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Pain - Basic Science Implications for Analgesia & Analgesics

Pain - Basic Science Implications for Analgesia & Analgesics. Clifford J. Woolf. Neural Plasticity Research Group Department of Anesthesia and Critical Care Massachusetts General Hospital and Harvard Medical School. Is there a basis for the separation of pain on the basis of Chronicity

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Pain - Basic Science Implications for Analgesia & Analgesics

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

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

  3. Pain Chronicity Acute Chronic Persistence or Recruitment

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

  5. Pain Intensity Mild Moderate Severe Continuum or Discrete Stimulus or Response

  6. Etiological Factors inflammation/tissue damage/nerve lesions Pain Mechanism 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. Nociception Transduction Conduction Transmission Modulation Noxious stimulus “Ouch” Pain primary sensory neuron central neuron

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

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

  13. Nociception is not COX-2Sensitive

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

  15. Skin Naive 6h 12h Peripheral Sensitization Tissue damage Macrophage IL1b, IL6TNFa Mast cell Cox-2 PGS AA PG COX-2 Sensitive VR1 EP/IP H+ Ca2+ PKC PKA (SNS/SNS2) Primary sensory neuron peripheral terminal There are prostanoid and non-prostanoid sensitizers

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

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

  18. src pERK NMDA PKC Tyr S/T AMPA Activity Glutamate S/T Ca2+ PKA mGluR Sub P IP3 NK1 Central Terminal Central Sensitization - Acute Phase COX-2 Insensitive

  19. COX-2 Induction in the Spinal Cord - Inflammation 12 Hrs 24 Hrs 48 Hrs Naïve tRNA 2 Hrs 4 Hrs 6 Hrs 1 Hr COX-2 b-actin

  20. Sham 12 h 24 h 72 h 7 d Cox2 b-Actin 97 88 115 100 112 Cox2 band intensity Cox-2 is not induced in the Spinal Cord by Peripheral Nerve Injury

  21. Primary sensory neuron central terminal + Nociceptive dorsal horn neuron EP + EP/IP + COX-2 PGE2 Glycine receptor – Inhibitory interneuron EP 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.   1 2 3 A B C Etiology Mechanism Symptom

  24.   1 2 3 A B C 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?

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