Concomitant Medical Disease and Headache

Headache

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Concomitant Medical Disease and Headache

Glen D. Solomon, MD, FACP*

Headache is the most common pain syndrome seen in clinical practice. Because of its prevalence, headache is commonly seen in patients who suffer with other illnesses. The management of the headache patient with concomitant medical disease requires knowledge of the illnesses that are associated with headache and an understanding of the potential medications available for headache therapy. Headache may be a presenting symptom of several medical conditions (Table 1). Fever, of any etiology, is probably the most common medical problem that causes headache. Pheochromocytoma often presents with a pounding headache associated with hypertension, diaphoresis, tachycardia, and palpitations. Immunologic diseases such as systemic lupus erythematosus, polyarteritis nodosa, and giant cell arteritis may have headache as an early symptom. '7 Headache is reported in almost 60% of patients with fibromyalgia. Although Sjiigren's syndrome often is manifest by neuropsychiatric disturbances, we have reported one patient with headache as the initial complaint. Other types of vasculitis may cause headache, but are less common. Sleep apnea may present with the symptom of headache upon awakening that improves as the day progresses. This is most commonly seen in obese, middle-aged men. Associated symptoms of sleep apnea may include snoring and daytime somnolence; examination often reveals an obese man with a short neck, hypertension, and arrhythmias. Less common diseases presenting with headache include chronic renal failure, hyperthyroidism, and malignant hypertension. The organic etiologies of headache are found in a very small (less than 1%) proportion of headache patients. The vast majority of headache sufferers have a benign headache disorder (i.e., migraine, tension-type, or cluster headache). Patients with chronic benign headache disorders often will have concomitant medical problems. Featherstone lO evaluated the prevalence of concomitant medical disease in headache sufferers by reviewing 1414 life insurance applications to obtain 200 headache cases and matched controls. His group had an average age of 45 years and was equally divided by gender. Headaches were not classified into migraine and nonmigraine headache. Six conditions were found to occur more often in the

*Attending Physician,

Section of Headache, Department ofInternal Medicine, The Cleveland Clinic Foundation, Cleveland, Ohio; and Clinical Associate Professor of Medicine, Pennsylvania State University College of Medicine, Hershey, Pennsylvania

Medical Clinics of North America-Vo!' 75, No. 3, May 1991

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Table 1. Diseases That May Present with Headache Febrile illness/infection Pheochromocytoma Malignant hypertension Systemic lupus erythematosus Vasculitis (temporal arteritis, PAN) Fibromyalgia Sleep apnea Chronic renal failure

Hyperthyroidism Depression Adrenal insufficiencv

Hyperparathyroidis~

Polycythemia H yponatremia Hypoxia

headache group: hypertension, dizziness (or vertigo), gastroesophageal reflux, depression or anxiety, peptic ulcer disease, and irritable bowel syndrome. Three conditions were significantly more common in the nonheadache population: nephrolithiasis, alcohol abuse in men, and abdominal pain in women. Several conditions had the same prevalence in headache and nonheadache groups: ischemic heart disease, mitral valve prolapse, cardiovascular disease, chest pain, diabetes mellitus, central nervous system ischemia, cigarette smoking, emphysema, and previous surgery. Although Featherstone's paper examined "idiopathic" headache, other investigators have noted certain diseases that occur with increased frequency in patients with specific headache diagnoses. Disorders such as coronary vasospasm (variant or Prinzmetal's angina), 12,21 Raynaud's phenomenon,23 aspirin-sensitive asthma,'5 mitral valve prolapse,13 and hypertension l4 are all found more commonly in migraine patients, Peptic ulcer disease is three times more common in men with cluster headache than in control populations,6 Symptoms of depression are more common in patients with chronic tension-type headache than in controls. PHARMACOLOGY OF HEADACHE MEDICATIONS Medications That Exacerbate Headache Many medications are thought to exacerbate headache in patients with an underlying headache disorder (Table 2), Other medications may cause de novo headache, Askmark et aP evaluated data from the World Health Organization Collaborating Centre for International Drug Monitoring, Drug-related headache was most frequently reported with the following medications: indomethacin, nifedipine, cimetidine, atenolol, trimethoprim-sulfamethoxazole, zimeldine, nitroglycerin, isosorbide dinitrate, ranitidine, isotretinoin, captopril, piroxicam, metoprolol, and diclofenac, When the data were compiled to determine the relative frequency of headache per amount of drug sold, the drugs most likely to cause headache were zimeldine, nalidixic acid, trimethoprim, griseofulvin, ranitidine, and nifedipine. Table 2. Drugs That May Exacerbate Headache Nonsteroidal Antiinflammatory Drugs Indomethacin Diclofenac Piroxicam Vasodilators Nitroglycerin Isosorbide dinitrate Others Isotretinoin Erythropoietin

Antihypertensives Nifedipine Captopril Atenolol Prazosin Metoprolol Reserpine Minoxidil H 2-blockers Ranitidine Cimetidine

Antibiotics Trimethoprim-sulfamethoxazole Griseofulvin Hormones Estrogens Oral contraceptives Clomiphene Danazol

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Several drugs were reported to cause migraine headache. These included cimetidine, oral contraceptives, atenolol, indomethacin, danazol, nifedipine, diclofenac, and ranitidine. Medications that aggravate existing migraine include hormonal therapy, such as oral contraceptives, clomiphene, and postmenopausal estrogens. Vasodilators, such as nitrates, hydralazine, minoxidil, nifedipine, and prazosin, may worsen both migraine and cluster headaches. Vitamin A and its retinoic acid derivatives may also exacerbate migraine. Reserpine depletes catecholamine and serotonin stores within the brain, often leading to depression and increased migraine and tension-type headache. Indomethacin, although useful in treating cluster variant headaches, can cause a generalized headache. Medications Used to Treat Headaches A number of medications have been used in the prophylaxis of migraine, including methysergide, beta-blockers, calcium-channel blockers, nonsteroidal antiinflammatory drugs, and cyproheptadine (Table 3). Medications used in the prophylaxis of cluster headache include ergots, corticosteroids, methysergide, verapamil, and lithium carbonate. The antidepressants, particularly tricyclic agents, have been used in the treatment of tension-type headache and in the prophylaxis of migraine for a number of years. These drugs are most useful in patients with tension-type headache, the mixed headache syndrome, or in migraine patients with depressive features. Both tricyclics and monoamine oxidase inhibitors have been effective. Tricyclics are the first choice because of the lower incidence of side effects and potentially serious drug interactions. In order to prescribe the appropriate drug for a headache patient with concomitant medical problems, an understanding of the potential physiologic effects of the drug is needed. Tricyclic antidepressants have several potential cardiac effects. 26 Although these agents have no significant negative inotropic effects, they may cause orthostatic hypotension. Orthostatic hypotension is most common with the tertiary amines (i.e., amitriptyline, imipramine) and is mediated through alphaj-adrenergic receptor blockade. All tricyclics except trazadone, fluoxetine, and bupropion may cause cardiac conduction problems. Tricyclics slow the process of depolarization and prolong repolarization, a quinidine-like effect. On electrocardiogram (ECG), there may be increased lengths of P-R, QRS, and Q-T intervals. This effect is usually negligible, except in patients with second-degree heart block, right or left bundle branch block, or intraventricular conduction delays (QRS width> 0.11 seconds). Treatment with tricyclics do not cause patients with first-degree heart block (P-R > 0.2 seconds) to develop higher degrees of heart block. Patients who need antidepressant drugs and who also have advanced heart block or intraventricular conduction delays should be treated with monoamine oxidase inhibitors, fluoxetine, bupropion, or trazadone. Beta-blockers are often considered as first-line drugs for migraine prophylaxis. Table 3. Drugs Used in the Prophylaxis of Headache Beta-blockers Calcium-channel blockers Tricyclic antidepressants Nonsteroidal anti-inflammatory drugs

++

+

= effective = =

sometimes helpful no effect

MIGRAINE

TENSION·TYPE

++ ++ ++ ++

+ ++ +

CLUSTER

++

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They are generally well tolerated but are contraindicated in patients with congestive heart failure, bronchospastic diseases (i.e., asthma, emphysema, chronic bronchitis), diabetes mellitus, or Wolff-Parkinson-White syndrome. Beta-blockers may exacerbate Raynaud's phenomenon. Altbough depression, fatigue, and sleep disorders occur with beta-blockers, the depression may exacerbate the tension headache component of the mixed headache syndrome. Beta-blocker therapy should not be abruptly discontinued, because abrupt discontinuation may lead to myocardial infarction even in patients without prior history of heart disease. Beta-blockers have multiple uses other than the prophylaxis of migraine. Originally developed as antianginal drugs, they are effective as antihypertensives and anxiolytics, and are useful for the secondary prevention of myocardial infarction. Calcium-channel blockers are useful in migraine and cluster prophylaxis. They constitute a diverse group of drugs with differing effects on the heart and vascular system. From a cardiovascular perspective, verapamil and diltiazem have negative inotropic effects and slow conduction through the atrioventricular node. Although nifedipine and nicardipine cause marked vasodilation, they have no effect on cardiac conduction. Verapamil and diltiazem should be avoided in patients with congestive heart failure, advanced heart block, or sick sinus syndrome. Calcium-channel blockers have a multitude of potential uses. They are indicated for the treatment of hypertension and angina pectoris, including vasospastic angina. Verapamil is also approved as an antiarrhythmic for paroxysmal supraventricular tachycardia and for atrial fibrillation and flutter (used with digoxin). Other (nonapproved) uses include prophylaxis of migraine and cluster headaches,2' relief of esophageal spasm, treatment of bipolar affective disorder (verapamil), and adjunctive therapy of irritable bowel syndrome (verapamil). Nonsteroidal anti-inflammatory drugs (NSAIDs) are widely prescribed for the treatment of arthritis and for analgesia. They are useful in both the acute treatment and prophylaxis of migraine headache, and as adjunctive therapy of chronic tensiontype headache. Unlike the beta-blockers and calcium-channel blockers used in migraine prophylaxis, NSAIDs do not lower blood pressure or affect cardiac conduction. Adverse effects of NSAIDs are relatively common and include gastrointestinal reactions such as dyspepsia, heartburn, nausea, vomiting, diarrhea, constipation, and generalized abdominal pain. Most NSAIDs can cause bleeding of the upper gastrointestinal tract. Renal effects of NSAIDs are of potential significance in elderly patients, hypertensive patients, or patients taking diuretics. These effects include decreased glomerular filtration rate with sodium, water, and chloride retention. Hyperkalemia is occasionally seen. Analgesic nephropathy, the most common cause of drug-induced renal failure, has been attributed to excessive use of NSAIDs along with phenacetin or acetaminophen.

MANAGEMENT OF CONCOMITANT DISEASES Hypertension Several studies have linked hypertension to migraine. 10, 14 Equally important, several medical conditions can present with both elevated blood pressure and headache.17 These include malignant hypertension (hypertensive crisis), pheochromocytoma, hyperthyroidism, vasculitis, chronic renal disease, increased intracranial pressure, and sleep apnea. Several medications that are known to exacerbate migraine also can elevate blood pressure. These include amphetamines, cocaine, estrogens, and oral contraceptives.

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Medications used in the treatment of hypertension can often exacerbate migraine. These include the vasodilators hydralazine, minoxidil, nifedipine, prazosin, and reserpine. Several medications used in the treatment of hypertension are also effective in the prophylaxis of migraine (Table 4). The antihypertensives with proven value in migraine prophylaxis are the beta-blockers, calcium-channel blockers, clonidine, angiotensin converting enzyme inhibitors, and guanfacine. The beta-blockers have been studied in migraine prophylaxis, and it appears that only the drugs lacking intrinsic sympathomimetic activity are effective. In his review of beta-blockers in migraine, Dalessio' concluded that nonselective betablockers (propranolol, nadolol, and timolol) are somewhat more effective than cardioselective beta-blockers (metoprolol and atenolol). The only beta-blocker currently approved by the Food and Drug Administration for migraine and hypertension is propranolol. Several calcium-channel blockers have been approved for the treatment of hypertension: verapamil, diltiazem, nifedipine, and nicardipine. In several studies, verapamil has been found to be effective in the prophylaxis of both migraine and cluster headache. 27 Limited data suggest that diltiazem may be useful in migraine prophylaxis. Nifedipine has significantly greater vasodilating properties than the other calcium-channel blockers and may exacerbate migraine. There are no studies on the use of nicardipine in migraine, although the author has found the drug effective in small numbers of patients. Two other calcium-channel blockers that have no antihypertensive use, nimodipine and fiunarizine, are effective in the prophylaxis of migraine and cluster headache. Nimodipine is approved for the prevention of cerebral vasospasm following subarachnoid hemorrhage. None of the calcium-channel blockers have been approved by the Food and Drug Administration for the treatment of migraine. Clonidine, an alpha-agonist, has been widely used in Scandinavia for migraine prophylaxis. This drug is unique in its ability to block the symptoms of opiate withdrawal and may be useful in the early management of patients with narcotic dependency.l6 The angiotensin converting enzyme inhibitor captopril has been reported to inhibit the enzyme enkephalinase. 8 It may thereby slow the breakdown of the naturally occurring opioid enkephalin. This drug has been reported to be effective in migraine prophylaxis 8 and as an adjunct to antidepressive therapy in musclecontraction headache. 24 The other clinically available angiotensin converting enzyme inhibitors (enalapril and lisinopril) have not been studied in headache, although the author has found these medications effective in small numbers of patients. Table 4. Hypertensive Therapy for Specific Headache Patients MIGRAINE

TENSION·TYPE

CLUSTER

+ +

N* N N

N

Beta-blockers Calcium-channel blockers Diuretics Angiotension converting enzyme inhibitors Clonidine Guanfacine Vasodilators Reserpine

+ = useful, - = exacerbate, N = no effect. *Depression can exacerbate headache. tRarely, it may worsen migraine.

t

+ +

+

+

N N N -*

+

N N N N N

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Cardiac Disease The prevalence of coronary artery disease (ischemic heart disease) did not vary between headache patients and controls in Featherstone's study of life insurance applications. 9 In addition, the reviews of ECGs from insurance applications revealed that ischemic ECG changes were less common in the headache group than in control patients. In this group of 161 pairs of ECGs, there were no differences in the frequency of smoking, diabetes mellitus, or hyperlipidemia between control patients and headache sufferers. Ischemic ECG changes found in 50 control patients and 30 headache sufferers showed a significantly different frequency. Pathologic Q waves were found in 21 controls and 14 headache sufferers, whereas ST depressions were found in 12 controls and 6 headache sufferers. There were no differences in the frequency of left ventricular hypertrophy, premature ventricular contractions, or conduction defects. Although Featherstone 9 did not find an increase in the prevalence of coronary artery disease in patients with idiopathic headache, other authors have found an association between migraine and coronary artery vasospasm (Prinzmetal's angina). 12. 21, 23. 29 Fournier et aF2 reported on onc family with both migraine and coronary artery spasm. Kuritzky et aPl found transient ST-segment elevations associated with chest pain during migraine attacks in some patients, suggesting variant angina. Both studies suggest that vasospastic angina is frequently associated with migraine and may possibly be part of a generalized vasospastic disorder. It is suggested that migraine sufferers with nonexertional chest pain during migraine attacks may warrant evaluation for vasospastic angina. 29 This group would include many young women who would otherwise not be considered at risk for coronary artery disease. Treatment of choice for vasospastic angina in a migraine patient would be a calcium-channel blocker. 29 Certain medications used in the treatment of coronary artery disease may induce migraine attacks. Primarily, these include the nitrates. Nitrates also may trigger headaches during cluster headache cycle. Because there are no reasonable alternatives to nitrates in the acute treatment of angina pectoris,4 these drugs will continue to be needed in patients with vascular headaches. It is crucial that these drugs not be prescribed for headache patients unless an appropriate diagnosis of angina pectoris is made. Excluding the nitrates, the usual prophylactic medications for angina, such as beta-blockers and calcium-channel blockers, are also useful in the prophylaxis of migraine. Several of the calcium-channel blockers also may be used in the prophylaxis of cluster headache. The problem of treating cluster headaches in patients with coronary artery disease was brought out in a paper by Solomon and Kunkel. 28 In their review of elderly patients with cluster headache, 4 of 14 cluster headache sufferers had a diagnosis of coronary artery disease, yet 3 of these 4 patients were treated with methysergide. Methysergide (being a major vasoconstrictor) is contraindicated in patients with coronary artery disease. Many of these patients may have benefited from treatment with a calcium-channel blocker that would possibly be effective in both angina and cluster headache prophylaxis. Some medications used in the treatment of headache disorders may exacerbate coronary artery disease. Among these drugs are ergotamine tartrate, which can cause vasospasm, even in the absence of atherosclerosis 3 ; methysergide, a vasoconstrictor that can also cause pericardial, cardiac, and pulmonary fibrosis; and tricyclic antidepressants, which may increase the risk of arrhythmias in certain patients. 26 Conditions that exacerbate the vasoconstrictor properties of ergotamine will therefore increase the risk of coronary vasospasm. These disorders include sepsis, thyrotoxicosis, anemia, and vascular disease. 30 Isometheptene mucate, a sympathetic amine found in the drug Midrin, is a weaker vasoconstrictor than ergotamine but generally should be avoided in patients with ischemic heart disease. Because

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ergotamine and isometheptene are contraindicated in patients with coronary artery disease, the abortive agent of choice for migraine appears to be the NSAIDs. Among the NSAIDs that are effective in aborting migraine attacks are naproxen sodium,20 meclofenamate, and flurbiprofen. These drugs have the advantage of not having vasoconstrictive properties. Paroxysmal supraventricular tachyarrhythmias (PSVT) are also assoeiated with migraine headache. 18 Attaeks of PSVT may oecur with a migraine attack or may occur as a migraine equivalent (acephalgic migraine). One ease report shows improvement both in PSVT and in migraine after treatment with digoxin. 19 The effeets of serum lipids on headache are still being evaluated. Leviton and Camenga22 reported an association between migraine and hyperprebeta-lipoproteinemia. They also reported that treatment of the hyperlipidemia with clofibrate improved both the hyperlipidemia and the frequency of migraine attacks. Because some fatty acids may cause the release of serotonin, it is possible that other lipid abnormalities may eventually be found in migraine sufferers. Mitral valve prolapse, like migraine, is a common disorder of young women. Gamberini et aP3 reported a prevalence of mitral valve prolapse of 23% in female migraine sufferers. This compares with a population prevalence of about 6% in women without migraine. In their patients with mitral valve prolapse, 51% suffered with migraine, a percentage well above the usual population prevalence of 24% to 29%. The treatment of choice for symptomatic mitral valve prolapse in patients with migraine would include beta-blocker therapy. The use of a beta-blocker should reduce the chest pain, anxiety, and palpitations of mitral valve prolapse while effectively reducing the frequency of migraine attacks. Asthma Although there is no known association between headache and asthma, one study 15 has found an association between aspirin-sensitive asthma and migraine headache. The prevalence of migraine in non-aspirin-sensitive asthmatics is 13%, whereas in aspirin-sensitive asthmatics, a 45.7% prevalence of migraine was noted. Aspirin-sensitive asthma constitutes from 4% to 20% of all asthma cases. Aspirinsensitive asthma is also known as triad asthma and constitutes an illness that includes anaphylactic reaction to aspirin or NSAIDs, nasal polyps, and asthma . .Many patients who suffer with this condition are also sensitive to tartrazine dye (yellow no. 5), which is used to color certain medications. The treatment of concomitant migraine in these patients can be difficult because the NSAIDs may lead to anaphylaxis, and the beta-blockers must be avoided because of the risk of bronchospasm. Treatment of choice for migraine in this group appears to be the calcium-channel blockers and angiotensin converting enzyme inhibitors. The treatment of the asthma sufferer with concomitant headache does not differ widely from the routine treatment of asthma. Beta2 -agonist drugs appear to be the drugs of choice and may cause fewer headaches than nonspecific betaagonists. Theophylline is a known trigger of headache and should be relegated to a secondary position in the asthmatic patient with migraine. Cromolyn sodium is particularly useful in atopic asthma and may have some beneficial effects in those migraine sufferers whose attacks are related to diet. 25 Peptic Ulcer Disease Featherstone lO reported that peptic ulcer disease is more common in headache sufferers than in nonheadache controls. In patients with cluster headache, the prevalence of peptic ulcer disease may be three times greater than in control populations. 6 Aspirin and NSAIDs should be used with caution in patients with peptic ulcer disease. Drugs that are used to treat peptic ulcer disease may occasionally trigger

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migrainc hcadaches. The H 2 -antagonist ranitidine caused a 3% incidence of headache and may exacerbate attacks in susceptible individuals. 7 Famotidine, a ncwer H 2 antagonist, causes a 4.7% incidence of headache. Headache due to cimetidine therapy is rare. For these reasons, the H 2-antagonist of choice in the headache suffercr appears to be cimetidine. Sucralfate and antacids arc also useful agents. in the treatment of peptic ulcer diseasc and do not cause an increase in headache. Somc tricyclic antidcpressant drugs, especially doxepin, have histamine-antagonist propertics and are useful in the treatment of peptic ulccr disease. Recurrent abdominal pain is a disorder of children that many consider to bc a migraine equivalent; it is somctimes called the recurrent syndrome. ' It is defined as recurrent abdominal pain with or without nausea and vomiting, associated fever, and autonomic symptoms such as pallor and sweating. A study by Amery and Forget' suggcsted that there is an increased gut permeability in children with recurrent syndrome. They feel that the increased permeability of the gut to certain noxious substances may explain the dietary triggers of migraine in select groups of patients. Obesity Obcsity is a major medical problem in the United States, with an estimated prevalence of between 25% and 45% in the population over the age of 30. 11 Problems that have been associated with obesity include degenerative joint disease, respiratory compromise, cardiomegaly, hypertension, diabetes mellitus, menstrual irregularities, gout, and fatty liver. Obesity is one of the most common concomitant disorders of hcadache sufferers. It is possible that societal attitudcs towards obesity may increase the psychological stresses of our obcse patients and further worsen their headache condition. Many drugs used in the treatment of headache may lead to incrcased appetitc and resultant wcight gain. Drugs that increase appetite include tricyclic antidepressants, monoamine oxidase inhibitors, valproic acid, and antihistamines such as cyproheptadine. In obesc paticnts or in patients who gain an unacceptable amount of weight from antidepressant drugs, thc antidepressant drugs of choice should be fluoxetine, trazadone, or bupropion. These drugs do not cause weight gain; in fact, fluoxetine may cause a mild weight reduction. Patients must also be encouraged to reduce caloric intake as well as to increase caloric expenditure through an exercise program in order to achieve optimal weight. SUMMARY The treatment of headache disorders in patients with concomitant medical illness constitutes one of the more challenging areas of headache therapy. As new agents are added to our pharmacologic armamentarium, it will become easier to tailor therapy to our patients. The physician who treats the headache paticnt with concomitant medical illness must be particularly aware of drug side effects and pharmacology in order to prevent a worsening of underlying medical conditions or an exacerbation of headaches. REFERENCES 1. Amery WK, Forget PP: The role of the gut in migraine: The oral 51-Cr EDTA test in recurrent abdominal pain. Cephalalgia 9:227-229, 1989 2. Askmark H, Lundberg PO, Olsson S: Drug-related headache. Headache 29:441-444, 1989

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3. Benedict CR. Robertson 0: Angina pectoris and sudden death in the absence of' atherosclerosis following ergotamine therapy for migraine. Am J Med 67:177-178. 1979 4. Cohn PF, Braunwald E: Chronic ischemic heart disease. In Braunwald E (ed): Heart Disease: Textbook of Cardiovascular Medicine, vol 2. Philadelphia, WB Saunders, 1984, p 1347 5. Dalessio DJ: Beta blockers and migraine. JAMA 252:2614, 1984 6. Diamond S, Solomon GO, Freitag FG: Cluster headache. Clin J Pain 3:171-176, 1987 7. Epstein CM, Klopper J: Ranitidine headache. Headache 25:392-393, 1985 8. Fanciullacci M, Spillantini MG, Michelacci S, et al: Pharmacological "enkephalinase" inhibitions in man. Adv Exp Med Bioi 198:153-160, 1986 9. Featherstone HJ: Headaches and heart disease: The lack of' a positive association. Headache 26:39-41, 1986 10. Featherstone HJ: Medical diagnoses and problems in individuals with recurrent idiopathic headaches. Headache 25:136-140, 1985 11. Fitzgerald FT: The problem of obesity. Annu Rev Med 32:221-231, 1981 12. Fournier JA, Fernandez-Cortacero J, Granado C, et al: Familial migraine and coronary artery spasm in two siblings. Clin Cardiol 9:121-127, 1986 13. Gamberini G, D'Alessandro R, Labriola E, et aI: Further evidence on the association of mitral valve prolapse and migraine. Headache 24:39-40, 1984 14. Gardner JW, Mountain GE, Hines EA: The relationship of migraine to hypertension headaches. Am J Med Sci 200:50-53, 1940 15. Grzelewska-Rzymowska I, Bogucki A, Szmidt M, et al: Migraine in aspirin-sensitive asthmatics: Allergol Et ImmunopathoI13:13-16, 1985 16. Gold MS, Pottash AC, Sweeney OR, et al: Opiate withdrawal using clonidine. JAMA 243:343-346, 1980 17. Haber E, Slater EE: High blood pressure. In Rubenstein E, Federman DD (eds): Scientific American Medicine, vol 8. New York, Scientific American, Inc., 1988, pp 130 18. Johansson BW: Migraine and the heart. Acta Med Scand 213:241-243, 1983 19. Johansson BW: Migraine: Effect of digoxin. J R Soc Med 75:215, 1982 20. Johnson ES, Ratclifl'e OM, Wilkinson M: Naproxen sodium in the treatment of migraine. Cephalalgia 5:5-10, 1985 21. Kuritzky A, Zehavi I, Appel S, et al: Cardiac arrhythmias in migraine: A 24-hour Holter study. Headache 25:161, 1985 22. Leviton A, Camenga 0: Migraine associated with hyper-pre-beta lipoproteinemia. Neurology 19:963-965, 1969 23. Miller 0, Waters DD, Warnica W, et al: Is variant angina the coronary manifestation of a generalized vasospastic disorder? N Engl J Med 304:763-766, 1981 24. Minervini MG, Pinto K: Captopril relieves pain and improves mood depression in depressed patients with classical migraine. Cephalalgia 7(suppl 6):485, 1987 25. Momo J, Carini C, BrostoffJ: Migraine is a food-allergic disease. Lancet 2:719-721,1984 26. Roose S, Glassman A, Giardina E, et al: Tricyclic antidepressants in depressed patients with cardiac conduction disease. Arch Gen Psychiatry 44:273-275, 1987 27. Solomon GD: Comparative efficacy of calcium antagonist drugs in the prophylaxis of migraine. Headache 25:368-371, 1985 28. Solomon GO, Kunkel RS, Frame J: Demographics of headache in elderly patients. Headache 30:273-276, 1990 29. Wayne VS: A possible relationship between migraine and coronary artery spasm. Aust NZ J Med 16:708-710, 1986 30. Ziegler OK: The treatment of migraine. In Dalessio DJ (ed): Wolff's Headache and Other Head Pain. New York, Oxford University Press, 1987, p 90

Address reprint requests to Glen D. Solomon, MD, FACP Department of Internal Medicine Cleveland Clinic Foundation 9500 Euclid Avenue Cleveland, OH 44195-5039