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

Christine Oryhan, MDVirginia Mason Medical Center

WSSA/BCAS Joint Winter MeetingDecember 8th, 2018

How to Administer an Opioid-Free General Anesthetic

© 2014 Virginia Mason

Disclosures• I have no disclosures.


Learning objectivesAt 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

Effects

Mu1 Euphoria, supraspinal analgesia, confusion, dizziness, nausea

Mu2 Respiratory depression, cardiovascular depression, constipation, miosis, urinary retention

Delta Spinal analgesia, cardiovascular depression, decreased brain and myocardial oxygen demand

Kappa Spinal analgesia, dysphoria, psychomimetic effects, feedback inhibition of endorphin system




Effects


Mu2 Respiratory depression, cardiovascular effects, constipation, miosis, urinary retention






Effects








Effects





ImmunosuppressionAcute toleranceOpioid induced hyperalgesiaEffect on malignancy/metastasis?

Sexual dysfunctionDepressionDecreased energyObesity?


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

• 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 post-

operatively– Resulted in permanent brain damage

or death– Were deemed preventable

Primary mechanism of opioid-related fatality


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 effectsDesirable• 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 Anaesth2012)

• 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 Anaesth2011)

• 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 post-operatively 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 post-operatively

• 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/hrForget 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 non-opioid 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 IV2. Induction: propofol 1-2.5mg/kg and NMBD of choice3. Dexamethasone 4-10mg about 10 minutes after induction4. Acetaminophen 1000mg IV about 20 minutes after induction5. Ketorolac 30mg IV about 20 minutes prior to emergence6. Ketamine 0.5 mg/kg bolus prior to incision7. Dexmedetomidine 0.5 mcg/kg bolus over 10 min, followed by

infusion of 0.1-0.3 mcg/kg/hr8. 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 objectivesAt 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


References• 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.• Manchikanti L, Helm SI, Fellows B, et al. Opioid epidemic in the United States. Pain Physician 2012;15(3):ES9-ES38.• Kessler ER, Shah M, Gruschkus SK, et al. Cost and quality implications of opioid-based postsurgical pain control using administrative claims

data from a large health system: opioid-related adverse events and their impact on clinical and economic outcomes. Pharmacotherapy 2013;33(4):383-91.

• Stanley TH. The fentanyl story. The Journal of Pain 2014;15(12):1215-1226.• Forget P. Opioid-free anaesthesia. Why and how? A contextual analysis. Anaesthe Crit Care Pain Med 2018;in press.• Richebe P, Capdevila X, Rivat C. Persistent postsurgical pain: Pathophysiology and preventative pharmacologic considerations.

Anesthesiology 2018;129:590-607.• van Gulik L, Ahlers SJ, van de Garde EM, et al. Remifentanil during cardiac surgery is associated with chronic thoracic pain 1 yr after

sternotomy. Br J Anaesth 2012; 109:616–22.• Cox BM, Ginsburg M, Osman OH. Acute tolerance to narcotic drugs in rats. Br J Pharmacol 1968;33:245-56.• Vinik HR, Kissin I. Rapid development of tolerance to analgesia during remifentanil infusion in humans. Anesth Analg 1998;86:1307-11.• Lee LA, Caplan RA, Stephens LS, et al. Postoperative opioid-induced respiratory depression: a closed claims analysis. Anesthesiology

2015;122(3);659-665.• Lavand’homme P, Steyaert A. Opioid-free anesthesia opioid side effects: Tolerance and hyperalgesia. Best Prac & Res Clin Anaesth 2017;487-

498.• Fletcher D, Martinez V. Opioid-induced hyperalgesia in patients after surgery: a systemic review and a meta-analysis. Br J Anaesth

2014;112(6):991-1004.• Angst MS. Intraoperative use of remifentanil for TIVA: postoperative pain, acute tolerance, and opioid-induced hyperalgesia. J Cardiothorac

Vasc Aaesth 2015;29(suppl 1):516-22.• Chia YY, Liu K, Wang JJ, et al. Intraoperative high dose fentanyl induces postoperative fentanyl tolerance. Can J Anaesth 1999;46(9):872-7.• Pavlin DJ, Chen C, Penaloza DA, et al. Pain as a factor complicating recovery and discharge after ambulatory surgery. Anesth Analg

2002;95:627-34.


References• Jibril F, Sharaby S, Mohamed A, Wilby KJ. Intravenous versus oral acetaminophen for pain: systematic review of current evidence to support

clinical decision making. Can J Hosp Pharm 2015;68(3):238-47.• Meng J, Li L. The efficiency and safety of dexamethasone for pain control in total joint arthroplasty: a meta-analysis of randomized controlled

trials. Medicine 2017;96(24):e7126.• Elia N, Lysakowski C, Tram r MR. Does multimodal analgesia with acetaminophen, nonsteroidal anti-inflammatory drugs, or selective

cyclooxygenase-2 inhimitors and patient-controlled analgesia porphine offer advantages over morphine alone? Anesthesiology 2005;103(6):1296-304.

• Mauermann E, Ruppen W, Bandschapp O. Different protocols used today to achieve total opioid-free general anesthesia without locoregional blocks. Best Pract Res Clin Anaesthesiol 2017; 31;533-45.

• Ziemann-Gimmel P, Goldfarb AA, Koppman J et al. Opioid-free total intravenous anaesthesia reduces postoperative nausea and vomiting in bariatric surgery beyond triple prophylaxis. Br J Anaesth 2014; 112: 906-11.

• Feld JM, Laurito CE, Beckerman M, Vincent J, Hoffman WE. Non-opioid analgesia improves pain relief and decreases sedation after gastric bypass surgery. Can J Anesth 2003;50(4):336-341.

• Nielsen RV, Fomsgaard JS, Siegel H, et al. Intraoperative ketamine reduces immediate postoperative opioid consumption after spinal fusion surgery in chronic pain patients with opioid dependency: a randomized, blinded trial. Pain 2017;158(3):463-470.

• Chang YC, Liu CL, Liu TP, Yang PS, Chen MJ, Cheng SP: Effect of perioperative intravenous lidocaine infusion on acute and chronic pain after breast surgery: A meta-analysis of randomized controlled trials. Pain Pract 2017;17:336-43.

• Boysen PG et al. An Evidence-based opioid-free anesthetic technique to manage perioperative and periprocedural pain. Ochsner Journal 2018;18:121-125.

• Forget P, Cata J. Stable anesthesia with alternative to opioids: Are ketamine and magnesium helpful in stabilizing hemodynamics during surgery? A systematic review and meta-analyses of randomized controlled trials. Best Pract Res Clin Anaesthesiol 2017;31:523-531.

• Sultana A, Torres D, Schumann R. Special indications for opioid free anaesthesia and analgesia, patient and procedure related: Including obesity, sleep apnoea, chronic obstructive pulmonary disease, complex regional pain syndromes, opioid addiction and cancer surgery. Best Pract Res Clin Anaesthesiol 2017;31:547-560.

• Sanchez Munoz MC, De Kock M, Forget P. What is the place of clonidine in anesthesia? Systemic review and meta-analyses of randomized controlled trials. J Clin Anesth 2017;38:140-53.

• Bahr MP, Williams BA. Esmolol, antinociception, and its potential opioid-sparing role in routine anesthesia care. Reg Anesth Pain Med 2018;43:815-818.


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