Background Concomitant gabapentinoid and dihydropyridine calcium channel blocker (DHP-CCB) use amplifies dementia risk, an interaction proposed to involve dual neuronal calcium channel blockade. Whether this risk depends on the sequence of drug initiation—and is therefore preventable by prescribing order—remains unknown.

Methods Using the Rutgers Clinical Research Data Warehouse (2015–2024), we conducted three complementary analyses. The primary analysis (Population 4) compared gabapentin versus pregabalin in 4,451 patients on chronic DHP-CCB therapy who newly initiated a gabapentinoid (55 dementia events; IPTW Cox model). The asymmetry confirmatory analysis (Population 3) compared DHP-CCB versus ACE/ARB initiation in 1,740 patients on chronic gabapentinoid therapy (29 dementia events). A sensitivity analysis replicated prior findings in a broader CCB-first cohort (N=9,383). A dementia acceleration analysis examined outcomes in 273 patients with established dementia initiating gabapentinoid.

Results In Population 4, gabapentinoid initiation on a background of chronic CCB therapy was associated with a 2.23-fold elevated dementia risk compared to pregabalin (IPTW HR 2.23, 95% CI 1.43–3.48, p=0.0004). The Population 3 asymmetry test yielded a null result: adding DHP-CCB to chronic gabapentinoid therapy carried no differential dementia risk versus adding ACE/ARB (IPTW HR 0.995, 95% CI 0.595–1.664, p=0.98). This directional asymmetry—elevated risk only when gabapentinoid is added to pre-existing CCB therapy, not the reverse—is the central finding. Lagged analyses showed HRs increasing monotonically from 2.23 to 2.87 across 0- to 180-day lag windows, reducing concern for protopathic bias. In the dementia acceleration cohort, DHP-CCB use at gabapentinoid initiation was associated with encephalopathy (IPTW HR 2.09, 95% CI 1.19–3.67, p=0.010); zero encephalopathy events occurred among non-DHP CCB users (N=16), consistent with DHP subtype specificity.

Conclusions The gabapentinoid–CCB cognitive interaction is directionally asymmetric: risk concentrates in patients adding gabapentinoid to pre-existing CCB therapy, not the reverse. This pattern is mechanistically consistent with impaired homeostatic synaptic plasticity in neurons compensating for chronic L-type calcium channel blockade. For patients already on CCB therapy requiring neuropathic pain management, pregabalin may be preferable to gabapentin, pending external validation. The asymmetry also implies that initiating a CCB in a patient already on gabapentin may not carry equivalent risk.

The authors have declared no competing interest.

This research did not receive specific grant funding. Computing resources were provided by the Rutgers Office of Advanced Research Computing (Amarel HPC cluster). J.G. is supported in part through the Rutgers School of Health Professions doctoral program.

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The Rutgers University Institutional Review Board, Rutgers, The State University of New Jersey, gave ethical approval for this work (Protocol Pro2026000471).

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The Rutgers Clinical Research Data Warehouse (CRDW) data that support the findings of this study are available through the Rutgers University health system subject to institutional data governance review. Analytic code is available from the corresponding author upon reasonable request.