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pharmacotherapy for neuropathic pain, including studies published in peer-reviewed journals since January , 1966, and unpublished trials retrieved from ClinicalTrials.gov and websites of pharmaceutical companies.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 Studies published in peer-reviewed journals reported greater eff ects than did unpublished studies (r² 9·3%, p=0·009).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: Clinically, particularly in primary care (where time for assessment is limited), it is important to identify (possible) neuropathic pain, distinguishing it from other pain types, as it generally fails to respond to standard analgesics but requires a different analgesic approach.
Abstract: Neuropathic pain arises as a direct consequence of a lesion or disease affecting the somatosensory system. It can be peripheral in origin, as a result of nerve injury or disease (eg, lumbar radiculopathy, postherpetic neuralgia, diabetic or HIVrelated neuropathy, or postsurgical pain), or central (eg, poststroke or spinal cord injury). It is characterized by unpleasant symptoms, such as shooting or burning pain, numbness, allodynia, and other sensations that are very difficult to describe. Clinically, particularly in primary care (where time for assessment is limited), it is important to identify (possible) neuropathic pain, distinguishing it from other pain types (including nociceptive pain), as it generally fails to respond to standard analgesics (eg, nonsteroidal anti-inflammatories) but requires a different analgesic approach. As all analgesics potentially cause harm as well as benefit, the distinction will promote safe and effective prescribing. However, “definite” neuropathic pain can relatively rarely be confirmed, particularly in nonspecialist settings. According to the widely accepted grading system proposed by the International Association for the Study of Pain (IASP)’s Special Interest Group on Neuropathic Pain (NeuPSIG), this diagnosis requires (1) a history of a relevant neurological lesion or disease, and pain in a neuroanatomically plausible distribution; (2) sensory signs in the same distribution; and (3) a diagnostic test confirming the lesion or disease in the somatosensory system. Diagnostic testsmight include imaging (eg, magnetic resonance imaging to demonstrate nerve lesion), intraepidermal nerve fibre density measurement on skin biopsy, neurophysiological testing (eg, nerve conduction studies), or genetic testing to demonstrate a relevant hereditary disorder (eg, erythromelalgia). Note that the term “definite” in this grading system is itself relative, and the above tests do not always confirm causality. Much therefore depends on the sharing of a clear history and the elicitation of positive or negative sensory signs. Again, however, in primary care settings, time and experience limit the possibility of detailed clinical examination, and it is therefore the history that assumes dominance in the assessment of pain. This can determine the presence of “possible” neuropathic pain and allow treatment to begin according to an evidence-based neuropathic pain prescribing pathway. Moreover, there is recent and increasing recognition that some classically “nonneuropathic” painful conditions can give rise to symptoms more commonly associated with neuropathic pain, and some evidence that these symptoms respond to “antineuropathic” medicines, such as tricyclic antidepressants and gabapentinoids. For example, a systematic review found that pain was neuropathic in character in 23% of people with knee or hip osteoarthritis, and this was found to be .6 times more likely in those who had experienced knee surgery. Similarly, a Finnish study found that 34%of people with fibromyalgia had clinically verified neuropathic pain. Systematic reviews have found that 18.7% to 27.6% of people with cancer pain have pain with a neuropathic mechanism. Not everyone who experiences a lesion or disease of the somatosensory system goes on to develop neuropathic pain. For example, only around 26%of thosewith type 2 diabetes and 21% of those who experience herpes zoster infection develop neuropathic pain. Although the mechanisms and associated risk factors for some of this variation are becoming understood, much remains unexplained and yet would inform prevention and mitigation. There is therefore an important role for epidemiology in our understanding of neuropathic pain. Epidemiology is, “The study of the occurrence and distribution of health-related states or events in specified populations, including the study of the determinants influencing such states, and the application of this knowledge to control the health problems.” Good information on the prevalence helps to determine the resources required to address the problem, while knowledge of risk helps with diagnosis and prevention, as well as the identification of possible treatment strategies. At the population level, to inform primary care (where most neuropathic pain presents and is managed), this requires communitybased studies, with large sample sizes. Just as nonspecialist assessment of possible neuropathic pain relies primarily on a clinical history, so too must population studies rely on efficient reports of symptoms, as clinical examination is generally not feasible in large studies. This review updates our understanding of the prevalence of neuropathic pain in the community, and genetic and nongenetic factors associated with its presence, severity, and response to treatment, mainly from population studies.
34 citations
TL;DR: Although further well-controlled studies are warranted, the 5% lidocaine medicated plaster is efficacious and safe in LNP and may have particular clinical benefit in elderly and/or medically compromised patients because of the low incidence of adverse events.
Abstract: Topical 5% lidocaine medicated plasters represent a well-established first-line option for the treatment of peripheral localized neuropathic pain (LNP). This review provides an updated overview of the clinical evidence (randomized, controlled, and open-label clinical studies, real-life daily clinical practice, and case series). The 5% lidocaine medicated plaster effectively provides pain relief in postherpetic neuralgia, and data from a large open-label controlled study indicate that the 5% lidocaine medicated plaster is as effective as systemic pregabalin in postherpetic neuralgia and painful diabetic polyneuropathy but with an improved tolerability profile. Additionally, improved analgesia and fewer side effects were experienced by patients treated synchronously with the 5% lidocaine medicated plaster, further demonstrating the value of multimodal analgesia in LNP. The 5% lidocaine medicated plaster provides continued benefit after long-term (≤7 years) use and is also effective in various other LNP conditions. Minor application-site reactions are the most common adverse events associated with the 5% lidocaine medicated plaster; there is minimal risk of systemic adverse events and drug-drug interactions. Although further well-controlled studies are warranted, the 5% lidocaine medicated plaster is efficacious and safe in LNP and may have particular clinical benefit in elderly and/or medically compromised patients because of the low incidence of adverse events.
34 citations
Cites background from "Pharmacotherapy for neuropathic pai..."
...In contrast, a recent systematic review/meta-analysis, using Grading of Recommendations Assessment, Development, and Evaluation criteria and an assessment of number needed to treat (NNT) for 50% pain relief as a primary measure, recommends the 5% lidocaine medicated plaster as a second-line treatment of peripheral neuropathic pain.(29) The analysis included randomized, double-blind, placebocontrolled studies with parallel group or crossover study designs that had at least ten patients per group – from these data, NNTs were generated....
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...However, due to differences in data analysis and without significant changes in the available data in the last 5 years (see “Discussion” section), recommendations are not always aligned.(29) The topical 5% lidocaine medicated plaster is approved in ∼50 countries worldwide for the symptomatic relief of neuropathic pain associated with previous herpes zoster infection; in nine of these countries, it is also approved for the treatment of LNP....
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...Indeed, the most recent NeuPSIG recommendations also acknowledge the first-line use of the 5% lidocaine medicated plaster as a safe and well-accepted option, particularly in frail or elderly individuals, where adverse effects or safety issues associated with systemic therapy are of concern.(29) Extensive postmarketing surveillance has confirmed the favorable safety profile of the 5% lidocaine medicated plaster, supporting its first-line use in the treatment of LNP after herpes zoster infection....
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TL;DR: This study was adequately powered, but treatment with gabapentin did not result in significantly lower pain scores in women with chronic pelvic pain, and was associated with higher rates of side-effects than placebo.
34 citations
TL;DR: Data indicate that the upregulation of Cav2.2 in uninjured DRG neurons via IL-1β over-production contributes to neuropathic pain by increasing neuronal excitability following peripheral nerve injury.
Abstract: N-type voltage-gated calcium (Cav2.2) channels are expressed in the central terminals of dorsal root ganglion (DRG) neurons, and are critical for neurotransmitter release. Cav2.2 channels are also expressed in the soma of DRG neurons, where their function remains largely unknown. Here, we showed that Cav2.2 was upregulated in the soma of uninjured L4 DRG neurons, but downregulated in those of injured L5 DRG neurons following L5 spinal nerve ligation (L5-SNL). Local application of specific Cav2.2 blockers (ω-conotoxin GVIA, 1–100 μM or ZC88, 10–1000 μM) onto L4 and 6 DRGs on the operated side, but not the contralateral side, dose-dependently reversed mechanical allodynia induced by L5-SNL. Patch clamp recordings revealed that both ω-conotoxin GVIA (1 μM) and ZC88 (10 μM) depressed hyperexcitability in L4 but not in L5 DRG neurons of L5-SNL rats. Consistent with this, knockdown of Cav2.2 in L4 DRG neurons with AAV-Cav2.2 shRNA substantially prevented L5-SNL-induced mechanical allodynia and hyperexcitability of L4 DRG neurons. Furthermore, in L5-SNL rats, interleukin-1 beta (IL-1β) and IL-10 were upregulated in L4 DRGs and L5 DRGs, respectively. Intrathecal injection of IL-1β induced mechanical allodynia and Cav2.2 upregulation in bilateral L4–6 DRGs of naive rats, whereas injection of IL-10 substantially prevented mechanical allodynia and Cav2.2 upregulation in L4 DRGs in L5-SNL rats. Finally, in cultured DRG neurons, Cav2.2 was dose-dependently upregulated by IL-1β and downregulated by IL-10. These data indicate that the upregulation of Cav2.2 in uninjured DRG neurons via IL-1β over-production contributes to neuropathic pain by increasing neuronal excitability following peripheral nerve injury.
34 citations
University of Oxford1, University of Bath2, National University of Ireland, Galway3, Aarhus University Hospital4, Aarhus University5, Queen's University6, Washington University in St. Louis7, University of Washington8, Stanford University9, Imperial College London10, California Pacific Medical Center11, University of California, San Francisco12, University of California, San Diego13, Ghent University14
TL;DR: A new high-quality systematic review of randomised controlled trials is needed to critically assess the clinical evidence for cannabinoids, cannabis, or CBM in pain.
Abstract: Cannabinoids, cannabis, and cannabis-based medicines (CBM) are increasingly used to manage pain, with limited understanding of their efficacy and safety We assessed methodological quality, scope, and results of systematic reviews of randomised controlled trials of these treatments Several search strategies sought self-declared systematic reviews Methodological quality was assessed using both AMSTAR-2 and techniques important for bias reduction in pain studies Of the 106 articles read, 57 were self-declared systematic reviews, most published since 2010 They included any type of cannabinoid, cannabis, or CBM, at any dose, however administered, in a broad range of pain conditions No review examined the effects of a particular cannabinoid, at a particular dose, using a particular route of administration, for a particular pain condition, reporting a particular analgesic outcome Confidence in the results in the systematic reviews using AMSTAR-2 definitions was critically low (41), low (8), moderate (6), or high (2) Few used criteria important for bias reduction in pain Cochrane reviews typically provided higher confidence; all industry-conflicted reviews provided critically low confidence Meta-analyses typically pooled widely disparate studies, and, where assessable, were subject to potential publication bias Systematic reviews with positive or negative recommendation for use of cannabinoids, cannabis, or CBM in pain typically rated critically low or low (24/25 [96%] positive; 10/12 [83%] negative) Current reviews are mostly lacking in quality and cannot provide a basis for decision-making A new high-quality systematic review of randomised controlled trials is needed to critically assess the clinical evidence for cannabinoids, cannabis, or CBM in pain
34 citations
Cites background from "Pharmacotherapy for neuropathic pai..."
...For example, Finnerup et al.27 had a critically low AMSTAR rating, but met 6 of 8 critical pain criteria,whereasBrettshneider et al.15 hadahighAMSTAR ratingbut scoredonly 1of 8 criteria....
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...For example, Finnerup et al.(27) had a critically low AMSTAR rating, but met 6 of 8 critical pain criteria,whereasBrettshneider et al....
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...Finnerup et al.(27) Cannabinoids Any Neuropathic 5/815 $50% reduction RD 0....
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References
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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