Headache is one of the most common complaints among patients presenting to an outpatient practice. Once secondary causes of headache are excluded and a primary headache diagnosis has been established, selecting appropriate pharmacotherapy can be a very complex process. Medications must be tailored to each patient’s unique combination of comorbidities and lifestyle considerations. In this chapter, treatment strategies for some of the more common primary headache disorders are reviewed. This discussion will focus on migraine, tension-type headache (TTH), and the trigeminal autonomic cephalalgias (TACs). Our discussion of TACs will include cluster headache, paroxysmal hemicrania, short-lasting unilateral neuralgiform headaches with conjunctival injection and tearing or autonomic features (SUNCT/SUNA), and hemicrania continua.

ABORTIVE MIGRAINE TREATMENT

Nonsteroidal anti-inflammatory medications (NSAIDs), triptans, dihydroergotamine, and antiemetics are the mainstays of abortive treatment for migraine headaches. Other commonly used, nonspecific analgesics include acetaminophen, aspirin, cyclooxygenase-2 inhibitors, opiates, and combination analgesics. In general, opiates and most combination analgesics are avoided due to the high potential for medication overuse headaches.

NSAIDs are some of the most commonly used and effective first-line agents for abortive migraine treatment. They can be used as monotherapy or in combination with other medications.^2,3 Commonly used NSAIDs include ibuprofen, naproxen sodium, diclofenac, ketoprofen, and ketorolac. These drugs are relatively inexpensive, readily available, and are available in a variety of administration routes. For example, intravenous ketorolac is often used in the emergency department setting, but it is also available in tablet form and as an intranasal spray. Renal toxicity is an important side effect with any NSAID, but extra caution should be exercised with ketorolac use. Diclofenac is available in tablet form, but it also comes in a powdered form for oral solution that has proven efficacy in acute migraine.⁴ In addition to nephrotoxicity, NSAIDs as a class are associated with dyspepsia and fluid retention. It is important to note that NSAIDs carry U.S. Food and Drug Administration Black Box warnings for cardiovascular risks, gastrointestinal ulceration, and bleeding risks. Despite these risks, moderate NSAID use is generally quite well tolerated.

Several different triptans are available for the treatment of migraines (Table 33-1). As a class of medications, the differences between oral triptans are relatively small, but the effects can vary among individual patients.⁵ When choosing a triptan, it is important to consider the formulary coverage and costs associated with an individual’s insurance plan. Sumatriptan, naratriptan, zolmitriptan, and rizatriptan are currently the only generic triptans on the market. Sumatriptan has been a generic medication longer than any other triptan and is almost universally the preferred triptan from an insurance coverage standpoint. Studies have demonstrated that triptan use decreases as copayment increases. In addition, demand for pharmaceuticals was relatively unchanged with copayment increases.⁶

If a triptan is tolerated, but only somewhat beneficial, this may be due to delayed administration. It has clearly been established that triptans tend to be more effective when taken during the early phase of migraine, and delays in administration can lead to significant reductions in efficacy.⁷ In clinical practice, some patients may report complete ineffectiveness of a triptan if administration is delayed for an excessive period of time. The ability of a triptan to terminate a headache can be enhanced by coadministration with an NSAID and/or an antiemetic. In addition to oral formulations, triptans are available in orally dissolving, intranasal, injectable, and needle-free subcutaneous delivery systems. These routes of administration may be particularly useful for migraine patients with early and prominent vomiting. In cases where sumatriptan is ineffective, switching to a different triptan or different formulation would be a reasonable approach.⁸

It is essential to warn patients that triptans often induce transient side effects, including chest or throat tightness, flushing, a hot sensation, dizziness, nausea, drowsiness, and tingling. Warning patients of these transient side effects can prevent patient anxiety related to future triptan use and may even prevent emergency department visits for what patients erroneously perceive to be an anaphylactic reaction. Triptans should be avoided in patients with a history of coronary artery disease, stroke, transient ischemic attack (TIA), and peripheral vascular disease. Other relative contraindications include uncontrolled blood pressure, smoking, hormone replacement, pregnancy, and breast-feeding (though some triptans, like eletriptan, are only minimally excreted in breast milk and may still be considered in the appropriate clinical setting). Triptans carry a very low risk of serotonin syndrome when used concomitantly with selective norepinephrine reuptake inhibitors (SNRIs), selective serotonin reuptake inhibitors (SSRIs), and/or tricyclic antidepressants. The use of these medications should not prevent appropriate patients from receiving treatment with triptans.⁹ However, patients should be warned of the symptoms of serotonin syndrome and should seek medical attention immediately if those symptoms occur.

In patients who fail to respond to NSAIDs and triptans, dihydroergotamine (DHE) is a reasonable option. DHE has similar contraindications to triptans, and pregnancy is an absolute contraindication to dihydroergotamine use. Due to poor bioavailability, DHE is not available in an oral form. It is, instead, available in intranasal, injectable, and intravenous formulations. Intravenous DHE is often used in the emergency department and inpatient settings for the treatment of status migrainosis. It commonly causes nausea, so most patients are pretreated with an antiemetic prior to dosing. Intravenous DHE administration requires close monitoring as rare, but serious, side effects include arterial spasm (sometimes resulting in limb necrosis) and myocardial infarction.

Antiemetics and neuroleptics have long been used alone or in combination with other drugs to treat acute migraine. Like NSAIDs, neuroleptics/antiemetics come in multiple different administration routes, enabling parenteral use in the emergency department as well as at home with oral or suppository formulations. The mechanism of action for most of these medications is primarily the dopamine D2 receptor antagonism, though other neurotransmitter systems are thought to be involved. This D2 receptor activity can help relieve migraine-associated nausea in addition to relieving the headache itself.^10,11 Orthostatic hypotension and sedation are potential side effects of the D2 antagonists. Extrapyramidal symptoms may also occur, including akathisia, parkinsonism, and acute dystonic reactions. With long-term use, tardive dyskinesia may also occur. Prochlorperazine, metoclopramide, and chlorpromazine are commonly used dopamine antagonists used in the treatment of acute migraine. Prochlorperazine is available in tablet, suppository, and parenteral forms. Metoclopramide is available in tablet and oral suspension. Chlorpromazine is available in tablet and parenteral forms. Promethazine is an antihistamine that is quite effective for the treatment of migraine-associated nausea, but little evidence supports its use in the treatment of migraine pain.¹² Although ondansetron has no pain-specific effect, it may be helpful in conjunction with other therapies.

PREVENTIVE MIGRAINE TREATMENT

Preventive medications should be considered in cases in which migraines occur with high frequency or significantly interfere with the patient’s level of function. Preventives should also be considered when abortive treatments are contraindicated, ineffective, poorly tolerated, or overused. There are several different classes of drugs used to prevent migraines (Table 33-2), which include beta-blockers (propranolol, atenolol, nadolol, metoprolol, timolol), calcium-channel blockers (verapamil), anticonvulsants (topiramate, divalproex sodium, gabapentin), and tricyclic antidepressants (amitriptyline, nortriptyline).