Hyperpolarization-activated cyclic nucleotide-gated ion channels a new target for neuropathic pain? A proof-of-concept study with ivabradine
Aim: Mouse data suggest that ivabradine (a nonselec5ve hyperpolariza5on-ac5vated cyclic nucleo5de-gated [HCN] ion channel antagonist) in high concentra5ons is equianalgesic with gabapen5n. The authors sought to translate these findings to pa5ents with chronic peripheral neuropathic pain.
Methods: An open-label design, administering increasing doses of ivabradine to target a heart rate of 50 to 60 beats per minute (bpm), up to a maximum of 7.5 mg twice daily. Par5cipants scored their pain on an 11-point numerical ra5ng scale (NRS).
Results: Seven (7) par5cipants 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 reduc5on=0.878, 95% CI=−2.07 to 0.31, P=0.1). Exploratory analysis, however, revealed a highly significant correla5on between ivabradine dose and pain scores (χ2(1)=74.6, P<0.001), with a reduc5on of 0.12±0.01 (SEM) NRS points per milligram. The 2 par5cipants with painful diabe5c neuropathy (pDN) responded par5cularly well.
Conclusions: Ivabradine may be efficacious at higher doses, par5cularly in pa5ents with pDN. Importantly, par5cipants reported no adverse effects, sugges5ng that ivabradine, a peripherally restricted drug (devoid of central nervous system side effects), is well tolerated. Ivabradine is now off- patent, and its analgesic poten5al merits further inves5ga5on in clinical trials.
Comments. The drive to discover novel targets and therapies for neuropathic pain is s5ll extremely high. The current study is the first of its kind to explore the use of ivabradine, a nonselec5ve HCN blocker, in neuropathic pain. Ivabradine is currently licensed in most countries as an adjuvant in the management of angina and heart failure. Preclinical work has shown that ivabradine has analgesic proper5es in neuropathic pain states. In itself, the above study was an open-label, uncontrolled and underpowered in that they were only able to recruit only 7 of their intended 36 par5cipants due to recruitment challenges, of which 2 had pDN. The maximum dose was gradually increased to 7.5mg BD or a heart rate between 50-60 bpm, as one would for cardiac indica5ons. There was no significant difference in the primary endpoint noted in this short-dura5on study (6-9 weeks of treatment). What the inves5gators noted however was that there was indeed a significant correla5on between increments in ivabradine dosing and NRS reduc5on. Analysis of the 7-day moving average suggested that the 2 par5cipants with pDN showed the best response.
While this sets the scene for a puta5ve role in the use of HCN antagonism for neuropathic pain, it is difficult to derive any clinical management conclusions as yet and plenty of scope to view the work with scep5cism. Ivabradine is the only HCN antagonist agent currently available. Furthermore, its true analgesic effec5veness may be limited by its impact on heart rate – indeed it only achieves approximately 10% of HCN2 (the isoform expressed in nociceptors) blockade at the doses that give an acceptable reduc5on (drop) in heart rate. The way forward would be the development of selec5ve HCN2 antagonists, which if proven to be clinically effec5ve, may add another arsenal to our rather currently weak armamentarium of drugs for neuropathic pain.
Prashanth Vas
Reference. Bernard Healey SA, Scholtes I, Abrahams M, McNaughton PA, Menon DK, Lee MC. Role of hyperpolarizaEon-acEvated cyclic nucleoEde-gated ion channels in neuropathic pain: a proof-of-concept study of ivabradine in paEents with chronic peripheral neuropathic pain. Pain Rep. 2021 Oct 18;6(4):e967.doi: 10.1097/PR9.0000000000000967.
