Are Warnings About the Side Effects of Drugs Making Us Sick?

Patient receiving a vaccine. Photo by Flickr user Noodles and Beef.

Photo by Flickr user Noodles and Beef.

Your doctor doesn’t like what’s going on with your blood pressure. You’ve been taking medication for it, but he wants to put you on a new drug, and you’re fine with that. Then he leans in close and says in his most reassuring, man-to-man voice, “I should tell you that a small number of my patients have experienced some minor sexual dysfunction on this drug. It’s nothing to be ashamed of, and the good news is that this side effect is totally reversible. If you have any ‘issues’ in the bedroom, don’t hesitate to call, and we’ll switch you to another type of drug called an ACE inhibitor.” OK, you say, you’ll keep that in mind.

Three months later, your spouse is on edge. She wants to know if there’s anything she can “do” (wink, wink) to reignite the spark in your marriage. She’s been checking out  websites advertising romantic getaways. No, no, you reassure her, it’s not you! It’s that new drug the doctor put me on, and I hate it. When you finally make the call, your doctor switches you over to a widely prescribed ACE inhibitor called Ramipril.

“Now, Ramipril is just a great drug,” he tells you, “but a very few patients who react badly to it find they develop a persistent cough…” Your throat starts to itch even before you fetch the new prescription. Later in the week, you’re telling your buddy at the office that you “must have swallowed wrong” — for the second day in a row. When you type the words ACE inhibitor cough into Google, the text string auto-completes, because so many other people have run the same search, desperately sucking on herbal lozenges between breathless sips of water.

In other words, you’re doomed. Cough, cough!

Coughing man

Photo by Flickr user Jeff and Colin.

What’s going on here? Just medicine-as-usual in a world where valuable drugs have annoying side effects and conscientious health professionals do their best to protect their patients from unpleasant (and potentially litigious) surprises? Sure. But a provocative new report by Winfried Häuser, Ernil Hansen, and Paul Enck in the journal of the German Medical Association suggests that the side effects of some drugs, and the discomfort of certain medical procedures, may be inadvertently intensified by doctors and nurses trying to keep patients fully informed of the consequences of their medical care. The culprit behind this phenomenon is the nocebo effect.

You can think of the nocebo effect as the evil twin of the placebo effect — the body’s healing response to the act of taking a pill or receiving medical care, even if the pill itself is inert. The most familiar example of the placebo effect is what happens in trials of experimental drugs. One group of volunteers is randomly assigned to take the drug in question; another group is assigned to take placebo — a fake drug designed to look just like the real one. Neither the volunteers nor the staff know which group is which. If the drug group improves significantly more than the placebo group, the drug is judged to be effective. This kind of test — the double-blind, placebo-controlled trial — has been the gold standard of drug development in medicine for half a century.

In real life, gauging the effectiveness of a new medication is not quite that easy. In 2009, I wrote a widely-circulated article in Wired magazine about a mysterious increase in placebo effects in trials in recent years that is making it harder for Big Pharma to bring new drugs to market. I explored some of the reasons that might be happening in the article.

A placebo, you might say, is an ersatz drug that makes you feel better, while a nocebo is a fake drug that makes you feel worse. Of course, in both cases, it’s not the pill that’s doing the work; it’s your own body, responding to the social context in which you take the pill. If a skilled doctor with kindly bedside manner tells you that drug X will reduce the inflammation of a minor injury, it often will — even if the drug itself is nothing but a capsule full of lactose, milk sugar. One of the astonishing things we’ve discovered about the placebo effect in recent years is how wide a range of ailments can be ameliorated by it, at least temporarily — from chronic pain, to high blood pressure, to inflammation, to depression and anxiety, to sexual dysfunction, to the nausea and vomiting caused by chemotherapy. Perhaps unsurprisingly, it turns out that the nocebo effect is equally capable of making you feel more miserable, in a similarly broad range of ways.

One of the most interesting findings in the new report from Germany is about the underappreciated — and under-studied — role of nocebo effects in clinical trials.

If you tell a group of trial volunteers that they’re testing a new drug that may relieve the pain of migraines, a significant number of volunteers will experience pain relief after taking the drug — even if they’ve been randomly assigned to the placebo group and are receiving nothing but sugar pills. The placebo effect in action.

But here’s where it gets interesting.  If you tell the volunteers that the side effects of this new medicine may include dry mouth, tingling in the hands and feet, and slight dizziness, some volunteers will experience precisely these side effects — in both groups. In fact, some volunteers who are taking nothing but sugar pills will be made so uncomfortable by these symptoms that they will choose to drop out of the trial early.

Pills for pain

Photo by Flickr user MadcowIV.

The relevance of the nocebo effect is not limited to clinical trials. A particularly nasty demonstration of its power can be provided by patients who are being treated for Parkinson’s disease with small doses of electrical current delivered to certain structures in the brain. This technique, known as Deep Brain Stimulation (DBS), has been shown to be effective in controlling tremor and other motor issues in patients who are resistant to drugs. But if you tell a DBS patient that the current has been switched off — even though it remains on — their coordination and other motor functions will abruptly decline until you tell them that the juice has been switched on again. Classic nocebo.

The German researchers cite many other examples. In one study, 50 patients with chronic back pain were randomly divided into two groups before a leg flexion test. One group was informed that the test could lead to a slight increase in pain, while the other group was instructed that the test would have no effect. Guess which group reported more pain and was able to perform significantly fewer leg flexions?

Another example from the report: Patients undergoing chemotherapy for cancer treatment who expect these drugs to trigger intense nausea and vomiting suffer far more after receiving the drugs than patients who don’t. That’s not to say that this nausea is imaginary, purely psychological, or “all in their heads.” Like placebo effects, nocebo effects are physiological, not just mental. Researchers like Franklin Miller at the National Institutes of Health and Tor Wager at the University of Colorado are learning that nocebo effects are mediated by neurotransmitters like dopamine, endogenous opioids, and cholecystokinin. Telling a volunteer that the scented Vaseline you’re slathering on their arm is a pain-intensifying gel triggers a cascade of chemicals in the body that magnify sensations of discomfort.

Skull made of pills

Photo by Flickr user markkilner.

How evil can the evil twin of the placebo effect get? Even setting aside anecdotal accounts of evil eyes and “voodoo death” (first reported by a doctor named William Cannon in 1942), nocebo effects can kill, or at least accelerate the progress of disease. In traditional Chinese astrology, some potentially fatal maladies like cancer are associated with certain birth years. A 1993 study of Chinese-Americans who came down with these diseases found that they were more likely to die faster if they were born in an “ill-fated” year associated with the disease — but only if they believed in traditional Chinese astrology. (In these tragic cases, a dose of skepticism could have at least staved off the inevitable for a little while.)

In recent years, the phrase “informed consent” has become a mantra in public health, which is good news for many reasons. But what if the lengthy litanies of side effects we’ve become accustomed to skimming over — on printouts at the pharmacy, in ads for the latest antidepressants — are self-fulfilling prophecies? What if our well-intentioned desire to prepare patients for the worst increases the probability that the worst will happen?

Even the specific words employed by a doctor can influence the course of a patient’s treatment. Some particularly dreadful word choices cited by the German researchers include doctors telling patients:

You must strictly avoid lifting heavy objects — you don’t want to end up paralyzed.

You are a high-risk patient.

We’re putting you to sleep now. It will soon be all over.

Though the German report focuses on clinical practice and bedside manner, it’s hard not to think about the broader implications of nocebo effects in daily life.  If you’re ever been told twice in one afternoon that you “look a little worn out,” you know that it’s a miracle if you don’t feel utterly exhausted – if not physically ill — by the end of the day. Knowing about nocebo has made me much more careful when making observations about a friend’s physical condition.

Gluten allergy icon from Kids Aware

The German report also points out that nocebo effects deserve much more study. One promising avenue for research might be examining the role of negative messaging in large-scale social phenomena like the apparent increase in food allergies in recent years, or the surge in popularity of gluten-free diets. Having friends with celiac disease and autism, I’m fully aware that some people are truly gluten intolerant, and that banishing the dreaded protein from the menu can avert serious medical problems. But the new report makes me wonder if the flood of anti-gluten “awareness” messages on social networks isn’t lengthening the lines for pricey GF pasta, crackers, and doughnuts at my neighborhood Whole Foods Market.

The conflict between the need for informed consent in medicine and our bodies’ propensity to take social factors into consideration when calculating our own health status is not an easy problem. In recent years, the pendulum has swung so far in the direction of more-bad-news-is-better that it seems almost like heresy to suggest that some of this paternalistic advice may actually be making us sicker.

The new generation of placebo and nocebo research is teaching us that how we feel is highly dependent on the feedback we get from the people around us, particularly from trusted health professionals. The next time I get a headache, you’ll forgive me if I don’t re-read the label on the aspirin bottle warning me about the possibility of hives, facial swelling, asthma, shock, Reye’s Syndrome, nausea, vomiting, severe stomach bleeding, allergic reactions, and distressingly vague “changes in behavior.”

I’ll just take two and hope for the best.

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22 Responses to Are Warnings About the Side Effects of Drugs Making Us Sick?

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  5. I wonder if drug addiction is an example of the nocebo effect. Don’t take drugs, kids. Because if you start, you might not be able to stop: Addiction!

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  11. BigSoph says:

    I am now wondering how often sick office syndrome is caused by people seeing a news article and feeling the symptoms!

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  12. William Brenner says:

    Has anyone tested for a nocebo effect from viewing medication TV ads with their scary multiple side effect disclaimers? The ads must sell the drugs else there would not be so many.

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  13. Kelly says:

    I can believe this. The mind is a powerful thing. I’ve dealt with a mild herniated disk for a few years. I ran across one of those magnetic bracelets you see athletes wearing and on a whim bought it. Within a few hours of putting on the bracelet I went from limping to being totally pain free. My husband says it is all in my head, I say so what if it is? The pain isn’t there any longer and that is all that counts.

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  15. Jim Campbell says:

    I have a story similar to Ben. On my first job, some one asked another guy in my department, Steve, if he felt ok. Then he saw that it was just a trick of the light or something and Steve didn’t look so bad at all. However, he started calling around the department, telling people to tell Steve that he didn’t look well. Steve was gone by ten o’clock. When that many people tell you are sick, you are sick.
    As I remember, Steve was lost in the Bermuda Triangle about thirty years ago. I doubt if there is a connection.

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  17. daniel.lende says:

    Great post. Really appreciated. And just from a blogging point of view, love the images and how you use them so effectively to break up text and also provide additional commentary…

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  19. ben says:

    True story, if my mom was telling the truth.

    When she was young, gorgeous, and just starting in an office job (during WWII, she rebuilt aircraft generators…but that’s another story), one of the mid-level managers made a crude, physical, and distinctly unwelcome pass at her first thing one morning. She was pissed.

    She got together with all the ladies in the office and had a quick meeting. They’d all been groped by this guy at one time or another and were happy to help. The plan: they all, individually and randomly that morning, would walk by his desk. Then stop and look at him with a look of concern. Then move on. If he asked (and he did, to almost every one of them), they’d ask him if he was OK and mention that he didn’t look well. According to mom, when they got a chance they really poured on the sympathy.

    He took it all to heart and left on sick leave before lunch. They had so completely convinced him that he was sick that he stayed gone for an extra day.

    Costing the guy a day and a half of sick time was a small price for his forwardness but, given management attitudes back then, it was considered by all the ladies in the office to be a major win.

    In sum: I didn’t realize this “nocebo effect” was news. I thought this was just something that everyone sorta instinctively knew.

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  21. John says:

    I was doing fine until I read this caution about the effects of warning about drug side-effects.

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