SAN DIEGO—Noninhaled intranasal carbon dioxide was well tolerated and safe for patients with migraine, according to findings from a pair of studies conducted by Egilius L.H. Spierings, MD, PhD. Preliminary efficacy results showed that carbon dioxide provided statistically significant benefit versus placebo at one-half, one, and two hours. Regarding tolerability, adverse events were mostly local and short-lived, noted Dr. Spierings.

“[Noninhaled intranasal carbon dioxide] is a very innocuous treatment with demonstrated efficacy in relieving migraine headache, now in two phase II studies,” Dr. Spierings told Neurology Reviews. “No serious or clinically significant adverse events were reported by the patients.” Dr. Spierings is an Associate Clinical Professor of Neurology at the Brigham and Women’s Hospital, Harvard Medical School, in Boston. He presented his findings at the 130th Annual Meeting of the American Neurological Association.

Dr. Spierings compiled his results from two randomized, double-blind, placebo-controlled studies, one of which focused on tolerability and safety and the other on efficacy. Patients in both studies were 18 or older with a history of moderate or severe migraine headaches with or without aura, as defined by the International Headache Society.

SAFETY AND TOLERABILITY

In the tolerability and safety trial, all participants had moderate or severe headache and were examined within six hours of headache onset. They received either 100% carbon dioxide or 100% nitrogen through a nosepiece that fit into a nostril; they then selected their own flow rate, depending on preference and tolerance. “The treatment was administered intranasally through a nostril, while the patient either held his or her breath or breathed through the mouth,” explained Dr. Spierings. The study included 54 patients—26 were exposed to carbon dioxide, 24 to nitrogen, and four to open-label carbon dioxide. About 88% of subjects were women, and the median age was 44 in the carbon dioxide group and 48 in the nitrogen group.

No clinically significant changes were observed in either treatment group regarding heart rate, blood pressure, and blood carbon dioxide pressure, according to Dr. Spierings. The leading adverse events were intranasal irritation (50%), intranasal discomfort (20%), and watery eyes (20%). “There were no serious or clinically significant adverse events in the groups, and none of the subjects had a change from baseline in respiratory rate or electrocardiogram,” stated Dr. Spierings. “The adverse events reported by the subjects were transient and short-lived, with the exception of nausea and a sensation of odor in one subject each, which lasted for a few days.”

INVESTIGATING EFFICACY

In the efficacy trial, participants were treated for mild, moderate, or severe headache with 100% carbon dioxide at 5 or 15 mL/s or a placebo that released no gas. The gas was administered with a handheld dispenser that consisted of a nosepiece containing a flow-control valve; this was connected to a small, pressurized cylinder filled with liquid carbon dioxide. Each patient then chose the flow rate as low (5 mL/s) or high (15 mL/s) and sealed the nosepiece of the dispenser to a nostril. Participants allowed the gas to fill the nasal passages for 60 to 90 seconds while they minimized their breathing. The dose was repeated up to six times with two- to three-minute intervals within the two-hour treatment period.

About 78% of patients were female, and the average age was 42 in the carbon dioxide group and 44 in the placebo group. Sixty-seven subjects received carbon dioxide, and 65 were in the placebo group. Within one-half hour, 19.4% of participants who received carbon dioxide were pain-free, compared with 6.2% of placebo recipients. At one hour, the pain-free rates were 22.4% for the carbon dioxide group versus 9.2% for the placebo group. At two hours, the rates were 29.8% for the carbon dioxide group, compared with 9.2% for those who took placebo.

The differences between the two groups were “statistically significant at all time points,” noted Dr. Spierings. “There were no serious or clinically significant adverse events in the intent-to-treat population of the study.” The most common adverse events observed were intranasal irritation (31.3%); nausea (11.9%); and dizziness, watery eyes, and intranasal numbness (7.5% for each); all of which were more frequent in the carbon dioxide group than in the placebo group, with the exception of dizziness (7.7%). “All were transient in nature and resolved spontaneously without treatment,” stated Dr. Spierings.

Dr. Spierings pointed out that in contrast with many clinical migraine trials, especially those conducted with triptans, patients with cardiovascular or cerebrovascular disease or those older than 65 were not excluded from the studies due to the “implicit safety of noninhaled, intranasally administered carbon dioxide versus the systemic administration of triptans, potent vasoactive agents.” Monitoring in the safety study “confirmed the nonsystemic nature of the treatment through continuous, transcutaneous measurement of the blood carbon dioxide pressure. In addition, no changes were observed in cardiovascular or respiratory functioning,” Dr. Spierings concluded.

NR

—Colby Stong

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