Intranasal civamide for the treatment of episodic cluster headaches.
Authors: Saper JR , Klapper J , Mathew NT , Rapoport A , Phillips SB , Bernstein JE 
Published: December 2004

Arch Neurol. 2002 Jun;59(6):990‐994Objective: To evaluate the safety and efficacy of intranasal civamide solution for preventive treatment during an episodic cluster headache period. Subjects And Methods: This was a multicenter, double‐blind, randomized, vehicle‐controlled study with a 7‐day treatment period and a 20‐day posttreatment period performed at 14 headache/neurology centers in the United States. Twenty‐eight subjects were randomized to receive civamide or its vehicle in a 2:1 ratio; 18 received civamide and 10 received the vehicle. Subjects received 100 microL of 0.025% civamide (25 microg) or 100 microL of the vehicle to each nostril via dropper once daily for 7 days. The total daily dose of civamide was 50 microg. Main Outcome Measures: The number of cluster headaches per week during the treatment and posttreatment periods, pain intensity, presence of associated symptoms, and the incidence of adverse events were assessed.Results: Subjects in the civamide group had a significantly greater percent decrease in the number of headaches from baseline to posttreatment during days 1 through 7 (−55.5% vs −25.9%; P  =  .03) and a trend toward significance during days 8 through 14 (−66.9% vs −32.3%; P  =  .07) and days 15 through 20 (−70.6% vs −34.9%; P  =  .07), as well as a near‐significant decrease during the entire posttreatment period (days 1 through 20 [P  =  .054]) compared with the vehicle group. There were larger decreases in the number of headaches per week during the posttreatment period in the civamide‐treated group, with trends toward significance during posttreatment days 8 through 14 (−8.6 vs −3.6; P  =  .09) and days 15 through 20 (−8.9 vs −3.6; P  =  .07). There were no significant differences between groups in cluster headache pain intensity, number of severe headaches, or associated symptoms. The most common adverse events included nasal burning (14 of 18 civamide‐treated subjects, 1 of 10 vehicle‐treated subjects; P  =  .001) and lacrimation (9 of 18 civamide‐treated subjects, 0 of 10 vehicle‐treated subjects; P  =  .01).Conclusion: Intranasal civamide solution at a dose of 50 microg may be modestly effective in the preventive treatment of episodic cluster headache.Comment: Civamide is a capsaicin‐like medication being studied for the prevention of cluster headache, a follow‐up compound to an idea first described in a study published in 1993 suggesting that intranasal capsaicin appeared useful in preventing episodic cluster (Marks DR, Rapoport A, Padla D, Weeks R, Rosum R, Sheftell F, Arrowsmith F. A double‐blind placebo‐controlled trial of intranasal capsaicin for cluster headache. Cephalalgia. 1993;13:114‐116). The current study did not meet several primary endpoints; the question is whether a larger study would. The issue is not insignificant. Dr. Peter Goadsby has pointed out that there is a specific need for nonvascular treatments for cluster, given the epidemiology of patients with cluster as smoking, middle‐aged men at high risk for vascular disease. Civamide, if it can be shown effective in prophylaxis, depletes substance P and other nociceptive peptides, without causing vascular changes or cardiac effects, as can be seen with calcium‐channel blockers. It has far less systemic toxicity than lithium or antiepileptic drugs. Further study seems warranted, even if overall clinical effect is moderate. SJT