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Associations between gabapentinoids and suicidal behaviour, unintentional overdoses, injuries, road traffic incidents, and violent crime: population based cohort study in Sweden

Author/s: 
Molero, Y., Larsson H., D'Onofrio B.M., Sharp D.J., Fazel S.

Abstract

OBJECTIVE:

To examine associations between gabapentinoids and adverse outcomes related to coordination disturbances (head or body injuries, or both and road traffic incidents or offences), mental health (suicidal behaviour, unintentional overdoses), and criminality.

DESIGN:

Population based cohort study.

SETTING:

High quality prescription, patient, death, and crime registers, Sweden.

PARTICIPANTS:

191 973 people from the Swedish Prescribed Drug Register who collected prescriptions for gabapentinoids (pregabalin or gabapentin) during 2006 to 2013.

MAIN OUTCOME MEASURES:

Primary outcomes were suicidal behaviour, unintentional overdoses, head/body injuries, road traffic incidentsand offences, and arrests for violent crime. Stratified Cox proportional hazards regression was conducted comparing treatment periods with non-treatment periods within an individual. Participants served as their own control, thus accounting for time invariant factors (eg, genetic and historical factors), and reducing confounding by indication. Additional adjustments were made by age, sex, comorbidities, substance use, and use of other antiepileptics.

RESULTS:

During the study period, 10 026 (5.2%) participants were treated for suicidal behaviour or died from suicide, 17 144 (8.9%) experienced an unintentional overdose, 12 070 (6.3%) had a road traffic incident or offence, 70 522 (36.7%) presented with head/body injuries, and 7984 (4.1%) were arrested for a violent crime. In within-individual analyses, gabapentinoid treatment was associated with increased hazards of suicidal behaviour and deaths from suicide (age adjusted hazard ratio 1.26, 95% confidence interval 1.20 to 1.32), unintentional overdoses (1.24, 1.19 to 1.28), head/body injuries (1.22, 1.19 to 1.25), and road traffic incidents and offences (1.13, 1.06 to 1.20). Associations with arrests for violent crime were less clear (1.04, 0.98 to 1.11). When the drugs were examined separately, pregabalin was associated with increased hazards of all outcomes, whereas gabapentin was associated with decreased or no statistically significant hazards. When stratifying on age, increased hazards of all outcomes were associated with participants aged 15 to 24 years.

CONCLUSIONS:

This study suggests that gabapentinoids are associated with an increased risk of suicidal behaviour, unintentionaloverdoses, head/body injuries, and road traffic incidents and offences. Pregabalin was associated with higher hazards of these outcomes than gabapentin.

Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://group.bmj.com/group/rights-licensing/permissions.

Keywords 
Lyrica suicide motor vehicle accidents

Baloxavir Marboxil for Uncomplicated Influenza in Adults and Adolescents

Author/s: 
Hayden, Frederick G., Sugaya, Norio, Hirotsu, Nobuo, Lee, Nelson, de Jong, Menno D., Hurt, Aeron C., Ishida, Tadashi, Sekino, Hisakuni, Yamada, Kota, Portsmouth, Simon, Kawaguchi, Keiko, Shishido, Takao, Arai, Masatsugu, Tsuchiya, Kenji, Uehara, Takeki, Watanabe, Akira, Baloxavir Marboxil Investigators Group

BACKGROUND:

Baloxavir marboxil is a selective inhibitor of influenza cap-dependent endonuclease. It has shown therapeutic activity in preclinical models of influenza A and B virus infections, including strains resistant to current antiviral agents.

METHODS:

We conducted two randomized, double-blind, controlled trials involving otherwise healthy outpatients with acute uncomplicated influenza. After a dose-ranging (10 to 40 mg) placebo-controlled trial, we undertook a placebo- and oseltamivir-controlled trial of single, weight-based doses of baloxavir (40 or 80 mg) in patients 12 to 64 years of age during the 2016-2017 season. The dose of oseltamivir was 75 mg twice daily for 5 days. The primary efficacy end point was the time to alleviation of influenza symptoms in the intention-to-treat infected population.

RESULTS:

In the phase 2 trial, the median time to alleviation of influenza symptoms was 23.4 to 28.2 hours shorter in the baloxavir groups than in the placebo group (P<0.05). In the phase 3 trial, the intention-to-treat infected population included 1064 patients; 84.8 to 88.1% of patients in each group had influenza A(H3N2) infection. The median time to alleviation of symptoms was 53.7 hours (95% confidence interval [CI], 49.5 to 58.5) with baloxavir, as compared with 80.2 hours (95% CI, 72.6 to 87.1) with placebo (P<0.001). The time to alleviation of symptoms was similar with baloxavir and oseltamivir. Baloxavir was associated with greater reductions in viral load 1 day after initiation of the regimen than placebo or oseltamivir. Adverse events were reported in 20.7% of baloxavir recipients, 24.6% of placebo recipients, and 24.8% of oseltamivir recipients. The emergence of polymerase acidic protein variants with I38T/M/F substitutions conferring reduced susceptibility to baloxavir occurred in 2.2% and 9.7% of baloxavir recipients in the phase 2 trial and phase 3 trial, respectively.

CONCLUSIONS:

Single-dose baloxavir was without evident safety concerns, was superior to placebo in alleviating influenza symptoms, and was superior to both oseltamivir and placebo in reducing the viral load 1 day after initiation of the trial regimen in patients with uncomplicated influenza. Evidence for the development of decreased susceptibility to baloxavir after treatment was also observed. (Funded by Shionogi; JapicCTI number, 153090, and CAPSTONE-1 ClinicalTrials.gov number, NCT02954354 .).

Keywords 
baloxavir marboxil oseltamivir influenza
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