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pharmacotherapy for neuropathic pain, including studies published in peer-reviewed journals since January , 1966, and unpublished trials retrieved from ClinicalTrials.gov and websites of pharmaceutical companies.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 Studies published in peer-reviewed journals reported greater eff ects than did unpublished studies (r² 9·3%, p=0·009).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 overall prevalence of chronic pain was 28.2% (95% CI: 26.3-30.5), ranging from 22.5% to 35.4%, depending on the location of the primary tumor, and neuropathic characteristics were present in 20.9% of patients with chronic pain.
Abstract: This prospective national multicenter study was carried out to estimate the prevalence and incidence of chronic pain with or without neuropathic characteristics in patients with cancer in France. All consecutive outpatients (n = 1885) seen over 2 weeks for cancer treatment in 12 oncology units were invited to participate in the study, and 1805 were included. Patients underwent a clinical examination during visit 1, and a questionnaire was completed to detect chronic pain (defined as daily pain for at least 3 months), and to characterize its intensity, location, and neuropathic characteristics (ie, DN4 score ≥4). The impact of pain on quality of life was assessed with the Brief Pain Inventory. Patients without pain at visit 1 were included in the incidence study and were seen at 3 and 6 months after visit 1. The overall prevalence of chronic pain was 28.2% (95% CI: 26.3-30.5), ranging from 22.5% to 35.4%, depending on the location of the primary tumor. Neuropathic characteristics were present in 20.9% of these patients, with a prevalence of 2.9% to 9.7%, depending on primary tumor location. Pain intensity and interference were higher in patients with neuropathic characteristics. In total, 1285 patients were included in the incidence study, 873 of whom were seen at least once, 3, or 6 months after the first visit. The incidence of chronic pain during the 6-month follow-up period ranged from 13% to 28%, depending on primary tumor location, and neuropathic characteristics were found in 19.9% of patients with chronic pain.
70 citations
Cites result from "Pharmacotherapy for neuropathic pai..."
...Consistent with this hypothesis, less than 30% of our patients received one of the first-line treatments recommended for neuropathic pain.(12) Similar results have been reported before, suggesting that neuropathic pain is still undertreated, or inadequately treated, in patients with cancer pain....
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TL;DR: This review describes a taxonomy of preclinical procedures organized into an “antinociception matrix” by reference to their types of pain stimulus and pain behavior and particular emphasis is devoted to pain behaviors and the behavioral principals that govern their expression, pharmacological modulation, and preclinical-to-clinical translation.
Abstract: All preclinical procedures for analgesic drug discovery involve two components: 1) a "pain stimulus" (the principal independent variable), which is delivered to an experimental subject with the intention of producing a pain state; and 2) a "pain behavior" (the principal dependent variable), which is measured as evidence of that pain state. Candidate analgesics are then evaluated for their effectiveness to reduce the pain behavior, and results are used to prioritize drugs for advancement to clinical testing. This review describes a taxonomy of preclinical procedures organized into an "antinociception matrix" by reference to their types of pain stimulus (noxious, inflammatory, neuropathic, disease related) and pain behavior (unconditioned, classically conditioned, operant conditioned). Particular emphasis is devoted to pain behaviors and the behavioral principals that govern their expression, pharmacological modulation, and preclinical-to-clinical translation. Strengths and weaknesses are compared and contrasted for procedures using each type of behavioral outcome measure, and the following four recommendations are offered to promote strategic use of these procedures for preclinical-to-clinical analgesic drug testing. First, attend to the degree of homology between preclinical and clinical outcome measures, and use preclinical procedures with behavioral outcome measures homologous to clinically relevant outcomes in humans. Second, use combinations of preclinical procedures with complementary strengths and weaknesses to optimize both sensitivity and selectivity of preclinical testing. Third, take advantage of failed clinical translation to identify drugs that can be back-translated preclinically as active negative controls. Finally, increase precision of procedure labels by indicating both the pain stimulus and the pain behavior in naming preclinical procedures.
69 citations
Cites background from "Pharmacotherapy for neuropathic pai..."
...Cannabinoids are generally thought to have their best therapeutic effectiveness for treatment of chronic pain, including neuropathic pain; however, even here, a growing body of evidence from clinical trials suggests that THC and cannabis products have weak and unreliable analgesic effectiveness despite being tested up to doses that produce problematic side effects (Finnerup et al., 2015; Aviram and Samuelly-Leichtag, 2017; Mücke et al., 2018; Stockings et al., 2018)....
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...…with neuropathic insults (Park et al., 2013; Bannister et al., 2017) is not consistent with its relatively weak effectiveness to treat neuropathic pain (Pachman et al., 2011; Finnerup et al., 2015), but may be related to its effectiveness to treat neuropathy-associated itch (Maciel et al., 2014)....
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..., 2017) is not consistent with its relatively weak effectiveness to treat neuropathic pain (Pachman et al., 2011; Finnerup et al., 2015), but may be related to its effectiveness to treat neuropathy-associated itch (Maciel et al....
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...ing clinical data suggest that it has limited clinical effectiveness both in absolute terms and in comparison with other analgesics such m opioid receptor agonists or monoamine uptake inhibitor antidepressants (Pachman et al., 2011; Finnerup et al., 2015; Wiffen et al., 2017)....
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...…pain, but prevailing clinical data suggest that it has limited clinical effectiveness both in absolute terms and in comparison with other analgesics such m opioid receptor agonists or monoamine uptake inhibitor antidepressants (Pachman et al., 2011; Finnerup et al., 2015; Wiffen et al., 2017)....
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TL;DR: This unique multicentre approach provided high-quality evidence evaluating suppressed burrowing as robust and reproducible, supporting its use as tool to infer the global effect of pain on rodents.
Abstract: Burrowing, an ethologically relevant rodent behaviour, has been proposed as a novel outcome measure to assess the global impact of pain in rats. In a prospective multicentre study using male rats (Wistar, Sprague-Dawley), replication of suppressed burrowing behaviour in the complete Freund adjuvant (CFA)-induced model of inflammatory pain (unilateral, 1 mg/mL in 100 µL) was evaluated in 11 studies across 8 centres. Following a standard protocol, data from participating centres were collected centrally and analysed with a restricted maximum likelihood-based mixed model for repeated measures. The total population (TP-all animals allocated to treatment; n = 249) and a selected population (SP-TP animals burrowing over 500 g at baseline; n = 200) were analysed separately, assessing the effect of excluding "poor" burrowers. Mean baseline burrowing across studies was 1113 g (95% confidence interval: 1041-1185 g) for TP and 1329 g (1271-1387 g) for SP. Burrowing was significantly suppressed in the majority of studies 24 hours (7 studies/population) and 48 hours (7 TP, 6 SP) after CFA injections. Across all centres, significantly suppressed burrowing peaked 24 hours after CFA injections, with a burrowing deficit of -374 g (-479 to -269 g) for TP and -498 g (-609 to -386 g) for SP. This unique multicentre approach first provided high-quality evidence evaluating suppressed burrowing as robust and reproducible, supporting its use as tool to infer the global effect of pain on rodents. Second, our approach provided important informative value for the use of multicentre studies in the future.
69 citations
Cites background from "Pharmacotherapy for neuropathic pai..."
...Furthermore, pharmacological validation studies should be conducted, preferably informed by robust meta-analyses of clinical trials to guide both drug and dose selection.(17,53) First, it should be demonstrated to what extent clinically efficacious drugs reverse suppression of burrowing....
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Yale University1, University of Alabama at Birmingham2, University of California, San Francisco3, Long Island University4, University of Maryland, Baltimore5, University of North Carolina at Chapel Hill6, Memorial Sloan Kettering Cancer Center7, Cornell University8, Johns Hopkins University9, Albert Einstein College of Medicine10
TL;DR: The types of chronic pain commonly seen among persons living with HIV (PLWH) are reviewed and the limited evidence base for treatment of chronic noncancer pain in this population is reviewed.
Abstract: Pain has always been an important part of human immunodeficiency virus (HIV) disease and its experience for patients. In this guideline, we review the types of chronic pain commonly seen among persons living with HIV (PLWH) and review the limited evidence base for treatment of chronic noncancer pain in this population. We also review the management of chronic pain in special populations of PLWH, including persons with substance use and mental health disorders. Finally, a general review of possible pharmacokinetic interactions is included to assist the HIV clinician in the treatment of chronic pain in this population.It is important to realize that guidelines cannot always account for individual variation among patients. They are not intended to supplant physician judgment with respect to particular patients or special clinical situations. The Infectious Diseases Society of American considers adherence to these guidelines to be voluntary, with the ultimate determination regarding their application to be made by the physician in the light of each patient's individual circumstances.
69 citations
Cites background from "Pharmacotherapy for neuropathic pai..."
...meaningful pain reduction or improvement that have not been validated for chronic neuropathic pain [116, 117]....
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...Pain’s Special Interest Group on Neuropathic Pain (NeuPSIG) [116]....
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TL;DR: The step-function inhibitory channelrhodopsin, SwiChR, can be used to persistently inhibit pain for long periods of time through infrequent transdermally delivered light pulses, reducing required light exposure by >98% and resolving a long-standing limitation in optogenetic inhibition.
Abstract: Spatially targeted, genetically-specific strategies for sustained inhibition of nociceptors may help transform pain science and clinical management. Previous optogenetic strategies to inhibit pain have required constant illumination, and chemogenetic approaches in the periphery have not been shown to inhibit pain. Here, we show that the step-function inhibitory channelrhodopsin, SwiChR, can be used to persistently inhibit pain for long periods of time through infrequent transdermally delivered light pulses, reducing required light exposure by >98% and resolving a long-standing limitation in optogenetic inhibition. We demonstrate that the viral expression of the hM4D receptor in small-diameter primary afferent nociceptor enables chemogenetic inhibition of mechanical and thermal nociception thresholds. Finally, we develop optoPAIN, an optogenetic platform to non-invasively assess changes in pain sensitivity, and use this technique to examine pharmacological and chemogenetic inhibition of pain.
69 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