Opening of BK_Ca channels alters cerebral hemodynamic and causes headache in healthy volunteers

Abstract

Introduction Preclinical data implicate large conductance calcium-activated potassium (BKCa) channels in the pathogenesis of headache and migraine, but the exact role of these channels is still unknown. Here, we investigated whether opening of BKCa channels would cause headache and vascular effects in healthy volunteers. Methods In a randomized, double-blind, placebo-controlled, cross-over study, 21 healthy volunteers aged 18–39 years were randomly allocated to receive an intravenous infusion of 0.05 mg/min BKCa channel opener MaxiPost and placebo on two different days. The primary endpoints were the difference in incidence of headache and the difference in area under the curve (AUC) for headache intensity scores (0–12 hours) and for middle cerebral artery blood flow velocity (VMCA) (0–2 hours) between MaxiPost and placebo. The secondary endpoints were the differences in area under the curve for superficial temporal artery and radial artery diameter (0–2 hours) between MaxiPost and placebo. Results Twenty participants completed the study. Eighteen participants (90%) developed headache after MaxiPost compared with six (30%) after placebo ( p = 0.0005); the difference of incidence is 60% (95% confidence interval 36–84%). The area under the curve for headache intensity (AUC0–12 hours, p = 0.0003), for mean VMCA (AUC0–2 hours, p = 0.0001), for superficial temporal artery diameter (AUC0–2 hours, p = 0.003), and for radial artery diameter (AUC0–2 hours, p = 0.03) were significantly larger after MaxiPost compared to placebo. Conclusion MaxiPost caused headache and dilation in extra- and intracerebral arteries. Our findings suggest a possible role of BKCa channels in headache pathophysiology in humans. ClinicalTrials.gov, ID: NCT03887325.

Nocebo response in human models of migraine: A systematic review and meta-analysis of randomized, double-blind, placebo-controlled, two-way crossover trials in migraine without aura and healthy volunteers

“…Of these, 27 studies met the inclusion criteria (1994 and 2020) and were included in the qualitative and quantitative analysis (9–35) (Figure 1). Twelve studies (10 published and two studies under review) reported data on the incidence of migraine attacks after placebo in individuals with migraine without aura (9–17,31,33), whereas 10 studies did so in healthy volunteers (18,19,22,23,25,27,29,30,32,34). Furthermore, 16 studies reported data on the incidence of delayed headache after placebo in healthy volunteers (13,18–30,32,34).…”

“…Twelve studies (10 published and two studies under review) reported data on the incidence of migraine attacks after placebo in individuals with migraine without aura (9–17,31,33), whereas 10 studies did so in healthy volunteers (18,19,22,23,25,27,29,30,32,34). Furthermore, 16 studies reported data on the incidence of delayed headache after placebo in healthy volunteers (13,18–30,32,34). A summary of the included studies is presented in Table 1 and Table 2.…”

“…Furthermore, all studies used randomisation with 1:1 allocation and a wash-out period of at least 7 days between the two experimental days. Carry-over and/or period effects were assessed in seven of 12 included studies, in which none were found (12,13,15–17,31,32) (Table 1) (Figures 2, 3).…”

“…Eleven studies were included in the primary analysis, comprising a total of 138 healthy volunteers (13,18,19,22,23,25,27,29,30,32,34). The random effects meta-analysis showed that the incidence of migraine attacks after placebo was 0.5% (95% CI = 0.0–3.8%, I 2 = 0.0%).…”

Novel Analgesics with Peripheral Targets

“…Maxipost (BMS 204352) acts via multiple channels, including K Ca 1.1, K v 7.2, K v 7.3, and K v 7.4, but the anxiolytic effect demonstrates that this has a relevant central component [241,242]. A headache-focused trial shows headacheinduction by maxipost, indicating a role of BK Ca channels in headache pathophysiology [243]. The same group has also reported that opening of ATP-sensitive potassium channels was associated with occurrence of headache [244].…”