Highlights
- Pregabalin initiation is associated with a significantly higher risk of heart failure (HF) hospitalization or ED visits compared to gabapentin in older adults with chronic noncancer pain.
- The risk is most pronounced in patients with pre-existing cardiovascular disease.
- No significant difference in all-cause mortality was observed between groups.
- Clinical decision-making should factor in HF risk when prescribing pregabalin, especially for vulnerable populations.
Study Background and Disease Burden
Chronic pain affects up to 30% of the population, especially in the elderly, and is a leading cause of disability and diminished quality of life. Nonopioid medications such as pregabalin and gabapentin are widely prescribed for neuropathic and musculoskeletal pain due to their efficacy and relatively favorable safety profile compared to opioids. However, both drugs, which act by binding to the α2δ subunit of voltage-gated calcium channels, have been linked to adverse cardiovascular effects in case reports. Notably, pregabalin exhibits greater binding potency than gabapentin, raising concerns about its potential for causing fluid retention and precipitating HF, particularly in older adults with multiple comorbidities. Given the prevalence of both chronic pain and heart failure in the Medicare population, clarifying the relative safety of these agents is a critical unmet need.
Study Design
This retrospective cohort study by Park et al. (JAMA Netw Open, 2025) analyzed U.S. Medicare data between January 1, 2015, and December 21, 2018. The study population included beneficiaries aged 65 to 89 years with chronic noncancer pain, explicitly excluding individuals with a history of heart failure or terminal illnesses. After careful selection, 246,237 patients were included: 18,622 new users of pregabalin and 227,615 new users of gabapentin. The cohort was predominantly female (66.8%) with a median age of 73 years (IQR 69–78).
The primary exposure was initiation of either pregabalin or gabapentin. The primary outcome was hospitalization or ED visit with a primary discharge diagnosis of heart failure. Secondary outcomes included outpatient HF diagnosis and all-cause mortality. To address confounding, the investigators used inverse probability of treatment weighting based on propensity scores derived from 231 covariates, including demographic, clinical, healthcare utilization, and medication variables.
Key Findings
During 114,113 person-years of follow-up, there were 1,470 primary endpoint events (hospitalization or ED visit for HF). The rate of HF was significantly higher among pregabalin users (18.2 per 1,000 person-years; 95% CI, 15.3–21.6) compared to gabapentin users (12.5 per 1,000 person-years; 95% CI, 11.9–13.2). The adjusted hazard ratio (AHR) for HF events with pregabalin versus gabapentin was 1.48 (95% CI, 1.19–1.77), indicating a 48% increased risk.
Subgroup analysis revealed even greater risk for patients with pre-existing cardiovascular disease (AHR, 1.85; 95% CI, 1.38–2.47). A modestly increased risk of outpatient HF diagnosis was also observed for pregabalin (AHR, 1.27; 95% CI, 1.02–1.58). Importantly, all-cause mortality did not differ significantly between the groups (AHR, 1.26; 95% CI, 0.95–1.76), suggesting that the excess HF risk does not translate into increased short-term mortality in this cohort.
A summary of the main results is provided in the table below:
| Outcome | Pregabalin (per 1,000 PY) | Gabapentin (per 1,000 PY) | Adjusted Hazard Ratio (AHR) | 95% CI |
|---|---|---|---|---|
| Hospitalization/ED for HF | 18.2 | 12.5 | 1.48 | 1.19–1.77 |
| Hospitalization/ED for HF (with CVD history) | — | — | 1.85 | 1.38–2.47 |
| Outpatient HF Diagnosis | — | — | 1.27 | 1.02–1.58 |
| All-cause Mortality | — | — | 1.26 | 0.95–1.76 |
These findings are robust given the comprehensive adjustment for confounders and the large sample size, providing credible evidence for differential cardiovascular risk.
Expert Commentary
The results align with prior mechanistic hypotheses: pregabalin’s higher affinity for the α2δ subunit can increase peripheral edema and fluid retention, both recognized contributors to heart failure decompensation. The risk signal is most pronounced in those with underlying cardiovascular disease, a subgroup already predisposed to HF events. Notably, the lack of excess mortality suggests that while the risk of HF events is higher, these do not immediately translate to poorer survival, though the clinical burden and healthcare utilization remain considerable.
Guidelines on chronic pain emphasize careful patient selection and risk assessment when prescribing adjuvant analgesics, particularly in older adults with multiple comorbidities. The present findings reinforce the need for heightened vigilance in this population, especially when considering pregabalin for patients with a history of cardiac disease.
Study limitations include potential residual confounding, reliance on administrative diagnosis codes, and lack of granular data on HF severity or ejection fraction. Nevertheless, the consistency of the findings across multiple endpoints and the size of the effect lend credibility to the conclusions.
Conclusion
In summary, this large retrospective cohort study demonstrates that initiation of pregabalin is associated with a significantly increased risk of heart failure events compared to gabapentin among older adults with chronic noncancer pain, particularly in those with pre-existing cardiovascular disease. Clinicians should weigh these risks when choosing therapy and consider alternative agents or closer monitoring for high-risk patients. Further research should focus on elucidating the mechanisms and identifying which patients are most susceptible to adverse cardiac outcomes.
References
1. Park EE, Daniel LL, Dickson AL, Corriere M, Nepal P, Hall K, Plummer WD, Dupont WD, Murray KT, Stein CM, Ray WA, Chung CP. Initiation of Pregabalin vs Gabapentin and Development of Heart Failure. JAMA Netw Open. 2025 Aug 1;8(8):e2524451. doi: 10.1001/jamanetworkopen.2025.24451 IF: 9.7 Q1 2. Wiffen PJ, Derry S, Bell RF, et al. Gabapentin and pregabalin for chronic neuropathic pain in adults. Cochrane Database Syst Rev. 2017 Jun 9;6(6):CD007938.
3. American Geriatrics Society 2019 Updated Beers Criteria for Potentially Inappropriate Medication Use in Older Adults. J Am Geriatr Soc. 2019 Apr;67(4):674-694.