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My patient was a preteen who could usually manage her acute migraines with acetaminophen, ibuprofen, and intranasal sumatriptan, but it wasn't working this time. Her mother had called the pediatric neurologist to see if they could try anything else at home, but the neurologist suspected the patient needed IV medications and fluids, so here they were.

I'm perfectly happy to see something this easy. It will likely be a rewarding interaction where I discharge a happy patient. But as a parent, I can think of a better way to spend my day than sitting in an emergency department.

Why not try ondansetron at home? Good old po Zofran! In particular, the sublingual formulation. To be clear, this would be for the headache, not nausea. In fact, my patient had no nausea.

The mother and patient were game, especially because it had potential to identify a new home therapy. Ten minutes after the dose, her headache had resolved. Her mother was incredulous. I prescribed eight tablets prn migraine (but only when other treatments had failed), and, of course, told her to talk to her neurologist.

Sublingual medicines diffuse almost instantly into the oral vasculature. (Think about nitro for chest pain.) It's comparable with an IV in onset.

Moreover, how many patients with a headache or a hangover or a day or two of gastro upset are truly dehydrated to the point of needing intravenous rehydration? Answer: None. If you can get ondansetron SL on board and a patient can tolerate sips of an electrolyte drink, that's clearly better than bringing the patient to the hospital (a hassle and expensive), starting an IV (painful and a risk of thrombophlebitis), and pumping her veins full of sea water (nonphysiologic, kind of ridiculous, pure medical theatrics).

Migraine treatment is an area where the evidence base is weak. This is true in the adult and pediatric literature. Or as a recent review of intravenous pediatric migraine treatments put it: “Most current treatment is based on retrospective evidence, and there is a lack of well-designed randomized double-blinded controlled pediatric studies.” (Curr Pain Headache Rep. 2020;24[8]:45.)

The authors reviewed 19 studies that variously used intravenous fluids, prochlorperazine, diphenhydramine, metoclopramide, dexamethasone, magnesium, valproate and propofol, and dihydroergotamine, and then threw up their hands: “No definite conclusions can be drawn.”

Missing from that list? Ondansetron!

A retrospective study of ondansetron's emergency department use for pediatric migraine patients confirmed that glaring absence, noting that the research so far has focused on the antidopaminergics like metoclopramide (Reglan) and prochlorperazine (Compazine). (Pediatr Neurol. 2020;103:52.) Meanwhile, despite its better side effect profile, “no [pediatric] migraine treatment research has included ondansetron.” Wow. The authors reported their retrospective findings that ondansetron worked for 90 percent of migraine patients and suggested it be studied further.

Metoclopramide and prochlorperazine are dopamine D2 receptor antagonists (haloperidol is another), and they have side effects ranging from dystonias and akathisias, which can be uncomfortable and frightening, to something as disabling as a tardive dyskinesia. Meanwhile, ondansetron is an antiserotonergic that does not cause any of those problems. (It does sometimes cause, ahem, headaches. But let's skip that for a moment.)

My go-to migraine cocktail for adults has been metoclopramide with a sprinkling of diphenhydramine to prevent the akathisia, that abrupt “Get this IV out of my arm!” restlessness and anxiety. A randomized trial of 100 patients published 20 years ago found adding diphenhydramine cut the rates of D2 blocker-associated akathisia in half. (Ann Emerg Med. 2001;37[2]:125.) Other studies confirmed that. (J Emerg Med. 2004;26[3]:265; Ann Emerg Med. 2009;53[3]:379.)

(The studies often use large doses of diphenhydramine, like 50 mg IV, but I usually give diphenhydramine 12.5 mg when using it as a D2 chaser, which seems to work just as well. Lower doses mean less sedation, and are also less euphoric. Don't turn your patients into Benadryl-seekers! One patient I've seen over the years always declares an allergy to hospital bed sheets and demands “Benadryl 50 mg IV push!” the second she is transferred to an ED bed. Deliver this as a drip if you give it IV.)

My migraine cocktail, like everyone's, is always evolving. I've sometimes subbed prochlorperazine or ondansetron for the antiemetic and sometimes added ketorolac, dexamethasone, and IV fluids. Lots of things work, as a review of headache therapies confirmed. (Headache. 2015;55[1]:3.)

Going over the literature again for this article, I wondered if I shouldn't just use ondansetron as a first-line therapy because it's so much safer. Imagine treating a patient's frequent migraines with D2 blockers for a year and then learning he had been permanently disfigured with tardive dyskinesia!

Zofran has been off patent since 2006, and these days a 4 mg intravenous dose is only about $3. (StatPearls [Internet]. Sept. 29, 2021; https://bit.ly/3JxDtoj .)

We could use the second-generation version, palonosetron (Aloxi), which at $50 an intravenous dose is 17 times more expensive. Seventeen! I found 31 studies of palonosetron v. ondansetron on PubMed, and you'll be shocked to learn that it is not 17 times more effective. In fact, there's a raging debate about whether it's even noninferior.

Of course, there's no marketing behind ondansetron anymore and generally no incentive for pharmaceutical companies to invest in RCTs to document its usefulness. It joins that category of misfit medical toys—cheap generics like tranexamic acid for trauma, famotidine for GI bleed, and desmopressin for antiplatelet agent reversal—that everyone forgets even though they are safe and pretty obviously effective.

Dr. Bivensworks at emergency departments in Massachusetts, including St. Luke's in New Bedford and Beth Israel Deaconess Medical Center in Boston.

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