The Dr. Is In: The Curious Case of the Missing Range
Dr. Aston shares a mysterious missing range in a patient, and the medication change that solved it.
It was a regular day in my performing arts medicine clinic. The clinic schedule was normal and the list of complaints was unremarkable. I entered the exam room of my next patient Bill*, a young college student studying voice. As we began to discuss the reason for his visit, it was apparent that this was not going to be a regular run-of-the-mill appointment. He said, “I’ve lost half an octave at the top end of my voice range.” Intrigued, I asked if he had any other struggles with his voice. “Yes,” he responded, “I am not able to sing for more than a few minutes before my voice feels tired, and I’ve been feeling hoarse, too.”
This was a mystery indeed! Bill hadn’t been feeling sick. He wasn’t feverish and had no headache, chills, or cough. So, he didn’t have a head cold or the flu. “Bill,” I asked, “what medications are you taking?” He replied, “Just a medication for my allergies and a cream for my acne. I started the cream about a month ago.” Hmm, nothing unusual there. Bill’s physical exam was not unusual, either, and he didn’t look or sound sick. His voice was not hoarse, he didn’t look uncomfortable or worn out, and he did not have a runny nose. Bill appeared to be well, but he was understandably worried about what was happening to his voice. This change made choir rehearsals difficult, and he had no explanation to give his voice instructor.
Normally, I would have thought that a change like this was connected to a viral infection of the respiratory tract. Swelling of the tissues surrounding the larynx often deepens a voice, but Bill didn’t exhibit any of those symptoms that I’d expect with that type of infection. It just may be a medication reaction, but which medication? He hadn’t started either medication in the past couple of weeks. “Bill, I think you should stop your antihistamine. We know those medications preferentially dry out the vocal folds, so maybe this is the culprit.” “Okay,” he replied, and he stopped the medication and I referred him to an ENT so his vocal folds could be visualized.
Two weeks went by, and I called Bill to check in on him. To my chagrin, he reported that his voice had not improved a bit. I sighed to myself—this was not going as either of us anticipated. “Bill,” I said, “your antihistamine is not the problem. Go ahead and stop your acne medicine.” I surmised that although it may be a topical cream, maybe it’s being absorbed too much and causing the problem? Bill agreed and stopped the medication. Not two days later, Bill’s voice was normal again! His range was no longer stunted, and his voice was no longer hoarse or tired. The topical medication was actually the problem.
The medication was Isotretinoin, a common synthetic vitamin A analog, regularly used to treat acne. I was unfamiliar with this side effect, so I dug into the package insert data to learn more. I was shocked to find that there was absolutely nothing in the manufacturer’s literature about this. This type of side effect is called ergolysis in the sports medicine world, and it refers to the negative effect of a treatment on physical performance. In this case, topical vitamin A was somehow affecting the performance of Bill’s larynx. What was the problem here?
The truth is, we don’t really know—but I have some ideas. Vitamin A is fat soluble, which means it is difficult to get rid of once it is concentrated in the body. Normally, it collects in organs like the liver and kidneys. It can also concentrate in the vocal folds, and this is where the problem begins. Vitamins A and D do not play well together—vitamin A actually stops vitamin D from working correctly. Since vitamin D is needed for healthy calcium utilization, too much vitamin A in a localized setting may have an effect on surrounding muscles by making too much calcium available, eventually leading to muscle fatigue and even weakness.
For Bill, localized vitamin A toxicity may have caused the laryngeal muscles to fatigue easily (leading to vocal fatigue) and to be weak (leading to vocal range stunting). What is striking with Bill’s case is how quickly his voice recovered—simply a matter of days. My next question is why have the medication manufacturers not observed these types of reactions in the past? I suspect that the average member of the general population is not using their voices up to the edge of their range, so they would not notice vocal range stunting. Also, engaging speech for general conversation is not as strenuous as with singing—thus, vocal fatigue would not be reported either.
Vocalists, and performers in general, should be aware that medications that have been considered safe for the broader population may have ergolytic effects. Even over-the-counter medications like antihistamines or NSAIDs that are generally “well tolerated” and GRAS (Generally Regarded As Safe) may not be ideal. If you notice that your voice has changed, and not just with age, sit down with your physician to discuss your recent medical history. Reviewing your medication list, including new medications, is of vital importance. Even if the new medication was started a month or more previously (as was in Bill’s case,) its effect should be ruled out as part of the workup.
Please note: do not stop any medication without counseling with your physician beforehand! If that medication is controlling a disease (like high blood pressure) that has significant morbidity and/or mortality, the risks of stopping the medication can be greater than continuing it! Also, some medications, like Isotretinoin, may have undocumented side effects. An absence of reports of the effect in the literature does not mean that the medication is not the cause. Your physician can help you figure this out!
This story has not been shared to frighten or dissuade someone from taking any medication. Medications are valuable tools that improve quality of life for many patients and they have their place. Rather, it is meant to stimulate conversations between vocalists and their physicians by encouraging the consideration of possible ergolytic effects of medications that have been prescribed to them.
*The patient’s name has been changed to protect his privacy. His story is shared with his consent. A case report is published on this patient with references to vitamin A metabolism discussed in this story: www.sciencedirect.com/science/article/pii/S2468548825000086
