Clinical manifestations

Presentation and course

Status migrainosus, by definition, must occur in a patient with underlying diagnosis of migraine. Therefore, physicians should review the patient’s history for symptoms of migraine as part of the diagnostic process.

Typically, patients with status migrainosus report a headache that is similar to their usual migraines (with or without aura) with the exception of prolonged duration of pain and associated symptoms (eg, nausea, vomiting, photophobia, phonophobia, osmophobia) with refractoriness to their usual treatments. Precipitants of status migrainosus include medication overuse, menstruation/other hormonal changes, stress, dietary factors (eg, alcohol intake or fasting), anxiety, and depression. A review of possible triggers is warranted to aid diagnosis and treatment.

In those with migraine with aura, the aura itself should be similar to the patient’s usual auras; entirely new or prolonged auras different from the patient’s usual experiences should warrant further investigation into potential secondary causes (eg, seizure, intracranial mass, stroke). Pain that is drastically different in character or quality from patients’ usual migraines should always raise the clinician’s suspicion for secondary causes of headache.

When an attack of migraine headache lasts more than 72 hours, it is defined as status migrainosus. When it lasts much longer, it may become designated as chronic (previously known as transformed) migraine. In this process of transformation, headache frequency increases, and the historical characteristics used to differentiate migraine from episodic tension-type headache diminish as pain intensity and associated migrainous features become less prominent. No clear distinction is made between chronic migraine and prolonged status migrainosus because no upper time limit is given to status migrainosus. Both are intractable headaches and are often associated with abortive medication overuse and comorbid psychological conditions.

Patients seeking medical care during a bout of status migrainosus have typically exhausted first-line home-based treatments without response and require a higher level of care.

Prognosis and complications

With adequate treatment, most patients with status migrainosus can achieve pain reduction.

When an attack of migraine headache lasts more than 72 hours, it is defined as status migrainosus. When it lasts much longer and occurs on greater than or equal to 15 days of the month for more than 3 months, it is designated as chronic migraine (Table 2). No clear distinction is made between chronic migraine and prolonged status migrainosus because no upper time limit is given to status migrainosus. Both are intractable headaches and are often associated with social/occupational impairment.

The yearly rate of transformation from episodic to chronic migraine has been estimated to be approximately 2.5%, with risk factors of high baseline attack frequency, older age, obesity, stressful life events, mood disorders, and use of certain medications such as barbiturates and opiates (05; 48; 57). Patients with chronic migraine are more likely to suffer socioeconomic impacts, more psychiatric and medical comorbidities, reduced quality of life, and lower social and occupational function (52).

Status migrainosus and chronic migraine are the most frequent complications of migraine, but other rare complications include persistent aura without infarction, migrainosus infarction, and migraine aura-triggered seizure.

Table 2. International Classification of Headache Disorders 3rd Edition Diagnostic Criteria for Chronic Migraine

Description: Headache occurring on 15 or more days per month for more than 3 months, which, on at least 8 days of month, has the features of migraine headache.
Diagnostic criteria:
A. Headache (migraine-like or tension-type-like) on ≥15 days per month for >3 months, and fulfilling criteria B and C
B. Occurring in a patient who has had at least 5 attacks fulfilling criteria B to D for 1.1 migraine without aura and/or criteria B and C for 1.2 migraine with aura
C. On ≥ 8 days per month for > 3 months, fulfilling any of the following:
	1. Criteria C and D for 1.1 Migraine without aura
	2. Criteria B and C for 1.2 Migraine with aura
	3. Believed by the patient to be migraine at onset and relieved by a triptan or ergot derivative
D. Not better accounted for by another ICHD-3 diagnosis

Clinical vignette

A 33-year-old woman presented to the local emergency department with a severe right-sided headache for the past 4 days associated with nausea and repeated vomiting.

Sumatriptan injections, which usually successfully treat her headaches, only provided temporary reduction of pain and the over-the-counter medication did not help at all. Her last sumatriptan injection was 36 hours prior to arrival in the emergency department.

She has a history of episodic headaches that usually occur near menstruation and are accompanied by nausea, vomiting, photophobia, and phonophobia. This headache is typical of her usual headaches, but of longer duration and increased severity. Her father died in the past week, and she has had poor sleep and increased level of stress surrounding this event.

A thorough neurologic examination and a head CT were normal. The patient was treated with intravenous dihydroergotamine and metoclopramide. Her headache subsided, and she was sent home the next morning.

Comment. This is a fictitious case.

Biological basis

Etiology and pathogenesis

Status migrainosus is 1 of the many clinical manifestations of migraine disorder and its etiology is related to the underlying causes of migraine itself. Migraine is a polygenetic syndrome with non-Mendelian inheritance and significant gene-environment interactions (70). A comprehensive review of the pathogenesis of migraine is provided in a separate MedLink Neurology article on migraine. Here, the discussion is focused on status migrainosus.

An internet-based survey of migraineurs’ self-reported migraine triggers showed factors of stress, lack of sleep, diet, hormonal changes, and other environmental factors as triggers for increased migraines (Migraine in America 2012).

Patients with frequent or severe headache are at risk for escalating use of analgesics, opioids, ergotamine, or a combination thereof, which can lead to medication overuse headache (MOH). There is no universal threshold at which individual patients may develop medication overuse headache. As a general guideline, nonspecific analgesics should be kept to less than or equal to 15 days of the month, and triptans should be limited to less than or equal to 9 days a month (49; 75). In the American Migraine Prevalence and Prevention Study, compared to participants using acetaminophen, participants using barbiturates (OR = 2.06, 95% CI = 1.3-3.1) or opioids (OR = 1.98, 95% C I= 1.4-2.2) were more likely to have transformation of episodic migraine to chronic migraine within 1 year (05). Stopping the symptomatic medication usually causes withdrawal symptoms, a period of increased headache, and eventually headache improvement in many, but not all, patients (76).

Although medication overuse headache is a generally accepted idea, there are some controversies as patients may very well have frequent migraine independent of any medication use, and invoking medication overuse headache may alienate some patients who perceive their actions are blamed for the headaches rather than the disease.

Epidemiology

Migraine itself is a common disorder affecting approximately 17% of women and 6% of men based on a 120,000 person survey as part of the American Migraine Prevalence and Prevention Study (05). A portion of migraineurs, amounting to 2% of the general population, have chronic migraine (52).

The prevalence of status migrainosus, as a separate entity from chronic migraine, is not reported. Patients with high headache burden are at higher risk for developing status migrainosus, but it can also occur in those with infrequent or well controlled migraines, particularly if precipitated by triggers such as illness or stress.

Status migrainosus lacks a clear epidemiological profile (11). One 11-year retrospective analysis of a French tertiary headache center (n = 8821 cases) reported a status migrainosus prevalence of 3% (02) whereas a multicenter study (n = 253 cases) reported a status migrainosus prevalence of 24.3% in those with aura and 20.6% in those without aura (68).

In a large retrospective cohort study of youth ranging from 1- to 26-years-old (n = 5316 cases) with migraine, a history of status migrainosus was present in 559 (10.5%) of the patients and the strongest factors associated with status migrainosus were older age and medication overuse headache (66). Patients with status migrainosus had greater odds of poor short-term prognosis (defined as increase in 4 or more headache days per month) and greater odds of follow-up visit to infusion center for acute headache.

The authors proposed as a neurobiological model that status migrainosus patients have a tendency for sensitization of trigeminovascular pain pathways. This mechanism was supported by their observation that older patients and those with delayed diagnosis and treatment had higher odds of status migrainosus, suggesting a link between repeated exposures to migraine attacks, sensitization, and status migrainosus risk over time. The authors also observed an association between migraine with aura and status migrainosus, and given that migraine with aura may be associated with cutaneous allodynia, the authors proposed the association between aura and status migrainosus can again be explained by sensitization (66).

Prevention

Patients with undertreated or inappropriately treated migraines are at risk for developing status migrainosus.

Many patients with migraine have milder tension-type headaches in between disabling episodes of migraine or status migrainosus. The current consensus is to treat the mild headache of migraine before it becomes severe. Early and appropriate treatment of migraine pain can reduce headache time and associated disability (47). Migraine headache may progress to involve cutaneous allodynia through a process of central sensitization after which abortive medications such as triptans may have reduced efficacy (46).

For additional review on the prevention of episodic and chronic migraine, see MedLink Neurology article Migraine.

Differential diagnosis

The differential diagnosis for a severe and prolonged headache is numerous. As there is no confirmatory laboratory or imaging test for migraine, clinical history is key to narrowing the differential diagnosis and deciding on appropriate investigations. In Table 3, the differential diagnosis based on the presenting characteristics is reviewed.

Table 3. Differential Diagnosis of Status Migrainosus*

Acute single headache
	• Subarachnoid hemorrhage • Reversible cerebral vasoconstriction syndrome • First attack of migraine • Acute glaucoma • Hypertensive encephalopathy • Meningitis • Pituitary apoplexy • Postconcussive or posttraumatic syndrome • Retroclival hematomas • Sinusitis • Spontaneous intracranial hypotension • Cerebral venous sinus thrombosis • Systemic infection
Acute recurrent headache
	• Reversible cerebral vasoconstriction syndrome • Cerebral tumors • Cerebrovascular insufficiency • Idiopathic intracranial hypertension • Intermittent hydrocephalus • Migraine • Subarachnoid hemorrhage
Subacute headache (days or weeks)
	• Brain abscess • Pseudotumor cerebri • Subdural hematoma • Temporal arteritis (in elderly) • Chronic daily headache (months or years) • Analgesic rebound • Chronic tension-type headache • Psychiatric state • Tumor

*(List is not all inclusive.)

In a series of 3799 patients who were seen over a 3-month period at an emergency headache center in Paris, 3299 patients (86.3%) were diagnosed with primary headaches; 244 (6.4%) had secondary headaches, 38 (1%) cranial neuralgias, and 218 patients (5.7%) had no precise diagnosis (20). Sinusitis was the most frequently reported cause of secondary headache (66 patients, 1.7%), followed by post-traumatic headache (58 patients, 1.5%) and CSF hypotension (24 patients, 0.6%). Vascular disorders were detected in only 20 patients (0.5%), including subarachnoid hemorrhage (7), cervical artery dissection (5), and cerebral venous thrombosis (2).

Serious vascular conditions were rare but often misleading, presenting only with headache and without the other classical signs of these conditions. New or changed headaches should always prompt a careful history and exam in addition to neuroimaging study and/or CSF studies before diagnosing a primary headache.

Acute headache. The first or worst attack of apparent status migrainosus requires careful history, examination, and other appropriate studies to assess for secondary causes of headache. Changes in awareness or cognition are atypical for migraine and always require further assessment. Older patients presenting with their first headache are less likely to have migraine and should be evaluated for underlying inflammatory disease, CNS tumors, or infection.

The first or worst attack of migraine may be difficult to differentiate from a subarachnoid hemorrhage, particularly if the pain is of acute onset. Meningitis or meningoencephalitis is possible if the headache is associated with a febrile illness, stiff neck, and changes in cognition; under these circumstances, neuroimaging and lumbar puncture can be used to confirm the diagnosis. Nonbacterial (aseptic) meningitis may be more difficult to diagnose and can mimic status migrainosus.

Patients with acute purulent sinusitis are usually acutely ill and febrile and with localized pain and tenderness. This disorder is more difficult to diagnose when it involves the sphenoid sinus, which is not accessible to direct clinical examination and may not be seen clearly on routine radiologic examination.

Spontaneous internal carotid or vertebral artery dissection can cause unilateral headache. In the case of carotid dissections, pain is located in the orbital, periorbital, and frontal regions. With vertebral dissections, pain is more frequently located in the cervical region (71). The pain is usually moderate to severe and steady or throbbing in nature. A history of head or neck trauma (even if minor), bruit, or Horner syndrome may assist in the diagnosis of vascular dissection. Focal cerebral symptoms (transient ischemic attack or stroke) can precede the headache but frequently follow it by as long as 2 weeks. Imaging of the cervical arteries with CTA, MRA, or traditional arteriography should be performed based on clinical suspicion.

Reversible cerebral vasoconstriction syndrome is a recently characterized syndrome that can cause nonaneurysmal thunderclap headache. In a prospective study of patients with nonaneurysmal thunderclap headaches treated in a hospital in the Netherlands, 8.8% of those who consented for follow-up were subsequently diagnosed via vascular imaging to have reversible cerebral vasoconstriction syndrome (32).

The presentation of reversible cerebral vasoconstriction syndrome commonly consists of recurrent thunderclap that may be triggered by activity or occur spontaneously over the course of a week with a female predominance (21).

The vascular constriction is thought to occur due to dysregulation of cerebral arterial tone and has been associated with disorders affecting autonomic balance (eg, catecholamine secreting tumors), illicit drugs (eg, cocaine, amphetamines, cannabis), alpha-sympathomimetic drugs (eg, pseudoephedrine), vasoconstrictive drugs (eg, dihydroergotamine), hormonal changes (eg, pregnancy, postpartum status), and severe stress (eg, surgery or trauma). The large vessel vasoconstriction associated with reversible cerebral vasoconstriction syndrome may not be angiographically visible until several weeks after onset of clinical symptoms; there must be a high clinical suspicion based on history in order to correctly follow and diagnose the condition (21). For those suspected of having reversible cerebral vasoconstriction syndrome, follow-up with vascular imaging via MRA, CTA, conventional angiography, and/or transcranial Doppler ultrasound may be necessary (08; 71).

Although most patients with reversible cerebral vasoconstriction syndrome had spontaneous resolution of angiographic vasoconstriction in weeks to months, a significant percentage suffered ischemic complications (transient ischemic attack or infarct at 16% and 4% respectively), cerebral hemorrhage (6%), posterior reversible encephalopathy syndrome (9%), and seizure (3%) (21). When reversible cerebral vasoconstriction syndrome is clinically suspected, it is imperative to avoid vasoconstrictive medications such as triptans or ergotamines, which worsen the disease process and increase the risk of complications such as ischemic stroke.

Idiopathic intracranial hypertension (pseudotumor cerebri) may occur with or without papilledema and mimic either migraine or tension-type headache. Patients typically have risk factors of female gender, younger age, and obesity. The presence of these risk factors, a history of pulsatile tinnitus, and transient visual obscurations with Valsalva are suggestive of idiopathic intracranial hypertension. Physical findings may include papilledema or cranial nerve palsies. The diagnosis is made with a spinal tap that is performed with the patient lying down either in the lateral decubitus or prone position (not seated). Opening pressures greater than 25 cm of water may be consistent with this diagnosis (25).

Cerebral sinus venous thrombosis most commonly affects women aged 20 to 50 years. Risk factors include oral contraceptives, pregnancy, HRT, hereditary thrombophilia, malignancy, and other systemic diseases. In a retrospective cohort study, all patients exhibited at least 1 red flag, most frequently abnormal neurologic exam (79%), other neurologic symptom (68%), headache with alarm feature (63%), or recognizable risk factor (47%) (28). MRI with MR venography is the most commonly recommended, CT venography with contrast is a reliable alternative, and angiography is reserved if MRI/CT is inconclusive, dural AV fistula is suspected, or endovascular intervention is required (58). The mainstay of treatment is heparin or LMWH with bridge to heparin.

Subacute headache. A new headache that has been present for days or weeks may be the beginning of a chronic daily headache or prolonged status migrainosus. The differential diagnosis is, of course, quite broad, and appropriate medical and neurologic investigation is warranted.

Chronic nonprogressive headache. Chronic daily headache may be related to a primary headache disorder such as migraine or tension type headache or secondary disorder such as idiopathic intracranial hypertension, systemic disease (eg, sleep apnea), or underlying psychopathology.

Chronic migraine. Chronic migraine may evolve from episodic migraine through status migrainosus. The symptoms of chronic migraine include the progressive intensification of severe, debilitating pain accompanied by the usual characteristics of acute migraine (nausea, vomiting, light sensitivity, etc.) functional impairment. Dehydration, electrolyte alterations, autonomic disturbances, and emotional despair are frequently present.

Chronic tension-type headache. Chronic daily headache may also develop in patients with a history of episodic tension-type headache. The headaches are often diffuse and bilateral, frequently involve the posterior aspect of the head and neck, and may have some migrainous features. Due to the overlapping clinical features of tension type headache and migraine, patients may meet criteria for both disorders.

Diagnostic workup

An extensive neurologic evaluation, including CT or MRI scan and/or lumbar puncture, is indicated in patients presenting with their first or worst prolonged headache, particularly if it is of sudden onset or associated with focal neurologic signs, stiff neck, or changes in cognition. Follow-up vascular imaging may be indicated for those with suspected reversible cerebral vasoconstriction syndrome as vascular changes may not be apparent on imaging until several weeks later (08; 71).

Newer citations for workup of secondary headache disorder.

SNOOP4 is a popular mnemonic of “red flags” developed to help clinicians determine whether a secondary workup is warranted. A new systemic mnemonic, SNNOOP10, has been proposed to increase the likelihood of detecting a secondary cause of headache, which represents a minority of headaches but may cause catastrophic consequences (17). SNNOOP10 stands for:

Systemic symptoms including fever
Neoplasm history
Neurologic deficit (including decreased consciousness)
Onset is sudden or abrupt
Older age (≥ 65)
Pattern change or recent onset of new headache
Positional headache
Precipitated by sneezing, coughing, or exercise
Papilledema
Progressive headache and atypical presentations
Pregnancy or puerperium
Painful eye with autonomic features
Post-traumatic onset of headache
Pathology of the immune system such as HIV
Painkiller (medication overuse headache) or new drug at onset of headache

Management

Many patients present to the hospital emergency department for evaluation and treatment of severe persistent headache. The initial and paramount goal of the emergency department team is to establish whether there is a serious and/or life-threatening secondary cause of the head pain. Assuming an appropriate and thorough evaluation has taken place in the emergency department, the next decision is to identify the most appropriate venue for continued treatment: the emergency department, inpatient hospitalization, outpatient treatment, or some combination thereof.

As patients often present to the emergency room for initial treatment after exhausting home treatments, physicians may use this as an opportunity for robust treatment with intravenous medications to reduce pain and disability.

The treatment of status migrainosus often takes place in the emergency department initially, with a goal of breaking the pain cycle or decreasing the severity significantly. The emergency department staff may choose to send a patient home with a specific abortive therapy for the head pain. Prescriptions for opioids or butalbital are not recommended. Lifestyle changes, prophylactic medications, or comorbid psychological conditions may be broached during the emergency department visit and should be further addressed by outpatient physicians.

Acute inpatient hospitalization for the treatment of migraine should be considered in the appropriate circumstances (see Table 4), and the goals of admission should be clearly defined. In addition to treatment of severe pain, hospitalization should address concurrent medication overuse, particularly of drugs containing butalbital or opiates, as the detoxification progress can be difficult and requires symptomatic treatment to prevent dehydration from intractable nausea or vomiting, seizures, or other severe acute withdrawal effects (Table 5).

Table 4. Hospital-Based Treatment Options

The principles of treatment for status migrainosus include the following:
	(1) Fluid and electrolyte replacement (if indicated)
	(2) Drug detoxification
	(3) Intravenous pharmacotherapy to control pain
	(4) Treatment of associated symptoms of nausea and vomiting
	(5) Concurrent implementation of migraine prophylaxis (if indicated)

Criteria for hospital-based treatment include severe, intractable headache accompanied by (1) dehydration (requiring parenteral therapy for pain interruption); (2) dependence on analgesic or ergotamine medication; or (3) significant comorbid neurologic, medical, or psychiatric illnesses (76).

Table 5. Detoxification guidelines

	(1) Fluid replacement for 24 to 48 hours
	(2) Oral ergotamine tartrate can be discontinued abruptly if intravenous dihydroergotamine is administered. Otherwise, it should be tapered over 2 to 3 days.
	(3) Analgesics not containing opiates or barbiturates can be stopped abruptly.
	(4) Combined analgesics containing barbiturate should be discontinued gradually, particularly if there has been daily use for extended period of time to prevent withdrawal syndromes. If rapid discontinuation is more appropriate, then phenobarbital may be used to prevent withdrawal.
	(5) Opioid withdrawal must be carried out slowly or through replacement with methadone and subsequent rapid taper. Side effects can be reduced by giving clonidine hydrochloride, phenobarbital, or a benzodiazepine derivative (63).

(76)

Treatment of status migrainosus should be tailored to the patient’s history, medication tolerances, presence of potential contraindications, and responses from past treatments. Table 6 reviews the general strategies and classes of medications that are frequently used in combination to treat status migrainosus.

Table 6. Infusion-Based Treatment of Status Migrainosus

(1) IV fluids
(2) Pretreat with:
	• prochlorperazine (5 to 10 mg IV) or • metoclopramide (10 mg IV)
(3) Treat with:
	• dihydroergotamine (0.5 to 1.0 mg IV)
(4) If headache persists:
	• in 8 hours give additional dihydroergotamine (0.5 to 1.0 mg IV)
(5) Additions:
	• ketorolac (30 to 60 mg intramuscularly or IV) • valproate (500 to 1000 mg IV) • diphenhydramine (25 to 50 mg IV) • magnesium sulfate (1 gram IV push)
(6) Alternatives:
	• dexamethasone (4 to 10 mg IV) • chlorpromazine (2.5 to 12.5 mg IV after 250 cc saline bolus)
	or
	• droperidol (0.3125 to 2.5 mg IV) • opioids - rare use

Intravenous dihydroergotamine. Intravenous dihydroergotamine is a mainstay in the inpatient treatment of migraine because it has been shown to be a safe and effective means of terminating a migraine attack (69; 23; 61).

Repetitive intravenous doses of dihydroergotamine were first shown to be effective by Raskin in 1986 with 49 of 55 patients (89%) being headache-free after 48 hours. After hospitalization for treatment with intravenous dihydroergotamine, patients may be able to maintain the significant improvements, particularly if medication overuse and detoxification are concurrently addressed.

Hospitalization is typically necessary for treatment with repetitive intravenous dihydroergotamine as it is given every 8 hours and generally requires aggressive premedications to reduce risk of nausea/vomiting as side effects and close followup for associated side effects (eg, QT prolongation).

The patient is pretreated with metoclopramide (10 mg IV) and then given dihydroergotamine (0.5 mg IV). If the patient has no nausea and the headache persists, another 0.5 mg of dihydroergotamine is given. If the patient's headache is not gone, 0.5 to 1 mg of dihydroergotamine is continued every 8 hours. If nausea develops, the dose is decreased, and the antiemetic adjusted or increased. Both drugs are continued as needed, the dihydroergotamine every 8 hours until the patient is headache-free, at which time it is tapered and discontinued.

Standard dosage. Following 10 mg of intravenous metoclopramide, dihydroergotamine 0.5 mg is administered intravenously. Subsequent doses are adjusted based on pain relief and side effects. Most patients eventually take dihydroergotamine 1.0 mg intravenously every 8 hours (69).

Contraindications. Pregnancy, coronary artery disease, prinzmetal angina, peripheral vascular disease, prolonged aura, hemiplegic migraine, and poorly controlled hypertension.

Main drug interactions. Administration with other potential vasoconstrictors (triptans, ergots, isometheptene, nicotine, and beta-blockers) may potentiate the vasoconstrictor effect of dihydroergotamine. Macrolide antibiotics, especially erythromycin, may increase plasma levels of dihydroergotamine.

Main side effects. Noncardiac chest pain, neck or trunk pressure, head or body warmth, nausea, leg pain, diarrhea.

Special points. Dihydroergotamine must be given slowly (intravenous push over 2 to 3 minutes or intravenous drip over 10 to 15 minutes) to reduce nausea, flushing, and chest symptoms. Diluting with an equal volume of saline reduces side effects.

Cost and cost-effectiveness. Dihydroergotamine is moderately expensive. Dihydroergotamine is moderately expensive; disturbances in manufacture supply has led to costs fluctuations in recent years.

Pediatric consideration. Children under 25 kg or under age 9 may be given dihydroergotamine at 0.5 mg intravenous every 8 hours) (37).

Neuroleptics. Multiple drugs from the neuroleptic class have been used for the treatment of acute migraine. Of this class, intravenous prochlorperazine has the highest level of evidence (74; 65).

Intravenous prochlorperazine was shown to be vastly superior to placebo (36) in a double-blinded, randomized control trial (n = 42 each arm) with 74% of the treatment group reporting complete headache relief at 60 minutes compared to 14% of the placebo group. Additionally, intravenous prochlorperazine 10 mg combined with intravenous diphenhydramine 12.5 mg was shown to be superior to subcutaneous sumatriptan 6 mg for migraine relief at 80 minutes (41). Prochlorperazine infusion over 15 minutes versus bolus push over 2 minutes was shown to have similar rates of side effects (12). A metaanalysis of 11 moderate- to high-quality randomized control trials statistically bolstered the utility of prochlorperazine for acute migraine in the emergency department. In the metaanalysis, the odds of 10 mg IV of prochlorperazine aborting acute migraine attacks were nearly 3 times higher than the odds with metoclopramide and nearly 4 times higher than the odds with other standard migraine therapies including sumatriptan, ketorolac, and sodium valproate (31). Fewer patients in the prochlorperazine group required rescue analgesia.

Prochlorperazine has also been shown to be effective in children; Kabbouche and colleagues (38) studied prochlorperazine in 20 consecutive children with acute migraine and showed that 95% improved at 3 hours and 90% remained headache-free at 24 hours.

Neuroleptics are more effective when given intravenously compared to suppository intramuscular forms. However, when intravenous access is limited, rectal prochlorperazine 25 mg may be an effective alternative (35).

Metoclopramide is also frequently used for the acute treatment of migraine, though it has not been as intensively investigated as prochlorperazine through randomized trials. In a blinded, randomized control study, 67% of treatment patients reported pain relief at 1 hour compared to 19% of placebo patients (84).

In a randomized, controlled trial comparing intravenous prochlorperazine and metoclopramide, prochlorperazine 10 mg was superior to metoclopramide 10 mg (13). Intravenous prochlorperazine 10 mg and metoclopramide 20 mg were similarly effective in another trial (24).

Intravenous haloperidol has also been shown to be superior to placebo in a double-blind, randomized trial with 16 of 20 (80%) treatment patients reporting significant pain relief and only 3 of 20 (15%) placebo patients reporting significant pain relief 1 to 3 hours after the infusion. Although patients receiving haloperidol had better pain relief, they were also more likely to have bothersome sedation or akathisia (34).

Droperidol, a butyrophenone with strong neuroleptic and antiemetic properties, has also been used for treatment of acute migraine. In an open, ambulatory infusion center study, intravenous droperidol provided significant relief (no pain to mild pain) for 22 of 25 patients with status migrainosus, although sedation and akathisia were common (85).

In a randomized, double-blind, placebo-controlled, multicenter study, 305 patients with moderate to severe migraine received intramuscular droperidol at doses of 2.75 mg, 5.5 mg, and 8.25 mg (78). At 2 hours, those treated with any dose of droperidol reported significantly higher rates of headache improvement (81% to 87% with mild pain or no pain) compared to those receiving placebo (57%). The frequency of headache recurrence (within 24 hours) for patients initially responding by 2 hours was lower in patients treated with droperidol than with placebo, but differences were not statistically significant. A significantly greater percentage of patients receiving droperidol also reported the elimination of migraine-associated symptoms (nausea, vomiting, photophobia, and phonophobia) than those who received placebo. Although most adverse events were mild or moderate, anxiety, akathisia, and somnolence were rated as severe in 30% of patients who experienced those symptoms. Hypotension was uncommon. No patients had QT prolongation. This study suggested the use of diphenhydramine or benztropine to manage droperidol-induced akathisia.

Intravenous droperidol 2.5 mg and prochlorperazine 10 mg were found to have similar efficacy for acute headache relief with similar rates of akathisia in a blinded, randomized study of emergency department patients (86).

Chlorpromazine at 0.1 mg/kg can also be used effectively for the treatment of pain and associated symptoms in acute migraine (03), although its side effects of drowsiness and postural hypotension may require extra caution.

Intravenous neuroleptics may be used as primary therapy or as adjunct treatment for migraine and its associated features of nausea. If intravenous access is limited, oral, rectal, or intramuscular forms may be used. Patients receiving neuroleptics must be monitored carefully for hypotension, sedation, dystonic reactions, and akathisia. Use of diphenhydramine with neuroleptics may mitigate the development of akathisia and/or dystonia. Orthostatic hypotension may be reduced by intravenous fluids and supination post infusion.

Standard dosage. Prochlorperazine, 25 mg rectally every 6 hours as necessary, 5 to 10 mg intramuscularly or intravenously every 8 hours; chlorpromazine 25 mg orally every hour as necessary, max 5 doses per day, 12.5 to 25 mg intravenously after 250 cc saline bolus; and droperidol 1.25 to 2.5 mg intravenously every 6 hours or 1.25 to 2.5 mg intravenously every hour, maximum 10 mg in 24 hours (85).

Contraindications. Known hypersensitivity to agent, prolonged QTC.

Main drug interactions. Other sedative medication, other drugs that might cause QT prolongation on EKG.

Main side effects. Dystonia, akathisia, sedation, hypotension, tachycardia, restless leg syndrome, neuroleptic malignant syndrome, cholestatic jaundice, rarely QT prolongation. Extrapyramidal side effects, especially akathisia, may be particularly common in daily headache patients.

Special points. Akathisia must be dealt with promptly.

Cost and cost-effectiveness. Some intravenous neuroleptics are relatively expensive; however, the cost is low compared to the cost of an emergency room visit or hospitalization.

Nonsteroidal antiinflammatory drugs (NSAIDS). Ketorolac is frequently used in conjunction with neuroleptics, triptans, or dihydroergotamine in the treatment of migraine due to its availability in intravenous and intramuscular forms.

In a double blind, randomized control study comparing intravenous ketorolac (n = 13) against intranasal sumatriptan (n = 16), ketorolac was found to be superior to the triptan at reducing pain score 1 hour after administration (59). Additional comparison studies of intravenous ketorolac against agents such as meperidine, chlorpromazine, or prochlorperazine generally showed similar pain relief efficacy (80).

Standard dosage. Ketorolac can be given as a 60 mg intramuscular injection or a 30 mg intravenous injection. The total daily dose of parenteral ketorolac is recommended to be 60 mg or less. Due to the risk of gastrointestinal and renal adverse effects, parenteral ketorolac should not be given for more than 3 days in a row.

Contraindications. Renal impairment, gastrointestinal perforation or ulcer, gastrointestinal bleeding, suspected intracranial bleeding, hemorrhagic diathesis, inflammatory bowel disease, pregnancy, use of anticoagulants, concurrent use of probenecid, or pentoxifylline.

Main drug interactions. Other nonsteroidal antiinflammatory drugs (ibuprofen, naproxen, etc.).

Main side effects. Upset stomach, abdominal pain, nausea, diarrhea, renal impairment, bleeding.

Cost and cost-effectiveness. Injected forms of ketorolac are generally inexpensive, although insurance limitations may apply.

Corticosteroids. Parenteral corticosteroids, either alone or in combination with other symptomatic medications, have been used to treat severe, resistant headache. Dexamethasone 4 mg in conjunction with a triptan and a nonsteroidal anti-inflammatory drug will decrease recurrence in a limited population (43).

A comprehensive metaanalysis by Woldeamanuel and colleagues in 2015 showed reduced risk of headache recurrence with generally tolerable adverse side effects (88). Although steroids may be effective acute treatment, physicians should be aware of the long-term adverse effects (immunosuppression, adrenal insufficiency, Cushing syndrome, osteonecrosis, osteoporosis, etc.) and should monitor/limit cumulative exposure.

Standard dosage. Methylprednisolone sodium succinate 100 to 200 mg IV q 12° for 3 days. Outpatient oral dosing typical dose range is prednisone 40 to 60 mg for 6 to 8 days.

Contraindications. Active peptic ulcer disease, severe diabetes or hypertension, acute viral or other systemic infection, or psychosis.

Main drug interactions. May cause hypokalemia if given with NSAIDs. May increase the risk of gastrointestinal bleeding if given with ethacrynic acid, furosemide, or thiazide diuretics.

Main side effects. Aseptic necrosis of femoral head or occasionally other bones is the main concern (risk factors are prolonged duration of use and high doses, cigarette smoking and ethanol consumption; earliest reports after continuous use of prednisone occurs at approximately 1 month), fluid retention, nausea, insomnia, mood variability, hypertension, hyperglycemia, or hypokalemia.

Cost and cost-effectiveness. Methylprednisolone sodium succinate is inexpensive.

Anticonvulsants. The FDA has officially approved valproate sodium for the prophylactic treatment of migraine headaches. An intravenous form of this agent, which is primarily used for the acute treatment of seizures, may be a safe, effective, and well-tolerated treatment for intractable migraine (64; 22; 72). An open study using intravenous valproate 300 mg in 61 patients showed the treatment was generally well tolerated and significantly reduced pain in more than half of treated attacks (55).

There is 1 comparative study of intravenous sodium valproate 500 mg verus prochlorperazine 10 mg which showed that 79% of those treated with valproate required additional rescue treatment compared to 25% of those treated with prochlorperazine (81).

Standard dosage. Intravenous valproate at 300 mg to 500 mg.

Contraindications. Pregnancy, liver disease.

Main drug interactions. Coadministration of valproate and phenobarbital may rarely result in sedation and reversible coma. Aspirin may increase free valproate concentrations, and many drugs (phenytoin, carbamazepine, phenobarbital) increase valproate clearance. Rare cases of hepatic failure have occurred (usually in young children 2 years old or in patients receiving multiple anticonvulsants).

Main side effects. Sedation, dizziness, tremor.

Cost and cost-effectiveness. IV valproate is moderately expensive.

Other intravenous acute treatment. Intravenous lignocaine was used in 19 chronic daily headache patients, 3 of whom had status migrainosus (33). Five infusions were given to those 3 patients, with 4 of the infusions relieving headache. Another study by Williams and Stark in 2003 focused on 71 patients with chronic daily headache who were admitted for lidocaine infusion (also received other treatments such as nonsteroidal antiinflammatory drugs during admission) (87). After an average of 8.7 days of treatment, 90% of these patients noted improved headache, with 70% reporting improved pain at 6-month follow-up.

In a case series of 68 patients with chronic daily headache (mostly chronic migraine) who were treated with intravenous lidocaine, 57% had some improvement and 25% were able to be pain free after an average of 8.5 inpatient days. Of note, the patients in this study also received other treatments such as intravenous dihydroergotamine (54). Major side effects of intravenous lidocaine reported were nausea, hallucinations, lightheadedness, tachycardia, tremor, and blood pressure changes (hypotension or hypertension).

A metaanalysis of 6 randomized controlled trials revealed those who received intranasal lidocaine had a lower pain severity at 5 minutes and 15 minutes and less frequent need for rescue medication than the control group of nasal saline (09). However, intranasal lidocaine did not provide an add-on effect in patients who also received an antiemetic. Adverse effects were limited to local symptoms of burning or numbness in the nose. Intranasal lidocaine may block the sphenopalatine ganglion, inactivating intracranial nociceptors that contribute to cerebral vasodilatation.

A double-blind study of repeated intranasal capsaicin in 8 patients with chronic migraine (26) demonstrated improvement between 50% and 80% in the 4 patients in the active group.

Several studies have suggested a role for intravenous magnesium sulfate in the treatment of acute migraine attacks. Demirkaya and colleagues (15) and Bigal and colleagues (04) performed randomized, placebo-controlled studies in acute migraines and demonstrated significant relief. Mauskop and colleagues reported that IV magnesium was successful in treating menstrual migraine in patients with low interictal free ionized magnesium levels (56). A randomized, double-blind, placebo-controlled trial of emergency room patients with migraine showed that magnesium given as an adjunctive treatment with metoclopramide appeared to be less effective than metoclopramide alone (14); there are no other similar studies to verify this finding.

In a retrospective study, 9 doses of diphenhydramine given over 3 days significantly reduced headache level but did not appear as effective as dihydroergotamine with metoclopramide (79). As dihydroergotamine is contraindicated for some patients, repetitive doses of diphenhydramine may be used for headache control.

Calcitonin gene-related peptide small molecule and antibody treatments. Triptans are the gold standard for acute migraine treatment, yet 30% to 40% do not respond adequately to treatment and triptans are contraindicated in patients with cardiovascular disease.

Calcitonin gene-related peptide plays an important role in the pathophysiology of migraine via neuronal modulation of pain and vascular activity. “Gepants” are small molecule calcitonin gene-related peptide receptor antagonists.

Gepants are a new nonvasoconstrictive approach to acute migraine treatment. They are considered first-line in patients with cardiovascular risk or second-line treatment in triptan nonresponders.

For preventive treatment, there are 4 FDA-approved monoclonal antibody calcitonin gene-related peptide inhibitors that are administered via IM or IV route.

The FDA approved ubrogepant (ubrelvy©) in December 2019 for the acute treatment of migraine with and without aura. In ACHIEVE-1, significantly more patients who received ubrogepant 50 mg and 100 mg achieved pain freedom at 2 hours postdose than placebo (19.2 % and 21.2% vs. 11.8%, respectively) as well as absence of most bothersome migraine-associated symptoms (19). A significantly higher proportion of ubrogepant-treated patients versus placebo-treated patients reported return to normal function at 2 hours postdose (18). The adverse event profile was similar to placebo. There were no altered transaminase levels after intake of ubrogepant 100 mg as compared with placebo group.

Ubrogepant may also be an effective treatment for acute migraine in triptan nonresponders (06). Data from ACHIEVE I and ACHIEVE II was pooled for patients receiving ubrogepant 50 mg and matched with placebo. Amongst patients who deemed triptans ineffective (approximately 25% of study patients), 2-hour pain freedom following initial dose was achieved by 16% of patients in the ubrogepant group versus 8% in the placebo group. In the triptan-ineffective group, absence of most bothersome migraine-associated symptoms was achieved by 36% of patients in the ubrogepant group versus 23% in the placebo arm.

In February 2020, the FDA approved rimegepant (nurtec©) for the acute treatment of migraine. In 4 phase 3 clinical trials, rimegepant 75 mg resulted in a higher percentage of patients who were pain-free at 2 hours (20.6% vs. 12.5%) and most bothersome symptoms-free at 2 hours posttreatment (36% vs. 25.1%) (27). One randomized controlled trial found that 75 mg rimegepant produced similar effect to 100 mg of sumatriptan with fewer adverse events (53). In a metaanalysis, the adverse events of 75 mg of rimegepant were similar to those of placebo. The most common adverse events were nausea and urinary tract infection. Metaanalysis showed no significant liver damage in rimegepant compared with placebo (2.2% vs. 2.9%) (27).

Standard dosage. Rimegepant 75 mg PO or ODT. Ubrogepant 50 mg and 100 mg PO.

Contraindications. Concomitant use of strong CYP3A4 inhibitors (eg, ketoconazole, itraconazole, clarithromycin).

Main drug interactions. Strong CYP3A4 inducers: should be avoided as concomitant use will result in reduction of ubrogepant exposure. Dose modifications are recommended when using the following: moderate or weak CYP3A4 inhibitors and inducers, BCRP, and/or P-gp only inhibitors.

Main side effects. Rimegepant-adverse events were similar to those of placebo. The 4 most common adverse events were nausea, UTI, dizziness, and AST or ALT above the upper limit of normal. Ubrogepant-adverse event profile was similar to that of placebo. The most common adverse events were nausea (4% vs. 2% placebo) and somnolence (3% vs. 1% placebo).

Four anti-calcitonin gene-related peptide monoclonal antibodies have been FDA-approved for the prevention of episodic and chronic migraine. Three of the 4 monoclonal antibodies (eptinezumab, freanezumab, galcanezumab) target calcitonin gene-related peptide itself whereas the fourth, erenumab, targets the calcitonin gene-related peptide receptor. Of the 4 monoclonal antibodies, eptinezumab is administered via intravenous infusion every 3 months whereas the other monoclonal antibodies are a monthly subcutaneous injection. In the PROMISE-2 randomized controlled trial, eptinezumab produced greater than 50% headache reduction on the first day after administration, which was maintained at 1 month throughout the study (50). Its intravenous administration and rapid onset of action suggests that eptinezumab may have potential as an acute abortive agent and it is currently undergoing investigation for acute migraine attack in the RELIEF randomized controlled trial.

Standard dosage. 100 mg every 3 months; some patients may benefit from 300 mg.

Main drug interactions. Virtually none.

Main side effects. Treatment-emergent adverse events were similar across the treatment and placebo groups; most events were mild or moderate in severity. The most frequently reported treatment-emergent adverse event was fatigue and nausea.

Special populations. Not used in pregnancy or during lactation due to limited safety data. Not approved in children age 17 and younger.

Cost and cost-effectiveness. Likely more costly for health insurance plans and patients than currently available oral triptans which may have generic option. It’s important to understand the indications for initiating treatment: patients with contraindications to the use of triptans or who have failed to respond to or tolerate at least 2 oral triptans.

5-HT1F receptor agonists – ditans. The FDA approved lasmiditan in October 2019 for the acute treatment of migraine. Lasmiditan is a highly selective 5-HT1F receptor agonist. By activating prejunctional 5-HT1F receptors, lasmiditan may exert its antimigraine effect by suppressing calcitonin gene-related peptide release. Unlike activation of the 5-HT1B receptor subtype, activation of 5HT1F does not constrict blood vessels and therefore, lasmiditan can be considered first line antimigraine treatment in patients with cardiovascular risk or second-line treatment in triptan nonresponders.

In the study SAMURAI, more patients dosed with lasmiditan 100 mg and 200 mg were pain-free at 2 hours and most bothersome symptom-free (photophobia, phonophobia, nausea) at 2 hours posttreatment as compared with placebo (44). Similar results were obtained in SPARTAN, in which doses of 50 mg, 100 mg, and 200 mg were compared to placebo (30). Although the percentage of patients who responded to lasmiditan increased with the dosage, lasmiditan was effective at 2 hours postdose at all the doses tested.

Safety data integrated from SAMURAI and SPARTAN revealed treatment-emergent adverse events were mild or moderate in severity, most commonly dizziness, paresthesias, and somnolence. There were no treatment-emergent events related to vasoconstriction (42). Pooled results from SAMURAI and SPARTAN showed no statistical difference of likely cardiovascular treatment-emergent adverse events (73). The GLADIATOR study to assess long-term safety of the 100 mg and 200 mg dose is still ongoing, with interim analysis at 1 year showing both doses are effective for acute migraine and well-tolerated.

The efficacy of lasmiditan seems to be in the same range as the triptans, with improved cardiovascular safety as compared to the triptans, although no head-to-head comparisons have been performed (16). In a pooled subgroup analysis of SAMURAI and SPARTAN, lasmiditan showed efficacy in both triptan good responders and triptan insufficient responders compared with placebo at doses 100 mg and 200 mg (40). This suggests lasmiditan offers a possible alternative option for acute migraine therapy regardless of prior triptan response.

Standard dosage. Lasmiditan 50 mg, 100 mg, and 200 mg.

Contraindications. None.

Main drug interactions. No significant effect on hepatic safety, EKG findings, or vital signs and no probable cases of serotonin syndrome.

Main side effects. Lasmiditan has a driving impairment warning due to side effect of dizziness reported by patients. Most common treatment-emergent adverse events were neurologic and were typically mild to moderate with dizziness, paresthesias, somnolence, fatigue, nausea, muscular weakness, and hypoesthesia. Unlike triptans, which have affinity for 5-HT1B located on vascular smooth muscle receptors, lasmiditan has high affinity for 5-HT1F receptor and is not a vasoconstrictor.

Cost and cost-effectiveness. Likely more costly for health insurance plans and patients than currently available oral triptans which may have generic option. It’s important to understand the indications for initiating treatment: patients with contraindications to the use of triptans or who have failed to respond to or tolerate at least 2 oral triptans.

Other procedures. Greater occipital nerve blocks with an anesthetic (typically 1% to 2% lidocaine, or 0.25% bupivacaine) with or without steroids (typically methylprednisolone 20 to 40 mg) are generally safe and frequently performed by physicians for acute treatment of migraine. Retrospective data show it may reduce pain intensity and medication use but not pain duration (90).

Device-based treatments. Transcutaneous electrical nerve stimulation (TNS; Cefaly) is a mode of intervention (using electrical micropulses to the supraorbital branch of the trigeminal nerve. Cefaly is FDA approved for the treatment of chronic and acute migraine with or without aura. In the randomized ACME study, 1-hour treatment with the device resulted in superior pain reduction compared with sham at 1-hour, 2-hour, and 24-hour time points, although there was no difference in rescue medication intake following device use (Chou et al 2019). The net reduction on Visual Analog Scale (0-no pain, 10-maximum pain) was 1.68 points (p = 0.0001), 1.02 points (p = 0.028), and 1.08 points (p = 0.062) at 1, 2, and 24 hours postintervention, respectively. No serious adverse events occurred. TEAM, a phase 3 trial for use of the device in acute migraine, has completed enrollment with results pending.

Noninvasive vagus nerve stimulation (nVNS; gamma-Core©) is a hand-held neuromodulation device that when applied to the neck stimulates the vagus nerve’s afferent fibers. Noninvasive vagus nerve stimulation is FDA approved for the acute treatment of episodic migraine and episodic cluster headache. The randomized PRESTO study demonstrated that noninvasive vagus nerve stimulation was superior to sham in aborting acute migraine attacks at 30 and 60 minutes (82). There were no serious adverse events; the most common adverse event was application site discomfort (2.5%) and nasopharyngitis (1.6%). Benefits of noninvasive vagus nerve stimulation include benign adverse event profile, may be used for multiple attacks without risk of medication overuse headache, and can be used in combination with any existing migraine treatment as a nonpharmacologic agent.

Remote electrical neuromodulation (REN; nerivio™) is a novel device approved by the FDA for treatment of acute migraine with or without aura in adult patients with episodic migraine. Remote electrical neuromodulation is a stimulation unit applied to the upper arm (median and musculocutaneous nerves) that uses smartphone-controlled electronic pulses to create a conditioned pain modulation response. A randomized, double-blind sham-controlled study demonstrated that active stimulation was more effective than sham in achieving pain relief (66.7 vs. 38.8%), pain-free (37.4% vs. 18.4%), and relief of most bothersome symptoms (46.3% vs. 22.2%) at 2 hours posttreatment (89).

Maintenance therapy. After acute treatment is completed, many patients with status migrainosus and chronic daily headache require continuing care, including a preventive treatment program using standard migraine preventive drugs. This may be initiated in the inpatient setting and then modified accordingly in the outpatient setting by the patient’s primary care physician or neurologist.

Outcomes

Treating patients who had intractable headache in a comprehensive inpatient unit demonstrated long-term benefits as measured by a prospective outcome evaluation (45), which showed a 64% reduction in the mean number of days that severe or incapacitating headache was sustained and a corresponding increase in the mean number of headache-free days. Dysfunctional days dropped by 70% and clinical depression by 69%. The mean percentage of subjective improvement was 70%, with 87% of patients reporting at least a 50% reduction in headache. Silberstein and Silberstein reported similar long-term benefits (77). Most patients (87%) detoxified from analgesic or ergotamine overuse as part of an inpatient program continued to do well when reevaluated at 2-year follow-up.

Special considerations

Pregnancy

As migraine is more common in women, particularly during the third to fourth decade of life, physicians should appropriately monitor/assess whether female patients may be pregnant or planning as many migraine treatments may pose significant risks to fetal development.

Migraine may worsen during the first trimester but generally improves during the second and third trimesters. For pregnant women with migraines, nonpharmacologic therapy such as biofeedback, relaxation techniques, rest, and massage should be optimized. Ergotamine and dihydroergotamine are absolutely contraindicated due to the risk of fetal abortion (29).

Acute treatments that may be used during pregnancy include acetaminophen, opioids such as hydrocodone (pregnancy category B), and magnesium; nonsteroidal antiinflammatory drugs may be used early in the pregnancy but should be avoided in the third trimester due to risk of preterm labor (07).

Triptans are generally avoided in pregnancy due to lack of dedicated studies in pregnant women. However, a comprehensive Norwegian registry-based study showed no evidence of increased risk of congenital malformations for children exposed to triptans during pregnancy (62). Additional pregnancy registry data for sumatriptan/naratriptan/Treximet, which can be accessed at http://pregnancyregistry.gsk.com/sumatriptan.html), does not show significant rate of adverse events. Based on the prescriber and patient’s level of comfort and the patient’s severity of migraine, sumatriptan (the most commonly encountered triptan in registries), may be an option for treatment during pregnancy (51).

The Cefaly supraorbital transcutaneous stimulator is reported by the manufacturer as safe for use in pregnancy, as other forms of transcutaneous electrical nerve stimulation for back pain have been safely used in pregnant women (39).

Pediatric populations. See MedLink Neurology article Headache in children: overview and treatment approaches.

The AAN and AHS released a practice guideline update on the acute treatment of migraine in children and adolescents (67).

There is probable evidence that acute migraine treatment is more likely to be effective earlier on in the attack (level B). There is probable evidence that ibuprofen oral solution 10 mg/kg is effective as an initial treatment to reduce pain in children and adolescents with migraine. For adolescents with migraine, there is level B evidence for the following medicines to reduce headache pain: sumatriptan/naproxen oral tablet (10/60 mg, 30/180 mg, 85/500 mg), zolmitriptan nasal spray 5 mg, sumatriptan nasal spray 20 mg, rizatriptan oral disintegrating tablet 5 or 10 mg, or almotriptan oral tablet (6.25 mg or 12.5 mg) (67).

Only the following triptans have FDA approval for use in children: rizatriptan (6-17 years), and almotriptan, sumatriptan/naproxen, and zolmitriptan nasal spray (patients aged 12 years and older). Ergots and oral naproxen alone have not been studied in children.