The Interaction Between Conditioned Pain Modulation and Expectation in Understanding the Placebo Effect of Pain Reduction

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

Study Overview

• Status: Completed
• Conditions: Healthy
• Intervention / Treatment: Behavioral: placebo manipulation

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.

• Study Type: Interventional
• Enrollment (Actual): 35
• Phase: Not Applicable

Contacts and Locations

Study Locations

• Israel
  • Haifa, Israel
    • Rambam Medical center, Neurology Department

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 40 years (Adult)
• Accepts Healthy Volunteers: Yes
• Genders Eligible for Study: Male

Description

Inclusion Criteria:

• healthy subjects

Exclusion Criteria:

• attention deficit.
• pain disorders.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Basic Science
• Allocation: Randomized
• Interventional Model: Crossover Assignment
• Masking: Double

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Placebo Comparator: High-expectation placebo manipulation; application of nonactive body cream on forearm for 10 minutes	Behavioral: placebo manipulation; application of nonactive body cream on forearm
Other: Low-expectation placebo manipulation; application of nonactive body cream on forearm for 10 minutes	Behavioral: placebo manipulation; application of nonactive body cream on forearm

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Change in pain perception	pain units on a scale of 0-100. 0 no pain. 100 = the maximum pain	up to 2 weeks
Change in conditioned pain modulation (CPM)	change in pain units on a scale of 0-100. 0 no pain. 100 = the maximum pain	up to 2 weeks

Collaborators and Investigators

• Sponsor: Rambam Health Care Campus

Study record dates

Study Major Dates

• Study Start (Actual): March 27, 2018
• Primary Completion (Actual): December 31, 2019
• Study Completion (Actual): June 30, 2020

Study Registration Dates

• First Submitted: January 31, 2018
• First Submitted That Met QC Criteria: March 25, 2018
• First Posted (Actual): April 2, 2018

Study Record Updates

• Last Update Posted (Actual): May 20, 2021
• Last Update Submitted That Met QC Criteria: May 19, 2021
• Last Verified: May 1, 2021

More Information

Terms related to this study

• Keywords: pain; placebo; Conditional pain modulation
• Other Study ID Numbers: 574-17_RMB_CTIL

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No