Background Pharmacotherapy remains an important modality for the treatment of neuropathic pain. However, as monotherapy current drugs are associated with limited e icacy and dose-related side e ects. Combining two or more di erent drugs may improve analgesic e icacy and, in some situations, reduce overall side e ects (e.g. if synergistic interactions allow for dose reductions of combined drugs). Objectives This review evaluated the e icacy, tolerability and safety of various drug combinations for the treatment of neuropathic pain. Search methods We identified randomised controlled trials (RCTs) of various drug combinations for neuropathic pain from CENTRAL, MEDLINE, EMBASE and handsearches of other reviews and trial registries. The most recent search was performed on 9 April 2012. Selection criteria Double-blind, randomised studies comparing combinations of two or more drugs (systemic or topical) to placebo and/or at least one other comparator for the treatment of neuropathic pain. Data collection and analysis Data extracted from each study included: proportion of participants a) reporting ≥ 30% pain reduction from baseline OR ≥ moderate pain relief OR ≥ moderate global improvement; b) dropping out of the trial due to treatment-emergent adverse e ects; c) reporting each specific adverse e ect (e.g. sedation, dizziness) of ≥ moderate severity. The primary comparison of interest was between study drug(s) and one or both single-agent comparators. We combined studies if they evaluated the same drug class combination at roughly similar doses and durations of treatment. We used RevMan 5 to analyse data for binary outcomes. Main results We identified 21 eligible studies: four (578 participants) evaluated the combination of an opioid with gabapentin or pregabalin; two (77 participants) evaluated an opioid with a tricyclic antidepressant; one (56 participants) of gabapentin and nortriptyline; one (120 participants) of gabapentin and alpha-lipoic acid, three (90 participants) of fluphenazine with a tricyclic antidepressant; three (90 participants) of an N-methyl-D-aspartate (NMDA) blocker with an agent from a di erent drug class; five (604 participants) of various topical medications; one (313 participants) of tramadol with acetaminophen; and another one (44 participants) of a cholecystokinin blocker (L-365,260) with morphine. The majority of combinations evaluated to date involve drugs, each of which share some element of central nervous system (CNS) depression (e.g. sedation, cognitive dysfunction). This aspect of side e ect overlap between the combined Combination pharmacotherapy for the treatment of neuropathic pain in adults (Review)

IMPORTANCE Harms and benefits of opioids for chronic noncancer pain remain unclear. OBJECTIVE To systematically review randomized clinical trials (RCTs) of opioids for chronic noncancer pain. DATA SOURCES AND STUDY SELECTION The databases of CENTRAL, CINAHL, EMBASE, MEDLINE, AMED, and PsycINFO were searched from inception to April 2018 for RCTs of opioids for chronic noncancer pain vs any nonopioid control. DATA EXTRACTION AND SYNTHESIS Paired reviewers independently extracted data. The analyses used random-effects models and the Grading of Recommendations Assessment, Development and Evaluation to rate the quality of the evidence. MAIN OUTCOMES AND MEASURES The primary outcomes were pain intensity (score range, 0-10 cm on a visual analog scale for pain; lower is better and the minimally important difference [MID] is 1 cm), physical functioning (score range, 0-100 points on the 36-item Short Form physical component score [SF-36 PCS]; higher is better and the MID is 5 points), and incidence of vomiting. RESULTS Ninety-six RCTs including 26 169 participants (61% female; median age, 58 years [interquartile range, 51-61 years]) were included. Of the included studies, there were 25 trials of neuropathic pain, 32 trials of nociceptive pain, 33 trials of central sensitization (pain present in the absence of tissue damage), and 6 trials of mixed types of pain. Compared with placebo, opioid use was associated with reduced pain (weighted mean difference [WMD], −0.69 cm [95% CI, −0.82 to −0.56 cm] on a 10-cm visual analog scale for pain; modeled risk difference for achieving the MID, 11.9% [95% CI, 9.7% to 14.1%]), improved physical functioning (WMD, 2.04 points [95% CI, 1.41 to 2.68 points] on the 100-point SF-36 PCS; modeled risk difference for achieving the MID, 8.5% [95% CI, 5.9% to 11.2%]), and increased vomiting (5.9% with opioids vs 2.3% with placebo for trials that excluded patients with adverse events during a run-in period). Low-to moderate-quality evidence suggested similar associations of opioids with improvements in pain and physical functioning compared with nonsteroidal anti-inflammatory drugs (pain: WMD, −0.60 cm [95% CI, −1.54 to 0.34 cm]; physical functioning: WMD, −0.90 points [95% CI, −2.69 to 0.89 points]), tricyclic antidepressants (pain: WMD, −0.13 cm [95% CI, −0.99 to 0.74 cm]; physical functioning: WMD, −5.31 points [95% CI, −13.77 to 3.14 points]), and anticonvulsants (pain: WMD, −0.90 cm [95% CI, −1.65 to −0.14 cm]; physical functioning: WMD, 0.45 points [95% CI, −5.77 to 6.66 points]). CONCLUSIONS AND RELEVANCE In this meta-analysis of RCTs of patients with chronic noncancer pain, evidence from high-quality studies showed that opioid use was associated with statistically significant but small improvements in pain and physical functioning, and increased risk of vomiting compared with placebo. Comparisons of opioids with nonopioid alternatives suggested that the benefit for pain and functioning may be similar, although the evidence was from studies of only low to moderate quality.

Analysis 1.9. Comparison 1 Ketamine versus placebo comparisons, Outcome 9 Incidence of any pain at 12 months. Analysis 2.1. Comparison 2 Gabapentin versus placebo, Outcome 1 Incidence of any pain at 3 months (all studies).. Analysis 2.2. Comparison 2 Gabapentin versus placebo, Outcome 2 Incidence of any pain at 3 months (drug administration

There is evidence of short-term efficacy (moderate for pain and small for function) of opioids to treat CLBP compared with placebo. The effectiveness and safety of long-term opioid therapy for treatment of CLBP remains unproven.

EERW trial designs appear not to bias the results of efficacy, but they underestimate the adverse effects. The present updated meta- analysis shows that weak and strong opioids are effective for CNCP of both nociceptive and neuropathic origin.