Headache in General Medical Conditions

Headache disorders are very common, and therefore they often co-exist with one or more significant medical illnesses. This pairing can complicate the diagnosis of both the headache disorder and general medical conditions, while raising a number of treatment conflicts. In patients with multiple complex medical conditions, management decisions can be difficult. However, if the clinician is armed with an understanding of the key features of common headache disorders as well as a good basic background in clinical pharmacology, a successful approach to managing headaches in these patients is possible. This chapter will summarize epidemiologic observations regarding the co-occurrence of headaches and medical illnesses, explore the ways in which medical illness and headaches co-exist, and describe specific considerations regarding treatment of headaches in particular medical disease states.

Association of Headache and General Medical Illness

Headache is the most common category of neurologic disease, and it has been estimated that around half of the world’s adult population have experienced head pain in the last 12 months. Therefore, the comorbidity of headache with other medical illnesses is not surprising. For example, migraine has significant comorbidity with asthma and allergic conditions such as rhinitis, food allergies, hay fever, and bronchitis ( Table 59-1 ). Migraine also seems to be more prevalent in people with gastrointestinal (GI) conditions such as peptic ulcer disease, hiatal hernia, and colitis, but the confounding factor of analgesic medication effects on the GI tract may complicate this relationship. There is suggestive evidence that hyperthyroidism and hypothyroidism are more commonly associated with migraine than would be predicted, and these patients should be screened for headaches at regular medical visits. All headache disorders are likely more prevalent in obesity, and worsening migraine frequency (“migraine chronification”) is more common in those who are obese. Among the autoimmune disorders, celiac disease, Raynaud phenomenon, and systemic lupus erythematosus (SLE) are comorbid with migraine, as are chronic fatigue syndrome and fibromyalgia.

Table 59-1

Medical Conditions in Which Headache Disorders Are More Common

Anemia

Asthma

Celiac disease

Chronic fatigue syndrome

Fibromyalgia

Human immunodeficiency virus (HIV) infection

Hyperthyroidism

Hypothyroidism

Leukemia

Malignant hypertension

Obesity

Chronic pulmonary disease

Raynaud syndrome

Renal failure

Chronic rhinitis

Systemic lupus erythematosus

Rheumatoid arthritis

Psychiatric disease including depression, anxiety, and bipolar affective disorder

Migraine, especially with aura, increases the risk of stroke, although evidence tends to be conflicting, with substantial differences seen across age groups and genders. There is no clear epidemiologic association between migraine and epilepsy, although spells of each can be mistaken for one another. Recent data suggest that migraine is an independent risk factor for developing multiple sclerosis, but the pathophysiology that would link these two conditions is uncertain. Psychiatric comorbidity with migraine and other headache disorders has long been noted and there do seem to be significant bidirectional risks in patients with anxiety, depression, and bipolar disorder. There is a well-established increased co-occurrence of headache disorders in patients with sleep disorders, with probable bidirectional causality, since pain certainly can disrupt sleep, and sleep deprivation is a common trigger for headaches. Interestingly, little evidence exists for a higher prevalence of migraine in people with hypertension despite this common belief. There is an unclear association between migraine and ischemic heart disease, with the best evidence for an association being found in young women and in those who have migraine with aura. The association between migraine and patent foramen ovale (PFO) has been noted, especially in patients with migraine with aura, although there is no evidence that PFO closure improves the severity or frequency of migraine.

In children, similar associations between headache disorders and medical illness have been noted. In particular, depression, anxiety, and sleep disorders are more common in children and adolescents with migraine and there does seem to be, unlike in adult populations, an increase in headache disorders in patients with epilepsy. In children and adolescents, attention deficit hyperactivity disorder (ADHD) and Tourette syndrome are comorbid with migraine, as are PFO, cardiovascular disease, and stroke.

Underlying mechanisms by which medical illnesses might cause headaches include: (1) activation of dormant migraine or other primary headache disorders; (2) production of painful cranial or pericranial inflammation as a component of the underlying medical condition; (3) irritation or compression of cranial or pericranial nociceptive nerves; and (4) medication or other treatments causing headache as an adverse effect ( Table 59-2 ).

Table 59-2

Common Medications and Substances Known to Cause Headache

Alcohol

Amantadine, levodopa

Antihypertensive medications including nifedipine, enalapril, hydralazine

Carbon monoxide

Cyclophosphamide

Estrogen, progesterone, tamoxifen

Food additives (monosodium glutamate, aspartame)

Illicit drugs including cocaine, marijuana, amphetamines

Interferons

Interleukin inhibitors

Monoamine oxidase inhibitors (e.g., phenelzine)

Nitric oxide donors (e.g., isosorbide, nitroglycerin)

Nonsteroidal anti-inflammatory analgesics (NSAIDs)

Phenothiazines

Pseudoephedrine, sympathomimetics

Ranitidine, famotidine, cimetidine

Selective serotonin reuptake inhibitors

Sildenafil, vardenafil, tardalafil

Tetracyclines, trimethoprim

Theophylline

Medication overuse of opioids, barbiturates, NSAIDS, simple analgesics, and combinations such as aspirin, acetaminophen

Substance withdrawal from opioids, barbiturates, benzodiazepines, cannabis, caffeine, estrogen

In the other causal direction, headache conditions can lead to or exacerbate medical illnesses via the use (or overuse) of medications employed in preventing or alleviating headache attacks. Examples include nonsteroidal anti-inflammatory drugs (NSAIDs) leading to GI irritation, ulceration, and bleeding; corticosteroid-induced complications such as bone necrosis; exacerbation of vascular disease by ergot medications; worsening of asthma by β-blockers; renal and hepatic toxicity from a number of headache prophylactic medications; and dependency and addiction to opioids and other analgesics. Medication interactions that result from simultaneously treating headache and general medical disorders are also common and can lead to systemic illness. Headache disorders can lead to a deterioration in general health by reducing activity, worsening sleep function, limiting social involvement, and causing financial stress.

Specific Medical Diseases and Headaches

Cardiovascular Disease

Patients with coronary artery disease commonly experience headaches as a consequence of vasodilating medications used for cardiovascular benefit. Attempting to reduce the dose and frequency of these drugs can improve headache control. Treating primary headache disorders in patients with cardiovascular disease poses unique challenges. Ergots are contraindicated due to their vasoconstrictive effects, which are especially prominent in patients with co-existing peripheral vascular disease. NSAIDs used for headache can reduce the benefits of antithrombotics used to treat coronary artery disease and may also lead to an increased risk of myocardial infarction via unclear mechanisms.

A number of medications used in headache management can prolong the QT interval, leading to a risk of torsade de pointes. Commonly used agents in headache treatment that share this propensity include tricyclic antidepressants, dopamine blocking agents (including prochlorperazine, metoclopramide, chlorpromazine, and promethazine), and ondansetron. Patients with a tendency for palpitations and tachyarrhythmias should probably avoid tricyclic antidepressants, and patients with bradyarrhythmias should avoid β-blockers. All patients with cardiac conduction issues should use β-blockers and calcium-channel blockers carefully and only after careful consideration by their cardiologist. In the appropriate patient, β-blockers may be useful for both migraine prophylaxis and angina reduction.

A headache type termed “cardiac cephalalgia” is a relatively rare but important entity, as it can signal the onset of acute coronary disease. The mechanism for the head pain is not clear, although it is perhaps related to an unusual pattern of referred pain. The headache is notable that it resolves with antianginal medication.

Approximately 25 percent of the population has a PFO and the prevalence seems to be nearly double that in patients with migraine. Larger PFOs are found in persons who experience migraine with aura compared with those without aura. Based on observational data showing improvement in migraine following PFO closure for other reasons, it was suggested that PFO closure could help in preventing migraine attacks. However, a randomized controlled study examining PFO closure for migraine was negative, and people with migraine and PFO should not use closure as a means of controlling their headache frequency.

Hypertension

While hypertension alone seems not to be associated particularly with headache disorders, rapidly rising and malignant hypertension is commonly accompanied by head pain, reported by some to be posteriorly predominant. The presence of this headache can serve as an early indication for more aggressive blood pressure control to prevent hypertensive complications such as hypertensive encephalopathy, which itself is virtually always accompanied by headache in awake, communicative patients. The very small number of severely hypertensive patients who harbor an underlying pheochromocytoma will also commonly present with headaches, often highly unresponsive to treatment.

In hypertensive patients, posterior reversible encephalopathy syndrome can occur from the blood pressure rise itself, and the initial presentation may include, or even be limited to, headache. A possibly related condition, reversible cerebral vasoconstriction syndrome (RCVS) can occur in a number of settings including pregnancy and typically presents with one or more sudden severe thunderclap headaches. RCVS is diagnosed using noninvasive imaging which typically reveals multiple areas of intracerebral arteriolar narrowing, often with evidence of focal, cortical subarachnoid hemorrhage.

Some antihypertensive medications can be very useful in preventing migraine, including propranolol, atenolol, and nadolol. Angiotensin-converting enzyme inhibitors do not have significant antimigraine properties, but the angiotensin receptor blocker candesartan can be an efficient agent for patients with both hypertension and migraine. Verapamil and amlodipine are particularly useful in limiting cluster headache attacks, although the dosage used must often be high. Some antihypertensives have the tendency to worsen headaches, including the calcium-channel blocker nifedipine and some of the angiotensin-converting enzyme inhibitors. Treatment with triptans is contraindicated in patients with severely elevated blood pressure as they can worsen hypertension, but they are considered to be generally safe in hypertensive patients with good blood pressure control by medications.

Cerebrovascular Disease

It has long been known that headache can be a common presentation for stroke, both ischemic and hemorrhagic, in addition to more traditional focal neurologic symptoms and signs. A vexing problem is the distinction between migraine aura with minor or no headache and transient ischemic attack (TIA). Positive visual phenomena are the most common migraine aura and include scintillations, oscillating “zig-zag” lines, and wavy vision; this presentation is rare in TIA. In some elderly patients with visual phenomena from migraine, there may be no history of headache, a condition termed “late-life migrainous accompaniments.” While transient sensory loss, aphasia, and hemianopic loss of vision are common TIA symptoms, they also can occur as part of a migraine aura. Some of these patients are misdiagnosed as having a stroke and are commonly treated as such with the intravenous administration of thrombolytics. A progression of sensory changes beginning distally and progressively moving centrally is very suggestive of migraine aura rather than stroke, as is the short duration of most auras, which usually last less than 30 minutes. Motor auras are quite rare in migraine, and can be compelling for a TIA diagnosis. Monocular vision loss is extremely unlikely in migraine.

In patients with a history of stroke who require acute migraine treatment, ergots are contraindicated, as they are in cardiovascular and peripheral vascular disease. Triptans, as weak vasoconstrictors, are generally considered contraindicated in patients with cerebrovascular disease, but this concern is probably exaggerated and not supported by strong evidence.

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