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

TY - JOUR

T1 - Role of hyperpolarization-activated cyclic nucleotide-gated ion channels in neuropathic pain

T2 - A proof-of-concept study of ivabradine in patients with chronic peripheral neuropathic pain

AU - Bernard Healey, Shannon A.

AU - Scholtes, Ingrid

AU - Abrahams, Mark

AU - McNaughton, Peter A.

AU - Menon, David K.

AU - Lee, Michael C.

N1 - Publisher Copyright: © 2021 Lippincott Williams and Wilkins. All rights reserved.

PY - 2021/11/29

Y1 - 2021/11/29

N2 - 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.

AB - 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.

KW - Chronic pain

KW - Clinical trial

KW - Diabetic neuropathies

KW - Hyperpolarization-activated cyclic nucleotide-gated channels

KW - Ivabradine

UR - http://www.scopus.com/inward/record.url?scp=85133043219&partnerID=8YFLogxK

U2 - 10.1097/PR9.0000000000000967

DO - 10.1097/PR9.0000000000000967

M3 - Article

AN - SCOPUS:85133043219

SN - 2471-2531

VL - 6

SP - E967

JO - Pain Reports

JF - Pain Reports

IS - 4

ER -