Status Migrainosus

Status migrainosus is a migraine complication in which the attack is unremitting for at least 72 hours and symptoms are associated with significantly more disability than migraine (Table 1), which is the second highest cause of years lived with disability according to the World Health Organization.^1-3 The severity of status migrainosus with its high disability, including risk for suicide, emphasizes the importance of treatment.

All-cause headache is estimated to represent approximately one-fourth of neurologic presentations to emergency departments (EDs); the proportion comprised by status migrainosus, which is unknown and estimated to be at least 10%.^4,5 There is little data on community incidence and prevalence,⁶ but within a neurology practice, an unremitting migraine attack of 72 hours or more is common, especially when superimposed on a background of chronic migraine, which can be a challenge even for the most seasoned neurologist.

Although medications are available for treatment, evidence-based guidelines for management of status migrainosus are lacking with no international consensus guidelines and no randomized trials. A study showed the average duration of status migrainosus to be 4.8 weeks, raising the question if resolution was from medical management or the attack self-abating with time.⁶ Ideally, a cost-effective, easily administered, stepwise home treatment approach is devised in the outpatient setting before progression into status migrainosus. It is also important to balance some acute treatments with the potential for causing medication-overuse headache, further emphasizing the need for studies to provide clear treatment guidelines. This review provides a practical approach to mananging status migrainosus in the outpatient setting including intravenous (IV) options to consider, when available.

Status Migrainosus Evaluation

It is important in the evaluation of status migrainosus to exclude secondary causes of headache. A discussion of the evaluation of secondary headaches is beyond the scope of this paper, but SNOOP4 criteria (Box) should be considered, with diagnostic imaging and laboratory studies when indicated.⁷ MRI is preferred over CT when available, except for circumstances requiring immediate imaging such as thunderclap headache, headache with loss of consciousness, trauma, or stroke. For this discussion, we will assume the patient does not have a secondary headache syndrome.

Status Migrainosus Outpatient Treatment

First-line At-Home Treatment

The American Headache Society recommends that everyone with a diagnosis of migraine be offered an acute rescue medication.⁸ The goals of acute migraine treatment are elimination of pain and associated symptoms without recurrence and with minimal side effects, allowing for return to normal functioning. Resolution or improvement at 2 hours is considered good control, and after that time, patients are often counseled to take a repeat rescue medication. For attacks that last beyond 4 hours, there are no evidence-based guidelines for next steps. Although confirmed status migrainosus is defined as longer than 72 hours, treatment for status migrainosus often begins earlier, including when status migrainosus is managed in the ED.

When dealing with a prolonged migraine attack, realistic expectations of treatment first need to be set based on the individual’s chronicity and/or frequency of headaches. For example, when a person with a 10-year history of chronic daily headache presents with an exacerbation, the goal is to provide adequate relief back to their baseline. In contrast, the goal for someone with episodic migraine is sustained pain freedom.

Acknowledging that not every attack is alike, a stratified care approach in which the patient has an arsenal of tools and is given autonomy to make appropriate treatment decisions based on experience and preference is often used. At-home oral, subcutaneous (SC), intramuscular (IM), and intranasal (IN) treatments for acute treatment of migraine attack, including the complication of status migrainosus, are accessible, cost-effective, and easy to use. Treatment with oral hydration nonsteroidal anti-inflammatory drugs (NSAIDs), acetaminophen, combination simple analgesics, triptans, gepants, or ditans at the initial onset of symptoms, when pain is mild, can often ward off a severe attack.⁸ Such treatment is often stratified with analgesics used for mild attacks and migraine-specific treatments (eg, triptans, gepants, or ditans) used for moderate-to-severe attacks. Single-dose data from both ubrogepant and rimegepant had study participants wait until the attack was moderate to severe to treat,^9,10 although the typical teaching is that medications like triptans need to be used early in an attack (see Table 2 for all doses).⁸ The potential for effective use later in attacks is encouraging because in reality, many patients wait to ensure it is a “true” migraine attack before treating.

Clinical experience has repeatedly shown subconscious “hoarding” behavior with patients waiting until an attack is “severe enough” to warrant “wasting” a rescue medication. Patients are given limited supplies of rescue medications, owing to insurance limitations or concern for medication-overuse headache, but this “wait and see approach” can result in refractory attacks, potentially leading to status migrainosus.

When attacks are severe at onset or present upon waking, the use of IN or SC triptans or IN or IM dihydroergotamine (DHE) are preferred because these bypass the gastrointestinal tract and thus have faster onset of effects. Oral, rectal, and IM antidopaminergic agents (Table 2) are available as suppositories for those with intractable nausea and/or vomiting. Another strategy for attacks that are severe from onset, with high risk for progression to status migrainosus, is acute combination therapy. In this case, a NSAID, triptan, and antidopaminergic agent may be taken at the first sign of an attack (see Rational Polypharmacy for Migraine in this issue).

Second-line At-home Treatments

Once the stratified treatment approach is deemed unsuccessful, additional tools must be deployed, and this is often done prior to 72 hours of symptoms despite length of time being part of the diagnostic criteria for status migrainosus. There is insufficient evidence to guide at-home treatment of status migrainosus, and off-label use of medication, including higher doses or increased frequency with once or twice daily dosing are most used based on expert opinion.

NSAIDs. Ketorolac is frequently used and available in oral, IM, and IN formulations. An oral liquid formulation of celecoxib 120 mg was recently approved for acute migraine treatment, however usefulness for status migrainosus is yet to be determined.

DHE. In the inpatient setting (see Inpatient Headache Treatment in this issue), use of repeated escalating doses of DHE with antiemetics has been effective.¹¹ A recent precision olfactory device (POD) for administration of DHE to the upper nasal cavity had similar efficacy as that seen with IV DHE, from 30 minutes to 48 hours with approximately 4 times more bioavailability compared with previously available DHE nasal sprays.¹² This raises the potential for an at-home modified Raskin protocol, administering IN DHE every 8 hours via POD for 3 to 5 days, with consideration of an antiemetic 15 minutes prior to each dose if nausea occurs. It should be noted that this use of DHE mesylate is off-label and may prompt a call from the pharmacy, with potential delays in treatment as well as quantity limitations that could make it impractical.

Gepants and Ditans. New options have emerged with the introduction of the gepants (ie, rimegepant and ubrogepant) and lasmiditan. Clinical experience has shown the efficacy of lasmiditan in refractory cases. Interestingly, 1 of the authors (JD) has 2 patients who each experienced complete resolution of status migrainosus with lasmiditan 100 mg at 5 and 7 days of treatment, raising the question of whether peripheral and central agonism of the 5HT_1F serotonin receptors, as occurs with lasmiditan, may be effective well into a migraine attack.

Steroids. In a retrospective chart review, oral dexamethasone at 4 mg twice daily for 4 days significantly improved pain levels in persons with status migrainosus who were treated in an outpatient setting.¹⁵ Prednisone and methylprednisolone are often used as well.

Lidocaine IN. Sphenopalatine (SPG) blocks have shown efficacy in the treatment of migraine. In the clinic setting, a catheter device is used to deliver the anesthetic to the sphenopalatine fossa. At home, lidocaine can be self-administered using viscous lidocaine with a syringe,¹⁶ or compounded lidocaine with an atomizer.

Antiseizure medications. Clinically, antiseizure medications (ASMs), typically used as preventive migraine treatment, can be considered and are useful, although evidence-based guidelines for outpatient use are lacking.

Self-Injectable Monoclonal Antibodies. Erenumab, fremanezumab, and galcanezumab are SC monoclonal antibodies (MAbs) that inhibit calcitonin gene-related peptide (CGRP) activity. Although these are approved for migraine prevention, use for status migrainosus is suggested by studies showing response in some individuals as early as the first week after injection.^17-19

Care in the Infusion Suite or in Clinic

Once at-home treatments have been exhausted, escalation to IV treatment in an infusion suite may be necessary (see Table 3 for dosing strategies). Expert consensus recommends IV fluids, dopamine antagonists, NSAIDS, corticosteroids, IV magnesium sulfate, or nerve blocks.

In-Clinic Options. For patients who are unable to self-administer IM or SC injections, administration of these options in clinic may be required. Peripheral nerve blocks are another in-clinic option with minimal side-effects. Common targets of nerve blocks are the supraorbital, supratrochlear, auriculotemporal, and the greater and lesser occipital nerve complexes. No standard injection protocol exists, and injection technique is highly variable as is the type of medication used. Lidocaine or bupivacaine are commonly used. The addition of steroids is controversial. Peripheral nerve blocks may have the added benefit of helping with allodynia. The relative safety of nerve blocks when done by a trained proceduralist, and consideration during pregnancy with steroids omitted (lidocaine is considered pregnancy class B) are other advantages. A SPG block is another noninvasive, safe, and effective technique that can be offered. Although catheters specific for this block are marketed, at-home use of IN lidocaine as well as angiography catheters have been proposed as cheap alternatives.¹⁶

Infusion Suite Options. A systematic approach to treat acute pain and decrease cortical irritability and central sensitization can be accomplished via consecutive administration of IV agents. Dehydration from vomiting or lack of oral intake is common in status migrainosus, therefore IV fluid resuscitation is typically started upon arrival. Although some studies have suggested no benefit from IV fluids,^20,21 in the absence of contraindications, we recommend generous IV fluid hydration, considering its favorable safety profile and potential benefit for pretreatment before medications that may cause hypotension (eg, dopamine antagonists or magnesium).

Antidopaminergic agents, metoclopramide, and phenothiazines (ie, prochlorperazine, promethazine, and chlorpromazine), are often used as IV antiemetics to treat the nausea and vomiting that often accompany severe migraine attacks.Anticholinergic and antihistaminergic effects may also provide beneficial sedative effects. Dopamine antagonism can relieve pain and aura symptoms, but may be associated with greater risk of adverse events, including extrapyramidal symptoms (ie, akathisia or dystonic reaction). Caution is advised and diphenhydramine preadministration recommended to reduce the risk of akathisia. Antihistaminergic effects may also have migraine-attenuating properties.²² Preadministration of IV fluid boluses is suggested because these agents may cause hypotension.

NSAIDs are often a key tool to treat status migrainosus. The IV form of ketorolac has the highest bioavailability and thus is most utilized. Systematic reviews have shown benefit of both dexketoprofen and ketorolac, with studies showing efficacy as high as 80% with ketorolac.^23-25

Studies have shown corticosteroids improve head pain and response to NSAIDS and reduced recurrence of headache after discharge.²⁶ IV corticosteroids, including IV dexamethasone and IV methylprednisolone are commonly recommended if other treatments fail.

A modified Raskin protocol can be done in an outpatient infusion suite. In this approach, 2 doses of IV DHE 0.5-1 mg separated by 6 hours, typically pretreated with an antiemetic. IV metoclopramide is preferred; however, if patients are intolerant to a dopamine antagonist, IV ondansetron, may be considered. This protocol can be repeated for 3 to 5 days provided the infusion center can accomplish 2 infusions/day. A third nighttime dose of DHE IN or SC can also be considered. There are no clinical studies supporting this use of DHE.

Magnesium sulfate is thought to exert therapeutic effect on migraine through antagonism of N-methyl Δ aspartate receptors and/or blockade of cortical spreading depression. Studies have conflicting results regarding therapeutic benefit, with some suggesting low serum ionized magnesium levels may predict response to treatment.²⁷ A systematic review of IV magnesium sulfate infusion showed benefit for pain after 1 hour, and reduced aura duration and need for analgesia.²⁸ Similar to IV fluids, IV magnesium sulfate is frequently used despite clear evidence-based guidelines because of its relative safety and multiple potential targets for therapeutic benefit.

A final consideration in the infusion suite is IV eptinezumab, a MAb antagonizing calcitonin gene-related peptide activity. There is interest in use of eptinezumab for acute treatment of attacks because it has 100% immediate bioavailability postinfusion and response to treatment has been reported as early as day 1 postinfusion.²⁹

In the first study detailing hour-by-hour and day-by-day change in headache intensity during status migrainosus treatment, dexamethasone (31%) and lidocaine-only nerve blocks (24%) were more likely to achieve pain-free status within 24 hours compared with both ketorolac and naratriptan. These differences, however, were not observed at 48, 72, and 96 hours’ posttreatment and all treatments approached equivalent efficacy on posttreatment day 4. These findings further emphasize the importance of developing consensus guidelines for conducting trials for management of status migrainosus. Defined outcomes need to be developed, considering the high variability of status migrainosus presentations and the limitations of current treatment approaches.³⁰

Inpatient and Emergency Department Treatment

Inpatient treatment is sometimes a needed option for people with status migrainosus, particularly when it is long-lasting or recurrent (see Inpatient Headache Treatment in this issue).

Avoid Referral to ED

Status migrainosus represents an estimated one-fifth of headache-related ED presentations; however, the bright, noisy, bustling environment of the ED is arguably among the least appealing places for an individual having a migraine attack.^31,32 Many studies also show that 30% or more of those treated for a migraine attack in the ED have pain return within 1 day of discharge, emphasizing the importance of the treating neurologist’s role in management of status migrainosus.^23,31-33 In a review of 44 studies by the Canadian Headache Society evaluating the acute treatment of migraine in the ED, 4 treatments were strongly recommended for migraine: sumatriptan, prochlorperazine, metoclopramide, and ketorolac.²⁷

Limitations of migraine management in the ED may include inadequate IV fluid hydration, lack of combination therapies and/or migraine specific therapies, and overuse of opioids.²² Opioids should be avoided; they are typically less effective or in some cases equally effective as multiple nonopioid acute treatments, but with an increased risk for abuse, dependence, and habituation, leading to an increase in attacks and ultimately more or longer ED stays.^22,24,25

Exceptions for opioid use are rare and include pregnancy (after IV fluids, antiemetics, and IV magnesium sulfate have been tried), individuals with no history of drug or alcohol abuse, or multiple documented contraindications to almost every other class of acute migraine medications.²² Although an ED visit is unavoidable in certain circumstances, outpatient management of status migrainosus should be employed first, making awareness of outpatient treatment options for status migrainosus imperative.

Follow-up Care

Follow-up care is important to determine what additional management tools may be needed to avoid recurrence of status migrainosus, which is not uncommon and may evolve into episodic status migrainosus. Most patients with status migrainosus have infrequent attacks that do not appear to increase after an individual episode.⁶ In follow-up care, it is important to reevaluate an acute treatment plan, consider how best to optimize acute migraine management, and identify those for whom preventive treatment is indicated. Not every migraine attack is the same and having a “tool bag” of medications with various mechanisms of action and routes of administration is imperative for persons at risk for status migrainosus. Treating early at the first sign of migraine is important, although clinical experience shows that this is not always done. Fast-acting tools such as an injectable or nasal spray may be key to those attacks that escalate quickly by bypassing the gastrointestinal tract. In patients with severe nausea and/or vomiting, having a nonoral alternative (eg, an IM, IN, oral disintegrating formulation, or suppository) may also be necessary. For some with infrequent episodic migraine, consideration of acute combination therapy (see Rational Polypharmacy for Migraine in this issue) may be warranted. It is important to keep in mind the frequent association of status migrainosus with medication-overuse headache; this type of treatment would not be appropriate for those with frequent episodic migraine or chronic migraine.

Conclusion

Treatment of status migrainosus poses a significant challenge for even the most experienced neurologist. Having a plan in place is imperative to avoid unnecessary ED visits. Knowledge of various combination treatments, including those with migraine-specific targeted therapies, as well as multiple routes of administration can better equip a clinician when faced with unremitting migraine. Although various pharmacologic and nonpharmacologic agents are available, quality evidence-based research is lacking, and it would be useful to develop consensus guidelines on how to conduct trials and define outcomes to improve the management of status migrainosus.