Interaction between expectancies and drug effects: an experimental investigation of placebo analgesia with caffeine as an active placebo

Abstract

Rationale: In a randomised placebo-controlled clinical trial it is assumed that psychosocial effects of the treatment, regression to the mean and spontaneous remission are identical in the drug and placebo group. Consequently, any difference between the groups can be ascribed to the pharmacological effects. Previous studies suggest that side effects of drugs can enhance expectancies of treatment effects in the drug group compared to the placebo group, and thereby increase placebo responses in the drug group compared to the placebo group.

Objectives: The hypothesis that side effects of drugs can enhance expectancies and placebo responses was tested.

Method: Painful laser stimuli were delivered to 20 healthy subjects before and after administration of a drink with 0 or 4 mg/kg caffeine. The drink was administered either with information that it contained a painkiller or that it was a placebo. Laser-evoked potentials and reports of pain, expectancy, arousal and stress were measured.

Results: Four milligrammes per kilogramme of caffeine reduced pain. Information that a painkiller was administered increased the analgesic effect of caffeine compared to caffeine administered with no drug information. This effect was mediated by expectancies. Information and expectancies had no effect on pain intensity when 0 mg/kg was administered.

Conclusion: The analgesic effect of caffeine was increased by information that a painkiller was administered. This was due to an interaction of the pharmacological action of the drug and expectancies. Hence, psychosocial effects accompanying a treatment can differ when an active drug is administered compared to a placebo.

Fig 1

Arousal. Mean subjective arousal (± SEM) in all four conditions before and after administration of the drink

Fig. 2

Pain report. a Mean pain intensity (± SEM) across conditions. Subjects reported larger reductions in pain after 4 mg/kg caffeine (caffeine, active placebo) compared to after 0 mg caffeine (control, placebo). b Pain reduction displayed as the difference scores (posttest–pretest) for all four blocks of the posttest and pretest (mean ± SEM). A significant interaction between drug, information and block was observed towards the end. This was due to the difference between the active placebo and caffeine conditions. A steady increase in pain relief was observed in the active placebo condition, whereas pain relief was disrupted in the caffeine condition. c Certainty of pain relief correlated with pain reduction in the active placebo condition (r = −.55, p = .012). d Active placebo responding (difference score active placebo − difference score caffeine) (positive scores indicate larger reduction in pain in the active placebo condition) correlated with certainty of pain relief (r = 46, p = .039)

Fig. 3

N2 amplitudes. a Mean N2 amplitudes (± SEM) across conditions. There was a tendency towards a larger reduction in N2 amplitude after 4 mg/kg caffeine compared to 0 mg. b Reduction in N2 amplitude correlated with reduction in pain in the placebo condition (r = .48, p = .03). c Reduction in N2 amplitude correlated with reduction in pain in the active placebo condition (r = .54, p = .01)

Fig. 4

P2 amplitudes. a Mean P2 amplitudes (± SEM) across conditions. b There was a correlation between reduction in P2 amplitude and reduction in pain in the placebo condition (r = .49, p = .03). c Reduction in P2 amplitude correlated with reduction in pain in the active placebo condition (r = .59, p < .01)