Neuropharmacological Dissection of Placebo Analgesia: Expectation-Activated Opioid Systems versus Conditioning-Activated Specific Subsystems

Abstract

We investigated the mechanisms underlying the activation of endogenous opioids in placebo analgesia by using the model of human experimental ischemic arm pain. Different types of placebo analgesic responses were evoked by means of cognitive expectation cues, drug conditioning, or a combination of both. Drug conditioning was performed by means of either the opioid agonist morphine hydrochloride or the nonopioid ketorolac tromethamine. Expectation cues produced placebo responses that were completely blocked by the opioid antagonist naloxone. Expectation cues together with morphine conditioning produced placebo responses that were completely antagonized by naloxone. Morphine conditioning alone (without expectation cues) induced a naloxone-reversible placebo effect. By contrast, ketorolac conditioning together with expectation cues elicited a placebo effect that was blocked by naloxone only partially. Ketorolac conditioning alone produced placebo responses that were naloxone-insensitive. Therefore, we evoked different types of placebo responses that were either naloxone-reversible or partially naloxone-reversible or, otherwise, naloxone-insensitive, depending on the procedure used to evoke the placebo response. These findings show that cognitive factors and conditioning are balanced in different ways in placebo analgesia, and this balance is crucial for the activation of opioid or nonopioid systems. Expectation triggers endogenous opioids, whereas conditioning activates specific subsystems. In fact, if conditioning is performed with opioids, placebo analgesia is mediated via opioid receptors, if conditioning is performed with nonopioid drugs, other nonopioid mechanisms result to be involved.

Pain Free Efficacy of Sumatriptan in the Early Treatment of Migraine

“…Activation of pain modulation systems including endogenous opioid pathways may play a role. 27 One could speculate that such placebo induced pain modulating mechanisms are more likely to render a migraine attack pain-free at two hours if the placebo is taken very early in the course of the migraine attack. As the pathophysiology of the migraine attack unfolds, a point may be reached quite early in the process where the mechanisms underlying the placebo response are much less likely to terminate the attack.…”

Outcome of transcutaneous electrical nerve stimulation in chronic pain: short-term results of a double-blind, randomised, placebo-controlled trial

“…Therefore, it cannot be exclud-ed that the similar pain reductions achieved in the two groups are accomplished by different mechanisms. In this case it is interesting to know that in animal research high-frequency TENS decreased central sensitisation induced by inflammation in spinal dorsal horn neurons by activating delta-opioid receptors (for review see [30]), and in contrast, the placebo response in man is accomplished by the activation of mu-opioid receptors [7,31]. However, further research in the underlying working mechanisms of TENS compared to sham TENS in man seems warranted.…”

How price moderates assessments of coffee quality across profiles of gender and experience

“…Experiential learning of this sort has been shown to be susceptible to systemic errors of judgement (see for example Kahneman, Slovic & Tversky, 1982;Myers, 2002;Nisbett & Ross, 1980;and Shermer, 1997), errors that in the medical and marketing literature have been interpreted as placeboeffects (Amanzio & Benedetti, 1999;and Shiv et al, 2005, respectively).…”