June 14, 2013
IMMPACT-XVI meeting
Washington, DC
Conditioned Pain Modulation (CPM)
Diffuse Noxious Inhibitory Controls (DNIC)
for Phase 2 and 3 Trials
Simon Haroutiunian
B.Sc.Pharm, M.Sc (Clinical Pharmacy), PhD
Danish Pain Research Center
Aarhus University Hospital
Aarhus, Denmark
OUTLINE
Introduction
• Descending pain modulation
• CPM/DNIC testing paradigm and terminology
What does CPM/DNIC measure?
CPM/DNIC testing approaches
CPM/DNIC and chronic pain
CPM/DNIC and response to pharmacotherapy
Discussion: Key methodological issues for inlcuding CPM testing in trials
INTRODUCTION
Descending Pain Modulation
Electric shocks, burns and cuts in dogs, followed consistently by
presentation of food resulted eventually in dogs responding to these stimuli
as signals of food, failing to show “even the tiniest” signs of pain.
Either “the dogs were out to fool Pavlov and refused to reveal they
were feeling pain…” or “intense noxious stimulation can be
prevented from producing pain…”
Pavlov IP. “Conditioned Reflexes” 1927
Melzack and Wall, Science 1965
INTRODUCTION
Descending Pain Modulation
Recording from lumbar convergent (Lamina V, WDR) neurons in anesthetized rats
Sustained
paw pinch
Tail
Stroking the
receptive field
No DNIC effect was observed when recording from non convergent (noxious
only, non-noxious and proprioceptive) neurons in the dorsal horn
Le Bars et al, Pain 1979
INTRODUCTION
Clinical DNIC/HNCS
No effect of ischemic pain on tactile
sensitivity in contralateral arm
Le Bars 1979
INTRODUCTION
Clinical DNIC/HNCS
Brushing
Conditioning
Allodynic area
Test
Electrical stimulation of
the sural nerve
Bouhassira et al, Brain 2003
Contralateral area
Cold pressor test
/tourniquet
on normal upper limb
INTRODUCTION
Descending Pain Modulation
Ossipov et al, Journal of Clinical Investigation 2010
Dogrul et al, Progress in Neuro-Psychopharmacology & Biological Psychiatry 2012
Millan MJ. Progress in Neurobiology 2002
INTRODUCTION
CPM/DNIC Testing Paradigm
The activity of pain-signaling neurons in the spinal dorsal horn (and in
trigeminal nuclei) is attenuated in response to noxious stimuli applied to a
remote area of the body
DNIC/CPM/HNCS testing: psychophysical measure to characterize a
person’s capability to modulate pain (effect of endogenous analgesia)
TERMINOLOGY
DNIC / HNCS → Conditioned Pain Modulation (CPM)
Conditioning Stimulus: to induce the change in pain perception
Test Stimulus: the painful stimulus upon which the conditioning effect is tested
CPM: The phenomenon through which the conditioning affects the test
• Counterirritation vs. Conditioning
• Separating HNCS from DNIC, as these are “overlapping but not homogenous”
• Using ”perceptual DNIC-analogous effects” instead of CPM
Michaux et al, Eur J Pain 2010
CPM TEST PARADIGM
Temp
NPS
CPM = ∆ NPS
Rt
Rt
Lt
Test-stimulus baseline
Test-stimulus conditioned
Conditioning stimulus
Courtesy: David Yarnitsky
OBJECTIVE
Using CPM testing for patient phenotyping
1. What are we REALLY measuring?
 Identifying a neurotransmitter-specific malfunction in a descending pathway?
 Combined output of all descending control mechanisms?
 Capability of “placebo response”?
2. What factors affect DNIC/CPM?




Age/Gender/Genetics
Psychological variables
Painful conditions (and their duration)
Pharmacological and other treatments
CPM PROTOCOLS
Examples
Conditioning stimulus
 Hot water bath immersion
 Cold water bath immersion
 Tourniquet: ischemia
Spatial summation procedure
(cold conditioning)
Most common
conditioning, UE
Test stimulus
 Fixed stimulus
Contact heat: Fixed intensity of stimulus (e.g. Pain-60)
Electrical stimulation
Mechanical stimulation
 Threshold measurement
Thermal or mechanical
Spatial summation (cold conditioning)
12°C water bath
Julien et al, Pain 2005
CONDITIONING vs. TEST STIMULI
Variability in protocols
Pud et al, Pain 2009
CONDITIONING vs. TEST STIMULI
Variability in protocols
Conditioning: Hot bath 46.5°C
Test stimulus: Heat Pain-60
Yarnitsky el al, Pain 2008
DNIC>0: efficient pain
modulation
Nahman-Averbuch et al,
J Pain Sympt Manage 2011
Yarnitsky et al, Pain 2012
CPM<0: efficient pain
modulation
CPM<0: efficient pain
modulation
Test stimulus application: Dominant / Right / Dominant arm
FACTORS AFFECTING CPM
Variables that may affect the extent of the CPM response:
 Gender
 Age
 Testing site
 Surface area
 Duration
 Intensity of conditioning and test stimuli
 Parallel vs. sequential stimulation
 ISI
 Genetic variability
FACTORS AFFECTING CPM
The relationship between conditioning stimulus intensity vs. CPM response
magnitude is unclear
Positive correlation: Le Bars 1995; Villanueva and Le Bars 1995; Fujii 2006
No correlation: Pud 2005; Baad-Hansen 2005
Does conditioning stimulus need to be painful to induce endogenous analgesia?
Yes: Le Bars 2002
No: Lautenbacher and Rollman 1997, Lautenbacher et al. 2002
Pain intensity of conditioning stimuli:
Granot et al, Pain 2008
12°C
46.5°C
VAS 20-25
VAS 40-50
FACTORS AFFECTING CPM
Is CPM merely attributable to distraction?
Two stimuli, whether innocuous or noxious, produce joint effects, which are greater than
either presented alone but the combined perceptual effect is far from additive.
“…Distraction had a very small effect, suggesting that the “pain inhibits pain”
phenomenon attributable to DNIC is not due to attentional processes”.
CPM & CHRONIC PAIN
Temporomandibular disorders
Maixner et al, Pain 1995
King et al, Pain 2009
Fibromyalgia
Julien et al, Pain 2005
Kosek and Hansson, Pain 1997
Osteoarthritis
Arendt-Nielsen et al, Pain 2010
Kosek etal, Pain 2000
Tension type headache and migraine
Pielsticker et al, Pain 2005
Sandrini et al, Cephalgia 2006
Irritable Bowel Syndrome
Wilder-Smith et al, Gut 2004
Piché et al, Pain 2010
Conditioning
Cold (n=17)
Limb ischemia (n=8)
Heat (n=4)
Capsaicin (n=1)
Test
Mechanical pressure (n=15)
Electrical stimulus (n=9)
Thermal stimulus (n=8)
Lewis et al, J Pain 2012
CPM& CHRONIC PAIN
Can CPM protect us against chronic pain?
De Felice et al, Pain 2011
Yarnitsky et al, Pain 2008
CPM & PHARMACOTHERAPY RESPONSE
Duloxetine for DPN
Yarnitsky et al, Pain 2012
CPM & PLACEBO RESPONSE
Brain and brainstem structures essential for DNIC (e.g. ACC,
Thalamus, PAG, RVM) play a key role in placebo analgesia
Eippert et al, Neuron 2009
Nir et al, Pain 2012
TREATMENT EFFECT on CPM
Pregabalin treatment has only moderate effect on CPM
Bouwense et al, PLoS One 2012
IV Ketamine treatment reduces DNIC
towards more pronounced pain
facilitation following noxious thermal
stimulation in healthy volunteers
Niesters et al, Pain 2011
The effect of Duloxetine on CPM different in
patients with efficient vs. inefficient CPM
Yarnitsky et al, Pain 2012
PHARMACOTHERAPY RESPONSE PREDICTORS
May other biomarkers/predictors actually measure CPM response?
P=0.07
P<0.05
P<0.01
PHARMACOTHERAPY RESPONSE PREDICTORS
May other biomarkers/predictors actually measure CPM response?
Unilateral PNI in foot.
Baseline topical capsaicin testing (10% cream for 30 min) (pain, flare response by laser Doppler)
US-guided peripheral nerve block with 2% Lidocaine (innervation of painful area)
Topical capsaicin testing on C/L foot 90 min after block (with complete pain relief)
100
PNI, contralateral
dorsal foot
Healthy, dorsal foot
80
60
R² = 0.0431
50
PNI, contralateral
foot blocked
100
R² = 0.2953
40
R² = 0.2698
50
20
0
0
0
50
550
50
150
250
350
50
250
450
Individual capsaicin-induced pain
scores, uncorrected for flare response
100
NRS 0-100
80
Baseline
(ongoing pain)
With nerve
block
Flare response
248.7
232.2
Pain
24.2
38.3
60
40
20
0
0
1
2
PHARMACOTHERAPY RESPONSE PREDICTORS
May other biomarkers/predictors actually measure CPM response?
DISCUSSION
 Is CPM mechanism-specific, or may be useful for predicting any
(placebo?) treatment response?
 Study design optimization for prospective testing in Phase 2 and
Phase 3 studies
 Optimal / standardized CPM protocols
THANK YOU