Older adults taking pregabalin for chronic pain had up to an 85% higher risk of heart failure than gabapentin users, raising fresh caution for prescribing practices in high-risk groups.
Study: Initiation of Pregabalin vs Gabapentin and Development of Heart Failure. Image Credit: Vector_Leart / Shutterstock
In a recent study published in JAMA Network Open, researchers compared heart failure (HF) incidence between users of gabapentin and pregabalin.
Non-opioid medications, such as gabapentin and pregabalin, are gabapentinoids (analogs of gamma-aminobutyric acid) prescribed for chronic pain disorders. They are preferred over opioids for chronic non-cancer pain treatment due to the higher risks of overdose, addiction, and death associated with opioids. Non-opioids are specifically indicated for older individuals, as they are among those with the most risk for adverse effects related to opioids.
Both gabapentin and pregabalin bind specific subunits of N-type and P/Q-type voltage-gated neuronal calcium channels, reduce neurotransmitter release, and exhibit antinociceptive effects. However, adverse cardiovascular effects, including peripheral edema and HF, have been associated with gabapentin and pregabalin due to their additional effects on α2δ subunits of L-type calcium channel subunits on ventricular cardiomyocytes and arteries.
Moreover, the risk of adverse effects may be higher with pregabalin compared to gabapentin due to its higher potency and receptor binding affinity. However, there are only a few studies that assessed the comparative HF risk between gabapentin and pregabalin users. In addition, most of these studies did not focus on older individuals, limited their analyses to neurological indications, or lacked a rigorous HF definition.
To address these gaps, the researchers used a target trial emulation design, a framework that mimics a randomized controlled trial using observational data to estimate causal effects more robustly. They adjusted for 231 covariates using inverse probability of treatment weighting to minimize confounding.
About the study
In the present study, researchers compared the incidence of HF among individuals prescribed gabapentin or pregabalin for chronic non-cancer pain. A 20% sample of Medicare beneficiaries between January 1, 2015, and December 21, 2018, was included. The cohort comprised beneficiaries aged 65–89 and was limited to those with outpatient medical care, prescription drug, and hospitalization coverage. Patients enrolled in Medicare Advantage (Part C) were excluded due to incomplete claims data.
Patients with a chronic pain diagnosis and a new prescription of gabapentin or pregabalin were included in the cohort. Individuals with terminal illnesses, a history of HF, hospitalization on the day of prescription, hospital stay more than 29 days, or a stay more than 29 days at a long-term care facility were excluded. Subjects were followed up until an emergency department (ED) visit or hospitalization for HF, death, or the end of the study.
The primary outcome was an ED visit or hospitalization for a primary HF diagnosis. Secondary outcomes included outpatient encounters with a primary HF diagnosis and all-cause mortality. Hazard ratios for gabapentin and pregabalin were estimated using Cox proportional hazards regression. The models were adjusted using inverse probability of treatment weighting based on a propensity score that incorporated 231 demographic, clinical, and medication-use variables. Further, stratified analyses were performed by sex, race, ethnicity, and history of cardiovascular disease (CVD).
Findings
The cohort comprised 246,237 Medicare beneficiaries, with a median age of 73. Of these, 92.4% used gabapentin and 7.6% used pregabalin. Most participants were female (66.8%) and White (79.9%). Neuropathic, back, and musculoskeletal pain were the most common diagnoses associated with gabapentin and pregabalin prescriptions. Gabapentin and pregabalin users had overall comparable frequencies of diagnoses of cardiovascular and other conditions.
Nevertheless, pregabalin users had an increased prevalence of fibromyalgia, diabetic neuropathy, greater use of duloxetine and cyclooxygenase-2 inhibitors, and a lower proportion of White individuals. Overall, 1.3% of the cohort developed HF during a follow-up of 114,113 person-years. HF incidence per 1,000 person-years was 12.5 for gabapentin users and 18.2 for pregabalin users.
Pregabalin was associated with a higher HF risk compared to gabapentin in females, White individuals, and those with a CVD history. Further, the risk of outpatient HF was significantly higher for pregabalin users compared to gabapentin users. However, all-cause mortality did not significantly differ between these groups.
In a negative control analysis using hip fracture, a condition unrelated to the exposure or outcome, no significant difference was observed between the two drugs, supporting the specificity of the HF findings. Additionally, E-values were calculated to assess robustness to unmeasured confounding.
Conclusions
In sum, pregabalin initiation was associated with an increased risk of incident HF compared to gabapentin initiation in older individuals with chronic pain. This risk was especially pronounced among individuals with pre-existing CVD, supporting current recommendations for caution when prescribing pregabalin to older people with CVD.
The study’s limitations include a sample skewed toward female and White individuals, sample restriction to those aged ≥ 65, exclusion of Medicare Advantage enrollees, and limited power for ethnic and racial minority groups. Furthermore, unmeasured confounders such as body mass index, smoking, physical activity, and socioeconomic status were not available in the Medicare dataset but were partially addressed through negative control and E-value analyses. Overall, clinicians should assess ongoing cardiovascular risk factors and provide adequate risk-benefit counseling to older people before prescribing pregabalin for chronic pain.
