Introduction to intravenous headache treatments for patients and families
A good acute treatment plan for migraine at home consists of quick hydration with electrolyte solution (sports drink) and appropriately dosed medicine (Anti-inflammatory medications such as Ibuprofen and or specific triptan migraine medications recommended by your physician) taken as soon as possible.
Despite a robust acute treatment plan and appropriate 2nd dose of NSAID and/or triptan taken within the allocated time, many children may still end up with a “stubborn” headache that refuses to go away. In this case, children may benefit from intravenous medications administered either in infusion center/inpatient or the emergency department. Intravenous medications are a group of medications administered through the vein and require needle insertion. An Emergency room or infusion center visit for intravenous medications may cause stress in both children and their caregivers. A basic knowledge regarding these medications may help to better prepare the children and their caregivers and may help relieve some stress. We will briefly discuss various intravenous medications used for intractable migraine when home therapy fails.
Intravenous Hydration : Over 60% of our body is made of water and electrolytes. Many children with attack of migraine experience nausea, vomiting, and decreased appetite resulting in dehydration and loss of electrolytes. Many times, it is not possible to adequately hydrate our body by drinking electrolyte solution alone and intravenous hydration is warranted. The majority of children coming to emergency department require needle insertion for various reasons, hence we suggest intravenous fluid bolus depending upon degree of dehydration, age, and weight. A quick intravenous fluid bolus may replete essential fluid and electrolytes and prepares our body to safely handle other medications.
Intravenous non-steroidal anti-inflammatory drugs (NSAIDs): Ketorolac : Ketorolac belongs to the same group of medicines as ibuprofen, naproxen etc. called non-steroidal anti-inflammatory drugs (NSAID). Once oral NSAIDs fail, you may respond to intravenous NSAIDs. A single dose of ketorolac is given along with intravenous fluid and dopamine antagonists. Together these are over 85% effective with good tolerance and minimal side effects.
Intravenous dopamine receptor antagonists : Dopamine receptors are found to be important in initiation of attack of acute migraine so medicines targeted against those receptors in the brain may provide quick relief. There are different medicines included in this group including metoclopramide, prochlorperazine, and chlorpromazine. In children, prochlorperazine (Compazine) is found to be more effective in relieving headache especially when combined with ketorolac and hydration. Prochlorperazine is usually tolerated well but around 5% children report side effects. Most common side effects include agitation or uneasiness, anxiety (akathisia) and muscle rigidity or tightness (dystonia). These side effects are dose dependent and may not occur in lower doses. These side effects resolve by oral or intravenous diphenhydramine (Benadryl). Those children who respond to prochlorperazine but have some side effect, may be given lower dose next time or use a different medication that works on the same receptors.
Intravenous Steroids : Inflammation is an important part of acute migraine; steroids help to decrease inflammation. There is no evidence that oral steroids help in acute migraine, but intravenous steroids may help to decrease the relapse of acute headache in selected cases. Intravenous steroids may result in side effects including serious injury of joints and bones called avascular osteonecrosis. At present, not everyone is being offered intravenous steroids, but selected group of children may benefit with single intravenous steroid (dexamethasone) to reduce relapse of headache.
Intravenous Dihydroergotamine (DHE) : DHE is one of the oldest medicines used to treat intractable migraine not responding to usual intravenous treatments or migraine lasting > 72 h. DHE modulates the nerves carrying pain signals in the trigeminovascular system and also constricts blood vessels. DHE can be given in the ED as a single dose or in the inpatient setting where it is given every 8 h for up to 15 doses. Most children respond after 5 doses. DHE is very effective in treating intractable migraine or migraine lasting > 72 h. DHE is tolerable in children aged 6 and above but is usually associated with nausea, and vomiting, so anti-nausea medications may be given prior to DHE. Some children may also experience chest tightness. The goal of DHE treatment is either to achieve headache freedom or reduce the pain back to the “usual” level. Once this goal is achieved, usually one extra dose of DHE is given for sustained response.
Intravenous Valproic Acid infusion : Valproic acid is one of the anti-seizure medications which helps to resolve the acute migraine by acting at various ion channels in the brain. Valproic acid can be given either as single intravenous load or multiple loads including continuous infusion. In children it has been observed that valproic acid load, followed by continuous infusion for 24–48 h may help to resolve attack of migraine lasting > 72 h. It may also be given to those children who cannot take DHE or are unresponsive to DHE. The continuous infusion of valproic acid is tolerated well with similar risk profile as single dose. No major side effects are reported in various studies. It is suggested to check liver function tests, blood cell counts, and valproic acid levels while on the infusion. Youngsters of childbearing age need a pregnancy test, since valproic can cause defects in the fetus.
Novel Intravenous Drugs: CGRP antibodies. Calcitonin Gene Related Peptide (CGRP) is a small neuropeptide involved in the pathogenesis of migraine. There is a new class of drugs called CGRP antibodies which block the CGRP (molecule or receptor) and treat the migraine. Recently, an intravenous CGRP antibodies drug, eptinezumab, has been used to treat acute attack of migraine in adults and found to be effective . The side effects are limited to injection site reactions only. Currently it is approved only for adults, but is being trialed in children. In the near future, intravenous CGRP antibodies may provide safe, efficient, and cost-effective way to treat acute migraine unresponsive to oral treatment. For more information please see chapter on Treatments that Target CGRP.
Other intravenous treatments : There are other intravenous medicines trialed in some cases of intractable migraine in children including different anesthetic drugs like propofol and lidocaine. At present there may be more risk than benefit and these medicines are usually not recommended for general use.
Other injectable treatments (not IV) : Peripheral nerve blocks are injections of local anesthetic medicines over nerves in the scalp. Nerve blocks can be helpful to treat “stubborn” headaches. See more information in the chapter on Preventive Injections.
What to do when the headache does not respond to an infusion in the emergency room
Advice for the primary care clinician and headache specialist
About 7% of patients who receive the “Migraine cocktail” of Intravenous hydration,ketorolac, and an antidopaminergic medication, will still need further treatment. The next step would be to admit into a hospital bed for longer and more aggressive treatment. The main therapy used in an inpatient neurology service is dihydroergotamine (DHE). Treatment protocol and modality will be detailed in the following paragraphs.
The goal of the above intravenous treatments is to reduce the pain to 0/10 or to the patient’s baseline pain level. Some patients function with a low-grade continuous headache and they call you because they are going through a severe exacerbation where the headache is disabling, and they are unable to function at school or at home. For these patients the goal for an ED visit is to get them to a functioning level which may not be a 0/10 level.
Migraine headache is mostly treated in outpatient setting. Headache specialists and primary care physicians usually focus on maximizing the outpatient treatment as reviewed in previous chapters in this book. Most of the outpatient treatments include a high dose of abortive medication (NSAID and/or triptan), combined with preventive approaches that may include preventive medication but also emphasizes healthy habits as well as coping skills and stress management.
Once in a while, an acute situation will occur where the usual outpatient plan will not work. This is frequent during teenager years especially in girls, but boys can have it too. When a headache lasts 72 h or more the patient is considered to be in status migrainosus and a more aggressive approach is necessary. So, when the headache gets bad, IV therapy should be discussed with the child and the family. If the headache is disabling, prolonged, and severe then the next step is to involve the youngster in the decision about coming into the ED. Usually children are agreeable if the headache is severe and disabling. The goal of treatment is not only to abort the acute disabling headache but to prevent it from becoming a chronic daily occurrence.
The child will need to be referred to the Emergency room (ED) or infusion center. Good communication with the center is very important. Staff in that facility need to be made aware of the specific instructions for appropriate treatment which should never include narcotics. A note can be faxed to them with recommendations with clear instructions of the treatment you recommend usually known as the “Migraine cocktail” (IV hydration, ketorolac, and an antidopaminergic medication).
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Intravenous hydration:
Intravenous hydration is essential in migraine headache due to the theory of an underlying inflammatory process occurring and fluid leakage. Also, most patients with an acute intractable headache are usually dehydrated and the fluids will help decrease the risk of any possible side effects of the abortive therapies that will be given during the visit.
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The dopamine receptor antagonists
Different dopamine antagonists are used in the acute treatment of migraine. The most frequent medications used are Prochlorperazine (Compazine) and metoclopramide (Reglan). One pediatric study in the ED showed that these medications are both effective in treating an acute attack but Prochlorperazine had a much higher positive response. Both had a better response at 1–2 h when combined with ketorolac. Dopamine antagonists are tolerated well but side effects may occur.
The most frequent antidopaminergic side effects are not limited to feeling anxious and restless (akathisia), but sometime patients will have a more prominent dystonic reaction including muscle spasms and “feeling stuck.” This requires Diphenhydramine orally or IV depending on the severity of the reaction and the patient’s comfort level. Diphenhydramine (Benadryl) should not be used as a preventive therapy since it blocks the effect of the antidopaminergic and eliminates its therapeutic effect on the migraine. It should only be used to treat a reaction only.
Another benefit of these medications is the control of the severe nausea and or the vomiting that frequently occur during a severe migraine.
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Intravenous non-steroidal anti-inflammatory drug (NSAID)
A multi-center non-placebo double blind cross over study compared intravenous prochlorperazine (0.15 mg/kg; maximum 10 mg) with Ketorolac (0.5 mg/kg; maximum 30 mg) in patients simultaneously receiving an intravenous saline bolus of 10 mL/kg. Patients who received both medications had a much higher response rate at 1 and 2 h. Based upon that, the usual recommendation is to use both IV ketorolac (0.5 mg/kg with maximum 30 mg) + IV prochlorperazine (0.15 mg/kg with 10 mg maximum) for an acute intractable attack of migraine that is unresponsive to home treatment. Ketorolac as you know is a parenteral non-steroidal anti-inflammatory medication with higher bioavailability acutely then over the counter medications when given through the IV for acute headache. It is widely used as part of the Migraine cocktail with limited side effects and contraindications such as bleeding disorders, or kidney disease.
Intravenous dihydroergotamine (DHE)
DHE is part of the ergot family. Ergot is a natural potent vasoconstrictor and has affinity for various serotonin, dopamine, and adrenergic receptors. DHE has an affinity for various serotonin receptor (5-HT) subtypes, but its anti-migraine effect is thought to be due to agonism at 5-HT 1B and 5-HT 1D . The 5-HT 1B receptors are widely distributed in cranial vessels and their stimulation leads to vasoconstriction. 5-HT 1D receptors are richly distributed in trigeminal nucleus caudalis and their stimulation leads to inhibition of inflammatory and vasoactive peptides including CGRP and Substance P. Thus, DHE may help to decrease vasogenic edema and block nociceptive pathways in the trigeminal vascular system. There is a lack of placebo-controlled studies for DHE but there is good evidence for tolerability, dosing, and efficacy in pediatric patients with an intractable attack of migraine. IV DHE is usually reserved for status migrainosus (migraine lasting > 72 h) or an attack of migraine that has been refractory to outpatient and ED management including other IV therapies.
Intravenous DHE is usually given to children and adolescents aged 6 years and above. Based on clinical experience and retrospective outcome studies, dosing, response, and tolerability of DHE in pediatric population has been established. Patients age ranging from 6–10 years (or < 30 kg) are treated with 0.5 mg/dose up to 15 doses, while patients aged 10 years and above (or ≥ 30 kg) are given 1 mg/dose up to 15 doses. Doses are given at 8 h intervals. Patients usually receive 1 additional dose after reaching the goal of treatment. Most patients respond by the 5th dose of IV DHE, which may be a good time to evaluate overall response ( Fig. 1 ), although a smaller patient group responded after 12th dose which may justify doses up to 15 mg.
