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Chronic Pain Management in the Perioperative Period Conflicts Rachael Rzasa Lynn, MD Chronic Pain Management in the Perioperative Period Conflicts • None Chronic Pain Management in the Perioperative Period Rachael Rzasa Lynn, MD Department of Anesthesiology University of Colorado School of Medicine Learning Objectives Learning Objectives • Develop management strategies for surgical • Develop management strategies for surgical patients taking buprenorphine patients taking buprenorphine • Understand the peri‐operative implications of • Understand the peri‐operative implications of common implantable devices for pain common implantable devices for pain • Develop a peri‐operative pain management • Develop a peri‐operative pain management plan for the chronic pain patient plan for the chronic pain patient Management of Patient on Chronic Pain Chronic Opioid Therapy • Why is it challenging? • Pain lasting >3 months or beyond the “normal – Tolerance and inadequate analgesia from standard opioid regimens time” of tissue healing • Fear of respiratory depression at high doses – Lower pain threshold among patients on chronic opioid therapy • Opioid‐induced hyperalgesia? – Fear of relapse if history of OUD • No evidence that exposure to opioids for acute pain increases relapse risk • In 2012, it was estimated that almost 40 – Has been suggested that the stress of uncontrolled pain may trigger relapse million Americans have persistent pain that – Concern about diversion occurs daily or on most days • Important part of pre‐operative evaluation includes Expectations – What is patient’s pre‐operative pain baseline? – 1 out of 5 patients with chronic non‐cancer pain is – What is patient’s target number? being treated with opioids • 0/10 is not a reasonable goal! • Focus on function (ambulation, PT, sleep) rather than # Nahin RL. Estimates of pain prevalence and severity in adults: United States, 2012. J Pain. 2015;16(8):769‐80. Dowell D, Haegerich TM, Chou R. CDC Guideline for prescribing opioids for chronic pain –United States, 2016. JAMA. 2016;315(15): 1624–1645. Rachael Rzasa Lynn, MD Chronic Pain Management in the Perioperative Period Rates of drug overdose deaths by state, Rates of drug overdose deaths by state, 2014 2015 Rate per 100,000 Rate per 100,000 https://www.cdc.gov/drugoverdose/data/statedeaths.html https://www.cdc.gov/drugoverdose/data/statedeaths.html Rates of drug overdose deaths by state, Opioid Overdose Deaths 2016 • The opioid prescribing rate has dropped since its peak in 2012, Rate per 100,000 but the rate of death due to opioid overdose is on the rise https://www.cdc.gov/drugoverdose/data/statedeaths.html Management of Patient with OUD Methadone • No RCTs of acute pain management in patients on • Long‐acting maintenance therapy for OUD – Half‐life is >1 day (15‐40 hours) • Has not actually been studied in opioid‐tolerant • Highly lipophilic patients, but it is widely recommended to use a multi‐ – High bioavailability (36‐100%) modal approach in such patients where opioids may be • Protein bound: α1‐acid glycoprotein • Metabolized by CYP450 inactive metabolites (fecal and renal ineffective clearance) – regional anesthesia • High inter‐individual variability! – NSAIDs or COX‐2 Inhibitors – 2 isomers – acetaminophen • R‐isomer is NMDA receptor antagonist – 40% of pain relief from methadone is via non‐opioid activity (ie, can’t – NMDA antagonists block with naloxone) – α2 agonists • S‐isomer is an agonist at mu and delta opioid receptors – anti‐convulsants – Binding at mu receptor prevents withdrawal, reduces craving – Causes tolerance that reduces euphoria with additional opioid use Sen (2016) (Goodman and Gilman Sen S, Arulkumar S, Cornett EM, Gayle JA, Flower RR, Fox CJ, et al. New Pain Management Options for J Pain Symp Mgmt 28(5):497‐504, 2004 the Surgical Patient on Methadone and Buprenorphine. Curr Pain Headache Rep. 2016;20(3):16. *** Rachael Rzasa Lynn, MD Chronic Pain Management in the Perioperative Period Methadone: Perioperative Methadone Management • Variable • morphinemethadone ≠ • Continue daily dose before, during and after surgery opioid methadonemorphine – Verify correct dose with prescribing physician – • Conversions for chronic opioid use: If cannot take daily PO methadone post‐op, can give IV: conversion • Given high but wide‐ranging bioavailability (30‐100%), variable • Higher doses 101‐ 301‐ 601‐ 801‐ pharmacokinetics, use 2:1 ratio for oral:IV MED/day <100 300 600 800 1000 >1001 – May need to escalate to 3:2, 1:1 or even 1:2 of chronic – Best to divide parenteral dose into BID to QID MED:methadone opioid 3:1 5:1 10:1 12:1 15:1 20:1 • Rapid onset IV (4 min) despite long half‐life equivalent to Methadone Factor – Commonly held that duration of analgesic effect is 8hr vs 24hr dosing for OUD maintenance/withdrawal avoidance less Up to 20 mg/day 4 methadone/ • Thus may divide single daily dose into TID to help with pain 21‐40 mg/day 8 • Pharmacokinetics suggest that a single large dose (>20mg IV) MED than 41‐60 mg/day 10 provides a prolonged analgesic effect (but in opioid‐naïve patients) – Relationship between elimination half‐life and effect depends on dose lower doses >60 mg/day 12 http://www.agencymeddirectors.wa.gov/MethadoneFactors.asp Anesth Analg. 2011 Jan; 112(1): 13–16 Journal of Community Hospital Internal Medicine Perspectives. 2012;2(4):10.3402/jchimp.v2i4.19541. Ther Clin Risk Manag. 2017;13:1163‐73 Methadone Pharmacokinetics: Pharmacokinetics: Dose and duration of analgesic effect Big dose/long interval vs Small dose/short interval 60mg dose 20mg dose No No No pain pain pain relief relief relief Kharasch, E. D. (2011). Intraoperative methadone: Rediscovery, reappraisal, and Holford NG. Pharmacokinetics & Pharmacodynamics: Rational Dosing & the Time Course of Drug Action. reinvigoration? Anesthesia and Analgesia, 112(1), 13–16. In: Katzung BG. eds. Basic & Clinical Pharmacology, 14eNew York, NY: McGraw‐Hill Buprenorphine Buprenorphine • Growing in use with the rise in OUD • 33 times as potent at morphine (IV to IV) – Antagonist at kappa‐opioid receptors – Buprenorphine prescriptions increased from • May be involved in efficacy in opioid‐induced hyperalgesia, but this 48,000 in 2003 1.9 million in 2007 phenomenon only studied in healthy volunteers – Partial agonist at mu‐opioid receptors >9 million in 2012 and 2013 • High affinity for the receptor: binds tightly, but doesn’t activate fully – Slow dissociation (t1/2= 166 min vs 7min for fentanyl; 50% by 1 hr vs 100% by 1 hr) plasma levels may not parallel clinical effects • Less respiratory depression – Why? • Ceiling effect (no increase in agonist effects at dose >32mg/day) – 16mg SL occupies 79‐90% of μ‐opioid receptors but doses >24‐32mg do not result in greater opioid effect despite >95% receptor occupancy – Reduced risk of respiratory depression vs full μ‐opioid receptor agonists • Can precipitate withdrawal in opioid dependent patient https://www.deadiversion.usdoj.gov/drug_chem_info/buprenorphine.pdf. Am J Psychiatry. 2007; 164:979. Drug Alcohol Depend. 2009; 99: 345‐349. Br J Anaesth. 1985;57(2):192‐6. Acta Anaesthesiol Scand. 1980;24(6):462‐8. Rachael Rzasa Lynn, MD Chronic Pain Management in the Perioperative Period Buprenorphine Buprenorphine • Long half‐life, highly variable (24‐60 hours) • 30‐35% bioavailable SL but high first‐pass – 20‐30 hours (buccal, transdermal or SL) vs 3‐5 hepatic metabolism when taken orally hours IV – Hepatic metabolism by CYP450 to active • Used as maintenance therapy for OUD, most metabolite, norbuprenorphine (20% of parent commonly SL: compound activity) – Subutex or Suboxone (buprenorphine:naloxone in • Renal clearance of metabolites, but most drug is 4:1 ratio) film excreted unchanged in feces – Relatively easy to get a Waiver to rx for OUD – Can be prescribed for chronic pain with “opioid dependence” https://www.deadiversion.usdoj.gov/drug_chem_info/buprenorphine.pdf. Am J Psychiatry. 2007; 164:979. Drug Alcohol Depend. 2009; 99: 345‐349. Br J Anaesth. 1985;57(2):192‐6. Acta Anaesthesiol Scand. Sen 2016. Walter and Inturrisi, 1995. Anderson, 2017. Johnson, 2005. Palliat Ved 20:S17‐S23 (2006) 1980;24(6):462‐8. Goodman and Gilman Buprenorphine for Pain Buprenorphine Induction • Butrans • Belbuca • Patient must be in withdrawal from chronic – transdermal patch – buccal film opioid use: – 5‐20mcg/hr dose – 75‐900mcg – Patch worn for 7 days • Bioavailability 46‐51% – “first dose of buprenorphine SL should only be • Mean C 1200mcg 1.43+‐ administered when objective and clear signs of • Single application Cmax for max 20mcg/hr patch 0.48ng/ml 0.45ng/mL moderate opioid withdrawal appear, and not less • Steady state achieved after – Once to twice daily than 4 hours after the patient last used an opioid.” 3 days • T1/2 4‐15 hours (Subutex website) • For 10mcg/hr patch, steady – Must taper to ≤30mg MED state C 0.2ng/ml max • “may not provide adequate • 24 hours if using long‐acting opioid like methadone – Must taper to ≤30mg MED analgesia” for patients – 8‐16mg/day is approximately equivalent to • “may not provide adequate requiring >160 mg analgesia” for patients MED/day methadone 60mg/day requiring >80 MED/day Drug Alcohol Depend. 2003;70(2 Suppl):S59‐77. https://www.accessdata.fda.gov/drugsatfda_docs/label/2015/207932s000lbl.pdf https://www.suboxone.com/content/pdfs/SUBUTEX_Prescribing_Information.pdf Buprenorphine: perioperative Buprenorphine challenges • In non‐opioid‐tolerant • High affinity, only partial agonism acute pain patients, low doses of BUP difficult to treat with other opioids produce analgesia like a full • Case reports mu‐agonist – 47 y/o
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