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pharmacotherapy for neuropathic pain, including studies published in peer-reviewed journals since January , 1966, and unpublished trials retrieved from ClinicalTrials.gov and websites of pharmaceutical companies.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 Studies published in peer-reviewed journals reported greater eff ects than did unpublished studies (r² 9·3%, p=0·009).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: Although this drug has long been considered extremely safe, recent clinical studies have pointed to potential safety issues on long-term use, and data suggest that the initial clinical efficacy of pregabalin may have been overestimated.
Abstract: We read with interest the recent systematic review and metaanalysis of pregabalin preclinical studies conducted by Federico et al. This meta-analysis shows a huge positive effect of pregabalin for neuropathic pain behavior in rodents, with 68% of complete analgesia on average (ie, return to prebaseline outcome measures at all time points after drug administration). Such observed benefit was of similar magnitude in very recent high-quality preclinical studies as compared with initial studies using lower standards. Is this high and maintained preclinical effect translated into similar benefit in clinical trials? Admittedly, almost all initial large-scale studies were positive for pregabalin in neuropathic pain, although efficacy tended to decrease in more recent studies. This decline in efficacy is even more remarkable now. Thus, in a recent systematic study of all potential treatment options for chronic neuropathic pain, we identified 12 placebocontrolled trials assessing the efficacy of pregabalin as a primary outcome from 2014 to 2019. These studies generally used pregabalin at doses mimicking routine clinical practice (150-300 mg daily). Of these studies, only 2 came out positive on the primary outcome (Table 1). An additional metaanalysis performed according to PRISMA guidelines, showed that the standardized mean difference between pregabalin and placebo was only 20.11 (95% confidence interval: 20.21 to 20.02), estimated by the DerSimonian and Laird randomeffects model (Fig. 1). Another multicenter study of high dosages of pregabalin (600 mg daily) conducted in patients with mainly acute sciatica was totally negative. Finally, although pregabalin has long been considered as effective as gabapentin, a recent double-blind comparative study indicated that gabapentin was more effective. Altogether, these data suggest that the initial clinical efficacy of pregabalin may have been overestimated. The meta-analysis by Federico et al. only focused on the efficacy of pregabalin and not on safety. This probably reflects the fact that drug-related side effects are difficult to assess in rodents, particularly if they concern long-term safety. Unpredictable safety issues represent a major cause for treatment development discontinuation in humans despite favorable outcome in animals. Recent examples in neuropathic pain concern in particular nicotine agonists, angiotensin type II antagonists, and TRPV1 antagonists. Could it be the same for pregabalin? Although this drug has long been considered extremely safe, recent clinical studies have pointed to potential safety issues on long-term use. In particular, abuse with pregabalin and gabapentin has been reported in 1.6% of patients taking gabapentinoids in the general population and in up to 68% of opioid abusers, patients self-administering higher than recommended doses to achieve euphoric highs. Misuse, defined as a use of higher daily doses than recommended, has been documented in 12.8% of new users of pregabalin. Such risks were probably underestimated for many years because they were not mentioned in official recommendations and not routinely included in toxicological screening for coroners’ cases. Finally, the concomitant use of pregabalin with opioids has also been reported to increase the risk of opioid-related death. Even without opioids, the long-term use of gabapentinoids, especially pregabalin, has recently been associated with an increased risk of suicidal behavior, unintentional overdoses, head/body injuries, and road traffic incidents. Pregabalin is a “commercially successful drug,” with more than a 2-fold increase in prescriptions in the United States between 2012 and 2016 not only in neuropathic pain but also in many other pain conditions, such as fibromyalgia, arthritis, or low back pain. In the United Kingdom, prescriptions for pregabalin have increased more than 15-fold in 14 years, from 476,102 in 2006 to 7,332,981 in 2019 (openprescribing.net). Thus, around 1% of the general UK population has received at least 1 pregabalin prescription during the past month. According to Pharma Marketing (2018), worldwide sales of pregabalin in 2017 have reached the 10th position in terms of gross sales (about 5.1 billion USD), with an annual growth rate of 2.8%. However, clinicians are now strongly advised to prescribe pregabalin with caution. The drug has recently been downgraded for the first time as second line in the latest evidence-based French guidelines on neuropathic pain, and gabapentinoids have been reclassified as a class C-controlled drug since April 2019 in the United Kingdom. The discrepancies between observed benefits or harms in animal models of pain and those reported in clinical trials have been repeatedly outlined. Despite its qualities, this new meta-analysis does not seem to escape the rule.
6 citations
TL;DR: There is no recommendation in Europe for the use of ketamine in patients with chronic pain, but the heterogeneity of practice highlights the need to seek the advice of experts in order to establish a national consensus.
6 citations
09 Nov 2018
5 citations
Journal Article•
TL;DR: The results confirm that statin therapy can improve peripheral atherosclerosis and reverse atherosclerotic plaques.
Abstract: Previous studies have shown that the commonly used statin lipid lowering drugs can delay the progression of atherosclerotic plaque. Atorvastatin can stabilize atherosclerotic plaque, but it can not reverse atheromatous plaque. This study will compare the efficacy of rosuvastatin and atorvastatin in the treatment of atherosclerosis and try to prove that the use of statins can improve peripheral atherosclerosis and reverse atherosclerotic plaque. The results showed that 10 mg rosuvastatin was more effective than 20 mg atorvastatin in lowering serum lipid level and elevating ABI index, ABI as rosuvastatin group (0.782±0.236) and atorvastatin group(0.541±0.196). After 6 months of treatment, the carotid artery IMT in rosuvastatin group and atorvastatin group decreased compared with before treatment, and the difference was statistically significant (P<0.05). The TC/mmol⋅L-1 is 2.83±0.56 in rosuvastatin group and 3.24±0.71 in atorvastatin group. In addition, rosuvastatin did not increase the risk of adverse reactions compared with atorvastatin. The results confirm that statin therapy can improve peripheral atherosclerosis and reverse atherosclerotic plaques.
5 citations
Cites background from "Pharmacotherapy for neuropathic pai..."
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TL;DR: In this article, the authors show that 6 weeks of wheel running prior to nerve injury can attenuate neuropathic pain by supporting redox homeostasis after sciatic nerve injury in male and female rats.
Abstract: Animal and human studies have shown that exercise prior to nerve injury prevents later chronic pain, but the mechanisms of such preconditioning remain elusive. Given that exercise acutely increases formation of free radicals, triggering antioxidant compensation, we hypothesized that voluntary running preconditioning would attenuate neuropathic pain by supporting redox homeostasis after sciatic nerve injury in male and female rats. We show that 6 weeks of voluntary wheel running suppresses neuropathic pain development induced by chronic constriction injury (CCI) across both sexes. This protection was associated with reduced nitrotyrosine immunoreactivity—a marker for peroxynitrite—at the sciatic nerve injury site. Our data suggest that prior voluntary wheel running does not reduce production of peroxynitrite precursors, as expression levels of inducible nitric oxide synthase and NADPH oxidase 2 were unchanged. Instead, voluntary wheel running increased superoxide scavenging by elevating expression of superoxide dismutases 1 and 2. Prevention of neuropathic pain was further associated with activation of the master transcriptional regulator of the antioxidant response, nuclear factor E2-related factor 2 (Nrf2). Six weeks of prior voluntary wheel running increased Nrf2 nuclear translocation at the sciatic nerve injury site; in contrast, 3 weeks of prior wheel running, which failed to prevent neuropathic pain, had no effect on Nrf2 nuclear translocation. The protective effects of prior voluntary wheel running were mediated by Nrf2, as suppression was abolished across both sexes when Nrf2 activation was blocked during the running phase. This study provides insight into the mechanisms by which physical activity may prevent neuropathic pain.
5 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