An anti-seizure medication prescribed for common pain has been linked to an increased risk of heart failure, particularly in people with a history of cardiovascular disease (CVD), suggests new evidence.
Medscape reports that in a cohort of more than 240 000 Medicare beneficiaries with non-cancer chronic pain, initiation of pregabalin was associated with a 48% higher risk for new-onset HF overall and an 85% higher risk in those with a history of CVD than initiation of gabapentin, according to the investigators, led by Elizabeth Park, MD, Columbia University Irving Medical Centre in New York City.
Chronic pain affects up to 30% of adults over 65, with non-opioid medications like the gabapentinoids pregabalin and gabapentin, being commonly prescribed.
Pregabalin has greater potency than gabapentin in binding to the α2δ subunit of the L-type calcium channel and therefore may be associated with an increased risk for HF through actions to cause sodium/water retention.
The investigators evaluated 246 237 Medicare beneficiaries between 2014 and 2018, including 18 622 (8%) new pregabalin users and 227 615 (92%) new gabapentin users. All of the patients were between 65 and, had chronic non-cancer pain, and had no history of HF.
The researchers used inverse probability of treatment weighting to adjust for an extensive list of 231 covariates to reduce confounding and attempted to closely emulate a hypothetical target trial in which Medicare patients filled new prescriptions for pregabalin or gabapentin for non-cancer pain.
During 114 113 person-years of follow-up, 1 470 patients had a hospital admission or emergency department visit for HF. The rate of HF per 1000 person-years was 18.2 for pregabalin and 12.5 – translating to roughly six additional HF events annually for every 1 000 patients treated with pregabalin – with an adjusted hazard ratio (HR) of 1.48.
The difference was even more pronounced in patients with a history of CVD, with an adjusted HR of 1.85. An increased risk for outpatient HF diagnoses was also seen (adjusted HR, 1.27), but there was no difference in all-cause mortality between groups.
In their findings, published online in JAMA Network Open, the authors said the findings further support current recommendations from the European Medicines Agency to exercise caution when prescribing pregabalin to older adults with CVD.
The American Heart Association currently lists pregabalin, but not gabapentin, as a medication that may cause or exacerbate HF.
Immediate clinical implications
The co-authors of an invited commentary noted that the study provides “timely and clinically relevant insights” into the cardiovascular safety of these two widely used gabapentinoids.
From a clinical standpoint, the findings have “immediate clinical implications”, wrote Robert Zhang, MD, with Weill Cornell Medicine, New York City, and Edo Birati, MD, Tzafon (Poriya) Medical Centre, Poriya, Israel.
For older adults with chronic pain, particularly those with CVD, “clinicians should weigh the potential cardiovascular risks associated with pregabalin against its analgesic benefits”.
“This is particularly relevant given the growing use of gabapentinoids in older populations and ongoing polypharmacy issues in this age group,” Zhang and Birati advised.
“Furthermore, if pregabalin use is associated with new-onset HF, it raises the possibility that the drug may unmask underlying subclinical cardiovascular disease, which suggests a need for careful cardiac evaluation prior to prescribing this medication,” they added.
“The study serves as an important reminder that not all gabapentinoids are created equal and that in the pursuit of safer pain control, vigilance for unintended harms remains paramount,” the investigators concluded.
Study details
Initiation of Pregabalin vs Gabapentin and Development of Heart Failure
Elizabeth Park, Laura Daniel, Alyson Dickson, et al.
Published online by JAMA Network Open on 1 August 2025
Abstract
Importance
Both pregabalin and gabapentin are common non-opioid medications used to treat chronic pain, which affects up to 30% of patients. Because pregabalin has greater potency than gabapentin in binding to the α2δ subunit of the L-type calcium channel, pregabalin may be associated with an increased risk for heart failure (HF).
Objective
To compare incident hospitalisations and emergency department (ED) visits for HF among new users of pregabalin vs gabapentin among Medicare beneficiaries with non-cancer chronic pain.
Design, Setting, and Participants
This retrospective cohort study included data collected between January 1, 2015, and December 21, 2018, for Medicare beneficiaries aged 65 to 89 years with chronic non-cancer pain and without a history of HF and terminal illnesses. Data were analysed from March 21 to December 2, 2024.
Exposure
New use of pregabalin or gabapentin.
Main Outcomes and Measures
The primary outcome was hospital admission or ED visit with a primary discharge diagnosis of HF. Secondary outcomes were incidence of outpatient HF diagnosis and all-cause mortality. Adjusted hazard ratios (AHRs) were calculated using inverse probability of treatment weighting propensity score adjustment accounting for 231 covariates, including demographic, clinical, and health care utilisation variables and medication use.
Results
The cohort included 246 237 Medicare beneficiaries, of whom 18 622 (7.6%) were new users of pregabalin and 227 615 (92.4%) were new users of gabapentin; the cohort was predominantly female (66.8%), with a median age of 73 years (IQR, 69-78 years). During 114 113 person-years of follow-up, 1470 patients had a hospital admission or ED visit for HF. The rate of HF was 18.2 (95% CI, 15.3-21.6) per 1000 person-years for pregabalin and 12.5 (95% CI, 11.9-13.2) for gabapentin (AHR, 1.48 [95% CI, 1.19-1.77]). When restricted to patients with a history of cardiovascular disease, pregabalin was associated with an elevated HF risk compared with gabapentin (AHR, 1.85 [95% CI, 1.38-2.47]). Increased risk of outpatient HF incidence was also noted among patients receiving pregabalin compared with those receiving gabapentin (AHR, 1.27 [95% CI, 1.02-1.58]). All-cause mortality was not significantly different between groups (AHR, 1.26 [95% CI, 0.95-1.76]).
Conclusions and Relevance
In this retrospective cohort study of Medicare beneficiaries with chronic non-cancer pain, incident HF was increased in new users of pregabalin compared with new users of gabapentin. These findings should be considered, especially in patients with a history of cardiovascular disease.
Medscape article – Common Painkiller Tied to Heart Failure Risk in Older Adults (Open access)
See more from MedicalBrief archives:
Doctors flag painkiller prescribed ‘for everything’
Two-fold increase in gabapentinoids use for cancer pain ‘problematic’ – study