The nocebo effect: Evil twin brother of the placebo effect

Dear Dr. Roach: Over the past year, I have taken three different statins, all with disastrous side effects. I am currently getting a month off before my doctor tries another one. I have talked to everyone I know or meet about these drugs. My decidedly unscientific survey results are that about a third of the people take them without problems, a third cannot take them because of side effects, and the last third tell their doctors they take them but they actually don’t. Are the reported side-effect statistics somehow being manipulated? — J.T.

Answer: Statin drugs, used to reduce the risk of a heart attack and stroke in people at high risk, are generally well-tolerated drugs. The numbers from your unscientific survey do not match the results of placebo-controlled studies. In people who were enrolled in clinical trials, about 13 percent could not tolerate the statin drug during an average of four years in the trial; however, 14 percent of people on placebo pills, which contain no active medication, could not tolerate the placebo and had to stop it. This suggests that, compared with placebo, statin drugs are well-tolerated.

However, when people know they are taking a statin, the risk of having a side effect, especially muscle aches, is much higher than in people who don’t know what they are taking. In some observational trials, as many as 25 to 30 percent of people are unable to tolerate statin drugs (which is much closer to what your informal survey showed).

I frequently discuss the placebo effect, where people get benefit from taking a medication or supplement that they think will help them. It is real and powerful at relieving symptoms. The findings from open-label statin drug trials show the opposite, called the “nocebo effect.” This is when you expect a medication to cause a side effect, and it does.

A powerful lesson can be drawn from a trial of a new class of cholesterol-lowering medication, called the PCSK-9 inhibitors. One study took people who, like you, had been unable to tolerate three different statins. The participants in the study went four weeks with no medication. They were then randomized to statin or placebo, and 60 percent of those who were unable to tolerate any statin were able to do so (even ones they were unable to take previously) — when they were unaware of what they were taking. This shows that while some people truly develop side effects due to the statin, much or most of the apparent statin intolerance was due to the nocebo effect.

Deciding what to do for an individual like you is difficult, as one can never know in an individual whether the effects are “real” or nocebo. Statins are the most effective class of drug to reduce heart disease risk, so on the one hand, you don’t want to withhold medication that is likely to improve and extend someone’s life. On the other hand, you don’t want the risk of “disastrous” side effects.