Gabapentinoid Use in COPD Associated With Increased Severe Exacerbation Risk, Study Says

Gabapentinoid use in patients with chronic obstructive pulmonary disease (COPD) was associated with an increased risk of severe exacerbation, according to a study published in Annals of Internal Medicine.

The researchers explained that gabapentinoids, namely gabapentin and pregabalin, are anticonvulsant drugs used to treat epilepsy and neuropathic pain. Although the approved indications for gabapentinoids currently vary worldwide, prescriptions have surged across North America and Europe as physicians are reportedly using them as safer alternatives to opioids.

The prescription uptick is of concern to the researchers, as gabapentinoids are exposing patients to potentially serious adverse effects. For example, they noted that 49 case reports submitted to the FDA have shown severe breathing difficulties in patients using gabapentinoids, resulting in the agency releasing a warning in 2019, particularly for patients with respiratory risk factors, including COPD.

Despite the risks and warnings, no population-based studies have been done among patients with COPD on the potential respiratory adverse effects of gabapentinoids. Consequently, the researchers assessed whether gabapentinoid use was associated with severe exacerbation in patients with COPD who had an approved or off-label indication for them.

In an interview with The American Journal of Managed Care^® (AJMC^®), Alvi Rahman, a PhD candidate at McGill University, and one of the study’s authors, expanded on why this topic was of interest to them.

"Recently, there's been a few articles published that have been discussing that there's a possibility, due to physicians wanting to avoid opioid prescriptions nowadays, that gabapentinoids may be perceived as a safer alternative to these medications," Rahman said. "They are prescribed very widely these days for any type of pain, which is not what they're indicated for. So, this study was trying to bring more awareness to the fact that these drugs may also have potential risks to consider."

COPD | Image Credit: peterschreiber.media - stock.adobe.com

To create their study population, the researchers used patient data from the 3 computerized health care databases of Quebec, Canada, which included information on medical services and prescription medications for all residents covered by the Public Prescription Drug Insurance Plan. The researchers first assembled a base cohort of all patients aged 55 or older who received 3 or more prescriptions for a respiratory drug (long-acting β-agonists [LABA], long-acting muscarinic antagonist [LAMA], or a combination of LABA-LAMA or LABA-inhaled corticosteroid [ICS]) on at least 2 dates within 1 year between January 1, 1994, and December 31, 2015; patients with COPD were identified as those using relevant respiratory medications.

From the base cohort, the researchers identified all patients initiating treatment with a gabapentinoid with a potential indication for epilepsy, neuropathic pain, or other chronic pain. They then matched these patients 1:1 with nonusers. Both the user and nonuser groups were followed until the date of the outcome, date of death, end of prescription drug coverage, or end of the study period, whichever occurred first.

Consequently, the cohort included 13,504 patients with COPD who initiated gabapentinoid treatment, 9411 of which with neuropathic pain, 3737 with other chronic pain, and 356 with epilepsy, which they matched to equal numbers of nonusers. The researchers associated gabapentinoid use with increased severe COPD exacerbation risk both overall (HR, 1.39; 95% CI, 1.29-1.50) and across the 3 indications of epilepsy (HR, 1.58; 95% CI, 1.08-2.30), neuropathic pain (HR, 1.35; 95% CI, 1.24-1.48), and other chronic pain (HR, 1.49; 95% CI, 1.27-1.73). Notably, the peak increase in severe exacerbation risk occurred approximately 6 months after continuous gabapentinoid use.

The researchers acknowledged their study’s limitations, one being that they identified patients with COPD using relevant medications instead of International Classification of Diseases (ICD) codes. Because of this, they may have misclassified patients with asthma as patients with COPD since they could be prescribed the same medications. Also, they noted that residual confounding must be considered, including the lack of smoking history information.

Despite these limitations, Christel Renoux, MD, PhD, of McGill University, who was one of the study’s authors, suggested areas for further research based on their findings in an interview with AJMC.

“We looked at COPD, but there may be many other respiratory diseases where this risk could be assessed,” Renoux said. “Also, something we didn’t look at is the dose of the drug, so that could be something that could be of interest. People are not going to stop prescribing the drug [gabapentinoids], so we need to see if there is a dose where it is less problematic that would be an option.”

Reference

Rahman A A, Dell'Aniello S, Moodie M, et al. Gabapentinoids and risk for severe exacerbation in chronic obstructive pulmonary disease. Ann Intern Med. Published January 15, 2024. doi:10.7326/M23-0849