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

Abstract. 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...

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Autores principales:	Shannon A. Bernard Healey, Ingrid Scholtes, Mark Abrahams, Peter A. McNaughton, David K. Menon, Michael C. Lee
Formato:	article
Lenguaje:	EN
Publicado:	Wolters Kluwer 2021
Materias:	Anesthesiology RD78.3-87.3
Acceso en línea:	https://doaj.org/article/df891575fcf64e7b880192e384a1a0da
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spelling	oai:doaj.org-article:df891575fcf64e7b880192e384a1a0da2021-11-25T07:59:39ZRole of hyperpolarization-activated cyclic nucleotide-gated ion channels in neuropathic pain: a proof-of-concept study of ivabradine in patients with chronic peripheral neuropathic pain2471-253110.1097/PR9.0000000000000967https://doaj.org/article/df891575fcf64e7b880192e384a1a0da2021-11-01T00:00:00Zhttp://journals.lww.com/painrpts/fulltext/10.1097/PR9.0000000000000967https://doaj.org/toc/2471-2531Abstract. 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.Shannon A. Bernard HealeyIngrid ScholtesMark AbrahamsPeter A. McNaughtonDavid K. MenonMichael C. LeeWolters KluwerarticleAnesthesiologyRD78.3-87.3ENPAIN Reports, Vol 6, Iss 4, p e967 (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	Anesthesiology RD78.3-87.3
spellingShingle	Anesthesiology RD78.3-87.3 Shannon A. Bernard Healey Ingrid Scholtes Mark Abrahams Peter A. McNaughton David K. Menon Michael C. Lee 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
description	Abstract. 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.
format	article
author	Shannon A. Bernard Healey Ingrid Scholtes Mark Abrahams Peter A. McNaughton David K. Menon Michael C. Lee
author_facet	Shannon A. Bernard Healey Ingrid Scholtes Mark Abrahams Peter A. McNaughton David K. Menon Michael C. Lee
author_sort	Shannon A. Bernard Healey
title	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
title_short	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
title_full	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
title_fullStr	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
title_full_unstemmed	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
title_sort	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
publisher	Wolters Kluwer
publishDate	2021
url	https://doaj.org/article/df891575fcf64e7b880192e384a1a0da
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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

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