Pre-emptive/early intervention with triptans in migraine: hope, hype and hazard

To the Editor: Dowson et al. have crystallised the steadily advancing notion about the use of triptans for migraine prophylaxis; the ostensible rationale for this treatment strategy is the prevention of central neuronal sensitisation (1). In effect, these authors (1) underscore that ‘migraine begets migraine’. The development of cutaneous allodynia in some migraine patients (2) is, in general, a common non-specific feature of pain neurophysiology in health as well as in disease (3–7). Migraine is a disorder that is characterised by predictable short- or long-term remissions characteristically related to the season, stress, pregnancy and age (8). Other than menstrual migraine that occurs with a degree of cyclicity for some variable part of the child-bearing age in some female migraine patients, it is extremely uncommon for migraine attacks to occur predictably or invariably for years or decades or for life as might be expected following central neuronal sensitisation. Conversely, each migraine attack is followed by a period of relative refractoriness during which the usual precipitants of migraine attacks for that patient do not seem to operate. Patients with more than two typical migraine attacks per week are the exception rather than the rule. In other words, migraine attack-related central neuronal or brain sensitisation offers a variable and transient degree of protection from subsequent attacks. Although pain levels are not significantly different between migraine attacks with allodynia or without allodynia (9), episodic pain, and particularly pain associated with migraine, is a subjective relatively soft endpoint. On different occasions, the same migraine patient may manifest allodynic or non-allodynic attacks; as discussed further, the duration of the painful episode might be more relevant to development or otherwise of allodynia as well as for the evaluation of triptan therapy. Next, oral triptan treatment when migraine headache pain is mild is more efficacious than oral therapy initiated when pain has progressed to moderate or severe intensity (1). Triptans can be expected to be maximally effective for the early pulsatile-throbbing phase of migraine headache; once the late sterile ‘arteritis’ phase has set in the therapeutic role of triptans is probably limited. Also, while treatment in clinical trials with triptans (almotriptan, eletriptan, sumatriptan, naratriptan) during aura or prodrome resulted in headache prevention, headache delay, or improved outcomes (1), prodromal symptoms are widely divergent and not always followed by headache. For example, episodic daytime sleeping might serve as a defensive physiological mechanism to prevent onset of headache (8,10). Moreover, barring the scintillating scotoma, retinal migraine and lateralising sensori-motor symptoms, aura-related symptoms associated with migraine and acephalgic migraine are non-specific and diverse (11,12). The use of triptans before onset of headache is therefore confounded by the intrinsically protean nature of migraine disorder and such results are to be viewed with reservation. With up to 25% of all migraine sufferers and up to 40% of all attacks not responding to a triptan (13) – regardless of the underlying reasons – and given the economics of triptan therapies (1), it is essential to re-emphasise that the basis for evolution of migraine into a more frequent or daily headache occurrence remains unknown and to re-analyse the preliminary data that seem to strengthen the conceptual basis of this new evolving trend in migraine management. The hypothesis surrounding the role of peripheral and central sensitisation in migraine is based on possible pathogenetic contribution by the parasympathetic nervous system (14) and has further clouded mechanistic perception (15). With the left hemisphere predominantly controlling parasympathetic function, increased parasympathetic activation in response to pain in left-side migraine patients compared with right-side migraineurs has been suggested to be an inherent part of the migraine pathophysiology in these patients (16). Nevertheless, the nature or biological role of autonomic aberrations recorded in migraine remains uncertain and involvement of sympathetic or parasympathetic dysfunction in migraine pathogenetic algorithms remains speculative and counterintuitive. At the outset, the autonomic nervous system is fundamentally adaptive. With the attenuation of the hypothesis of mutual antagonism between the sympathetic and the parasympathetic nervous systems (17), stress- or pain-related parallel activation of both component systems is conceivable (18,19). Parasympathetic hyperfunction prevails during migraine attacks in concert with sympathetic hyperfunction and likely underlies pupillary miosis, delayed gastric emptying and significant prolongation of the electrocardiographic atrio-ventricular conduction time (PR interval) (20). As reviewed, acetylcholine stimulates arginine vasopressin (AVP) release by its nicotinic action on the supraoptic nucleus; AVP, in turn, in concert with noradrenergic and serotonergic hyperfunction exerts adaptive vasomotor, antinociceptive and behavioural control actions that might significantly delay onset of migraine attacks (18). Second, intrathecal applications of nicotine prevent isoflurane's pronociceptive effect (21). Third, evidence for a potent antinociceptive effect of nicotine (22) is increasing and the rationale for using nicotine agonists as analgesics (23) is evolving. The antinociceptive effect of nicotine appears to be mediated via nicotinic and μ-opioid receptors (22,23). AVP probably subserves the neuroendocrine link between these two receptor systems (18). Fourth, donepezil – a second-generation parasympathomimetic central and peripheral antinociceptive cholinesterase inhibitor that maintains acetylcholine levels at neuromuscular and other cholinergic junctions, readily crosses the blood–brain barrier and induces dose-dependent antinociception in mice – offered significant prophylaxis to patients of migraine with aura or migraine without aura comparable to propranolol (40 mg b.i.d.) (24). Finally, allodynia has been suggested to imply a defect in antinociception in migraine patients (25). Antinociception, however, is reportedly enhanced during migraine attacks (26). Overall, the relevance of the concept of cutaneous allodynia to migraine pathogenesis itself or to its transformation to chronic daily headache is uncertain and speculative. Triptan therapy has certain subtle features that have particularly important bearing on migraine management. Besides theoretical limitations as discussed, the thrust to prevent cutaneous allodynia with early use of triptans (1,9) also has practical drawbacks. Triptans are emerging as the commonest pharmacological agent, alone or in combination, associated with medication overuse headache (27). With a shift in thinking about the headache-preventive role of triptans in migraine at the tertiary-care level, abuse of triptans is reportedly common in a fraction of tertiary-care primary headache patients who are refractory to most management strategies, have complex psychological backgrounds, are prominently susceptible to placebo or nocebo effects, invariably seek or demand particular therapeutic attention and actively seek alternative therapies; practically, there is little behavioural difference between such patients and those who are drug dependent (28). Abuse of triptans is likely to increase as the presumed migraine preventive action of triptans becomes common or lay knowledge. Furthermore, the brain penetrability of sumatriptan is poor; vasoconstriction, rather than neuronal modulation, best explains the rapid antimigraine action of subcutaneous sumatriptan (29). No triptan is known to significantly alter any brain neuronal function in humans. Finally, whereas migraine attacks can last 4–72 h if untreated or unsuccessfully treated (30), sumatriptan, unlike ergotamine (31), is a rapid-cycle vasoconstrictor with a short half-life and biological effect. Triptans can well reset the stage for a rebound vasodilatation – with increased requirement of triptans and other antimigraine abortive agents – in those migraine patients in whom the primary aberration has not fully run its natural or spontaneous course within 6–8 h. As a common disorder that considerably consumes limited health resources, migraine has assumed public health importance. Prudence and reflection must guide migraine researchers and headache therapists. Triptan pharmacotherapy is one area of migraine preventive management largely being propelled by theoretical assumptions and extrapolations that challenge logical and scientific thinking. Cutaneous allodynia is not peculiar or unique to migraine pathophysiology. There appears to be an untenable dissociation between statistical and biological significances in the pre-emptive/early triptan strategy (1) for management of migraine.