1. The evolving concept of pain Dr E. Frohlich March 2005 GEMP III

4. Pain most frequent cause of suffering and Disability. Seriously impairing quality of life in millions of people around the globe. Acute easy to understand. Chronic ?

5. Epidemiological data: Annually in the USA 15-20% population suffer acute pain 25-30% -suffer chronic pain

6. Traditional Clinico - pathological training Traditional Clinico - pathological training PAIN = SYMPTOM PAIN = SYMPTOM warning of serious illness or pathology. warning of serious illness or pathology. Chronic pain = Often no pathology found Chronic pain = Often no pathology found Examinations, investigations to establish Examinations, investigations to establish responsible pathology responsible pathology time consuming expensive time consuming expensive delay treatment. delay treatment.

7. Pain Universal described throughout history Egyptians related pain to injury Plato - referred to pain as an EMOTION GENESIS Pain = grief, sorrow Pain = grief, sorrow Linking physical to emotional Linking physical to emotional

8. Decartes-(17 th century) Decartes-(17 th century) Separate biological from Emotional Emotional Nociceptors → Rope → Rope → Bell Bell

9. 19 th century 2 physiological theories developed 1. Specificity (sensory) 2. Intensity (summation) BY end of the 19th century physiologists physiologists MIND AND BODY ARE SEPARATE PSYCHOLOGY separated from separated from NEUROLOGY psychologists NEUROLOGY psychologists

10. Unfortunate separation (Bio-Psycho-Social) BUT leading to the differentiation between leading to the differentiation between NOCICEPTION and PAIN NOCICEPTION and PAIN NOCICEPTION ≠ PAIN NOCICEPTION ≠ PAIN -GA, LA -Trauma (Endorphine, Psychological?) -Beecher (2 nd world war) -Denervation (Nociception reaching brain as evidenced by sympathetic response.)

11. NOCICEPTION WITH NO PAIN -GA- PAIN NEEDS CONCIOUSNESS -GA- PAIN NEEDS CONCIOUSNESS -LA -LA -Trauma, Beecher’s report, -Trauma, Beecher’s report,  PAIN with no Nociception -Chronic pain -Chronic pain CRPS, NEUROPATHIC CRPS, NEUROPATHIC PHANTOM LIMB PHANTOM LIMB -PHN,HIV, Multiple sclerosis -PHN,HIV, Multiple sclerosis

12. The 20th century The gate control theory The gate control theory 1965 Melzack and Wall integrated -specialization of receptors -specialization of receptors - central summation - central summation - patterning and modulation - patterning and modulation - influence of psychological factors. - influence of psychological factors.

13. GATE THEORY Specificity theory Specialized Nociceptors- - YES Skin to brain-straight through Push button? - NO Push button? - NO Summation theory Intensity of stimulus ≠ pain perception Amount and quality of pain determined by physiological and psychological variables

14. Pain not limited to specific Nociceptive pathways Result of Activity in several interacting pathways. Gate control theory Central control Central control Large diameter - Large diameter - excitatory + action excitatory + action system system inhibitory - + inhibitory - + Small diameter Small diameter SG Central transmission cells gate control

15. The gate theory No Nociceptive pathways Transmission cells in spinal cord get excited or inhibited by large or small fibers 1982 Gate theory modified to include inhibitory descending mechanisms from brainstem

17. IASP Pain Definition Unpleasant sensory AND emotional sensation. Associated with Actual OR potential tissue damage. OR described in such terms. Pain = Bio- Psycho- Social Phenomenon Bio- Psycho- Social Phenomenon PAIN ≠ NOCICEPTION ≠ PAIN PAIN ≠ NOCICEPTION ≠ PAIN

18.  Pain is always subjective, always personal.  Pain expression and pain behavior depend on cultural and environmental factors.  There are more similarities then differences between cultures /sexes re experience of pain.

19. acute pain acute pain Acute pain (musculoskeletal / visceral organs.) - signal for tissue damage, protective phenomenon. phenomenon. -prompts withdrawal, flight or fight sympathetic response, inflammation and healing. response, inflammation and healing. -Therapy is usually effective. Acute pain/ injury well understood and accepted well understood and accepted by patient/Dr/society by patient/Dr/society

20. Somatic pain differs from visceral pain in quality and localizing ability. quality and localizing ability. cutaneous pain - from ectoderm, -well localizes, sharp in nature. -well localizes, sharp in nature. -Cutaneous tenderness, -Cutaneous tenderness, -Hyperalgesia -primary / secondary -Hyperalgesia -primary / secondary -Allodynia.

21.  Deep somatic structures (bone, periosteum, muscle tendon fascia) mesoderm - less well localized - less well localized - mimic visceral pain. - mimic visceral pain. -pain can be referred/ radiate -pain can be referred/ radiate -cause cutaneous hyperalgesia, -cause cutaneous hyperalgesia, -provoke autonomic responses -provoke autonomic responses and reflex muscle spasm and reflex muscle spasm

22. Visceral pain - Endodermal Visceral pain - Endodermal viscera or peritoneum/pleura. viscera or peritoneum/pleura. -Dull aching,diffuse and poorly localized - autonomic phenomena (sweating, nausea,bradycardia). (sweating, nausea,bradycardia).

23. Neurophysiologic endocrine and metabolic response to injury:  ↑sympathetic tone- ↑ HR, CO,BP myocardial work. ↑ HR, CO,BP myocardial work.  ↑ metabolic rate and 02 consumption  ↓ GI tone and motility (↓gastric emptying, ileus) ileus)  -↓ Urinary tract tone →urinary retention  -↑skeletal muscle tone  spasm  -↑ catabolism, hyperglycemia  ANXIETY, FEAR AND SUFFERING

24. General considerations of chronic pain General considerations of chronic pain Arbitrary definition- -more then 3-6 months. -The pain Outlasts the noxious stimulus and often the stimulus can not be identified. often the stimulus can not be identified. Traditionally referred to as cancer / non cancer related. cancer / non cancer related.

25. Viewed as a disease on its own right not a symptom. Like any other disease it has specific : Peripheral Bio 1 st analgesics Central Psycho 2 nd analgesics Metabolic Social Inflammatory l surgical inter- Neuropathic -ventions Traumatic/neoplastic CHRONIC PAIN ETIOLOGY SIGNS & SYMPTOMS TRETMENT

26. 1982 Loeser published a conceptual model of the patient with pain.  PAIN BEHAVIOR SUFFERING PAIN NOCICEPTION PAIN BEHAVIOR PAIN BEHAVIOR

27. Neuroplasticity Experiences can change synapses and Experiences can change synapses and intracellular expressions. intracellular expressions. CNS LEARNS FROM EXPERIENCE CNS LEARNS FROM EXPERIENCE Information does not simply move through. changes in neurotransmitter signals, neurotransmitter signals, Receptor expression nature and number of synapses, nature and number of synapses, neuronal structure and neural circuits, neuronal structure and neural circuits, NERVOUS SYSTEM ADAPTS TO INFORMATION AND CHANGES NERVOUS SYSTEM ADAPTS TO INFORMATION AND CHANGES WITH IT. WITH IT...

32. NEUROTRANSMITTERSExcitatory Subst P, Neurokinine 1, Glutamate Activate AMPA receptor Activate AMPA receptor Sensitize NMDA Sensitize NMDA Acting on nervous system -Central -peripheral. -peripheral. central sensitization, wind up Long Tem Potentiation and modulation.

33. Inhibitory  Glycin  GABA  Endorphines  NE  Serotonin  Somatostatin

34. Receptors Opiate At spinal AND supraspinal level AND periphery Receptors Ligands μ β Endorphines μ β Endorphines δ Enkephalines δ Enkephalines κ Dynorphine κ Dynorphine excite inhibitory neurons

35. ANALGESIA AND ANTIHYPERALGESIA Different mechanisms Opioids - not prevent central sensitization not prevent central sensitization not have antihyperalgesic effects not have antihyperalgesic effects Mu receptor agonists produce hyperalgesia produce hyperalgesia

36. Buprenorphine partial Mu agonist partial Mu agonist K and Delta antagonist K and Delta antagonist COX inhibitors- produce antihyperalgesia Ketamine - antihyperalgesia

37. RECEPTORS GABA - in brain and SC GABA A GABA B GABA A GABA B Ligand GABA GABA Baclofen Baclofen Function inhibitory Ca K Channels Channels Modulated Benzo By Barbiturate Steroids Steroids Anaesthetics Anaesthetics

38. Transient receptors VR1 VRL-1 Vaniloid receptor like Voltage gated channels, Voltage gated channels, detect noxious heat detect noxious heat

39. f MRI Superficial versus deep somatic pain. Stimulate different areas of the brain. Deep somatic in brain area linked to depressive withdrawn behavior.

40. Ion channels – Target for analgaesics (GABA(A)) inhibitory And NMDA – Excitatory receptors complex ion channels Ligands regulate Voltage gated Ca channels targets for analgesics

41. Antiepileptics work via three major mechanisms -Block of voltage-activated Na channels. -Potentiation of GABA -Reduction of glutamate excitatory transmission. transmission.

42. Ketamine Blocks -sodium channels -voltage-gated potassium channels -voltage-gated potassium channels blocks NMDA receptor blocks NMDA receptorANALGESIA +ANTI-HYPERALGESIAReduces excitability in superficial dorsal horn

43. NOVEL DRUGS Ziconotide – Marine snail toxin N-type voltage-gated Ca channel blocker, preventing the conduction of nerve signals. Narrow therapeutic window, lag time for onset offset of analgesia and adverse events. severe psychiatric and central nervous system adverse effects.

44. Activation of GLIAL cells

45. Nerve growth factor - NGF  Role in pain generation hyperalgesia hyperalgesia Expressed in injured tissue Expressed in injured tissue NGF antagonists – being developed

46. Take home message -Continuously evolving. - Concept changing from dualistic to integrative. (mind - body.) (mind - body.) -CNS undergoes structural changes - Not static. -Chronic pain is a disease on its own right Requiring Requiring multidisciplinary approach, multidisciplinary approach, aiming to improve aiming to improve COPING not eliminate pain. COPING not eliminate pain.

47. We are only beginning to understand pain MechanismS Receptor agonists antagonists, channelopathies, genetic factors Grouping of different pains according to their mechanism of action will provide means for specific Rx and management.