Commentary

β noradrenergic antagonists have broad utility, but they are considered to have troublesome side effects. Ko et al found that β blockers were associated with increased fatigue and increased withdrawal because of fatigue or sexual dysfunction. Yet, closer examination sheds doubt on whether the evidence supports differential effects across the 3 problems and raises questions about the interpretation of side effects in placebo controlled trials.

Both placebo and active drug effects ranged widely across studies and were strongly correlated (table 2). The range across studies dwarfed the relatively small apparent differences between placebo and active drug. The significant difference between placebo and active drug for withdrawal because of fatigue or sexual dysfunction may reflect a true adverse effect of β blockers, although with sexual dysfunction the difference may not be meaningful because almost all withdrawals were in the same study.

The heterogeneity across trials, with close tracking of placebo and active drug effects, is consistent with a nocebo effect, whereby negative expectations can result in unfavorable outcomes.¹ Side effects of placebo have been documented to resemble those of the reference drug.² Patients in randomised clinical trials receive detailed information about potential side effects of the reference drug. This contributes to similar “side effect” rates for active drug and placebo but would not account for the wide range of event rates. Such a range could result from varying sources, including patient characteristics, actual β blockers used, or study design.

In summary, a prominent apparent nocebo effect probably biases toward underdetection of side effects in placebo controlled trials. Furthermore, the studies were so heterogeneous in event rates that it is difficult to interpret their results in combination. Even with these biasing factors, differences in the incidence of fatigue and sexual dysfunction emerge.