Pharmacotherapy for neuropathic pain in adults: a systematic review and meta-analysis.
Aarhus University1, French Institute of Health and Medical Research2, Washington University in St. Louis3, Tufts Medical Center4, University of Rochester5, Queen's University6, Helsinki University Central Hospital7, Oslo University Hospital8, Karolinska Institutet9, Aarhus University Hospital10, University of the Witwatersrand11, Churchill Hospital12, Johns Hopkins University13, Imperial College London14, Chelsea and Westminster Hospital NHS Foundation Trust15, California Pacific Medical Center16, University of Edinburgh17, Florey Institute of Neuroscience and Mental Health18, University of Sydney19, Greenwich Hospital20, University of Dundee21, University of California, San Diego22
TL;DR: The results support a revision of the NeuPSIG recommendations for the pharmacotherapy of neuropathic pain and allow a strong recommendation for use and proposal as first-line treatment in neuropathicPain for tricyclic antidepressants, serotonin-noradrenaline reuptake inhibitors, pregabalin, and gabapentin.
Abstract: 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 E valuation (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pharmacotherapy for neuropathic pain, including studies published in peer-reviewed journals since January , 1966, and unpublished trials retrieved from ClinicalTrials.gov and websites of pharmaceutical companies.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 fi xed-eff ects Mantel-Haenszel method. Findings 229 studies were included in the meta-analysis. Analysis of publication bias suggested a 10% overstatement of treatment eff ects. Studies published in peer-reviewed journals reported greater eff ects than did unpublished studies (r² 9·3%, p=0·009). T rial 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, fi nal 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 fi ndings permitted a strong recommendation for use and proposal as fi rst-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 effi cacy, large placebo responses, heterogeneous diagnostic criteria, and poor phenotypic profi ling 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.
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TL;DR: The goal of the present study was to assess the efficacy of the combination of antidepressants with a peptide able to disrupt the interaction between serotonin type 2A (5-HT2A) receptors and associated PDZ proteins and to develop small molecules acting like TAT-2ASCV in order to treat neuropathic pain as a monotherapy or in combination with antidepressants.
9 citations
01 Jan 2015
TL;DR: Poststroke pain can reduce quality of life, increase fatigue, complicate rehabilitation, disturb sleep, affect mood and social functioning, and increase long-term mortality.
Abstract: Henriette M. Klit, MD Henriette M. Klit, MD Danish Pain Research Center Aarhus, Denmark Email: henriette.klit@clin.au.dk Nanna Brix Finnerup, MD Danish Pain Research Center Aarhus, Denmark Email: finnerup@clin.au.dk Troels Staehelin Jensen, MD, DMSc Danish Pain Research Center Aarhus, Denmark Email: tsjensen@clin.au.dk P ain is a common complaint f llowing stroke, reported in 11–55% of stroke survivors. Poststroke pain can arise from muscles, joints, or viscera, or from the peripheral or central nervous system. The most common types of poststroke pain include hemiplegic shoulder pain, pain due to painful spasms or spasticity, poststroke headache, and central poststroke pain. Patients may have several types of poststroke pain concomitantly. Risk factors for poststroke pain include young age, female sex, stroke severity, spasticity, diabetes, sensory disturbance, depression, and pain before stroke onset. Up to 40% of stroke patients who develop poststroke pain have other pre-existing pain conditions. Poststroke pain can reduce quality of life, increase fatigue, complicate rehabilitation, disturb sleep, affect mood and social functioning, and increase long-term mortality. Since the incidence of stroke increases with age and life expectancy is rising, the prevalence of poststroke pain, including central poststroke pain (CPSP), is also likely to increase in the future. It is important to assess the presence of pain in stroke survivors because of its negative impact on quality of life and rehabilitation.
9 citations
Cites background from "Pharmacotherapy for neuropathic pai..."
...PAIN: CLINICAL UPDATES • APRIL 2015 5 line-treatment.(15) At present there is no evidence for combination therapy in CPSP and only limited evidence for its use in other neuropathic pain conditions....
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...Tramadol can be used as an add-on medication.(15,16) The most common side effects of gabapentin and pregabalin include sedation, dizziness, and edema....
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TL;DR: Poorly described procedures and incomplete reporting of rescue and concomitant analgesic use in trials of pharmacotherapy for neuropathic pain and low back pain are suggested to hinder the interpretation, critical appraisal, and replication of trial results.
Abstract: Rescue medication is commonly offered to participants in placebo-controlled trials of analgesic drugs. The use of pain medication in addition to the placebo or experimental drug may complicate the interpretation of effects and tolerability, but this issue has received little methodological attention. This study examined the handling and reporting of rescue and concomitant analgesic use in trials of pharmacotherapy for neuropathic pain and low back pain. We based our review on 265 trials included in 2 recent systematic reviews: 83 trials of low back pain and 182 of neuropathic pain. In total, 117 (44%) trials permitted rescue medication and 126 (48%) allowed participants to continue all or some of their usual analgesics. The utilization of rescue medication increased over time, occurring in 18% of trials before 2000 compared with 55% after 2000. Forty-one trials (16%) permitted both rescue analgesics and continued use of prestudy analgesics. More than one-third of the trials permitting rescue medication did not report the actual rescue drug consumption, and over half of the trials allowing concomitant analgesics did not report whether intake changed during the trial. Only 22 (19%) of the trials permitting rescue medication included complete information about whether rescue medication was used as an outcome, specified the drugs used, specified how consumption was assessed and measured, and reported and analyzed the use of rescue medication in each trial arm. Our findings suggest that poorly described procedures and incomplete reporting are likely to hinder the interpretation, critical appraisal, and replication of trial results.
9 citations
Cites methods from "Pharmacotherapy for neuropathic pai..."
...We identified trials using the reference list in the supplementary appendices 7 and 11.(11) The low back pain review included randomized controlled trials and previous systematic reviews of therapies for nonradicular or radicular low back pain....
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01 Jan 2015
TL;DR: Herpes zoster represents a reactivation of the vari- cella zoster virus (VZV), a ubiquitous, highly neurotropic, exclusively human α-herpesvirus, andostherpetic neuralgia is the most frequent chronic complication of herpes zoster (shingles).
Abstract: ostherpetic neuralgia (PHN) is the most frequent chronic complication of herpes zoster (shingles). 1 Herpes zoster (HZ) represents a reactivation of the vari- cella zoster virus (VZV), a ubiquitous, highly neurotropic, exclusively human α-herpesvirus. Primary infection causes varicella (chickenpox), after which VZV becomes latent in sensory ganglia along the entire neuraxis. With the decline in VZV-specific cell-mediated immunity in elderly and immunocompromised individuals, VZV reactivates to cause HZ, characterized by a painful maculo- papular or vesicular rash in all or part of the skin territory innervated by a single dorsal root ganglion. 2 The most common site of HZ is thoracic, comprising about half of all cases, followed by trigemi- nal (usually the ophthalmic branch), cervical, and lumbar distributions. HZ generally resolves within a few weeks, but a minority of patients experience pain (PHN) persisting for months, years, or even a lifetime.
9 citations
Cites background or methods from "Pharmacotherapy for neuropathic pai..."
...PAIN: CLINICAL UPDATES • MAY 2015 5 to prepare recommendations for neuropathic pain in general instead of for various etiologies.(32) First-line agents for neuropathic pain are TCAs, SNRIs, and gabapentinoids on the basis of evidence of their efficacy and safety....
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...A PHN-specific meta-analysis was published in 2005,(31) but recommendations provided here are largely based on analyses from 2014 and 2015.(1,32) Tricyclic antidepressants (TCAs), gabapentinoids, opioids, and topical capsaicin have strong evidence Editorial Board...
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...Strong opioids (particularly oxycodone and morphine) and botulinum toxin A are recommended as third line mainly because of safety concerns (opioids) or weak quality of evidence (botulinum toxin A).(32) Strong opioids (oxycodone, morphine and methadone) have shown efficacy in PHN....
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...Randomized trials suggest that the combination of pregabalin or gabapentin and duloxetine or tricyclic antidepressants is an alternative option to increasing doses of one class of drugs for patients unresponsive to moderate doses of monotherapy.(32) As multiple pain mechanisms coexist in PHN, combining drugs with different mechanisms of action is rational and should be studied further to better understand its value in the clinic....
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...this treatment is recommended only for specialist use in refractory cases.(32)...
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TL;DR: In this paper, a pooled analysis using data from the two pivotal Phase III studies in Asian patients with diabetic peripheral neuropathic pain and post-herpetic neuralgia, aimed to provide clinicians with more detailed and precise information relating to mirogabalin's safety and efficacy.
9 citations
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TL;DR: Moher et al. as mentioned in this paper introduce PRISMA, an update of the QUOROM guidelines for reporting systematic reviews and meta-analyses, which is used in this paper.
Abstract: David Moher and colleagues introduce PRISMA, an update of the QUOROM guidelines for reporting systematic reviews and meta-analyses
62,157 citations
Journal Article•
TL;DR: The QUOROM Statement (QUality Of Reporting Of Meta-analyses) as mentioned in this paper was developed to address the suboptimal reporting of systematic reviews and meta-analysis of randomized controlled trials.
Abstract: Systematic reviews and meta-analyses have become increasingly important in health care. Clinicians read them to keep up to date with their field,1,2 and they are often used as a starting point for developing clinical practice guidelines. Granting agencies may require a systematic review to ensure there is justification for further research,3 and some health care journals are moving in this direction.4 As with all research, the value of a systematic review depends on what was done, what was found, and the clarity of reporting. As with other publications, the reporting quality of systematic reviews varies, limiting readers' ability to assess the strengths and weaknesses of those reviews.
Several early studies evaluated the quality of review reports. In 1987, Mulrow examined 50 review articles published in 4 leading medical journals in 1985 and 1986 and found that none met all 8 explicit scientific criteria, such as a quality assessment of included studies.5 In 1987, Sacks and colleagues6 evaluated the adequacy of reporting of 83 meta-analyses on 23 characteristics in 6 domains. Reporting was generally poor; between 1 and 14 characteristics were adequately reported (mean = 7.7; standard deviation = 2.7). A 1996 update of this study found little improvement.7
In 1996, to address the suboptimal reporting of meta-analyses, an international group developed a guidance called the QUOROM Statement (QUality Of Reporting Of Meta-analyses), which focused on the reporting of meta-analyses of randomized controlled trials.8 In this article, we summarize a revision of these guidelines, renamed PRISMA (Preferred Reporting Items for Systematic reviews and Meta-Analyses), which have been updated to address several conceptual and practical advances in the science of systematic reviews (Box 1).
Box 1
Conceptual issues in the evolution from QUOROM to PRISMA
46,935 citations
TL;DR: Funnel plots, plots of the trials' effect estimates against sample size, are skewed and asymmetrical in the presence of publication bias and other biases Funnel plot asymmetry, measured by regression analysis, predicts discordance of results when meta-analyses are compared with single large trials.
Abstract: Objective: Funnel plots (plots of effect estimates against sample size) may be useful to detect bias in meta-analyses that were later contradicted by large trials. We examined whether a simple test of asymmetry of funnel plots predicts discordance of results when meta-analyses are compared to large trials, and we assessed the prevalence of bias in published meta-analyses. Design: Medline search to identify pairs consisting of a meta-analysis and a single large trial (concordance of results was assumed if effects were in the same direction and the meta-analytic estimate was within 30% of the trial); analysis of funnel plots from 37 meta-analyses identified from a hand search of four leading general medicine journals 1993-6 and 38 meta-analyses from the second 1996 issue of the Cochrane Database of Systematic Reviews . Main outcome measure: Degree of funnel plot asymmetry as measured by the intercept from regression of standard normal deviates against precision. Results: In the eight pairs of meta-analysis and large trial that were identified (five from cardiovascular medicine, one from diabetic medicine, one from geriatric medicine, one from perinatal medicine) there were four concordant and four discordant pairs. In all cases discordance was due to meta-analyses showing larger effects. Funnel plot asymmetry was present in three out of four discordant pairs but in none of concordant pairs. In 14 (38%) journal meta-analyses and 5 (13%) Cochrane reviews, funnel plot asymmetry indicated that there was bias. Conclusions: A simple analysis of funnel plots provides a useful test for the likely presence of bias in meta-analyses, but as the capacity to detect bias will be limited when meta-analyses are based on a limited number of small trials the results from such analyses should be treated with considerable caution. Key messages Systematic reviews of randomised trials are the best strategy for appraising evidence; however, the findings of some meta-analyses were later contradicted by large trials Funnel plots, plots of the trials9 effect estimates against sample size, are skewed and asymmetrical in the presence of publication bias and other biases Funnel plot asymmetry, measured by regression analysis, predicts discordance of results when meta-analyses are compared with single large trials Funnel plot asymmetry was found in 38% of meta-analyses published in leading general medicine journals and in 13% of reviews from the Cochrane Database of Systematic Reviews Critical examination of systematic reviews for publication and related biases should be considered a routine procedure
37,989 citations
TL;DR: An instrument to assess the quality of reports of randomized clinical trials (RCTs) in pain research is described and its use to determine the effect of rater blinding on the assessments of quality is described.
15,740 citations
TL;DR: The advantages of the GRADE system are explored, which is increasingly being adopted by organisations worldwide and which is often praised for its high level of consistency.
Abstract: Guidelines are inconsistent in how they rate the quality of evidence and the strength of recommendations. This article explores the advantages of the GRADE system, which is increasingly being adopted by organisations worldwide
13,324 citations