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Levetiracetam for neuropathic pain in adults

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

Editorial Group: Cochrane Pain, Palliative and Supportive Care Group

Published Online: 7 JUL 2014

Assessed as up-to-date: 3 JUL 2014

DOI: 10.1002/14651858.CD010943.pub2


How to Cite

Wiffen PJ, Derry S, Moore RA, Lunn MPT. Levetiracetam for neuropathic pain in adults. Cochrane Database of Systematic Reviews 2014, Issue 7. Art. No.: CD010943. DOI: 10.1002/14651858.CD010943.pub2.

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: 7 JUL 2014

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Characteristics of included studies [ordered by study ID]
Falah 2012

MethodsRandomised, double-blind, placebo-controlled, cross-over study (2 x 6 weeks of treatment with 1 week washout)

Pain medication tapered and stopped during pre-study period of ≥ 1 week

Medication taken twice daily, titrated slowly over 15 days to maximum tolerated dose; target 3000 mg daily, reduction to minimum 2000 mg daily allowed for intolerable side effects


ParticipantsCentral neuropathic pain due to multiple sclerosis (specialist confirmed). Median total pain rating ≥ 4/10 during week off pain medication

N = 30

M 2, F 22

Median age 47 years (31 to 63)

Median baseline pain 5.8/10 (4 to 9)


InterventionsLevetiracetam 2000 to 3000 mg daily (maximum tolerated)

Placebo

Rescue medication: up to 6 x 500 mg paracetamol + 50 mg tramadol daily


OutcomesPR at end of treatment period: 6 point scale

PI: NRS (0 to 10) for total pain and specific pain symptoms, daily

Sleep disturbance: NRS (0 to 10), daily

Phasic spacticity: NRS (0 to 4), daily

Rescue medication

Adverse events


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

Study drugs provided by UCB Pharma, who also provided some financial support


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Low risk"computer-generated randomization list"

Allocation concealment (selection bias)Low riskRemote allocation. Packaged and numbered by pharmacy, allocated consecutively. Sealed opaque envelopes with treatment details for emergencies

Blinding of participants and personnel (performance bias)
All outcomes
Low riskplacebo tablets "identical in appearance, dosed similarly"

Blinding of outcome assessment (detection bias)
All outcomes
Low riskplacebo tablets "identical in appearance, dosed similarly"

Incomplete outcome data (attrition bias)
All outcomes
Unclear riskLOCF for withdrawals

SizeHigh risk< 50 participants per treatment arm (n ≤ 30)

Finnerup 2009

MethodsRandomised, double-blind, placebo-controlled, cross-over study (1 week baseline then 2 x 5 weeks of treatment with 1 week washout)

Medication taken twice daily, increased over 2 weeks to maximum tolerated dose; target 3000 mg daily, reduction to minimum of 2000 mg daily allowed for intolerable side effects


ParticipantsSCI with resulting at- or below-level of injury (or both) neuropathic pain for ≥ 3 months and median pain intensity ≥ 4/10 during baseline period

N = 36

M 29, F 7

Mean age 53 years (SD ± 11)


InterventionsLevetiracetam 2000 to 3000 mg daily (maximum tolerated)

Placebo

Antidepressant medication tapered off during pre-study period, other spasmolytics, antiepileptics, opioids, simple analgesics continued if constant and unchanged

Rescue medication: up to 6 x 500 mg paracetamol daily


OutcomesPI: NRS (0 to 10), daily

Sleep interference: NRS (0 to 10), daily

Change in median pain score from baseline week to end of study

PR: 6 point scale (overall, at-level, below-level pain)

≥ 33% pain relief

Change in specific pain symptoms

Spasm intensity and severity: NRS (0 to 10)

PGIC: 5-point scale

Rescue medication

Adverse events


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

Study drugs provided by UCB Pharma, who also provided some financial support


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Low risk"computer-generated randomization list"

Allocation concealment (selection bias)Low riskRemote allocation. Packaged and numbered by pharmacy, allocated consecutively. Sealed opaque envelopes with treatment details for emergencies

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

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

Incomplete outcome data (attrition bias)
All outcomes
Unclear riskLOCF for withdrawals

SizeHigh risk< 50 participants per treatment arm (n ≤ 36)

Holbech 2011

MethodsRandomised, double-blind, placebo-controlled, cross-over study (1 week baseline then 2 x 6 weeks of treatment with 1 week washout)

All pain medication tapered and stopped during pre-study period of ≥ 1 week

Medication taken twice daily, titrated slowly over 15 days to maximum tolerated dose; target 3000 mg daily, reduction to minimum 2000 mg daily allowed for intolerable side effects


ParticipantsPolyneuropathy with pain ≥ 6 months and sensory disturbance in area of pain. Median total pain rating ≥ 4/10 during week off pain medication

N = 39

M 22, F 13 (participants with sufficient data from both periods)

Median age 57 years (21 to 74)

Median total pain at baseline 5.7 (4 to 9)


InterventionsLevetiracetam 2000 mg to 3000 mg daily (maximum tolerated)

Placebo

Rescue medication: up to 6 x 500 mg paracetamol + 50 mg tramadol daily


OutcomesPR: 6-point scale at end of each week

PI:NRS (0 to 10) for total pain and specific pain symptoms, daily

Sleep disturbance: NRS (0 to 10), daily

Quality of life: SF-36 at end of each treatment period

Rescue medication

Adverse events


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

Study drugs provided by UCB Pharma, who also provided some financial support


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Low risk"computer-generated randomization list"

Allocation concealment (selection bias)Low riskRemote allocation. Packaged and numbered by pharmacy, allocated consecutively. Sealed opaque envelopes with treatment details for emergencies

Blinding of participants and personnel (performance bias)
All outcomes
Low risk"Placebo tablets with identical appearance were dosed similarly"

Blinding of outcome assessment (detection bias)
All outcomes
Low risk"Placebo tablets with identical appearance were dosed similarly"

Incomplete outcome data (attrition bias)
All outcomes
Unclear riskLOCF for withdrawals

SizeHigh risk< 50 participants per treatment arm (n ≤ 39)

Jungehulsing 2013

MethodsRandomised, double-blind, placebo-controlled, cross-over study (4-week baseline then 2 x 8 weeks of treatment with 2 week washout after each)

Medication taken twice daily, starting at 1000 mg daily and increased every second week to target 3000 mg daily, reduction to previous tolerated dose allowed for intolerable side effects


ParticipantsCentral spot-stroke pain for > 3 months with pain intensity ≥ 4/10 at baseline

N = 42

M 26, F 16

Mean age 62 years (40 - 76)

Median baseline pain 7/10


InterventionsLevetiracetam to 3000 mg daily (maximum tolerated)

Placebo

Antidepressants, antipsychotics, antiepileptics and analgesics allowed if stable and unchanged


OutcomesPI: NRS (0 to 10) three times daily

Responder = PI reduction of ≥ 2/10 in final week compared to end of baseline

Pain assessment: McGill Pain Questionnaire

Depression: Beck Depression Inventory

Quality of life: SF-12

Adverse events


NotesOxford Quality Score: R = 2, DB = 1, W = 1. Total = 4/5

Study drugs provided by UCB Pharma, who also provided some financial support


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Low risk"computer-generated randomization list"

Allocation concealment (selection bias)Unclear riskIndependent generation of list. Sequential allocation of numbers. Sealed envelopes with treatment details for emergencies

Blinding of participants and personnel (performance bias)
All outcomes
Unclear riskMethod not described

Blinding of outcome assessment (detection bias)
All outcomes
Unclear riskMethod not described

Incomplete outcome data (attrition bias)
All outcomes
High riskWithdrawals > 10%. Per protocol data reported. Imputation method not described

SizeHigh risk< 50 participants per treatment arm (n ≤ 42)

NCT00160511

MethodsRandomised, double-blind, placebo-controlled, parallel group. Multicentre

16 week duration: 1-week baseline, 4-week up titration, 8-week maintenance, taper blinded period, 1-week drug-free

Medication taken twice daily


ParticipantsPost herpetic neuralgia for ≥ 3 months and PI ≥ 40/100 at baseline with average daily score ≥ 4/10 for ≥ 4 days/week

N = 170

M 90, F 77 (ITT)

Mean age 70 years (± 12)


InterventionsLevetiracetam 1000 mg to 3000 mg daily

Placebo


OutcomesChange in PI from baseline to final week of treatment

Adverse events


NotesOxford Quality Score: R = 1, DB = 1, W = 1. Total = 3/5

Completed 2005. Study sponsor: UCB, Inc.

Unpublished study; methods from clinicaltrials.gov, results from clinical study summary


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Unclear riskMethod of sequence generation not described

Allocation concealment (selection bias)Unclear riskNot described

Blinding of participants and personnel (performance bias)
All outcomes
Unclear riskMethod of blinding not described

Blinding of outcome assessment (detection bias)
All outcomes
Unclear riskMethod of blinding not described

Incomplete outcome data (attrition bias)
All outcomes
Unclear riskWithdrawals > 20%. Mean data for efficacy with no mention of imputation method

SizeUnclear risk50 to 200 participants per treatment arm (n = 83 to 86)

Vilholm 2008

MethodsRandomised, double-blind, placebo-controlled, cross-over study (2 x 4 weeks of treatment with 1 week washout)

All pain medication tapered during pre-study period of ≥ 1 week

Medication taken twice daily, titrated over 11 days to 3000 mg daily


ParticipantsPost-mastectomy pain (in breast, axilla, arm) ≥ 6 months after surgery for breast cancer. Pain duration ≥ 3 months, present ≥ 4 days/week, with median rating ≥ 4/10 during week off pain medication

N = 27

All F

Median age 60 years (38 to 80)

Mean baseline pain 5.9/10 (4 to 9.6)


InterventionsLevetiracetam 3000 mg daily

Placebo

Rescue medication: up to 8 x 500 mg paracetamol + 50 mg tramadol daily


OutcomesPR: NRS (0 to 10) at end of treatment period

PI: NRS (0 to 10) for total pain and specific pain symptoms, daily

Rescue medication

Adverse events


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

Study drugs provided by UCB Pharma, who also provided some financial support


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Low risk"computer-generated randomization code"

Allocation concealment (selection bias)Low riskRemote allocation. Packaged and numbered by pharmacy, allocated consecutively

Blinding of participants and personnel (performance bias)
All outcomes
Low risk"placebo tablets with identical appearance were dosed similarly"

Blinding of outcome assessment (detection bias)
All outcomes
Low risk"placebo tablets with identical appearance were dosed similarly"

Incomplete outcome data (attrition bias)
All outcomes
Unclear riskLOCF for withdrawals

SizeHigh risk< 50 participants per treatment arm (n ≤ 27)

 
Characteristics of excluded studies [ordered by study ID]

StudyReason for exclusion

Rossi 2009Single blind

 
Characteristics of studies awaiting assessment [ordered by study ID]
NCT00156689

MethodsNone provided. Probably not randomised, controlled, double-blind.

ParticipantsChronic idiopathic axonal polyneuropathy. Pain for ≥ 3 months, with intensity ≥ 40/100 at baseline (average daily score ≥ 4/10 for ≥ 4 days/week)

M and F

Age ≥ 18 years

InterventionsLevetiracetam (no dose or duration of treatment provided, implies 6 weeks)

No comparator provided

OutcomesChange in PI from baseline to last week of evaluation

30% responder

50% responder

PGIC at final visit

NotesCompleted 2007. Study sponsor: Vanderbilt University. Principle investigator: Gary W Duncan, MD, Vanderbilt University

 
Comparison 1. Levetiriacetam versus placebo

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

 1 Participants with substantial pain relief (≥50% pain intensity reduction, or complete or good pain relief)4240Risk Ratio (M-H, Fixed, 95% CI)0.85 [0.43, 1.69]

 2 Participants with at least one adverse event5409Risk Ratio (M-H, Fixed, 95% CI)1.24 [1.06, 1.45]

 3 All cause withdrawal6501Risk Ratio (M-H, Fixed, 95% CI)1.90 [1.28, 2.81]

 4 Adverse event withdrawal6500Risk Ratio (M-H, Fixed, 95% CI)4.90 [2.17, 11.09]

 5 Lack of efficacy withdrawal6500Risk Ratio (M-H, Fixed, 95% CI)1.29 [0.66, 2.52]

 
Summary of findings for the main comparison.

Levetiracetam compared with placebo for neuropathic pain

Patient or population: neuropathic pain (6 studies in central neuropathic pain due to multiple sclerosis, spinal cord injury, polyneuropathy, central post-stroke pain, postherpetic neuralgia, and post-mastectomy pain)

Intervention: levetiracetam 2000 mg to 3000 mg daily

Comparison: placebo

OutcomesProbable outcome with comparator (placebo)Probable outcome with interventionRelative effect
(95% CI)
No. of participants
and studies
Quality of the evidence
(GRADE)
Comments

At least 50% reduction in pain9/579/59Not calculated2 studies, 59 participantsVery lowSmall numbers of studies and participants, cross-over studies, potential bias in analysis

At least 30% reduction in pain12/5711/59Not calculated2 studies, 59 participantsVery lowSmall numbers of studies and participants, cross-over studies, potential bias in analysis

Proportion below 30/100 mm on VASNo data






Patient Global Impression of Change very much improved (patient global evaluation of pain relief complete or good)6/864/86Not calculated3 studies, 86 participantsVery lowSmall numbers of studies and participants, cross-over studies, potential bias in analysis

Patient Global Impression of Change much or very much improved (patient global evaluation of pain relief complete, good or moderate)8/8613/86Not calculated3 studies, 86 participantsVery lowSmall numbers of studies and participants, cross-over studies, potential bias in analysis

Any measure of 'substantial' pain relief14/11912/121Not calculated4 studies, 121 participantsVery lowSmall numbers of studies and participants, cross-over studies, potential bias in analysis

Adverse event withdrawals24 in 1000130 in 1000RR 4.9 (2.2 to 11)

NNH 9.7 (6.7 to 18)
6 studies, 334 participants in totalVery lowSmall numbers of studies and participants

Serious adverse events2/3342/334Not calculated6 studies, 334 participants in totalVery lowSmall numbers of studies and participants

DeathNo deathsVery lowSmall numbers of studies and participants






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.

 CI: confidence interval; NNH: number needed to treat to harm; RR: risk ratio; VAS: visual analogue scale