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Letters: M F P Peres, M A Stiles, H C Siow, and S D Silberstein Excessive daytime sleepiness in migraine patients J Neurol Neurosurg Psychiatry 2005; 76: 1467-1468 [Full text] [PDF]

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Sleep remits and precipitates migraine: role of the monoaminergic-vasopressin system

Vinod K Gupta   (10 November 2005)

Sleep remits and precipitates migraine: role of the monoaminergic-vasopressin system 10 November 2005
Vinod K Gupta, Physician Dubai Police Medical Services, Dubai, United Arab Emirates Send letter to journal: Re: Sleep remits and precipitates migraine: role of the monoaminergic-vasopressin system dr_vkgupta{at}yahoo.com Vinod K Gupta	Dear Editor In their analysis of excessive daytime sleepiness (EDS), Peres and colleagues (1) have not considered the major migraine attack-remitting influence of sleep and the pathophysiological implications of this established clinical association. Sleep has a well-defined therapeutic effect in migraine (2, 3). Sleep commonly terminates migraine attacks; 14 out of 50 migraine patients could shorten their attacks by unscheduled daytime sleeping for ~2.5 hours (2). In another study, 85% of migraineurs indicated that they chose to sleep or rest because of headache and 75% were forced to sleep or rest because of headache (4). Sleep stimulates arginine vasopressin (AVP) secretion without any relation to electroencephalographic sleep stage; significantly, such physiological elevation occurs at a time when redistribution of blood volume from the extremities to the central vessels would otherwise suppress AVP secretion (5). With important vasomotor, antinociceptive, and behaviour control functions, AVP appears to have a prominent physiological role in migraine; as part of an adaptive / secondary neuroendocrine system involving central sympathetic and serotoninergic hyperfunction, AVP probably delays significantly the onset of migraine attacks in a variety of clinical situations and circumstances (6, 7). AVP might play a central role in the migraine-remitting influence of sleep (6). To understand the limited but definite "protective" effect of stress in migraine (8, 9), comprehension of the headache-remitting role of sleep is also essential; in the absence of such an endeavour, the role of the term “stress” in migraine expands to that of a misguiding, all-inclusive euphemism for ignorance (9). The two-fold increase in EDS seen in this study (1) possibly represents the operation of an adaptive mechanism. In patients with ongoing headache, EDS might abort the attack; in headache- free patients with sub-clinical physiological dysfunction of an impending attack, EDS might prevent the onset of yet another attack. Study of brain monoaminergic system is probably the most important issue in migraine pathophysiology. In hypothesizing about brain / hypothalamic dysfunction in migraine or chronic migraine (1), the critical issue is whether such involvement is primary or secondary. Orexin driven monoaminergic activity (1) must be understood in the broader context of the brain monoaminergic system dysfunction / alteration in migraine. Migraine theory and therapy over the last ~50 years has largely been dictated by the serendipitous discovery of the prophylactic efficacy of propranolol. Such thinking culminated in the postulation that intrinsic noradrenergic activation precipitates migraine (10). Much of migraine research rests on this assumption; the biobehavioral model of migraine is perhaps one of the most frequently quoted reference article. We have assumed – against the logic of the fundamentally adaptive nature of the autonomic / sympathetic nervous system – that central or brain sympathetic stimulation in migraine is pathogenetic. With this assumption, however, we have digressed from reason and logic. Not only does this theory leave unexplained the phenomena of post-stress or delayed-onset of headache in migraine, it cannot also integrate the widely accepted, first-line migraine prophylactic effect of amitriptyline, the prototypic tricyclic antidepressant. Tricyclic antidepressants unambiguously stimulate brain monoaminergic and serotonergic neurons, a feature that might contribute to their pro-convulsant effect. The clearest clinical expressions of brain neuronal stimulatory influence of amitriptyline is seen in the serotonin syndrome as well as the excitation / hypo-mania like state induced by amitriptyline (11). Caffeine, that characteristically induces migraine headaches during abstinence over the week-end (8), also directly stimulates the central nervous sytem noradrenergic system (12). Cocaine is a direct brain noradrenergic stimulant; cocaine withdrawal is associated with migraine-like vascular headaches (13, 14). The scientific costs of empiricism and conceptual diversion from clinical reality in primary headache research is incalculable. Precipitation of migraine by sleep or EDS (1) is an entirely different issue. Research efforts must be directed to peripheral mechanism(s) involved in generation of antidromic trigeminal, particularly ophthalmic, nerve discharge (15). Neuroanatomically, in contrast to the general consensus, pain in migraine is not distributed throughout the trigeminal nerve but is principally confined to the ophthalmic division of the trigeminal nerve. The primary afferent fibres of the three divisions of the trigeminal nerve are arranged in a complex manner at the spinal nucleus with only pain and temperature fibres from the ophthalmic area descending to the lower limit of the first cervical spinal segment; this long held view, although controversial, is supported by sectional studies in humans at and below the obex for severe trigeminal neuralgia (16). Occipital and nuchal pain in migraine attacks probably involves predominantly the link between ophthalmic trigeminal fibres and the upper cervical spinal segments. Moreover, a typical migraine attack -- with scintillating scotoma or pulsating headache or both – has not been reported following enucleation or evisceration of the eye (17, 18), reinforcing the pathogenetic role of the ophthalmic trigeminal division. Finally, photophobia is a reflex involving the ophthalmic nerve alone. The link between migraine and sleep phases, including rapid eye movement (REM) sleep (3), remains unexplained. In healthy persons, sleep is associated with fluctuations of the intraocular pressure (IOP) (19). A systemic and local / regional sympathetic hypofunction prevails between attacks in migraine patients (20, 21) that might impair IOP regulation (22). Given that several migraine prophylactic agents lower IOP (e.g., propranolol, atenolol, metoprolol, nadolol, verapamil, flunarizine, clonidine) (23, 24), the possibility that exaggerated fluctuations of IOP develop during sleep and contribute to antidromic trigeminal nerve discharge in migraine patients merits attention. Too much sleep – excessive III, IV and REM sleep (3) might exhaust AVP bioavailability; REM sleep is accompanied by autonomic activation but relative excess or unusual bouts of REM phase sleep can induce sympathetic nervous system (SNS) exhaustion, especially in migraine patients with pre-existing trait-SNS hypofunction. Morning arousals with migraine headache might also reflect SNS exhaustion / depletion; in the three hours before patients awoke with migraine, plasma total catecholamines and specifically plasma noradrenaline were significantly higher (25). SNS / AVP bioavailability exhaustion may also underlie migraine headache after brief periods of diurnal sleep (3) or EDS (1). Any clinical situation that might induce SNS hypofunction or impair / deplete AVP bioavailability can induce migraine headache. References 1. Peres MFP, Stiles MA, Siow HC, Silberstein SD. Excessive daytime sleepiness in migraine patients. J Neurol Neurosurg Psychiatry 2005;76:1467-68. 2. Blau JN. Resolution of migraine attacks: sleep and the recovery phase. J Neurol Neurosurg Psychiatry 1982;45:223-6. 3. Sahota PK, Dexter JD. Sleep and headache syndromes: a clinical review. Headache 1990;30:80-4. 4. Kelman L, Rains JC. Headache and sleep: examination of sleep patterns and complaints in a large clinical sample of migraineurs. Headache 2005;45:904-10. 5. Valiquette G. The neurohypophysis. Neurol Clin 1987;5:291-331. 6. Gupta VK. A clinical review of the adaptive potential of vasopressin in migraine. Cephalalgia 1997;17:561-69. 7. Gupta V. Stress, adaptation, and traumatic event headaches: pathophysiologic and pharmacotherapeutic insights. BMC Neurology 2004;4:17 (Published online 26 November 2004) Available at: http://www.biomedcentral.com/1471-2377/4/17/comments#106454 8. Blau JN. Migraine: theories of pathogenesis. Lancet 1992;339:1202- 7. 9. Gupta VK. Sympathetic nervous system dysfunction in migraine: pearls and pitfalls in the theorizing process. Headache 2004;44:841-2. 10. Welch KMA. Migraine. A biobehavioral disorder. Arch Neurol 1987;44:323-7. 11. Gupta VK. Amitriptyline versus cyproheptadine: opposite influences on brain 5-HT function. Headache (In press). 12. Gupta VK. Caffeine and migraine: analgesia and intrinsic brain noradrenergic activation. Headache (In press). 13. Satel SL, Gawin FH. Migrainelike headache and cocaine use. JAMA 1989;261:2995-6. 14. Dhuna A, Pascual –Leone, Belgrade M. Cocaine-related vascular headaches. J Neurol Neurosurg Psychiatry 1991;54:847-8. 15. Gupta VK. Migraine, cortical excitability and evoked potentials: a clinico-pharmacological perspective. Brain 2005;128:E36. 16. Bannister LH, Berry MM, Collins P, Dyson M, Dussek JE, Ferguson MWJ. Gray’s Anatomy. Thirty-eighth edition, 1995. New York: Churchill Livingstone, 1995. p 1232. 17. Soros P, Vo O, Husstedt IW, Evers S, Gerding H. Phantom eye syndrome: its prevalence, phenomenology, and putative mechanisms. Neurology 2003;60:1542--3. 18. Sörös P, Vo O, Gerding H, Husstedt IW, Evers S. Enucleation and development of cluster headache: a retrospective study. BMC Neurology 2005;5:6. 19. Buguet A, Py P, Romanet JP. 24-hour (nyctohemeral) and sleep- related variations of intraocular pressure in healthy white individuals. Am J Ophthalmol 1994;15;117:342-7. 20. Gotoh F, Komatsomoto S, Araki N, Gomi S. Noradrenergic nervous activity in migraine. Arch Neurol 1984;41:951-5. 21. Harle DE, Wolffson JS, Evans BJW. The pupillary light reflex in migraine. Ophthal Physiol Opt 2005;25:240-245. 22. Gupta VK. Disfunzioni visive nell’emicrania: possibile influenza della pressione intraoculare. Confinia Cephalalgica 1992;1:259-61. 23. Gupta VK. Visual function impairment in migraine: cerebral versus retinal deficit. Cephalalgia 1993;13:431-2. 24. Gupta VK. Visual field dysfunction and migraine: basic pathophysiological, pharmacological and clinical considerations. Ophthal Physiol Opt (In press). 25. Hsu LKG, Crisp AH, Kalucy RS, Koval J, Chen CN, Carruthers N, Zilkha KJ. Early morning migraine: nocturnal plasma levels of catecholamines, tryptophan, glucose and free-fatty acids and sleep encephalographs. Lancet 1977;ii:447-51.