Drug-free migraine treatment tested in pilot study

Researchers treated migraine with aura (MA) using a partial rebreathing device (PRD), according to a new study published in Cephalalgia.

“Studies measuring cerebral blood flow have shown that the early stages of migraine attacks are characterized by cerebral vasoconstriction, implicating hypoperfusion as a migraine trigger,” wrote authors, led by Cecilia H. Fuglsang, Department of Neurology, Aarhus University Hospital, Aarhus, Denmark.

In recent studies, researchers have found that migraine attacks may be due to a decrease in oxygen delivery to the brain (D_O2,brain). Hypoxia can trigger migraine attacks in patients with migraine and headache attacks in those without migraine. In addition, hypoxia can facilitate cortical spreading depression, which is a trigger in MA and possibly also in migraine without aura.

According to previous reports, hypercapnia is clinically effective at stopping migraine attacks via the use of either pressure bottles or closed rebreathing bags. However, both are impractical, and rebreathing bags may even be dangerous.

“Stable normoxic hypercapnia can be achieved by a PRD [that] works by capturing a controlled fraction of the expired air, which is then rebreathed together with a controlled amount of atmospheric air,” wrote the authors. The overall effect is a moderate decrease in alveolar ventilation—despite an increase in minute ventilation—caused by increasing arterial CO₂ tension (Pa_CO2).

In the current double-blinded, randomized, controlled, cross-over design, pilot study, investigators assessed the efficacy and safety of a PRD in 190 patients with MA. All had between one and six migraine attacks per month, with migraine onset before age 50 years

At the onset of aura, patients with MA self-administered a PRD or sham device for 20 minutes. The investigators adjusted for placebo effect and regression towards the mean via sham device as a control, with randomized, device cross-over sequence.

The team hypothesized that use of a PRD would raise D_O2,brain and Pa_CO2 early during MA attacks, thus decreasing migraine severity without negative side effects.

The primary endpoint for the study was headache intensity difference between the moment of the first aura symptoms and 2 hours later (HID2). Secondary endpoints included measures of nausea, light/sound intensity, functional disability, pain relief, as well as overall satisfaction, treatment preference, adverse events, and more.

In total, 11 patients (average age: 35.5 years) self-treated 41 migraine attacks (PRD, n=20; sham device, n=21). Use of a PRD increased mean end-tidal CO₂ by 24%, while keeping the mean oxygen saturation above 97%. Notably, the pain relief efficacy of PRD treatment increased significantly with each use of the inhaler, with 45% of participants experiencing pain relief on first use and 78% experiencing pain relief on second use.

The primary endpoint of HID2 did not achieve statistical significance (P=0.096). However, secondary endpoints reflecting device satisfaction and pain relief were found to be statistically significant. Although the remaining secondary endpoint measures did not reach statistical significance, they demonstrated favorability for a PRD vs sham device.

These promising secondary endpoint results provided support for further investigation of migraine treatment with a PRD in a full-scale trial.

The authors did not report any adverse events, and any negative side effects were mild or absent.

The team noted that compared with drugs, use of a PRD proffers certain advantages. First, it works quickly and its effects wash out quickly. Second, a PRD can be combined with or replace drugs. Third, unlike a PRD, drugs rely on absorption via the gastrointestinal tract and can be lost via emesis. Finally, the effects of general hypercapnia are mild.

 “Normoxic hypercapnia shows promise as an adjunctive/alternative migraine treatment, meriting further investigation in a larger population,” concluded the authors.