Elsevier

The Lancet Neurology

Volume 14, Issue 2, February 2015, Pages 162-173
The Lancet Neurology

Articles
Pharmacotherapy for neuropathic pain in adults: a systematic review and meta-analysis

https://doi.org/10.1016/S1474-4422(14)70251-0Get rights and content

Summary

Background

New drug treatments, clinical trials, and standards of quality for assessment of evidence justify an update of evidence-based recommendations for the pharmacological treatment of neuropathic pain. Using the Grading of Recommendations Assessment, Development, and Evaluation (GRADE), we revised the Special Interest Group on Neuropathic Pain (NeuPSIG) recommendations for the pharmacotherapy of neuropathic pain based on the results of a systematic review and meta-analysis.

Methods

Between April, 2013, and January, 2014, NeuPSIG of the International Association for the Study of Pain did a systematic review and meta-analysis of randomised, double-blind studies of oral and topical pharmacotherapy for neuropathic pain, including studies published in peer-reviewed journals since January, 1966, and unpublished trials retrieved from ClinicalTrials.gov and websites of pharmaceutical companies. We used number needed to treat (NNT) for 50% pain relief as a primary measure and assessed publication bias; NNT was calculated with the fixed-effects Mantel-Haenszel method.

Findings

229 studies were included in the meta-analysis. Analysis of publication bias suggested a 10% overstatement of treatment effects. Studies published in peer-reviewed journals reported greater effects than did unpublished studies (r2 9·3%, p=0·009). Trial outcomes were generally modest: in particular, combined NNTs were 6·4 (95% CI 5·2–8·4) for serotonin-noradrenaline reuptake inhibitors, mainly including duloxetine (nine of 14 studies); 7·7 (6·5–9·4) for pregabalin; 7·2 (5·9–9·21) for gabapentin, including gabapentin extended release and enacarbil; and 10·6 (7·4–19·0) for capsaicin high-concentration patches. NNTs were lower for tricyclic antidepressants, strong opioids, tramadol, and botulinum toxin A, and undetermined for lidocaine patches. Based on GRADE, final quality of evidence was moderate or high for all treatments apart from lidocaine patches; tolerability and safety, and values and preferences were higher for topical drugs; and cost was lower for tricyclic antidepressants and tramadol. These findings permitted a strong recommendation for use and proposal as first-line treatment in neuropathic pain for tricyclic antidepressants, serotonin-noradrenaline reuptake inhibitors, pregabalin, and gabapentin; a weak recommendation for use and proposal as second line for lidocaine patches, capsaicin high-concentration patches, and tramadol; and a weak recommendation for use and proposal as third line for strong opioids and botulinum toxin A. Topical agents and botulinum toxin A are recommended for peripheral neuropathic pain only.

Interpretation

Our results support a revision of the NeuPSIG recommendations for the pharmacotherapy of neuropathic pain. Inadequate response to drug treatments constitutes a substantial unmet need in patients with neuropathic pain. Modest efficacy, large placebo responses, heterogeneous diagnostic criteria, and poor phenotypic profiling probably account for moderate trial outcomes and should be taken into account in future studies.

Funding

NeuPSIG of the International Association for the Study of Pain.

Introduction

Neuropathic pain, caused by a lesion or disease affecting the somatosensory nervous system,1 has a substantial effect on quality of life and is associated with a high economic burden for the individual and society.2, 3, 4 It is now regarded as a distinct clinical entity despite a large variety of causes.5

Epidemiological surveys have shown that many patients with neuropathic pain do not receive appropriate treatment.2, 6, 7 The reasons might be low diagnostic accuracy and ineffective drugs, and perhaps also insufficient knowledge about effective drugs and their appropriate use in clinical practice.8 Evidence-based recommendations for the pharmacotherapy of neuropathic pain are therefore essential.

Over the past 10 years, a few recommendations have been proposed for the pharmacotherapy of neuropathic pain9, 10, 11 or specific neuropathic pain disorders, particularly painful diabetic neuropathies and post-herpetic neuralgia.12, 13, 14 Meanwhile, new pharmacological therapies have been developed and high-quality clinical trials have been done. Previously undisclosed and unpublished large trials can now be identified online (ClinicalTrials.gov and pharmaceutical industry websites), which, together with an analysis of publication bias, might reduce the risk of bias in reporting data. Furthermore, there were some discrepancies in previous recommendations due to inconsistencies in methods used to assess the quality of evidence.13, 15, 16 To address these inconsistencies, the Grading of Recommendations Assessment, Development, and Evaluation (GRADE) was introduced in 200017, 18 and received widespread international acceptance. Together, these reasons justify an update of the evidence-based recommendations for the pharmacotherapy of neuropathic pain.

We did a systematic review and meta-analysis of randomised controlled trials of all drug treatments for neuropathic pain published since 1966 and of unpublished trials with available results, and assessed publication bias. We used GRADE to rate the quality of evidence and the strength of recommendations.17, 18 On the basis of the updated review and meta-analysis, we revised the recommendations of the Special Interest Group on Neuropathic Pain (NeuPSIG) of the International Association for the Study of Pain for the systemic and topical pharmacological treatment of neuropathic pain.19 Non-pharmacological management strategies such as neurostimulation techniques were beyond the scope of this work.20

Section snippets

Search strategy and selection criteria

We followed the 23-item Appraisal of Guidelines for Research and Evaluation (AGREE II) for developing and reporting recommendations.21 For details of the working group, criteria for eligibility of studies for the analysis, search methods, reporting, and statistical analysis, see the appendix.

The systematic review of the literature complied with the PRISMA statement.22 We used a standardised review and data extraction protocol (unpublished, appendix). The full reports of randomised, controlled,

Results

Figure 1 shows the results of the database and registry search. 191 published reports and 21 unpublished studies were included in the quantitative synthesis. Study characteristics are summarised in the appendix. Additionally, five published and 12 unpublished studies were retrieved between April, 2013, and January, 2014. Thus, a total of 229 reports or studies were included (see appendix for details of the references).

In studies eligible for inclusion in the meta-analysis, the following drugs

Discussion

In accordance with previous reports,23 results of our meta-analysis show that the efficacy of systemic drug treatments is generally not dependent on the cause of the underlying disorder (appendix). Side-effects might, however, to some degree depend on the cause—eg, drugs with CNS-related side-effects might be tolerated less well in patients with CNS lesions.43 Pain due to HIV-related painful polyneuropathy and radiculopathy seems more refractory than other types of pain in our meta-analysis.

References (70)

  • AR Jadad et al.

    Assessing the quality of reports of randomized clinical trials: is blinding necessary?

    Control Clin Trials

    (1996)
  • I Gilron et al.

    Combination pharmacotherapy for management of chronic pain: from bench to bedside

    Lancet Neurol

    (2013)
  • S Tesfaye et al.

    Duloxetine and pregabalin: high-dose monotherapy or their combination? The “COMBO-DN study” – a multinational, randomized, double-blind, parallel-group study in patients with diabetic peripheral neuropathic pain

    Pain

    (2013)
  • A Thornton et al.

    Publication bias in meta-analysis: its causes and consequences

    J Clin Epidemiol

    (2000)
  • NI Cherny

    The treatment of neuropathic pain: from hubris to humility

    Pain

    (2007)
  • M Haanpaa et al.

    NeuPSIG guidelines on neuropathic pain assessment

    Pain

    (2011)
  • DT Demant et al.

    The effect of oxcarbazepine in peripheral neuropathic pain depends on pain phenotype: a randomised, double-blind, placebo-controlled phenotype-stratified study

    Pain

    (2014)
  • CM Campbell et al.

    Randomized control trial of topical clonidine for treatment of painful diabetic neuropathy

    Pain

    (2012)
  • D Bouhassira et al.

    Neuropathic pain phenotyping as a predictor of treatment response in painful diabetic neuropathy: Data from the randomized, double-blind, COMBO-DN study

    Pain

    (2014)
  • JT Farrar et al.

    Effect of variability in the 7-day baseline pain diary on the assay sensitivity of neuropathic pain randomized clinical trials: an ACTTION study

    Pain

    (2014)
  • N Attal et al.

    Assessing symptom profiles in neuropathic pain clinical trials: can it improve outcome?

    Eur J Pain

    (2011)
  • R Baron et al.

    Subgrouping of patients with neuropathic pain according to pain-related sensory abnormalities: a first step to a stratified treatment approach

    Lancet Neurol

    (2012)
  • R Freeman et al.

    Sensory profiles of patients with neuropathic pain based on the neuropathic pain symptoms and signs

    Pain

    (2014)
  • M Nolano et al.

    Topical capsaicin in humans: parallel loss of epidermal nerve fibers and pain sensation

    Pain

    (1999)
  • GP Davis et al.

    Association between cannabis use, psychosis, and schizotypal personality disorder: findings from the National Epidemiologic Survey on Alcohol and Related Conditions

    Schizophr Res

    (2013)
  • IASP taxonomy

  • PC Langley et al.

    The burden associated with neuropathic pain in Western Europe

    J Med Econ

    (2013)
  • V Martinez et al.

    Adherence of French GPs to Chronic Neuropathic Pain Clinical Guidelines: Results of a Cross-Sectional, Randomized, “e” Case-Vignette Survey

    PLoS One

    (2014)
  • N Attal et al.

    EFNS guidelines on pharmacological treatment of neuropathic pain

    Eur J Neurol

    (2006)
  • N Attal et al.

    EFNS guidelines on the pharmacological treatment of neuropathic pain: 2010 revision

    Eur J Neurol

    (2010)
  • DE Moulin et al.

    Pharmacological management of chronic neuropathic pain—consensus statement and guidelines from the Canadian Pain Society

    Pain Res Manag

    (2007)
  • RM Dubinsky et al.

    Practice parameter: treatment of postherpetic neuralgia: an evidence-based report of the Quality Standards Subcommittee of the American Academy of Neurology

    Neurology

    (2004)
  • V Bril et al.

    Evidence-based guideline: Treatment of painful diabetic neuropathy: report of the American Academy of Neurology, the American Association of Neuromuscular and Electrodiagnostic Medicine, and the American Academy of Physical Medicine and Rehabilitation

    Neurology

    (2011)
  • DL Hershman et al.

    Prevention and management of chemotherapy-induced peripheral neuropathy in survivors of adult cancers: American Society of Clinical Oncology Clinical Practice Guideline

    J Clin Oncol

    (2014)
  • T Tan et al.

    Pharmacological management of neuropathic pain in non-specialist settings: summary of NICE guidance

    BMJ

    (2010)
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