The FDA and other North American, as well as European, health agencies recently warned of severe breathing problems associated with use of the drugs in COPD patients, but supporting evidence has been limited, according to the study led by Canadian researchers from McGill University.
That is what led the study team to assess whether gabapentinoid use is linked to severe exacerbation in patients with COPD. The results were published in the Annals of Internal Medicine.
The time-conditional propensity score–matched, new-user cohort study used health insurance databases from the Régie de l’assurance maladie du Québec in Canada. It included patients initiating gabapentinoid therapy with an indication (i.e., epilepsy, neuropathic pain, or other chronic pain) within a base cohort of patients with COPD from 1994 to 2015. Those were matched 1:1 with nonusers on COPD duration, indication for gabapentinoids, age, sex, calendar year, and time-conditional propensity score.
The primary outcome was defined as severe COPD exacerbation requiring hospitalization. The cohort included 356 gabapentinoid users with epilepsy—9,411 with neuropathic pain and 3,737 with other chronic pain.
The results indicated that compared with nonuse, gabapentinoid use was associated with increased risk for severe COPD exacerbation across the indications of epilepsy (HR, 1.58; 95% CI, 1.08-2.30), neuropathic pain (HR, 1.35; CI, 1.24-1.48), and other chronic pain (HR, 1.49; CI, 1.27-1.73), as well as overall (HR, 1.39; CI, 1.29-1.50).
The researchers warned of residual confounding because the study lacked smoking information.
“In patients with COPD, gabapentinoid use was associated with increased risk for severe exacerbation,” the authors wrote. “This study supports the warnings from regulatory agencies and highlights the importance of considering this potential risk when prescribing gabapentin and pregabalin to patients with COPD.”
In 2019, the FDA warned healthcare professionals that serious breathing difficulties might occur in patients with respiratory risk factors using gabapentin, which is marketed under the brand names of Neurontin, Gralise, Horizant, or pregabalin, marketed as Lyrica.
“These include the use of opioid pain medicines and other drugs that depress the central nervous system (or CNS), and conditions such as chronic obstructive pulmonary disease that reduce lung function,” the FDA said in a press release. “The elderly are also at higher risk.”
Gabapentin and pregabalin are FDA approved for a range of conditions, including seizures, nerve pain, and restless legs syndrome. The FDA pointed out that pregabalin is a schedule V controlled substance, which means it has a lower potential for abuse among the drugs scheduled by the Drug Enforcement Administration (DEA) but may lead to some physical or psychological dependence.
“Our evaluation shows that use of these gabapentinoid medicines has been growing for prescribed medical use, as well as misuse and abuse,” the DEA advised. “Gabapentinoids are often being combined with CNS depressants, which increases the risk of respiratory depression. There is less evidence supporting the risk of serious breathing difficulties in healthy individuals taking gabapentinoids alone.”
The FDA then announced that it was requiring that new warnings about the risk of respiratory depression be added to the prescribing information of the gabapentinoids and have required the drug manufacturers to conduct clinical trials to further evaluate their abuse potential, especially in combination with opioids.
The regulatory group urged healthcare professionals to dose gabapentinoids at the lowest levels and monitor patients for symptoms of respiratory depression and sedation when coprescribing with an opioid or other CNS depressant.
“Among 49 case reports submitted to FDA from 2012 to 2017, 12 people died from respiratory depression with gabapentinoids, all of whom had at least one risk factor,” the group advised.
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