Glibenclamide Posttreatment Does Not Inhibit Levcromakalim Induced Headache in Healthy Participants: A Randomized Clinical Trial

Abstract

Intravenous infusion of ATP-sensitive potassium channel (K_ATP) opener levcromakalim causes headache in humans and implicates K_ATP channels in headache pathophysiology. Whether K_ATP channel blocker glibenclamide inhibits levcromakalim-induced headache has not yet been elucidated. We aimed to investigate the effect of posttreatment with glibenclamide on levcromakalim-induced headache in healthy participants. In a double blind, randomized, three-arm, placebo-controlled, crossover study, 20 healthy participants were randomized to receive 20 mL of levcromakalim (0.05 mg/min (50 mg/mL)) or 20 mL placebo (isotonic saline) intravenously over 20 min followed by oral administration of 10 mg glibenclamide or placebo. Fifteen participants completed all three study days. The primary endpoint was the difference in incidence of headache (0-12 h) between glibenclamide and placebo. More participants developed headache on levcromakalim-placebo day (15/15, 100%) (P = 0.013) and levcromakalim-glibenclamide day (13/15, 86%) compared to placebo-placebo day (7/15, 46%) (P = 0.041). We found no difference in headache incidence between levcromakalim-placebo day and levcromakalim-glibenclamide day (P = 0.479). The AUC_{0-12 h} for headache intensity was significantly larger in levcromakalim-placebo day and levcromakalim-glibenclamide day compared to placebo-placebo day (106.3 ± 215.8) (P < 0.01). There was no difference in the AUC_{0-12 h} for headache intensity between the levcromakalim-placebo day (494 ± 336.6) and the levcromakalim-glibenclamide day (417 ± 371.6) (P = 0.836). We conclude that non-specific K_ATP channel inhibitor glibenclamide did not attenuate levcromakalim-induced headache in healthy volunteers. Future studies should clarify the involvement of the distinct isoforms of sulfonylurea receptor subunits of K_ATP channels in the pathogenesis of headache and migraine.

Keywords: Adenosine triphosphate-sensitive potassium channel; Cromakalim; Humans; KATP-channel; Migraine.

Fig. 1

Experimental design. Healthy participants (n = 20) were randomly allocated in a double-blind crossover design, to receive levcromakalim followed by placebo (n = 7), levcromakalim followed by glibenclamide (n = 7), and placebo followed by placebo (n = 6) on three separate study days. There was a washout period of at least one week between each study day

Fig. 2

Experimental timeline. There was a 240-min in-hospital phase of the experiment and 8 h of outpatient headache diary. MABP mean arterial blood pressure, HR heart rate

Fig. 3

CONSORT flow chart of the study

Fig. 4

Headache intensity. Numerical rating scale (NRS) scores for headache intensity after infusion of levcromakalim or placebo and administration of oral glibenclamide or placebo, from baseline to 12 h. Dots represent individual headache scores of each participant on each study day. Thick line represents the median headache on A levcromakalim-placebo day, B levcromakalim-glibenclamide day, and C placebo-placebo day. The area under the curve (AUC) for headache intensity did not differ between the levcromakalim-placebo (494 ± 336.6) and the levcromakalim-glibenclamide day (417 ± 371.6) (P > 0.05). The AUC for headache intensity was significantly larger in the levcromakalim-placebo day (494 ± 336.6) compared to the placebo-placebo day (106.3 ± 215.8) (95% mean difference CI: 194.4–580.9) (P < 0.01)

Fig. 5

Hemodynamic parameters. A Mean change in heart rate (HR). Heart rate after infusion of levcromakalim/placebo and administration of oral glibenclamide/placebo, from baseline to T240 min. There was no difference in the AUC_0-240 min for HR on the levcromakalim-placebo day (17512 ± 1282) compared to levcromakalim-glibenclamide days (17148 ± 1477) (P > 0.05). The AUC_0-240 min for HR was significantly larger in levcromakalim-placebo day and levcromakalim-glibenclamide day compared to the placebo-placebo day (14017 ± 2136) (P < 0.001). B Mean arterial blood pressure (MABP) after infusion of levcromakalim/placebo and administration of oral glibenclamide/placebo, from baseline to T240 min. Mean change in mean arterial blood pressure. There was no difference in the AUC_0-240 min for MABP between the three study days (levcromakalim-placebo: 20601 ± 2136, levcromakalim-glibenclamide: 20556 ± 1711, placebo-placebo: 20593 ± 1960) (P > 0.05)