US Pharm. 2018;43(3):HS2-HS8.

ABSTRACT: Headache disorders are one of the most common reasons that patients present to the emergency department (ED). For proper patient care, it is vital for the headache to be differentiated as a primary or secondary headache disorder. Primary headaches are more common than secondary headaches; however, secondary headaches are potentially life-threatening, whereas primary headaches possess straightforward treatment regimens and benign long-term outcomes. Classifying primary headaches as tension-type, cluster, or migraine headache with or without aura will guide pharmacotherapy selection in the ED setting. The pharmacist can impact the clinical management of headache disorders by providing effective medication counseling, ensuring that the medication regimen has the appropriate indication and route, and monitoring for adverse effects of treatment.

Headache is one of the most frequent causes of presentation to the emergency department (ED). It is estimated that nearly 50% of adults worldwide are affected by headache disorders, making headaches the most prevalent pain disorder.1 In the United States, headache is the fifth leading cause of ED visits, accounting for an estimated 5 million visits annually.2 The majority of headaches presenting to the ED are primary headache disorders (tension-type, cluster, and migraine headaches). Overall, tension headaches are the most common type, cluster headaches are the least common type, and migraine headaches are the most disabling.1 Migraine headaches are the most frequent headache type to present to the ED, and they are responsible for approximately $17 billion in direct and indirect healthcare costs annually in the U.S.3

Primary Versus Secondary Headache Disorders

Patients presenting to the ED with a complaint of headache should be assessed, and differentiation should be made between common primary and potentially life-threatening secondary headaches.

As discussed earlier, primary headache disorders include tension-type, cluster, and migraine (with and without aura) headaches. Secondary headache disorders include headaches attributed to any of the following: head or neck trauma; cranial or cervical vascular disorder; nonvascular intracranial disorder; substance use or withdrawal; infection; disturbance of homeostasis; psychiatric disorder; and (along with facial pain) disorders of the cranium, neck, eyes, ears, nose, sinuses, teeth, mouth, or other facial or cranial structures.1,4 Medication overuse headache is a secondary headache disorder that is a consequence of regular overuse of acute headache treatment options. Acute and abortive agents used to treat headaches should be limited in order to prevent medication overuse headaches.

Differentiating potentially dangerous, life-threatening headaches from benign, low-risk primary headaches is critical. Low-risk headaches do not require neuroimaging.5 Criteria for low-risk headache classification include age <30 years; features similar to those of other primary headaches; history of similar headaches; absence of abnormal neurologic findings; no changes in usual headache presentation; lack of high-risk comorbid disease states; and no red-flag signs and symptoms.5

Red-flag signs and symptoms indicate potential serious underlying pathology for the patient’s headaches and signal the need for neuroimaging or other tests for headache evaluation.5 The following are red-flag signs and symptoms: focal neurologic signs (not typical aura); age >50 years; rapid onset; papilledema; neck stiffness; immunocompromised state; headache pain worsened by exertion; no similar headache history; concomitant infection; altered mental status or seizure; visual disturbances; family history of subarachnoid hemorrhage; certain medications (e.g., anticoagulants, glucocorticoids, nonsteroidal anti-inflammatory drugs [NSAIDs]; analgesics (which mask severe symptoms); illicit drugs (e.g., cocaine, methamphetamine); and toxic exposure (i.e., carbon monoxide poisoning).5

Differentiating Primary Headache Disorders

The ability to differentiate common primary headache disorders is crucial to proper treatment of the headache. The International Headache Society has created a classification system and diagnostic criteria for headache disorders. An assessment of the patient’s presenting signs and symptoms will help guide the pharmacotherapy decision-making process.

Tension-Type Headache: Tension-type headaches are the most common primary headache, affecting approximately 40% of the adult population worldwide.1,6 Women experience tension-type headaches slightly more than men do, with onset usually before age 20 years and peaking between ages 20 and 50 years.7 Diagnostic criteria for tension-type headache include mild-to-moderate bilateral pain characterized as dull, nonpulsating tightness or pressure; absence of nausea, vomiting, and aura; mild or absent phonophobia and photophobia; and headache not worsened by exertion.4

Cluster Headache: Cluster headache is the least common (1% of adults), but most severe, primary headache disorder; an estimated 500,000 people experience them in their lifetime.1,8 Cluster headache develops after the age of 20 years and affects more men than women. Diagnostic criteria include severe or excruciating unilateral pain, sudden onset, absence of aura, and attacks occurring in clusters of episodes lasting days to weeks; additionally, each headache episode lasts 15 to 180 minutes and is accompanied by ipsilateral autonomic symptoms (e.g., conjunctival lacrimation, nasal congestion, rhinorrhea, eyelid edema, facial sweating, miosis, restlessness, or agitation).4 Comorbid conditions associated with cluster headache include depression (24%), sleep apnea (14%), restless legs syndrome (11%), and asthma (9%).9

Migraine Headache: The usual onset for migraine headaches occurs from age 10 to 14 years; these headaches usually continue until age 35 to 39 years and then gradually decline.10 Migraines affect 10% of adults (18% of women and 9% of men) in the U.S.1,11,12 Migraine headaches, which account for 1.2 million ED visits each year, may present with or without aura; approximately 30% of migraineurs experience aura. Aura, which occurs within 60 minutes of migraine onset, warns the patient that a migraine may soon follow. Characteristics of migraine headaches with and without aura are presented in TABLE 1.4

Treatment Overview

The most important treatment outcome in patients with headache disorders is relief of symptoms (e.g., pain, nausea, vomiting). The ideal medication should provide rapid and sustained symptom relief, cause minimal or no adverse effects, and allow the patient to return to normal activities of daily living.13 The treatment regimen comprises acute agents for current treatment of the headache and agents for the prevention of future headaches. In the ED, the main focus is on treating the presenting problem. Preventive treatment for primary headache disorders will not be discussed in this article unless it is applicable to the ED setting.

Treatment of Tension-Type Headache: Tension-type headache is the most common primary headache, but the pain usually is mild. This leads to patient self-diagnosis and self-treatment with OTC medications. The sooner after onset a tension-type headache is treated, the more effective the agent is at aborting the headache. Owing to successful self-treatment, the vast majority of these headaches do not present to the ED. First-line acute treatment options for tension-type headaches include acetaminophen, ibuprofen, naproxen sodium, ketoprofen, and diclofenac.14,15 ED treatment recommendations have limited evidence, but options include IM ketorolac, parenteral chlorpromazine with or without diphenhydramine, and metoclopramide with or without diphenhydramine (TABLE 2).16-19 The most common side effects of chlorpromazine and metoclopramide are drowsiness, orthostatic hypotension, and akathisia. Coadministration of diphenhydramine helps reduce the risk of akathisia. Metoclopramide, which is Pregnancy Category B, should be the agent of choice in this situation. Triptans, opioids, and muscle relaxants have no role in the treatment of tension-type headaches.

Treatment of Cluster Headache: Because cluster headache attacks have a rapid onset and peak quickly, treatment options with a quick onset are necessary. Treatment options should involve the nonoral route, as the onset of action for the oral route is insufficiently rapid for of cluster headache. Acute therapy is useful in treating the current headache, but it does not reduce the duration of the entire cluster headache attack. For this reason, a preventive agent should be started in the ED.20

The first-line treatment options for cluster headaches include inhaled 100% oxygen (15 minutes), sumatriptan SC, sumatriptan intranasal (IN), and zolmitriptan IN (TABLE 3).21 Oxygen should be avoided in patients with severe chronic obstructive pulmonary disease. Oxygen alone may be completely effective in some patients, but most patients require a combination of oxygen and an SC or IN triptan for complete relief. An IN triptan should be administered in the nostril contralateral to the pain.21 There is no evidence supporting the use of oral triptans to treat cluster headache.

Treatment of Migraine Headache: When a patient presents to the ED with a migraine headache, he or she has more than likely exhausted self-treatment options (e.g., OTC medications, acute oral prescription medications) and should be evaluated for alternative routes of administration (e.g., parenteral, IN). Migraine attacks should be treated as early as possible, before symptoms become severe; this practice is associated with greater efficacy than delayed treatment administration. When a medication regimen is being selected for migraine treatment, the patient’s previous experience with a particular medication and the risk of adverse effects should be the most important considerations.13 There are no treatment differences between migraines with and those without without aura.

Three medication classes are considered first-line treatment options for acute migraine headaches: antidopaminergics, triptans, and NSAIDs.11,13 Significant evidence supports the use of antidopaminergics as monotherapy for acute migraine treatment. These medications not only provide headache relief, they also treat the migraine-related nausea and vomiting. Unfortunately, the exact mechanism of action is unknown at this time. Effective agents in this class include parenteral metoclopramide, prochlorperazine, and chlorpromazine (TABLE 4).11,13 In pregnant patients, metoclopramide is the agent of choice because of its favorable pregnancy rating. All three agents have the potential to cause akathisia (this may occur in one-third of patients), drowsiness, and orthostatic hypotension.22 To prevent akathisia, a slower rate of administration may be implemented, diphenhydramine may be coadministered, or both.

Triptans, specifically SC and IN sumatriptan and IN zolmitriptan, are considered first-line options for acute migraine treatment (TABLE 4).11,13 Triptans, which are serotonin 5-HT1B/1D receptor agonists, lead to vasoconstriction, decrease nociceptive transmission in the trigeminal pathway, and inhibit vasoactive peptide release.11,19 Common side effects of triptans include noncardiac chest pain, flushing, paresthesias, and worsening of headache. Triptans are contraindicated in pregnancy, previous myocardial infarction, ischemic stroke, Prinzmetal angina, and ergotamine use within the past 24 hours. Up to two-thirds of patients receiving SC sumatriptan report headache recurrence within 24 hours.23 Based on the side-effect profile, contraindications, and lack of efficacy, triptan use for acute migraine treatment in the ED has limited value.

Ketorolac has parenteral formulations, making it the NSAID of choice for acute migraine treatment in the ED setting in the U.S.11 Ketorolac may be administered IV or IM and for a maximum therapy duration of 5 days (TABLE 4).19 Ketorolac may be combined with triptans or antidopaminergic agents for acute migraine relief. Side effects associated with ketorolac include acute kidney injury, nausea, and dyspepsia. NSAIDs should be avoided in renal insufficiency, severe asthma, and active peptic ulcer disease. Other parenteral NSAID formulations are available; however, there is a lack of evidence for their efficacy in acute migraine treatment. NSAIDs are generally a safe and well tolerated option for acute migraine treatment.

Other options are available for acute migraine treatment, but they possess less evidence or efficacy for successful migraine treatment. Magnesium has not shown consistent treatment success. Ergotamines have been surpassed by other available agents for acute treatment, owing to their side-effect profile and lack of superiority over the agents discussed earlier. IV fluids are particularly helpful in patients with dehydration and/or nausea and vomiting. Parenteral opioids, the most common class of medications used for acute migraine treatment in the ED setting, are used in approximately 50% of all migraine visits.11,24 Opioids have been linked to repeat ED visits, reduced effectiveness of first-line acute migraine treatment options, increased recurrence rates of migraines, and poor treatment outcomes.25 Opioids are not as effective for acute headache treatment compared with other acute headache agents (i.e., triptan, antidopaminergics, dihydroergotamine, ketorolac).26 Opioids are further complicated by the potential for developing tolerance, addiction, overdose, and dependence. As a result, opioids should considered a last resort for acute headache relief.

Before discharge from the ED, patients with migraine headaches should be administered parenteral dexamethasone (TABLE 4). The addition of dexamethasone to the regimen does not treat the current migraine, but it has been found to reduce rates of migraine recurrence within 72 hours of ED discharge. Approximately two-thirds of migraine patients discharged from the ED will experience headache recurrence within 24 hours of discharge.27 For preventing headache recurrence, IV dexamethasone was found to have a number needed to treat of 9.28 Oral dexamethasone was not studied.

The Pharmacist’s Role

The pharmacist plays an important role in the treatment and management of headache disorders presenting in the ED. Pharmacists can use their expert knowledge of medications to evaluate a patient’s current medication regimen for a potential headache etiology and provide appropriate pharmacotherapy recommendations based on patient-specific factors and headache-disorder classification. The pharmacist can also provide insight and patient counseling to help prevent, or reduce the risk of, medication overuse headaches in the future. A pharmacist can also have an impact on the overprescribing of opioids for headache disorder treatment. Pharmacists should possess the knowledge to help persuade providers not to use opioids for headache disorder treatment unless it is specifically indicated.


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