Status migrainosus

Management
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By Michael A Ament MD and Sahar Swidan PharmD

Many patients present to the hospital emergency department, either at the behest of their treating primary physician or on their own, 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.

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, but they are most often addressed by the patient’s primary physician in the outpatient setting.

Acute inpatient hospitalization for the treatment of headache without a serious underlying organic medical condition should be considered rarely, and the goals of admission should be clearly defined. Patients with a severe, persistent headache (status migrainosus or chronic daily headache) may have headache despite, or because of, the use of analgesics, narcotics, ergots, and triptans (Silberstein 1992a). If the headache is of long duration, depression, low frustration tolerance, and physical and emotional dependency on abortive medication may coexist. Overused drugs must be withdrawn  for prophylactic medication to be effective. Detoxification can be difficult, and, if the headache persists and is associated with intractable nausea and vomiting, hospital admission may be required (Silberstein et al 1990; Silberstein and Silberstein 1992b; Silberstein and Lipton 2001).

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 (Silberstein et al 2001).

Detoxification guidelines (Silberstein et al 2001):

  1. Fluid replacement for 24 to 48 hours
  2. Ergotamine tartrate can be discontinued abruptly if 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. Rapid discontinuation can be achieved by giving phenobarbital.
  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 (Gold et al 1980; Bakris et al 1982).

An overview of treatment is presented in Table 3.

Table 3. Treatment of Status Migrainosus

  • Consider IV fluids
  • Pretreat with:
    • prochlorperazine (5 to 10 mg IV) or
    • metoclopramide (10 mg IV)
  • Treat with:
    • dihydroergotamine (0.5 to 1.0 mg IV)
  • If headache persists:
    • in 1 hour give additional dihydroergotamine (0.5 mg IV)
  • Additions:
    • ketorolac (30 to 60 mg intramuscularly or IV)
    • valproate (500 to 1000 mg IV)
    • diphenhydramine (25 to 50 mg IV)
    • levetiracetam (1500 mg IV)
    • magnesium sulfate (1 gram IV push)
  • 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. Prochlorperazine (5 mg IV) or metoclopramide (10 mg IV) followed by intravenous dihydroergotamine is a safe and effective means of terminating a migraine attack (Callaham and Raskin 1986; Evers et al 2009; Morren and Galvez-Jimenez 2010). The combination of intravenous metoclopramide and intravenous dihydroergotamine is more effective in treating an acute migraine attack than is intramuscular meperidine (Belgrade et al 1989). Raskin has advocated mixing 10 mg (2 mL) of prochlorperazine and 1 mg (1 mL) of dihydroergotamine in a syringe and injecting 2 cc of the mixture intravenously. If the headache is not relieved in 15 to 30 minutes, the remainder of the dose can be injected. At times the addition of diazepam (5 to 10 mg IV) will help terminate the headache attack (Raskin 1990).

Repetitive intravenous dihydroergotamine. Patients who have truly intractable headaches should be admitted to the hospital and treated with repetitive intravenous dihydroergotamine (Raskin 1986; Silberstein et al 1990; Silberstein 1992a; Silberstein and Young 1995). 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 mg of dihydroergotamine is continued every 8 hours. If nausea develops, the dose is decreased, and the metoclopramide 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 (Raskin 1986).

Contraindications. Coronary artery disease, prinzmetal angina, peripheral vascular disease, prolonged aura, basilar migraine, pregnancy, 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) to reduce nausea, flushing, and chest symptoms. Mixing with an equal volume of saline reduces side effects.

Cost and cost-effectiveness. Dihydroergotamine is moderately expensive.

Pediatric consideration. Children are given low doses of IV dihydroergotamine (0.1 to 0.5 mg IV every 8 hours) (Linder 1991).

Neuroleptics. Controlled studies have shown that intravenous chlorpromazine (Lane and Ross 1985; Lane et al 1989; Bell et al 1990; Da Costa et al 1998; Bigal et al 2002b) and prochlorperazine (Callaham and Raskin 1986; Jones et al 1989; Tanen et al 2003) are effective in controlling intractable headaches. Lane found that chlorpromazine (0.1 mg per kg repeated up to 3 times) is more effective (73% with complete relief) than the combination of meperidine and dimenhydrinate. Da Costa used an IV dose of 0.7 mg/kg with a total dose of less than 50 mg. Bigal demonstrated an effectiveness of 64.9% (using 0.1 mg/kg) in a group of patients suffering from migraine without aura and 70% among patients with migraine with aura (Bigal and Tepper 2003). Marmura provides a good review of the topic (Marmura 2012).

Callaham and Raskin found that prochlorperazine (5 mg intravenously) was effective in treating emergency room patients, and Jones and colleagues found that prochlorperazine (10 mg intravenously) was more effective than placebo in the same cohort (Callaham and Raskin 1986; Jones et al 1989). Tanen compared intravenous sodium valproate to intravenous prochlorperazine in a prospective double-blind trial and demonstrated that 79% of those patients receiving valproate required rescue treatment compared to 25% of those treated with prochlorperazine. In 2001, Kabbouche and colleagues (Kabbouche et al 2001) 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.

Although neuroleptics are locally irritating when given intravenously, they are more effective than when given by suppository or intramuscularly. However, in a randomized, double-blind, placebo-controlled trial, rectal prochlorperazine (25 mg) has been shown to be an effective migraine treatment in the Emergency Department (Jones et al 1994). The neuroleptics haloperidol and thiothixene given intramuscularly and metoclopramide (10 mg intravenously or intramuscularly) are anecdotally effective as adjunct or primary treatment for severe migraine headache (Silberstein et al 1990). Prochlorperazine, 10 mg intravenously, was found to be more effective than the same dose of metoclopramide in a randomized, placebo-controlled trial of patients with migraine headache (Coppola et al 1995). In an open study, 5 mg IV haloperidol was shown to be effective in the acute treatment of migraine (Fisher 1995). Wang and colleagues, in an open, ambulatory infusion center study, used intravenous droperidol to treat 25 patients with status migrainosus and to treat an additional 10 patients with refractory migraine (Wang et al 1997). Droperidol, a butyrophenone with strong neuroleptic and anti-emetic properties, is used to supplement anesthesia. Droperidol, a butyrophenone with strong neuroleptic and anti-emetic properties, is used to supplement anesthesia. Droperidol (2.5 mg) was given intravenously every 30 minutes until either 3 doses were given or the patient was completely or almost headache-free. Most of the patients studied (88%) responded with a recurrence rate of 23%. Sedation and akathisia were common, whereas hypotension was rare. 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 (87%), 5.5 mg (81%), and 8.25 (85%) or matching placebo (57%) (Silberstein et al 2001b). The percentage of patients achieving a pain-free response at 2 hours post treatment was significantly greater than placebo for the treatment groups. 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 failed to reach statistical significance. A significantly greater percentage of patients receiving droperidol 2.75 mg 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.

Oral, rectal, intramuscular, or intravenous neuroleptics may be used as primary therapy or as adjunct treatment for nausea. Patients receiving neuroleptics must be monitored carefully for hypotension, sedation, and dystonic reactions. Orthostatic hypotension can be avoided by maintaining the patient supine for several hours following neuroleptic administration (Silberstein et al 2001).

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 (Wang and Silberstein 1997).

Contraindications. Known hypersensitivity to agent.

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.

Corticosteroids. Parenteral corticosteroids, either alone or in combination with other symptomatic medications, have been used to treat severe, resistant headache. One study suggests that dexamethasone (4 mg intravenously) following pretreatment with intravenous metoclopramide is effective in the treatment of acute migraine headache (Klapper 1991). Another study notes that adding dexamethasone to a narcotic regimen provides additional relief (Gallagher 1986). A third study proposes that 4 mg of dexamethasone in conjunction with a triptan and a nonsteroidal anti-inflammatory drug will decrease recurrence in a limited population (Krymchantowski and Barbosa 2001). Methylprednisolone may also be helpful in the treatment of status migrainosus (Robbins et al 2010). Clinical experiences also support the view that steroids, such as a rapidly tapering short course of prednisone (starting with 80 to 100 mg/day) or dexamethasone (starting with 8 to 20 mg/day), will assist in terminating an otherwise refractory migraine (Rozen 2002). Inpatients can be treated with high dose intravenous corticosteroids, alone or in conjunction with neuroleptics or dihydroergotamine, to help terminate a headache cycle (Silberstein et al 2001).

Standard dosage. Methylprednisolone sodium succinate 100 to 200 mg IV q 12° for 3 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 but in national shortage.

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, has been marketed. Clinical results suggest that it is a safe, effective, and well-tolerated treatment for intractable migraine (Norton 2000; Edwards 2001; Krusz 2001; Shahien et al 2011).

Standard dosage. Intravenous valproate 500 mg every 8 hours was as effective as dihydroergotamine and metoclopramide (in this case 0.5 mg dihydroergotamine with 5 mg metoclopramide every 6 hours) with few side effects (Mathew and Kailasam 2000).

Contraindications. Pregnancy, preexisting 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). Dizziness, tremor.

Main side effects. This is a relatively new use for this drug. Its overall role in treating medication overuse headaches is still to be determined.

Cost and cost-effectiveness. Hospitalization is expensive. Intravenous medication that might improve treatment and shorten the hospitalization is cost-effective. Repetitive IV valproate is moderately expensive.

Intravenous propofol. A treatment for intractable headache using subanesthetic doses of intravenous propofol has been studied (Krusz et al 2000). In this study, intravenous propofol was given in an outpatient setting; some, however, only use this treatment in a monitored inpatient setting.

Standard dosage. Propofol 20 to 30 mg intravenous push, repeat every 5 minutes based on patient alertness, blood pressure, and respiration. The average dose in a published outpatient study was 110 mg (Krusz et al 2000). A higher dose (400 mg) has been used in a headache center (Young 2001).

Contraindications. Asthma, respiratory muscle weakness, and known hypersensitivity.

Main drug interactions. Lower doses may be needed in patients using other sedating medications.

Main side effects. Bradycardia, hypotension, decreased cardiac output, hyperlipidemia, apnea, respiratory acidosis, talkativeness, sedation.

Special points. Different clinicians have different approaches to assuring cardiovascular safety.

Cost and cost-effectiveness. Intravenous propofol is expensive but doses are low compared to those given during anesthesia and those given to hospitalized intensive care patients, who receive continuous drips.

Other acute treatment. Other forms of pharmacotherapy have been suggested as potential treatment for status migrainosus. Hand and Stark (Hand and Stark 2000) studied intravenous lignocaine in 19 chronic daily headache patients, 3 of whom had status migrainosus. Five infusions were given to those 3 patients, with 4 of the infusions relieving headache. Another study by Stark and Williams focused on 71 patients with chronic daily headache who were admitted for lignocaine infusion. 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.

A double-blind study of repeated intranasal capsaicin in 8 patients with chronic migraine (Fusco et al 2003) 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 (Demirkaya et al 2001) and Bigal and colleagues (Bigal et al 2002a) 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 (Mauskop et al 2002). However, Corbo and Esses (Corbo and Esses 2001) also studied intravenous magnesium as adjuvant therapy in 44 emergency room patients. Approximately half of these received metoclopramide plus magnesium. Data analysis suggests that the addition of magnesium may have attenuated the effectiveness of other treatment.

Levetiracetam, an antiepileptic medication, has also been used with varied efficacy. The data are less robust; however, several studies indicate its potential usefulness in the treatment of status migrainosus and as a migraine prophylactic agent (Brighina et al 2006; Mechtler 2006; Farooq et al 2007).

As a second-line agent, diphenhydramine can be used in conjunction with phenothiazines (metoclopramide) or other therapies. Swidan and colleagues published their experience with diphenhydramine at a national tertiary center for head pain treatment, indicating efficacy (Swidan et al 2005). Friedman and colleagues studied trimethobenzamide/diphenhydramine (TMB/DPH) versus sumatriptan in the treatment of acute migraine (Friedman et al 2006). Although not as efficacious as sumatriptan, 80% of patients treated with TMB/DPH achieved headache relief at 2 hours.

In addition to pharmacotherapy, other approaches have been considered. At least 1 case report has been written detailing the use of botulinum toxin in status migrainosus (Poungvarin 2001). Further research is currently being done. Popeney and Alo (Popeney and Alo 2003) studied 25 patients with transformed migraine who had C1 to C3 peripheral nerve stimulators implanted. The average improvement in MIDAS score was 88.7%. However, it is unclear how many of these patients would have met the definition of status migrainosus.

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.

In This Article

Introduction
Historical note and nomenclature
Clinical manifestations
Clinical vignette
Etiology
Pathogenesis and pathophysiology
Epidemiology
Prevention
Differential diagnosis
Diagnostic workup
Prognosis and complications
Management
Pregnancy
References cited
Contributors