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

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Presentation on theme: "Whats New In Acute Pain Management: Reducing Our Dependence On Opioids Trevor D. Schack, MD University of Michigan."— Presentation transcript:

1 Whats 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: Apfelbaum JL, et al. Anesth Analg. 2003;97:

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 1664Today

14 Molecular Mechanisms

15 Pain Pathophysiology

16 Opioid Induced Hyperalgesia *Koppert (2007)

17 Anesthesia, Analgesia, and Cancer *CDC 2010


19 93% 78% 84% 49% 37 Epidural Patients 57% Lower Risk Recurrence

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 SurgeryA 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 diseasemicroscopic 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 circulationsupported by PCR Release of growth factorsPGE2, VEGF, TGF-b And pro-inflammatory cytokinesIL-1, TNF-a, PGE2 Decreased levels of anti-angiogenic compoundsendostatin, 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 activity and promotes tumor development in animals Analgesia has been shown to attenuate this effect *Page (2001) 4x Tumor Retention

25 *Beilin (2003) Levels IL-1 and IL-6 With Different Analgesics

26 Opioids and Immune Function *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 NK Cell Activity In Rats With Various OpioidsNK Cell Activity In Humans

27 OpioidsDirect Effect on Cancer Progression? *Gupta (2002) control () morphine ( ) morphine + naloxone () naloxone ( ) 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 *Lennon (2012) Breast Tumor Volume In Mice

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 no tumor development Same cells injected into controls developed lethal tumors in 12 days *Mathew (2011)

29 *Borstov (2012) MOR With A118G Polymorphism Most common polymorphism in MOR Results in decreased responsiveness 5% African-American women 24% Caucausian Survival Probability in Carriers of A118G

30 *Zylla (2013) MOR expression and long-term requirement independently associated with inferior survival For every unit MOR + area, risk of cancer progression incr 65% and death 55% For every 5 mg/d MEQ, risk of progression incr 8% and death 5% 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 Transversus abdominis Quadratus lumborum

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 *

41 Classic Technique Identifty spinous 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 GabapentinoidsWhat 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 ( mg) vs high ( 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


51 Nonspecific NSAIDs (COX 1 and 2 activity) Ketorolac, Ibuprofen Use limited perioperatively due to platelet dysfunction, GI and renal toxicity Coxibs (COX 2) Celebrex Potential cardiac/renal toxicity Reduced GI side effects, no platelet inhibition Both May lead to dose-dependent increase of cardiovascular toxicity and impaired osteogenesis 15-55% reduction in perioperative opioid use (Elia 2005)

52 COX Inhibitors and Cancer COX-2 inhibitors: Induce apoptosis Decrease levels of angiogenic factors Decrease microvascular density in animal models Attenuate opioid-induced immunosuppression COX-2 inhibition decreased PGE2 direct impact on cancer cell mutation, proliferation, and survival Overexpression of COX-2 is associated with increased cancer recurrence and is a poor prognostic indicator Farooqui et almouse model showed chronic morphine use increases COX-2 expression in tumor cells, and can impair analgesia while promoting tumor angiogenesis

53 TylenolNow Available By IV Effective, well tolerated Caution with severe hepatic impairment Safe with renal dysfunction Max 3g/day 1g IV acetaminophen reduced morphine use after orthopedic surgery approximately 30% (Sinatra, 2005)

54 Liposomal Bupivacaine Exparel – bupivacaine loaded in multivesicular liposomes FDA approved for local infiltration –Hemorrhoidectomy –Bunionectomy No delay in wound healing after orthopedic surgery Acceptable adverse effect profile *Chahar (2012)

55 Attempted dose response study for 14 volunteers having femoral n block Tested quad strength and tolerance to electrical current Found dose response in opposite directionhigher the dose, lower the effect

56 Other Adjuvants Alpha-2 Agonists Clonidine, dexmedetomidine Can provide sedation, hypnosis, anxiolysis, sympatholysis and analgesia Antinociceptive effect due to action on alpha-2 receptors in brain and spinal cord Can cause profound hypotension, bradycardia Meta-analysis shows % reduction morphine at hrs postop (Blaudszun, 2012) NMDA R Antagonists Ketamine At subanesthetic doses (0.5 mg/kg) may exert NMDA blockade modulating central sensitization and OIH Hallucinations, bad dreams, dizziness, blurred vision Inhibits NK cell activity in animal models

57 The Future PROSPECT (Procedure Specific Postoperative Pain Management)

58 The Future

59 Questions???

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