The Efficacy Of Continuous Non-Inhaled Intranasal Carbon Dioxide (CO2) In The Abortive Treatment Of Migraine: Results From Three Randomized, Double-Blinded, Placebo-Controlled Trials

Objective: Determining the efficacy, tolerability, and safety of continuous non-inhaled intranasal carbon dioxide (CO2) in the acute or abortive treatment of migraine. Background: Carbon dioxide gas infused in the nose and sinuses potentially blocks trigeminal nerve activation and subsequent neuropeptide release, probably through inhibition of voltage-gated channels. The pathogenesis of the migraine headache involves activation of the trigeminocervical system, which establishes the nociceptive innervation of the head through the trigeminal and occipital nerves. Methods: In three randomized, double-blinded, placebo-controlled trials, we randomized 350 subjects with migraine as defined by the International Headache Society (intent-to-treat population). We determined tolerability and safety in the 317 subjects who we exposed to treatment up to 24 hours post-dose (modified intent-to-treat population). We determined efficacy in the modified intent-to-treat and per-protocol populations at 15 minutes, half, one, two, and twenty-four hours post-dose in terms of pain freedom, freedom from headache-associated symptoms, and headache relief, treating migraine headaches of mild, moderate, or severe intensity. Results: We did not observe clinically significant systemic effects, either on blood carbon dioxide pressure or on the cardiovascular or respiratory system. No serious or clinically significant adverse events occurred and those reported were predominantly local, transient, and short-lived. Headache intensity strongly and in a negative way determined the efficacy of treatment with carbon dioxide but not with placebo, and even when placebo consisted of no gas, blinding seemed adequate. Conclusions: Continuous non-inhaled intranasal carbon dioxide seems safe, relatively well tolerated, and moderately effective for the acute or abortive treatment of migraine.