Headaches in Patients with Coexisting Medical Disease

Vincent Martin

Markus Farkkila

INTRODUCTION

Headache disorders may coexist with a variety of common diseases such as hypertension, diabetes, and asthma or rare diseases such as temporal arteritis and polycythemia vera. Coexisting disorders may be the cause of the underlying headache disorder or bear no relationship to it. Their presence, however, may significantly affect the management of the underlying headache disorder. The purposes of this chapter are to (1) describe the prevalence and clinical significance of coexisting diseases within the headache patient and (2) review the use of headache medications in those with coexisting medical disorders.

PREVALENCE

Most of the large epidemiologic studies defining the prevalence of coexisting headache disorders have been conducted within cohorts of migraine patients. Diseases such as hypertension, coronary artery disease, arrhythmias, and mitral valve prolapse have a similar prevalence between migraine and nonmigraine patients. Other diseases such as cerebrovascular accidents, epilepsy, allergic diseases, asthma, depression, anxiety, panic disorder, and bipolar disorder are more common in migraine patients (14). The most prevalent diseases that coexist with migraine patients include hypertension (7 to 29%), asthma (13%), obesity (12%), and hypercholesterolemia (3 to 33%) (6,7,10).

Certain diseases may be more common in those with chronic daily headache than episodic headache disorders. Allergic disease, asthma, hypertension, and hypothyroidism were more common in those with chronic migraine when compared with episodic migraine in a study conducted in a headache-clinic population (4). The presence of obesity may also increase the likelihood of progression of episodic headache disorders to their more severe and refractory chronic forms (16). These studies could suggest that these disorders may play an important role in the “chronification” of headache disorders.

CLINICAL SIGNIFICANCE

The clinical significance of coexisting diseases depends upon their effect on the headache disorder and/or its treatment. They could affect a headache disorder in the following ways: (1) the disease or its treatment could be the cause of the headache syndrome; (2) the disease or its treatment could modulate the frequency, severity, duration, or disability of an existing headache disorder without being a causative factor; (3) the presence of the disease or its treatment could influence the choice of abortive or preventative medications in the headache patient; or (4) the use of headache medications could lead to drug interactions with those used to treat the coexisting medical disease.

DISEASES ASSOCIATED WITH HEADACHE

A number of medical diseases have been associated with the development of headache disorders and have been discussed elsewhere in this book. Medical diseases could theoretically lead to headaches through a direct or indirect effect on the trigeminal vascular pain pathways. Those diseases with a direct effect are located within the brain, meninges, dural sinuses, and intra- or extracranial arteries; most of these structures are innervated by the trigeminal nerve and pathologic processes directly activate trigeminal nociceptors. Those with an indirect effect reside distant from the head and neck and likely produce headache through their release of cytokines/hormones or
alterations in serum oxygen saturations, electrolytes, viscosity, or hemoglobin concentrations. Others induce a secondary disease that produces headache. Examples include a hypercoagulable state leading to a thrombotic event causing headache, thrombocytopenia leading to an intracerebral hemorrhage, or a disease predisposing to intracranial hypertension.

MEDICATIONS ASSOCIATED WITH HEADACHE

A variety of medications have been associated with the development of headaches and have been discussed elsewhere. The mechanisms through which medications produce headache are not completely known. Postulated mechanisms include alterations in neurotransmitter systems (e.g., selective serotonin reuptake inhibitors, nitrates, L-DOPA, monoamine oxidase inhibitors, phenothiazines), direct neurotoxicity (e.g., cyclosporin), induction of a hypercoagulable state (e.g., estrogen, tamoxifen), potent vasoditation (e.g., nifedipine, hydralazine, minoxidil), release of cytokines (e.g., interferons, interleukin-2, monoclonal antibodies, OKT3), and production of a chemical meningitis (nonsteroidal anti-inflammatory drugs [NSAIDs], sulfa drugs).

MEDICATION USE AND COEXISTING MEDICAL DISORDERS

Medication use in the headache patient may be influenced by coexisting medical illnesses. Specific disorders such as renal or hepatic diseases may alter the metabolism or excretion of medications used to treat the headache patient. The pharmacokinetics of medications may also change in the geriatric patient. Some medications must be avoided altogether in patients with particular coexisting diseases. Beta-blockers may need to be avoided in those with asthma, and valproic acid should not be used in those with hepatic disease.

Medication use in those with coexisting medical diseases is often complicated by the potential for drug interactions. Most of the significant drug interactions involve the cytochrome (CYP) P450 metabolic pathways. Certain headache and psychiatric medications are substrates, inducers, or inhibitors of these metabolic pathways (Table 138-1). The coadministration of inducers or inhibitors of CYP pathways could alter the serum levels of substrates. An inducer would decrease serum levels of the substrate while an inhibitor would increase its levels. Headache medications that are inducers or inhibitors could pose a particular risk to patients receiving other substrate medications used to treat coexisting medical disorders. This is particularly true for medications with a narrow therapeutic index such as those used in oncologic, transplant, and human immuno deficiency (HIV) patients (discussed below). Alternatively, medications used to treat coexisting diseases that are inducers or inhibitors could alter levels of headache medications, leading to decreased efficacy or increased toxicity.

SPECIFIC DISORDERS AND POPULATIONS

Medical disorders may complicate the management of patients with headache disorders. In this section we will discuss the potential drug interactions that can occur between headache medications and those used to treat the coexisting disease. We will also review how coexisting medical disease influences our choice of headache medications.

Cancer and Chemotherapeutic Agents

There are a number of significant drug interactions between chemotherapeutic agents and headache medications. Many of the chemotherapeutic agents are substrates for cytochrome P450 pathways, and interactions typically involve these metabolic pathways. Headache medications that are inducers would lower serum concentrations of the chemotherapeutic agent, reducing their effectiveness, and inhibitors would increase levels, resulting in greater toxicity (22). Chemotherapeutic agents may also act as inducers or inhibitors for headache medications that are listed as substrates for CYP pathways (Table 138-2). Renal excretion of methotrexate may be reduced by NSAIDs, resulting in severe toxicity, and therefore this combination should be avoided (24).

Cardiovascular Diseases

Coronary artery disease can influence management of the headache patient. The triptans and ergots would be contraindicated in those with known coronary artery disease because of their propensity for mild vasoconstriction. Nonsteroidal anti-inflammatories (NSAIDs) that are nonselective cyclo-oxygenase (COX) inhibitors such as ibuprofen should be used cautiously because they could counteract the antiplatelet effects of aspirin (5). There is also evidence that some selective COX-II inhibitors may be prothrombotic, but these results remain highly controversial (11). Beta-blockers or calcium channel blockers would be a good choice for a migraine preventative because they may treat both the angina and migraine headaches.

The presence of sick sinus syndrome would lead to the avoidance of medications that depress atrioventricular nodal function (e.g., beta-blockers, some calcium channel blockers). Medications that produce arrhythmias
(e.g., tricyclic antidepressants) should not be used in those with ventricular tachycardia.

TABLE 138-1 Cytochrome P450 Metabolic Pathways of Common Headache and Psychiatric Medications

*Enzymes*	*Substrates*	*Inducers^	*Inhibitors^
CYP 1A2	Anticonvulsants: carbamazepine	Carbamazepine, phenobarbital, phenytoin	Fluvoxamine
	Antidepressants: amitriptyline, clomipramine, imipramine, fluvoxamine, mirtazapine	Carbamazepine, phenobarbital, phenytoin
	Antipsychotics: haloperidol, clozapine, olanzapine
	Triptans: frovatriptan
CYP 2B	Anticonvulsants: diazepam (?)	Phenobarbital, phenytoin	Fluoxetine, fluvoxamine
CYP 2C8	Anticonvulsants: carbamazepine, phenytoin	Phenobarbital
CYP 2C9	Anticonvulsants: diazepam, phenobarbital (?), henytoin, valproic acid	Carbamazepine (?), phenobarbital, phenytoin	Valproic acid, zonisamide
	NSAIDs: diclofenac, ibuprofen, naproxen, piroxicam	Carbamazepine (?), phenobarbital, phenytoin	Valproic acid, zonisamide
	Antidepressants: amitriptyline, clomipramine, imipramine, citalopram, moclobemide		Oxcarbazepine, topiramate, valproic acid (?), zonisamide (?), fluvoxamine
	Beta-blockers: propranolol
CYP 2E1	Anticonvulsants: phenobarbital, valproic acid	None	Zonisamide (?)
CYP 2D6	Antidepressants: amitriptyline, clomipramine, imipramine, desipramine, nortriptyline, trazodone, fluoxetine, paroxetine, citalopram, venlafaxine, mianserin, mirtazapine	None	Fluoxetine, paroxetine, perphenazine, thioridazine
	Antipsychotics: thioridazine, perphenazine, zuclopenthixol, haloperidol, risperidone, clozapine, olanzapine, sertindole		Fluoxetine, paroxetine, perphenazine, thioridazine
	Beta-blockers: alprenolol, Bufuralol, metoprolol, timolol, pindolol
	Opiates: codeine, dextromethorphan
CYP 3A4	Anticonvulsants: carbamazepine, diazepam, phenobarbital, tiagabine, zonisamide	Carbamazepine, dexamethasone, phenobarbital, phenytoin, topiramate	Cardizem, fluoxetine, fluvoxamine, verapamil, nefazodone, valproic acid (?)
	Antidepressants: amitriptyline, clomipramine, imipramine, trazodone, sertraline, nefazodone, mirtazapine
	Antipsychotics: haloperidol, clonazepam, risperidone, quetiapine, sertindole
	Ergots: dihydroergotamine, ergotamine, methergine
	Narcotics: methadone
	Triptans: eletriptan
Adapted with permission from (22) Vecht C, Wagner L, Wilms E. Interactions between antiepileptic and chemotherapeutic drugs. Lancet Neurol 2003;2:404-409; and (19) Spina E, Scordo M, D’Arrigo C. Metabolic drug interactions with new psychotropic agents. Fund Clin Pharm 2003;17:517-538.
^*Inducers would lower serum concentrations of the substrate medications, reducing their effectiveness, and inhibitors would increase levels, resulting in greater toxicity.
CYP, cytochrome; NSAIDs, nonsteroidal anti-inflammatory drugs.