

SEARCH

 
Characteristics of included studies [ordered by study ID]
Eisenberg 2001

MethodsRandomised DB placebo controlled, parallel group study for 11 weeks. One-week screening phase, 8-week treatment phase, 2-week post-treatment phase


Participants59 participants with painful diabetic neuropathy. Age 50 to 60 years

Excluded: participants who had received antiepileptics or antidepressants for reasons other than pain and those who had received opioids


InterventionsLamotrigine 25 mg dispersible tablets or matching placebo
25 mg daily for 2 weeks, 50 mg daily for 2 weeks, then 100 mg, 200 mg, 300 mg and 400 mg for 1 week at each dose level

Rescue analgesia as paracetamol, dipyrone or NSAIDs


OutcomesDaily pain intensity, McGill, Beck depression, Pain disability index, Global assessment. Responder: 50% reduction in pain measured in final 3 weeks of treatment


NotesOxford Quality Score: R2, DB2, W1 = 5


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Low risk"Randomisation was done in blocks of four according to a computer generated random code"

Allocation concealment (selection bias)Unclear riskNot stated

Blinding (performance bias and detection bias)
Assessors
Low risk"Patients in the placebo group received equal numbers of identical looking placebo tablets"

Selective reporting (reporting bias)Unclear riskNot stated

Missing dataHigh riskCompleter analysis - data from withdrawals not carried forward

DurationLow risk"Eight weeks treatment phase"

OutcomeUnclear riskLooked for reduction in pain intensity but reports numbers with 50% reduction. No mention of imputation method

Treatment arm sizeHigh risk59 participants: 29 active, 30 placebo

Finnerup 2002a

MethodsRandomised DB placebo controlled, cross-over study. One-week baseline assessment, two 9-week treatment periods separated by 2-week washout


Participants30 participants with neuropathic pain after traumatic spinal cord injury (SCI). Age 27 to 63 years


InterventionsLamotrigine tablets or identical placebo. Dose escalation to 400 mg a day. Weeks 1 and 2 at 25 mg daily, weeks 3 and 4 at 50 mg, 1 week each at 100 mg, 200 mg, and 300 mg then 2 weeks at 400 mg. Concomitant treatment with spasmolytics, sedatives for insomnia, and simple analgesics for other pain allowed in constant unchanged dose

Rescue analgesia: paracetamol up to 3 g daily


OutcomesAverage daily pain on 11-point numeric scale. Change in median weekly pain score from baseline to final week. Participant preference, other measures included details of types of pain, impact on sleep, and use of rescue medication


NotesOxford Quality Score: R2, DB2, W1 = 5


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Low risk"assignment to treatment was random via a computer generated randomisation list with blocks of four"

Allocation concealment (selection bias)Low risk"The primary investigator was provided with sealed code envelopes- one for each patient- containing information on the treatment given . . . and envelopes were returned unopened to the monitor after the study termination."

Blinding (performance bias and detection bias)
Assessors
Low risk"lamotrigine and identical placebo"

Selective reporting (reporting bias)Unclear riskNot stated

Missing dataHigh riskcompleter

DurationLow riskNine week per arm treatment period

OutcomeUnclear riskLooked for reduction in pain intensity but reports numbers with 50% reduction

Treatment arm sizeHigh risk30 participants total, 22 completers

Jose 2007

MethodsRandomised DB active controlled, cross-over study. Two 6-week treatment periods separated by 2-week washout


Participants53 participants, of whom 46 received both treatments, with Type 2 Diabetes and painful diabetic neuropathy for at least 1 month

Excluded: participants taking antidepressants, antiepileptics, opioids and local anaesthetic agents


InterventionsLamotrigine dose escalation to 100 mg twice daily over 6 weeks or amitriptyline to 50 mg at night with matching placebo in the morning. Two-week washout using placebo between treatment periods

Rescue analgesia: paracetamol up to 3 g daily


OutcomesPatient global assessment (> 50% pain relief = good, > 25% pain relief), VAS PI, short form McGill, 5-point categorical scale for pain and Hamilton depression scale


NotesCONSORT flow chart indicated 23 patients randomised to lamotrigine and 30 to amitriptyline on first cross-over arm, 23 each on second. 46 participants included in ITT analysis. Outcomes reported for both arms of cross-over, with 46 as denominator for efficacy

Oxford Quality Score: R2, DB2, W1 = 5


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Low risk"numbers generated using random number tables by block randomisation"

Allocation concealment (selection bias)Low risk"blinding and randomisation carried out by independent person unrelated to the study", "drug codes were maintained under lock and key"

Blinding (performance bias and detection bias)
Assessors
Low risk"drugs were blinded, packed and numbered serially"

Selective reporting (reporting bias)Unclear riskNot stated

Missing dataUnclear riskLOCF used

DurationHigh risk6 weeks dose escalation then cross over

OutcomeLow risk"VAS score showing improvement of > 50%, > 25% and < 25%" used

Treatment arm sizeHigh risk53 participants; 23 per treatment arm, with 46 completers

McCleane 1999

MethodsRandomised DB placebo controlled, parallel group study. Eight-week treatment period


Participants100 participants with intractable neuropathic pain. Mean age placebo group 44.7 years, lamotrigine group 47.1 years. All had failed response to codeine or NSAID-based analgesics

Excluded: participants taking antiepileptics


InterventionsLamotrigine 25 mg dispersible tablets or matching placebo
25 mg daily for 1 week, then 50 mg daily for 2 weeks, then 100 mg daily for 1 week, then 150 mg daily for 1 week, then 200 mg daily for 3 weeks

Rescue analgesia not reported


OutcomesDaily participant-recorded VAS for PI, shooting pain, burning pain, paraesthesia, numbness, QOL, mobility, sleep and mood. Daily analgesic consumption


Notes18 withdrew: 8 nausea (5 placebo, 3 lamotrigine); 2 skin rash (1 lamotrigine); 2 bad taste of tablets (1 lamotrigine); 6 due to lack of analgesia (2 placebo, 4 lamotrigine). Eight failed to attend final assessment

Oxford Quality Score: R2, DB2, W1 = 5


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Low risk"Patients randomly assigned in equal numbers to one of two groups using computer generated random number lists"

Allocation concealment (selection bias)Unclear riskNot stated

Blinding (performance bias and detection bias)
Assessors
Low risk"patients received either lamotrigine.. . . . or identical looking dispersible placebo tablets"

Selective reporting (reporting bias)Unclear riskNot stated

Missing dataUnclear riskNot stated

DurationLow risk8-week study

OutcomeUnclear riskVAS recorded

Treatment arm sizeHigh risk74 participants; placebo 38, lamotrigine 36

Rao 2008

MethodsRandomised DB placebo controlled, parallel group study. Ten-week treatment period, followed by 4-week tapered withdrawal


Participants125 participants (63 received lamotrigine) with diagnosis of symptomatic chemotherapy-induced peripheral neuropathy > 1 month due to neurotoxic agents. Age 29 to 84 years. Average pain > 4 on NRS

Excluded: participants taking drugs for treating neuropathic pain, including antiepileptics, opioids or topical analgesics at study entry; NSAIDs were permitted.


InterventionsLamotrigine or matching placebo. 25 mg once daily for 2 weeks, then 25 mg, 50 mg, 100 mg, 150 mg twice daily for 2 weeks at each dose, then 4 weeks taper down


OutcomesAverage daily pain score using NRS and ENS (Eastern Cooperative Oncology neuropathy scale).


NotesOxford Quality Score: R1, DB2, W1 = 4


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Unclear riskstated to be randomised

Allocation concealment (selection bias)Unclear riskNot statement

Blinding (performance bias and detection bias)
Assessors
Low risk"an identical appearing placebo"

Selective reporting (reporting bias)Unclear riskNot stated

Missing dataUnclear riskNot stated

DurationLow risk10 weeks

OutcomeUnclear riskAverage daily pain scores

Treatment arm sizeUnclear risk125 participants; lamotrigine 63, placebo 62

Silver 2007

MethodsRandomised DB placebo controlled, parallel group, 'add on study'. Fourteen-week treatment period consisting of 8 weeks dose escalation and 6 weeks at fixed dose, followed by 1 week tapered withdrawal


ParticipantsNeuropathic pain defined as DN, PHN, nerve injury, spinal cord injury, MS or HIV neuropathy. Mean age 60 years (SD 12). Mean weekly pain score > 4 on 11-point scale. Participants on stable (≥ 4 weeks) treatment with gabapentin, tricyclics or non-opioid analgesics

Excluded: back and neck pain


InterventionsLamotrigine 200 to 400 mg daily or placebo in addition to other (inadequate) treatments as above

Rescue analgesia: paracetamol up to 3 g daily


OutcomesNumerical PR (11-point), sleep interference, short form McGill, neuropathic pain scale, Patient Global Impression of Change


NotesOxford Quality Score: R1, DB2, W1 = 4


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Unclear risk"randomised in a 1:1 ratio"

Allocation concealment (selection bias)Unclear riskNot stated

Blinding (performance bias and detection bias)
Assessors
Unclear riskPlacebo tablets were "identical in appearance"

Selective reporting (reporting bias)Unclear riskNot stated

Missing dataUnclear riskLOCF

DurationLow risk14 week treatment

OutcomeUnclear riskChange in daily pain intensity

Treatment arm sizeUnclear risk111 participants lamotrigine, 109 placebo

Simpson 2000

MethodsMulticentre randomised DB placebo controlled, parallel study. Fourteen-week treatment period


Participants42 participants with painful HIV associated polyneuropathy. Mean age 44 years

Excluded: participants taking valproate


InterventionsLamotrigine or placebo. Week 1 and 2 at 25 mg daily, weeks 3 and 4 at 50 mg daily, week 5 at 100 mg daily, week 6 at 100 mg twice daily, then weeks 7 to 14 at 150 mg twice daily


OutcomesAverage and peak neuropathic pain using Gracely Pain Scale. Difference in weekly mean pain scores. Pain assessed in weeks 1 and 14, also slope of change in pain scores


NotesOxford Quality Score: R2, DB2, W1 = 5


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Low risk"The biostatistician generated a list of treatment assignments in random order using a program written in SAS"

Allocation concealment (selection bias)Low risk"The biostatistician had no contact with patients nor did he communicate these to anyone other than the pharmacists' (to supply the medicines)"

Blinding (performance bias and detection bias)
Assessors
Low risk"Lamotrigine and matching placebo"

Selective reporting (reporting bias)Unclear riskLOCF used for part of the analysis

Missing dataHigh riskCombination of LOCF and completer

DurationLow risk14 weeks including dose escalation

OutcomeUnclear riskDifference in weekly mean pain scores between baseline and final week

Treatment arm sizeHigh risk42 participants in total at start

Simpson 2003

MethodsRandomised DB placebo controlled parallel multicentre trial. One-week screening phase, then 11-week treatment period. Randomisation stratified according to use of neurotoxic antiretroviral therapy (ART)


Participants227 participants with HIV-associated sensory neuropathy. Age 32 to 67 years

Excluded: participants with previous or current use of lamotrigine


InterventionsLamotrigine or placebo. Weeks 1 and 2 at 25 mg on alternate days (daily if taking enzyme-inducing drugs), then dose escalation over 5 weeks to a target dose of 400 mg daily (up to 600 mg daily allowed if taking enzyme-inducing drugs), followed by 4-week maintenance phase. Concomitant medication allowed if stable (≥ 4 weeks) and unchanged

Rescue analgesia: opioid and non-opioid analgesics as needed


OutcomesDaily pain rating of average pain and worst pain on Gracely Pain Scale. VAS PI and short form McGill at end of baseline and beginning and end of maintenance phase, PGIC


NotesOxford Quality Score: R1, DB1, W1 = 3


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Unclear risk"randomised"

Allocation concealment (selection bias)Unclear riskNot stated

Blinding (performance bias and detection bias)
Assessors
Unclear risk"double blind placebo controlled"

Selective reporting (reporting bias)Unclear riskNot stated

Missing dataUnclear riskobserved scores used - meaning unclear

DurationLow risk13 weeks including dose escalation

OutcomeUnclear risk"average pain and worse pain" recorded

Treatment arm sizeUnclear risk227 participants; 150 lamotrigine, 77 placebo

Vestergaard 2001

MethodsRandomised DB placebo controlled, cross-over study. Two 8-week treatment periods, separated by 2-week washout


Participants30 participants with central post-stroke pain with score of > 4 on an 11-point scale. Age 37 to 77 years


InterventionsLamotrigine soluble tablets or matching placebo. Initial dose of 25 mg daily increased every 2nd week to 200 mg daily. No concomitant use of antidepressants, antiepileptics or analgesics allowed

Rescue analgesia: paracetamol 500 mg as needed


OutcomesAverage daily pain score during last week of treatment (11-point Likert scale). Clinical responders defined as 2/10 reduction on lamotrigine compared with placebo period. CAT PR and CAT PI. Use of rescue medication


NotesOxford Quality Score: R2, DB2, W1 = 5


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Low risk"patients were randomised to treatment according to a computer generated randomisation list with a cluster size of six"

Allocation concealment (selection bias)Low risk"code envelopes were kept by the investigator during the trial and returned unopened to the monitor at the termination of the study. The blinding was maintained throughout"

Blinding (performance bias and detection bias)
Assessors
Low risk"soluble lamotrigine and identical placebo"

Selective reporting (reporting bias)Unclear riskNot stated

Missing dataHigh riskCompleter analysis

DurationLow riskTwo 8-week cross-over periods

OutcomeHigh riskClinical response stated to be 2 or more points lower for lamotrigine compared to placebo

Treatment arm sizeHigh risk30 participants; 16 lamotrigine, 13 placebo at initial randomisation, with 20 completers

Vinik 2007a

MethodsRandomised DB placebo controlled parallel group. Nineteen-week treatment period comprising 7-week dose escalation and 12-week fixed dose maintenance phase. Study no NPP30004


Participants360 participants with diabetic neuropathy (type1 or type 2 diabetics). Pain > 6 months and pain score > 4 on 11-point Likert scale. Mean age 59 years (SD 11).


InterventionsLamotrigine at daily dose of 200 mg, 300 mg, 400 mg, or placebo. Dose doubled initially every 2nd week, then weekly to target dose. Concomitant gabapentin and TCAs allowed

Rescue analgesia: paracetamol up to 4 g daily

91/360 received gabapentin, 17/360 received TCAs


OutcomesAverage pain intensity (11 point pain NRS). Sleep disturbance. Short form McGill


NotesOxford Qulaity Score: R2, DB1, W1 = 4


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Low risk'in accordance with a computer generated randomisation schedule. A central randomisation procedure was used'

Allocation concealment (selection bias)Low risk'the study center called into a central system'

Blinding (performance bias and detection bias)
Assessors
Unclear riskstated to be double blind

Selective reporting (reporting bias)Unclear riskNot stated

Missing dataUnclear riskLOCF

DurationLow riskSeven week dose escalation and 12 weeks fixed dose

OutcomeLow risk50% reduction in pain intensity

Treatment arm sizeUnclear risk360 participants; 90 patients randomised per group

Vinik 2007b

MethodsRandomised DB placebo controlled parallel group. Nineteen week treatment period comprising 7 week dose escalation and 12 week fixed dose maintenance phase. Study no NPP30005


Participants360 participants with diabetic neuropathy (type 1 or type 2 diabetics). Pain > 6 months and pain score > 4 on 11 point Likert scale. Mean age 60 years (SD 11). Gabapentin and TCAs allowed. Paracetamol as rescue.


InterventionsLamotrigine at daily dose of 200 mg, 300 mg, 400 mg, or placebo. Dose doubled initially every 2nd week, then weekly to target dose. Concomitant gabapentin and TCAs allowed.

Rescue analgesia: paracetamol up to 4 g daily

76/360 received gabapentin, 23/360 received TCAs


OutcomesAverage pain intensity (11-point pain NRS). Sleep disturbance. Short form McGill

Greater than 50% reduction in average pain intensity


NotesOxford Quality Score: R2, DB1, W1 = 4


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Low risk"in accordance with a computer generated randomisation schedule. A central randomisation procedure was used"

Allocation concealment (selection bias)Low risk"the study center called into a central system"

Blinding (performance bias and detection bias)
Assessors
Unclear riskstated to be double blind

Selective reporting (reporting bias)Unclear riskNot stated

Missing dataUnclear riskLOCF

DurationLow risk7-week dose escalation and 12 weeks fixed dose

OutcomeLow risk50% reduction in pain intensity

Treatment arm sizeUnclear risk360 participants; 90 randomised per group

Zakrzewska 1997

MethodsRandomised DB placebo controlled, cross-over, 'add on study'. Two 2-week treatment periods separated by 3-day washout. Lamotrigine added to existing antiepileptic treatment


Participants14 participants with refractory trigeminal neuralgia. Age 44 to 75 (mean 60 years)


InterventionsLamotrigine or placebo added to existing stable regimen of carbamazepine or phenytoin, or both. Day 1 at 50 mg, day 2 at 100 mg, day 3 at 200 mg, then days 4 to 14 at 400 mg.

Rescue analgesia: increased dose of carbamazepine or phenytoin used for uncontrollable pain


OutcomesNo of pain paroxysms. CAT PI, CAT PR and global assessment at the end of each treatment period


NotesOxford Quality Score: R1, DB2, W1 = 4


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Unclear risk"randomised"

Allocation concealment (selection bias)Unclear riskNot stated

Blinding (performance bias and detection bias)
Assessors
Low risk"dispersible lamotrigine and identical placebo"

Selective reporting (reporting bias)Unclear riskNot stated

Missing dataUnclear riskunclear

DurationHigh risk2 weeks per arm

OutcomeUnclear riskcomposite efficacy index

Treatment arm sizeHigh risk14 participants

 
Characteristics of excluded studies [ordered by study ID]

StudyReason for exclusion

Bonicalzi 1997Pre-emptive study but all participants also received a known analgesic-buprenorphine

Breuer 2007RCT of multiple sclerosis pain. Not neuropathic pain

Carrieri 1998Case study

Devulder 2000Survey not RCT

Di Vadi 1998Case report only

Eisenberg 1998Not randomised

Eisenberg 2003Not randomised

Eisenberg 2005Review article

Lunardi 1997Case series

Petersen 2003RCT but healthy volunteers

Sandner-Kiesling 2002Case report

Shaikh 2011Not randomised or double blind

 
Comparison 1. Painful diabetic neuropathy: lamotrigine versus placebo

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

 1 50% pain relief3773Risk Ratio (M-H, Fixed, 95% CI)1.08 [0.82, 1.42]

 
Comparison 2. All conditions: lamotrigine versus placebo

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

 1 At least one adverse event71121Risk Ratio (M-H, Fixed, 95% CI)1.11 [1.01, 1.22]

 2 Rash121715Risk Ratio (M-H, Fixed, 95% CI)1.43 [1.01, 2.03]

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

Lamotrigine compared with placebo for painful diabetic neuropathy

Patient or population: neuropathic pain (three studies in painful diabetic neuropathy)

Settings: Community

Intervention: oral lamotrigine 200 to 400 mg daily

Comparison: placebo

OutcomesProbable outcome withRisk ratio

NNTor NNH

(95% CI)
No of studies, attacks, eventsQuality of the evidence
(GRADE)
Comments

comparatorintervention

At least 50% of maximum pain relief240 in 1000260 in 1000RR 1.1 (0.82 to 1.4)

NNT not calculated
3 studies, 773 participants, 195 eventsHighUnlikely that further research would reveal significant benefit, especially as potential high positive bias exists in the calculations we have because of LOCF imputation or completer analyses

Participants with at least 1 adverse event (all conditions)622 in 1000717 in 1000RR 1.1 (1.01 to 1.2)

NNH 10 (6.5 to 27)
7 studies, 1121 participants, 768 eventsHighLarge numbers of events

Participants with a serious adverse event (all conditions)No dataVery lowNo data




Participants with rash (all conditions)56 in 100095 in 1000RR 1.4 (1.01 to 2.0)

NNH 27 (16 to 89)
12 studies, 1715 participants, 138 eventsModerateModest number of events

Deaths (all conditions)No dataVery lowNo data




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; NNT: number needed to treat for an additional beneficial outcome: NNH: number needed to treat for an additional harmful outcome; RR: risk ratio