June 14, 2013IMMPACT-XVI meeting

Washington, DC

Simon HaroutiunianB.Sc.Pharm, M.Sc (Clinical Pharmacy), PhD

Danish Pain Research CenterAarhus University Hospital

Aarhus, Denmark

Conditioned Pain Modulation (CPM)Diffuse Noxious Inhibitory Controls (DNIC)

for Phase 2 and 3 Trials

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

OUTLINE

Descending Pain ModulationINTRODUCTION

Pavlov IP. “Conditioned Reflexes” 1927

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.

Melzack and Wall, Science 1965

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…”

INTRODUCTIONDescending Pain Modulation

Sustained paw pinch

Tail Stroking the receptive field

Recording from lumbar convergent (Lamina V, WDR) neurons in anesthetized rats

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

Clinical DNIC/HNCSINTRODUCTION

No effect of ischemic pain on tactile sensitivity in contralateral arm

Le Bars 1979

Conditioning

Test

Electrical stimulation of the sural nerve

Allodynic area

Contralateral area

BrushingCold pressor test

/tourniquet on normal upper limb

Bouhassira et al, Brain 2003

INTRODUCTIONClinical DNIC/HNCS

INTRODUCTION

Ossipov et al, Journal of Clinical Investigation 2010

Descending Pain Modulation

Dogrul et al, Progress in Neuro-Psychopharmacology & Biological Psychiatry 2012

Millan MJ. Progress in Neurobiology 2002

CPM/DNIC Testing ParadigmINTRODUCTION

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 perceptionTest Stimulus: the painful stimulus upon which the conditioning effect is tested CPM: The phenomenon through which the conditioning affects the test

Michaux et al, Eur J Pain 2010

• Counterirritation vs. Conditioning• Separating HNCS from DNIC, as these are “overlapping but not homogenous”• Using ”perceptual DNIC-analogous effects” instead of CPM

Rt Rt

Lt

CPM = ∆ NPS

Test-stimulus baseline Test-stimulus conditioned

Conditioning stimulus

NP

STe

mp

Courtesy: David Yarnitsky

CPM TEST PARADIGM

Using CPM testing for patient phenotypingOBJECTIVE

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

Conditioning stimulus Hot water bath immersion Cold water bath immersion Tourniquet: ischemia

Test stimulus Fixed stimulus

Contact heat: Fixed intensity of stimulus (e.g. Pain-60)Electrical stimulationMechanical stimulation

Threshold measurementThermal or mechanical

Examples

Most common conditioning, UE

Spatial summation procedure (cold conditioning)

12°C water bath

Julien et al, Pain 2005

Spatial summation (cold conditioning)

CONDITIONING vs. TEST STIMULI

Pud et al, Pain 2009

Variability in protocols

Yarnitsky el al, Pain 2008 Nahman-Averbuch et al, J Pain Sympt Manage 2011

Yarnitsky et al, Pain 2012

DNIC>0: efficient pain modulation

CPM<0: efficient pain modulation

Test stimulus application: Dominant / Right / Dominant arm

Conditioning: Hot bath 46.5°CTest stimulus: Heat Pain-60

CONDITIONING vs. TEST STIMULI

CPM<0: efficient pain modulation

Variability in protocols

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 2006No correlation: Pud 2005; Baad-Hansen 2005

Does conditioning stimulus need to be painful to induce endogenous analgesia?Yes: Le Bars 2002No: Lautenbacher and Rollman 1997, Lautenbacher et al. 2002

Pain intensity of conditioning stimuli: 12°C VAS 20-2546.5°C VAS 40-50

Granot et al, Pain 2008

FACTORS AFFECTING CPMIs 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 disordersMaixner et al, Pain 1995King et al, Pain 2009

Fibromyalgia Julien et al, Pain 2005Kosek and Hansson, Pain 1997

OsteoarthritisArendt-Nielsen et al, Pain 2010Kosek etal, Pain 2000

Tension type headache and migrainePielsticker et al, Pain 2005Sandrini et al, Cephalgia 2006

Irritable Bowel SyndromeWilder-Smith et al, Gut 2004Piché et al, Pain 2010

Lewis et al, J Pain 2012

ConditioningCold (n=17)Limb ischemia (n=8)Heat (n=4)Capsaicin (n=1)

TestMechanical pressure (n=15)Electrical stimulus (n=9)Thermal stimulus (n=8)

CPM& CHRONIC PAIN

De Felice et al, Pain 2011 Yarnitsky et al, Pain 2008

Can CPM protect us against chronic pain?

CPM & PHARMACOTHERAPY RESPONSE

Yarnitsky et al, Pain 2012

Duloxetine for DPN

CPM & PLACEBO RESPONSE

Eippert et al, Neuron 2009

Brain and brainstem structures essential for DNIC (e.g. ACC, Thalamus, PAG, RVM) play a key role in placebo analgesia

Nir et al, Pain 2012

TREATMENT EFFECT on CPM

Bouwense et al, PLoS One 2012

Pregabalin treatment has only moderate effect on CPM

Niesters et al, Pain 2011

IV Ketamine treatment reduces DNIC towards more pronounced pain facilitation following noxious thermal stimulation in healthy volunteers

The effect of Duloxetine on CPM different in patients with efficient vs. inefficient CPMYarnitsky et al, Pain 2012

PHARMACOTHERAPY RESPONSE PREDICTORSMay other biomarkers/predictors actually measure CPM response?

P=0.07 P<0.05 P<0.01

PHARMACOTHERAPY RESPONSE PREDICTORSMay other biomarkers/predictors actually measure CPM response?

50 100 150 200 250 300 3500

20

40

60

80

R² = 0.295282076192487

Healthy, dorsal foot

50 150 250 350 4500

20406080

100

R² = 0.269764959901536

PNI, contralateral foot blocked

50 150 250 350 450 5500

20406080

100

R² = 0.0430865915050787

PNI, contralateral dorsal foot

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)

0 1 20

20

40

60

80

100

Individual capsaicin-induced pain scores, uncorrected for flare response

NR

S 0-

100

Baseline (ongoing pain)

With nerve block

Flare response 248.7 232.2

Pain 24.2 38.3

PHARMACOTHERAPY RESPONSE PREDICTORSMay 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