Gabapentinoids May Increase Risk of Severe COPD Exacerbations, Warns New Study

Use of gabapentinoids (gabapentin, pregabalin) by people with chronic obstructive pulmonary disease (COPD) was associated with a 39% increased risk for severe disease exacerbation, according to investigators from McGill University and Lady Davis Institute for Medial Research in Montreal, Canada.

Findings from the population cohort study, published in the Annals of Internal Medicine, are the latest support for a December 2019 warning published by the US Food and Drug Administration about serious respiratory issues associated with the class of anticonvulsants, and particularly among people with COPD, Alvi A. Rahman, MSc, a PhD candidate in the department of epidemiology at McGill University, and colleagues wrote.

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"Public health agencies have released warnings of respiratory depression as a potentially serious adverse effect of gabapentinoids, including for patients with COPD," wrote investigators. "However, these directives are yet to be echoed in clinical practice guidelines for the management of COPD and of neuropathic pain."

Prescriptions for gabapentinoids, whose approved indications are for epilepsy and neuropathic pain, have risen steadily across North America in recent years, largely in response to the opioid epidemic, the researchers pointed out, as physicians reportedly use them as alternatives to opioids to treat a wide range of painful conditions.

Gabapentinoids are recommended as first-line treatment for neuropathic pain by leading clinical practice guidelines, the research team added. "Although one guideline noted gabapentinoids' potential for misuse and dependence, none mentioned the potential for respiratory adverse effects.” Moreover, there have been no population-level studies performed among individuals with COPD to investigate the dangerous—and potentially fatal—respiratory adverse effects of these drugs.

To assemble the study cohort, Rahman and colleagues tapped 3 digital health insurance databases from the Régie de l’assurance maladie du Québec in Canada, including data for 13 504 individuals aged 55 years and older with a diagnosis of COPD between 1994 to 2015. Within this cohort, researchers matched individuals who initiated gabapentinoid therapy for epilepsy (n = 356), neuropathic pain (n = 9411), or other chronic pain (n = 3737) 1:1 with a group not treated with gabapentinoids for duration of COPD, indication for gabapentinoids, age, sex, calendar year, and time-conditional propensity score.

The primary outcome of interest was severe COPD exacerbation requiring hospitalization.

FINDINGS

The investigators reported that compared with individuals with COPD and 1 of the 3 indications who were not taking gabapentinoids, the increased risk for severe COPD exacerbation among those who were exposed was:

• Epilepsy: Hazard ratio (HR) 1.58 (95% CI 1.08-2.30)
• Neuropathic pain: HR 1.35 (95% CI 1.24-1.48)
• Other chronic pain: HR 1.49 (95% CI 1.27-1.73)

As reported earlier, among the overall cohort, the HR for increased risk of exacerbation among gabapentinoid users was 1.39 (95% CI, 1.29-1.5) compared with nonusers. Risk of an exacerbation, the investigators found, was highest following “approximately 6 months of continuous gabapentinoid use.” Their findings were consistent across age, sex, and COPD severity, the authors wrote.

The trends in off-label use of gabapentinoids are reason for concern because the agents “are not effective” for some of the indications, Ahman et al wrote. "In particular, their propensity to cause central nervous system depression leading to sedation and respiratory depression has been reported in both animal and human studies."

Among the study’s limitations the authors note is identification of persons with COPD based on relevant medication prescriptions rather than ICD codes, introducing the possible inclusion of patients treated for asthma. They also called out the potential for residual confounding based on the study’s lack of data on race/ethnicity and smoking status.

These limitations notwithstanding, Rahman et al concluded that their results “support the warnings from regulatory agencies and highlight the importance of considering this potential risk when prescribing gabapentin and pregabalin to patients with COPD.”

Source: 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 online January 16, 2024. doi:10.7326/M23-0849