Combination pharmacotherapy for the treatment of neuropathic pain in adults: systematic review and meta-analysis.

ABSTRACT: Neuropathic pain causes substantial morbidity and healthcare utilization. Monotherapy with antidepressants or anticonvulsants often fails to provide relief. Combining different drugs sometimes provides improved analgesia and/or tolerability. More than half of patients receive 2 or more analgesics, and combination trials continue to emerge. This review comprehensively searched CENTRAL, MEDLINE, and EMBASE for relevant trials. Included studies are double-blind randomized controlled trials evaluating combinations of 2 or more drugs vs placebo or at least one monotherapy in adults with neuropathic pain. Outcomes included measures of efficacy and adverse effects. Risk of bias was assessed. Meta-analyses compared combination to monotherapy wherever 2 or more similar studies were available. Forty studies (4741 participants) were included. Studies were heterogenous with respect to various characteristics, including dose titration methods and administration (ie, simultaneous vs sequential) of the combination. Few combinations involved a nonsedating drug, and several methodological problems were identified. For opioid-antidepressant, opioid-gabapentinoid, and gabapentinoid-antidepressant combinations, meta-analyses failed to demonstrate superiority over both monotherapies. In general, adverse event profiles were not substantially different for combination therapy compared with monotherapy. Despite widespread use and a growing number of trials, convincing evidence has not yet emerged to suggest superiority of any combination over its respective monotherapies. Therefore, implementing combination therapy-as second- or third-line treatment-in situations where monotherapy is insufficient, should involve closely monitored individual dosing trials to confirm safety and overall added benefit. Further research is needed, including trials of combinations involving nonsedating agents, and to identify clinical settings and specific combinations that safely provide added benefit.

Glial-modulating agents for the treatment of pain: protocol for a systematic review.

INTRODUCTION: Evidence suggests a role for Central nervous system glia in pain transmission and in augmenting maladaptive opioid effects. Identification of drugs that modulate glia has guided the evaluation of glial suppression as a pain management strategy. This planned systematic review will describe evidence of the efficacy and adverse effects of glial-modulating drugs in pain management. METHODS AND ANALYSIS: A detailed search will be conducted on the Cochrane Central Register of Controlled Trials, Medline, and Embase from their inception until the date the final searches are run to identify relevant randomised controlled trials. The reference lists of retrieved studies, as well as online trial registries, will also be searched. English language, randomised, double-blind trials comparing various glial-modulating drugs with placebo and/or other comparators, with participant-reported pain assessment, will be included. Two reviewers will independently evaluate studies for eligibility, extract data and assess trial quality and potential bias. Risk of bias will be assessed using criteria outlined in the Cochrane Handbook for Systematic Review of Interventions. Primary outcomes for this review will include any validated measure of pain intensity and/or pain relief. Dichotomous data will be used to calculate risk ratio and number needed to treat or harm. The quality of evidence will be assessed using Grading of Recommendations Assessment, Development and Evaluation. ETHICS AND DISSEMINATION: This systematic review does not require formal ethics approval. The findings will be disseminated through peer-reviewed publications and conference presentations. PROSPERO REGISTRATION NUMBER: CRD42021262074.

Scoping review of the association between postsurgical pain and heart rate variability parameters.

Surgical interventions can elicit neuroendocrine and sympathovagal responses, leading to cardiac autonomic imbalance. Cardiac complications account for approximately 30% of postoperative complications. Altered heart rate variability (HRV) was initially described in the 1970s as a predictor of acute coronary syndromes and has more recently been shown to be an independent predictor of postoperative morbidity and mortality after noncardiac surgery. In general, HRV reflects autonomic balance, and altered HRV measures have been associated with anesthetic use, chronic pain conditions, and experimental pain. Despite the well-documented relationship between altered HRV and postsurgical outcomes and various pain conditions, there has not been a review of available evidence describing the association between postsurgical pain and HRV. We examined the relationship between postsurgical pain and HRV. MEDLINE and EMBASE databases were searched until December 2020 and included all studies with primary data. Two reviewers independently assessed risk of bias for each study using the criteria outlined in the Cochrane Handbook for Systematic Review of Interventions. A total of 8 studies and 1002 participants were included. Studies examined the association of postsurgical pain and HRV or analgesia nociception index derived from HRV. There was a statistically significant association between HRV measures and postsurgical pain in 6 of 8 studies. Heterogeneity of studies precluded meta-analyses. No studies reported cardiovascular outcomes. There is a potential association between postsurgical pain and HRV or analgesia nociception index, although results are likely impacted by confounding variables. Future studies are required to better delineate the relationship between postsurgical pain and HRV and impacts on cardiovascular outcomes.