This is a story about cough syrup. Well, actually, it’s a story about cough syrup in Norway.
We Americans sometimes are not all that interested in stories that take place in other parts of the world, but this is one story that we all should hear. It’s got everything: Mystery, doctors in ORs struggling to save patients teetering on the edge of annihilation, dedicated Norwegian researchers, a potential environmental disaster, and a French invention of questionable character. Oh, and of course, cough syrup.
It all began with anaphylaxis, a five-syllable word that doesn’t ring a bell for many people. Anaphylaxis is a rapid, systemic, life-threatening emergency. It is usually, but not always, caused by an allergic reaction to a substance, and if not treated quickly and aggressively, it can kill whoever is unlucky enough to have it.
Now, one of the things that surgeons fear is losing a patient to an anaphylactic reaction to one of the drugs being used to anesthetize him or her. And during the 90s Norwegian anesthesiologists were reporting that there were more and more cases of patients having life-threatening reactions to general anesthesia.
Over 93% of these reactions were to what are called neuromuscular blocking agents, which is most often considerately shortened to NMBA. Since up to half of the patients who had NMBA-related anaphylaxis had never been exposed to anesthetic drugs before, it was a mystery how they had been sensitized to something containing the same QAI epitope — which is a key piece of the same chemical structure as these anesthetics.
Researchers found that of Norwegians who had high blood levels of IgE (the immunoglobulin involved in allergic reactions), 30% had antibodies to a substance containing the QAI epitope.
And the worst part was that when the Norwegian researchers compared how often Swedish doctors were reporting such reactions (the Norwegians felt that it was most appropriate to compare themselves to a country with a similar genetic, cultural and geographic setting), they found that anaphylactic reactions to NMBAs were ten (10!) times higher in Norway.
And when researchers compared the blood of allergic Swedes and Norwegians they found that none of the Swedes were sensitized to the QAI epitope, whereas a percentage of the Norwegians were.
The initial theory was that Norwegians were being exposed to some environmental substance, unavailable in Sweden, that sensitized them to the QAI epitope. So researchers went to work analyzing 84 household and environmental chemicals — things like skin and hair care products, cough syrups, toothpaste, lozenges, cleansers, and motor oils. A few items did have the ability to sensitize someone somewhat, but it turned out that both Norwegians and Swedes were exposed to roughly the same products, in chemical terms.
However, there was one thing that was different. In Norway, cough syrup contained pholcodine (abbreviated PHO), while in Sweden, the substance had been phased out in the late 80s.
What is PHO? It’s a neutered form of morphine, chemically altered to remove it’s ability to relieve pain or cause addiction. It was created in France back in the 1950s to be a cough suppressant that worked its magic by acting directly on the central nervous system’s cough center.
As you can probably guess, further research and experimentation suggested that the PHO-containing cough syrup was systematically making allergically prone Norwegians become sensitive to the QAI epitope that was part of the NMBAs that might later be used to put them under for surgery.
Because this happened in Norway, instead of in the US, the manufacturer of the PHO-containing cough syrup made the unprofitable decision not to renew its marketing license for the product, and it was taken off the market in 2007. (If this had happened in the US, I’m sure the courts would be litigating the issue for at least ten years.)
So why should we Americans find this story interesting? Well, first of all, it illustrates how arcane and unexpected the connections between things can be. PHO didn’t kill anybody who took it in cough syrup, but it posed a markedly increased possibility of a life-threatening reaction to anesthesia administered to its allergy-prone users.
If Sweden had not, for unrelated reasons, phased out use of PHO in the late 80s, both Norwegians and Swedes might be standing around, scratching their heads, wondering at the surge in life-threatening attacks of anaphylaxis occurring in their operating rooms.
I think there’s a lesson in this story, a cautionary tale. I was born into a world (the 1950s) in which people thought that they had conquered nature, but I hope to die in a world that is aware that we can be too clever for our own good, or not clever enough to see the far-reaching ramifications of the choices we make.
Reference: Florvaag E. The pholcodine story. Immunol Allergy Clin N Am 29 (2009) 419–427.
Copyright © 2009 by Candace L. Van Auken. All rights reserved.