I’ve been blogging semi-regularly for almost 15 years and whenever I feel like I’m “blogged out” with nothing more to say, I inevitably find a topic that I’ve missed or forgotten to blog. When I read this post and then this paper about the dubious justification for the sale of a common cough and cold ingredient, I was frankly embarrassed that I hadn’t already written about it – years ago. Because the ineffectiveness of some cough and cold products is something everyone should be aware of.
We all suffer from coughs and colds. Surprisingly, while there are dozens of brands and formulations of cough and cold remedies on pharmacy shelves, they all use combinations of the same core handful of ingredients. And the evidence supporting some of these products is very, very weak. In the case of phenylephrine, included to treat “congestion”, it’s widely considered ineffective. Yet the FDA and regulators around the world continue to allow this ingredient to be included in cold products, as if it has medicinal benefits. Considering the evidence, this seems unwarranted.
What is phenylephrine?
In 1976, the FDA concluded that three medicines were safe and effective for the treatment of nasal congestion caused by colds, allergies, and sinusitis: phenylpropanolamine, pseudoephedrine, and phenylephrine. Almost 25 years later, phenylpropanolamine was withdrawn from the market after use was associated with strokes. Pseudoephedrine is an effective decongestant that is chemically very similar to methamphetamine, a addictive and controlled drug that subject to abuse. Pseudoephedrine does not share the same stimulant properties as methamphetamine, though it can cause jitteriness, mild tremors, and insomnia. However, because pseudoephedrine can be used to manufacture methamphetamine, the over-the-counter sale of cough and cold products that contain this ingredient are not permitted. Sales were moved “behind the counter” in the US, with the requirement for the customer to produce photo identification and the requirement for the pharmacy to maintain a log of all sales, tracked by customer name and address.
When pseudoephedrine was moved behind the counter, manufacturers of cough and cold products either had to accept a much smaller market for their (effective) product, or…pivot.
Some companies reformulated their products to contain phenylephrine instead, the last remaining non-prescription ingredient that the FDA had approved for congestion. Phenylephrine is from a category of drugs called alpha-1 agonists, that stimulate alpha-1 receptors that are present throughout the body, including the nasal passages. It is used as a nasal spray but more commonly as a oral product take to treat nasal congestion. There was a problem with FDA’s approval, however. There was little convincing evidence phenylephrine, when taken orally, was effective.
The evidence against phenylephrine
Phenylephrine is a poorly-absorbed drug (i.e., it has low bioavailability). Most of the drug is broken down during the absorption process and after passing through the liver. Only an estimated 38% of a dose actually reaches the bloodstream (compared with 90% for pseudoephedrine). In clinical trials, phenylephrine has been compared to other decongestants in a randomized controlled trial of 20 patients (way back in 1971) and found to be no more effective than placebo in reducing airway resistance. Another trial compared single doses of four different decongestants against placebo in 88 patients with congestion. It also found that phenylephrine was no more effective than placebo. In a review of the data that the FDA had considered, that review noted that for the 10mg dose, 4 studies showed efficacy and seven showed no difference from placebo. The authors concluded that a systematic review did not support the FDA’s decision. Other trials conducted since that time (like this one in 2009) are supportive of the conclusion that the 10mg dose is ineffective.
The fact that we are relying on trials conducted in the 1970’s pretty much tells us what we need to know about phenylephrine. Given how poorly it is absorbed, there is the question of whether simply giving bigger doses will work – and it turns out it may. However, the 10mg dose is what’s available in US cough and cold products – and the best evidence shows that this drug is effectively a placebo at that dose. I will point out that the manufacturers of the consumer products that contain this ingredient continue to write their own papers suggesting that there is evidence of efficacy.
The FDA is petitioned…and is finally acting
In 2015, pharmacy professors Randy Hatton and Leslie Hendeles of the University of Florida College of Pharmacy filed a citizen’s petition with the FDA, asking it to remove phenylephrine from the monograph of over-the-counter cold remedies, noting the absence of a decongestant effect at the approved dose of 10mg. They noted that since the FDA’s Nonprescription Drugs Advisory Committee had called for more research in 2007, four studies had been conducted, and none of those studies demonstrated that phenylephrine was more effective than a placebo. This petition is supported by the American Academy of Allergy, Asthma and Immunology:
The low bioavailability of pharmacologically active oral PE explains the lack of nasal therapeutic efficacy and cardiovascular effects. It is extensively metabolized in the gut mucosa causing insufficient systemic PE levels to produce vasoconstriction of nasal and other blood vessels. Available data do not support whether a dose greater than 40mg of oral PE would be effective or safe. Furthermore, the American Academy of Allergy, Asthma & immunology and the American College of Allergy, Asthma & Immunology in their role as patient advocates have concluded that keeping oral phenylephrine over‐the‐counter does a disservice to patients who might be prone to taking higher doses than recommended due to lack of effect and/or delay their visit to their primary care clinician or a specialist who could help resolve their symptoms.
Ineffective drugs don’t deserve stamps of approval
Professors Hatton and Hendeles reiterated their call for the FDA to take action in 2022, and finally the FDA may act this April:
The committee will discuss the adequacy of efficacy data available for oral phenylephrine as a nasal decongestant and whether oral nasal decongestants phenylephrine hydrochloride and phenylephrine bitartrate should be reclassified as not ‘Generally Recognized as Safe and Effective’ (GRASE) due to lack of efficacy.
Why the approval has persisted so long is puzzling from an evidence perspective, but perhaps it was sensible to the FDA. Phenylephrine is safe at the 10mg dose, and withdrawing the drug might raise more questions about why this drug was permitted in cough and cold products, for decades, without clear evidence of effectiveness. Until that time, remember that the only available non-prescription oral decongestant that has been shown to actually be effective is pseudoephedrine. Ask your pharmacist if pseudoephedrine is right for you.