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Journal ArticleDOI

Pharmacotherapy for neuropathic pain in adults: a systematic review and meta-analysis.

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pharmacotherapy for neuropathic pain, including studies published in peer-reviewed journals since January , 1966, and unpublished trials retrieved from ClinicalTrials.gov and websites of pharmaceutical companies.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 Studies published in peer-reviewed journals reported greater eff ects than did unpublished studies (r² 9·3%, p=0·009).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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Citations
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Journal ArticleDOI
TL;DR: Topical AmiKet has the potential to be a first-line treatment option for PHN, and to be useful in other NP conditions, as well as an adjunct to systemic therapies, with the targeting of a peripheral compartment in addition to central sites of action representing a rational drug combination.
Abstract: Introduction: Neuropathic pain (NP) has several therapeutic options but efficacy is limited and adverse effects occur, such that additional treatment options are needed. A topical formulation containing amitriptyline 4% and ketamine 2% (AmiKet) may provide such an option.Areas covered: This report summarizes both published and unpublished results of clinical trials with AmiKet. In post-herpetic neuralgia (PHN), AmiKet produces a significant analgesia which is comparable to that produced by oral gabapentin. In diabetic painful neuropathy, AmiKet showed a strong trend towards pain reduction. In mixed neuropathic pain, case series reports suggest a favourable response rate, but are limited by trial characteristics. AmiKet is absorbed minimally following topical administration. Over 700 patients have now received topical AmiKet in clinical regimens, and it is well-tolerated with the adverse effects mainly being application site reactions. Both agents are polymodal, and several mechanisms may contribut...

24 citations


Cites background from "Pharmacotherapy for neuropathic pai..."

  • ...Initial studies of amitriptyline and ketamine combinations focused on 2%/1% concentrations based on prior case studies in NP....

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  • ...[20,21] In preclinical studies, localized peripheral administration of amitriptyline produces antinociception including in models of NP.[22–27] In these studies, amitriptyline was delivered by local injection into the rodent hindpaw, and peripheral actions were validated by demonstrating actions occur in the hindpaw ipsilateral to the injection site but not on the contralateral side....

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  • ...Topical analgesics consisting of creams/gels or patches are applied directly to the surface of the skin and alter pain responses following dermal absorption and actions on peripheral aspects of sensory nerves and adjacent cellular structures, and several have been demonstrated to produce analgesia in NP.[10] This approach has the potential advantage of producing low systemic drug levels with minimal systemic AEs and drug interactions, and this safety feature allows for combining several topical agents within the same formulation, as well as with systemic agents....

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  • ...%) did not produce significant analgesia compared to placebo over 1–4 weeks in several forms of NP.[54–56]...

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  • ...An additional consideration is that AmiKet may represent a potential adjuvant or combination therapy for treatment of NP....

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Journal ArticleDOI
TL;DR: To examine the rates and predictors of long‐term opioid therapy in older cancer survivors, a large number of patients diagnosed with cancer in the 1980s and 90s received treatment with morphine or heroin.
Abstract: Objectives To examine the rates and predictors of long-term opioid therapy in older cancer survivors. Design Retrospective cohort study. Setting Texas, United States. Participants Cancer survivors (5 years or more postcancer diagnosis) diagnosed from 1995 to 2008 and who were also Medicare Parts A, B, and D beneficiaries. Measurements We used Medicare Part D event data to calculate the proportion of cancer survivors with a prolonged opioid prescription (90-day or more supply of opioids/year). Adjusted odds ratios were calculated to identify predictors of prolonged opioid prescribing. All analyses were repeated with a subcohort of opioid-naive cancer survivors. Results The rate of prolonged opioid therapy for cancer patients diagnosed in 2008 was 7.1% prior to cancer diagnosis; it rose to 9.8% within a year of cancer treatments, and to 13.3% at 5 years postdiagnosis. The rate at the sixth year varied by cancer sites: 19.4% in lung cancer and 9.6% in prostate cancer. Among opioid-naive survivors, the rate increased from 1.4% to 7.1%, from 5 to 18 years postcancer diagnosis. Cancer survivors diagnosed in 2004 to 2008 had higher rates of opioid prescribing compared to those diagnosed in 1995 to 1998 and 1999 to 2003. Years since diagnosis, a later year of diagnosis, female sex, urban location, lung cancer diagnosis, disability as reason for Medicare entitlement, Medicaid eligibility, one or more comorbidity, and history of depression or drug abuse were predictors of prolonged opioid therapy. Among opioid-naive cancer survivors, diagnosis in 2004 to 2008 was the strongest predictor, while a history of drug abuse was the strongest predictor for all the survivors. Conclusion The rates of prolonged opioid prescribing for older cancer survivors remained high at 5 or more years after cancer diagnosis. Our findings have potential to inform the development of clinical guidelines and public policy to ensure safer and more effective pain treatment in older cancer survivors. J Am Geriatr Soc 67:945-952, 2019.

24 citations

Journal ArticleDOI
TL;DR: In this article, the authors explored the relationship among gut microbiota disturbances and serum and spinal cord metabolic disorders in neuropathic pain and found that changes in the gut microbiota was significantly correlated with changes in serum metabolite levels.
Abstract: The aim of this study was to explore the relationships among gut microbiota disturbances and serum and spinal cord metabolic disorders in neuropathic pain. 16S rDNA amplicon sequencing and serum and spinal cord metabolomics were used to identify alterations in the microbiota and metabolite profiles in the sham rats and the chronic constriction injury (CCI) model rats. Correlations between the abundances of gut microbiota components at the genus level, the levels of serum metabolites, and pain-related behavioural parameters were analysed. Ingenuity pathway analysis (IPA) was applied to analyse the interaction networks of the differentially expressed serum metabolites. First, we found that the composition of the gut microbiota was different between rats with CCI-induced neuropathic pain and sham controls. At the genus level, the abundances of Helicobacter, Phascolarctobacterium, Christensenella, Blautia, Streptococcus, Rothia and Lactobacillus were significantly increased, whereas the abundances of Ignatzschineria, Butyricimonas, Escherichia, AF12, and Corynebacterium were significantly decreased. Additionally, 72 significantly differentially expressed serum metabolites and 17 significantly differentially expressed spinal cord metabolites were identified between the CCI rats and the sham rats. Finally, correlation analysis showed that changes in the gut microbiota was significantly correlated with changes in serum metabolite levels, suggesting that dysbiosis of the gut microbiota is an important factor in modulating metabolic disturbances in the context of neuropathic pain. In conclusion, our research provides a novel perspective on the potential roles of the gut microbiota and related metabolites in neuropathic pain.

24 citations

Journal ArticleDOI
TL;DR: In this paper, the authors summarized current recommendations of leading national and international societies regarding prevention and treatment options in chemotherapy-induced peripheral neuropathy (CIPN), and a special focus was placed on current evidence for topical treatment of CIPN with high-dose capsaicin.
Abstract: Cancer diagnosis and treatment are drastic events for patients and their families. Besides psychological aspects of the disease, patients are often affected by severe side effects related to the cancer itself or as a result of therapeutic interventions. Particularly, chemotherapy-induced peripheral neuropathy (CIPN) is the most prevalent neurological complication of oral or intravenous chemotherapy. The disorder may require dose reduction of chemotherapy and is accompanied by multiple symptoms with long-term functional impairment affecting quality of life (QoL), e.g., sensory and functional deteriorations as well as severe pain. Although CIPN may reverse or improve after termination of the causative chemotherapy, approximately 30-40% of patients are faced with chronicity of the symptoms. Due to the advantages in cancer diagnosis and treatments, survival rates of cancer patients rise and CIPN may occur even more frequently in the future. In this review, we summarize current recommendations of leading national and international societies regarding prevention and treatment options in CIPN. A special focus will be placed on current evidence for topical treatment of CIPN with high-dose capsaicin. Finally, an algorithm for CIPN treatment in clinical practice is provided, including both pharmacologic and non-pharmacologic modalities based on the clinical presentation.

24 citations

Journal ArticleDOI
TL;DR: Facial neuralgias are rare and many physicians do not see such cases in their lifetime, so patients with a suspected diagnosis within this group should be referred to a specialized center where multidisciplinary team diagnosis may be available.
Abstract: Premise In this article we review some lesser known cranial neuralgias that are distinct from trigeminal neuralgia, trigeminal autonomic cephalalgias, or trigeminal neuropathies. Included are occipital neuralgia, superior laryngeal neuralgia, auriculotemporal neuralgia, glossopharyngeal and nervus intermedius neuralgia, and pain from acute herpes zoster and postherpetic neuralgia of the trigeminal and intermedius nerves. Problem Facial neuralgias are rare and many physicians do not see such cases in their lifetime, so patients with a suspected diagnosis within this group should be referred to a specialized center where multidisciplinary team diagnosis may be available. Potential solution Each facial neuralgia can be identified on the basis of clinical presentation, allowing for precision diagnosis and planning of treatment. Treatment remains conservative with oral or topical medication recommended for neuropathic pain to be tried before more invasive procedures are undertaken. However, evidence for efficacy of current treatments remains weak.

24 citations


Cites background from "Pharmacotherapy for neuropathic pai..."

  • ...Management of pain should follow the guidelines drawn for neuropathic pain in general, with gabapentinoids, SNRIs, and tricyclics used initially, and opioids reserved for severe cases only (106)....

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References
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Journal ArticleDOI
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

Journal ArticleDOI
13 Sep 1997-BMJ
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

Journal ArticleDOI
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

Journal ArticleDOI
24 Apr 2008-BMJ
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

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