Efficacy of opioids versus placebo in chronic pain: a systematic review and meta-analysis of enriched enrollment randomized withdrawal trials.

INTRODUCTION: Opioids have been used for millennia for the treatment of pain. However, the long-term efficacy of opioids to treat chronic non-cancer pain continues to be debated. To evaluate opioids' efficacy in chronic non-cancer pain, we performed a meta-analysis of published clinical trials for µ-opioid receptor agonists performed for US Food and Drug Administration approval. METHODS: MEDLINE and Cochrane trial register were searched for enriched enrollment randomized withdrawal studies (before June 2016). Selection criteria included: adults, ≥10 subjects per arm, any chronic pain condition, double-blind treatment period lasting ≥12 weeks, and all µ-agonist opioids approved in the USA. RESULTS: Fifteen studies met criteria. Opioid efficacy was statistically significant (p<0.001) versus placebo for pain intensity (standardized mean difference: -0.416), ≥30% and ≥50% improvement in pain (risk difference: 0.166 and 0.137), patient global impression of change (0.163), and patient global assessment of study medication (0.194). There were minor benefits on physical function and no effect on mental function. CONCLUSION: Opioids are efficacious in the treatment of chronic non-cancer pain for up to 3 months in randomized controlled trials. This should be considered, alongside data on opioid safety, in the use of opioids for the treatment of chronic pain.

Comparative Effectiveness of Management Strategies for Renal Artery Stenosis: An Updated Systematic Review.

BACKGROUND: Atherosclerotic renal artery stenosis (ARAS) is associated with high blood pressure (BP), decreased kidney function, renal replacement therapy (RRT), and death. PURPOSE: To compare benefits and harms of percutaneous transluminal renal angioplasty with stent placement (PTRAS) versus medical therapy alone in adults with ARAS. DATA SOURCES: MEDLINE, EMBASE, and Cochrane Central Register of Controlled Trials from 1993 to 16 March 2016; gray literature; and prior systematic reviews. STUDY SELECTION: Randomized, controlled trials (RCTs); nonrandomized, comparative studies (NRCSs); single-group studies; and selected case reports that reported all-cause and cardiovascular mortality, RRT, kidney function, BP, and adverse events. DATA EXTRACTION: Six researchers extracted data on design, interventions, outcomes, and study quality into a Web-based database. DATA SYNTHESIS: Eighty-three studies met eligibility criteria. In 5 of 7 RCTs, PTRAS and medical therapy led to similar BP control in patients with ARAS, and no RCTs showed statistically significant differences in kidney function, mortality, RRT, cardiovascular events, or pulmonary edema. Eight NRCSs had more variable results, finding mostly no significant differences in mortality, RRT, or cardiovascular events but heterogeneous effects on kidney function and BP. Procedure-related adverse events were rare, and medication-related adverse events were not reported. Two RCTs found no patient characteristics that were associated with outcomes with either PTRAS or medical therapy. Single-group studies found various but inconsistent factors that predict outcomes. Case reports provided examples of clinical improvement after PTRAS in patients with acute decompensation. LIMITATION: Limited clinical applicability and power in RCTs, and possible publication bias and lack of adjusted analyses in NRCSs. CONCLUSION: The strength of evidence regarding the relative benefits and harms of PTRAS versus medical therapy alone for patients with ARAS is low. Studies have generally focused on patients with less severe ARAS. PRIMARY FUNDING SOURCE: Agency for Healthcare Research and Quality.

Omega-3 Fatty Acids and Cardiovascular Disease: An Updated Systematic Review.

BACKGROUND: The effect and association of omega-3 fatty acids (n-3 FA) intake and biomarker levels with cardiovascular (CV) clinical and intermediate outcomes remains controversial. We update prior Evidence Reports of n-3 FA and clinical and intermediate CV disease (CVD) outcomes. OBJECTIVES: Evaluate the effect of n-3 FA on clinical and selected intermediate CV outcomes and the association of n-3 FA intake and biomarkers with CV outcomes. The n-3 FA under review include eicosapentaenoic acid (EPA), docosahexaenoic acid (DHA), docosapentaenoic acid (DPA), stearidonic acid (SDA), and alphalinolenic acid (ALA). DATA SOURCES: MEDLINE®, Embase®, the Cochrane Central Register of Controlled Trials, Cochrane Database of Systematic Reviews, and CAB Abstracts from 2000 or 2002 to June 8, 2015, and eligible studies from the original reports and relevant existing systematic reviews. REVIEW METHODS: We included randomized controlled trials (RCTs) of any n-3 FA intake compared to no, lower, or other n-3 FA intake with an outcome of interest conducted in healthy adults, those at risk for CVD, or those with CVD. We also included prospective observational studies of the association between baseline n-3 FA intake or biomarker level and followup outcomes. We required 1 year or more of followup for clinical outcomes and 4 weeks for intermediate outcomes (blood pressure [BP] and lipids). RESULTS: From 11,440 citations (from electronic literature searches and existing systematic reviews), 829 abstracts met basic eligibility criteria; 61 RCTs and 37 longitudinal observational studies (in 147 articles) were included. Most RCTs and observational studies had few risk-of-bias concerns.Total n-3 FA: There is low strength of evidence (SoE) of no association between total n-3 FA intake and stroke death or myocardial infarction. There is insufficient evidence for other outcomes.Marine oils, total: There is moderate to high SoE that higher marine oil intake lowers triglycerides (Tg), raises high density lipoprotein cholesterol (HDL-c), and lowers the ratio of total cholesterol to HDL-c but raises low density lipoprotein cholesterol (LDL-c); also that higher marine oil intake does not affect major adverse CV events, all-cause death, total stroke, sudden cardiac death, coronary revascularization, atrial fibrillation, or BP. There is low SoE of associations between higher marine oil intake and decreased risk of CVD death, coronary heart disease (CHD), myocardial infarction, ischemic stroke, and congestive heart failure (CHF). There is low SoE of no association with CHD death or hemorrhagic stroke. There is insufficient evidence for other outcomes.Marine oil FA individually: There is low SoE of no associations between EPA or DHA intake (separately) and CHD, and between EPA or DPA and atrial fibrillation. There is low SoE of no association between EPA biomarkers and atrial fibrillation, but moderate SoE of no effect of purified DHA supplementation on BP or LDL-c. There is insufficient evidence for other specific marine oil FA and outcomes.ALA: There is moderate SoE of no effect of ALA intake on BP, LDL-c, HDL-c, or Tg. There is low SoE of no association between ALA intake or biomarker level and CHD, CHD death, atrial fibrillation, and CHF. There is insufficient evidence for other outcomes.Other n-3 FA analyses: There is insufficient evidence comparing n-3 FA with each other or for SDA.Subgroup analyses: Nineteen of 22 studies found no interaction of sex on any effect of n-3 FA. Likewise, 19 of 20 studies found no differential effect by statin co-use. Within 16 studies evaluating diabetes subgroups, 2 found statistically significant beneficial effects of n-3 FA in those with diabetes but not in those without diabetes, but no test of interaction was reported. CONCLUSIONS: The 61 RCTs mostly compared marine oil supplements with placebo on CVD outcomes in populations at risk for CVD or with CVD, while the 37 observational studies mostly examined associations between various individual n-3 FA and long-term CVD events in generally healthy populations. Compared with the prior report on n-3 FA and CVD, there is more robust RCT evidence on ALA and on clinical CV outcomes; also, by design there are newly added data on associations between n-3 FA biomarkers and CV outcomes. However, conclusions regarding the effect of n-3 FA intake on CV outcomes or associations with outcomes remain substantially unchanged. Marine oils statistically significantly raise HDL-c and LDL-c by similar amounts (≤2 mg/dL), while lowering Tg in a dose-dependent manner, particularly in individuals with elevated Tg; they have no significant effect on BP. ALA has no significant effect on intermediate outcomes. Limited data were available from RCTs on the effect of n-3 FA on clinical CVD outcomes. Observational studies suggest that higher marine oil intake (including from dietary fish) is associated with lower risk of several CVD outcomes. No clear differences in effects or associations were evident based on population, demographic features, or cointerventions. Future RCTs would be needed to establish adequate evidence of the effect of n-3 FA on CVD outcomes or to clarify differential effects in different groups of people. However, future trials are unlikely to alter conclusions about the effects of n-3 FA supplementation on intermediate cardiovascular outcomes (BP, LDL-c, HDL-c, or Tg).