How to Administer an Opioid-Free General Anesthetic

How to Administer an Opioid-Free General Anesthetic Christine Oryhan, MD Virginia Mason Medical Center WSSA/BCAS Joint Winter Meeting December 8 th, 2018

Disclosures I have no disclosures.

Learning objectives At the conclusion of this session, learners will be able to: 1) Review both the analgesic and non-analgesic effects of opioids in the perioperative setting 2) Describe available perioperative opioid sparing techniques 3) Discuss the role of the anesthesiologist in the climate of the opioid crisis

Brief Opioid History 3000 BC: Opium poppy cultivated for its active ingredient 1804: Morphine first distilled from opium 1962: Fentanyl is the first synthetic opioid described for anesthetic use 1980s: World Health Organization develops WHO Ladder of pain treatment Late 1990 s: Pharmaceutical companies reassured that patients would not become addicted to opioid pain relievers Late 1990 s: VA and JCAHO identify pain as the fifth vital sign 2011: Institute of Medicine (IOM) reports opioid crisis 2017: HHS declared the opioid epidemic a public health emergency

Opioids in the perioperative setting Historically, primary treatment for post-surgical pain Potent analgesics effective for acute, mod-severe, nociceptive pain More effective than placebo for nociceptive and neuropathic pain of less than 16 weeks duration (Furlan et al, 2011) 99% of all surgical patients receive opioids during their periop care (Kessler et al, 2013) Balanced anesthesia inhalational agents, opioids, NMBDs Suppress the sympathetic system stable hemodynamics

Fentanyl Potent analgesic with rapid onset Minimal CV effects = stable hemodynamics No increase in plasma histamine Relatively short acting Easy and inexpensive to synthesize Familiar to perioperative clinicians

Opioid mechanisms of action Opioid Receptor Class Mu 1 Mu 2 Delta Kappa Effects Euphoria, supraspinal analgesia, confusion, dizziness, nausea Respiratory depression, cardiovascular depression, constipation, miosis, urinary retention Spinal analgesia, cardiovascular depression, decreased brain and myocardial oxygen demand Spinal analgesia, dysphoria, psychomimetic effects, feedback inhibition of endorphin system

Opioid mechanisms of action Opioid Receptor Class Mu 1 Mu 2 Delta Kappa Effects Euphoria, supraspinal analgesia, confusion, dizziness, nausea Respiratory depression, cardiovascular effects, constipation, miosis, urinary retention Spinal analgesia, cardiovascular depression, decreased brain and myocardial oxygen demand Spinal analgesia, dysphoria, psychomimetic effects, feedback inhibition of endorphin system

Opioid mechanisms of action Opioid Receptor Class Mu 1 Mu 2 Delta Kappa Effects Euphoria, supraspinal analgesia, confusion, dizziness, nausea Respiratory depression, cardiovascular depression, constipation, miosis, urinary retention Spinal analgesia, cardiovascular depression, decreased brain and myocardial oxygen demand Spinal analgesia, dysphoria, psychomimetic effects, feedback inhibition of endorphin system

Opioid mechanisms of action Opioid Receptor Class Mu 1 Mu 2 Delta Effects Euphoria, supraspinal analgesia, confusion, dizziness, nausea Respiratory depression, cardiovascular depression, constipation, miosis, urinary retention Spinal analgesia, cardiovascular depression, decreased brain and myocardial oxygen demand Kappa Spinal analgesia, dysphoria, psychomimetic effects, feedback inhibition of endorphin system Immunosuppression Sexual dysfunction Acute tolerance Depression Opioid induced hyperalgesia Decreased energy Effect on malignancy/metastasis? Obesity?

Post-surgical opioid effects Analgesia Sedation Respiratory depression Delirium Dizziness Ileus Nausea/Vomiting (PONV) Pruritis

Primary mechanism of opioid-related fatality Analysis of Anesthesia Closed Claims Project database between 1990 and 2009 92 cases found to be definitely, probably, and possibly related to opioid overdose out of 357 acute pain claims (9,799 total claims). Majority of cases: Occurred within first 24 hours postoperatively Resulted in permanent brain damage or death Were deemed preventable

Opioids and PONV Incidence of PONV as high as 42.7% in bariatric surgery patients despite triple PONV prophylaxis. Replacing post-operative opioids with a multimodal approach decreased rescue anti-emetics by 14.6% PONV reduced by 17.3% with addition of opioid-free TIVA with propofol, ketamine and dexmedetomidine (20% vs volatile anesthetics plus opioids, 37.3%)

Intraoperative opioid effects Desirable Analgesia Hemodynamic stability Undesirable Tolerance Hyperalgesia

Acute opioid tolerance Tolerance to morphine infusion starts at 2 hours with diminishing analgesic benefit thereafter

Acute opioid tolerance Tolerance to remifentanil by 90 minutes of infusion Resolution of analgesia by 3-4 hours

Opioid-induced hyperalgesia (OIH) Clinical syndrome involving Development of increased pain intensity over time Spreading of pain beyond initial site of injury Increase in pain sensation Dose- and time-exposure dependent In animal models, morphine given prior to incision prolongs subsequent pain hypersensitivity High doses of opioids administered during incision in animal models may facilitate pain sensitization by surgery via NMDA receptors and activated glial cells Richebe 2018, Lavand homme 2017

Remifentanil Higher doses of remifentanil: Increase pain scores, morphine consumption, and areas of hyperalgesia (Fletcher and Martinez, Br J Anaesth 2014) Associated with higher incidence of persistent postoperative pain up to 1 year after cardiac surgery (van Gulik et al, Br J Anaesth 2012) Threshold for acute tolerance and OIH? (Angst, J Cardithorac Vasc Anesth 2015) 50 mcg/kg for acute tolerance 40 mcg/kg for remifentanil-induced hyperalgesia

Fentanyl Increased post-op pain and fentanyl use after hysterectomy in patients who received high dose (15 mcg/kg) vs low dose (1 mcg/kg) intraoperative fentanyl (Chia et al, Can J Anaesth 1999) Higher/repeated doses of pre- and intraoperative fentanyl associated with more post-operative fentanyl use and increased PONV (Pavlin et al, Anesthe Analg 2002)

Retrospective study of 36,177 patients having minor (80.3%) and major (19.7%) surgery between 2013-2014 Similar rates of development of new persistent opioid use Rate of new chronic opioid use 5.9-6.5% Risk factors: preoperative tobacco use, alcohol and substance abuse disorders, mood disorders, anxiety and preoperative pain

Opioid SPARING analgesia/anesthesia Opioid sparing techniques Decrease post-operative opioid consumption Decrease incidence of PONV Hasten post-operative recovery Alternative medications/techniques available to achieve Analgesia Anti-hyperalgesia Hemodynamic stability Lavand homme et al 2018

Who benefits from OFA? Not fully understood but consider in: Patients at risk for developing chronic post-surgical pain Patients at risk for developing PONV Patients with morbid obesity, +/- OSA

Multimodal approach Acetaminophen NSAIDs Gabapentinoids Dexamethasone Ketamine IV lidocaine Dexmedetomidine Magnesium Esmolol Regional techniques Peripheral nerve blocks, +/- perineural catheter Truncal blocks (PVB, ESB, TAP, Rectus sheath, QL) Neuraxial techniques Epidural, spinal

Acetaminophen (APAP) Demonstrated analgesic and opioid sparing effects Can reduce postoperative opioid use by 30% Can give oral, IV or rectally with similar efficacy (Jibril et al, Can J Hosp Pharm 2015) Dose: 975mg PO pre-operatively or 1000mg IV pre/intra-op Continue scheduled dosing post-operatively Use caution/reduced doses in patients with liver disease Koepke et al 2018

NSAIDs Nonsteroidal anti-inflammatory drugs are potent non-opioid analgesics 600mg ibuprofen as efficacious as 15mg oxycodone (Wick et al, JAMA Surg 2017) Can decrease opioid use at 24 hours by 40-50% (Elia et al, Anesthesiology 2015) Several recent studies demonstrate no increased risk of postoperative bleeding Dose: Celecoxib 300-600mg PO pre-op, or 15-30mg ketorolac IV intraop. Can continue post-operatively depending on surgery Caution in patients with advanced age, renal disease, IBD

Gabapentinoids Gabapentin and pregabalin have both been shown to reduce postoperative opioid requirements and opioid related side effects (Wick et al, JAMA Surg 2017) Pre-operative gabapentin 300-1200mg PO can decrease opioid use by 30 MED in first 24 hours post-op (Tippana et al, Anesth Analg 2007) Dose: Preoperatively 600-900mg gabapentin or 150-300mg pregabalin, continue scheduled dosing post-op when tolerating clears

Dexamethasone Can reduce and prevent PONV (4-8mg IV intraop) Can decrease acute postoperative pain (4-20mg IV intraop) Shown to reduce post-operative pain scores and opioid use for up to 48 hours after total joint arthroplasty (Meng et al, Medicine 2017) Caution in poorly controlled diabetic patients

Ketamine NMDA receptor antagonist At subanesthetic doses, has analgesic, anti-hyperalgesic, local anesthetic and anti-inflammatory properties Decreases acute post-op pain and opioid requirements Can reduce/prevent opioid induced hyperalgesia Ketamine can attenuate central sensitization and hyperalgesia in opioid tolerant patients, and can reduce pain up to 6 weeks after surgery (Nielsen et al, Pain 2017) Can produce hemodynamic (BP) stability (sympathetic stimulation) Dose: 0.5mg/kg bolus dose prior to incision, followed by infusion of 0.05-0.2mg/kg/hr (based on IBW, can continue 24-48hr post-op) Low side effect profile at subanesthetic doses

IV Lidocaine Demonstrated analgesic, anti-inflammatory and anti-hyperalgesic properties Reduces postoperative pain scores, nausea/vomiting, time to flatus and bowel movements, length of stay (Vigneault et al, Can J Anaesth 2011) Can contribute to slight decreased risk of persistent postoperative pain (Chang et al, Pain Pract 2017) Dose: 1.5mg/kg IV bolus, followed by infusion of 0.5-2 mg/kg/hr (based on IBW, can continue 24-48hr post-op) Avoid concomitant use with other high dose or continuous local anesthetics to avoid toxicity (LAST)

IV Lidocaine Pharmakodynamics well established due to use in cardiac arrhythmia treatment Use with caution in patients with advanced age, hepatic or renal dysfunction, or heart failure Consider monitoring plasma level if continued postoperatively Boysen PG et al. An Evidence-based opioid-free anesthetic technique to manage perioperative and periprocedural pain. Ochsner Journal 2018;18:121-125.

Dexmedetomidine Central alpha-2 adrenergic agonist Provides sedation (locus ceruleus) and analgesia (spinal cord) Reduces post-operative pain scores, opioid consumption, nausea and shivering without prolonging recovery time Minimal respiratory depression, preserves sleep architecture and airway patency Can cause bradycardia and hypotension (avoid rapid bolus) Dose: 1 mcg/kg over 10 minutes, followed by infusion of 0.2-0.7 mcg/kg/hr (based on IBW, can continue 24-48hr post-op) Sanchez 2017

Magnesium Anti-arrhythmic with NMDA receptor antagonist properties Anti-inflammatory effect due to reducing plasma interleukin 6 (IL- 6) and tumor necrosis factor- alpha (TNF-alpha levels postoperatively Can reduce pain scores and opioid requirements, synergistic with ketamine Potentiates neuromuscular blockade and can lower blood pressure (Ca channel blockade) but can stabilize heart rate variability Dose: 40-50mg/kg (IBW), followed by infusion of 5-10mg/kg/hr Forget 2017, Sultana 2017

Esmolol Ultra short-acting cardioselective beta adrenergic blocker Unclear mechanism but shown to decrease intraoperative nociceptive response, reduce postoperative opioid consumption (no change in pain scores), and recovery time in ambulatory surgery Dose dependent decrease in serum IL-6 and C-reactive protein (Kim et al, Surg Innov 2015) Shown to attenuate pain during propofol injection Dose: Intermittent boluses, consider 5-50 mcg/kg/min infusion Bahr MP et al, Reg Anesth Pain Med 2018

Supplemental truncal blocks Paravertebral block (PVB) Erector spinae plane block (ESPB) Transversus abdominus plane (TAP) block Quadratus lumborum (QL) block Rectus sheath block (RSB) Avoid IV lidocaine infusion if supplemental block or neuraxial local anesthetic used to avoid local anesthetic systemic toxicity (LAST)

Multimodal approach Acetaminophen NSAIDs Gabapentinoids Dexamethasone Ketamine IV lidocaine Dexmeditomidine Magnesium Esmolol Regional techniques Peripheral nerve blocks, +/- perineural catheter Truncal blocks (PVB, ESB, TAP, Rectus sheath, QL) Neuraxial techniques Epidural, spinal

OFA Results 30 obese patient randomized to receive sevoflurane with fentanyl or sevoflurane with non-opioid regimen (ketorolac, clonidine, lidocaine, ketamine, magnesium and methylprednisolone) OFA produced non-inferior pain relief and less sedation within first 16 hours post-op Fentanyl use in recovery room 5.2 +/- 2.6mg/hr in OFA vs 7.8 +/- 3.3 mg/hr in opioid GA group (P<0.05)

OFA Results 155 cases of OFA from 2016-2018 for elective colon resections after ERAS implementation Utilized pre-op patient education, pre-emptive analgesia, ketamine based non-opioid GA, liposomal bupivacaine nerve block, post-op scheduled nonopioid analgesics 83% of patients required NO post-op opioids Patient satisfaction and patients perception of pain control were improved

OFA Protocols 1. Pre-op: midazolam 2-4mg IV 2. Induction: propofol 1-2.5mg/kg and NMBD of choice 3. Dexamethasone 4-10mg about 10 minutes after induction 4. Acetaminophen 1000mg IV about 20 minutes after induction 5. Ketorolac 30mg IV about 20 minutes prior to emergence 6. Ketamine 0.5 mg/kg bolus prior to incision 7. Dexmedetomidine 0.5 mcg/kg bolus over 10 min, followed by infusion of 0.1-0.3 mcg/kg/hr 8. Propofol infusion of 75-150 mcg/kg/min titrated to BIS 40-60

Who benefits from OFA? Not fully understood but consider in: Patients at risk for developing chronic post-surgical pain Patients at risk for developing PONV Patients with morbid obesity, +/- OSA

A paradigm shift Koepke EJ, Manning EL, Miller TE, et al. The rising tide of opioid use and abuse: the role of the anesthesiologist. Perioperative Medicine 2018;7:16.

Perioperative Management Pre-operative Identify risk factors for increased post-operative pain Review PMP for prior opioid prescriptions Patient education (set expectations) Intraoperative/post-operative Start with non-opioid based anesthesia/analgesia and only use low dose opioid sparingly as needed Post-operative Partner with surgeons to ensure safe and appropriate opioid discharge prescriptions (Taper, +/- intranasal naloxone)

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Learning objectives At the conclusion of this session, learners will be able to: 1) Review both the analgesic and non-analgesic effects of opioids in the perioperative setting 2) Describe available perioperative opioid sparing techniques 3) Discuss the role of the anesthesiologist in the climate of the opioid crisis

Summary Intraoperative opioids can lead to increased post-operative pain scores, opioid consumption, hyperalgesia and possibly persistent post-op pain Opioid free (or opioid sparing) general anesthesia is a safe option that can improve patient outcomes, provide analgesia and minimize opioid requirements and opioid adverse effects Anesthesiologists play a key role in helping address the opioid crisis

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Questions? Christine.Oryhan@virginiamason.org