The psychological mechanisms of placebo responses studied in greatest detail are those of expectancies and conditioning. Other potential mechanisms that require further investigation include changes in anxiety and desire for pain relief (8,9). The conditioning mechanism is based upon the theory of classical conditioning, whereby a previously neutral stimulus (such as the treatment characteristics or the environment in which treatment is delivered) is paired or “conditioned” with an unconditioned stimulus (the active drug) that is able to elicit a response (conditioned response) (10,11). In the case of injections, the pairing of the context of treatment with an active drug and analgesia may result in a conditioned analgesic response to an injection of a placebo at a later stage (Fig. 36-1). The conditioning mechanism has gained support through a variety of trials both in animals (12,13) and humans (14,15). A recent study demonstrated that placebo analgesic responses were able to be conditioned using both opiate and nonopiate drugs (16). This study also looked at expectancy mechanisms and found that the placebo analgesic response was greatest when both conditioning and expectancy were involved. There is, however, a degree of difficulty in distinguishing the conditioning mechanism from the expectancy mechanism in placebo analgesia, as the conditioning process may influence the expectations of the patient toward the treatment, and thus the placebo analgesic response may in fact be mediated by expectancies (17,18,19).

One study was able to demonstrate the conditioning mechanism in a clinical population (20). In this study, patients were given standard postoperative analgesia, and ventilatory function was monitored. On the third postoperative day, a placebo was given that resulted in similar changes in ventilatory
function (respiratory depression) as had been experienced with the opioids. In this study, the placebo was able to cause a “side effect” similar to that of the active drug. More recent work has also shown that the conditioning mechanism, particularly when involving unconscious processes, such as hormone secretion (18) and immune responses (21,22), may contribute to placebo effects. In the case of placebo analgesia, it would seem that the expectancy mechanism plays a significant role and may be integrated with the conditioning process.

The expectations of the patient regarding the treatment being administered, also termed response expectancies, are those held by an individual about his automatic emotional and physiological responses to a particular stimulus (23,24). A variety of studies have investigated the expectancy mechanism using simple verbal cues (suggestibility) (16,25,26,27), as well as more complicated conditioning protocols aimed at increasing expectations prior to placebo administration (17,28,29). These studies have shown that expectations are powerful contributors to placebo responses, particularly the placebo analgesic response.

The neurobiologic mechanisms of the placebo response were highlighted for the first time in 1978, by Levine, Gordon, and Fields, who showed that placebo analgesia was reversed by the administration of naloxone, an endogenous opioid antagonist, suggesting a role of endogenous opioids in the placebo analgesic response (30). The majority of research into the neurobiologic mechanisms of the placebo response has looked at the role of endogenous opioids, although in some studies naloxone has had no effect on placebo analgesia (16,31,32). The occurrence of both positive and negative results for the effects of naloxone suggests that placebo analgesia is mediated by both opioid and nonopioid mechanisms.

One interesting example of the variable role of endogenous opioids is the study by Amanzio and Benedetti in 1999 (16). In this study, both conditioning and expectancy mechanisms were manipulated. Two different types of drugs were used for the conditioning protocol, an opiate analgesic (morphine) and the nonsteroidal anti-inflammatory drug (NSAID) ketorolac. The same drugs were used to explore expectancy manipulations. Placebo analgesic responses were seen following conditioning with both these drugs, and the responses in the expectancy groups were reversed by naloxone, demonstrating that the expectancy mechanism is mediated by endogenous opioids. Interestingly, in the conditioning groups, only the placebo analgesic response that was conditioned with morphine was able to be reversed by naloxone, whereas the placebo response conditioned with the NSAID was not. This variability demonstrates that different mechanisms (both opioid and nonopioid) are involved in the placebo response and that the drug used to condition the response plays a role in the mechanism of the response.

The role of endogenous opioids has been supported by numerous experiments that have indicated that naloxone can fully (33,34) or partially (35) reverse placebo analgesia, including placebo analgesia elicited through expectation and opioid conditioning (16,25). Interestingly, naloxone is able to reverse spatially or target-specific placebo analgesia in specific parts of the body, suggesting a somatotopic organization of endogenous opioid systems at the level of higher centers in the brain (25). This is a particularly important finding as it demonstrates that the placebo analgesic response acts through release of endogenous opioids at a variety of sites in the nervous system that are involved in the experience of pain. The reversal of placebo-induced respiratory depression (20), decreased heart rate, and decreased β-adrenergic response (36) indicates that the opioid mechanisms of the placebo response also act on other regions and neural circuits, such as the respiratory and cardiovascular centers.

Further interesting examples of the involvement of other neurochemical systems are seen in other recent studies. In one study, preconditioning with a serotonin agonist (sumatriptan) prior to placebo administration resulted in placebo-induced increases in plasma growth hormone and decreases in cortisol (18). Studies of the placebo response in Parkinson disease have added to our understanding of the neurobiology of the placebo response. In Parkinson disease, placebo administration can lead to an increase in dopamine in the ventral (37) and dorsal striatum (38) of sufferers, and this increase in dopamine correlates with improvement in motor function (38). Electrophysiologic evidence has also shown improvements in motor function, along with placebo-induced changes in subthalamic nucleus neuronal activity (39). The relevance of
placebo-induced dopamine release for placebo analgesia is that dopamine has been shown to play an important role in reward mechanisms, and placebo administration activates brain areas associated with both reward system and opioid system circuitry (40,41,42,43). Parkinson disease has thus emerged as an interesting model to study the placebo response, particularly in light of the increasingly evident anatomic and biochemical relationship between reward and opioid circuitry.

Advances in imaging technology have allowed the investigation of regional brain activation during the experience of pain and during the placebo analgesic response. Positron emission tomography (PET) and functional magnetic resonance imaging (fMRI) studies have shown consistent activation of certain cortical and subcortical areas during the experience of pain compared to control groups who are not experiencing pain (44,45). These areas encompass the neural pathways believed to be responsible for the sensory, affective, and evaluative dimensions of the pain experience. This pattern of activation, termed the pain matrix, corresponds to the neuronal substrate of multiple dimensions of pain according to the neuromatrix model described by Katz and Melzack in Chapter 35.