Role of hyperpolarization-activated cyclic nucleotide-gated ion channels in neuropathic pain: a proof-of-concept study of ivabradine in patients with chronic peripheral neuropathic pain.

Bernard Healey, Shannon A 
Scholtes, Ingrid 
Abrahams, Mark 
McNaughton, Peter A 
Menon, David K 

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INTRODUCTION: Hyperpolarization-activated cyclic nucleotide-gated (HCN) ion channels mediate repetitive action potential firing in the heart and nervous system. The HCN2 isoform is expressed in nociceptors, and preclinical studies suggest a critical role in neuropathic pain. Ivabradine is a nonselective HCN blocker currently available for prescription for cardiac indications. Mouse data suggest that ivabradine in high concentrations is equianalgesic with gabapentin. We sought to translate these findings to patients with chronic peripheral neuropathic pain. OBJECTIVES: We sought to translate these findings to patients with chronic peripheral neuropathic pain. METHODS: We adopted an open-label design, administering increasing doses of ivabradine to target a heart rate of 50 to 60 BPM, up to a maximum of 7.5 mg twice daily. All participants scored their pain on an 11-point numerical rating scale (NRS). RESULTS: Seven (7) participants received the drug and completed the study. There was no significant treatment effect on the primary endpoint, the difference between the mean score at baseline and at maximum dosing (mean reduction = 0.878, 95% CI = -2.07 to 0.31, P = 0.1). Exploratory analysis using linear mixed models, however, revealed a highly significant correlation between ivabradine dose and pain scores (χ2(1) = 74.6, P < 0.001), with a reduction of 0.12 ± 0.01 (SEM) NRS points per milligram. The 2 participants with painful diabetic neuropathy responded particularly well. CONCLUSION: This suggests that ivabradine may be efficacious at higher doses, particularly in patients with diabetic neuropathic pain. Importantly, participants reported no adverse effects. These data suggest that ivabradine, a peripherally restricted drug (devoid of central nervous system side effects), is well tolerated in patients with chronic neuropathic pain. Ivabradine is now off-patent, and its analgesic potential merits further investigation in clinical trials.

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Chronic pain, Clinical trial, Diabetic neuropathies, Hyperpolarization-activated cyclic nucleotide-gated channels, Ivabradine
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Pain Rep
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Ovid Technologies (Wolters Kluwer Health)
Evelyn Trust (RECORD-Pain 14/31)
MRC (via King's College London) (RCZB/010)
National Institute for Health Research (IS-BRC-1215-20014)
Medical Research Council (MR/J013129/1)
This research was supported by the NIHR Cambridge Biomedical Research Centre (BRC-1215-20014). The authors acknowledge support from the East of England NIHR Clinical Research Network who facilitated identification of participants, and the staff at the Cambridge NIHR Clinical Investigation Ward, who cared for our participants during their visit. The authors are grateful to Mr Abhishek Dixit who built and maintained OpenClinica for data capture. The in-house development and use of FAST-diary are supported by Evelyn Trust (RECORD-Pain) and AAGBI (Anaesthesia-Wiley) research grants.