In randomized controlled trials, medication side effects may lead to beliefs that one is receiving the active intervention and enhance active treatment responses, thereby increasing drug-placebo differences. We tested these hypotheses with an experimental double-blind randomized controlled trial of a nonsteroidal anti-inflammatory drug with and without the addition of
atropine to induce side effects. One hundred healthy volunteers were told they would be randomized to either combined
analgesics that might produce dry mouth or inert
placebos. In reality, they were randomized double blind, double-dummy to 1 of the 4 conditions: (1) 100 mg
diclofenac + 1.2 mg
atropine, (2) placebo + 1.2 mg
atropine, (3) 100 mg
diclofenac + placebo, or (4) placebo + placebo, and tested with heat-induced
pain. Groups did not differ significantly in demographics, temperature producing moderate
pain, state anxiety, or depression.
Analgesia was observed in all groups; there was a significant interaction between
diclofenac and
atropine, without main effects.
Diclofenac alone was not better than double-placebo. The addition of
atropine increased
pain relief more than 3-fold among participants given
diclofenac (d = 0.77), but did not enhance the response to placebo (d = 0.09). A chain of mediation analysis demonstrated that the addition of
atropine increased dry mouth symptoms, which increased beliefs that one had received the active medication, which, in turn, increased
analgesia. In addition to this indirect effect of
atropine on
analgesia (via dry mouth and beliefs), analyses suggest that among those who received
diclofenac,
atropine directly increased
analgesia. This possible synergistic effect between
diclofenac and
atropine might warrant future research.