1. Pain - Basic Science Implications for Analgesia & Analgesics Neural Plasticity Research Group Department of Anesthesia and Critical Care Massachusetts General Hospital and Harvard Medical School Neural Plasticity Research Group Department of Anesthesia and Critical Care Massachusetts General Hospital and Harvard Medical School Clifford J. Woolf

2. Is there a basis for the separation of pain on the basis of Chronicity Chronicity Intensity Intensity Mechanisms Mechanisms

3. Pain Chronicity AcuteChronic Persistence or Recruitment

4. Pain Chronicity Acute - Transient / Recurrent - Reversible Chronic- Long lasting/Reversible - Persistent / Irreversible

5. Pain Intensity MildModerateSevere Continuum or Discrete Stimulus or Response

6. Pain Mechanism Etiological Factors inflammation/tissue damage/nerve lesions Pain Sydromes post-operative/arthritic/back pain/neuropathic

7. Multiple Pain Mechanisms Nociception Peripheral sensitization Central sensitization Ectopic excitability Decreased inhibition/ Structural reorganization

8. Multiple Pain Symptoms Spontaneous Pain Superficial/Deep Continuous/Intermittent Evoked Pain Thermal/Mechanical Allodynia Hyperalgesia

9. Role of COX-2 selective/specific inhibitors

10. Noxious stimulus TransductionConductionTransmission primary sensory neuron central neuron Modulation Nociception “Ouch” Pain

11. Nociceptor Activators Heat H + VR1 ASIC TRPV3 Bradykinin B1/B2 DRASIC/mDEG Mechanical generator potential action potentials Nociception – Transduction Cold CRM1 COX-2 Insensitive

12. Afferent Central Terminal Glutamate Sub P Activity NK1 mGluR NMDA AMPA VGCC GABA A Adensosine Opiate CB1 Dorsal Horn Neuron Transmission/Modulation COX-2 Insensitive

13. Nociception is not COX-2 Sensitive

14. Innocuous/Noxious stimulus Reduced Transduction Threshold primary sensory neuron central neuron Peripheral Sensitization Primary hyperalgesia Primary heat allodynia Inflammation

15. There are prostanoid and non-prostanoid sensitizers Peripheral Sensitization PKC PKA (SNS/SNS2 ) VR1 Ca 2+ PG EP/IP AA Cox-2 PGS Primary sensory neuron peripheral terminal Tissuedamage Macrophage Mastcell IL1 , IL6 TNF  H+H+ COX-2 Sensitive Naive 12h6h Skin

16. Noxious stimulus Increased Pain Responsiveness primary sensory neuron central neuron Central Sensitization Secondary hyperalgesia Tactile allodynia Irritants Tissue damage Inflammation

17. Brush-Evoked Mechanical Allodynia Weak synapse innocuous stimulus non-painful sensation innocuous stimulus painful sensation Increased synaptic strength A  fibre mechanoreceptor Central Sensitization – Central Pain Hypersensitivity

18. Central Terminal Glutamate Sub P PKC Activity PKA NK1 mGluR NMDA Tyr S/T IP3 Ca 2+ AMPA pERK src Central Sensitization - Acute Phase COX-2 Insensitive

19. tRNA Naïve 1 Hr 2 Hrs4 Hrs6 Hrs 24 Hrs12 Hrs48 Hrs COX-2  -actin COX-2 Induction in the Spinal Cord - Inflammation

20. Cox-2 is not induced in the Spinal Cord by Peripheral Nerve Injury Cox2  Actin Sham 12 h 24 h72 h 7 d 100112 115 9788 Cox2 band intensity

21. Primary sensory neuron central terminal PGE2 EP EP/IP COX-2 Nociceptive dorsal horn neuron Inhibitory interneuron EP Glycine receptor + + + – Central Sensitization Late Phase (Inflammation) COX-2 Sensitive

22. There are COX-2 sensitive peripheral and central components of inflammatory pain Cox-2 inhibitors can only act when COX-2 is induced - time lag for induction There are non-prostanoid contributors to inflammatory pain - ceiling effect Peripheral nerve injury may not be sensitive to COX-2 inhibitors

23. A B C 1 2 3    Etiology Mechanism Symptom

24. A B C 1 2 3    Etiology Mechanism Symptom

25. Need to differentiate Analgesic and Anti-hypersensitivity drugs Temporal and Intensity characteristics of pain do not reflect mechanisms and may not be useful predictors of analgesic action Pain Mechanisms and Drug Mechanisms may provide the most useful input for determining Indication and Efficacy

26. Need mechanism sensitive/specific outcome measures in addition to global pain scores Need clinical trials that validate mechanistic hypotheses Need to consider labeling claims in light of action of a drug with specific pain mechanism(s) as well as empirical clinical data on efficacy Are there global analgesics?