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Updated: Aug 11, 2025
Author Spotlight: Exploring the Role of Ion Channels in Cancer: Characterization and Potential Treatment Approaches
Published on: June 16, 2023
Sodium channel-inhibiting drugs and cancer-specific survival: a population-based study of electronic primary care
Caroline Fairhurst1, Fabiola Martin2, Ian Watt1
1Health Sciences, University of York, York, UK.
Objectives:
Antiepileptic and antiarrhythmic drugs inhibit voltage-gated sodium (Na+) channels (VGSCs), and preclinical studies show that these medications reduce tumour growth, invasion and metastasis. We investigated the association between VGSC inhibitor use and survival in patients with breast, bowel and prostate cancer.
Design:
Retrospective cohort study.
Setting:
Individual electronic primary healthcare records extracted from the Clinical Practice Research Datalink.
Participants:
Records for 132 996 patients with a diagnosis of breast, bowel or prostate cancer.
Outcome Measures:
Adjusted Cox proportional hazards regression was used to analyse cancer-specific survival associated with exposure to VGSC inhibitors. Exposure to non-VGSC-inhibiting antiepileptic medication and other non-VGSC blockers were also considered. Drug exposure was treated as a time-varying covariate to account for immortal time bias.
Results:
During 1 002 225 person-years of follow-up, there were 42 037 cancer-specific deaths. 53 724 (40.4%) patients with cancer had at least one prescription for a VGSC inhibitor of interest. Increased risk of cancer-specific mortality was associated with exposure to this group of drugs (HR 1.59, 95% CI 1.56 to 1.63, p<0.001). This applied to VGSC-inhibiting tricyclic antidepressants (HR 1.61, 95% CI 1.50 to 1.65, p<0.001), local anaesthetics (HR 1.49, 95% CI 1.43 to 1.55, p<0.001) and anticonvulsants (HR 1.40, 95% CI 1.34 to 1.48, p<0.001) and persisted in sensitivity analyses. In contrast, exposure to VGSC-inhibiting class 1c and 1d antiarrhythmics was associated with significantly improved cancer-specific survival (HR 0.75, 95% CI 0.64 to 0.88, p<0.001 and HR 0.54, 95% CI 0.33 to 0.88, p=0.01, respectively).
Conclusions:
Association between VGSC inhibitor use and mortality in patients with cancer varies according to indication. Exposure to VGSC-inhibiting antiarrhythmics, but not anticonvulsants, supports findings from preclinical data, with improved survival. However, additional confounding factors may underlie these associations, highlighting the need for further study.
Insights
Voltage-gated sodium channel (VGSC) inhibitors used for epilepsy and arrhythmias showed varied effects on cancer survival. While some VGSC inhibitors increased mortality risk in breast, bowel, and prostate cancer patients, specific antiarrhythmics improved survival.
Area of Science:
- Oncology
- Pharmacology
- Clinical Epidemiology
Background:
- Voltage-gated sodium (Na+) channels (VGSCs) are implicated in tumor growth, invasion, and metastasis.
- Antiepileptic and antiarrhythmic drugs are known VGSC inhibitors.
- Preclinical studies suggest VGSC inhibitors may impact cancer progression.
Purpose of the Study:
- To investigate the association between the use of voltage-gated sodium channel (VGSC) inhibitors and survival outcomes in patients diagnosed with breast, bowel, or prostate cancer.
- To differentiate the impact of various types of VGSC inhibitors on cancer-specific mortality.
Main Methods:
- Retrospective cohort study utilizing electronic health records from the Clinical Practice Research Datalink.
- Inclusion of 132,996 patients diagnosed with breast, bowel, or prostate cancer.
- Adjusted Cox proportional hazards regression with time-varying covariates to analyze cancer-specific survival and VGSC inhibitor exposure.
Main Results:
- Increased cancer-specific mortality risk was associated with exposure to certain VGSC inhibitors, including tricyclic antidepressants, local anesthetics, and anticonvulsants (HRs ranging from 1.40 to 1.61).
- Conversely, exposure to VGSC-inhibiting class 1c and 1d antiarrhythmics was linked to significantly improved cancer-specific survival (HRs of 0.75 and 0.54, respectively).
- These associations persisted in sensitivity analyses.
Conclusions:
- The association between VGSC inhibitor use and cancer patient mortality differs based on the drug's indication.
- VGSC-inhibiting antiarrhythmics, unlike anticonvulsants, demonstrated improved survival, aligning with some preclinical findings.
- Further research is warranted to explore potential confounding factors influencing these observed associations.
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