Specifying the non-specific factors underlying opioid analgesia: expectancy, attention, and affect

Psychological processes such as expectancy, attention, and affect directly influence clinical outcomes. These factors are grouped together as "nonspecific" factors, or placebo effects, in the medical literature, and their individual contributions are rarely considered. The pain-reducing effects of analgesic treatments may reflect changes in these psychological factors, rather than pure drug effects on pain. Furthermore, drug effects may not be isolated by drug vs. placebo comparisons if drugs interact with relevant psychological processes. We sought to determine whether the analgesic effects of opioid and placebo treatment are mediated by changes in attention, expectancy, or affect. We crossed intravenous administration of a potent opioid analgesic, remifentanil, with information about drug delivery (treatment expectancy or placebo) using a balanced placebo design. We measured drug and treatment expectancy effects on pain, attention, and responses to emotional images. We also examined interactions with cue-based expectations about noxious stimulation or stimulus expectancy. Pain was additively influenced by treatment expectancy, stimulus expectancy, and drug concentration. Attention performance showed a small but significant interaction between drug and treatment expectancy. Finally, remifentanil enhanced responses to both positive and negative emotional images. The pain-relieving effects of opioid drugs are unlikely to be mediated by changes in threat or affective processing. Standard open-label opioid administration influences multiple clinically relevant cognitive and emotional processes. Psychological factors can combine with drug effects to influence multiple outcomes in distinct ways. The influence of specific psychological factors should be considered when developing and testing pharmacological treatments.