Why Has a Useless Cold Medication Been Allowed on Shelves for Years?

You wake up with a stuffy nose, so you head to the pharmacy, where a plethora of options awaits in the cold-and-flu aisle. Ah, how lucky you are to live in 21st-century America. There’s Sudafed PE, which promises “maximum-strength sinus pressure and nasal congestion relief.” Sounds great. Or why not grab DayQuil in case other symptoms show up, or Tylenol Cold + Flu Severe should whatever it is get really bad? Could you have allergies instead? Good thing you can get Benadryl Allergy Plus Congestion, too.

Unfortunately for you and me and everyone else in this country, the decongestant in all of these pills and syrups is entirely ineffective. The brand names might be different, but the active ingredient aimed at congestion is the same: phenylephrine. Roughly two decades ago, oral phenylephrine began proliferating on pharmacy shelves despite mounting—and now damning—evidence that the drug simply does not work.

“It has been an open secret among pharmacists,” says Randy Hatton, a pharmacy professor at the University of Florida, who filed a citizen petition in 2007 and again in 2015 asking the FDA to reevaluate phenylephrine. This week, an advisory panel to the FDA voted 16–0 that the drug is ineffective orally, which could pave the way for the agency to finally pull the drug.

If so, the impact would be huge. Phenylephrine is combined with fever reducers, cough suppressants, or antihistamines in many popular multidrug products such as the aforementioned DayQuil. Americans collectively shell out $1.763 billion a year for cold and allergy meds with phenylephrine, according to the FDA, which also calls the number a likely underestimate. That’s a lot of money for a decongestant that, again, does not work.

Over-the-counter oral decongestants weren’t always this bad. But in the early 2000s, states began restricting access to pseudoephedrine—a different drug that actually is effective against congestion—because it could be used to make meth; the Combat Methamphetamine Epidemic Act, signed in 2006, took the restrictions national. You can still buy real-deal Sudafed containing pseudoephedrine, but you have to show an ID and sign a logbook. Meanwhile, manufacturers filled over-the-counter shelves with phenylephrine replacements such as Sudafed PE. The PE is for phenylephrine, but you would be forgiven for not noticing the different name.

“Thet switch from pseudoephedrine to phenylephrine was a big mistake,” says Ronald Eccles, who ran the Common Cold Unit at Cardiff University until his retirement. Eccles was critical of the switch back in 2006. The evidence, he wrote at the time, was already pointing to phenylephrine as a lousy oral drug.

Problems started showing up quickly. Hatton, who was then a co-director of the University of Florida Drug Information Center, started getting a flurry of questions about phenylephrine: Does it work? What’s the right dose? Because my patients are complaining that it’s not doing anything. He decided to investigate, and he went deep. Hatton filed a Freedom of Information Act request for the data behind FDA’s initial evaluation of the drug in 1976. He soon found himself searching through a banker’s box of records, looking for studies whose raw data he and a postdoctoral resident typed up by hand to reanalyze. The 14 studies the FDA had considered at the time had mixed results. Five of the positive ones were all conducted at the same research center, whose results looked better than everyone else’s. Hutton’s team thought that was suspicious. If you excluded those studies, the drug no longer looked effective at its usual dose.

All told, the case for phenylephrine was not great, but the case against was no slam dunk either. When Hatton and colleagues at the University of Florida, including Leslie Hendeles, filed a citizen petition, they asked the agency to increase the maximum dose to something that could be more effective. They did not ask to pull the drug entirely.

There was more damning evidence to come, though. The petition led to a first FDA advisory committee meeting, in 2007, where scientists from a pharmaceutical company named Schering-Plough, which later became Merck, presented brand-new data. The company had begun studying the drug, Hatton and Hendeles recalled, because it was interested in replacing the pseudoepinephrine in its allergy drug Claritin-D. But these industry scientists did not come to defend phenylephrine. Instead, they dismantled the very foundation of the drug’s supposed efficacy.

They showed that almost no phenylephrine reaches the nasal passages, where it theoretically could reduce congestion and swelling by causing blood vessels to constrict. When taken orally, most of it gets destroyed in the gut; only 1 percent is active in the bloodstream. This seemed to be borne out by what people experienced when they took the drug—which was nothing. The scientists presented two more studies that found phenylephrine to be no better than placebo in people congested because of pollen allergies.

These studies, the FDA later wrote, were “remarkable,” changing the way the agency thought about how oral phenylephrine works in the body. But experts still weren’t ready to write the drug off entirely. The 2007 meeting ended with the advisory committee asking for data from higher doses.

The story for phenylephrine only got worse from there. In hopes of making an effective product, Merck went to study higher doses in two randomized clinical trials published in 2015 and 2016. “We went double, triple, quadruple—showed no benefit,” Eli Meltzer, an allergist who helped conduct the trials for Merck, said at the FDA-advisory-panel meeting this week. In other words, not only is phenylephrine ineffective at the labeled dosage of 10 milligrams every four hours, it is not even effective at four times that dose. These data prompted Hatton and Hendeles to file a second citizen petition and helped prompt this week’s advisory meeting. This time, the panel didn’t need any more data. “We’re kind of beating a dead horse … This is a done deal as far as I’m concerned. It doesn’t work,” one committee member, Paul Pisarik, said at the meeting. The advisory’s 16–0 vote is not binding, though, so it’s still up to the FDA to decide what to do about phenylephrine.

In any case, phenylephrine is not the only cold-and-flu drug with questionable effectiveness in its approved form. The common cough drugs guaifenesin and dextromethorphan have both come under fire. But we lack the robust clinical-trial data to draw a definitive conclusion on those one way or the other. “What really helped our case is the fact that Merck funded those studies,” Hatton says. And that Merck let its scientists publish them. Failed studies from drug companies usually don’t see the light of day because they present few incentives for publication. Changing the consensus on phenylephrine took an extraordinary set of circumstances.

It also required two dogged guys who have now been at this work for nearly two decades. “We’re just a couple of older professors from the University of Florida trying to do what’s best for society,” Hatton told me. When I asked whether they would be tackling other cold medications, he demurred: “I don’t know if either one of us has another 20 years in us.” He would instead like to see public funding for trials like Merck’s to reevaluate other over-the-counter drugs.

There are other effective decongestants on pharmacy shelves. Even though phenylephrine does not work in pill form, “phenylephrine is very effective if you spray it into the nose,” Hendeles says. Neo-Synephrine is one such phenylephrine spray. Other nasal sprays containing other decongestants, such as Afrin, are also effective. But the only other common oral decongestant is pseudoephedrine, which requires that extra step of asking the pharmacist.
Restricting pseudoephedrine has not  curbed the meth epidemic, either. Meth-related overdoses are skyrocketing, after Mexican drug rings perfected a newer, cheap way to make methamphetamine without using pseudoephedrine at all. This actually effective drug still remains behind the counter, while ineffective ones fill the shelves.