Opening of ATP-sensitive potassium channels causes migraine attacks: a new target for the treatment of migraine

Abstract

Migraine is one of the most disabling and prevalent of all disorders. To improve understanding of migraine mechanisms and to suggest a new therapeutic target, we investigated whether opening of ATP-sensitive potassium channels (KATP) would cause migraine attacks. In this randomized, double-blind, placebo-controlled, crossover study, 16 patients aged 18–49 years with one to five migraine attacks a month were randomly allocated to receive an infusion of 0.05 mg/min KATP channel opener levcromakalim and placebo on two different days (ClinicalTrials.gov number, NCT03228355). The primary endpoints were the difference in incidence of migraine attacks, headaches and the difference in area under the curve (AUC) for headache intensity scores (0–12 h) and for middle cerebral artery blood flow velocity (0–2 h) between levcromakalim and placebo. Between 24 May 2017 and 23 November 2017, 16 patients randomly received levcromakalim and placebo on two different days. Sixteen patients (100%) developed migraine attacks after levcromakalim compared with one patient (6%) after placebo (P = 0.0001); the difference of incidence is 94% [95% confidence interval (CI) 78–100%]. The incidence of headache over the 12 h observation period was higher but not significant after levcromakalim (n = 16) than after placebo (n = 7) (P = 0.016) (95% CI 16–71%). The AUC for headache intensity was significantly larger after levcromakalim compared to placebo (AUC0–12h, P < 0.0001). There was no change in mean middle cerebral artery blood flow velocity after levcromakalim compared to placebo (AUC0–2hP = 0.46). Opening of KATP channels caused migraine attacks in all patients. This suggests a crucial role of these channels in migraine pathophysiology and that KATP channel blockers could be potential targets for novel drugs for migraine.

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).…”

“…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 163 adults with migraine without aura (9–17,31,33). The random effects meta-analysis showed that the incidence of delayed headache after placebo was 25.9% (95% CI = 18.5–34.1%, I 2 = 18.9%).…”

The metabolic face of migraine — from pathophysiology to treatment

“…Ketone body transport is not GLUT1dependent and ketosis has a variety of other effects that are potentially beneficial in migraine pathophysiology, including: increased mitochondrial biogenesis; increased anti oxidant capacity; upregulation of GLUT1 and ketone body transporters; increased GABA but inhibition of gluta mate transport and, therefore, reduced excitatory syn aptic transmission pain and inflammation (reviewed in detail elsewhere 192,193 ). Ketone bodies can also stabilize neuronal excitability by inhibiting ATP sensitive potas sium channels (K ATP ) that might play a crucial role in migraine attack generation 194 (see below). Several case studies have shown that ketosis can protect against migraine [195][196][197][198][199][200] .…”

The vascular effect of glibenclamide: A systematic review

“…Intravenous infusion of K ATP channel opener (KCO) levcromakalim provokes headache in healthy volunteers and migraine attacks in migraine patients. 2 The precise mechanisms by which the opening of K ATP channels induces headache in healthy volunteers and migraine attacks in migraine patients are unclear. Interestingly, levcromakalim dilates cranial arteries and the dilation is associated with headache.…”