Illustration: Olivier Heiligers
Mention the anti-nausea medication Zofran in conversation, and like me, you may find that just about everyone you know has a story about it. My friend Laura says her husband keeps a stockpile for his migraines. Liz does, too, as well as Meaghan, who also uses it for vertigo. Emma used it to curtail a bout with norovirus this winter, and is “guarding the remainder of the prescription like it’s solid gold.” Leah tells me, “I have the teeniest dose always on hand for my 6 ½ year old who gets carsick—we refer to it as her ‘magic pill.’” Eva says she’s been “a Zofran girlie since 2013,” popping it whenever nausea rears its queasy head. “ I used it for pregnancy,” she continues, “but I also used it recently when I was feeling slightly off and had dinner reservations at this amazing restaurant and didn’t want to throw up.” Ashley Grady, who I found deep in an Instagram comment section, says she’s used the drug near-daily for fifteen years to manage the nausea that arises from Crohn’s disease. “It’s a godsend,” she says.
It’s not surprising that people would welcome a drug that so seemingly miraculously makes the agony of nausea disappear. Often taken as a dissolving capsule placed under the tongue (it’s tough to swallow a pill when you can’t keep anything down), Zofran, the brand name for ondansetron, is both quick and effective, all but eliminating nausea in as little as thirty minutes. Approved by the FDA in 1991 for use in patients undergoing chemotherapy or surgery, it’s changed the game for chemo-induced nausea, with one study’s authors calling it a “necessary medication” in a cancer patient’s arsenal. But as the aforementioned applications of the drug make clear, there are countless off-label uses, too. Zofran makes a stomach virus tolerable, reducing not only discomfort but also dehydration. The drug is a boon for those who are pregnant, hungover, or living with Cyclic Vomiting Syndrome. (Yes, that’s a thing.) Grady tells me that because Zofran helps her live with Crohn’s, she can eschew other medications for the condition, such as “steroids and biologics and immunosuppressants.” She explains, “as long as I’m able to manage my nausea, I’m saving my kidneys, I’m saving my liver. I’m saving myself 30 pounds of weight that being on Prednisone my whole life gave me.”
Zofran works by binding to the gut and brain’s 5-HT3 receptors and blocking the action of serotonin to curb the trigger to vomit, and it’s a go-to antiemetic for clinicians, with roughly 5.7 million patients taking it each year. While you can get it from a variety of online pharmacies—those sites where a two-minute telehealth visit gets you your Tretinoin or Semaglutide—Zofran remains prescription-only, to the consternation of the chronically nauseous and just generally health-anxious. Conducting a telehealth Zoom while holding back vomit sounds like misery—why should someone have to?
Nausea remains one of the only quotidian ailments for which there isn’t a great OTC solution, and no over the counter antiemetic comes close to being as effective. So why is such a well-tolerated, non-addictive, widely proffered medication gate kept in this way?
It turns out that the answer depends greatly on who you ask.
The main argument doctors offer as to why Zofran is prescription-only is somewhat straightforward: In some people, it carries side effects and risks, the most significant of which is that it could lead to the development of a rare syndrome called QT prolongation. (If people have this condition congenitally, it may be exacerbated by Zofran). Dr. Camille Thélin, an associate professor in the University of South Florida’s division of digestive diseases and nutrition, explains that in QT prolongation, “the interval between heartbeats is longer than normal, which causes the heart to beat irregularly.” This type of arrhythmia is called Torsades de Pointes (TdP); it’s a rapid and unpredictable heart rhythm with a mortality rate of between 10 and 20 percent.
Zofran can also interact negatively with a variety of medications, including drugs that treat everything from Parkinson’s to yeast infections, persistent heartburn, Tourette’s syndrome, or psychosis. Many of these drugs also prolong the QT interval, but others impact the body’s serotonin receptors, just as Zofran does. Simultaneously taking Zofran and, say, a Selective Serotonin Reuptake Inhibitor, or SSRI (the medication class of antidepressants like Prozac and Zoloft) could result in a condition known as Serotonin Syndrome. If it’s severe enough and left untreated, it can be fatal within 24 hours.
How much of these interacting drugs do you have to take before Serotonin Syndrome becomes a concern? It’s hard to say, says Thélin, because “we all have a different liver makeup based on our genetics. Some people might be fast metabolizers or slow metabolizers, and that can really change the level of serotonin in the brain.”
Combine these two concerns—long QT intervals and drug interactions—and the situation can get dangerous quickly, says Jill Deutsch, MD, a gastroenterologist and assistant professor of digestive diseases at The Yale School of Medicine. “When people have nausea, it’s often because of something else,” she says — a respiratory infection, a migraine, whatever it might be. “So, the patient is likely taking something for that condition in addition to Zofran. When you use multiple medications with the risk of prolonging the QT, it raises the hairs on the back of my neck.” Some migraine medications and antibiotics are known to prolong the QT interval, as well as certain OTC drugs, including Benadryl and Pepcid.
Similarly, Thélin points out that nausea “is a symptom, not a diagnosis,” and says that if you remove that symptom with Zofran, you both muddy the diagnostic waters and potentially hinder a patient from seeking care. You may be thinking that anyone with chronic nausea would seek help even if they addressed their symptoms in the short term—but research has shown that as many as a third of people avoid seeing a doctor even when they suspect they should. It’s conceivable that Zofran could help a doctor-wary sufferer retreat into denial.
Arrhythmia and Serotonin Syndrome and potentially dangerous disease-masking do feel like significant hurdles to making Zofran just another medication on the shelf at Walgreens. But from there things get more complicated, and more subjective.
I’m on the other side of the debate,” says Marlena Fejzo, Ph.D., a geneticist and professor at the University of Southern California’s Keck School of Medicine. Fejzo’s research focuses on women’s health, with a particular interest in Hyperemesis Gravidarum (HG), a condition during pregnancy that causes almost incessant nausea and vomiting, sometimes for the pregnancy’s full duration. I had just told her that the gastroenterologists I’d spoken with had highlighted the risks of making Zofran too accessible. She does not hold back in her disagreement. “If doctors were more willing to prescribe this drug for women to help them during pregnancy, then my answer would be different,” Fejzo says. “But it’s withheld in so many cases because of this fear of adverse outcomes. I think it would be great to have it available and let women make their own choice about it.”
Fejzo herself suffered from HG, so wracked by her symptoms that she was bedridden and had to receive nourishment first intravenously, then via feeding tube. Ultimately, she miscarried—an outcome that, along with preterm birth, she tells me occurs in 1 in 3 cases of HG. Fejzo says she was dismissed by her doctor, who implied that she was exaggerating her symptoms. This attitude is not uncommon among physicians, Fejzo says. “It’s rooted in historical sexism,” she continues. “I got a recording of an OBGYN, a woman doctor, teaching her medical students that when women are hospitalized with hyperemesis, it’s usually because there’s something going on at home or because they just don’t want to get better. Those were her exact words. She’s repeating this misogynistic nonsense to the next generation of medical students, and they believe her, and it just gets perpetuated.” It’s this attitude that may be what keeps Zofran out of the hands of the pregnant people who need it, Fejzo says: If a doctor doesn’t believe your symptoms are real, they’re unlikely to prescribe you a drug to cure them. Fejzo tells me she has seen cases in which wanted pregnancies were terminated because the HG symptoms were simply too much to bear.
Hoping to counteract the misconceptions about Zofran’s risks in pregnancy, Fejzo conducted a study. “We compared people who took Zofran who had HG to people who did not take Zofran and had HG, and then we had controls who did not have HG,” she says. “The risk of adverse outcomes was increased in people with HG compared to the people who did not have it, but the risk was identical for people who had HG whether or not they took Zofran.” In other words, it’s not the drug that’s dangerous to a fetus, it’s the condition it treats.
Fejzo believes that the tendency she’s observed for physicians to withhold Zofran from those with HG comes down to a paternalistic belief that women can’t evaluate the drug’s risks on their own and weigh them against the benefits. (This is not dissimilar to the demonstrated underprescribing of pain medication to women, who are more likely to be given sedatives than painkillers as compared to their male counterparts.) Case in point, Fejzo says, is research that found a miniscule increase in oral clefts of the fetus among pregnant subjects who took Zofran. “The increased risk is tiny. Eleven out of 10,000 people who did not take Zofran during pregnancy got an oral cleft in their fetus versus 14 out of 10,000 among those who did take it. So, there were only three more out of 10,000, which is a way lower risk than, for example, the risk of miscarrying after an amniocentesis, which is one in 200 to one in 400. Yet doctors allow women to make that choice all the time.”
I also spoke with Dr. Nicholas Ghionni, a Baltimore-based pulmonologist who works in the ICU. He had commented on an Instagram post regarding the dangers of Zofran by Dr. Zachary Rubin, the doctor behind @rubin_allergy, an account with 1 million followers. The post explored the QT interval and Torsades de Pointes concerns, with countless people ringing alarm bells in the comments. “I take this medicine every single morning,” one person wrote. “Now I’m freaked out.” Another said, “I had no idea. I thought it was safe.” But Ghionni’s retort called for a dose of perspective. “Torsades was seen in patients who took massive doses in a chemo study (32 mg at a time),” he wrote; the standard dosage for run-of-the-mill nausea in adults is far lower, around 4 milligrams. “Furthermore,” Ghionni continued, “how does this matter if you go to your PCP and get Zofran and then go home? You’re not on continuous monitoring.” In fact, in his daily work in the ICU, Ghionni tells me, he doesn’t bother with heart monitors for a low dose of Zofran.
“Medicine is very dogmatic,” Ghionni says. “And all of these rules are hammered into you as an intern—one of which is ‘Zofran causes QT prolongation, be careful.’” To Ghionni, this is just an echo of how medicine has always operated: Everyone practices in the way they’ve been taught to, until “people come along and challenge the dogma and ask, okay, do we have evidence of harm or benefit?” Zofranophobe doctors might start by reading the actual FDA warning attached to the drug, because Ghionni’s comment was correct about the discrepancy between the standard dose of 4 milligrams of ingested Zofran and the 32 milligram intravenous dose that was was associated with prolonged QT. Per that warning, the 32 milligram dose should be “avoided,” but there’s no risk mentioned regarding the far lower doses of Zofran that most people receive. So why, Ghionni wonders, should Zofran be, “picked out as the bad boy on the block?”
Which brings us to a glaring logical flaw in the prescription-only side of the Zofran debate: Ondansetron is arguably no more dangerous or prone to side effects than any number of OTC medications. Take acetaminophen (aka Tylenol) for example, too much of which can cause a rare fatal skin reaction and liver failure, or cough syrups with Dextromethorphan, which is hallucinogenic in high doses and famously prone to abuse. “I totally get why people say, yes, Zofran should be available, and others say, no, it shouldn’t be available,” says Deutsch. “I tend to argue that things like Advil and Tylenol shouldn’t be so readily available over the counter, even though they’re likely safe in most cases.” She thinks it all comes down to timing, and the way the FDA has changed its approach to regulation over the years: “It’s very, very, very infrequent that you see a new medication regulated by the FDA available over the counter anymore. If Zofran had been around 20 or 30 years earlier, it probably would’ve been OTC.”
Deutsch also taught me an industry term: therapeutic misadventure. It refers to adverse effects stemming from the attempt to address a medical problem—and, in this context, to the ways in which the average person consumes medications they don’t realize are dangerous. “You’re trying to treat your pain or nausea,” Deutsch says, offering a hypothetical. “You take one pill, and it helps a little but you’re still in discomfort, so you think, wouldn’t a second pill help more? It makes perfect sense, except that with medications, more is not necessarily better.” It’s easier to make OTC medication mistakes than you may realize, and every year, roughly 178,000 people wind up in the hospital for this reason. A Zofran misadventure doesn’t seem outside the realm of possibility; if you’re nauseous, you’re distracted. Did you take the last dose two hours ago, or three? You took it in tablet form, then threw up—do you take it again? You skipped a dose because you felt okay, but now you’re queasy. If the directive on the package is to take no more than 24 mg per day, and you’d still be below that threshold, can you take two? The point is, it’s easy to get lost in the nuances, and hidden in all that medicine minutiae are opportunities for mistakes.
But is it likely that one of those mistakes will be to accidentally take 32 milligrams of Zofran intravenously? No, probably not.
So, should Zofran be stocked near the Pepto Bismol, freely bought and used by all who need it? Is it kept from patients because of sexism, or inflated fears, or dogmatic thinking, or because it was created thirty years too late? It’s hard to say. But the case for OTC ondansetron is compelling. Prolonged QT intervals are rare, as is Serotonin Syndrome. The FDA could require, as it does for cold medicines containing pseudoephedrine (a key ingredient in methamphetamine), that Zofran only be sold in limited doses to those able to present a government ID. And anyway, as Fejzo points out, even in hospital settings there’s often not as much attention paid to arrhythmia-related concerns as you might think. “Even when Zofran is prescribed,” Fejzo says, echoing Ghionni, “are people on it being monitored? Are they checking their hearts? No, I doubt it.” A Reddit post from late last year in r/nursing suggests not: “When I worked med/surg, we gave [Zofran] to almost everyone who needed antiemetics and we didn’t need the patients on tele or EKG to do so”—meaning nurses were not asked to monitor patients’ heart rhythms.
During our conversation, Fejzo had asked, “What were the doctors you spoke to worried about, the QT interval? Constipation?”
“The QT interval and drug interactions, mostly,” I said.
“Yeah, well,” Fejzo answered, “you can put that on the bottle.”
Note: This article is for informational purposes only and is not intended to serve as medical advice, consult your doctor before undergoing medical treatment.
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