Mechanisms of placebo analgesia: A dual-process model informed by insights from cross-species comparisons

Abstract

Placebo treatments are pharmacologically inert, but are known to alleviate symptoms across a variety of clinical conditions. Associative learning and cognitive expectations both play important roles in placebo responses, however we are just beginning to understand how interactions between these processes lead to powerful effects. Here, we review the psychological principles underlying placebo effects and our current understanding of their brain bases, focusing on studies demonstrating both the importance of cognitive expectations and those that demonstrate expectancy-independent associative learning. To account for both forms of placebo analgesia, we propose a dual-process model in which flexible, contextually driven cognitive schemas and attributions guide associative learning processes that produce stable, long-term placebo effects. According to this model, the placebo-induction paradigms with the most powerful effects are those that combine reinforcement (e.g., the experience of reduced pain after placebo treatment) with suggestions and context cues that disambiguate learning by attributing perceived benefit to the placebo. Using this model as a conceptual scaffold, we review and compare neurobiological systems identified in both human studies of placebo analgesia and behavioral pain modulation in rodents. We identify substantial overlap between the circuits involved in human placebo analgesia and those that mediate multiple forms of context-based modulation of pain behavior in rodents, including forebrain-brainstem pathways and opioid and cannabinoid systems in particular. This overlap suggests that placebo effects are part of a set of adaptive mechanisms for shaping nociceptive signaling based on its information value and anticipated optimal response in a given behavioral context.

Failure to Find a Conditioned Placebo Analgesic Response

“…There could be several reasons for the lack of placebo analgesia in the present study, as noted. Placebo analgesia is mainly a top-down process initiated in frontal regions associated with expectations of treatment effects, that in turn activate mid-brain areas involved in modulation of pain via descending pathways ( Schafer et al, 2018 ). In effect, reduced activity in pain-responsive areas in the brain has often been observed (e.g., Wager et al, 2004 ).…”

Multiple brain networks mediating stimulus-pain relationships in humans

“…For example the dorsolateral prefrontal cortex (dlPFC) -a brain region involved in high-level 20 cognitive functions -responds to painful stimulation, shows alterations in chronic pain 21 conditions, and contributes to placebo analgesia (Krummenacher et al, 2010;Bushnell et al, 22 2013;Seminowicz and Moayedi, 2017;Schafer et al, 2018). Other brain regions, including the 23 ventromedial prefrontal cortex (vmPFC) Roy et al, 2012;Geuter et al, 2017b) 24 and the nucleus accumbens (NAc) (Baliki et al, 2012;Chang et al, 2014;Lee et al, 2015;Woo 25 et al, 2015;Ren et al, 2016), key structures for reinforcement learning, also contribute to pain 26 modulation.…”

A Context-Based Analgesia Model in Rats: Involvement of Prefrontal Cortex

“…Distinct pharmacological mechanisms underlying expectation and conditioning have been revealed by a carefully designed human study, which has shown that expectation triggers endogenous opioids, while conditioning activates specific subsystems not necessarily dependent on the opioid system [ 44 ]. Expectation-dependent placebo analgesia mediated by the opioid system has been reliably reported in the literature [ 45 ]. Morphine (an opiate analgesic)-induced placebo analgesia is dependent on expectation and can be blocked by opioid antagonists.…”