Double-Blind Placebo-Controlled Trial of Lithium in Episodic Cluster Headache

Abstract

Lithium is widely used in the prophylaxis of episodic cluster headache without formal evidence of efficacy. Placebo-controlled clinical trials are not easy in conditions characterized by frequent severe pain. In this study, it was assumed that lithium would work quickly if at all, and placebo response would be zero. Strict diagnostic criteria excluded uncertain or atypical cases. Patients were male in so-far untreated episodes expected to last for at least 3 weeks more. In a double-blind, placebo-controlled comparison of matched parallel groups, treatment was either slow-release lithium carbonate, 800 mg/day, or placebo. After 7 days, compliance was estimated by tablet count, blood was taken for lithium assay, efficacy was assessed (attacks stopped or substantially improved) and adverse reactions were recorded. The study was stopped after planned sequential analysis of the 27th patient (13 on lithium, 14 on placebo). Estimated compliance was usually but not always good. Plasma lithium levels were mostly in the range 0.5-0.6 mmol/l on lithium, zero on placebo. Cessation of attacks within 1 week occurred in two patients in each group, substantial improvement in 6/14 (43%) on placebo, 8/13 (62%; NS) on lithium. Only minor adverse events were reported. Lithium treatment was therefore associated with a useful subjective improvement rate but the assumptions made at outset had proved wrong. The trial was stopped because superiority over placebo could not be demonstrated. There were lessons for future trials.

Botulinum toxin type-A therapy in cluster headache: an open study

“…In a placebo-controlled trial on the suboccipital injection of steroids no placebo response was noticed, just like in five studies on the efficacy of oral drugs in prophylactic CH therapy [28]. Two studies, which described placebo rates of 14-42%, included only patients with episodic CH [29,30]. Concerning the acute treatment of CH, the response to hyperbaric normoxic placebo was just as high as to hyperbaric 100% oxygen (25% in chronic and 83% in episodic CH patients).…”

Drug therapy in headache

“…Only open-label studies exist for the former, and while one crossover study suggested that the latter was as effective as verapamil, 59 a subsequent placebo-controlled randomised controlled trial of lithium carbonate (modifi ed release) 800 mg daily did not demonstrate superiority over placebo. 60 Similarly, the positive results seen in open studies of sodium valproate could not be replicated in a controlled trial. 61 There is one trial that shows that melatonin 10 mg can be effective for the prevention of cluster headache.…”

Evidence base for the medical treatments used in cluster headache

“…One RCT failed to show the superiority of lithium, 800 mg, over placebo in 27 ECH patients [18]. Cessation of attacks occurred in two patients in each group within 1 week of commencing treatment, and substantial improvement was noted in 43% on placebo and 62% on lithium, although this was not statistically signifi cant.…”