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pharmacotherapy for neuropathic pain, including studies published in peer-reviewed journals since January , 1966, and unpublished trials retrieved from ClinicalTrials.gov and websites of pharmaceutical companies.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 Studies published in peer-reviewed journals reported greater eff ects than did unpublished studies (r² 9·3%, p=0·009).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 results showed that daily i.p. administrations of pregabalin but not gabapentin or baclofen significantly decreased DI and RI compared to saline group, and suggested that preGabalin alone or in combination with bacl ofen significantly caused cognitive deficits.
Abstract: Memory impairment is one of the greatest concerns when it comes to long-term CNS-affecting drug administration Drugs like gabapentin, pregabalin and baclofen are administered in a long-term period in conditions such as epilepsy, neuropathic pain, spasticity associated with spinal cord injury or multiple sclerosis Despite their wide spread use, few data are available on the effects of these drugs on cognitive functions, such as learning memory In the present study, the effects of long-term administration of gabapentin, pregabalin and baclofen on memory were investigated in a comparative manner Male Wistar rats received intraperitoneal (ip) injection of gabapentin (30 mg/kg), pregabalin (30 mg/kg), baclofen (3 mg/kg), combination of gabapentin/baclofen (30/3 mg/kg) and combination of pregabalin/baclofen (30/3 mg/kg) once a day for 3 weeks respective to their groups After the end of treatments, rat memories were assessed using the object-recognition task The discrimination and recognition indices (RI and DI) in the T2 trials were used as the memory indicating factors The results showed that daily ip administrations of pregabalin but not gabapentin or baclofen significantly decreased DI and RI compared to saline group In combination groups, either gabapentin or pregabalin impaired discrimination between new and familiar objects Our findings suggested that pregabalin alone or in combination with baclofen significantly caused cognitive deficits
15 citations
Cites background or methods from "Pharmacotherapy for neuropathic pai..."
...The object recognition task (ORT) is used to evaluate cognition, particularly recognition memory, in rodent models of CNS disorders....
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...It has varied causes such as spinal cord injury, stroke, multiple sclerosis, diabetes mellitus, neoplasia tumors and other diseases affecting the CNS (1,2)....
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...We used two different sets of objects consisted of (1) a heavy aluminum cube (10....
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...Neuropathic pain (NP) is a pain incepted or caused by a primary disease, lesion or dysfunction in the nervous system (1)....
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TL;DR: The use of the interventional therapies can be limited by the requirement of specific trained healthcare teams and technical support, or the lack of health policies, but these interventional strategies need to be proposed as soon as possible to each patient requiring them, as they can greatly improve quality of life.
Abstract: Interventional therapies are important to consider when facing cancer pain refractory to conventional therapies. The objective of the current review is to introduce these effective strategies into dynamic interdisciplinary pain management, leading to an exhaustive approach to supportive oncology. Critical reflection based on literature analysis and clinical practice. Interventional therapies act on the nervous system via neuromodulation or surgical approaches, or on primitive or metastatic lesions via interventional radiotherapy, percutaneous ablation, or surgery. Interventional therapies such as neuromodulations are constantly evolving with new technical works still in development. Nowadays, their usage is better defined, depending on clinical situations, and their impact on quality of life is proven. Nevertheless their availability and acceptability still need to be improved. To start with, a patient’s interdisciplinary evaluation should cover a wide range of items such as patient’s performance and psychological status, ethical considerations, and physiochemical and pharmacological properties of the cerebrospinal fluid for intrathecal neuromodulation. This will help to define the most appropriate strategy. In addition to determining the pros and cons of highly specialized interventional therapies, their relevance should be debated within interdisciplinary teams in order to select the best strategy for the right patient, at the right time. Ultimately, the use of the interventional therapies can be limited by the requirement of specific trained healthcare teams and technical support, or the lack of health policies. However, these interventional strategies need to be proposed as soon as possible to each patient requiring them, as they can greatly improve quality of life.
15 citations
TL;DR: Although the M leprae infection is curable, patients remain at long-term risk of complications (including neuropathic pain) from existing nerve damage and also further nerve damage from reactions, and all patients should receive multidrug treatment to treat the infection and reduce the development of drug-resistant M lePrae.
Abstract: Leprosy is a chronic granulomatous infectious disease that primarily affects the skin and peripheral nervous system. It is caused by Mycobacterium leprae, an acid-fast, gram-positive obligate intracellular organism, trophic for macrophages and Schwann cells and transmitted through nasal secretions from untreated lepromatous patients. Patients present with skin lesions and/or peripheral neuropathy and are diagnosed when one or more cardinal signs— loss of sensation in pale or reddish skin lesions, peripheral nerve thickening, or acid-fast bacilli in a slit-skin smear— are present, with histological evidence of leprosy inflammation being the gold standard. Leprosy continues to be a global health issue with approximately 250,000 new leprosy cases reported annually and persistent disability and pain afflicting many of those in whom infection has been eliminated by multidrug therapy. The clinical presentation of M leprae infection is determined by the host immune response, with a spectrum of disease from a limited tuberculoid type to a more widespread lepromatous type. In tuberculoid leprosy, a cell-mediated immune response is associated with epithelioid cell activation and granuloma formation, leading to nerve damage and hypopigmented anesthetic skin lesions. Conversely, lepromatous leprosy is associated with limited cell-mediated immunity and proliferation of M leprae, which infiltrate Schwann cells, resulting in cytokinemediated axonal degeneration and other systemic features. The 3 borderline states—borderline tuberculoid, mid-borderline, borderline lepromatous—represent a spectrum of disease. The clinical spectrum of leprosy is summarized in Figure 1. Patients can also be classified by the number of skin lesions present, with 5 or fewer lesions being paucibacillary and greater than 5 being multibacillary (MB). Classification is important because it determines treatment and prognosis, withMBpatients at higher risk of developing nerve damage and leprosy reactions. All patients should receive multidrug treatment to treat the infection and reduce the development of drug-resistant M leprae. Multidrug treatment with rifampicin, clofazimine, and dapsone is first line for MB leprosy and has a cure rate of 98%. Although the M leprae infection is curable, patients remain at long-term risk of complications (including neuropathic pain) from existing nerve damage and also further nerve damage from reactions. Type 1 reversal reactions represent delayed-type hypersensitivity with inflammatory painful skin lesions and neuritis and are treated with corticosteroids. Type 2 reactions, or erythema nodosum leprosum, represent a systemic inflammatory response to immune complexes in the extravascular space, are also associated with neuritis, and are treated with prednisolone or thalidomide. Appropriate patient selection and education is critical because of thalidomide’s teratogenicity. Pain is common among patients with leprosy and is multifactorial, but especially associated with nerve damage, leprosy reactions, and neuritis. This is an important consideration, as even after adequate treatment and bacteriological cure, pain may present as a new disabling condition. Although pain is often present in leprosy, it is frequently ignored because of the erroneous belief that leprosy-associated sensory loss prevents patients from perceiving noxious stimuli. In this regard, leprosy can be considered an archetypal neuropathic pain condition. Various types of acute and chronic pain have been described in the leprosy literature, and understanding the disparate underlying pathophysiologies is an important aspect of clinical management. We conducted a literature search with PubMed in April 2014 using the terms “pain” and “leprosy” that identified 272 articles; 86 of these articles directly involved pain associated with leprosy, and the most relevant are discussed in this article.
15 citations
TL;DR: In this paper, a selective ligand for the α2δ subunits of voltage-gated calcium channels (VGCC) was developed by Sankyo group for the management of neuropathic pain.
Abstract: The efficacy of neuropathic pain control remains unsatisfactory. Despite the availability of a variety of therapies, a significant proportion of patients suffer from poorly controlled pain of this kind. Consequently, new drugs and treatments are still being sought to remedy the situation. One such new drug is mirogabalin, a selective ligand for the α2δ subunits of voltage-gated calcium channels (VGCC) developed by Sankyo group for the management of neuropathic pain. In 2019 in Japan, mirogabalin was approved for peripheral neuropathic pain following the encouraging results of clinical trials conducted with diabetic peripheral neuropathic pain (DPNP) and postherpetic neuralgia (PHN) patients. The ligand selectivity of mirogabalin for α2δ-1 and α2δ-2 and its slower dissociation rate for α2δ-1 than for α2δ-2 subunits of VGCC may contribute to its strong analgesic effects, wide safety margin, and relatively lower incidence of adverse effects compared to pregabalin and gabapentin. This article discusses the mechanism of action of mirogabalin, presents data on its pharmacodynamics and pharmacokinetics, and reviews the available experimental and clinical studies that have assessed the efficacy and safety of the drug in the treatment of selected neuropathic pain syndromes.
15 citations
TL;DR: A clinically relevant pain reduction was observed with lidocaine plaster in patients with PSNP and the safety and tolerability profile is consistent with current knowledge.
Abstract: Objective: To assess the efficacy and safety of lidocaine 700 mg medicated plaster (lidocaine plaster) compared to placebo in patients with moderate to severe chronic post-surgical neuropathic pain...
15 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