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

The intestinal barrier as an emerging target in the toxicological assessment of mycotoxins

Mycotoxins, the secondary metabolites of fungal species, are the most frequently occurring natural food contaminants in human and animal diets. Risk assessment of mycotoxins focused as yet on their mutagenic, genotoxic and potential carcinogenic effects. Recently, there is an increasing awareness of the adverse effects of various mycotoxins on vulnerable structures in the intestines. In particular, an impairment of the barrier function of the epithelial lining cells and the sealing tight junction proteins has been noted, as this could result in an increased translocation of luminal antigens and pathogens and an excessive activation of the immune system. The current review aims to provide a summary of the available evidence regarding direct effects of various mycotoxins on the intestinal epithelial barrier. Available data, based on different cellular and animal studies, show that food-associated exposure to certain mycotoxins, especially trichothecenes and patulin, affects the intestinal barrier integrity and can result in an increased translocation of harmful stressors. It is therefore hypothesized that human exposure to certain mycotoxins, particularly deoxynivalenol, as the major trichothecene, may play an important role in etiology of various chronic intestinal inflammatory diseases, such as inflammatory bowel disease, and in the prevalence of food allergies, particularly in children. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (doi:10.1007/s00204-016-1794-8) contains supplementary material, which is available to authorized users