June 14, 2013 IMMPACT - XVI meeting Washington, DC

1. 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

2. 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

3. 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

4. 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

5. INTRODUCTION Clinical DNIC/HNCS No effect of ischemic pain on tactile sensitivity in contralateral arm Le Bars 1979

6. INTRODUCTION Clinical DNIC/HNCS Conditioning Cold pressor test /tourniquet on normal upper limb Allodynic area Brushing Test Electrical stimulation of the sural nerve Contralateral area Bouhassira et al, Brain 2003

7. INTRODUCTION Descending Pain Modulation Ossipov et al, Journal of Clinical Investigation 2010 Dogrul et al, Progress in Neuro-Psychopharmacology & Biological Psychiatry 2012

8. Millan MJ. Progress in Neurobiology 2002

9. 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)

10. 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

11. CPM TEST PARADIGM CPM = ∆ NPS NPS Rt Lt Rt Temp Test-stimulus conditioned Test-stimulus baseline Conditioning stimulus Courtesy: David Yarnitsky

12. 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

13. CPM PROTOCOLS Examples Spatial summation procedure (cold conditioning) • 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 stimulation • Mechanical stimulation • Threshold measurement • Thermal or mechanical Most common conditioning, UE

14. Spatial summation (cold conditioning) 12°C water bath Julien et al, Pain 2005

15. CONDITIONING vs. TEST STIMULI Variability in protocols Pud et al, Pain 2009

16. CONDITIONING vs. TEST STIMULI Variability in protocols Conditioning: Hot bath 46.5°C Test stimulus: Heat Pain-60 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 CPM<0: efficient pain modulation Test stimulus application: Dominant / Right / Dominant arm

17. 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

18. 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; Fujii2006 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: 12°C VAS 20-25 46.5°C VAS 40-50 Granot et al, Pain 2008

19. 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”.

20. CPM & CHRONIC PAIN Temporomandibulardisorders Maixner et al, Pain 1995 King et al, Pain 2009 Fibromyalgia Julien et al, Pain 2005 Kosekand Hansson, Pain 1997 Osteoarthritis Arendt-Nielsen et al, Pain 2010 Koseketal, Pain 2000 Tension type headache and migraine Pielstickeret al, Pain 2005 Sandrini et al, Cephalgia 2006 Irritable Bowel Syndrome Wilder-Smith et al, Gut 2004 Piché et al, Pain 2010

21. 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

22. CPM& CHRONIC PAIN Can CPM protect us against chronic pain? Yarnitsky et al, Pain 2008 De Felice et al, Pain 2011

23. CPM & PHARMACOTHERAPY RESPONSE Duloxetine for DPN Yarnitsky et al, Pain 2012

24. 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

25. 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

26. PHARMACOTHERAPY RESPONSE PREDICTORS May other biomarkers/predictors actually measure CPM response? P<0.01 P=0.07 P<0.05

27. 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)

28. PHARMACOTHERAPY RESPONSE PREDICTORS May other biomarkers/predictors actually measure CPM response?

29. 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

30. THANK YOU