‘Prescribing of drugs is a balance of risks’

Young people taking pregabalin may be at increased risk of harm including suicidal behaviour and injury, according to a cohort study

Swedish and British researchers have explored a possible association between gabapentinoids and adverse outcomes related to coordination disturbances, mental health, and criminality.

Their population-based cohort study looked at 191,973 people from the Swedish Prescribed Drug Register who collected at least two consecutive prescriptions for gabapentinoids (pregabalin or gabapentin) between 2006 and 2013.

Gabapentinoids are indicated for epilepsy and neuropathic pain. Pregabalin is also used for anxiety disorders. Off-label use has included restless leg syndrome, migraine, menopausal flushes, and alcohol dependency.

Primary outcomes for the study were suicidal behaviour, unintentional overdoses, head/body injuries, road traffic incidents and offences, and arrests for violent crime, according to the study published in BMJ.

During the study period, 70,522 (36.7%) presented with head/body injuries, 17,144 (8.9%) experienced an unintentional overdose, 12,070 (6.3%) had a road traffic incident or offence, 10,026 (5.2%) participants were treated for suicidal behaviour or died from suicide, and 7,984 (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.

Stratification showed age as the only factor associated with differential risk, and participants aged 15-24 were the most vulnerable group.

“Subanalyses showed that only pregabalin, not gabapentin, was associated with increased risks of harm, and that this was largely in a dose-response manner,” writes Derek K Tracy, consultant psychiatrist at London’s Queen Mary’s Hospital in a linked BMJ editorial.

“The findings challenge the clinical utility of the broad categorisation ‘gabapentinoid’ and suggest it might be time to uncouple pregabalin and gabapentin for the purposes of legislation and guidelines. Both might need to be more specific about age group,” he says.

“This work could not determine causality—namely, that gabapentinoids definitively produced these adverse outcomes. The important issues of drug adherence and any acute interplay of alcohol and illicit drug use also could not be determined. However, within-individual analyses allow participants to act as their own controls, removing important confounders, particularly confounding by indication, where bias is introduced when people prescribed gabapentinoids already have conditions such as depression or dyspraxias that are associated with the outcomes of interest.”

Dr Tracy says: “The prescribing of drugs is a balance of risks. All drugs can cause harm, although the extent of this varies among different people, drugs, dosages, and durations of use.

“Despite reasonable concerns, gabapentinoids remain a valued therapeutic option for many people. Medicines can harm as well as heal, and the best treatment decisions are made in full partnership with patients, after consideration of all available evidence on both.”

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