Gabapentinoids Tied to Hip Fractures in Older Adults

Gabapentinoids — gabapentin (Neurontin) and pregabalin (Lyrica) — were tied to an increased risk of hip fracture in older adults.

In a population-based analysis of more than 28,000 adults over age 50 who were hospitalized for their first hip fracture, the use of gabapentinoids was associated with increased odds of hip fracture (OR 1.96, 95% CI 1.66-2.32), reported J. Simon Bell, PhD, of Monash University in Melbourne, Australia, and co-authors.

Odds of hip fracture remained high after adjusting for exposure time and concomitant use of other central nervous system (CNS) medications (OR 1.30, 95% CI 1.07-1.57), the researchers wrote in JAMA Network Open.

Subgroup analyses showed the association between gabapentinoid dispensing and hip fracture was high in people with Hospital Frailty Risk Scores of 5 or higher (OR 1.75, 95% CI 1.31-2.33) and in people with chronic kidney disease (OR 2.41, 95% CI 1.65-3.52).

“These findings suggest that in addition to the known risk associated with kidney impairment, gabapentinoids should be used with caution among patients at risk of hip fractures, especially those who are frail,” Bell and colleagues wrote.

Despite limited indications, gabapentin and pregabalin are widely prescribed off-label for various syndromes, including chronic pain.

Gabapentin is approved for seizures and nerve pain associated with shingles; gabapentin enacarbil is approved for restless leg syndrome. Pregabalin is indicated for fibromyalgia and pain associated with diabetic peripheral neuropathy or spinal cord injury, in addition to seizures and post-herpetic neuralgia.

Common side effects of both drugs include drowsiness, dizziness, blurry or double vision, or difficulty with coordination and concentration.

“Gabapentinoids are actively transported across the blood-brain barrier and inhibit neurotransmitter release via multiple pathways,” Bell and colleagues noted.

“This explains why gabapentinoids have efficacy for various central nervous system disorders, including seizures and neuropathic pain,” they observed. “It is also why gabapentinoids have CNS adverse drug events including somnolence, dizziness, gait disturbance, and balance disorder. These adverse events may increase the risk of falls and fractures in older people.”

Bell and co-authors used a case case-crossover analysis and a future case-control case-crossover analysis in their study to help minimize confounding.

In the case case-crossover analysis, the odds of dispensing gabapentinoids during an index period (1 to 60 days before the index date) were compared with the odds of dispensing in a reference period (121 to 180 days before the index date). To adjust for underlying trends in gabapentinoid use and to minimize persistent user confounding, each index case was matched with up to five controls, selected from future cases of the same age and sex.

The researchers assessed 28,293 patients ages 50 or older who were hospitalized for a first hip fracture in Australia from March 2013 through June 2018. The main analysis included 2,644 patients who had been dispensed gabapentinoids before being admitted; about 71% were women and more than half were ages 80 or older. Most were dispensed pregabalin.

The findings suggested that gabapentinoids were associated with a similar risk of hip fracture as other fall risk-increasing medications, Bell and co-authors noted.

“In addition to previous studies on antiseizure medications and fragility fractures, our study quantifies the specific risk associated with gabapentinoids. Such specificity is useful as fragility fractures vary widely in terms of treatment and prognosis, wherein hip fractures entail the largest morbidity and mortality burden,” they wrote.

“In light of increasing gabapentinoid prescribing, our results have important implications for clinicians and policymakers,” they added.

The study had several limitations, the researchers acknowledged. It measured medication dispensing, not whether the drugs actually were used. While most adverse effects related to falls — like dizziness or somnolence — were reported soon after gabapentinoids, the drugs also have long-term adverse effects on bone health due to interference with calcium homeostasis, they pointed out.

“Our results may, therefore, underestimate the overall effect of gabapentinoids on hip fractures,” they stated.

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