1. Sponsored by Integrity Continuing Education, Inc. Supported by an educational grant from Mylan. The Role of Short-acting Opioids in Current Anesthesia Practice

2. Bernadette Henrichs, PhD, CRNA Professor & Director Nurse Anesthesia Program Goldfarb School of Nursing Barnes-Jewish College St. Louis, Missouri 2

3. Overview of General Anesthesia Goals of general anesthesia –Rapid induction and maintenance of optimal operating conditions –Reduction of side effects –Rapid emergence and recovery A combination of agents is used to induce and maintain general anesthesia in current practice –IV hypnotics and sedatives –Volatile inhalational agents –Opioids –Muscle relaxants 3 Mandel, J. E. J Clin Anesth. 2014;26(1 Suppl):S1-7.

4. Volatile Inhalation Agents for the Maintenance of General Anesthesia Common agents include sevoflurane (SEVO), desflurane (DES), and nitrous oxide (N 2 O) N 2 O with SEVO or DES provides fast, reliable recovery and lowers risk of myocardial depression Associated adverse events: 4 * May have deleterious effects in critically ill and pediatric patients; Mandel, J. E. J Clin Anesth. 2014;26(1 Suppl):S1-7. SEVO/DES Isolated cases of hepatotoxicity N2ON2O Nausea and vomiting Diffusional hypoxemia Pulmonary bleb rupture Pneumothorax expansion Inactivation of vitamin B 12 *

5. Total Intravenous Anesthesia (TIVA) An alternative to the use of volatile agents for maintenance of anesthesia Anesthesia is produced entirely using IV anesthetics administered by target-controlled infusion or manual injection Short-acting opioids play a central role (though not always required for minimally stimulating procedures) Short-acting agents enable rapid recovery even after long infusions 5 Cole CD, et al. Neurosurgery. 2007;61(5 Suppl 2):369-377. DeConde AS, et al. Int Forum Allergy Rhinol. 2013;3(10):848-854. Lerman J, et al. Paediatr Anaesth. 2009;19(5):521-534. Mandel JE. J Clin Anesth. 2014;26(1):S1-S7. Mani V, et al. Paediatr Anaesth. 2010;20(3):211-222.

6. IV Agents for the Induction and Maintenance of General Anesthesia 6 IV AGENTPOTENTIAL ADVANTAGESPOTENTIAL DISADVANTAGES Propofol – Good recovery profile – Short half-life – Low PONV incidence – Bradycardia – Hypotension – Burning sensation Etomidate – Preferred if vasodilation and cardiac depression are contraindicated – Adrenal insufficiency – Higher PONV incidence – Burning sensation Ketamine – Preferred for reactive airway patients (bronchodilatory) – Cardiovascular stimulation – Hallucinations, vivid dreams, delirium – Benzodiazepines can improve but may slow emergence and recovery Mandel, J. E. J Clin Anesth. 2014;26(1 Suppl):S1-7.

7. Clinical Comparisons of Anesthesia Techniques TIVA compared to inhalation anesthesia (IA) in vertebral disk surgery: –Shorter recovery times (spontaneous ventilation, extubation, eye opening, and ability to give name and date of birth)* –Less PONV –Greater analgesic demand TIVA compared to IA in pediatric ENT surgery: –Lower perioperative heart rate –Less postoperative agitation TIVA and balanced volatile anesthesia in intracranial surgery were found to be comparable 7 *P<.05 Gozdemir M, et al. Adv Ther. 2007;24(3):622-631. Grundmann U, et al. Acta Anaesthesiol Scand. 1998;42(7):845-850. Magni G, et al. J Neurosurg Anesthesiol. 2005;17(3):134-138.

8. Monitoring of Vital Signs to Assess Depth of Anesthesia Potential signs of intraoperative awareness/stress: –Tachycardia (rapid heart rate) –Hypertension –Sweating –Lacrimation (tear production) –Movement/grimacing –Tachypnea (rapid breathing) New technologies for monitoring (EEG, BIS) –Helps to indicate the level of unconsciousness –Does not guarantee against intraoperative awareness 8 Shepherd J. Health Technology Assessment 2013;17:34.

9. Maintaining Appropriate Depth of Anesthesia Excessive level of anesthesia –Increases risk of postoperative nausea, vomiting, and cognitive dysfunction Insufficient level of anesthesia –Places patient at risk for intraoperative awareness –Although relatively rare, intraoperative awareness can cause depression, anxiety, and post-traumatic stress disorder 9 Shepherd J. Health Technology Assessment. 2013;17:34.

10. Hemodynamic Stability During Surgery Hemodynamic instability can result in complications Hemodynamic measures are important indicators of the following: –Sufficient cardiac output –Adequate SV; Volume status –Organ perfusion –Adequacy of pain control –Depth of anesthesia 10 Lendvay V, et al. J Anesthe Clinic Res. 2010;1:103. Cove ME, Pinsky MR. Best Pract Res Clin Anaesthesiol. 2012;26(4):453-462.

11. Rationale for the Use of Short-acting Opioids in General Anesthesia 11

12. Opioid Receptors and Response to Stimulation 12 ReceptorResponse Mu-1Supraspinal analgesia Mu-2 Depression of ventilation Cardiovascular effects Physical dependence Euphoria DeltaModulate mu receptors Kappa Spinal analgesia Sedation Miosis Sigma Dysphoria Hypertonia

13. Advantages of the Use of Opioids for General Anesthesia Analgesia –Blunts neuroendocrine activation Hemodynamic stability –No direct myocardial depression –Blunts catecholamine response to noxious stimuli Decreased stress response –Attenuates stress response during surgery Decreased need for hypnotic anesthetics –Less propofol needed Brown EN., et al. Annu Rev Neurosci. 2011;34:601-628. Fukuda K (2010). Opioids. In RD Miller et al., eds., Miller's Anesthesia, 7th ed., pp. 2519-2700. Wilmore DW. Ann Surg. 2002;236(5):643-648.

14. Specific Benefits Associated with the Use of Short-acting Opioids Minimal effects of drug accumulation Predictable and rapid onset and offset Rapid patient response to titration allows close management of intraoperative status Potential for faster recovery time and reduced PONV Benefits are not generally affected by gender, age, weight, or renal/hepatic function Wilhelm W, et al. Crit Care. 2008;12 (Suppl 3):S5. Egan TD. Curr Opin Anaesthesiol. 2000;13(4):449-455. Egan TD, et al. Anesthesiology. 1996;84(4):821-833. Minto CF, et al. Anesthesiology. 1997;86(1):10-23.

15. 15 CharacteristicAlfentanilFentanylRemifentanilSufentanil µ-Opioid receptor selectivity XXXX No histamine releaseXXXX Rapid response to titrationX Rapid, predictable offset of opioid effects (5-10 min) X Elimination independent of renal or hepatic function X Desirable Characteristics of the µ-Opioids

16. Remifentanil Hydrolysis by Non-specific Esterases in the Blood and Tissues N-C-CH 2 - CH 3 C-O- CH 3 Remifentanil CH 3 -O-C-CH 2 -CH 2 - N O O O C-O-CH 3 N-C-CH 2 - CH 3 H-O-C-CH 2 -CH 2 - N O O O GR90291 N-C-CH 2 - CH 3 C-O- CH 3 H-N O O GR94219 Nonspecific Esterases >95% Major Metabolite (Inactive) Egan TD. Clin Pharmacokinet. 1995;29(2):80-94.

17. Pharmacokinetic Properties of µ-Opioids *The time required for drug concentrations in blood or at effect site to decrease by 50%. Based on a 3-hour infusion. † Increases with increasing infusion duration due to accumulation.. Data derived from manufacturers’ labeling and Egan TD, et al. Anesthesiology. 1993;79:881-892. Egan TD, et al. Anesthesiology. 1996;84:821-833. Scott JC, et al. Anesthesiology. 1991;74:34-42. PharmacokineticsAlfentanilFentanylRemifentanilSufentanil Onset: blood-effect site equilibration, mean 0.96 min 6.6 min 1.6 min 6.2 min Organ-independent elimination NoNoYesNo Nonspecific esterase metabolism NoNoYesNo Offset: context-sensitive half-time, mean* 50-55 min † >100 min † 3-6 min 30 min † 17

18. Practical Considerations: Rapid Onset ADVANTAGES Rapid response to titration and bolus Control of anesthetic depth Hemodynamic stability Predictable plasma & receptor level DISADVANTAGES Increased risk for: –Bradycardia –Hypotension –Chest wall rigidity –Apnea

19. Opioid Infusion Front-end Kinetics: Quick to Steady State 19 Egan TD (in Miller & Pardo). Elsevier;2011. Proportion of Steady-State Ce (%) Infusion Duration (min) Morphine Sufentanil Fentanyl Alfentanil Remifentanil 100 80 60 40 20 0 0100200300400500600 Infusion begins at time zero

20. Opioid Infusion Back-end Kinetics: Rapid Offset After Infusion 20 Egan TD (in Miller & Pardo). Elsevier;2011. Time to 50% Decrement in Ce (%) Infusion Duration (min) Morphine Sufentanil Fentanyl Alfentanil Remifentanil 400 350 300 250 200 150 100 50 0 010020030400500600

21. Mean Concentration Over Time With Short-acting Opioids Time (min) Mean Concentration (ng/mL) (n=5) 0.5 mcg/kg/min (n=6) 0.05 mcg/kg/min Discontinuation of infusion 21 Alfentanil Remifentanil ULTIVA [Mylan Inc.] Available at: http://www.ultiva.com/files/Ultiva-Prescribing-Info.pdf

22. Practical Considerations: Rapid Offset ADVANTAGES Rapid response to titration Predictable emergence High-dose opioid technique without need for post-op ventilation Ideal for TIVA DISADVANTAGES No residual analgesia –Hemodynamic instability

23. Procedure-associated Variability in Opioid Pharmacodynamics Ausems ME, et al. Anesthesiology. 1986;65:362-373. Plasma Alfentanil (ng/mL) 100 50 0 02004006008001000 Intubation Skin Incision Skin Closure Probability of No Response (%) (n=37)

24. Opioid Pharmacodynamic Variability Ausems ME, et al. Anesthesiology. 1988;68:851-861. Probability of No Response to Surgical Incision (%)

25. Risks Associated with the Use of Opioids in General Anesthesia Respiratory depression Bradycardia Chest wall/laryngeal muscle rigidity PONV Pruritus Delayed emergence Dependency Potential hyperalgesia Bowdle TA. Drug Saf. 1998;19(3):173-189. Egan TD. Clin Pharmacokinet. 1995;29(2):80-94. Fletcher D, et al. Br J Anaesth. 2014;112(6):991-1004. Komatsu R, et al. Anaesthesia. 2007;62(12):1266-1280.

26. Choosing an Anesthetic Technique 26

27. Discussion Questions: Technique Considerations How do you determine which technique is most appropriate for a given patient? What are the primary concerns associated with each technique?

28. Impact of Inhalation vs Intravenous (IV) Administration of Agents Less PONV and greater patient satisfaction has been observed with the following: –IV induction compared to inhalation induction* –TIVA compared to an inhalation component Emergence and discharge for outpatients is essentially identical Inhalational anesthesia may be economically advantageous over TIVA 28 *Both followed by inhalation maintenance. Kumar, G., et al. Anaesthesia. 2014. *Both followed by inhalation maintenance. Kumar, G., et al. Anaesthesia. 2014. [Epub ahead of print] Joshi GP. Anesthesiol Clin North Am. 2003;21(2):263-272. Joshi GP. Anesthesiol Clin North Am. 2003;21(2):263-272.

29. The Anesthesia Technique You Use Should Be Based on Your Goals Balanced anesthesia with opioid and volatile agent –Safe –Practiced for decades TIVA –Safe –Relative newcomer to the OR –Outpatient > inpatient –May impact patient satisfaction OR, Operating Room

30. Goals of Neuroanesthesia Hemodynamic stability without vasodilators Improved ability to rapidly change anesthetic depth Rapid recovery with early ability to assess neurologic function Improved SSEP monitoring with TIVA SSEP, somatosensory evoked potential.

31. Goals of ENT Hemodynamic stability without vasodilators Decreased bleeding, improved operative conditions during nasal/sinus surgery or tonsillectomy Rapid awakening, rapid ability to protect airway, rapid recovery

32. Case Study #1 32

33. Case Study #1: 17-year-old Female Procedure: Septoplasty and sinus endoscopy History: –Significant history of nasal passage obstruction and difficulty breathing –History of chronic sinusitis beginning at age 3 Surgical history: –Tonsillectomy at age 7 related to obstructive sleep apnea (OSA); complicated by prolonged paralysis to succinylcholine

34. Case Study #1: 17-year-old Female (cont’d) Comorbidities: –Asthma –Obesity –OSA with nasal obstruction Current medications: –Saline nasal irrigation qd –Albuterol prn Allergies: –Penicillin –No other known allergies

35. Case Study #1: Consideration of Patient Characteristics How do the patient’s characteristics influence your approach to formulating a plan for anesthesia? –OSA –Obesity –Asthma –Atypical pseudocholinesterase deficiency Specific concerns with regard to this type of surgical procedure: May be stimulating at times but no incision to close at end of case

36. Emergence & Recovery 36

37. Short-acting Opioid Improves Time to Orientation Compared With N 2 O 37 Proportion Not Oriented Time (min) Infusion of remifentanil 0.085 µg/kg/min compared with 66% N 2 O 1.0 0.8 0.6 0.4 0.2 0.0 0510152025 Remifentanil Nitrous oxide Mathews DM, et al. Anesth Analg. 2008;106:101-108.

38. 38 Comparison of the Short-acting Opioids: Impact on Patient Recovery Similar PONV is observed with fentanyl, remifentanil, alfentanil, and sufentanil Use of remifentanil vs other short-acting opioids is associated with the following: –Faster postoperative recovery –Less respiratory depression –Higher postoperative analgesic requirements –More shivering Reviewed in: Komatsu R, et al. Anaesthesia. 2007;62(12):1266-1280.

39. Case Study #2 39

40. Case Study #2: 73-year-old Male Procedure: Right carotid endarterectomy Comorbid conditions: –Coronary artery disease –Type 1 diabetes –Hypertension –Peripheral vascular disease Surgical history: –Left femoral popliteal bypass at age 71 –Stent inserted at age 68

41. Case Study #2: 73-year-old Male (cont’d) Current medications: –Lisonopril 20 mg qd –Insulin glargine 0.2 units/kg/day Renal evaluation: –Renal insufficiency determined by glomerular filtration rate (GFR) of 61 mls/min/1.73m 2 Vascular evaluation: –90% occlusion of right carotid –50% occlusion of left carotid Allergies: –No known allergies

42. Case Study #2: Questions for Consideration What considerations should be given for: –Regional vs general anesthesia? –Tracheal intubation vs laryngeal mask airway (LMA) device? What monitoring would you employ intraoperatively? Consider the patient’s medical history (HTN) and renal impairment in the anesthetic plan Important to consider quick emergence to assess neurological function

43. Case Study #3 43

44. Case Study #3: 42-year-old Female Procedure: –Multi-level laminectomy with lumbar fusion –Intraoperative neurophysiologic monitoring (sensory evoked potentials, motor evoked potentials) Surgical history: –Previous back surgery to repair herniated disc 3 years ago Medical history: –Current smoker Current medications: –Naproxen sodium 500 mg bid (discontinued 10 days ago)

45. Case Study #3: Questions for Consideration What considerations are given for TIVA vs mixed anesthesia in this patient? Consider intraoperative monitoring of this patient Consider surgeon request for possible intraoperative wake up for neurologic examination Consider patient’s history of chronic pain medication

46. Intraoperative Neurophysiological Monitoring Main modalities: –Somatosensory evoked potentials (SSEPs) –Motor evoked potentials (MEPs) –Electromyography (EMGs); transcranial monitoring While both inhaled and intravenous agents blunt signal attainment, depression is greater with inhaled agents 46 Deiner S. Semin Cardiothorac Vasc Anesth. 2010;14(1):51-53.

47. Case Study #3: Anesthetic Plan TIVA with propofol and fast-acting opioid infusion If intraoperative wake up is necessary, it will be possible Consider patient’s history of chronic pain medication –Give pain medicine before emergence –IV Acetaminophen; IV NSAID; longer-acting narcotic

48. Emergence and Recovery: Considerations Goal is to prepare for and have a smooth transition to postoperative analgesia Early planning is essential with an agent with a rapid offset of action (within 5-10 minutes) –Non-cumulative effects are beneficial during surgery, but a disadvantage postoperatively in terms of pain control –Need to be prepared and address pain Risks for obstruction and for pulmonary aspiration are also important to consider

49. Propofol Emergence Data 49 DIPRIVAN (propofol) injection, emulsion [APP Pharmaceuticals, LLC]. Available at: http://dailymed.nlm.nih.gov/dailymed/lookup.cfm?setid=ee0c3437-614d-4631-a061-257f5f60c70b. Plasma Propofol Concentration (mcg/mL) 1.00 0.75 0.50 0.25 0.00 Minutes After End of Infusion 020406080 Target plasma concentration Recovery after: 10-day infusion 10-hour infusion 1-hour infusion Awakening

50. Postoperative Management: Analgesia 50

51. Postoperative Pain Postoperative pain is a significant cause of delayed discharge after ambulatory surgery Good pain control is important for prevention of negative outcomes: –Tachycardia –Hypertension –Myocardial ischemia –Decreased alveolar ventilation –Poor wound healing Pain control must be individualized 51 Vadivelu N, et al. Yale J Biol Med. 2010;83(1):11-25.

52. Options for Postoperative Pain Management Choice of analgesia should be a multimodal approach: –Nonsteroidal agent administered IV or IM –IV acetaminophen –Major nerve block –Local anesthetic wound infiltration –Long-acting opioids administered 20 to 30 minutes before discontinuation of certain short-acting opioids –Consider epidural administration of an opioid and/or local anesthetic IM, intramuscular

53. Opioids in Postoperative Analgesia Give opioids prior to emergence as needed –IV Acetaminophen if not given at induction –Ketorolac 30 mg IV ~30 min or Caldolor IV –Dilaudid 0.2-2.0 mg IV ~ 20-30 min –MSO 4 0.1 to 0.2 mg/kg IV ~20 to 30 min –Fentanyl 1 to 1.5 u/kg IV ~5 min Dose epidural if epidural placed Surgeon: Infiltrate with long-acting local anesthetic Consider continuing remifentanil 0.05 to 0.1 mcg/kg/min in PACU

54. Considerations for Special Populations Age; Elderly more sensitive to narcotics Body mass effects; Obese more sensitive to narcotics Comorbid conditions Current medications 54 Strom C, et al. Anaesthesia. 2014;69(S1):35-44. Lerman J. Eur J Anaesthesiol. 2013;30(11):645-650. Ingrande J, et al. Br J Anaesth. 2010;105 (S1):16-23. Hachenberg T, et al. Curr Opin Anaesthesiol. 2014;27(4):394-402.Licker M, et al. Int J Chron Obstruct Pulmon Dis. 2007;2(4):493-515.

55. Summary Opioids used in anesthesia play a critical role in minimizing surgical pain and the associated adverse effects on patient outcomes The pharmacokinetic profiles of newer short-acting opioids are characterized by lower drug accumulation and rapid, predictable onset and offset The resulting rapid response to titration of short-acting opioids enables close intraoperative management of hemodynamics, patient stress response, and depth of anesthesia With appropriate use, short-acting opioids have the potential to improve recovery and overall patient experience and satisfaction 55

56. Thank you!