Inpatient Headache Treatment

With over 2 million annual visits to emergency departments (EDs) and over 80,000 hospital admissions for headache annually,^1,2 there is a tremendous need for headache management in the hospital setting. There is high prevalence of primary headache disorders (40% for tension-type headache and 10% to 15% for migraine),^3,4 such that approximately 4% of people experience headache in the US.⁵ The impact on people with headache and their communities is high with approximately 112 million migraine-associated bedridden (4-6 hours in bed due to symptoms) days per year.⁶ Associated direct medical costs of migraine exceed $1 billion dollars annually and indirect costs of absenteeism and presenteeism (being at work but not functioning optimally) secondary to migraine symptoms is more than $13 billion dollars annually.⁶

Considering the social and economic burdens and high rates of hospital admission, there is an impetus for health care professionals to develop inpatient strategies for treating headache. Data support an integrative approach using a multidisciplinary format to drive better outcomes.⁷ Individuals who need headache management in the inpatient setting need safer, more controlled environments, access to medical management for medication overuse, comorbid condition management, increased levels of care to maintain appropriate safety, and options when previous outpatient care has failed.² Most importantly, the data show that the application of inpatient treatment for headache disorders (eg, migraine) decreases disability, better treats pain, reduces use of acute rescue analgesic medication, and provides improved long-term benefits.^2,8,9 In a study of people with refractory headache symptoms, inpatient treatment resulted in over a 50% reduction in baseline symptoms in nearly 60% of all who presented for care, and 10% achieved and maintained headache freedom.⁹

Admission Criteria

Many who struggle with headache symptoms can be treated in the outpatient setting; however, for those meeting specific criteria (Box), there is a critical need to pursue inpatient treatment.^2,10-13

Interestingly, comorbid conditions have not been shown to impact clinical outcomes of inpatient treatment but do impact the overall treatment cost and complexity.⁸ For this reason, comorbid conditions are not primary considerations in the decision to admit a patient for headache management but do affect the course of treatment a person will receive. Regardless of comorbid conditions, almost 78% of persons with chronic headache symptoms treated in a comprehensive, multidisciplinary inpatient program have a moderate to major improvement in their overall pain and significant improvements in other areas, including mood, function, and behavior.⁸ To that end, it is critical to realize that owing to the severity of symptoms and disability in those who meet the criteria for admission, the length of stay will be longer than for other medical conditions. For headache management in multidisciplinary inpatient programs with the strongest outcomes, the average length is 13 days, which allows for the fundamental improvements in pain and disability and the long-term benefits of focused programs for inpatient headache treatment.^2,8,9

Inpatient Treatment Strategy

Successful multidisciplinary inpatient headache treatment relies on both scheduled (Table 1) and as-needed medications being offered simultaneously. The addition of nonpharmacologic treatments is key to success as well.

Inpatient Scheduled Cycle-Breaking Medications

Dihydroergotamine. Approved by the Food and Drug Administration (FDA) since 1946, dihydroergotamine (DHE) is a commonly used medication for headache. A specific protocol for use of repeated doses of intravenous (IV) DHE for migraine is known as the Raskin Protocol.^14,15 DHE is an ergot alkaloid with structural similarities to serotonin, norepinephrine, and dopamine thought to act on several catecholamine receptors. This activity includes inhibition of neurogenic inflammation and blockade of neurotransmission in the trigeminal nucleus caudalis that reduces central sensitization. DHE has vasoactive effects thought to be caused by potent agonist activity at 5-HT_1B, 5-HT_1D, and 5-HT_1F serotonin receptors. The side effect profile of DHE is secondary to agonist activity at 5-HT_1A, 5-HT_2A, and dopamine D2 receptors and includes nausea, vasoconstriction, and dizziness, suggesting effects at dopaminergic, muscarinic, and adrenergic receptors.^14-17

In inpatient headache centers, DHE 0.5 to 1.0 mg IV is often given over 2 to 3 hours, which is better tolerated, with less nausea, than IV bolus delivery often used in EDs. Antiemetics are often coadministered to avoid the common side effect of mild-to-moderate nausea. This process is repeated every 8 hours for 9 doses with regular nursing staff monitoring patients over the course of the entire treatment. After the first 9 doses, no DHE is used for 24 hours, and the treatment can be repeated after that if symptoms remain. Because of vascular constriction associated with DHE, inpatient cardiac screening with electrocardiography (ECG) and strong history taking are done. For individuals with a history of cerebrovascular or coronary disease, DHE is contraindicated. DHE is also contraindicated in pregnancy because of the tocolytic effect that can reduce uterine blood flow.^16,18

IV DHE with antiemetics is an appropriate and effective treatment choice for moderate-to-severe migraine, compared with parenteral opiates. DHE plus antiemetics has known benefits for medication-overuse headache and prolonged migraine attacks because DHE reduces central sensitization. Repeat administration of IV DHE with antiemetics is especially effective for status migrainosus (see Status Migrainosus in this issue) and chronic daily headache (see New Daily Persistent Headache in this issue).¹⁷ In a study of DHE use in the inpatient setting for headache, 84% of participants had improvement and more 53% had at least a moderate improvement of 50% reduction in pain scores. Full resolution was experienced by 18% and only 6.5% returned for care within 30 days of discharge after their initial admission.¹⁴ Another study of chronic migraine treated with IV DHE showed 67% of those treated reported headache freedom at discharge, and 75% reported headache freedom 1 month after discharge.¹⁹ Data also support extended benefit of up to 24 months among those treated with a repetitive DHE strategy.^16,20

Valproate. Alone or in combination with other scheduled cycle-breaking options, valproate can break the headache cycle. Valproate increases GABA levels in the brain, and this is thought to suppress migraine-related events in the cortex, perivascular parasympathetics, and trigeminal nucleus caudalis.^21,22 Valproate is also thought to suppress neurogenic inflammation and directly attenuate nociceptive neurotransmission. In addition, valproate reportedly alters levels of excitatory and inhibitory neurotransmitters, and exerts direct effects on neuronal membranes in vitro^.23,24 It is likely that valproate effects on the brain and the symptomatic presentation of headache results from a combination of actions at different loci.²⁵

Adverse effects include hyperammonemia as a frequent and short-lived finding after the loading dose is given, but this has not been associated with altered consciousness or hepatic transaminase elevations.²⁶ Typically monitoring for pre- and posttreatment ammonia levels is advised because of this risk for hyperammonemia and the related potential for delirium caused by increased serum ammonia levels. Hyperammonemia is easily managed with oral agents levocarnitine or lactulose.

Typically, 500 to 1,000 mg IV is given over 5 to 10 minutes every 12 to 24 hours. IV valproate has been shown to have superior efficacy to dexamethasone and lysine-acetylsalicylic acid.²⁷ A loading dose of IV valproate provided significant reduction in migraine headache pain severity in 75% of participants within 60 minutes of treatment.²⁷ Valproate also has evidence of efficacy for headache in as much as 80% of those with chronic daily headache, cluster headache, transformed migraine, and medication-overuse headache.²⁸

Levetiracetam. Another IV option for treatment of headache in the inpatient setting is IV levetiracetam, which inhibits L- and N-type voltage-dependent calcium ion channels with resulting reduction in perimeningeal vasodilation and neurogenic inflammation.²⁹ The most common adverse effects of levetiracetam are somnolence, dizziness, and behavioral effects, but these generally do not require discontinuation.³⁰ Levetiracetam is typically given as 500 to 1,000 mg IV every 8 to 12 hours. Data support significantly improved frequency and severity of the symptoms by more than 50% among people with chronic migraine.^31,32

Lidocaine. The use of lidocaine for cycle-breaking headache therapy is well established and effective.³³ Lidocaine is an amide anesthetic that inhibits voltage-gated sodium channels and is thought to affect transmission of pain in the peripheral nervous system at these channels.³⁴ Lidocaine treatment requires a pretreatment ECG and lab studies for serum levels of magnesium and potassium. Telemetry heart monitoring for the entirety of the treatment is needed, and ECGs should be repeated every 2 to 4 days of treatment or if cardiac symptoms present. Lidocaine is given 1 mg/min for the first 4 hours of treatment and then 2 mg/min thereafter,³³ a goal blood level of 4 to 5 mcg/mL, which should be checked daily. Lidocaine is effective; in 1 study, there was complete response in 25% of participants and a significant, although partial, response in an additional 57% of those treated.³⁵

Magnesium Sulfate. Alone or in combination with other treatments, magnesium sulfate reduces pain intensity, but toxicity can occur. Monitoring for loss of normal reflexes is critical because these can be the first signs of toxic levels (>1.5 normal ranges). Magnesium sulfate should be avoided in anyone with active renal insufficiency. Serum magnesium levels should be checked every 48 to 72 hours, if infusions are scheduled daily.³³ The typical dose is 1 g IV magnesium sulfate every 12 to 24 hours. Data suggest pain intensity is improved within 60 to 120 minutes, and complete pain relief has been observed along with reduced need for rescue analgesia at any point. Recurrence of headache within 24 hours is also reduced with magnesium sulfate.³⁶ Compared with dexamethasone/metoclopramide treatment, magnesium sulfate is a more effective and fast-acting medication for acute treatment of migraine headaches.³⁷

Other headache types (eg, chronic tension type and chronic cluster headache) also benefit from magnesium sulfate infusion, which has been shown to provide rapid relief of headache pain in persons with low serum magnesium. Low serum and brain tissue ionized magnesium levels may precipitate headache symptoms in susceptible individuals.³⁸

Ketamine. Use of subanesthetic ketamine treatment has grown as an off-label option in outpatient headache treatment either as an infusion or nasal spray. There is very limited adoption, however, for sustained treatment of headache in the inpatient setting. The mechanism by which ketamine treats headache is not understood, although it may reduce chronic pain by inhibiting glutamate-induced neurotoxicity mediated by NMDA receptors, where ketamine has antagonist activity. Inhibition of NMDA receptors may thereby decrease central sensitization and specifically, in migraine, inhibiting cortical spreading depression. Psychomimetic adverse events (eg, hallucinations, vivid dreams, and central nervous system agitation) deter many from using ketamine. Rigorous data on use of ketamine beyond single-visit use in the ED in people with medication-refractory headache not admitted to the hospital is limited. Data that do exist support potential improvement with ketamine, although the dose strategy that will best achieve successful outcomes and reduce risks is not yet determined. Ketamine is an underdeveloped tool with limited utility for inpatient headache treatment.

IV Hydration. As a formal treatment for inpatient management of headache, IV hydration is not a tool for headache care but rather an appropriate supplemental treatment for fluid loss due to nausea/vomiting or overall low volume status. There is limited data supporting it as a primary treatment option and should not be considered a formal treatment modality for inpatient cycle breaking.

Inpatient As-Needed Medications

The goal of as-needed medications in the inpatient setting is to provide continued support for breakthrough pain and capitalize on the improvements from scheduled medications (Table 2).³³ Such a synergistic approach allows for best clinical outcomes.

Diphenhydramine. Although it may be used in a scheduled fashion, diphenhydramine also serves as a beneficial as-needed medication for managing status migrainosus. Important considerations include monitoring the ECG for QT prolongation. Typical dosing is 50 to 100 mg every 6, 8, or 12 hours as needed up to a maximum dose of 100 mg IV every 6 hours.³³

Ketorolac. Ketorolac is used as needed in the inpatient setting for breakthrough pain in chronic migraine. Ketorolac is a nonsteroidal anti-inflammatory drug (NSAID) that exerts its effects by blocking prostaglandin production. Ketorolac is not to be used in those with renal insufficiency; individuals over age 65 should have the dose limited to 15 mg IV. For others, the typical dose is 30 mg IV every 8 to 12 hours. Ketorolac is an important as-needed medication to consider because it does not have sedating properties and does not affect the QT.³⁹

Levetiracetam. Levetiracetam, discussed earlier as a scheduled medication, is also vital for as-needed utilization. It is valuable in that it does not affect the QT and is not overly sedating for most patients. For most, dosing can be increased to 750 to 1,000 mg, but typical dosing is 500 mg every 8 to 12 hours as needed.³³

Olanzapine. A second-generation antipsychotic, olanzapine is also commonly used as needed. Olanzapine has antagonist activity at D2 receptors in the mesolimbic pathway and can be quite sedating for some individuals.³³ Typical dosing is 2.5 to 5 mg administered 2 to 4 times/day as needed.

Divalproex. Divalproex is not overly sedating and does not affect QT but may cause ammonia elevations. If lethargy, slurred speech, or confusion occur, the ammonia level should be checked and hyperammonemia managed if present. A serum pregnancy test prior to administration is appropriate in persons of childbearing potential.³⁹ The typical dose is 500 mg IV, piggyback and can be increased to 750 mg or 1,000 mg as needed.

Droperidol. Commonly used with either benztropine or diphenhydramine IV to avoid unwanted side effects including restlessness and agitation, droperidol provides favorable responses with side effects of anxiety, akathisia, and somnolence.⁴⁰ It is important to monitor the ECG with droperidol because it can prolong the QTc.⁴¹ Typical dosing is 0.625 to 2.5 mg IV every 6 to 12 hours as needed.

Chlorpromazine. Similar to droperidol, chlorpromazine is commonly used with either benztropine or diphenhydramine to avoid unwanted side effects. Thorazine can be quite sedating for some, and typically if both chlorpromazine and droperidol are used, one or the other will not be prescribed on an as-needed basis.⁴² As with droperidol, it is important to monitor the ECG for QTc prolongation. Typical dosing is 12.5 to 25 mg IV, piggyback every 6 to 12 hours as needed.

Nonpharmacologic Treatments

There are also several nonpharmacologic approaches to inpatient migraine treatment that together with medications contribute to a successful multidisciplinary approach.⁴³

Biofeedback. Biofeedback is a behavioral technique in which the end goal is to develop self-awareness and control over heart rate, breathing, and muscle tension through relaxation techniques.⁴⁴ Biofeedback has been shown to reduce disability and improve function in people with migraine.⁴⁴ There are certain individuals for whom a behavioral approach such as biofeedback is warranted including those with preference for a nondrug approach, who are pregnant or plan to become pregnant, or have intolerance of or medical contraindications to drug treatment.⁴⁵ In a study, most improvements in migraine frequency came after thermal biofeedback training, with almost complete elimination of migraine attacks by the end of training and usefulness for 54% of participation.⁴⁶

Acupuncture. Acupuncture is a safe and effective alternative for those whose headaches have not responded to pharmacologic treatment.⁴⁷ Acupuncture is a form of traditional Chinese medicine that involves placing needles or pressure (acupressure) in specific locations along the skin, primarily to achieve pain control. Many studies suggest acupuncture is beneficial, including a meta-analysis of 22 trials comparing acupuncture with no acupuncture in 4,985 participants. The main results showed 41% of patients who had acupuncture vs no treatment had at least a 50% reduction in migraine frequency.⁴⁷

Neurostimulation. Medical devices used in the inpatient setting include peripheral neuromodulation and trigeminal nerve stimulation. Classic techniques act by stimulating the nervous system centrally or peripherally, either with electric current or a fluctuating magnetic field.⁴⁷ Examples include supraorbital nerve stimulation which is a form of transcutaneous cranial nerve stimulation. Noninvasive vagus nerve stimulation is another medical device commonly used, delivering transcutaneous current to the cervical branch of the vagus nerve.⁴⁷

Psychiatric treatment. Cognitive behavioral therapy (CBT) for migraine is shown to reduce headache frequency and improve pain scores.⁴⁸ CBT uses cognitive factors to improve mental disorders and psychologic distress. It is a selective psychotherapy that can help in problems ranging from depression and anxiety to chronic pain conditions and addiction.⁴⁸ Migraines are difficult to treat, and it is beneficial to have a wide variety of nonpharmacologic approaches to treatment that serve as an alternative to avoid unwanted side effects.⁴⁷

Inpatient Headache Unit Focused Accommodations

Managing the environment and support systems in place where a patient is cared for becomes even more critical for patients who are in crisis. There are simple changes to inpatient units that are invaluable for patients:

• Dedicated headache-focused staff who support the mission of the headache unit vs float staff who will be less familiar with the headache management protocols;
• Carpeted floors wherever possible to reduce noise;
• Dimmable lights;
• Double blackout shades or curtains;
• All private rooms;
• Comfortable home clothing vs a hospital gown;
• No scents on the floor for staff, patients, visitors;
• Computer screens off in rooms after documentation;
• Decaffeinated coffee only on the floor;
• Modest exercise equipment;
• Hospital nutrition service comfortable with developing a low tyramine diet option;
• Visitor policy allowing a loved one to stay with patient
• Family-sized room to support visitor policy; and
• Dedicated in house/on floor clinical pharmacy, clinical nutrition, clinical physical therapy, clinical psychology, yoga, acupuncture, massage, pain management, and case management.

These tools ought to be employed to offer the most productive experience and most positive short term and long-term outcomes for patients receiving a multidisciplinary and multimodal inpatient treatment strategy.

Conclusion

Headache morbidity causes tremendous social and economic burdens.⁴⁹ Using a multimodal and multidisciplinary approach for management of refractory and severe headache symptoms will drive the best possible outcomes. This result is most effectively realized with strong initial admission considerations, scheduled IV medications, timely as-needed IV medications, and broad nonpharmacologic treatment tools.^50,51