ER Secrets on How to Treat a Headache

Generic medical advice over the Internet! What could go wrong?

All physicians are trained to worry about dangerous headaches — from tumors, brain bleeding, occult carbon monoxide poisoning, or other life-threatening causes. If you’re concerned at all about a headache you have, please see a healthcare professional. Also: I have no financial interests in / disclosures regarding anything written below.

The sad state of international affairs gives me головні бoлі (I’ll return to Ukraine shortly). And, as it happens, I recently wrote about headaches for Emergency Medicine News — in particular, about treating migraines with a generic anti-nausea medication, ondansetron (brand name Zofran®). So let’s take a break from the world’s madness and think about how to care for ourselves and our families.

An old neurologist I trust used to say that ibuprofen (brand names Motrin®, Advil®), taken with a whopping dose of acetaminophen (brand name Tylenol®) and “a strong cup of coffee”, would abort nearly any headache. (In an ideal world I could just use the generic names, but the brands are ubiquitous and confusing. So I’ll include brand names throughout and flag them with the “registered trademark” symbol.)

I sometimes include a fourth therapy, ondansetron (brand name Zofran®), when it’s a migraine — one of those recurrent, disabling headaches that tend to run in families, and often are associated with light sensitivity and nausea.

So, the headache cocktail. Let’s make it an explicit prescription — with the understanding that I’m an emergency medicine physician, so I’m thinking of a major headache, something you are frustrated with and want to stomp on with both feet:

ibuprofen (Motrin®, Advil®) 400 mg
acetaminophen (Tylenol®) 1,000 mg
a double espresso, black
+/- ondansetron (Zofran®) 4 mg sublingual

Some might think the ibuprofen dose looks low, the acetaminophen high, and that they’d prefer French press coffee. Let’s discuss, but first the caveats:

1) These are adult doses. Don’t give your kids an espresso, they won’t appreciate it.
2) It’s a one-time intervention. (Treating headaches with serial doses of ibuprofen and ondansetron in particular causes headaches over time; they are known as rebound headaches.)
3) If this headache seems unprecedentedly bad and you don’t know why you have it, you need to get checked out.

Ibuprofen (Motrin®, Advil®)

The official maximum single dose of ibuprofen is 800 mg, and the official maximum daily dose is 3,200 mg. But that’s a lot of ibuprofen! After reviewing the literature, my upper comfort limit on ibuprofen, for any indication, is 400 mg / dose. We know from recent research (for example here, here) that there’s no real extra pain relief when taking the higher 600-800 mg doses — only, presumably, an extra helping of the side effects.

The side-effects can be significant. Like all non-steroidal anti-inflammatories (NSAIDs), ibuprofen’s a great medication that can work wonders, and for pain caused by everything from kidney stones to broken bones, it’s as good as or even better than opioids. But especially when taken too often or too regularly, it can aggravate the kidneys; irritate the stomach, sometimes to the point of causing bleeding (so it’s best taken with food); and even increase risk for heart attack or stroke.

(A slightly gentler but still quite effective over-the-counter NSAID is naproxen (brand names Naprosyn®, Aleve®), taken at either 375 mg or 500 mg tablets, up to twice a day. It has less cardiovascular risk than ibuprofen, although it can still chew up one’s stomach. It’s a more gradual onset, taking an hour before it starts to kick in and another before it’s fully effective, and also longer lasting, hence the once- or twice-daily dose. That pharmokinetic profile explains why it’s a frequent go-to for naggingly prolonged issues, like arthritis or menstrual cramps, and less obviously first-line for things like headaches. It’ll still work for headache though, if you can be patient!)

So, back to ibuprofen 400 mg. How often can you take it? That’s a bit squishy. A good default answer would be “every 4 to 6 hours.” (Doctors love saying “every four to six hours.”) A more nuanced answer: It takes at least 20-30 minutes for it to kick in, so wait at least an hour, but if at any point thereafter you need a second dose, go ahead and have it (again, you’d just be spreading that maximum 800 mg single dose over an hour or two). For a third or further doses, space out to 4 hours.

Ibuprofen usually comes over-the-counter in 200 mg tablets, so you’ll have to do some math. By the way, for most indications — minor headaches, aches or pains, fevers — the 200 mg is more than enough! A single ibuprofen 200 mg is the go-to for, say, body aches of influenza or COVID-19; for the more severe pain of a broken rib, say, escalate to 400 mg. Meanwhile, even as I’m already talking here about talking less ibuprofen, people who use it often want more, and in the ER seek prescriptions for the 600 mg or 800 mg tablets. If you want to take that much, you don’t need a prescription, just the math skills you learned back in 3rd grade. But again, in my opinion that’s too much ibuprofen and you’re only signing up for more adverse effects.

Acetaminophen (Tylenol®)

Acetaminophen is a fascinating substance.

It’s one of the most widely used medications on Planet Earth, where outside the United States and Canada it’s known as paracetamol. We’re totally familiar with it — so familiar that we have no idea how it works.

This was the only medication we learned about in medical school where we were bluntly told the mechanism of action “remains unknown.”

“Unknown?” we’d ask incredulously, and eventually we’d get a grudging clarification: “We think it works in the brain.” To this day if you search for “acetaminophen / mechanism of action”, most authorities simply say unknown. (Others doing cutting edge research have theories.)

Acetaminophen is so safe we give it to everyone — little babies, pregnant women, the very ill, the very elderly — and we do so without a care in the world, because it’s so safe — safe, safe, safe! — even as it’s one of the most dangerous medications in the country, causing hundreds of deaths, thousands of cases of acute liver failure, and 10,000 hospitalizations every year.

The explanation for that seeming paradox is that acetaminophen is indeed very safe — as long as one doesn’t overdose. In normal dosing ranges, the liver metabolizes it completely harmlessly. Again, at normal doses, acetaminophen has no effect on the liver — unlike alcohol, say, where every drink is a dose-dependent liver hit, one could take acetaminophen regularly for a lifetime with no adverse effects.

That all changes with even just one overdose. In higher doses, the liver’s front-line system for metabolizing away the drug gets overwhelmed, and a backup system kicks in to help with all of the extra acetaminophen — but this backup system creates a terribly toxic metabolite that destroys the liver.

So don’t overdose.

For a painful condition, safe regimens include taking 1 gram (1,000 mg) two or three times a day as needed; or taking 500 mg or 650 mg (common tablet sizes) every 4 to 6 hours as needed.

Two important footnotes:

1) Acetaminophen (Tylenol®) can be safely taken with an NSAID such as ibuprofen or naproxen. They work differently, safely and well together.

2) Acetaminophen is in everything, and it’s the total daily dose that matters — make sure it stays under 4 grams (4,000 mg) a day. Many brand-name opioid pain medications, such as Vicodin® or Percocet®, are combination opioid-acetaminophen preparations. Many cough and cold medicines also include acetaminophen. It’s not uncommon for someone to accidentally overdose by not realizing that the Theraflu® and Excedrin® they’re taking for a viral illness, the Tylenol® they’re taking for a headache, and the Percocet® they’re taking for pain after a dental extraction, all contain acetaminophen.

Espresso

I’ll go over the data for coffee another day. But suffice to say that in medical school, I started to wonder if I was drinking too much coffee, so I reviewed the literature and concluded that I needed to be drinking more.

Ondansetron

I recently saw a pre-teen patient with a migraine. She could usually manage her acute headache attacks with acetaminophen, ibuprofen, and a migraine-specific intranasal medication, sumatriptan (Imitrex®). This time, it wasn’t working. Mom called the pediatric neurologist “to see if there was anything else we could try” at home. But the neurologist suspected the patient needed “IV medications and fluids.” So they reluctantly came to the emergency department.

As a physician, I’m perfectly happy to see something this easy. We have great intravenous medications for migraine headaches, so it will likely be a rewarding interaction where I discharge a happy patient.

But as a parent, I could think of a better way to spend my day. Why not first try one more thing at home — the anti-nausea medication ondansetron? Good old Zofran®! In particular, the sublingual formulation. To be clear, this would be for the headache, not nausea — and in fact my patient had no nausea. But the intravenous medications we use for nausea in the emergency department, including intravenous ondansetron, all work well for migraine, so why wouldn’t a sublingual formulation work the same way?

Sublingual and intranasal medicines diffuse near-instantly into the oral or nasal mucosal vasculature. (Think about nitroglycerin under the tongue for chest pain). So in speed of onset, sublingual medication is very comparable to intravenous.

Mom and patient were game, especially since it had potential to identify a new home therapy. Ten minutes after the ondansetron dissolved under her tongue, the headache was resolved. Mom was thrilled. What was that medication? I prescribed 8 tablets, to take as needed for migraines.

What about the IV fluids though, aren’t they important? Probably not. How many patients with a headache — or a hangover, or a day or two of gastro — are truly dehydrated, to the point of needing intravenous fluids for rehydration? Answer: None. Even with a very nauseated person, if you can get ondansetron sublingual on board, and a patient can tolerate sips of an electrolyte-rich drink of choice — Pedialyte®, Gatorade®, whatever — that’s clearly better than bringing the patient to the hospital (a hassle; expensive), starting an IV (painful; risk of thrombophlebitis), and pumping her veins full of sea water (non-physiologic; kind of ridiculous; pure medical theatrics).

Migraine treatment is an area where the evidence base is weak. This is true in both the adult and pediatric literature.

To quote a review in 2020 of intravenous pediatric migraine treatments: “Most current treatment is based on retrospective evidence [i.e. medical chart reviews of past practice].” The authors reviewed 19 studies but found them all too small or otherwise flawed to draw any strong conclusions. Those 19 studies had treated headaches with intravenous fluids, steroids, NSAIDs, magnesium, and anti-nausea medications — but conspicuously not ondansetron, which is hands down the most commonly used anti-nausea medication in the country.

A different 2020 retrospective study of ondansetron’s emergency department use for pediatric migraine patients confirmed that glaring absence from the literature, noting that the research so far has focused on the anti-dopaminergics like metoclopramide (Reglan®) and prochlorperazine (Compazine®). Meanwhile, and despite its better side effect profile, “no [pediatric] migraine treatment research has included ondansetron.” Wow.

That doesn’t mean doctors aren’t using it — we are! The authors reported their retrospective findings — meaning, they looked back at charts to see what doctors were prescribing and how patients were responding — and found ondansetron was used often for migraine patients, and apparently worked for 90 percent of them. They suggested it should be studied more formally.

Metoclopramide and prochlorperazine, go-to intravenous migraine treatments in an emergency department, are all dopamine receptor antagonists (haloperidol is another). As dopamine-system drugs, they thus have rare possible side effects ranging from brief dystonias (abrupt uncontrolled muscle spasms) and akathisias (anxious restlessness) — which can be uncomfortable and frightening — to something as disabling as a tardive dyskinesia (life-long uncontrolled muscle movements). Meanwhile, ondansetron works on serotonin receptors, not dopamine, and so it does not cause any of those problems. (It does sometimes cause, ahem, headaches. But let’s skip that for a moment).

My go-to intravenous migraine cocktail for adults has long been metoclopramide (Reglan®), plus a sprinkle of diphenhydramine (Benadryl®) 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 rates of dopamine blocker-associated akathisia in half. Other studies, in 2004 and in 2008, have confirmed that.)

Like every ER physician’s, my migraine cocktail is always evolving. Lots of things work, as this 2015 review of headache therapies confirms. Going over the literature again, I recently decided to just use ondansetron as first-line, since it’s so much safer. Imagine treating a patient’s frequent migraines with dopamine blockers for a few years and then learning they had been permanently disfigured with tardive dyskinesia! That’d be highly unusual — tardive dyskinesia usually happens only with prolonged, daily use of dopamine blockers for chronic conditions such as schizophrenia — but still.

One needs a prescription for ondansetron. But it’s so safe and familiar, it should probably be made over-the-counter by now, and most primary care physicians would be comfortable writing an as-needed-for-nausea prescription. It has been off-patent since 2006 and these days a 4 mg intravenous dose is only about $3. The sublingual tablets are even cheaper and can be had for less than 50 cents a dose:

The pharmaceutical industry would love us to transition away from ondansetron to their “second generation” versions, such as palonosetron (brand name Aloxi®), which at $50 an intravenous dose is 17 times more expensive. Seventeen times! I found 31 studies of palonosetron vs. ondansetron on PubMed, and you’ll be shocked to learn that it is not 17 times more effective. In fact, it’s a raging debate whether it’s even non-inferior.