Evidence for Opioid-Mediated Placebo Analgesia

In 2005, the first direct evidence of opioid-mediated placebo analgesia was published (Zubieta et al., 2005). In vivo receptor-binding techniques using the radiotracer carfentanil, a µ-opioid agonist, were used to show that a placebo procedure activates µ-opioid neurotransmission in the dorsolateral prefrontal cortex, the anterior cingulate cortex, the insula, and the nucleus accumbens (Fig. 4.7).

A more detailed account of µ-opioid neurotransmission after placebo administration was carried out in another study which used noxious thermal stimulation (Wager et al., 2007). Placebo treatment affected opioid activity in a number of predicted opioid-rich regions that play central roles in pain and affect, including the periaqueductal gray, dorsal raphe and nucleus cuneiformis, amygdala, orbitofrontal cortex, insula, rostral anterior cingulate, and lateral prefrontal cortex.

Opioid activity in many of these regions correlated with placebo effects in reported pain. Connectivity analyses on individual differences in opioid binding revealed that placebo treatment increased connectivity between the periaqueductal gray and the rostral anterior cingulate cortex, and increased functional integration among limbic regions and the prefrontal cortex.

Overall, the results suggest that endogenous opioid release in core affective brain regions is an integral part of the mechanism whereby expectations regulate affective and nociceptive circuits.

Fig. 4.7 Placebo administration induces the activation of µ-opioid neurotransmission in several brain regions, such as the dorsolateral prefrontal cortex (DLPFC), the anterior cingulate cortex (RACing), the nucleus accumbens (NAcc) and the insula (Ins). Reproduced from Jon-Kar Zubieta, Joshua A. Bueller, Lisa R. Jackson, David J. Scott, Yanjun Xu, Robert A. Koeppe, Thomas E. Nichols, and Christian S. Stohler, Placebo Effects Mediated by Endogenous Opioid Activity on μ-Opioid Receptors, The Journal of Neuroscience, 25 (34), pp. 7754–7762 Copyright 2005, The Society for Neuroscience, with permission.


Benedetti, Fabrizio. Placebo Effects (p. 128). OUP Oxford.

Wager TD, Scott DJ and Zubieta JK (2007). Placebo effects on human (micro)-opioid activity during pain. Proceedings of the National Academy of Sciences of the United States of America, 104, 11056-61.

Zubieta JK and Stohler CS (2009). Neurobiological mechanisms of placebo responses. Annals of New York Academy of Science, 1156, 198-210.