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Placebos Have Side Effects Too

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Aleks points me to this blog by Neuroskeptic, who reports on some recent research studying the placebo effect:

Because different drugs have different known side effects, if the nocebo effect is real, the side effects reported by the placebo group should depend on the drug they think they might be taking. . . .

Accordingly, Rief et al compared the side effects reported in the placebo groups of a large number of antidepressant drug trials. At the same time a separate group of researchers, Amanzio et al, did the same thing for trials of migraine drugs, which is a nice coincidence.

Both papers found that reported side effects do indeed depend on the drug being studied. In the antidepressant paper, people who believed they might be on tricyclic antidepressants (TCAs) reported many more “side effects” than those in trials of SSRIs. These included dry mouth, drowsiness, constipation, and sexual problems. This makes sense, because TCAs do have worse side effects than SSRIs.

Likewise, for the migraine trials, the placebo groups in trials of anticonvulsants reported more symptoms associated with those drugs, such as dizziness and sleepiness. Placebo groups in trials of NSAIDs (like aspirin) were more likely to report upset stomachs and so forth. Finally, in trials of triptans, which have very mild side effects, the placebo group reported few problems.

It’s also interesting to compare the two papers. None of the migraine trial placebo patients reported experiencing sexual problems, while many of the antidepressant placebo patients did. Some antidepressants can cause sexual problems, while migraine drugs generally don’t.

Neuroskeptic concludes:

So, was the “nocebo effect” really making people feel worse? It could well have been, although there are other interpretations. People might just be more willing to report symptoms that they believe are drug side effects. Researchers might be more likely to write them down. And different kinds of people end up in trials of different drugs . . . Nevertheless, there’s an important lesson here. Anecdotal evidence about drug’s side effects shouldn’t be accepted at face value, any more than anecdotes about their benefits. Drugs do, of course, cause adverse effects. But some drugs have worse reputations than they deserve in this regard. In such cases, nocebo effects might account for some of the reported problems.

4 Comments

  1. jonathan says:

    It's very difficult to distinguish anecdotal complaints because, for example, a cough may originate in an inflammation or in the mind and then that might manifest as inflammation though it was a habit cough originally.

    I would expect one could alter reported side effects by creating different expectations in the population. This might be best tested using a fake drug because then you could concentrate on establishing clear side effect differences in expectations.

  2. jeremy says:

    It would be interesting to add dummy (i.e. fake) side-effects for the placebo group and see what's reported. Of course, one would have to know what side-effects people would be more concerned about (sexual dysfunction more alarming than elbow numbness, e.g.)

  3. Megan Pledger says:

    1) My guess would be that it's not the patients who are selecting the "right" side effects but the investigators who are asking the patients about side effects.

    The investigators ought to be blind to which drugs the patients are taking so they are going to probe *everyone* for known side effects of the active drug.

    They'll have a fairly good idea about what the rate of side effects for their drug ought to be and they'll want to publish their own rates for the patients on the active drug, once the patients are unblinded, so that their study looks consistant with others i.e. there's an incentive to capture the "right" events even if they are asking the wrong people.

    2) People who are depressed are more likely to have sexual health problems (lack of labido etc) compared to people with migraines. It's probably not the drug that causing the placebo patients to give the "right" side effects but the actual health problem itself.

  4. Kjetil Halvorsen says:

    This findings does'nt seem to be very new. I told about this blog entry to my mother, whi is a retired
    medical doctor. She said she heard about this
    many years ago! (but no references…)