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Headache ISSN 0017-8748 © 2010 the Authors doi: 10.1111/j.1526-4610.2009.01597.x Journal compilation © 2010 American Headache Society Published by Wiley Periodicals, Inc. Expert Opinion

Rescue Me: Rescue for Migrainehead_1597 307..313

Chad Whyte, MD; Stewart J Tepper, MD; Randolph W. Evans, MD

(Headache 2010;50:307-313)

Treatment of a persistent when acute or (DHE) are not medication fails can be challenging. effective at all, what symptomatic options are available? CASE HISTORY A 35-year-old woman has a 15-year history of EXPERT OPINION migraine without aura occurring 1 time per week. She This case illustrates a very important point that has tried a variety of triptans, - may not be apparent to many physicians, namely that sodium, and dihydroergotamine nasal spray but the up to 40% of all attacks and 25% of all patients do not consistency of response is about 60% even when respond to therapy.1 If one factors in the taken when the headache is mild, with recurrence of number of patients intolerant to triptans as well as headache about 25% of the time. The headaches can those in whom triptans are contraindicated, there is a be severe, interfering with ability to function, and very large number of migraine sufferers who need occasionally with vomiting lasting up to 2-3 days.Trip- acute treatment other than triptans (and ergots). tans are inconsistently effective when taken for a Therefore, it is prudent for a physician treating second dose. She is on topirimate 100 mg, which has migraineurs to be aware of other options for abortive decreased the frequency of headaches from 3 per as well as what should not be used.We will week. She is otherwise healthy on no other medica- attempt to answer the questions posed above, begin- tions except for an oral contraceptive. ning with what is available as symptomatic treatment Questions:What rescue medication is available as aside from triptans and ergots, including both outpa- an outpatient and what is the evidence for efficacy? If tient and emergency treatments, and conclude with she were to go to the emergency department with a reasons as to why and -containing severe headache, are there other options? Are opiates mixtures should not be used (please see Table). and butalbital relatively contraindicated in the Most patients opt for over-the-counter (OTC) symptomatic treatment of migraine? If a patient has before seeing a physician, as they are contraindications to use of triptans or ergots or if readily available and inexpensive. Over half of the diagnosed migraineurs in the US use OTC analgesics, Expert opinion by: Chad Whyte, MD and Stewart J. Tepper, which are effective in up to 60% of cases.2,3 The major- MD, Center for Headache and Pain, Cleveland Clinic, 9500 Euclid Ave., Neurological Inst T-33, Cleveland, OH 44195, ity of the OTC analgesics contain a “simple analge- USA. sic,” that being a medication effective for mild to Case history by: Randolph W. Evans, MD, 1200 Binz #1370, moderate headache, such as a non-steroidal anti- Houston, TX 77004, USA. inflammatory drug (NSAID) or acetaminophen.

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Table.—Recommended Abortive Medications for Migraine Other NSAIDs that have been shown to be effec- Other Than Triptans and Ergots With Doses tive for migraine in randomized, placebo-controlled studies include tolfenamic acid, naproxen, , NSAIDs , , flurbiprofen, , and 500-1000 mg po .11-18 Although no placebo-controlled studies Ibuprofen 800-1200 mg po Naproxen 500-1100 mg po have been performed, is used frequently in Tolfenamic acid 200-400 mg po both the intramuscular and intravenous route for the Diclofenac 50-100 mg po Ketoprofen 75-150 mg po acute treatment of migraine.A small study of patients 100 mg pr self-administering injections of ketorolac found a 100-300 mg po significant improvement in their headaches, and intra- Pirprofen 200-500 mg po Ketorolac 15-60 mg po, im, iv venous ketorolac was superior to 20 mg nasal Indomethacin 25-75 mg po sumatriptan in another study.19,20 50 mg pr, im Piroxicam 40 mg sl Antiemetics, particularly when co-administered 200-400 mg po with other pain-relieving medicines, are effective Antiemetics in aborting the nausea and vomiting component of 10 mg po, im, iv 5-10 mg po, iv the migraine attack. They are often underutilized in 25 mg po, pr the emergency room setting.21 Neuroleptics are 50-100 mg po, pr 10-25 mg iv antagonists that are thought to exert 5 mg im, iv their anti-emetic action by antagonizing dopamine Droperidol 2.5 mg maximum im, iv receptors in the brainstem chemoreceptor trigger Corticosteroids Methylprednisone 500-1000 mg iv zone. Neuroleptics include metoclopramide, prochlor- Dexamethasone 2-8 mg po, iv perazine, chlorpromazine, promethazine, haloperi- Other sulfate 1 mg iv dol, and droperidol. Metoclopramide is the only Divalproex sodium 500-2000 mg iv neuroleptic that has been thoroughly studied in its 10-20 mg po oral form and has been shown to be effective in con- junction with other pain relievers, but not when used im = intramuscular; iv = intravenous; po = oral; pr = rectal; alone.7,8,22 sl = sublingual. Intramuscular and intravenous formulations of neuroleptics have been proven to abort nausea The use of NSAIDs for pain has been known and even the entire migraine attack.23-26 The most since Hippocrates, but their action of inhibiting pros- common side effect of neuroleptics is sedation/ taglandin synthesis was discovered in the 1970s.4 drowsiness. Acute extrapyramidal symptoms, such as Aspirin, the paradigm for NSAIDs, has been shown to dystonia and akathisia, tend to occur with the first be superior to placebo in clinical trials at a dose parenteral dose and are more prominently seen with ranging from 500 mg to 1000 mg.4 In its tablet form, prochlorperazine.27 These adverse events can be aspirin is as effective as acetaminophen, and acetami- counteracted with benztropine, trihexylphenidyl, or nophen plus .5,6 It appears that aspirin is most . efficacious in its effervescent form and in combina- Chlorpromazine and prochlorperazine can induce tion with other medications such as an anti-emetic.7,8 postural hypotension due to their a-adrenergic Data regarding the efficacy of acetaminophen in antagonistic properties.27 Droperidol was issued a migraine are rare in the available literature.Acetami- “black box” warning by the US Food and Drug nophen has been found to be effective vs placebo at a Administration as a potential cause of fatal arrhyth- dose of 1000 mg.9 It is often used in combination with mias due to QTc prolongation, although this is caffeine and aspirin and is effective when used with extremely rare.26 10 metoclopramide. More on combination analgesics Though the selective serotonin3 (5-HT3) antago- will be discussed below. nists, such as , are very effective for Headache 309 nausea in general, there is only anecdotal evidence Unfortunately, there is often lack of evidence that they work abortively in migraine attacks.28 regarding greater advantages of FDCs over single Diphenhydramine is typically used to induce drowsi- medications.36 FDCs can contain any combination ness, as sleep can relieve a migraine, but it also has an of a fixed dose of an NSAID, acetaminophen, ergot, anti-emetic effect as well. caffeine, butalbital, , anti-emetic, or other Corticosteroids are used quite often, not only medicine. For the sake of the topic of this article, intravenously to abort a migraine attack in the emer- isometheptene-containing FDCs, ergot-containing gency setting, but also in oral formulation for outpa- FDCs, and the recently approved sumatriptan- tients. There are no randomized, controlled studies naproxen sodium combinations will not be discussed regarding the use of any oral corticosteroid in a single due to the vasoconstrictive effects of these medica- dose for an acute attack, and the data for intravenous tions. Already mentioned above were the efficacies dexamethasone (the formulation most commonly of aspirin and acetaminophen when each is com- used) are still inconclusive when used alone as a single bined with an anti-emetic when compared with each dose.29 When co-administered with other migraine drug alone. Tolfenamic acid plus metoclopramide treatments, dexamethasone was more effective for has been shown to be more effective than placebo as attacks lasting longer than 72 hours and helped well.22 prevent recurrence but 9 patients needed to be treated One of the most commonly used FDCs is a com- to prevent one recurrence, a modest response.2,29 bination of 250 mg acetaminophen, 250 mg aspirin, Compared with placebo, intravenous dexamethasone and 65 mg caffeine (Excedrin Migraine®). Lipton et al had no significant acute adverse events in one random- confirmed efficacy of this FDC in 3 randomized, ized, controlled study.30 Diabetics will need to have double-blind, placebo-controlled studies.37 glucose monitored when steroids are given. An FDC suppository containing 25 mg of Other medications may also have benefit in indomethacin, 4 mg of prochlorperazine, and 75 mg aborting migraine. One gram of magnesium sulfate of caffeine was shown to be more effective than given intravenously is effective for migraine with sumatriptan suppository.38 However, caffeine may be aura, although it may attenuate the efficacy of meto- the drug causing the most medication overuse head- clopramide when co-administered in the emergency ache (MOH) in migraineurs, based on amount of setting.31,32 Magnesium can lower blood pressure, and people ingesting caffeine.39 this is a potentially beneficial adverse effect that can In other words, since NSAIDs work well in abort- create a window to give a triptan or DHE if needed. ing an attack, there should be no reason to use Intravenous valproic acid at a dose of 500- NSAIDs with caffeine, due to the potential to cause 1000 mg has been shown to relieve an attack even chronic daily headache. Furthermore, at low frequen- though there are no controlled studies available.33-35 cies of ingestion (<5 days of use per month), NSAIDs Although there is no literature on baclofen, it is can actually be protective against development of widely used successfully at 10-20 mg orally. Drowsi- MOH. It is only when NSAID usage reaches 10-13 ness and dizziness can occur with use of valproic acid days of use per month that NSAIDs precipitate or are and baclofen. associated strongly with MOH. It is likely, although Fixed-drug combinations (FDCs) are now com- not proven, that combining NSAIDs with caffeine monplace, not only as prescribed medications but also reduces the number of days per month of ingestion as OTCs. The rationale for use of FDCs stems from necessary to trigger rebound.40 the hypotheses that targeting multiple pathogenic Butalbital-containing FDCs are still commonly mechanisms may be more beneficial than targeting prescribed for the acute treatment of migraine. The only one, that there are advantageous synergistic United States Headache Consortium clinical guide- effects when compared with a single medication, and lines note that no randomized, placebo-controlled at times one drug in the FDC can counteract adverse studies prove or refute the efficacy of butalbital- effects of another in the same FDC.36 containing compounds for the treatment of acute 310 February 2010 migraine. Furthermore, use of these medications with those that were not using .47,48 Although a should be limited and monitored.41 few studies have shown efficacy of opioids compa- Side effects of butalbital are related to CNS rable with DHE, there are significantly more side- depression, ranging from simple sedation to coma. effects of the opioids.49 Drowsiness is very common and can linger for hours. Some physicians may justify that use of opioids in Intoxication is very similar to imbibing too much the emergency setting results in quick relief. Recently , in that patients can experience sluggishness, it has been shown that patients receiving opioids in incoordination, slowness of speech, memory difficul- the emergency room (ER) spend more time in the ties, disinhibition, and emotional lability.41 Also, ER than those receiving non-opioid medications.50 because of the dissociation of the short half-life of the In addition, patients with status migrainosus who analgesia (mean half-life: 3-6 hours), and the long came to Beth Israel Hospital in Boston were only pain elimination half-life of the medication (mean half- free after administration of parenteral ketorolac plus life: 61 hours), there is high propensity to develop sumatriptan if they had received no opioids at all in the tolerance, as patients will use more medication when previous 6 month. This raises the question as to there is a short half-life for analgesia, and yet build up whether the pro-nociceptive effects of opioids prevent plasma levels due to the long elimination half-life.42 migraine-specific medications from reversing the This characteristic most likely contributes to the central sensitization of migraine,yet another reason to recent finding that it takes as little as 5 days of acute avoid opioid usage in acute treatment of migraine. use of butalbital FDCs per month to induce MOH.40 There are always debates about whether opioids Weaning patients from butalbital can be life- should be prescribed in those that have a rare threatening if not carefully monitored. Withdrawal is migraine attack who cannot tolerate any other pain a very serious problem that can be lethal when butal- medication. We are fortunate in Ohio to have a reg- bital is not weaned properly. Seizures can occur from istry of patients to observe the types and amounts of 24 hours to 115 hours after the last dose. Delirium opioid prescriptions prescribed and filled for each tremens can begin in 24 hours and can last several patient and listed by prescriber and location for a days, with visual hallucinations being a prominent given year. If a patient met our “criteria” of having a symptom. Butalbital-dependent patients need to be rare, severe migraine attack which only responds to placed on a prolonged taper, often for opioids, then we would consider prescribing them weeks, so the CNS can adapt to its state prior to under the auspice of an opioid contract only if no butalbital tolerance.43,44 other prescribers were providing scheduled medica- Opioids are still prescribed quite frequently, even tion for that patient. Unfortunately, this type of reg- though there is mounting evidence against their use in istry is still unavailable in the majority of the USA. the treatment of migraine. One of us (S.J.T.) reviewed Returning back to the patient described in the a managed care database of over 109,000 subjects case, before ruling the patient a non-responder to with a diagnosis of migraine and found that the most triptans, subcutaneous sumatriptan or DHE should commonly prescribed pain medication was an opioid be utilized to improve the bioavailability of their both initially (26%) and when switched to a different respective medication classes. Adding an oral or treatment (43%).45 rectal anti-emetic may add to the efficacy of an Opioid receptors do modulate nociceptive input NSAID for this patient, and it is worth trying a to the trigeminocervical complex, and therefore triple combination of triptan or ergot, NSAID, and opioid -agonists can help alleviate pain.46 antinauseant. However, relatively low frequency of use of opioids (8 Oral baclofen is another acute option for this days or more per month) causes MOH.42 Also, patient. If she needs to go to the ED, an intravenous patients who were using opioids and then used anti-emetic should be added to an intravenous ketorolac or had significantly less efficacy NSAID and/or DHE, magnesium sulfate, and consid- with the non-opioid medications when compared eration given to using corticosteroids if the migraine Headache 311 is over 72 hours in duration. Other treatments that and classical migraine. Br J Clin Pract. 1985;39:388- may be tried include a greater occipital nerve block 392. and biofeedback.51,52 11. Myllylä VV, Havanka H, Herrala L, et al. 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