What is the clinical evidence from this study?

Study design: RCT. Population: Capsaicin-induced pain model (n=20). Intervention: Ivabradine vs. Placebo. Primary outcome: Capsaicin-induced spontaneous pain at 30 min (VAS score) (95% CI -6.1 to 4.3, p=0.7479).

What does this research mean for the field?

Two-day oral administration of ivabradine did not significantly reduce capsaicin-induced spontaneous pain compared to placebo in healthy volunteers, though it did reduce the area of secondary dynamic mechanical allodynia, suggesting HCN channels are differentially involved in human pain pathways. Novelty: ClaimNovelty.NOVEL_FINDING. Consensus alignment: ConsensusAlignment.ESTABLISHES_NEW_DIRECTION.

October 14, 2022Open Access

A randomized, double-blinded, placebo-controlled, crossover study of the HCN channel blocker ivabradine in a capsaicin-induced pain model in healthy volunteers

Key Result

Two-day oral administration of ivabradine did not significantly reduce capsaicin-induced spontaneous pain compared to placebo in healthy volunteers.

Study Design

Type

RCT (n=20)

Blinding

Double-blind

Randomization

Computer randomization

Multicenter

Structured PICO

Does ivabradine reduce capsaicin-induced spontaneous pain in healthy volunteers?

Population

20 healthy adult subjects (18 males, 2 females)

Intervention

Ivabradine (5-7.5 mg) administered 3 times over 2 days, followed by topical capsaicin (0.5%) on the volar forearm for 30 min

Comparator

Placebo administered 3 times over 2 days, followed by topical capsaicin (0.5%) on the volar forearm for 30 min

Outcome

Capsaicin-induced spontaneous pain at 30 min after capsaicin applicationpatient reported

Short-term administration of the HCN channel blocker ivabradine did not reduce capsaicin-induced spontaneous pain but significantly reduced secondary dynamic mechanical allodynia in healthy volunteers.

Main Result

Absolute Event Rate: 33.5% vs 34.4%

p-value: p=0.7479

Limitations

Significant period effect for punctate mechanical hyperalgesia prevented pooled analysis from both periods.
Ivabradine was administered before capsaicin application, demonstrating only preventive effects rather than alleviation of ongoing pain.
Not all sensory changes caused by capsaicin application were evaluated (e.g., mechanical pain threshold was only measured before capsaicin application).

Abstract

Hyperpolarization-activated cyclic nucleotide-gated (HCN) channels have been focused on as a potential therapeutic target for inflammatory and neuropathic pain in rodent models. However, roles of HCN channels in human pain states have been scarcely investigated. We evaluated analgesic effects of 2-day administration of ivabradine, the only clinically available HCN channel blocker, on a capsaicin pain model in a randomized, double-blinded, placebo-controlled, crossover study. Twenty healthy adult subjects (18 males, 2 females) received ivabradine (5-7.5 mg) or a placebo 3 times in 2 days. Then capsaicin (0.5%) was topically applied on the volar forearm for 30 min. The primary outcome was capsaicin-induced spontaneous pain. The secondary outcomes included heat-pain threshold (HPT), flare size, and areas of secondary punctate mechanical hyperalgesia (PMH) and secondary dynamic mechanical allodynia (DMA). There was no significant difference in spontaneous pain (p = 0.7479), HPT (p = 0.7501), area of PMH (p = 0.1052) or flare size (p = 0.5650) at 30 min after capsaicin application between the groups. In contrast, the area of DMA in the ivabradine group was significantly smaller (p < 0.001) than that in the placebo group. HCN channels may be differentially involved in the various pain signal transmission pathways in humans.

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