My patient was a preteen girl who could usually manage her acute migraines with acetaminophen, ibuprofen, and intranasal sumatriptan, but it didn’t work this time. Her mother had called the pediatric neurologist to see if they could try something else at home, but the neurologist suspected the patient needed medication and intravenous fluids, so they were there.
I’m perfectly happy to see something so 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, it would be for the headache, not the nausea. In fact, my patient had no nausea.
Both mother and patient were up for it, not least because they had the potential to identify a new therapy at home. Ten minutes after the dose, her headache was gone. Her mother was in disbelief. I prescribed him eight migraine prn pills (but only when other treatments had failed) and, of course, told him to talk to his neurologist.
Sublingual drugs diffuse almost instantly into the oral vasculature. (Think nitro for chest pain.) It’s comparable to an IV at first.
Also, how many patients with a headache or a hangover or a day or two of gastrointestinal 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 taking the patient to the hospital (pesky and expensive), starting a intravenous (painful and a risk of thrombophlebitis) and to pump his veins full of sea water (unphysiological, kind of ridiculous, pure medical theatrics).
Cocktail against migraine
The treatment of migraine is an area where the evidence base is weak. This is the case in the adult and pediatric literature. Or as a recent review of pediatric intravenous migraine treatments put it: “Most current treatments are based on retrospective evidence, and there is a lack of well-designed double-blind randomized controlled pediatric studies.” (Curr Pain Headache Rep. 2020;24:45.)
The authors reviewed 19 studies that variously used intravenous fluids, prochlorperazine, diphenhydramine, metoclopramide, dexamethasone, magnesium, valproate and propofol, and dihydroergotamine, then raised the hands: “No definitive conclusion can be drawn”.
Missing from this list? Ondansetron!
A retrospective review of ondansetron use in the emergency room of pediatric migraine patients confirmed this glaring absence, noting that research so far has focused on antidopaminergics like metoclopramide (Reglan) and prochlorperazine (Compazine ). (Pediatrician Neurol. 2020;103:52.) Meanwhile, despite its better side effect profile, “not [pediatric] migraine treatment research has included ondansetron. wow. The authors reported their retrospective findings that ondansetron worked for 90% 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 scary, to something just as disabling as tardive dyskinesia. Meanwhile, ondansetron is an antiserotonergic that does not cause any of these problems. (That sometimes causes, uh, headaches. But let’s put that aside for a moment.)
My adult migraine cocktail has been metoclopramide with a dash of diphenhydramine to prevent akathisia, that sudden “Get that IV out of my arm!” restlessness and anxiety. A randomized trial of 100 patients published 20 years ago found that adding diphenhydramine halved rates of akathisia associated with D2 blockers. (Ann Emergency Med. 2001;37:125.) Other studies have confirmed this. (J Med Urgent. 2004;26:265; Ann Emergency Med. 2009;53:379.)
(Studies often use high doses of diphenhydramine, like 50mg IV, but I usually give 12.5mg diphenhydramine 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!A patient I’ve seen over the years always reports an allergy to hospital bed sheets and asks “Benadryl 50 mg IV push!” second she is moved to an emergency bed (as a drip if you give her an IV.)
Safe and effective
My migraine cocktail, like everyone else, is constantly changing. I sometimes replaced prochlorperazine or ondansetron with the antiemetic and sometimes added ketorolac, dexamethasone and IV fluids. Many things work, as a review of headache therapies confirmed. (Headache. 2015;55:3.)
Going through the literature again for this article, I wondered if I shouldn’t just use ondansetron as a first-line treatment because it’s so much safer. Imagine treating a patient’s frequent migraines with D2 blockers for a year and then learning that he has been permanently disfigured by tardive dyskinesia!
Zofran has been off-patent since 2006, and nowadays a 4mg intravenous dose only costs about $3. (StatPearls [Internet]. September 29, 2021; https://bit.ly/3JxDtoj.)
We could use the second generation version, palonosetron (Aloxi), which at $50 per intravenous dose costs 17 times more. Seventeen! I found 31 studies of palonosetron versus ondansetron on PubMed, and you’ll be shocked to learn that it’s not 17 times more effective. In fact, there is a raging debate as to whether it is even non-inferior.
Of course, there is more marketing behind ondansetron and generally no incentive for pharmaceutical companies to invest in RCTs to document its usefulness. It joins that category of unsuitable medical toys—cheap generics like tranexamic acid for trauma, famotidine for gastrointestinal bleeding, and desmopressin for reversing antiplatelet agents—that everyone forgets even if they are safe and quite obviously effective.
Dr Bivensworks in Massachusetts emergency departments, including St. Luke’s in New Bedford and Beth Israel Deaconess Medical Center in Boston.