Side effects can enhance treatment response through expectancy effects: an experimental analgesic randomized controlled trial

Abstract

In randomized controlled trials (RCTs), medication side effects may lead to beliefs that one is receiving the active intervention and enhance active treatment responses, thereby majoring drug-placebo differences. We tested these hypotheses with an experimental double-blind RCT of a nonsteroidal anti-inflammatory medication (NSAID) 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 one of 4 conditions: 1) 100 mg diclofenac+1.2 mg atropine, 2) placebo+1.2 mg atropine, 3) 100 mg diclofenac+placebo, 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 threefold among participants given diclofenac (d= 0.77), but did not enhance the response to placebo (d= 0.09). A mediation analysis supported the hypothesized chain from atropine to dry mouth to beliefs one had received the active medication to analgesia. There was also a direct effect of atropine on analgesia among participants who received diclofenac, suggesting the possibility of a synergistic relation between diclofenac and atropine.

Placebo and Active Treatment Additivity in Placebo Analgesia: Research to Date and Future Directions

“…Fig. 4 shows the results of this search, in which only seven studies were found to have used one of these designs in placebo analgesia (Aslaksen, Zwarg, Eilertsen, Gorecka, & Bjørkedal, 2015; Atlas et al, 2012; Berna et al, 2017; Butcher & Carmody, 2012; Kam-Hansen et al, 2014; Lund, Vase, Petersen, Jensen, & Finnerup, 2014; Schenk, Sprenger, Geuter, & Buchel, € 2014). …”

“…Four of the seven studies used the balanced placebo design (Aslaksen et al, 2015; Butcher & Carmody, 2012; Kam-Hansen et al, 2014; Schenk et al, 2014), while two used the balanced open-hidden design (Atlas et al, 2012; Lund et al, 2014). The final study conducted by Berna et al (2017) used a novel design here described as a “balanced active placebo design.” In this variation of the balanced placebo design, receipt of an active treatment or placebo are factorially crossed with administration of an active placebo or placebo, with the second factor replacing the instructions of treatment allocation typical of the balanced placebo design.…”

“…Three studies examined lidocaine, a sodium channel blocker (Aslaksen et al, 2015; Lund et al, 2014; Schenk et al, 2014), two examined NSAIDs, namely diclofenac and ibuprofen (Berna et al, 2017; Butcher & Carmody, 2012), one examined maxalt, a triptan used to treat migraines (Kam-Hansen et al, 2014), and one examined the opioid remifentanil (Atlas et al, 2012). …”

“…The time course of the treatment relative to outcome assessment was reported in most studies and varied between 13.5 min and 4 h (Aslaksen et al, 2015; Atlas et al, 2012; Berna et al, 2017; Butcher & Carmody, 2012; Kam-Hansen et al, 2014). The two exceptions were Lund et al (2014) and Schenk et al (2014), who did not report the time course of treatment administration and outcome assessment.…”

“…The balanced active placebo design employed by Berna et al (2017) differs substantially from the typical balanced placebo design. Their between-subjects 2 2 factorial design manipulated receipt of analgesic (diclofenac versus placebo) and side effect induction (atropine versus placebo).…”