Research published today in Trials explores the negative effects that can be caused by participants being administered placebos in clinical trials, finding that half of people taking placebos reported side effects from the trial intervention. Here talk about these findings is Dr. Jeremy Howick, lead author of the study.

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New research has found that half of participants who took a placebo (usually an inert pill, like a sugar pill) in a clinical trial reported suffering from an adverse event (a side effect of the trial intervention). More surprisingly, 1 in 20 people who were taking placebos dropped out of their trials because of more serious adverse events. The study included data from 1,271 randomized trials and 250,726 trial participants. The adverse events ranged from abdominal pain and anorexia to burning, chest pain, fatigue, and even death.

But how can a sugar pill cause harm? The answer is: mistaken beliefs about the cause of the event (‘misattribution’) and negative beliefs (negative expectations).

Someone in a trial might have a stomachache for any number of reasons that are not related to the trial. Because they are in a trial, they think the trial intervention caused the ache, misattributing the cause. This gets reported as an adverse event, when in fact it would have happened anyways.

Sometimes the way patients are warned about adverse events makes patients believe they will get an adverse event (like a stomachache), and that can cause them to actually experience it. Effects of negative expectations are called ‘nocebo’ (‘negative placebo’) effects.

There was no data about what the trial participants in our study were provided in our study. However, we know from other studies that the way patients are warned about adverse events can affect whether they report them. For example a study published last year in The Lancet found that patients were more likely to report adverse events when they knew they were taking statins. When they had no idea, there was no increase in muscle-related effects.

Misattribution is hard to avoid because it is difficult for someone in a trial to know whether a symptom is caused by the trial intervention or the condition that led them to enter the trial in the first place.

Another study found that patients in a randomized trial of aspirin or sulfinpyrazone for treating unstable angina who received a statement outlining possible gastrointestinal adverse events were six times more likely to withdraw from the study due to reported gastrointestinal adverse events.

Finding ways to reduce adverse events among patients in placebo groups is important for improving trial quality, and may also improve the ethics of clinical trials. The question is: how?

Misattribution is hard to avoid because it is difficult for someone in a trial to know whether a symptom like a stomachache is caused by the trial intervention or the condition that led them to enter the trial in the first place. However it seems likely that we can reduce the harm caused by negative expectations.

For example, telling patients that a new treatment is safe for 90% of patients contains the same information as saying it causes adverse events like headaches in 10% of patients. But the second way may be more likely to actually cause the adverse events than the first.

Unfortunately, guidance for informing trial participants about trial intervention harms, in a way that does not produce nocebo effects, is currently under-researched. A recent systematic review suggested that information provided to participants often fails to meet their needs, presented in a way they sometimes find difficult to understand.

Ongoing research at the Universities of Oxford and Cardiff is looking at ways to inform patients in trials about the best way to provide balanced information about the benefits and harms of participating in trials.