Side effects can enhance treatment response through expectancy effects: an experimental analgesic randomized controlled trial.
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.
aPain Center, Department of Anesthesiology, Lausanne University Hospital (CHUV), Lausanne, Switzerland bProgram in Placebo Studies, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, USA cDepartment of Anesthesiology, Perioperative and Pain Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA dDivision of Rheumatology, Immunology and Allergy, Brigham and Women's Hospital, Boston, MA, USA eDepartment of Clinical Neuroscience, Karolinska Institute, Stockholm, Sweden fDepartment of Psychology, Wilfrid Laurier University, Waterloo, ON, Canada.
Chantal
C
Berna
Irving
I
Kirsch
Sean R
SR
Zion
Yvonne C
YC
Lee
Karin B
KB
Jensen
Pamela
P
Sadler
Ted J
TJ
Kaptchuk
Robert R
RR
Edwards
D000293:Adolescent; D000328:Adult; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000008:administration & dosage; D059031:Anticipation, Psychological; D001285:Atropine / Q000008:administration & dosage / Q000009:adverse effects*; D004008:Diclofenac / Q000008:administration & dosage*; D004311:Double-Blind Method; D005260:Female; D006801:Humans; D008297:Male; D010146:Pain / Q000188:drug therapy* / Q000523:psychology*; D010147:Pain Measurement / Q000187:drug effects; D015990:Placebo Effect; D016896:Treatment Outcome; D014987:Xerostomia / Q000139:chemically induced* / Q000523:psychology*; D055815:Young Adult
D000894:Anti-Inflammatory Agents, Non-Steroidal; D004008:Diclofenac; D001285:Atropine