Mechanisms Of Placebo Analgesia Research Articles

Placebo effects in pain therapy

In the past few decades, research on pain and placebo analgesia has gained importance both scientifically and clinically. In this article, the current findings and focus of research as well as the significance of placebo research for assessing the effectiveness of pain medication are illustrated. The underlying mechanisms of placebo analgesia not only have implications for theoretical models but also offer clinically relevant guidelines for everyday interventions in pain treatment. However, many placebo phenomena are not fully understood and have to be investigated further in order to exploit the full potential of placebo effects. Interindividual differences and their inclusion in treatment will play amajor role in this aspect.

Mechanisms of placebo analgesia: rACC recruitment of a subcortical antinociceptive network

Placebo analgesia is one of the most striking examples of the cognitive modulation of pain perception and the underlying mechanisms are finally beginning to be understood. According to pharmacological studies, the endogenous opioid system is essential for placebo analgesia. Recent functional imaging data provides evidence that the rostral anterior cingulate cortex (rACC) represents a crucial cortical area for this type of endogenous pain control. We therefore hypothesized that placebo analgesia recruits other brain areas outside the rACC and that interactions of the rACC with these brain areas mediate opioid-dependent endogenous antinociception as part of a top–down mechanism. Nineteen healthy subjects received and rated painful laser stimuli to the dorsum of both hands, one of them treated with a fake analgesic cream (placebo). Painful stimulation was preceded by an auditory cue, indicating the side of the next laser stimulation. BOLD-responses to the painful laser-stimulation during the placebo and no-placebo condition were assessed using event-related fMRI. After having confirmed placebo related activity in the rACC, a connectivity analysis identified placebo dependent contributions of rACC activity with bilateral amygdalae and the periaqueductal gray (PAG). This finding supports the view that placebo analgesia depends on the enhanced functional connectivity of the rACC with subcortical brain structures that are crucial for conditioned learning and descending inhibition of nociception.

Central Inhibition and Placebo Analgesia

Most neuroscientists measure neuronal activity in the brain to predict or explore the contribution of neurons to physiological/pathological functions of the brain. For example, if an increase in neuronal activity is detected in one brain region by peripheral noxious stimuli, we call this area the pain region or pain matrix. In the case of activity detected during conscious processes, such as placebo treatment, we label these regions as responsible for the placebo treatment. Due to limited access to the conscious brain and the reductionist nature of most modern neuroscience, we are all reluctant to explore more sophisticated hypotheses. Few studies have performed experiments at neuronal network levels. Like other higher order brain functions, the investigation into the neuronal mechanisms of placebo analgesia is proving to be difficult for clinicians and basic researchers. For example, there are individual differences in the response to placebos, called responders and non-responders. Certain populations of individuals show a significantly greater response to placebos than others. Evidence for environmental and social impacts on brain development is increasing; therefore, individual differences in higher order brain functions such as placebo analgesia is expected. Levine and colleagues (1978) performed a classic study on placebo analgesia [1]. Their hypothesis is based on the discovery of endogenous opioid peptides in the central nervous system. Placebo analgesia in patients was blocked by naloxone, an opioid receptor antagonist. These experiments indicate that the endogenous analgesia systems are likely to be activated during placebo analgesia, possibly at different levels of the central nervous system.

Where are the causes of placebo analgesia?: A behavioral experiential analysis

Environmental conditions that foster a placebo analgesic effect include prior exposure to an effective analgesic treatment and contextual cues associated with such treatment. This evidence for the role of classical conditioning in placebo analgesia suggests the potential use of animal models for studying this phenomenon and the possibility of understanding it at the level of neural mechanisms. In addition, cognitive dimensions, such as desire for and expectation of pain relief, can potentially extend explanations of how placebo analgesia occurs. Importantly, these experiential factors are measurable and could be incorporated into analyses of human placebo analgesia. Measures of experiential factors that may directly cause placebo analgesia, multiple measures of the different dimensions of pain, and adequate controls for the natural history could permit a refined analysis of the nature and mechanisms of placebo analgesia. Measurement of the critical experiential factors that cause placebo responses may have far-reaching implications for the evaluation of placebo effects in human clinical studies.