Dissociable influences of opiates and expectations on pain

Abstract

Placebo treatments and opiate drugs are thought to have common effects on the opioid system and pain-related brain processes. This has created excitement about the potential for expectations to modulate drug effects themselves. If drug effects differ as a function of belief, this would challenge the assumptions underlying the standard clinical trial. We conducted two studies to directly examine the relationship between expectations and opioid analgesia. We administered the opioid agonist remifentanil to human subjects during experimental thermal pain and manipulated participants' knowledge of drug delivery using an open-hidden design. This allowed us to test drug effects, expectancy (knowledge) effects, and their interactions on pain reports and pain-related responses in the brain. Remifentanil and expectancy both reduced pain, but drug effects on pain reports and fMRI activity did not interact with expectancy. Regions associated with pain processing showed drug-induced modulation during both Open and Hidden conditions, with no differences in drug effects as a function of expectation. Instead, expectancy modulated activity in frontal cortex, with a separable time course from drug effects. These findings reveal that opiates and placebo treatments both influence clinically relevant outcomes and operate without mutual interference.

Figure 1.

Balanced placebo design. We used a full factorial, balanced placebo design to examine the relationship between remifentanil analgesia and expectancy-based (placebo) analgesia in the behavioral experiment. Remifentanil was delivered during Hidden and Open administration with the pharmacokinetic profile pictured in the inset. Subjects were told that they would receive remifentanil during Placebo and Open conditions, and were told that they would receive no drug during Control and Hidden administration.

Figure 2.

FMRI design and behavioral results. A, Subjects received intravenous remifentanil during scanning in the FMRI experiment. We used a within-subjects design, where order of runs (Open or Hidden) was counterbalanced across subjects. Remifentanil infusion proceeded identically in both runs, allowing us to examine whether drug effects on the brain differ as a function of expectancy. Imaging began with a baseline period, followed by infusion (gray box), and we used a pharmacokinetic model to estimate the brain concentration of remifentanil across time (black line). Subjects received low and high painful thermal stimulation throughout the imaging run. B, Example fMRI model showing regressors for one run of high pain stimulation (Open or Hidden administration). For each run, we modeled average responses to high-pain events (black), a parametric regressor for drug concentration in brain tissue based on the pharmacokinetic model (orange; Drug effects), and a parametric regressor for Instruction-related expectancies, orthogonalized with respect to drug concentration effects (purple). C, Pain reports during Open administration (blue) were influenced by Instructions about drug administration, and the overall Context. However, the magnitude of the Drug effect on pain reports was identical during both Open and Hidden administration. This figure depicts a moving average of pain reports during high pain stimulation, smoothed within-subjects with a 5-point FWHM filter, which was used to create our behavioral regressor (Fig. 5B). The shaded area reflects SEM.

Figure 3.

Drug effects on PPN responses. Increases in the brain concentration of remifentanil were associated with reductions in pain-evoked responses throughout the PPN, evident in both ROI (red, top row) and voxelwise analyses (second row). Drug effects were similar during both Open administration (third row) and Hidden administration (fourth row), leading to no meaningful Drug × Context interactions (bottom row).

Figure 4.

Region of interest results. We defined 13 pain-processing network ROIs, using independent datasets, and averaged across voxels within each ROI. We tested whether each was modulated by remifentanil during Open administration (blue bars) and Hidden administration (red bars). While most regions showed significant differences between high and low intensity stimulation (gray bars), estimated Drug effects did not differ between Open and Hidden administration in any ROIs. We tested the following ROIs: pre-SMA, bilateral dACC, rdACC, secondary somatosensory cortex (SII), right dorsal posterior insula (R dpIns), bilateral insula (Ins), bilateral anterior insula (AIns), thalamus, and midbrain surrounding the periacqueductal gray. One-tailed *p < 0.05; **p < 0.01; ***p < 0.001.

Figure 5.

Expectancy effects during drug treatment. A, Information about drug delivery during Open administration was accompanied by increases in left DLPFC, relative to the same period during Hidden administration (“Instruction-related expectancy effects”). We also observed expectancy-related decreases in the left amygdala (Amyg.). B, A number of brain regions showed differences in activation that tracked within-subjects expectancy effects on pain reports over time (“Correlates of expectancy-related pain relief”). In particular, we observed report-related changes within the medial orbitofrontal cortex (mOFC), as well as several PPN regions, including right primary somatosensory cortex (SI), bilateral SII, bilateral thalamus, and pre-SMA. dACC showed significant expectancy-related reductions at a more liberal threshold, p < 0.005.