1. Ryan Dreikorn BSN SRNA York College of Pennsylvania / WellSpan Health Nurse Anesthesia Program

2. Objectives  Quick overview of the neuron and pain pathways  Go to “Receptorland”  Discuss traditional pain management techniques  Discuss the role of Ketamine in attenuating “wind- up”  Discuss the emerging research of Dexmedetomidine (Precedex) in attenuating “wind-up”

3. Wind-Up Phenomenon  Pain is pain and then its over.  Wind-Up phenomenon increases pain intensity  Wind-Up phenomenon increases pain duration  Wind-Up phenomenon is mediated and attenuated though the NMDA receptor  Wind-Up phenomenon can be attenuated by the Alpha 2 receptor

4. Wind-Up Phenomenon  Change in Neural Physiology  Innocuous Stimuli Becomes Noxious  Mediated by AMPA, NMDA, and NK1 Receptors  Involves the Neurotransmitters Glutamate and Substance P (SP)  Brain Perceives Pain Even in the Absence of Painful Stimuli  Occurs Within One Hour

5. The Neuron The Synapse

6. First Order / Second Order

7. Dorsal Root Ganglion

8. Anterolater Spinothalamic Tract

9. Spinothalamic Tract (Simplified)

10. Spatial Summation

11. What was incision? What time was antibiotic given? What's my blood loss? Patients awake! How much Neo? Now I understand why they call this the “Blood/Brain Barrier.”

12. Temporal Summation

13. High Intensity Temporal Summation TABLE UP! NO, DOWN! NO, UP! WHAT ARE YOU DOING TO ME!?!? I’m going to show him an “Action Potential.”

14. Lois, Lois, mom, mom, mummy, mummy, muma, muma, ma, ma, mum, mum, mummy, ma WHAT!?!?! HI! Persistent Low Intensity Temporal Summation

15. Review Neuron Physiology and the Action Potential

16. Ionic Movement (Quick Review) Intra-Cellular FluidExtra-Cellular Fluid  Increased K+  Decreased Na+  Decreased Ca++  Decreased K+  Increased Na+  Increased Ca++ Cellular Membrane

17. The Action Potential (Quick Review)

18. Action Potential Increases Na+ Permeability Fast Na+ Channels Impulse / AP Sent THIS CAN CHANGE

20. Ah Finally, Receptorland

21. Speaking The Local Dialect  Ligands  Neuroplasticity  Up-Regulation  Down-Regulation  Ionotropic Receptors  Metabotropic Receptors  Nociceptors / Free Nerve Endings

22. A Fiber & C Fibers (More Dialect) C-Fiber A-Fiber C-Fiber Only A-Fiber Only

23. Wide Dynamic Range Neuron

24. alpha-amino-3-hydroxy-5-methyl-4- isoxazole-propionic acid (AMPA) AMPA

25. Neurokinin 1 Receptor (NK1r)

26. N-methyl-D-aspartate (NMDA) Receptor 2 nd Order Neuron Intracellular Extracellular

27. Alpha 2 Receptor

28. Mu Opioid Receptor

29. Put The Pieces Together

30. This Is Very Graphic Material

31. Where Are We You Are Here

32. Our Neurons NMDArMUr α2rAMPArNK1rMUr α2r Threshold -45 Mv RMP -65Mv Threshold -45 Mv

33. Under General Anesthesia

34. Masked Man With A Knife

35. Initial Pain Impulses NMDArMUr α2rAMPArNK1rMUr α2r Threshold -45 Mv RMP -65Mv Glutamate Na+

36. More Pain Impulses NMDArMUr α2rAMPArNK1rMUr α2r Threshold -45 Mv RMP -65Mv Glutamate Na+ Glutamate Na+

37. Increased Pain Impulses NMDArMUr α2rAMPArNK1rMUr α2r Threshold -45 Mv RMP -65Mv Glutamate Na+ Glutamate Na+ Glutamate

38. NMDA Receptor

39. Beginnings of Wind-Up Phenomenon NMDArMUr α2rAMPArNK1rMUr α2r Threshold -45 Mv RMP -65Mv Glutamate Na+ Glutamate Na+ Glutamate Na+ RMP -60Mv

40. Wind-Up Phenomenon NMDArMUr α2rAMPArNK1rMUr α2r Threshold -45 Mv RMP -60Mv Glutamate Na+ Glutamate Na+ Glutamate Na+ SP Phospholipase-C DAGPKC Na+ Ca++ RMP -50Mv

41. Wind-Up Phenomenon NMDArMUr α2rAMPArNK1rMUr α2r Threshold -45 Mv RMP -50Mv Glutamate Na+ Glutamate Na+ Glutamate Na+ SP Ca++ CaMKII Na+

42. Hyperalgesia / Allodynia NMDArMUr α2rAMPArNK1rMUr α2r Threshold -45 Mv RMP -50Mv Glutamate Na+ Glutamate Na+ Glutamate Na+ SP Ca++Na+ Pain

43. Wind-Up on the WDR Neuron

44. Traditional Opioids NMDArMUr α2rAMPArNK1rMUr α2r Threshold -45 Mv RMP -65Mv Glutamate Na+ Fentanyl K+ RMP -75Mv RMP -65Mv

45. Opioid Problem NMDArMUr α2rAMPArNK1rMUr α2r Threshold -45 Mv RMP -75Mv Glutamate Na+ Fentanyl K+ Pain RMP -75MvRMP -65Mv Glutamate Na+ Glutamate Na+ RMP -65Mv SP NK1r SP Na+ RMP -60MvRMP -55MvRMP -50Mv

46. Opioid Problem NMDArMUr α2rAMPArNK1rMUr α2r Threshold -45 Mv RMP -65Mv Glutamate Fentanyl K+ K+K+ SP I’m out of gas! Help ! NK1r SP Pain

47. Ketamine NMDArMUr α2rAMPArNK1rMUr α2r Threshold -45 Mv RMP -60Mv Glutamate SP Na+ Ketamine Na+ Ca++ RMP -75Mv RMP -50MvRMP -65Mv Fentanyl K+ RMP -65Mv Fentanyl K+ Fentanyl K+ Fentanyl K+

48. Ketamine Without Opioids NMDArMUr α2rAMPArNK1rMUr α2r Threshold -45 Mv RMP -65Mv Glutamate SP Na+ Ketamine Na+ Ca++ RMP -75Mv Ca++ CaMKII Na+ RMP -55Mv Fentanyl K+ NK1r Fentanyl K+ Fentanyl K+ Fentanyl K+ RMP -65Mv RMP -60MvRMP -55Mv

49. Practicality of Ketamine

50. How Much Ketamine?  Less Painful Procedures  0.25mg / Kg Prior to Incision  0.125mg / Kg every 30 minutes  Painful Procedures  0.5mg / Kg prior to Incision  0.25mg / Kg every 30 minutes

51. Myths of Sub-Anesthetic Ketamine  Ketamine and emergence phenomenon  Ketamine and PONV  Ketamine and ischemic heart disease  Using high dose narcotics  do not need ketamine

52. What about Dexmedetomidine

53. Alpha 2 Receptor  α2 agonist binds with the receptor  Gi α subunit is released from the β and γ subunits  inhibits adenylate cyclase  decreases cAMP  decreased PKA  decreased membrane permiability to ions   K+ efflux  hyperpolarization  Inhibition of Ca++ entry  No vesicles out

54. More On the Alpha 2 Receptor

55. Dexmedetomidine Mechanism of Action NMDArMUr α2rAMPArNK1rMUr α2r Threshold -45 Mv RMP -65Mv Glutamate Na+ Glutamate Na+ Glutamate SP Precedex RMP -65Mv ↓Adenylate Cyclase ↓ cAMP ↓PKA ↓ Ca+ ↓Na+↑ K+ K+ RMP -75Mv ↓Adenylate Cyclase↓ cAMP↓PKA ↓ K+ K+ RMP -75Mv

56. Presynaptic or Postsynaptic

57. Effect of Dexmedetomidine on Attenuation of Nociceptive Impulses

58. Practicality of Dexmedetomidine

59. The Anesthetists Toolbox

60. Questions