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pharmacotherapy for neuropathic pain, including studies published in peer-reviewed journals since January , 1966, and unpublished trials retrieved from ClinicalTrials.gov and websites of pharmaceutical companies.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 Studies published in peer-reviewed journals reported greater eff ects than did unpublished studies (r² 9·3%, p=0·009).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: A review aimed to describe some essential elements for understanding neuropathic pain after peripheral nerve injury and to discuss its mechanisms with an emphasis on interneuronal disinhibition as mentioned in this paper.
Abstract: Context: Dysfunction of pain circuitry may alter normal pain perception, leading to neuropathic pain. The underlying mechanisms are still unclear, although several animal models of partial nerve injury have been developed. Objectives: This review aimed to describe some essential elements for understanding neuropathic pain after peripheral nerve injury and to discuss its mechanisms with an emphasis on interneuronal disinhibition. Evidence Acquisition: A PubMed search was undertaken with no date restrictions, using a combination of the following keywords: “mechanisms”, “allodynia”, “peripheral nerve injury”, “neuropathic pain”, and “interneuronal disinhibition”. Then, relevant papers on the underlying mechanisms of neuropathic pain after peripheral nerve injury were selected. Results: Several hypotheses have been proposed to explain neuropathic pain, which are not necessarily independent of each other. Interneuronal disinhibition is one of the most promising hypotheses, which includes several possible mechanisms, such as death of inhibitory interneurons (1), reduced afferent drive to inhibitory interneurons (2), depletion of gamma-aminobutyric acid (GABA) (3), GABA dysfunction (4), altered membrane properties of inhibitory interneurons (5), and specific glycine disruption (6). Currently, only some of these hypotheses are promising. Technical discrepancies among experimental studies are partially responsible for some of these controversial results. Conclusions: Formerly neglected circuitries including the glycinergic system, as well as other disturbances such as shift of GABA activity, currently constitute the most promising hypotheses on neuropathic pain. Additional studies on cell types involved in nociceptive transmission and dorsal horn connectivity of the spinal cord are still needed for a better understanding of pain circuitry and its disorders.
6 citations
TL;DR: A hierarchical cluster analysis to identify patient clusters in the Observational Study to which RCT patients could be matched using the coarsened exact matching (CEM) technique, thereby creating a matched dataset, and autoregressive moving average models (ARMAXs) to estimate weekly pain scores for pregabalin-treated patients in each cluster in the matched dataset using the maximum likelihood method.
Abstract: More patient-specific medical care is expected as more is learned about variations in patient responses to medical treatments. Analytical tools enable insights by linking treatment responses from different types of studies, such as randomized controlled trials (RCTs) and observational studies. Given the importance of evidence from both types of studies, our goal was to integrate these types of data into a single predictive platform to help predict response to pregabalin in individual patients with painful diabetic peripheral neuropathy (pDPN). We utilized three pivotal RCTs of pregabalin (398 North American patients) and the largest observational study of pregabalin (3159 German patients). We implemented a hierarchical cluster analysis to identify patient clusters in the Observational Study to which RCT patients could be matched using the coarsened exact matching (CEM) technique, thereby creating a matched dataset. We then developed autoregressive moving average models (ARMAXs) to estimate weekly pain scores for pregabalin-treated patients in each cluster in the matched dataset using the maximum likelihood method. Finally, we validated ARMAX models using Observational Study patients who had not matched with RCT patients, using t tests between observed and predicted pain scores. Cluster analysis yielded six clusters (287–777 patients each) with the following clustering variables: gender, age, pDPN duration, body mass index, depression history, pregabalin monotherapy, prior gabapentin use, baseline pain score, and baseline sleep interference. CEM yielded 1528 unique patients in the matched dataset. The reduction in global imbalance scores for the clusters after adding the RCT patients (ranging from 6 to 63% depending on the cluster) demonstrated that the process reduced the bias of covariates in five of the six clusters. ARMAX models of pain score performed well (R
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: 0.85–0.91; root mean square errors: 0.53–0.57). t tests did not show differences between observed and predicted pain scores in the 1955 patients who had not matched with RCT patients. The combination of cluster analyses, CEM, and ARMAX modeling enabled strong predictive capabilities with respect to pain scores. Integrating RCT and Observational Study data using CEM enabled effective use of Observational Study data to predict patient responses.
6 citations
Cites background from "Pharmacotherapy for neuropathic pai..."
...Ongoing efforts strive to identify psychosocial variables that could be used to identify patient subgroups [16] as well, even if the end goal of fully personalized or precision medicine cannot be achieved in the short term [5]....
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...Reasons include shortfalls in proper patient and pain assessment, insufficient diagnostic accuracy, and inadequate knowledge about medications and their appropriate clinical use, combined with relatively limited treatment efficacy [5]....
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...Association for the Study of Pain included pregabalin, among other medications, as having a ‘strong’ GRADE recommendation as first-line therapy for neuropathic pain [5]....
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...Neuropathic pain has a large variety of etiologies and many patients do not receive appropriate treatment for their pain [5], including those with pDPN....
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TL;DR: Emerging data suggest that modulating the primary afferent input may open new horizons for the treatment of central neuropathic pain, and certain non-pharmacologic approaches, neuromodulation in particular, may be helpful in refractory cases.
6 citations
TL;DR: In this paper , the authors provide an updated evidence-based approach for the management of painful diabetic peripheral neuropathy using highfrequency spinal cord stimulation, which has become a promising alternative for non-pharmacological interventions.
6 citations
TL;DR: 5% Lidocaine-medicated plaster may be useful as add-on therapy for a number of peripheral neuropathic pain conditions, including CRPS.
Abstract: Objectives Chronic neuropathic pain and chronic complex regional pain syndrome (CRPS), in particular, are debilitating and difficult-to-treat conditions that have a strong impact on patient's quality of life. The aim of this study was to evaluate the effectiveness of 5% lidocaine-medicated plaster as add-on therapy in patients with chronic peripheral neuropathic pain conditions, including CRPS. Patients and methods This was a single-center, prospective, observational study set in a specialized pain unit of a tertiary hospital in Spain. A total of 56 patients with long-standing peripheral neuropathic pain, ten of them with CRPS, received 5% lidocaine-medicated plaster as add-on analgesic therapy for 6 months. Results After 6 months of treatment, a ≥50% reduction in pain intensity was attained by 75% of patients, as measured by numeric rating scale (NRS) for pain. The average NRS score was reduced by 61% (4.7 points), from a baseline mean score of 7.8 to an end point mean score of 3.1. Marked improvements were also observed in the CRPS group: six out of ten patients achieved a ≥50% reduction in NRS score, and the average NRS score for patients with CRPS was reduced by 51% (4.0 points), from a baseline mean score of 7.9 to an end point mean score of 3.9. The improvements in pain intensity were partially translated into a decrease in disability index and in anxiety levels. Conclusion 5% Lidocaine-medicated plaster may be useful as add-on therapy for a number of peripheral neuropathic pain conditions, including CRPS.
6 citations
Cites background from "Pharmacotherapy for neuropathic pai..."
...Conventional analgesics, such as nonsteroidal anti-inflammatory drugs (NSAIDs) and opioids, usually provide little relief, and the use of nonconventional analgesics (ie, antidepressants, anticonvulsants, and psychotropics) is common in clinical practice,(5) although in case of CRPS the supporting clinical evidence is limited.(5,6) Topical treatments can be an alternative or add-on therapy particularly useful in case of localized neuropathic pain....
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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