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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 Clifford J. Woolf Neural Plasticity Research Group Department of Anesthesia and Critical Care Massachusetts General Hospital andHarvard Medical School
Is there a basis for the • separation of pain • on the basis of • Chronicity • Intensity • Mechanisms
Pain Chronicity Acute Chronic Persistence or Recruitment
Pain Chronicity Acute - Transient / Recurrent - Reversible Chronic - Long lasting/Reversible - Persistent / Irreversible
Pain Intensity Mild Moderate Severe Continuum or Discrete Stimulus or Response
Etiological Factors inflammation/tissue damage/nerve lesions Pain Mechanism Pain Sydromes post-operative/arthritic/back pain/neuropathic
Multiple Pain Mechanisms • Nociception • Peripheral sensitization • Central sensitization • Ectopic excitability • Decreased inhibition/ • Structural reorganization
Multiple Pain Symptoms • Spontaneous Pain • Superficial/Deep • Continuous/Intermittent • Evoked Pain • Thermal/Mechanical • Allodynia • Hyperalgesia
Role of COX-2 selective/specific inhibitors
Nociception Transduction Conduction Transmission Modulation Noxious stimulus “Ouch” Pain primary sensory neuron central neuron
Nociception – Transduction Nociceptor Activators Cold Heat H+ Bradykinin Mechanical VR1 ASIC TRPV3 B1/B2 CRM1 DRASIC/mDEG generator potential action potentials COX-2 Insensitive
Transmission/Modulation VGCC COX-2 Insensitive GABAA Adensosine Opiate CB1 NMDA Activity Glutamate AMPA Sub P mGluR NK1 Afferent Central Terminal Dorsal Horn Neuron
Peripheral Sensitization Reduced Transduction Threshold Primary hyperalgesia Primary heat allodynia Innocuous/Noxious stimulus Inflammation primary sensory neuron central neuron
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
Central Sensitization Increased Pain Responsiveness Secondary hyperalgesia Tactile allodynia Noxious stimulus Irritants Tissue damage Inflammation primary sensory neuron central neuron
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
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
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
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
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
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
1 2 3 A B C Etiology Mechanism Symptom
1 2 3 A B C Etiology Mechanism Symptom
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
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?