Evaluating the Effectiveness of Tonabersat for Migraine Prophylaxis

Migraine headache is one of the most prevalent neurologic conditions, but remains pathogenically poorly understood and often suboptimally treated.

One purported pathophysiologic mechanism for this acute disorder is cortical spreading depression, which involves the slow propagation of a depolarization wave in the gray matter of the cerebral cortex.^1,2 The most clinically apparent symptom of this benign phenomenon is the migraine's visual aura of migrating scintillations, representing an excitation-depression wave propagating across the human primary visual cortex.

During the cortical spreading depression, several biochemical changes occur, including perturbations of brain ion homeostasis and aberrant efflux of excitatory amino acids from neurons. Tonabersat is a novel agent aimed at selectively binding and blocking glial cell gap junction activity and thus interfering with excitation of nearby trigeminal neurons and propagation of cortical depolarization.³

In this systematic review, 133 studies were identified in the search, and only two randomized, double-blind placebo-controlled clinical trials (RCCTs) met criteria for the analysis. Tonabersat was administered at a dose of 40 mg at the onset of migraine with or without aura. In one of the studies, the medication was given at a pulse dose of 220 mg for two weeks, and then reduced to 40 mg for the rest of the testing period. The primary outcome measure was the change in mean number of migraine headache days of which no statistical difference was found. The secondary outcome measures were the following: change in the nature of migraines, 50% responder rates, reduction in rescue medication administration, and adverse events. There was a clinically-significant difference between treatment and control groups in Hauge’s study, showing a reduction in aura (with or without headache) over the 12-week study period. The 50% responder rate was not clinically significant in the study by Goadsby. Clinical significance likewise was not found for reduction of consumption of rescue medication with the study drug.

Adverse events were mild and included nausea, dizziness, and fatigue, as well as upper respiratory tract and urinary tract infections. Of the 199 patients studied, only one patient dropped out due to adverse events in the tonabersat group.

There was a lack of evidence to support use of tonabersat for migraine prophylaxis. Tonabersat was well-tolerated and long-term prospective trials with higher power may show a benefit from the targeted mechanism of this drug.

Commentary from Dr. Mitchell

Due to the rigor of inclusion criteria, only two RCCTs were included in the systematic review for a total patient trial number of 199 patients. This number represents a low-powered study and suboptimal trial number for a systematic review.

As with most systematic reviews, patient populations analyzed tend to be diverse. The study did attempt to assess for heterogeneity by subgroup analysis. It should be pondered whether the migraineurs included in the study were completely compliant with the medication restrictions of their respective trial. It is possible that they could have been taking other herbal or allopathic agents not otherwise mentioned which may have modified the outcomes of the study.

If there was a preponderance of occult migraine treatment in the placebo group, then the study would be prone to a type 2 statistical error. In other words, the study would fail to find a difference between groups when a difference truly exists with a favorable effect demonstrated in the tonabersat group. This particular sort of false-negative error could be clarified by a future prospective parallel group study that analyzed two cohorts of tonabersat-treated and placebo, which could be restricted from alternative prophylactic migraine agents during the course of the study so as to obviate confounding variables.

Of note, the study by Goadsby et al had a high attrition rate, including 33 patients who left for no identified cause. Data for the reasons for attrition may be useful to identify occult adverse effects of the medication. Therefore, this study is prone to attrition bias.

Also, in each trial, the effect of tonabersat was studied for only three months at a dose of 40 mg for the majority of the study period. The reported effective and safe dose range for tonabersat as reported from prior trials is 15 to 80 mg.⁴ Also, a longer treatment period would offer useful information about delayed therapeutic effects or adverse effects of Tonabersat. Thus, a longitudinal study undertaken for a longer period of time, such as six to 12 months and stratification of cohorts to include patients treated at 40 mg and 80 mg, may clarify if these modifications affect outcomes of efficacy.

In addition, comparison of tonabersat with a gold-standard migraine prophylactic agent or in combination with other prophylaxes would be clinically useful for cohorts of migraineurs with severe disease.

Amber N. Mitchell, MD, is a neurology resident at Albany Medical Center Hospital.

References:

1. Cao Y, Zheng OJ. Tonabersat for Migraine Prophylaxis: A systematic review. Pain Physic 2014; 17:1-8.

2. Lauritzen M, Dreier JP, Strong AS. Clinical relevance of cortical spreading depression in neurological disorders: migraine, malignant stroke, subarachnoid and intracranial hemorrhage, and traumatic brain injury. J Cereb Blood Flow Metab 2011; 31(1):17-35.

3. Damodaram S, Thalakoti S, Freeman SE, Garrett FG, Durham PL. Tonabersat inhibits trigeminal ganglion neuronal-satellite glial cell signaling. Headache 2009; 49(1):5-20.

4. Silberstein SD. Tonabersat, a novel gap-junction modulator for the prevention of migraine. Cephalalgia 2009; 29(Suppl 2):28-35.