migraine headache and its association with emesis and ... · migraine headache and its association...

PRACTICAL GASTROENTEROLOGY • MARCH 200466

CLINICAL MANIFESTATIONS AND EPIDEMIOLOGY

Migraine headache is a chronic, debilitating dis-order characterized by severe head pain that isusually unilateral and throbbing in nature (1). If

left untreated, a migraine can persist for up to 72 hours

(2). It is frequently associated with nausea (87%)and/or vomiting (56%), and other symptoms such asphotophobia and phonophobia are also quite common(3). As reported in a review in The New England Jour -nal of Medicine on the pathophysiology and treatmentof migraine headaches (4), fifteen percent of migrainesufferers will experience transient focal neurologicalsymptoms that typically precede their headaches. Thisphenomenon is known as "migraine with aura," andthe neurological symptoms are usually manifested asvisual disturbances. However, some studies show thatup to 31% of patients report the presence of aura withtheir migraines at one time or an another (5). It is the

Migraine Headache and Its Association with Emesis and Gastric Motility: A Brief Review

A SPECIAL ARTICLE

Jonathan Buscaglia, M.D., PGY-2, Albert EinsteinCollege of Medicine, Internal Medicine ResidencyProgram, Montefiore Medical Center, Bronx, NewYork and Aaron Tokayer, M.D., MHS, Assistant Pro-fessor of Medicine, Division of Gastroenterology,Albert Einstein College of Medicine, Montefiore Med-ical Center, Bronx, New York.

Jonathan Buscaglia

Migraine headache is a chronic and debilitating disorder that affects approximately17% of all adult women and 5% of all men. The duration of an attack may be between4 and 72 hours, but typically lasts one whole day. Migraines are frequently associatedwith nausea and vomiting in the majority of sufferers, as well as other symptoms suchas sensitivity to light and sound. In this review, we separately discuss the pathophysiol-ogy of both migraine headaches and emesis, as well as the effect of migraines on gastricmotility. We attempt to decipher the complex interplay between the central nervoussystem and the peripheral nervous system within the context of delayed gastric empty-ing and migraine-associated emesis.

Aaron Tokayer

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presence of these associated features that allows theclinician to distinguish a migraine headache from theother major types of primary headaches; namely, ten-sion headaches and cluster headaches.

Migraine headaches can begin at any age, althoughthe incidence typically peaks in mid-adolescence.Women are affected more commonly than men, with afemale:male ratio of 3:1 (6). It is estimated that up to

17.6% of all adult women, and5.6% of adult men, are affected bymigraines (3). The median fre-quency of an attack is approxi-mately 1.5 times per month, andthe median duration is 24 hours(7). Five percent of the generalpopulation has at least 18 days ofmigraine headaches per year (4).This translates into countlesshours of absence from work andschool, as well as millions of visitsto the offices of primary carephysicians each year.

PATHOPHYSIOLOGY OFMIGRAINEThe pathophysiology of migraineheadaches has long been debatedand incompletely understood. It isessentially regarded as a primarybrain disease involving the cranialblood vessels, but other neurogenicfactors are thought to play animportant role as well. Inappropri-ate activation of the trigeminalnerve fibers cause the release oflocal sensory neuropeptides which,in turn, promote vasodilation,perivascular edema, and the recruit-ment of certain inflammatory cells(8). The inflammation proximal tothe meninges (Figure 1) is thoughtto cause the severe pain experi-enced during a migraine. It isunclear as to what factors areresponsible for the initial stimula-

tion of the trigeminovascular system that leads to the cas-cade of events producing the headache. Imbalances inthe release of the neurotransmitter serotonin, however,have been implicated because of its ability to mediatevasoconstriction and trigeminal nerve activation (9). It isfor this reason that the current abortive therapies for anacute migraine attack are all serotonin (5-HT) receptorsubtype agonists.

A SPECIAL ARTICLE

Migraine Headache and Its Association with Emesis and Gastric Motility

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Figure 1. Pathophysiology of Migraine. Migraine involves dysfunction of brain-stempathways that normally modulate sensory input. The key pathways for the pain are thetrigeminovascular input from the meningeal vessels, which passes through thetrigeminal ganglion and synapses on second order neurons in the trigeminovervicalcomplex. These neurons, in turn, project through the quintothalamic tract, and afterdecussating in the brain stem, form synapses with neurons in the thalamus. There isa reflex connection between neurons in the pons in the superior salivatory nucleus,which results in a cranial parasympathetic outflow that is mediated through the ptery-gopalatine, otic, and carotid ganglia. This trigeminal–autonomic reflex is present innormal persons and is expressed most strongly in patients with trigeminal–autonomiccephalgias, such as cluster headache and paroxysmal hemicrania; it may be active inmigraine. Brain imaging studies suggest that important modulation of the trigemino-vascular nociceptive input comes from the dorsal raphe nucleus, locus ceruleus, andnucleus raphe magnus. Goadsby, PJ, et al: Drug Therapy: Migraine—current under-standing and treatment. N Engl J Med 2002;346:257-270. Copyright 2002 Massachu-setts Medical Society. All rights reserved.

Trigeminal nerve stimu-lation and intracranial vaso-dilation, however, are nots u fficient to explain all thefeatures associated with amigraine headache—espe-cially the aura (10). The auraof a migraine is felt to be dueto a wave of oligemia (4)that originates in the occipi-tal lobe of the cerebral cortexand progresses anteriorlytowards the frontal pole. It isthis spreading oligemia thatproduces the distinct focaland transient neurologicalsymptoms seen in migrainewith aura. This phenomenonis thought to be due to pri-mary disturbances in corticalmetabolism and function(10); a mechanism of actionthat is separate from stimula-tion of the trigeminovascularsystem.

PATHOPHYSIOLOGY OF EMESISEmesis is associated withseveral conditions other than migraine headaches. Nau-sea and vomiting are seen with head trauma, chemother-a p y, the extremes of emotion, drug withdrawl, distur-bances in the eighth cranial nerve, and several primarygastrointestinal diseases (11). The pathophysiology ofvomiting involves a complex interplay between the cen-tral and the peripheral nervous systems. Within the CNSexists the "vomiting center" of the brain located in thelateral reticular formation of the medulla (12). The vom-iting center is comprised of two major groups of brain-stem nuclei known as the nucleus tractus solitarius(NTS) and the dorsal motor nucleus of the vagus(DMNV). They are responsible for receiving informa-tion promoting emesis from several different areaswithin the CNS and PNS (Figure 2). For example, thegastric mucosa—via vagal and splanchnic aff e r e n t s —

communicates directly with the vomiting center of thebrainstem. Other areas of the nervous system that influ-ence the vomiting center include the chemoreceptortrigger zone, located in the area postrema below thefourth ventricle; the vestibular system; and higher corti-cal areas in charge of sight, smell, pain, etc. (11,13). Allof these areas send information to the vomiting center,which subsequently stimulates its gastrointestinal motorcorrelates to cause emesis.

Vomiting is ultimately achieved by relaxation ofgastric tone in preparation for a large retrograde con-traction that begins in the proximal small intestine andpropagates orally to the gastric antrum (11). While thelower esophageal sphincter is completely relaxed,undigested food is pushed up through the esophagus.This action is facilitated by contraction of the

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Figure 2. NTS = nucleus tractus solitarius, DMNV = dorsal motor nucleus of the vagus.Adapted from DePonti, F: Pharmacology of emesis and gastrointestinal motility: implicationsfor migraine. Functional Neurology 2000; 15, suppl 3.


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diaphragm and abdominal muscles against a closedpyloric sphincter (14).

MIGRAINE HEADACHES AND GASTRIC MOTILITYWhat exactly causes vomiting during a migraineheadache, and why do some patients have it worsethan others? For many years neuroscientists havedebated whether the central nervous system or theperipheral nervous system is responsible for the initia-tion of emesis during a migraine. In other words, is itmainly a central mechanism of action with stimulationof the trigeminovascular system that somehow acti-vates the vomiting center of the brain; or is it initiallya peripheral mechanism with alterations in gastricmotility that ultimately sends signals to the vomitingcenter via its vagal and splanchnic afferents.

Since the 1970’s researchers have studied theeffects of migraine headaches on gastric motility. Pre-vious studies have shown that there is a delay in drugabsorption during an acute migraine (15–18), and ithas been postulated that this slowed absorption iscaused by a delay in gastric emptying. These initialstudies essentially measured blood levels of certaincompounds such as paracetamol and tolfenamic acidboth at baseline and during an acute migraine attack.Drug levels were significantly reduced in patients dur-ing their migraine headaches. In one particular studythat utilized epigastric impedance recordings to detectchanges in gastric emptying, researchers found that theseverity of a headache correlated with the degree ofdelay in gastric emptying (17). Other studies looked atprokinetic agents such as metacloperamide and itseffect on drug absorption during an acute attack. Bloodlevels of both effervescent aspirin and tolfenamic acidwere improved during migraine headaches when meta-cloperamide was given just prior to the attack (16,19).This suggests that the prokinetic effect of metaclop-eramide is indirectly responsible for the improvedabsorption, and thus a disturbance in gastric motilitydoes exist during an acute migraine.

To the best of our knowledge, there have not beenany published studies utilizing radioscintigraphy as ameasure of gastric motility in patients during an acutemigraine headache. Nonetheless, with the informationfrom studies that are currently available, there is

enough evidence to suggest that there is a delay in gas-tric emptying during a migraine. It is thought that thisalteration in motility then produces gastric distention,which stimulates central receptors in the brainstem tosubsequently cause vomiting. For those patients whodo not experience vomiting with their migraineheadaches, one theory postulates that these patientsmay have a reduced perception to gastric distention;thus, the vomiting center of the brainstem is neverstimulated sufficiently to produce emesis. Altogether,it seems as though vomiting during a migraine may bethe direct result of changes in gastric motility; yetthose alterations in motility appear to be initially moti-vated by a central stimulus from the migraine itself.

MIGRAINE THERAPY AND GASTRIC MOTILITYThe treatment of migraine headaches raises anotherimportant point concerning gastric emptying. Over thelast decade, the class of drugs known as "the triptans"have risen to the forefront as the major anti-migrainetherapy for an acute attack. The leader in this group ofmedications is sumatriptan, a 5-HT1B/D agonist thatcrosses the blood-brain barrier. There are several theo-ries as to how it relieves migraines, and most of themare focused on 5-HT receptor-mediated vasoconstric-tion and inhibition of trigeminal nerve firing (20,21).The most intriguing aspect of sumatriptan, however, isits effect on gastric motility in dosages similar to thoseused in migraine patients. Sumatriptan has been shownto cause a delay in gastric emptying of both liquids andsolids (22–24). In a recent article by Cipolla, et al theauthor thoroughly reviews the current data on the gas-tric motor effects of sumatriptan in both humans andanimals (8). Within this review, he discusses priorstudies that have demonstrated a delay in gastric emp-tying with this medication. Furthermore, he also notesa more recent study in which sumatriptan was shownto relax the gastric fundus and allow for larger intra-gastric volumes before thresholds for pain and dis-comfort were reached (25).

By delaying gastric emptying, it is difficult toimagine how a medication such as sumatriptan wouldnot cause further symptoms of nausea and vomiting.Some studies, however, report a significant improve-

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A SPECIAL ARTICLE


ment in nausea with both sumatriptan and the newersecond generation triptans. On the other hand, thesesame studies report nausea as the principle side effectof these medications (26,27). As Cipolla, et al pointsout, no study has specifically differentiated betweendisease-associated nausea and nausea as a side effectof the medication (8).

One theory as to why sumatriptan improves symp-toms of nausea is because of its ability to relax the gas-tric fundus and allow for greater distention withoutperception of discomfort (25). Increased gastric dis-tention should typically induce nausea, and eventuallyvomiting. Sumatriptan, however, may be interferingwith the ability of the PNS to communicate with theappropriate central receptors; thus it masks the centralresponse to gastric distention.

The exact mechanism as to how sumatriptancauses proximal stomach relaxation and a reduced per-ception of discomfort remains to be discovered. Thisfinding, however, suggests that it may be beneficial forpatients with functional dyspepsia who suffer fromsymptoms of frequent bloating and early satiety. Fur-ther studies with specific 5-HT1B and 5-HT1D ago-nists/antagonists will help to elucidate this issue.Investigating more specific serotonin receptor subtypeagents will not only aid in the progression of researchfor migraine therapy, but it may also help to uncoveradditional agents used to relieve symptoms of func-tional dyspepsia. ■

References 1. Harrison. Principles of Internal Medicine, 15th Edition 2001; 1:

73-78.2. Headache Classification Committee of the International

Headache Society. Classification and diagnostic criteria forheadache disorders, cranial neuralgias and facial pain. Cephal,1998; 8: suppl 7:1-96.

3. Dambro MR, Lippincott, Williams, Wilkins. Griffith’s 5-minuteClinical Consult, December, 2000.

4. Goadsby PJ, Lipton RB, Ferrari MD. Migraine—current under-standing and treatment. N Eng J Med, 2002; 346: 257-270.

5. Launer LJ, Terwindt GM, Ferrari MD. The prevalence and char-acteristics of migraine in a population-based cohort: the GEMstudy. Neurology, 1999; 53: 537-542.

6. Mannix LK. Relieving migraine pain: sorting through theoptions. Cleveland Clinic J Med, 2003; 70: 8-28.

7 . Stewart WF, Lipton RB, Celentano DD. Reed ML. Prevalence ofmigraine headache in the United States: relation to age, income,race and other sociodemographic factors. JAMA, 1992; 276: 64-69.

8. Cipolla G, Sacco S. Gastric motor effects of triptans: open ques-tions and future perspectives. Pharmacol Research, 2001; 43:No. 3.

9. Spencer CM, Gunasekara NS, Hills C. Zolmitriptan: a review ofits use in migraine. Drugs, 1999; 58: 347-374.

10. Stein J. Internal Medicine, 5th Edition 1998; 137: 957-958.11. De Ponti F. Pharmacology of emesis and gastrointestinal motil-

ity: implications for migraine. Func Neur, 2000; 15: suppl 3.12. Borison HL, Borison R, McCarthy LE. Phylogenic and neuro-

logic aspects of the vomiting process. J Clin Pharmacol, 1981;21: suppl 23S-29S.

13. Dahlof CGH, Hargreaves RJ. Pathophysiology and pharmacol-ogy of migraine. Is there a place for antiemetics in future treat-ment strategies? Cephal, 1998; 18: 593-604.

14. Brizzee KR. Mechanics of vomiting: a minireview. Can J Phys -iol Pharmacol, 1990; 68: 221-229.

15. Tokola RA, Neuvonen PJ. Effect of migraine attacks on parac-etamol absorption. Br J Clin Pharmacol, 1984; 18: 867-871.

16. Tokola RA, Neuvonen PJ. Effects of migraine attack and meta-clopramide on the absorption of tolfenamic acid. Br J Clin Phar -macol, 1984; 17: 67-75.

17. Boyle R, Behan PO, Sutton A. Correlation between severity ofmigraine and delayed gastric emptying measured by an epigastricimpedance method. Br J Clin Pharmacol, 1990; 30: 405-409.

18. Tokola RA, The effect of metoclopramide and prochlorperazineon the absorption of effervescent paracetamol in migraine.Cephal, 1988; Sep, 8(3): 139-147.

19. Volans GN. The effect of metacloperamide on the absorption ofeffervescent aspirin in migraine. Br J Clin Parmacol, 1975; Feb,2(1): 57-63.

2 0 . Bateman DN. Triptans and migraine. Lancet, 2000; 355: 860-861.21. Hargreaves RJ, Shepheard SL. Pathophysiology of migraine—

new insights. Can J Neurol Sci, 1999; 26: suppl 3: S12-S19.22. Houghton LA, et al. Effect of sumatriptan, a new selective

5-HT1-like agonist, on liquid gastric emptying in man. AilmentPharacol Ther, 1992; 6: 685-691.

23. Tack J, Coulie B, et al. Actions of the 5-hydroxytriptamine 1receptor agonist, sumatriptan, on interdigestive gastrointestinalmotility in man. Gut, 1998; 42: 36-41.

24. Coulie B, Tack J, et al. Sumatriptan, a selective 5-HT1 receptoragonist, induces a lag phase for gastric emptying of liquids inhumans. Am J Physiol, 1997; 272: G902-G908.

25. Tack J, Coulie B, et al. Influence of sumatriptan on gastric fun-dus tone and on the perception of gastric distension in man. Gut,2000; 46: 468-473.

26. Sargent J, Kirchner JR, et al. Oral sumatriptan is effective andwell tolerated for the acute treatment of migraine. Neurology,1995; 45: suppl 7: S10-S14.

27. Mathew NT, et al. Naratriptan is effective and well tolerated forthe acute treatment of migraine. Neurology, 1997; 49:1485-1490.

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