By Dara G. Jamieson, MD

Clinical Associate Professor of Neurology, Weill Cornell Medical College

Dr. Jamieson reports no financial relationships relevant to this field of study.

SYNOPSIS: The opening of ATP-sensitive potassium channels by levcromakalim triggered migraine headaches in all migraineurs. In healthy volunteers, levcromakalim induced milder headaches associated with long-lasting dilation of extracerebral arteries.

SOURCES: Al-Karagholi MA, Hansen JM, Guo S, et al. Opening of ATP-sensitive potassium channels causes migraine attacks: A new target for the treatment of migraine. Brain 2019;142:2644-2654.

Al-Karagholi MA, Ghanizada H, Hansen JM, et al. Levcromakalim, an adenosine triphosphate-sensitive potassium channel opener, dilates extracerebral but not cerebral arteries. Headache 2019;10:1468-1480.

Researchers at the University of Copenhagen investigated whether the opening of ATP-sensitive potassium channels (KATP) using an infusion of a KATP channel opener, levcromakalim, would trigger migraine attacks in migraine patients and cause dilation of cranial arteries in healthy volunteers.

In this randomized, double-blind, placebo-controlled, crossover study published in Brain, 16 patients, ages 18 to 49 years, who had one to five migraine attacks a month, received either an intravenous infusion of 0.05 mg/min of levcromakalim or placebo on two different days. Primary clinical endpoints were the difference in migraine attacks, headaches, and the area under the curve (AUC) for headache intensity scores up to 12 hours after infusion. The middle cerebral artery (MCA) blood flow velocity for the initial two hours on transcranial Doppler, the diameters of the left superficial temporal artery (STA) and the radial artery on ultrasound, and the end-tidal partial pressure of CO2 also were determined. All patients with migraine (100%) developed immediate migraine attacks after levcromakalim, with a median time to onset of three hours, compared to one patient (6%) who developed a migraine attack after the placebo injection (P = 0.0001). The attacks triggered by levcromakalim were strongly associated with nausea, photophobia, and phonophobia, and the patients reported that the triggered headaches mimicked their usual migraines. The usual headache location was frontal and temporal, with nine out of the 16 patients reporting that the triggered migraine pain was bilateral. The AUC for headache intensity from time of injection to 12 hours was significantly larger after levcromakalim compared to placebo. The incidence of headache over the 12-hour observation period was higher after levcromakalim (n = 16) than after placebo (n = 7). The injection of levcromakalim was associated with palpitations, flushing, warm sensation, an increase in heart rate, and a decrease in mean arterial blood pressure. There was no change in MCA flow velocity or radial artery diameter, but there was a significant increase in the STA diameter.

The same researchers also published a double-blind, randomized, placebo-controlled investigation of the effect of levcromakalim on the cranial arteries in Headache. Twenty healthy volunteers without migraine or other significant headache history had six high-resolution magnetic resonance angiography (MRA) scans at baseline to 350 minutes after injection to measure the circumferential changes of the middle meningeal artery (MMA), STA, and MCA at baseline and after infusion of levcromakalim (n = 14) or placebo (n = 6). All participants received a subcutaneous injection of sumatriptan 6 mg before the last MRA scan. The MMA circumference was significantly larger after the levcromakalim injection as compared with placebo (P < 0.0001), with the dilation, which lasted over five hours, significantly associated with headache (P < 0.0001). Bilateral headache occurred in 12 of 14 (86%) volunteers after the levcromakalim injection and one of six (17%) after the placebo injection, with a median time of onset at 30 minutes, an intensity of 1 on a 4-point scale, and a duration of six hours. Two volunteers without a migraine history reported migraine-like attacks after the levcromakalim infusion, with none reporting migraine-like symptoms after the placebo injection. Injection with sumatriptan reduced the STA, but not the MCA, circumference. The headache intensity, and its associated MMA circumference, were significantly reduced after the sumatriptan injection. Although the STA circumference initially was significantly larger after the levcromakalim injection, over the entire observational period, there was no difference in the circumferences of the STA and MCA between levcromakalim and placebo. There was no difference in reaction between the right and left sides of the intracerebral or extracerebral vessels. Levcromakalim induced a long-lasting (five hour) dilation of extracerebral but not intracerebral arteries, with sumatriptan reversing the triggered headache and the associated MMA dilation.

COMMENTARY

The discovery of new therapeutic targets for migraine leading to specific and effective treatments is a major goal of migraine research, and the KATP channel appears to be a potential new prospect. These channels are expressed in smooth muscle and endothelial cells and, when opened, potassium efflux leads to hyperpolarization with resultant vasodilation. In these studies, the opening of KATP channels by levcromakalim caused triggering of migraine headaches in all migraine sufferers, as well as milder headaches in a majority of non-headache volunteers. The triggered headaches were associated with long-lasting dilation of extracerebral but not intracerebral arteries in the non-headache volunteers. The researchers suggested a crucial role for KATP channels in migraine pathophysiology and questioned if blockade of these channels could be therapeutic for migraine. However, the opening of KATP channels triggered headaches in both migraineurs and volunteers without headache history. Although this mechanism for headache triggering is intriguing, the generalized effect in all participants and the production of bilateral pain indicate a more general nociceptive effect, as compared to a more specific migraine mechanism with unilateral head pain produced only in vulnerable subjects. Compounds that produce vasodilation through multiple mechanisms can generate headaches, so it is not clear that the specific opening of the KATP channels has a direct effect on migraine-related nociceptors in general and that this opening is specifically associated with migraine provocation. The authors noted that further nociceptive effects of opening of KATP channels, specifically the activation and sensitization of perivascular nociceptors including trigeminovascular sensory neurons, remain to be explored.