migraineCase vignette: A 42-year-old female presents at 10 pm with a throbbing right frontal headache associated with nausea, vomiting, photophobia, and phonophobia. The headache is severe, rated as “10” on a 0 to 10 triage pain scale. The headache began gradually while the patient was at work at 2 pm. Since 2 pm, she has taken 2 tablets of naproxen 500 mg and 2 tablets of sumatriptan 100 mg without relief.

The patient has a diagnosis of migraine without aura. She reports 12 attacks per month. The headache is similar to her previous migraine headaches. She is forced to present to an Emergency Department (ED) on average 2 times per month for management of migraine refractory to oral therapy. She reports a history of dystonic reactions and akathisia after receiving IV dopamine antagonists during a previous ED visit. The physical exam is non-contributory including a normal neurological exam, normal visual fields and fundoscopic exam, and no signs of a head or face infection. When you are done evaluating her, the patient reports that she usually gets relief with 3 doses of hydromorphone 2 mg + diphenhydramine 50 mg IM, and asks that you administer her usual treatment. What do you do?


Migraine is a neurological disorder characterized by recurrent painful headaches and abnormal processing of sensory input resulting in symptoms such as photophobia, phonophobia, and osmophobia.1 Central to disease pathogenesis is abnormal activation of nociceptive pathways.2 Disease severity ranges from mild to severe. Patients at one end of the spectrum have rare episodic headaches. On the other end are patients who have headaches on more days than not, patients who are functionally impaired by their headaches, and patients who frequently cannot participate fully in work or social activities. Chronic migraine, a sub-type of migraine defined by ≥15 days with headache for at least 3 consecutive months, is experienced by 1-3% of the general population.3

ED use for treatment of migraine is common. 1.2 million patients present to U.S. ED’s annually for management of this primary headache disorder.4 Parenteral opioids are used to treat the acute headache in slightly more than 50% of all ED visits.4 Multiple authorities have cautioned against the use of opioids for migraine.5,6 However, the frequent use of opioids has continued unabated, despite the publication in the EM, neurology, and headache literature of dozens of randomized controlled trials (RCTs) demonstrating safety and efficacy of parenteral alternatives, most notably dopamine antagonists and non-steroidal anti-inflammatory drugs.7

Opioids have been associated with a variety of poor outcomes in migraine patients including:

  1. Progression of the underlying migraine disorder from episodic to chronic migraine8
  2. Increased frequency of return visits to ED9
  3. Less responsiveness to subsequent treatment with triptans10
  4. Less frequent headache relief than patients who received dihydroergotamine or dopamine antagonists11

In contrast, a high quality, ED-based RCT did not demonstrate more harm from 1 or 2 doses of meperidine than from dihydroergotamine.12 Hydromorphone, the parenteral opioid currently used most commonly in U.S. EDs,4 has never been studied experimentally in migraine patients. However, given the wide range of parenteral alternatives, the possibility that opioids may worsen the underlying migraine disorder, and the fact that they are less efficacious than other treatments, opioids should not be offered as first- or second-line therapy for patients who present de novo to an ED with an acute migraine (assuming no contraindications to alternative medications).


1) Other than opioids, what parenteral therapies can be offered to this patient?

The 3 classes of parenteral therapeutics with the most evidence supporting safety and efficacy for use as first-line therapy for migraine are the following13:

  1. Dopamine antagonists
  2. NSAIDs
  3. Subcutaneous sumatriptan

However, this patient has relative contraindications to each of these. Other parenteral medications used for migraine are listed in the following table.

Table: Alternative parenteral migraine therapies

Agent Dose Adverse events Evidence supporting efficacy Notes
Acetaminophen (APAP)14,15 1 gm IV Well tolerated In one trial, IV APAP did no better than placebo. In another, IV APAP was comparable to an IV NSAID.
Dihydroergotamine16 0.5 mg -1 mg IV infusion Nausea is common. Pre-treat with anti-emetics. In one trial, DHE was less effective than sumatriptan at 2 hours but more effective by 4 and 24 hours. Use cautiously in patients with cardiovascular risk factors.
Ketamine17 0.08 mg/kg SC Fatigue, delirium In one low quality cross-over RCT, ketamine outperformed placebo.
Magnesium18–21 1-2 gm IV Flushing In RCTs of varying quality, IV mg did not consistently outperform placebo Efficacy data is most compelling for migraine with aura.
Octreotide22 0.1 mg SC Diarrhea, injection site reactions In a high quality RCT, octreotide did not outperform placebo
Propofol23,24 10 mg IV every 10 minutes as needed up to 80 mg Or 30-40 mg IV with 10-20 mg bolus every 3-5 minutes up to 120 mg Sedation, hypoxia In a low quality RCT, propofol outperformed dexamethasone. In another low quality trial, propofol outperformed sumatriptan. It is not clear whether the migraine returns after propofol administration has been completed. Previous ALiEM post on migraines and propofol.
Valproic acid28,29 1000 mg IV Well tolerated In a high quality RCT, valproate was outperformed by metoclopramide and ketorolac. In a lower quality RCT, valproate was comparable to IV aspirin.
APAP= acetaminophen; DHE= dihydroergotamine; Mg= magnesium


In some patients, greater occipital nerve blocks with a long-acting local anesthetic such as bupivaciane may play a role.25 While the above alternative parenteral therapies may benefit this patient, available evidence regarding risks and benefits does not dictate that these other therapies must be offered prior to use of opioids.

2) Does the fact that this patient makes frequent use of the ED indicate an unmet medical need?

As with congestive heart failure and asthma, frequent use of an ED for migraine is associated with worse underlying disease.26 These frequent users are more likely to have chronic migraines (> 15 headache days per month) and psychiatric co-morbidities.26 Concomitant medication overuse headache, a disorder defined by an upward spiral of increasing headache frequency in the setting of increased usage of analgesic or migraine medication, is also common.27 Management of complicated patients with migraines is exceedingly difficult, particularly during a busy ED shift, and may lead to frustration for both the healthcare practitioner and the patient. Ideally, outpatient healthcare practitioners with appropriate expertise should direct management of complicated patients with migraines.

3) Should the patient be administered 3 doses of hydromorphone 2 mg + diphenhydramine 50 mg IM as she wishes?

Management of chronic pain patients can be trying and demoralizing for emergency physicians because the underlying problem cannot be solved, and all avenues of treatment are flawed.  Allowing the patient to suffer without appropriate justification is cruel. Delaying opioid administration during good faith efforts to identify alternative effective therapeutic agents is reasonable. Withholding opioids on principle is problematic because for most patients in most circumstances, published data do not establish that the benefit of pain relief is outweighed by the potential for opioid induced harm. On the other hand, thoughtlessly acquiescing to repeated requests for opioids during multiple ED visits is a violation of good medical practice, because of the concern of exacerbating the underlying migraine disorder, which could result in more ED visits, increased number of headache days, and the potential to cause refractoriness to standard migraine medication. One might compare it to administering antibiotics for bronchitis.

Case Resolution

The best solution for the patient in the case vignette is to administer parenteral opioids only as rescue therapy for patients who adhere to an established outpatient plan of care. Acutely, the patient should not be allowed to suffer. However distasteful it may be, the harm arising from 3 isolated doses of parenteral opioids during one ED visit is unlikely to be either long-lasting or severe. But a prerequisite to treatment with opioids during a subsequent visit should be adherence to appropriate outpatient treatment: specifically, patients who require parenteral opioids for migraines should regularly attend outpatient appointments with an appropriate healthcare provider within the ED’s healthcare system.

Department-wide opioid policies are essential, as physician to physician variability in care may undermine a strict approach to opioids. Ideally, a committee with relevant expertise can monitor frequently presenting pain patients and develop patient-specific interventions that will be enforced by all practitioners during subsequent visits. If need be, the terms of treatment can be reinforced with a written document (example in the Appendix). This written document is not meant to be legally binding, but should be used to establish expectations. The last thing a busy emergency physician needs is a battle over opioids with a frequently presenting migraine patient. But before discharge, there should be a conversation about expectations during future ED visits. This will contribute to increased satisfaction for both the provider and the patient.


Top image: (c) Can Stock Photo


APPENDIX: Sample document to establish expectations for ED patients who require opioids
Headache C. The International Classification of Headache Disorders, 3rd edition (beta version). Cephalalgia. 2013;33(9):629-808. [PubMed]
Goadsby P. Pathophysiology of migraine. Ann Indian Acad Neurol. 2012;15(Suppl 1):S15-22. [PubMed]
Lipton R. Chronic migraine, classification, differential diagnosis, and epidemiology. Headache. 2011;51 Suppl 2:77-83. [PubMed]
Friedman B, West J, Vinson D, Minen M, Restivo A, Gallagher E. Current management of migraine in US emergency departments: an analysis of the National Hospital Ambulatory Medical Care Survey. Cephalalgia. 2015;35(4):301-309. [PubMed]
Langer-Gould A, Anderson W, Armstrong M, et al. The American Academy of Neurology’s top five choosing wisely recommendations. Neurology. 2013;81(11):1004-1011. [PubMed]
Loder E, Weizenbaum E, Frishberg B, Silberstein S, American H. Choosing wisely in headache medicine: the American Headache Society’s list of five things physicians and patients should question. Headache. 2013;53(10):1651-1659. [PubMed]
Sumamo S, Dryden D, Pasichnyk D, et al. Acute Migraine Treatment in Emergency Settings. November 2012. http://www.ncbi.nlm.nih.gov/books/NBK115368/. [PubMed]
Bigal M, Serrano D, Buse D, Scher A, Stewart W, Lipton R. Acute migraine medications and evolution from episodic to chronic migraine: a longitudinal population-based study. Headache. 2008;48(8):1157-1168. [PubMed]
Colman I, Rothney A, Wright S, Zilkalns B, Rowe B. Use of narcotic analgesics in the emergency department treatment of migraine headache. Neurology. 2004;62(10):1695-1700. [PubMed]
Burstein R, Collins B, Jakubowski M. Defeating migraine pain with triptans: a race against the development of cutaneous allodynia. Ann Neurol. 2004;55(1):19-26. [PubMed]
Friedman B, Kapoor A, Friedman M, Hochberg M, Rowe B. The relative efficacy of meperidine for the treatment of acute migraine: a meta-analysis of randomized controlled trials. Ann Emerg Med. 2008;52(6):705-713. [PubMed]
Carleton S, Shesser R, Pietrzak M, et al. Double-blind, multicenter trial to compare the efficacy of intramuscular dihydroergotamine plus hydroxyzine versus intramuscular meperidine plus hydroxyzine for the emergency department treatment of acute migraine headache. Ann Emerg Med. 1998;32(2):129-138. [PubMed]
Orr S, Aubé M, Becker W, et al. Canadian Headache Society systematic review and recommendations on the treatment of migraine pain in emergency settings. Cephalalgia. 2015;35(3):271-284. [PubMed]
Turkcuer I, Serinken M, Eken C, et al. Intravenous paracetamol versus dexketoprofen in acute migraine attack in the emergency department: a randomised clinical trial. Emerg Med J. 2014;31(3):182-185. [PubMed]
Leinisch E, Evers S, Kaempfe N, et al. Evaluation of the efficacy of intravenous acetaminophen in the treatment of acute migraine attacks: a double-blind, placebo-controlled parallel group multicenter study. Pain. 2005;117(3):396-400. [PubMed]
Winner P, Ricalde O, Le F, Saper J, Margul B. A double-blind study of subcutaneous dihydroergotamine vs subcutaneous sumatriptan in the treatment of acute migraine. Arch Neurol. 1996;53(2):180-184. [PubMed]
Nicolodi M, Sicuteri F. Exploration of NMDA receptors in migraine: therapeutic and theoretic implications. Int J Clin Pharmacol Res. 1995;15(5-6):181-189. [PubMed]
Corbo J, Esses D, Bijur P, Iannaccone R, Gallagher E. Randomized clinical trial of intravenous magnesium sulfate as an adjunctive medication for emergency department treatment of migraine headache. Ann Emerg Med. 2001;38(6):621-627. [PubMed]
Shahrami A, Assarzadegan F, Hatamabadi H, Asgarzadeh M, Sarehbandi B, Asgarzadeh S. Comparison of therapeutic effects of magnesium sulfate vs. dexamethasone/metoclopramide on alleviating acute migraine headache. J Emerg Med. 2015;48(1):69-76. [PubMed]
Cete Y, Dora B, Ertan C, Ozdemir C, Oktay C. A randomized prospective placebo-controlled study of intravenous magnesium sulphate vs. metoclopramide in the management of acute migraine attacks in the Emergency Department. Cephalalgia. 2005;25(3):199-204. [PubMed]
Bigal M, Bordini C, Tepper S, Speciali J. Intravenous magnesium sulphate in the acute treatment of migraine without aura and migraine with aura. A randomized, double-blind, placebo-controlled study. Cephalalgia. 2002;22(5):345-353. [PubMed]
Levy M, Matharu M, Bhola R, Meeran K, Goadsby P. Octreotide is not effective in the acute treatment of migraine. Cephalalgia. 2005;25(1):48-55. [PubMed]
Soleimanpour H, Taheraghdam A, Ghafouri R, Taghizadieh A, Marjany K, Soleimanpour M. Improvement of refractory migraine headache by propofol: case series. Int J Emerg Med. 2012;5(1):19. [PubMed]
Moshtaghion H, Heiranizadeh N, Rahimdel A, Esmaeili A, Hashemian H, Hekmatimoghaddam S. The Efficacy of Propofol vs. Subcutaneous Sumatriptan for Treatment of Acute Migraine Headaches in the Emergency Department: A Double-Blinded Clinical Trial. Pain Pract. 2015;15(8):701-705. [PubMed]
Voigt C, Murphy M. Occipital nerve blocks in the treatment of headaches: safety and efficacy. J Emerg Med. 2015;48(1):115-129. [PubMed]
Friedman B, Serrano D, Reed M, Diamond M, Lipton R. Use of the emergency department for severe headache. A population-based study. Headache. 2009;49(1):21-30. [PubMed]
Kristoffersen E, Lundqvist C. Medication-overuse headache: epidemiology, diagnosis and treatment. Ther Adv Drug Saf. 2014;5(2):87-99. [PubMed]
Leniger T, Pageler L, Stude P, Diener H, Limmroth V. Comparison of intravenous valproate with intravenous lysine-acetylsalicylic acid in acute migraine attacks. Headache. 2005;45(1):42-46. [PubMed]
Friedman B, Garber L, Yoon A, et al. Randomized trial of IV valproate vs metoclopramide vs ketorolac for acute migraine. Neurology. 2014;82(11):976-983. [PubMed]

ALiEM Copyeditor, Dr. Matthew Zuckerman

>Concerned that this post tries to do a little too much. Includes background on migraine, recommendations for standard therapies, non-opioid therapies, when opioids are indicated, and pain contract. Perhaps focusing on less and decrease length of post by 25%.

  • Avoid cliché e.g. (“without blinking an eye”)
  • Reduce citations and focus on core references. Reference 22 is from a Serbian publication, did the authors have this translated?
  • Very concerned that this article cites numerous adjunctive therapies, many with little or poor evidence. Many of the references actually suggest therapies are not more effective than placebo (ref 20, 26, 27, 31).
  • Why IV acetaminophen rather than PO?
  • Not sure if data on opioids for headache is up to date. Haven’t seen Demerol used for pain in long time and anecdotally my department almost never uses opiates for headache. Is there more up to date data?
  • Is abstaining from medication overuse really “detoxification”? What toxin is being removed?
  • Table on ketamine refers to “feelings of insobriety”. Please clarify.
  • Happy to re-review post edits, great opportunity to talk about when how to use opiates in migraine or potential adjunctive meds for migraine.

    Matthew Zuckerman, MD
    Assistant Professor, Emergency Medicine
    University of Colorado, Anschutz Medical Campus

    Expert Peer Review, Dr. David Vinson

    The authors have done a fantastic job directing their case vignette and the following discussion straight to the issues that commonly complexify the emergency department (ED) management of refractory migraine. This patient’s situation is admittedly difficult: her migraines are frequent and disabling and fail about twice a month to respond to oral medications, precipitating ED visits in search of pain relief. The triad of first-line parenterals well known to the emergency physician (NSAIDs, triptans, and dopamine antagonists) is out of consideration (clever of our sly vignette writers). Our pain-afflicted patient has found high-dose opioids effective in the past and understandably solicits their aid. This forces the physician onto the horns of a familiar dilemma: concede to the request and resolve the pain but feel a pang of compunction while reinforcing the patient’s drug-requesting behavior, or refuse to comply and risk undertreating the pain and catalyzing an all-sides- lose confrontation (1).

    The solution the authors recommend is both highly sensible and far-sighted, avoiding the simplistic either-or dichotomy I just put forth. But it requires a high-level coordination of care on several fronts, first within the ED itself. A department-wide approach is essential so that with each of the patient’s visits she encounters the same expected treatment plan, regardless of the physician who happens to be on shift that day. What might such a plan include? A list recommended pharmacological interventions would be helpful. Select the better-performing agents from the authors’ table of second-tier therapies and create a patient-specific treatment plan that spells out the sequence of suggested parenteral medications for ED use. If the first medication were to fail at the first visit, the next parenteral on the list could be tried at the second visit, and so on, with careful documentation of each medication’s effects and side-effects. The process would continue until one drug was found that hit a home run with this patient—or at least a double. If the patient proved mostly resistant or intolerant to the whole lot, then the preferred agent might be the one that was only modestly effective; it could be employed as an adjunct treatment to help reduce the opioid need. Even that is progress.

    The second level of coordination the authors propose is between the ED and the patient’s primary care provider (thank goodness she has one!). Synchronizing efforts here is also vital. Ideally, her physician will serve as a supportive ally in patient care, designing a home management plan that complements our ED efforts. One pillar that is missing from this patient’s regimen is a prophylactic agent, recommended for patients with migraines of high frequency or disabling severity. Our migraineur qualifies on both counts. When effective, these medications can significantly reduce migraine frequency, duration, and attack severity. They can also improve responsiveness to abortive therapies and prevent progression or transformation of episodic migraine to chronic migraine. The American Academy of Neurology tops their list of prophylactics with specific antiepileptics and beta-blockers (2). The former agents need close follow-up, and some require monitoring. Propranolol, however, is less complicated and is more likely a drug that can be started out of the ED. The initial dose is 20 mg twice daily, which will need to be titrated up over time (3). Headache improvement may not be evident for several weeks. A higher dose should be maintained for at least three months before deeming the medication a failure.

    The third level of coordination the authors address is between the ED and the patient. This component is often overlooked, though it is crucial to the success of the treatment plan. Securing our patients’ understanding of what we’re doing—and why—is a minimum. If nothing else, communicating our objectives helps recalibrate expectations. This can go a long way to mitigate any unruly emotions that might emerge when a patient’s opioid ambitions are thwarted and may help preempt the unwarranted objection that we don’t care. On the contrary, it is precisely because we do care that we are going to these lengths to improve our management of patients with hard-to- control migraine.

    Management of a patient like this will vary across EDs as each works out a solution that seems most suitable to the several parties in play. Whatever the local variations, enlisting cooperation at these three levels—among the ED faculty, between the ED and the primary care provider, and with the ED and the afflicted patient—will help arrive at an approach that is thoughtful, sensible, and serviceable to the long- term interests of the patient and those who rally around to provide her the best care possible.

    I also have a few very minor editorial suggestions.

    • 42 year old should be hyphenated: 42-year- old
    • Emergency room might be better represented as emergency department
    • The first use of ED should be defined: emergency department (ED) and subsequent uses should follow the abbreviation
    • First or second line therapy might also benefit from hyphens: first- or second-line therapy
    • Does contra-indications need a hyphen?
    • Consider referencing the sentence on medication overuse headache so your readers can find supplemental information
    • The last sentence of the penultimate paragraph is a tad cumbersome. Consider breaking it up.
    • Department wide opioid practices in the last paragraph might be better written with a hyphen: department-wide opioid
    • References in the table should refer to the primary literature, and not just to summaries or guidelines. The propofol information will illustrate. Two studies are described: “In a low quality RCT, propofol outperformed dexamethasone. In another low quality trial, propofol outperformed sumatriptan.” Yet the only reference given is to a systematic review.
    1. Friedman BW, Vinson DR. Convincing the skeptic. How to fix emergency department headache management. Cephalalgia. 2015;35(8):641-3.
    2. Silberstein SD, Holland S, Freitag F, Dodick DW, Argoff C, Ashman E; Quality Standards Subcommittee of the American Academy of Neurology and the American Headache Society. Evidence-based guideline update: pharmacologic treatment for episodic migraine prevention in adults: report of the Quality Standards Subcommittee of the American Academy of Neurology and the American Headache Society. Neurology. 2012;78(17):1337-45.
    3. Pringsheim T, Davenport WJ, Becker WJ. Prophylaxis of migraine headache. CMAJ 2010;182:E269-76.
    David R. Vinson, MD
    The Permanente Medical Group, Oakland, California
    Kaiser Permanente Sacramento Medical Center, Sacramento, California
    Co-chair, KP CREST Network
    Adjunct Investigator, Kaiser Permanente Division of Research, Oakland, California
    Volunteer Clinical Faculty, University of California, Davis, Department of Emergency Medicine, Sacramento, California

    Our thanks to Dr. Vinson for his typical thoughtful, helpful, and detailed review. We have incorporated all of his grammatical suggestions and included the recommended references.

    We agree with his comments about initiating migraine preventive medication in the ED. Some may argue that initiating chronic medication is not within the purview of emergency medicine. We believe that it is the responsibility of the emergency physician to provide evidence-base care if the ED patient is not receiving appropriate treatment in the outpatient setting. This is particularly true for frequent ED visitors. Hopefully, this can be coordinated with the outpatient provider. Of all the evidence-based migraine preventive therapies, propranolol or metoprolol are the ones with which emergency physicians may be most comfortable. The target dose for propranolol is 80-160 mg per day [1]. Metoprolol should be dosed at 100-200 mg daily [1].


    1. Pringsheim, T., et al., Canadian Headache Society guideline for migraine prophylaxis. Can J Neurol Sci, 2012. 39(2 Suppl 2): p. S1-59.
    Cindy Prettypaul
    Medical Student
    Lake Erie College of Osteopathic Medicine
    Seton Hill
    Cindy Prettypaul

    Cindy Prettypaul

    Medical Student
    Lake Erie College of Osteopathic Medicine
    Seton Hill
    Cindy Prettypaul

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    Benjamin Friedman, MD MS

    Benjamin Friedman, MD MS

    Department of Emergency Medicine
    Montefiore Medical Center
    Albert Einstein College of Medicine
    Benjamin Friedman, MD MS

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