12/14/2018. Disclosures. Buprenorphine. Drug-Receptor Interactions. Affinity

Transcription

1 ECHO Ontario Chronic Pain Bootcamp OPIOID CHALLENGE Buprenorphine/Naloxone: What and How? Friday, December 7, 2018 Disclosures Presenters: John Flannery & Andrew Smith Conflicts of Interest: None John Flannery, MD, FRCPC Medical Director of the Musculoskeletal Rehabilitation Program at Toronto Rehabilitation Institute Andrew J Smith, MDCM Medical Lead, Interprofessional Pain and Addiction Recovery Clinic Staff Physician, Neurologist, Pain and Addiction Medicine Centre for Addiction and Mental Health, Toronto Buprenorphine Partial opioid agonist Ceiling effect Drug-Receptor Interactions Affinity Dissociation Dynamic nature of receptor regulation Bioavailability Activation Affinity The strength with which a drug physically binds to a receptor Buprenorphine has strong affinity; will displace full mu receptor agonists like heroin and methadone Receptor binding strength (strong or weak), is NOT the same as receptor activation Dissociation The speed of uncoupling from the receptor Buprenorphine dissociates slowly Occupies the receptor a long time and blocks newly introduced opioids (heroin, methadone, etc) from binding to those receptors 1

2 Mu Receptor Availability/Regulation Buprenorphine may reduce the effects of other opioids taken due to its high affinity for, and slow dissociation from, the mu receptor. However, buprenorphine is unlikely to block all effects from an opioid taken after initiation of buprenorphine treatment. Bioavailability Intravenous 98% Sublingual 44% Oral 10% This is because the availability of mu receptors is a dynamic process; while effects may be less, they are not likely to be completely eliminated. Receptor Activation Buprenorphine is a partial agonist How Buprenorphine Precipitates Withdrawal Displaces a full agonist from the mu receptors Only partially activates the receptors Resulting in net decrease in activation and rapid onset of withdrawal symptoms Formulations of Buprenorphine Parenteral: treatment of moderate to severe pain Transdermal patch: treatment of pain Sublingual tablets and films: treatment of Opioid Use Disorder; Off-Label Pain Management Implant : treatment of OUD Buprenorphine - Pharmacology Rapid absorption by buccal mucosa Slow release into bloodstream Peak plasma concentration in 1 4 hours Very low oral bioavailability due to first pass effect Can be abused intravenously (reason for naloxone) or intranasally Transmucosal route t1/ hr Agonist at delta -OR and OLR receptors 2

3 Buprenorphine - Pharmacology ORL-1 In brain- anti-analgesic effect in animals; dampens dopaminergic reward system At spinal level anti-nocicipetion Slows onset of opioid tolerance Agonism may be effective for treatment of neuropathic pain KAPPA-OR ANTAGONIST blocks dysphoric and psychotomimetic effects of K agonism Inhibition of voltage-gated Na channels Buprenorphine - Pharmacology Metabolized though hepatic CYP3A4 (primary), CYP2C8, CYP2C9 3 metabolites: norbup, norbup-3-glucuronide, bup-3-glucuronide Glucuronide-conjugated byproducts eliminated in feces by biliary excretion 4-6d after admin Minimal urinary excretion All analgesic EXCEPT norbup-3-gluc Norbup and norbup-3-gluc RESP DEPRESSION, SEDATION NOT so with bup and bup-3-glucuronide NB other meds that compete for metabolic parthways..eg benzos Hyperalgesia: Opioid-induced Pain Tolerance resistance to opioid Hyperalgesia hyperesthesia +/- allodynia anatomically distinct qualitatively different long- and short-term therapy desensitization down-regulation NMDA Dynorphin μ-opioidrc camp Journal of Pain Research 2015: Dose Dose Partial Agonist? Partial agonist = inability to produce the same level of effect as some reference full-agonist drug in a given situation What do we mean? Intrinsic activity biological stimulus imparted by drug to a receptor Efficacy level of drug-induced effect for a given outcome (manifested at a particular endpoint) eg ANALGESIA, RESP DEPRESSION BUP has low in vitro intrinsic activity as measured in several receptor binding assays PARTIAL AGONIST MONIKER Does BUP produce less effect compared to a reference drug? Partial Agonist? Morphine also produces <100% effect Bup acts at multiple receptors total analgesic effect results from activity at several receptors Bup displays > 98% noci efficacy in animal models PET scans of human brains show that full analgesia achieved with bup doses that occupy < 100% of opioid receptors Raffa et al. J. Clin Pharm and Therapeutics Raffa et al. J. Clin Pharm and Therapeutics

4 Buprenorphine Full Agonist Clinical Evidence Inclusion: human, within-study comparison of same pain type and with drugs commonly considered to be full agonists, quantification of pain severity or pain relief; comparison using the same pain scales EXCLUSION: non-human; use as part of a combination; use in opioid addiction (eg Suboxone) 24 clinical trials identified + 1 case report and 1 dose-response curve Based on complete or comparable pain relief, buprenorphine had full clinical analgesic efficacy in 25/26 of these studies Tiggerstedt et al (1980) im bup vs im morphone Post-op pain, Randomized, double-blind, multiple-dose, noncrossover trial 60pts p abdominal surgery Raffa et al. J. Clin Pharm and Therapeutics Buprenorphine? Ceiling Analgesic efficacy of iv buprenorphine Post-op over 24 hours 50 pts recovering from elective C-section Received bup in 0.2mg aliquots over 3-15 mins until pain relieved All px achieved complete analgesia with 0.4 7mg buprenorphine Budd K et al. Anaesthesia Potential Advantages of Buprenorphine in Chronic Pain Efficacy demonstrated in various pain conditions, comparable to full agonists Ceiling effect for respiratory depression Less development of tolerance via KAPPA antagonism, ORL agonism Antihyperalgesic effect Less effect on hypogonadism (ORT experience) Less immunosuppression compared with morphine and fentanyl (limited evidence preclinical and clinical) Ease of use un elderly and in renal impairment? Efficacy in neuropathic pain Buprenorphine: A Safe Ceiling Unlike full agonists, agonist effects of buprenorphine reach a ceiling 1 Less likely to cause respiratory depression in overdose Ceiling can be compromised by concomitant alcohol or other central nervous system depressants, or when buprenorphine is misused 1 Johnson RE, et al. Drug Alcohol Depend; Suboxone Product Monograph. Use of Buprenorphine with Alcohol and Other CNS Depressants Misuse of buprenorphine in combination with excessive use of alcohol or other CNS depressants CAN BE FATAL sedative effect of buprenorphine Dizziness, drowsiness, impaired thinking Can respiratory depression Limit use with benzodiazepines Death due to respiratory depression of central origin Tightly regulate benzodiazepine doses, especially where misuse is suspected Lintzeris N, et al. J Clin Psychopharmacol. 2006;26: Bup-Nal s/l for chronic pain AIM: systematic review of s/l bup for chronic pain ELIGIBILITY: cancer and noncancer pain using s/l bup and bup/nal EXCLUSION: acute pain, perioperative, opidep, opidep with pain, NAS, medically supervised w/d, non-s/l routes all excluded 10 studies met inclusion criteria ,190 px from US and Europe N: Duration: few days 8.8 months (2 didn t report duration) Cote J et al. Pain Medicine

5 Bup-Nal s/l for chronic pain ALL observational except 1 RCT 4 studies general chronic pain; others OA, SCD, nociceptive cancer pain, chronic pain in the elderly; pediatric chronic ca pain; chronic ca pain Manufacturer funding, provision of drug, or conflict of interest 5/10 trials 4 studies with prior opioid therapy MED up to 840mg/day 6 studies used initial low dose (<400ug) No trials deemed high quality evidence ALL Studies reported s/l bup demonstrated some effectiveness for analgesia in chronic pain Due to lack of high-quality trials there is insufficient evidence to determine effectiveness of s/l buprenorphine for the treatment of chronic pain NEEDS MORE HIGH-QUALITY TRIALS Cote J et al. Pain Medicine 2014 Chronic pain and buprenorphine Sublingual burprenorphine is effective in the treatment of chronic pain syndrome Herbert L. Malinoff, et al American Journal of Theraputics 12, (2005) Chronic pain and buprenorphine 95 patients referred from local pain clinics failed treatment Increased pain level Worse functional capacity Opioid addiction (8%) Rotated to sublingual Buprenorphine 4-16mg in divided doses Chronic pain and buprenorphine 86% reported moderate to substantial pain relief with improved mood and functioning 6 discontinued due to side effects or increased pain But. But. AIM: Evaluate effectiveness of conversion to Bup/Nal SL for patients with significant levels of persistent pain on high doses of full agonist opioid medication ( MEqD) Continuous or worsening pain despite opioid analgesia; MEq >200mg/day Remain on bup s/l after initial conversion for 60 days Conversion at home Primary outcome: reduction in self-reported pain after conversion to Bup/Nal S/L Secondary outcome: change in QOL Daitch D et al. Pain Medicine Daitch D et al. Pain Medicine

6 Daitch et al 2014 RESULTS: 51% reduction in pain score: (P <0.001) 34/35px reporting reduced pain QOL: (P= 0.005) Tolerance and poor analgesia with increasing doses of opioids may be exhibiting OIH Clinical experience: Many patients can and do begin to reduce dosage of bup/nal after 4-6 months of therapy post rotation Limitation: chart review with no control group Contraindications to Buprenorphine/Naloxone Pregnancy (Beta HCG) Allergy Severe liver dysfunction Acute severe respiratory illness Decreased level of consciousness Paralytic ileus Inability to provide informed consent Possibly elevated transaminases beyond 3-5x ULN Buprenorphine/Naloxone for Opioid Dependence: Clinical Practice Guideline. Handford, et al, 2010 Prior to induction Structured approach Ability to stabilize as rapidly as possible Avoiding oversedation and precipitated withdrawal Informed consent Tips Discourage Friday induction UDT Beta HCG Driving restrictions Buprenorphine/Naloxone for Opioid Dependence: Clinical Practice Guideline. Handford, et al, 2010 Induce rapidly Rapid induction is key to early treatment retention Titrate doses rapidly according to clinical response 1 Suboxone Product Monograph. 2 Doran C, et al. Heroin Add & Rel Clin Probl; Change to product monograph August 2015: First day dose can be up to 12mg Induction Day Patient should arrive in moderate withdrawal Assess withdrawal symptoms using tool (eg, COWS 1 ) COWS score >12 indicates moderate withdrawal Physician monitors induction to ensure the patient Is in moderate withdrawal Is taking medication appropriately (or pharmacist) Is having any withdrawal symptom properly managed COWS=Clinical Opiate Withdrawal Scale. 1. Wesson DR, Ling W. J Psychoactive Drugs. 2003;35(2): Buprenorphine/Naloxone for Opioid Dependence: Clinical Practice Guideline. Handford, et al,

7 Induction Dosing Induction Day (cont) Day 1 target Buprenorphine/Naloxone dose: 4 to 8 mg (now up to 12mg) 1 Administer 2-4 mg; monitor efficacy and adverse effects 2 Have patient wait for dose to take effect 1 to 2 hours after first dose Reassess the patient s withdrawal symptoms (COWS) Administer another 2-4 mg depending on the individual patient s requirement Departure from office Follow-up appointment is scheduled for the next day (or 2) Patient leaves with Prescription for additional dose of buprenorphine Prescription for any symptom-specific adjunctive medications Physician s after-hours contact information (or have patients contact #) 1. SUBOXONE Product Monograph. Scarborough, ON: Reckitt Benckiser Pharmaceuticals Limited, April Doran C et al. Heroin Addict Rel Clin Probl. 2005;7(1):7-18 Buprenorphine/Naloxone for Opioid Dependence: Clinical Practice Guideline. Handford, et al, 2010 Who to consider starting on a lower dose? Abstinent for a significant time Codeine users Past sensitivity to buprenorphine Thank you! 7