The Neuropharmacology of Cluster Headache and other Trigeminal Autonomic Cephalalgias

Abstract

Trigeminal autonomic cephalalgias (TACs) are a group of primary headaches including cluster headache (CH), paroxysmal hemicrania (PH) and short-lasting unilateral neuralgiform headache with conjunctival injection and tearing (SUNCT). Another form, hemicrania continua (HC), is also included this group due to its clinical and pathophysiological similarities. CH is the most common of these syndromes, the others being infrequent in the general population. The pathophysiology of the TACs has been partly elucidated by a number of recent neuroimaging studies, which implicate brain regions associated with nociception (pain matrix). In addition, the hypothalamic activation observed in the course of TAC attacks and the observed efficacy of hypothalamic neurostimulation in CH patients suggest that the hypothalamus is another key structure. Hypothalamic activation may indeed be involved in attack initiation, but it may also lead to a condition of central facilitation underlying the recurrence of pain episodes. The TACs share many pathophysiological features, but are characterised by differences in attack duration and frequency, and to some extent treatment response. Although alternative strategies for the TACs, especially CH, are now emerging (such as neurostimulation techniques), this review focuses on the available pharmacological treatments complying with the most recent guidelines. We discuss the clinical efficacy and tolerability of the currently used drugs. Due to the low frequency of most TACs, few randomised controlled trials have been conducted. The therapies of choice in CH continue to be the triptans and oxygen for acute treatment, and verapamil and lithium for prevention, but promising results have recently been obtained with novel modes of administration of the triptans and other agents, and several other treatments are currently under study. Indomethacin is extremely effective in PH and HC, while antiepileptic drugs (especially lamotrigine) appear to be increasingly useful in SUNCT. We highlight the need for appropriate studies investigating treatments for these rare, but lifelong and disabling conditions.

Fig. (1)

Diagram summarising the pathophysiology of cluster headache (CH) and other trigeminal autonomic cephalalgias (TACs) according to the most recent views and insights. The origin of the pain in CH and in the TACs may be peripheral or central. In the first case, the headache attack is suggested to originate from activation of the afferent trigeminal fibres induced by irritation of the structures of the face or of the cranial vault. In the second case (central origin), the attack is thought to be the consequence of direct activation of the posterior hypothalamus (PH), as findings of functional imaging studies have consistently shown. In both circumstances, activation of the superior salivatory nucleus – by the PH, or through the trigeminal-autonomic (or trigeminovascular) reflex (indirect activation)– results in an increased firing of parasympathetic fibres and thus in ipsilateral autonomic signs (conjunctival injection, tearing, nasal congestion and rhinorrhoea). Neurogenic inflammation is also produced by neurotransmitter release at the parasympathetic terminals, and the subsequent irritation of the trigeminal sensory nerves potentiates the vascular response via antidromic CGRP release. Symptoms such as miosis and ptosis (i.e. incomplete Horner’s syndrome) are suggested to result from parasympathetic-induced vasodilation of the internal carotid artery and functional impairment of the oculosympathetic fibres running through the cavernous sinus. Intense pain stimuli are carried through projections first to the trigeminal-cervical complex and then to the thalamus, up to the cortical sensory areas involved in pain processing. The PH is functionally connected to the ipsilateral trigeminal system and has an inhibitory role (dashed lines). Dysfunction of these projections may induce a permissive state not only facilitating attack occurrence, but also influencing the duration of single attacks. Attack duration is the main distinguishing feature of the different TACs. ACC=anterior cingulate cortex, SSC=somatosensory cortex, PH=posterior hypothalamus, TCC=trigeminal-cervical complex, SSN=superior salivatory nucleus, SCG=superior cervical ganglion, PPG=pterygopalatine ganglion.