What’s New I n Acute Pain Management: Reducing Our Dependence O n Opioids

1. What’s New In Acute Pain Management: Reducing Our Dependence On Opioids Trevor D. Schack, MD University of Michigan

2. Objectives • To review recent developments in the understanding of acute pain with focus on molecular pathophysiology and the repercussions of poorly controlled pain • To understand the role of opioids in acute pain management including new insights into their potential negative consequences • To understand current opioid-sparing strategies including multimodal analgesia and regional techniques

3. Introduction

4. Background • 1996 – WHO Pain Ladder • 1996 – APS “fifth vital sign” • 2000 – JCAHO Pain Management Standards

5. Background • 2000s – CMS introduces Hospital Consumer Assessment of Healthcare Providers and Systems (HCAHPS) survey • 2/18 questions directly relating to pain • 4/18 indirectly relating to pain • 2010 – The Patient Protection and Affordable Care Act includes HCAHPS to calculate value-based incentive payments

6. Pain Control Remains Inadequate Warfield CA, Kahn CG. Anesthesiology. 1995;83:1090-1094. Apfelbaum JL, et al. AnesthAnalg. 2003;97:534-540.

7. Effects of Uncontrolled Pain

8. Opioid Use Increases Frasco et al (2005)

9. As Do Side Effects • Vila et al (2005) reported a more than two-fold increase in the incidence of opioid related adverse events involving over-sedation • 11->24.5/100,000 patients (p < 0.001) • 94% had a documented decrease in level of consciousness preceding the event

10. Other Opioid Side Effects • Ileus/Constipation • Nausea/Vomiting • Sedation/Resp Depression • Cough suppression • Confusion/Delirium • Pruritus • Dry mouth • Sweats • Urinary retention • Tolerance/Dependence

11. Cost of Adverse Events • In addition to potential mortality risk, opioid-related adverse events have been associated with an increase in cost and length of stay (Oderda, 2007)

12. So, What Has Changed?

13. Advances in Understanding Descartes 1664 Today

14. Molecular Mechanisms

15. Pain Pathophysiology

16. Opioid Induced Hyperalgesia *Koppert (2007)

17. Anesthesia, Analgesia, and Cancer *CDC 2010

19. 93% 84% 78% 49% 3 7 Epidural Patients 57% LowerRiskRecurrence

20. Pathogenesis of Tumor Metastases

21. Immune Response to Tumor Cells • Natural Killer Cells • Spontaneously recognize and lyse tumor cells • Activated by IL-2 and IFN-y • Patients with low levels of NK cells have increased risk for recurrence • Stress-induced attenuation NK activity in rat model is associated with breast tumor growth and metastasis • Cytotoxic T-cells • Dendritic Cells *Dranoff (2004)

22. Surgery—A Critical Time • Surgery is the mainstay treatment for primary tumors • Can offer best prognosis for patients with solid tumors • Likely a critical period when metastases are either established or eradicated • Can result in minimal residual disease—microscopic deposits at margins or micrometastases • Fate of these neoplastic cells likely dependent on the competence of the host immune response perioperatively • Studies show the presence of neoplastic cells in circulation 24 hr following tumor resection assoc with increased recurrence

23. Effect of Surgery on Immune Function and Metastasis • Perioperative immunosuppression as a result of the neuroendocrine stress response and cytokine inflammatory response • Disrupting endothelial barriers during surgery releases tumor cells into circulation—supported by PCR • Release of growth factors—PGE2, VEGF, TGF-b • And pro-inflammatory cytokines—IL-1, TNF-a, PGE2 • Decreased levels of anti-angiogenic compounds—endostatin, angiostatin

24. Effect of Pain on Immune Function and Metastasis • Pain is a potent stimulant of the HPA axis and sympathetic nervous system, which can lead to immunosuppression • Acute pain suppresses NK cell activityand promotes tumor development in animals • Analgesia has been shown to attenuate this effect 4x Tumor Retention *Page (2001)

25. Levels IL-1 and IL-6 WithDifferentAnalgesics *Beilin (2003)

26. Opioids and Immune Function NK CellActivity In RatsWithVariousOpioids NK CellActivity In Humans *Beilin 1989 *Beilin 1996 • Both cellular and humoral immunity are suppressed by perioperative and chronic opioid use • NK cell activity is reduced by opioids • Whether this indirectly promotes cancer recurrence and metastasis is unknown

27. Opioids—Direct Effect on Cancer Progression? • Breast cancer cells implanted in mice show increased tumor volume and vascularization when treated with opioid • Likely through direct stimulation Mu receptor or its interaction with VEGF receptor Breast Tumor Volume In Mice control (▪) morphine (▵) morphine +naloxone (□) naloxone (▴) *Gupta (2002) *Lennon (2012)

28. Role For μ-Opioid Receptor? • NSCLC cells show 5x increase in MOR expression • Silencing MOR in animal model causes reduced tumor growth (35-50%) and metastasis (45-70%) • Similar results are obtained with a naltrexone infusion • Lung cancer cells injected into MOR knockout mice show notumor development • Same cells injected into controls developed lethal tumors in 12 days *Mathew (2011)

29. MOR With A118G Polymorphism SurvivalProbability in Carriers of A118G • Mostcommonpolymorphism in MOR • Results in decreasedresponsiveness • 5% African-American women • 24% Caucausian *Borstov (2012)

30. MOR expression and long-termrequirementindependentlyassociatedwith inferior survival • Foreveryunit MOR + area, risk of cancerprogressionincr 65% and death 55% • Forevery 5 mg/d MEQ, risk of progressionincr 8% and death 5% *Zylla (2013) 15% survival in high MOR group vs 70% in low MOR

31. Future Prospective Studies *Heaney (2012)

32. “Whenever possible, anesthesiologists should use multimodal pain management therapy. Central regional blockade with local anesthetics should be considered.”

33. Regional Anesthesia/Analgesia • Increased patient satisfaction • Improved analgesia • Decreased postoperative opioid use

34. Transversus Abdominal Plane (TAP) Blocks • First described by Rafi et al (2001) • Provides analgesia to the abdominal wall • Blocks anterior divisions of lower thoracic, subcostal and first lumbar nerves between IO and TA muscles • Efficacy established by RCT • Dye studies show reliable spread T10-L1 (iliac crest to costal margin) External oblique Internal oblique Transversusabdominis Quadratuslumborum

35. TAP Blocks For Donor Nephrectomy at UM Donor Nephrectomy Incisions

36. TAP Indications • Best for lower abdominal and pelvic incisions from the umbilicus and below • Donor nephrectomy • ‘Hand-assist’ lap port • Appendectomy • Hysterectomy • Cesarean Section • Alternative when epidural is not possible or ‘overkill’ • Smaller incision/outpatient surgery • Unable to tolerate placement • Coagulopathy • Infection • Spinal abnormalities

37. TAP Technique

38. Paravertebral Blocks • First described in 1905 by Sellheim, a German physician • Fell out of practice until 1979 • Efficacy supported by multiple RCTs • Complications are reportedly low with most feared being pleural puncture and pneumothorax (0.5%) • Cochrane Review 2013: may prevent persistent postsurgical pain after breast surgery in 1 out of every 4-5 patients

39. Paravertebral Indications • Best for thoracic procedures but can be performed from cervical to lumbar region • Good alternative to epidural • Single-shot • Breast surgery (T2-T6) • VATS (varies) • Small umbilical hernia (T7-T10) • Prostatectomy/hysterectomy (T10-L1) • Continuous • Breast surgery (T2-3) • Lateral nephrectomy (T6-7) • Thoracotomy/VATS (T4-5) • Rib fractures (varies) • Major abdominal (T7-8) • Pelvic (T10-11)

40. Paravertebral Anatomy *usra.ca

41. Classic Technique • Identiftyspinous processes • Entry point 2.5 cm lateral • Contact transverse process • Redirect caudally to “walk-off” • Advance 1 cm • Inject 5 ml local anesthetic • Repeat for additional levels

42. Ultrasound Technique *Narouze (2010)

43. Ultrasound Technique *Narouze (2010)

44. Thoracic Epidural Analgesia • Analgesia: lower pain scores than with systemic opioids • CV: reduced risk of MI and dysrhythmias • GI: earlier return of bowel function • Pulm: reduced risk of pulmonary complications, reduced mechanical ventilation • Endo: decreased postop protein catabolism and hyperglycemia *Manion (2012)

45. Thoracic Epidural Analgesia • Excellent for larger incisions • Benefit less well established for minimally invasive procedures • Higher systemic side effect profile than TAP or paravertebral blocks • Can be associated with hypotension, N/V, urinary retention, numbness, weakness • Require personnel to manage on floor *Manion (2012)

46. Opioid-Sparing Medications

47. Gabapentinoids • General: • Decrease pain scores and opioid use • Likely effective at reducing chronic postsurgical pain • Side effects include sedation, dizziness, visual disturbances • Mechanism: • Structural analogs of GABA but do not bind to its receptor • Bind to voltage-gated calcium channels, modulating the release of excitatory neurotransmitters • Pharmocodynamics: • Gabapentin absorption is limited to a small portion of the duodenum while pregabalin is absorbed throughout the small intestine • Gabapentin absorption can be significantly impaired by antacids • Both are renally excreted without significant metabolism

48. Gabapentinoids—What Dose and When? • Timing of Dosing • Studies indicate that postop dosing is just as effective as preop • Peak plasma level in 1-2hr but peak CSF level in 6-8 hr • So, preop dosing may have to occur earlier for max benefit • Dose • Studies looking low (300-600 mg) vs high (900-1200 mg) doses of gabapentin favor higher dosing • The same is true for pregabalin • Continuing medication thru recovery probably most effective *Schmidt (2013)

49. COX Inhibitors

50. COX Inhibitors