The Interaction Between Conditioned Pain Modulation and Expectation in Understanding the Placebo Effect of Pain Reduction
Condition: Healthy
Study type: Interventional

Summary: 
      The interaction between conditioned pain modulation and expectation in understanding the
      placebo effect of pain reduction
    

Detailed description: 
      Conditioned pain modulation (CPM) has recently been coined for the psychophysical protocols
      that assess the functioning of descending pain inhibitory pathways in humans. There is a
      growing body of evidence points to the important role of spinal serotonin (5-HT) and
      noradrenaline (NA) in mediation of pain inhibition via CPM. On the other hand, there is also
      evidence on synergistic modulatory effect of the opioidergic control on CPM, however this
      issue is under debates. It seems therefore, that pre-treatment CPM assessment may be relevant
      for prediction of analgesic drug interaction and additive effects.

      Placebo effects are inherent to every treatment and significantly contribute to clinical
      outcomes even in the presence of strong verum analgesic effects. From a psychological point
      of view, a series of recent studies supported the nature of the placebo effect as a learning
      phenomenon wherein verbally-induced expectations, cued and contextual conditioning or social
      learning are considered as the core mechanisms to produce a benefit. Placebo analgesic
      effects can be elicited by verbal instructions that generate anticipation for a benefit, thus
      creating expectations of analgesia. The effect of placebo is, primarily mediated by
      mu-receptors associated opioidergic neurotransmission. Alike brain structures activated by
      placebo manipulations, prefrontal cortex, cingulate cortex, PAG and RVM are the most
      important brain structures involved in initiating of opioid-mediated anti-nociception.

      An interesting question that emerges is the extent of overlap between the
      serotono-noradrenergic analgesia represented by CPM, and opioidergic analgesia represented by
      expectation-based placebo manipulation, for pain reduction. It seems that the final pathway
      for the two systems is the descending analgesia tract(s). It is unclear, though, if such
      final common pathway dictates a limited analgesic effect, i.e., it can only be activated to a
      certain extent, regardless of which system activates it, and therefore additive effects of
      expectation and CPM are limited to a certain ceiling. Alternatively, different tracts of
      descending pain inhibition are activated by each system, and the analgesic effect is
      additive.

      Cognitive cortical brain potentials (especially, a P300 waveform) evoked in response to a
      combination of rare and frequent innocuous sensory stimuli represent a neurophysiological
      tool for assessment attention. As this test bases on uncertainty and the expectation of
      upcoming stimuli, the recording of P300 may be relevant for evaluation cognitive processes
      associated with expectation-related placebo analgesia.

      The main aim of this study is to explore the interaction between serotono-noradrenergic and
      opioidergic systems of analgesia in healthy subjects. More specifically, the investigator
      will study whether these two systems work in an additive or a complementary way, and whether
      the neurophysiological assessment of individual expectation capabilities can predict the
      placebo magnitude.
    

Intervention name(s): placebo manipulation
Intervention type(s): Behavioral
Intervention description(s): application of nonactive body cream on forearm
Allocation: Randomized
Intervention model: Crossover Assignment
Intervention model description: CPM was tested before and after the placebo manipulation (body cream application on forearm); based on the expectation of the cream analgesic response (high or low), two types of placebo manipulations were performed for each participant.
Masking: Double (Participant, Investigator)
Primary purpose: Basic Science
Keywords: Conditional pain modulation; pain; placebo