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Harms associated with taking nalmefene for substance use and impulse control disorders: A systematic review and meta-analysis of randomised controlled trials.

ABSTRACT: Nalmefene is a newly approved drug for alcohol use disorder, but the risk of harms has not been evaluated from empirical trial evidence.To assess the harm of nalmefene administered to individuals diagnosed with substance use or impulse control disorders by performing a systematic review and meta-analysis of randomised controlled trials.A search was performed in Cochrane Central Register of Controlled Trials (CENTRAL, 2014), MEDLINE via PubMed (1950), EMBASE via Ovid (1974), and Clinicaltrials.gov through December 2014.This study included only randomised controlled trials with placebo or active controls that administered nalmefene to adult individuals for treating impulse control and/or substance use disorders. Both published and unpublished randomised controlled trials were eligible for inclusion.Internal validity was assessed using the Cochrane risk-of-bias tool. Published information from the trials was supplemented by contact between reviewers and industry sponsor. Data were combined using two meta-approaches in fixed effects models; Peto Odds Ratios and risk differences were reported with 95% confidence intervals (95%CIs).Number of patients with serious adverse events, including specific psychiatric serious adverse events and withdrawals due to adverse events.Of 20 potentially relevant studies, 15 randomised controlled trials met the inclusion criteria, and 8 of these provided data enabling the meta-analysis. Overall, serious adverse events did not occur more often in the nalmefene group than in the placebo group (Peto Odds Ratio = 0.97 [95% CI 0.64-1.44]; P = 0.86). Risk of psychiatric serious adverse events was slightly elevated, albeit not at a statistically significant level (Peto Odds Ratio = 1.32 [95% CI 0.62, 2.83]; P = 0.47). Withdrawals due to adverse events were significantly more likely to occur with nalmefene compared to placebo (Peto Odds Ratio = 3.22 [95% CI 2.46-4.22]; P<0.001).The three-fold increased risk of withdrawal from treatment on nalmefene due to adverse events is a matter of safety concern. The nature of these adverse events cannot be elucidated further without access to individual patients data.

SUBMITTER: Johansen KGV

PROVIDER: S-EPMC5574613 | biostudies-literature | 2017

REPOSITORIES: biostudies-literature

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Harms associated with taking nalmefene for substance use and impulse control disorders: A systematic review and meta-analysis of randomised controlled trials.

Johansen Karina Glies Vincents KGV Tarp Simon S Astrup Arne A Lund Hans H Pagsberg Anne K AK Christensen Robin R

PloS one 20170829 8

<h4>Importance</h4>Nalmefene is a newly approved drug for alcohol use disorder, but the risk of harms has not been evaluated from empirical trial evidence.<h4>Objective</h4>To assess the harm of nalmefene administered to individuals diagnosed with substance use or impulse control disorders by performing a systematic review and meta-analysis of randomised controlled trials.<h4>Data sources</h4>A search was performed in Cochrane Central Register of Controlled Trials (CENTRAL, 2014), MEDLINE via Pu ...[more]

PMID: 28850596

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Project description:Action preparation relies on the operation of control processes that modulate the excitability of the corticospinal tract. On the one hand, excitatory processes prepare the motor system for the forthcoming response; the stronger these influences, the stronger the tendency to act. On the other hand, inhibitory influences allow to suppress inappropriate actions and, more generally, to ensure some sort of impulse control. Because an impairment in these processes could foster inappropriate drinking behavior, the present study aimed at evaluating the motor correlates of such excitatory and inhibitory influences in non-treatment seeking heavy drinkers (HDs) and inpatients suffering from severe alcohol use disorder (SAUDs). Besides, as cue-elicited craving might further alter these processes, we also assessed the impact of an alcohol-related exposure. To do so, 15 healthy controls (HCs), 15 HDs and 15 SAUDs performed a choice reaction time task after having been immersed in a neutral or an alcohol-related environment, using virtual reality videos. Importantly, single-pulse transcranial magnetic stimulation was applied over the left and the right primary motor cortex during the task to elicit motor-evoked potentials in a set of hand muscles allowing us to specifically probe the impact of excitatory and inhibitory processes on motor activity. Our data indicate that excitatory influences are particularly high in both HDs and SAUDs, especially in the dominant hand, an effect that was not observed in HCs. By contrast, inhibitory influences were found to be perfectly normal in HDs, while they were lacking in SAUDs. Furthermore, the alcohol-related exposure enhanced the level of self-reported craving, but this effect only arose in HDs and did not significantly alter the strength of excitatory and inhibitory influences. Overall, although these results have to be taken with caution due to the small sample sizes, this study suggests that enhanced excitatory processes characterize both HDs and SAUDs, while weaker inhibitory influences only concern SAUDs. Hence, an abnormally strong tendency to act could represent a common feature of hazardous drinking, leading individuals to excessive alcohol consumption, whereas deficient impulse control would be a hallmark of more severe forms of AUD, potentially due to the chronic neurotoxic effects of alcohol. Finally, although an alcohol-related exposure does not seem to affect excitatory and inhibitory processes at play during action preparation per se, future works should evaluate changes in corticospinal excitability during the preparation of responses specifically targeting alcohol-related cues.

Project description:ObjectiveTo improve communication of harm in publications of randomised controlled trials via the development of recommendations for visually presenting harm outcomes.DesignConsensus study.Setting15 clinical trials units registered with the UK Clinical Research Collaboration, an academic population health department, Roche Products, and The BMJ.ParticipantsExperts in clinical trials: 20 academic statisticians, one industry statistician, one academic health economist, one data graphics designer, and two clinicians.Main outcomemeasures A methodological review of statistical methods identified visualisations along with those recommended by consensus group members. Consensus on visual recommendations was achieved (at least 60% of the available votes) over a series of three meetings with participants. The participants reviewed and critically appraised candidate visualisations against an agreed framework and voted on whether to endorse each visualisation. Scores marginally below this threshold (50-60%) were revisited for further discussions and votes retaken until consensus was reached.Results28 visualisations were considered, of which 10 are recommended for researchers to consider in publications of main research findings. The choice of visualisations to present will depend on outcome type (eg, binary, count, time-to-event, or continuous), and the scenario (eg, summarising multiple emerging events or one event of interest). A decision tree is presented to assist trialists in deciding which visualisations to use. Examples are provided of each endorsed visualisation, along with an example interpretation, potential limitations, and signposting to code for implementation across a range of standard statistical software. Clinician feedback was incorporated into the explanatory information provided in the recommendations to aid understanding and interpretation.ConclusionsVisualisations provide a powerful tool to communicate harms in clinical trials, offering an alternative perspective to the traditional frequency tables. Increasing the use of visualisations for harm outcomes in clinical trial manuscripts and reports will provide clearer presentation of information and enable more informative interpretations. The limitations of each visualisation are discussed and examples of where their use would be inappropriate are given. Although the decision tree aids the choice of visualisation, the statistician and clinical trial team must ultimately decide the most appropriate visualisations for their data and objectives. Trialists should continue to examine crude numbers alongside visualisations to fully understand harm profiles.

Dataset Information

Harms associated with taking nalmefene for substance use and impulse control disorders: A systematic review and meta-analysis of randomised controlled trials.

Publications

Harms associated with taking nalmefene for substance use and impulse control disorders: A systematic review and meta-analysis of randomised controlled trials.

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