Rizatriptan reduces vestibular-induced motion sickness in migraineurs

Abstract

A previous pilot study suggested that rizatriptan reduces motion sickness induced by complex vestibular stimulation. In this double-blind, randomized, placebo-controlled study we measured motion sickness in response to a complex vestibular stimulus following pretreatment with either rizatriptan or a placebo. Subjects included 25 migraineurs with or without migraine-related dizziness (23 females) aged 21-45 years (31.0 ± 7.8 years). Motion sickness was induced by off-vertical axis rotation in darkness, which stimulates both the semicircular canals and otolith organs of the vestibular apparatus. Results indicated that of the 15 subjects who experienced vestibular-induced motion sickness when pretreated with placebo, 13 showed a decrease in motion sickness following pretreatment with rizatriptan as compared to pretreatment with placebo (P < 0.02). This significant effect was not seen when subjects were exposed to more provocative vestibular stimulation. We conclude that the serotonin agonist, rizatriptan, reduces vestibular-induced motion sickness by influencing serotonergic vestibular-autonomic projections.

Fig. 1

a Motion-sickness score following pretreatment with rizatriptan vs. motion-sickness score following pretreatment with placebo in response to a complex vestibular stimulus, i.e. off-vertical axis rotation. Scores represent the increase in motion sickness above pre-stimulus baseline. Note that data are shown only from those subjects whose vestibular-induced increase in motion-sickness score exceeded 3 after pretreatment with placebo. Data from subjects with migraine-related dizziness are shown as filled circles. Data from subjects without migraine-related dizziness are shown as open circles. Note that for 13 of 15 subjects that the increase in motion-sickness score above baseline was greater following pretreatment with placebo as compared to that seen following treatment with rizatriptan. b Motion-sickness scores following a second off-vertical axis rotation. Data are shown for those subjects who could complete a second off-vertical axis rotation following pretreatment with rizatriptan and following pretreatment with placebo. Note the lack of an obvious effect of rizatriptan

Fig. 2

Subjective units of distress after off-vertical axis rotation following pretreatment with rizatriptan vs. placebo. Note that data are shown for those subjects whose data are illustrated in Fig. 1. Note the absence of a consistent influence of rizatriptan

Fig. 3

Schematic diagram to explain effects of rizatriptan on motion sickness in migraineurs. The enhanced motion-sickness susceptibility in migraineurs is hypothesized to reflect the net vestibular nuclear and solitary nucleus effects of vestibular stimulation. The trigeminal nociceptive pathway and vestibular nuclei also contribute ascending thalamic connections, which contribute to autonomic symptoms via projections to the cerebral cortex. Spinal trigeminal nuclear and vestibular nuclear neurons also project to the parabrachial nucleus. Stress responses and vasopressin release are mediated by interconnections of the parabrachial pathways with the hypothalamus. We propose that motion-sickness sensitivity is decreased by the actions of rizatriptan on 5-HT_1B and 5-HT_1D receptors on (1) vasculature (e.g. blocking vasodilatation), (2) vestibular ganglion cells, (3) trigeminal ganglion cells (for somatic, vascular and dural afferents), (4) several brainstem pathways and projections, and (5) neurons in the periaqueductal gray (PAG). The primary effect of rizatriptan is via presynaptic inhibition of terminals that can use either excitatory amino acids or GABA. These presynaptic effects can occur at primary afferent and in CNS pathways