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pharmacotherapy for neuropathic pain, including studies published in peer-reviewed journals since January , 1966, and unpublished trials retrieved from ClinicalTrials.gov and websites of pharmaceutical companies.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 Studies published in peer-reviewed journals reported greater eff ects than did unpublished studies (r² 9·3%, p=0·009).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: Small fiber neuropathy is a disorder of the thinly myelinated and unmyelinated nerve fibers most commonly presenting in a length-dependent form, but non-length-dependent neuropathies are seen in a small subset of patients.
Abstract: Small fiber neuropathy is a disorder of the thinly myelinated and unmyelinated nerve fibers most commonly presenting in a length-dependent form, but non–length-dependent neuropathies are seen in a small subset of patients.1 As in many other neuropathies, many underlying diseases may cause damage to the small nerve fibers, including diabetes, sarcoid, and Sjogren syndrome. There are also rare genetic forms such as Fabry disease and transthyretin amyloidosis. Small fiber neuropathies are characterized by is disruption to pain, thermal sensitivity, and autonomic nerve fibers.1 Clinically, neuropathic pain is the most common complaint.
3 citations
TL;DR: A graded approach, from least to most invasive interventions has the potential to improve outcomes in many patients with common refractory NP conditions, and preliminary promising data warrant further research on new indications.
Abstract: Background and Objectives: Interventional management of neuropathic pain (NP) is available to the patients who do not obtain satisfactory pain relief with pharmacotherapy. Evidence supporting this is sparse and fragmented. We attempted to summarize and critically appraise the existing data to identify strategies that yield the greatest benefit, guide clinicians, and identify areas that merit further investigation. Material and Methods: A two-round Delphi survey that involved pain clinic specialists with experience in the research and management of NP was done over an ad hoc 26-item questionnaire made by the authors. Consensus on each statement was defined as either at least 80% endorsement or rejection after the 2nd round. Results: Thirty-five and 29 panelists participated in the 1st and 2nd round, respectively. Consensus was reached in 20 out of 26 statements. There is sufficient basis to treat postherpetic neuralgias and complex regional pain syndromes with progressive levels of invasiveness and failed back surgery syndrome with neuromodulation. Radiculopathies and localized NP can be treated with peripheral blocks, neuromodulation, or pulsed radiofrequency. Non-ablative radiofrequency and non-paresthetic neuromodulation are efficacious and better tolerated than ablative and suprathreshold procedures. Conclusions: A graded approach, from least to most invasive interventions has the potential to improve outcomes in many patients with common refractory NP conditions. Preliminary promising data warrant further research on new indications, and technical advances might enhance the safety and efficacy of current and future therapies.
3 citations
TL;DR: In this paper , the authors outline a bench-to-bedside roadmap for this transition to mechanistically informed personalised pain medicine, and discuss general and specific aspects of human trial design to address heterogeneity in patient populations to increase the chance of identifying effective analgesics.
Abstract: Chronic pain is a constantly recurring and persistent illness, presenting a formidable healthcare challenge for patients and physicians alike. Current first line analgesics offer only low-modest efficacy when averaged across populations, further contributing to this debilitating disease burden. Moreover, many recent trials for novel analgesics have not met primary efficacy endpoints, which is particularly striking considering the pharmacological advances have provided a range of highly relevant new drug targets. Heterogeneity within chronic pain cohorts is increasingly understood to play a critical role in these failures of treatment and drug discovery, with some patients deriving substantial benefit from a given intervention whilst it has little-to-no effect in others. As such, current treatment failures may not result from a true lack of efficacy, but rather a failure to target them to individuals whose pain is driven by mechanisms which it therapeutically modulates. This necessitates a move towards phenotypical stratification of patients in order to delineate responders and non-responders in a mechanistically driven manner. In this article, we outline a bench-to-bedside roadmap for this transition to mechanistically informed personalised pain medicine. We emphasise how successful identification of novel analgesics is dependent on rigorous experimental design as well as validity of models and translatability of outcome measures between animal model and patients. Subsequently, we discuss general and specific aspects of human trial design to address heterogeneity in patient populations to increase the chance of identifying effective analgesics. Finally, we show how stratification approaches can be brought into clinical routine to the benefit of patients.
3 citations
TL;DR: Therapeutic management of the patient in this report can be considered effective, since five years after the end of the treatment there was no recurrence or presence of metastasis.
Abstract: Neuropathic pain occurs when there is a lesion or a dysfunction of the nervous system. Humans and veterinary patients may develop neuropathic pain, but in veterinary it is not often reported probably because of its mistaken diagnosis. A canine patient was admitted to the Veterinary Hospital of UNESP-Jaboticabal-SP, Brazil with a nodule on the left thoracic limb. The nodule was surgically removed, and histopathological analysis demonstrated the tumor was a soft tissue sarcoma (STS) and the margins were not clean. Based on the patient’s health condition and the lack of suitable equipment, the next procedure was limb amputation. The patient received analgesic medication in the post-surgery period; nevertheless, clinical signs of neuropathic pain were present, such as compulsive licking and other behavioral disorders. Medications were administered for forty days, but clinical signs ceased only when replaced with a tryciclic antidepressant drug, Amitriptyline. Therapeutic management of the patient in this report can be considered effective, since five years after the end of the treatment there was no recurrence or presence of metastasis.
3 citations
Cites background from "Pharmacotherapy for neuropathic pai..."
...The understanding of the neurobiology of pain is in constant advance, however, the pharmacological management of pain syndromes remain insufficient and several drugs have failed in the late-stage (Finnerup et al., 2015)....
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TL;DR: The aim was to investigate the effects of polymorphisms in genes encoding the dopamine active transporter and dopamine receptor D2 on preoperative pain expression among patients preparing for orthopedic surgery.
Abstract: OBJECTIVES The dopaminergic pathway plays a vital role in pain expression. Here, our aim was to investigate the effects of polymorphisms in genes encoding the dopamine active transporter (SLC6A3) and dopamine receptor D2 (DRD2) on preoperative pain expression among patients preparing for orthopedic surgery. METHODS Chinese elderly patients scheduled for orthopedic surgery were enrolled. The VAS was used to evaluate pain intensity (score range 0 to 10; 0 = no pain; 10 = worst pain possible). Depressive symptoms were evaluated via the 15-item Geriatric Depression Scale. DNA was isolated from venous blood samples, and single-nucleotide polymorphisms of SLC6A3 and DRD2 were genotyped. Multiple linear regressions analyses were carried out to adjust the results for confounders. RESULTS A total of 294 patients with a mean age of 73.82 ± 8.03 years were enrolled in this study. After adjustment for confounders, rs393795 in SLC6A3 showed a significant association with preoperative VAS scores. Patients with the A/A genotype reported lower mean pain scores than did those with the A/C genotype (P = 0.026). Subsequent depression-stratified analysis of rs6276 in DRD2 revealed that patients with the A/A genotype had higher pain scores than did those with the G/G genotype (P = 0.043). No associations were found for DRD2 rs6277 in the whole study population or depression-stratified groups. CONCLUSION Genetic variations in SLC6A3 and DRD2 may play an important role in pain expression among the elderly prior to orthopedic surgery.
3 citations
Cites result from "Pharmacotherapy for neuropathic pai..."
...especially serotonin and norepinephrine, in pain expression is well established, and clinical trials have shown that serotonin norepinephrine reuptake inhibitors are effective against neuropathic pain.(7) Additionally, the role of the dopaminergic system in pain expression received increasing attention in recent studies....
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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