— New patterns emerge, especially for young people

by Judy George, Senior Staff Writer, MedPage Today June 14, 2019

Gabapentinoid prescriptions were associated with an increased risk of suicidal behavior and unintentional overdose, a population cohort study in Sweden showed.

The risks were strongest for people who were prescribed pregabalin (Lyrica) over gabapentin (Neurontin), especially among young people, reported Seena Fazel, MD, of the University of Oxford in England, and colleagues in The BMJ.

“Our results also suggest an increased risk of head and body injuries, road traffic accidents, and criminal offenses,” co-author Yasmina Molero, PhD, of the Karolinska Institute in Stockholm, told MedPage Today. “Importantly, when we broke down the findings by 10-year age bands, increased associations were consistently found in younger people, particularly those age 15 to 24.”

For outcomes like suicidal behavior and overdose-related deaths, “this study provides precision to previous work, which has been based on small samples, and also investigates age-related effects,” she continued. “In relation to other adverse outcomes such as injuries, accidents, and crime, this is new information.”

Gabapentin and pregabalin, two main drugs in the gabapentinoid drug class, are approved for epilepsy and post-herpetic neuralgia in the U.S., but both frequently are used off-label. Pregabalin also is approved for fibromyalgia and neuropathic pain in the U.S. and for treating generalized anxiety disorder in Europe.

Evidence has emerged that gabapentinoids are being used “clinically (but ineffectively) as an opioid substitute and diverted to recreational use, and detection at post mortem has increased, along with direct attribution as cause of death,” noted Derek Tracey, a consultant psychiatrist at Queen Mary’s Hospital in London, in an accompanying editorial. “These concerns have led to legislative changes to restrict or control prescribing in several countries, including the United Kingdom.”

In the U.S., gabapentin and pregabalin have tripled in use from 2002 to 2015. Worldwide, pregabalin was among the top 15 best-selling drugs in 2016.

In this analysis, researchers followed 191,973 people ages 15 and older from the Swedish Prescribed Drug Register who filled prescriptions for gabapentinoids on at least two consecutive occasions from 2006 to 2013. The team used a within-individual design to assess outcomes, comparing periods when each person was taking gabapentinoids to periods when he or she was not taking them, to minimize confounding factors.

A total of 120,664 people received pregabalin and 85,360 received gabapentin (14,501 received both drugs) in the study. Most (59.1%) were women, and most were ages 45 or older.

Over the study period, 10,026 (5.2%) people were treated for suicidal behavior or died from suicide, 17,144 (8.9%) had an unintentional overdose, 12,070 (6.3%) had a road traffic incident or offense, 70,522 (36.7%) presented with head or body injuries, and 7,984 (4.1%) were arrested for a violent crime.

In within-individual analyses, gabapentinoid treatment was associated with increased age-adjusted hazards of:

• Suicidal behavior and deaths from suicide (HR 1.26, 95% CI 1.20-1.32)

• Unintentional overdoses (HR 1.24, 95% CI 1.19-1.28)

• Head and body injuries (HR 1.22, 95% CI 1.19-1.25)

• Road traffic incidents and offenses (HR 1.13, 95% CI 1.06-1.20)

Associations with arrests for violent crime were not statistically significant (age-adjusted HR 1.04, 95% CI 0.98-1.11).

In subanalyses, only pregabalin, not gabapentin, was linked to increased risks of harm, and individuals ages 15 to 24 had increased hazards of all outcomes. “This may be an age-related pharmacodynamic effect, as has been suggested for selective serotonin reuptake inhibitors,” Fazel and colleagues wrote. “Young people have faster metabolism, which could lead to withdrawal problems, affecting impulsivity and emotion.”

These findings are important and clinically helpful, Tracy observed: “The authors’ large dataset and study design cleverly overcome the limitations of case reports and small trials that fail to capture off-label prescribing or longer-term problems,” he noted.

The results suggest it may be time to uncouple pregabalin and gabapentin in legislation and guidelines, Tracy pointed out. “We also need to understand what is driving the age-related differences in risks and how recent legal restrictions will affect the illicit market in diverted drugs,” he added.

The study had several limitations, the researchers noted. It was observational and could not establish cause. While the design aimed to minimize the effect of confounding factors, the analysis could not account for drug adherence or interplay involving alcohol or illicit drug use. Despite these factors, guidelines for gabapentinoid treatment in young people may need review, the authors concluded.