1. Copyright Dr Andrew Dean Pain Classification and Opioid Physiology A Review

2. Copyright Dr Andrew Dean Analgesic Ladder Non-Opioid Non-Opioid + Adjuvant Analgesic Weak Opioid Weak Opioid + Adjuvant Analgesic Strong Opioid Strong Opioid + Adjuvant Analgesic

3. Copyright Dr Andrew Dean Visceral Pain Pain from abdominal & thoracic viscera Deep, squeezing, pressure. Poorly localised. Sometimes referred. Liver, pancreas, lung Mechanisms of Pain

4. Copyright Dr Andrew Dean Mechanisms of Pain Somatic Pain ‘Nociceptive’ Pain from nerve endings in tissues & bones Aching, gnawing. Well localised. eg Bone Metastases

5. Copyright Dr Andrew Dean Neuropathic Pain Pain from nerve irritation/damage. Flashing, sharp, electric, burning. Often follows nerve pathway. Plexus pain. Mechanisms of Pain

6. Copyright Dr Andrew Dean Pain Pathway Receptors Cortico-Spinal Peripheral Nerve Spino-thalamic 5HTNA

7. Copyright Dr Andrew Dean Synapse Spinal Nerve Peripheral Nerve Synaptic Cleft

8. Copyright Dr Andrew Dean Synapse Impulse Depolarisation

9. Copyright Dr Andrew Dean The Busy Gate Cortico-Spinal Sympathetic Spinothalamic Other

10. Copyright Dr Andrew Dean Opioid Receptors Mu Ca 2+ - - - -

11. Copyright Dr Andrew Dean Receptors Mu K/Ca To Spino- thalamic tract Excitatory receptors Inhibitory receptors

12. Copyright Dr Andrew Dean Opioid Response Opioid level Opioid Dose % opioid receptor binding 100%

13. Copyright Dr Andrew Dean Opioid Response Opioid level Opioid Dose % opioid receptor binding 100% Maximum opioid analgesia Side Effects

14. Copyright Dr Andrew Dean Opioid Receptor Sites Receptors Cortico-Spinal Peripheral Nerve Spino-thalamic 5HTNA

15. Copyright Dr Andrew Dean Peripheral Action of Morphine Mu K/Ca Nociceptor Inflammatory cell

16. Copyright Dr Andrew Dean Pain wind up

17. Copyright Dr Andrew Dean Receptors and Channels  AMPA  Short depolarisation  “Fast”  Sharp, pricking pain  NMDA  Enhance depolarisation  Greater response to stimulus  Response outlasts stimulus

18. Copyright Dr Andrew Dean Receptors Mu K/Ca To Spino- thalamic tract Excitatory Receptors AMPA

19. Copyright Dr Andrew Dean NMDA feedback K/Ca To Spino- thalamic tract NMDA receptors NMDA receptors

20. Copyright Dr Andrew Dean Receptor responses Impulses AMPANMDA Stimulus Time

21. Copyright Dr Andrew Dean Receptor co-operation AMPA NK 1-2 NMDA C-fibre response Stimulus number

22. Copyright Dr Andrew Dean NMDA Antagonists Very weak  Paracetamol Weak  Some NSAID’s  Methadone  Pethidine  Valproate  Amantidine

23. Copyright Dr Andrew Dean NMDA Antagonists Moderate  Ketamine  Dextromethorphan Strong  Experimental  Lethal

24. Copyright Dr Andrew Dean Opioid Response Opioid level Opioid Dose % opioid receptor binding

25. Copyright Dr Andrew Dean Opioid Receptor Sites Receptors Cortico-Spinal Peripheral Nerve Spino-thalamic 5HTNA

26. Copyright Dr Andrew Dean Receptors Mu K/Ca To Spino- thalamic tract Excitatory Receptors AMPA

27. Copyright Dr Andrew Dean Sodium Channels K/Ca To Spino- thalamic tract

28. Copyright Dr Andrew Dean Receptors K/Ca To Spino- thalamic tract 3. Receptors next to synapse bind opioids which stop chemical transmission of impulse Inhibitory receptors 1. Cell body receives electrical impulse producing Mu receptor 2. Mu receptors migrate down nerve cell membrane

29. Copyright Dr Andrew Dean Sodium Channel Blockers Valproate Gabapentin Carbamazepine

30. Copyright Dr Andrew Dean Pain Pathway Receptors Cortico-Spinal Peripheral Nerve Spino-thalamic 5HTNA

31. Copyright Dr Andrew Dean Paracetamol Receptors Cortico-Spinal Peripheral Nerve Spino-thalamic 5HTNA Paracetamol acts here

32. Copyright Dr Andrew Dean NSAID’s Receptors Cortico-Spinal Peripheral Nerve Spino-thalamic 5HTNA NSAIDs acts here

33. Copyright Dr Andrew Dean Morphine Receptors Cortico-Spinal Peripheral Nerve Spino-thalamic 5HTNA Morphine acts here 5% 25% 70%

34. Copyright Dr Andrew Dean Dorsal Horn

35. Copyright Dr Andrew Dean Dorsal Horn

36. Copyright Dr Andrew Dean Neuropathic Pain Has many mechanisms Therefore illogical to expect one drug to work every time Often need combination therapy

37. Copyright Dr Andrew Dean Pain Pathway Receptors Cortico-Spinal Peripheral Nerve Spino-thalamic 5HTNA

38. Copyright Dr Andrew Dean Opioid Receptors Mu Ca 2+ - - - -

39. Copyright Dr Andrew Dean Opioid Response Opioid level Opioid Dose % opioid receptor binding

40. Copyright Dr Andrew Dean Side Effect Threshold Opioid level Opioid Dose High threshold

41. Copyright Dr Andrew Dean Side Effect Threshold Opioid level Opioid Dose Low threshold

42. Copyright Dr Andrew Dean Methadone Potent Mu agonist NMDA receptor activity No active metabolites

43. Copyright Dr Andrew Dean Methadone Formulation –Oral liquid, tablets –Injection, SC, IM, IV Not predicable –Large inter-individual variation –1-2 hours onset, lasts 6-12 hours –t 1/2 <120 hrs, Steady state 2-10 days.

44. Copyright Dr Andrew Dean Methadone Formulation –Oral liquid, tablets –Injection, SC, IM, IV Not predicable –Large inter-individual variation –1-2 hours onset, lasts 6-12 hours –t 1/2 <120 hrs, Steady state 2-10 days.

45. Copyright Dr Andrew Dean Opioid level Opioid Dose Side Effect Threshold Morphine side effect threshold Methadone side effect threshold

46. Copyright Dr Andrew Dean Methadone Study Retrospective Case study - 68 patients Morphine side effects Co-analgesics unchanged Opioid changed to methadone

47. Copyright Dr Andrew Dean Methadone Study Pain Types n Somatic28 n Neuropathic 2 n Visceral11 n SV 3 n SN22 n SVN 1

48. Copyright Dr Andrew Dean Methadone Study Side Effects Confusion20 Drowsiness34 Hallucinations13 Nausea24 Pruritis 2

49. Copyright Dr Andrew Dean Methadone Study Case study - 68 patients n Resolution of adverse effects in 56 (82%) n Side effects same or changed in 12

50. Copyright Dr Andrew Dean Morphine/Methadone Conversion Average = 6.34

51. Copyright Dr Andrew Dean Methadone Study Ratios Neuropathic Pain Ratio 7.06 Non-Neuropathic Pain Ratio 5.78 Does this reflect NMDA antagonism?

52. Copyright Dr Andrew Dean Dose Regimen bd57 tds11

53. Copyright Dr Andrew Dean Methadone Study Conclusions Methadone is a suitable alternative to morphine for cancer pain Suggested ratio n Suggested regimen n May be better for neuropathic pain 6:1 bd n Consider threshold theory