Serious adverse events reported in placebo randomised controlled trials of oral naltrexone: a systematic review and meta-analysis

Background Naltrexone is an opioid antagonist used in many different conditions, both licensed and unlicensed. It is used at widely varying doses from 3 - 250 mg. The aim of this review was to evaluate the safety of oral naltrexone by examining the risk of serious adverse events (SAEs) in randomised controlled trials (RCTs) of naltrexone compared to placebo. Methods A systematic search of Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE, EMBASE, other databases and clinical trials registries was undertaken up to March 2018. Parallel placebo-controlled RCTs longer than 4 weeks published after 1/1/2001, of oral naltrexone at any dose were selected. Any condition and age group were included, excluding only studies for opioid or ex-opioid users, due to possible opioid/opioid antagonist interactions. The systematic review used the guidance of the Cochrane Handbook throughout. Numerical data was independently extracted by two people and cross-checked. Risk of bias was assessed with the Cochrane Risk of Bias Tool. Meta-analyses were performed using Stata 15 and R, using random and fixed effects models throughout. Results Eighty-nine RCTs with 11194 participants were found, studying alcohol use disorders, various psychiatric disorders, impulse control disorders, other addictions, obesity, Crohn’s disease, fibromyalgia and cancers. Twenty-six studies (4,960 participants) recorded SAEs occurring by arm of study. There was no evidence of increased risk of SAEs for naltrexone compared to placebo, relative risk (RR) 0.84 (95% CI: 0.66 to 1.06). Sensitivity analyses pooling risk differences supported this conclusion (RD = -0.01 (-0.02, 0.00)) and subgroup analyses showed that results were consistent across different doses and disease groups. The quality of evidence for this outcome was judged high using the GRADE criteria. Conclusions Naltrexone does not appear to increase the risk of SAEs over placebo. These findings confirm the safety of naltrexone when used in licensed indications and encourage investments to undertake efficacy studies in unlicensed indications

Recent Tropical Expansion: Natural Variability or Forced Response?

Previous studies have documented a poleward shift in the subsiding branches of Earth’s Hadley circulation since 1979 but have disagreed on the causes of these observed changes and the ability of global climate models to capture them. This synthesis paper reexamines a number of contradictory claims in the past literature and finds that the tropical expansion indicated by modern reanalyses is within the bounds of models’ historical simulations for the period 1979–2005. Earlier conclusions that models were underestimating the observed trends relied on defining the Hadley circulation using the mass streamfunction from older reanalyses. The recent observed tropical expansion has similar magnitudes in the annual mean in the Northern Hemisphere (NH) and Southern Hemisphere (SH), but models suggest that the factors driving the expansion differ between the hemispheres. In the SH, increasing greenhouse gases (GHGs) and stratospheric ozone depletion contributed to tropical expansion over the late twentieth century, and if GHGs continue increasing, the SH tropical edge is projected to shift further poleward over the twenty-first century, even as stratospheric ozone concentrations recover. In the NH, the contribution of GHGs to tropical expansion is much smaller and will remain difficult to detect in a background of large natural variability, even by the end of the twenty-first century. To explain similar recent tropical expansion rates in the two hemispheres, natural variability must be taken into account. Recent coupled atmosphere–ocean variability, including the Pacific decadal oscillation, has contributed to tropical expansion. However, in models forced with observed sea surface temperatures, tropical expansion rates still vary widely because of internal atmospheric variability

Baclofen for the treatment of alcohol use disorder: the Cagliari Statement

none26siAbstract non disponibileopenAgabio R; Sinclair JM; Addolorato G; Aubin HJ; Beraha EM; Caputo F; Chick JD; de La Selle P; Franchitto N; Garbutt JC; Haber PS; Heydtman M; Jaury P; Lingford-Hughes AR; Morley KC; Müller CA; Owens L; Pastor A; Paterson LM; Pélissier F; Rolland B; Stafford A; Thompson A; van den Brink W; de Beaurepaire R; Leggio LAgabio, R; Sinclair, Jm; Addolorato, G; Aubin, Hj; Beraha, Em; Caputo, F; Chick, Jd; de La Selle, P; Franchitto, N; Garbutt, Jc; Haber, Ps; Heydtman, M; Jaury, P; Lingford-Hughes, Ar; Morley, Kc; Müller, Ca; Owens, L; Pastor, A; Paterson, Lm; Pélissier, F; Rolland, B; Stafford, A; Thompson, A; van den Brink, W; de Beaurepaire, R; Leggio,