Optimization of the Conditioned Pain Modulation Protocol using the Q-sense

Activation of nociceptors (pain sensors) at peripheral sites leads to
trafficking of afferent sensory information to the brain where pain is
perceived as an unpleasant sensation or feeling. The afferent sensory
information undergoes complex modulation at various points of its trajectory,
both at the spinal cord and at higher brain centers. Central modulation of pain
responses occurs via descending pathways originating at higher centers in the
CNS including the prefrontal cortex, rostral anterior cingulate cortex (rACC)
and insula, which project to the periaqueductal gray (PAG), and rostral
ventromedial medulla (RVM) in the brainstem and modulate nociceptive input at
the level of the dorsal horn [2,9,10]. Expressions of the endogenous pain
modulation system are placebo- and stress-induced analgesia and conditioning
pain modulation (CPM) [6,7].
In experimental CPM studies, central inhibition of a focal pain stimulus is
induced by applying a noxious stimulus at a remote area, thereby reducing the
perception of the focal pain stimulus. Recently published guidelines on the
experimental set-up of CPM experiments report the need for standardization [8].
However, the studies on which these guidelines were based, used different
methodology to study endogenous pain modulation pathways in patients [1,3-5].
These discrepancies include different test stimuli (noxious heat, pressure
pain, electrical pain), different conditioning stimuli (hot water, cold water),
and different test locations (hands, feet, contralateral and ipsilateral
sites). The impact of these differences on assessment of CPM effects has never
been systematically evaluated.
The development of the guidelines has resulted in the development of an
easy-to-use CPM device (Q-sense, Medoc). This device uses two experimental heat
stimuli to evaluate the CPM effect.

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In the current study, we will 1) evaluate the usefulness and reliability of
this new device, and 2) evaluate whether the anatomic site used will impact the
measured CPM effect.

This is a randomized, cross-over study in 30 healthy volunteers.
Pain measurements. Thermal stimuli will be applied on the volar side of the
forearm or the front lower leg using the thermal test probe (a 3 × 3 cm
thermode) and a conditioning probe (a 3 × 3 cm thermode) of the Medoc CPM
Q-sense system (Medoc Ltd, Ramat Yishai, Israel). This is a computer-controlled
device with two thermodes capable of generating highly reproducible thermal
stimuli. The Visual Analogue Scale (VAS) will be used to quantify pain
intensity in response to a thermal stimulus. VAS will be measured
electronically (eVAS) using a slide potentiometer (length = 100 mm) that can be
moved from the left (0 mm or no pain) to the right (100 mm or most intense pain
imaginable). Using a hand the subject can move the slide during the heat
stimulator test. The eVAS is recorded and collected on disk for further
analyses.
In order to assess the temperature at which the subject has a specific eVAS
score, various short (5 s) test stimuli will be applied in the range from 42 to
51 °C. The study will be performed with the lowest stimulus strength (in °C)
which causes a specific eVAS value.
CPM paradigms. We will evaluate several CPM paradigms using the Q-sense CPM
system. First, the VAS response to a heat pain stimulus (5 seconds with an
intended VAS of 30 [conditioning] or 60 [test] out of 100) on the lower,
non-dominant forearm will be assessed with 3-min intervals (baseline testing).
Cold and hot water temperatures will be tested to assess the corresponding
temperatures to the conditioning VAS of 30 mm. Next, we will test 6 different
conditions in a random order, with 15-minute rest period in between (see below).
1. Test stimulus non-dominant arm, conditioning stimulus contralateral arm
(ARM-ARM)
2. Test stimulus leg ipsilateral to non-dominant arm, conditioning stimulus
contralateral leg (LEG-LEG)
3. Test stimulus non-dominant arm, conditioning stimulus contralateral leg
(ARM-LEG)
4. Test stimulus non-dominant arm, conditioning stimulus ipsilateral leg
(ARM-LEG)
5. Test stimulus leg ipsilateral to non-dominant arm, conditioning stimulus
ipsilateral arm (LEG-ARM)
6. Test stimulus leg ipsilateral to dominant arm, conditioning stimulus
ipsilateral arm (LEG-ARM)
The test stimulus will never be applied on the dominant arm, as this arm is
used to control the eVAS slider.
The type of conditioning stimulus will either be the Q-sense CPM conditioning
thermode, a cold-water bath or a hot-water bath. The size of the conditioning
stimulus will be standardized at a pain score of 30 mm (of 100 mm).

Pain measurements

Minimal risks and burden. We have ample experience with thermal stimuli
testing. Heat pain testing may give a short-lasting red coloration of the skin
due to vasodilatation. Subjects will undergo testing of thermal pain at VAS
scores between 0 and 100, however no temperatures will be reached that have a
risk of damage to the skin or any other structures.