Gabapentinoids like gabapentin and pregabalin are associated with an increased risk for poisoning, with the highest risk occurring around treatment initiation and when combined with benzodiazepines or opioids.
In a large UK study of nearly 17,000 primary care patients, those who had co-initiation of gabapentinoids and benzodiazepines showed double the risk for hospitalization due to drug poisoning within the first month, whereas those with concomitant opioid use showed a 30% increased risk compared with those who took neither medication.
“Prescription rates for gabapentinoids have been increasing rapidly in recent years as they are seen as a safe alternative to opioid,” lead author Kenneth Man, PhD, of the University College London School of Pharmacy, London, England, said in a news release.
“While they can be effective for pain relief and do have better perceived safety profiles than opioids, there are still substantial risks that clinicians and patients should be mindful of,” he added.
The study was published online on April 16 in PLOS Medicine.
Widely Prescribed
Gabapentinoids are widely prescribed for epilepsy, neuropathic pain, and anxiety disorders and are increasingly used off-label for chronic pain as an alternative to opioids.
They are among the most frequently prescribed drugs in the US, ranking seventh overall.
Previous studies have associated gabapentinoids with a higher overdose risk, particularly in patients using opioids. However, many earlier analyses were limited by high-risk populations or incomplete adjustment for concomitant medications.
For the current analysis, researchers assessed how drug-poisoning risk shifts within individuals, before and after gabapentinoid treatment.
Using the UK Clinical Practice Research Datalink Aurum database, the researchers analyzed patient data from 2010 to 2020 linked to hospital and mortality records. They excluded patients with epilepsy or cancer.
The study included 16,827 adults (mean age, 46.9 years; 53.5% women) who had both a gabapentinoid prescription and at least one hospitalization for drug poisoning. Mean follow-up was 8.18 years.
Over the study period, 45.4% of patients received gabapentin alone, 34.7% pregabalin alone, and 19.9% received both drugs.
Comorbidity was common: 83.7% had neuropathic or chronic pain, 76.2% had a mental health condition, and 47.6% had a history of illicit drug use.
Concomitant prescribing occurred frequently, with 89% of patients receiving opioids and 54.7% receiving benzodiazepines at some point during the study period.
Using a self-controlled case series design, researchers compared drug poisoning risk during periods of gabapentinoid exposure vs nonexposure within the same individuals, adjusting for age, season, and concomitant medications.
Drug Interactions
In the 90 days prior to treatment, the risk for drug poisoning was doubled (adjusted incidence rate ratio [aIRR], 2.09; 95% CI, 1.98-2.21; P < .001) compared with other nontreatment periods.
During the first 28 days of treatment, the risk remained high (aIRR, 1.81; 95% CI, 1.66-1.99; P < .001). Although risk declined over time, it remained elevated throughout the ongoing treatment periods (aIRR, 1.11; 95% CI, 1.05-1.17; P < .001).
Concomitant use with other medications further increased this risk.
In the first month of treatment, patients who took gabapentinoids with benzodiazepines had a nearly fourfold increased risk for drug poisoning (aIRR, 3.95; 95% CI, 3.07-5.07; P < .001). Those who took opioids had more than double the risk (aIRR, 2.14; 95% CI, 1.77-2.58; P < .001), compared with periods when neither drug was used.
Across the full treatment period, co-prescription with opioids increased risk by approximately 30%, whereas benzodiazepines approximately doubled the risk.
Use With Caution
Gabapentinoids may sometimes be prescribed to reduce drug poisoning risk associated with other medications, including opioids. However, that risk does not fully resolve after treatment.
“Although the incidence of drug poisoning gradually declined after treatment initiation, the risk remained elevated throughout gabapentinoid treatment period and did not return to nontreatment reference level,” the researchers wrote.
Man stressed that the findings should not discourage appropriate prescribing but rather highlight the need for careful monitoring.
“Our findings do not suggest that gabapentinoids are unsafe or should not be prescribed, but clinicians should be cautious when prescribing them, particularly if a patient is taking other medications as well, and clinicians should closely monitor patients who are taking them.”
Due to its observational nature, the study could not establish a direct causal link, particularly because prescriptions often coincide with periods of clinical decline. Moreover, the data relied on prescription records, which may miss actual consumption patterns or less severe poisoning cases.
“Our data do not allow us to determine the precise clinical reasons for the heightened risk observed in the 90 days preceding gabapentinoid initiation, and further research is warranted,” the researchers concluded.