Learning Objectives. Case Example. From Coke to Pepsi or a cocktail? Rotating and adding opioids in advanced pediatric pain medicine

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1 From Coke to Pepsi or a cocktail? Rotating and adding opioids in advanced pediatric pain medicine Stefan J. Friedrichsdorf, MD, FAAP Associate Professor of Pediatrics, University of Minnesota Medical School Medical Director, Department of Pain Medicine, Palliative Care & Integrative Medicine, Children's Hospitals and Clinics of Minnesota, Minneapolis/St. Paul, MN Simon A. Cohen, BSc MBChB MRCPCH (UK) FRACP FFPMANZCA Paediatric Pain Consultant, Monash Children s Hospital, Melbourne Chief Medical Officer, Very Special Kid s hospice, Melbourne Stefan.Friedrichsdorf@ChildrensMN.org Simon.cohen@monashhealth.org Learning Objectives Case Example [ hook ] Discuss indications for and misconceptions about opioid conversion [ attitude ] Review cross-tolerance and rationale for opioid rotation and combining Opioids [ knowledge ] Practice examples for opioid conversion [ skill ] Case Example Andrea is a 10-year-old girl in severe acute pain (VAS 8/10) due to metastasized osteosarcoma; weight: 20 kgs Andrea has been started on morphine 3 days ago - now the nurse calls you that she is poorly arousable, respiratory rate 9/min, oxygen saturation 82% when eyes closed What might be your next questions & steps? Over sedation Over sedation => good analgesia? => poor analgesia?

2 Management of Opioid Adverse Effect Over Sedation reduction If good analgesia Opioid rotation If poor analgesia and/or medium-severe side effects Adverse effect targeted therapy What arguments might you hear from parents, patients or colleagues/care team NOT to rotate the opioid? If mild side effects or opioid rotation not possible Analgesic Response Patients differ in their response to opioid analgesics Even in well designed, successful clinical trials, as much as 40% of patients do not respond well to analgesic being studied Argoff CE, Yanni LM. Pharmacogenetics and pain. Prim Care Q 2010;1-8 Unsurprising, patients may require trials of several opioids to find effective analgesia with acceptable tolerability μ-receptor Subtypes Individuals display variety of combinations of different mureceptor subtypes Generated through alternative splicing, known to enhance protein diversity Binding profiles & resulting pharmacologic effects of opioid receptor subtypes vary among μ-opioids dimer of μ receptors. Credit: Kobilka lab Contributing to individual variance in therapeutic response & incomplete cross-tolerance Review Brennan MJ. The clinical implications of cytochrome p450 interactions with opioids and strategies for pain management. Journal of Pain and Symptom Management Dec;44(6 Suppl):S15-22.

3 Cross-tolerance Tolerance: Decrease in drug effect as result to prior exposure to the drug (for analgesia and/or adverse effect) Cross-tolerance (between two opioids): Phenomenon whereby tolerance to a particular opioid effect from an existing opioid is conferred to a newly substituted opioid Effect: complete or incomplete Symmetric, asymmetric or unidirectional Review Friedrichsdorf SJ: From Coke to Pepsi to Mountain Dew? Rotating Opioids in Advanced Pediatric Palliative Care. AAHPM Winter Quarterly Clinical Pearls (4):8-9 Opioid tolerance: Nonpharmacodynamic factors Pain related Disease progression or infection at tumor site Impact of other therapies and adjuvant drugs Pharmacokinetic Absorption of opioid - change of route of administration Drug interactions Drug biotransformation and metabolism Antinociceptive metabolites (e.g. morphine-6-glucoronide) Nociceptive metabolites (e.g. morphine-3-glucoronide) Renal function Pharmacogenetics Behavior/psychological state Somatization, psychological distress Cognitive Status; delirium Switching Opioids Differences between opioids in the balance between analgesic cross-tolerance level and the level of cross-tolerance to adverse effects can be exploited to clinical advantage. Switching opioids can possibly achieve a more favorable balance between analgesia and adverse effects, hence the rationale for trial of a different opioid in the event of toxicity or inadequate analgesia. Lawlor P (2001) Ratios Among Different Opioids. In: Bruera E, Portenoy RK (ed) Topics in Palliative Care Vol 5; Oxford University Press, pp Analgesia Side effects Side effects Analgesia

4 Adding and Mixing Opioids Perceived Efficacy of Analgesic Drug Regimens Used for Koalas (Phascolarctos cinereus) in Australia De Kauwe T, Kimble B, Govendir M Journal of Zoo and Wildlife Medicine 2014 Jun;45(2): Analgesic drug combinations were generally thought efficacious CH3 N 8 CH3 N O CH3CH2CN N CH2CH2 HO 3 O 6 7 OH O CH3CO 3 O 6 O OCCH3 Heroin CH3 HO O N HO O O OH OH COOH CH 3CH 2 O C C CH 2 CH 3 CH N CH CH Glucuronide Methadone

5 Synergy between Opioid Ligands: Evidence for Functional Interactions among Opioid Receptor Subtypes ELIZABETH A. BOLAN, RONALD J. TALLARIDA, and GAVRIL W. PASTERNAK The journal of pharmacology and experimental therapeutics 303: , 2002 Vol. 303, No. 2 Synergy between Opioid Ligands: Evidence for Functional Interactions among Opioid Receptor Subtypes ELIZABETH A. BOLAN, RONALD J. TALLARIDA, and GAVRIL W. PASTERNAK The journal of pharmacology and experimental therapeutics 303: , 2002 Vol. 303, No. 2

6 British Journal of Cancer (2003) 89, & 2003 Cancer Research UK All rights reserved /03 $ Comparison of sustained-release morphine with sustained-release oxycodone in advanced cancer patients Support Care Cancer (2004) 12: DOI /s O R I G I N A L A R T I C L E Sebastiano Mercadante Patrizia Villari Patrizia Ferrera Alessandra Casuccio Addition of a second opioid may improve opioid response in cancer pain: preliminary data Clinical Therapeutics/Volume 34, Number 8, 2012 Analgesic Efficacy and Tolerability of Intravenous Versus Combined Intravenous and Oxycodone in a 2-Center, Randomized, Double-Blind, Pilot Trial of Patients With Moderate to Severe Pain After Total Hip Replacement Robin Joppich, MD 1, *; Patricia Richards, MD, PhD 2, *; Robin Kelen, MS, RN 2 ; 2 4 4

7 Analgesic and adverse effects of a fixed-ratio morphine-oxycodone combination (MoxDuo ) in the treatment of postoperative pain Patricia Richards, MD, PhD; Dennis Riff, MD; Robin Kelen, RN; Warren Stern, PhD; for the MoxDuo Study Team Journal of Opioid Management 7:3 May/June 2011

8 Take Home Messages Combining Opioids May cause analgesic synergy Unlikely to increase side effects Useful manoeuvre to employ as part of a multimodal therapy Opioid Rotation (at equianalgesic doses!)... eminence, not evidence based... Gold Standard : Route of administration: Oral (sublingual, rectal) Route of administration: Intravenous (subcutaneous) Oxycodone Hydromorphone Methadone Hydromorphone Methadone Problems with Equianalgesic Tables? (Real life example) 10 mg IV = 1.5 mg Hydromorphone? 1.5 mg Hydromorphone = 10 mg IV? 50 mcg/hour [0.05mg] IV = 5 mg IV/hour????

9 Relative Potency Equianalgesic tables oversimplify, Lawlor P (2001) Ratios Among Different Opioids. In: Bruera E, Portenoy RK (ed) Topics in Palliative Care Vol 5; Oxford University Press, pp e.g. :Hydromorphone 5:1 or 7:1 M:HM => (median) HM:M => (median) Bruera E (1996) Cancer 78:852-7; Lawlor P (1997) Pain 72: And what is the difference between 1:7 and 7:1...???? Relative Potency Published experience: Hydromorphone : Davis MP, McPherson ML. Tabling hydromorphone: do we have it right?j Palliat Med Apr;13(4): Single dose: 1:7 Initial steady-state (PO/IV): 1:5 Long-term infusion: 1: 3.5 Problems with Equianalgesic Tables Tremendous inter-individual variability in relative potency estimates Tolerance development with repetitive dosing: reduction 25-75% for incomplete cross-tolerance often inadequately portrayed No account for unidirectional crosstolerance No account for possibility of active metabolite accumulation Assumption that relative potency ratios remains irrespective of level of opioid

10 Schechter NE, Berde CB, Yaster M (eds) (2003): Pain in Infants, Children, and Adolescents, 2nd ed., Lippincott Williams & Wilkins, p.850 Suggested Opioid Conversion The rough (!) guide Oxycodone PO 3:1 3mg PO = 1mg IV 1 : 2 1mg IV = 2 mg PO Oxycodone PO 1.5 : 1 3 mg PO = 2 mg PO Oxycodone PO 5 : 1 5 mg PO = 1 mg PO Hydromorphone Hydromorphone PO 5 : 1 5mg PO = 1mg IV 1 : 1 3 mg PO Oxycodone = 3 mg PO 1 : 4 1 mg PO Hydromorphone = 4 mg PO 1 : mg IV = 3.5 mg PO Hydromorphone IV 3 : 1 3mg PO = 1mg IV 1 : 5 1 mg IV Hydromorphone = 5 mg IV I.V. I.V. Intravenous I.V. I.V. 1 : 3 1mg IV = 3 mg PO PO Clinical Context Incomplete Cross Tolerance: Decrease dose by (0-33% -) 50% (or more?) 7 : 1 7 mg IV = 1 mg IV Hydromorphone Hydromorphone IV IV 1 : mcg IV = 1000 mcg [1mg] IV Infants 1 : mcg IV = mcg [ mg) IV 40 : 1 1 mg [1000 mcg] IV = 25 mcg IV IV Friedrichsdorf SJ: 8th Pediatric Pain Master Class, Minneapolis, MN, June 20-26, 2015 Case Example [Conversion IV:IV] Andrea is a 10-year-old girl in severe pain (VAS 8/10) due to metastasized osteosarcoma; weight: 20 kg; now on morphine PCA Continuous Infusion (Basal Rate): 0.4 mg/hr -> 0.6mg/hr -> 0.9 mg/ hr -> 1.3 mg/hr PCA : 0.4 mg -> 0.6 mg -> 0.9 mg -> 1.3 mg (Lock out: 10 min; 4 Boluses/hr) Received 7 Boluses/24 hr [count or not count...?] Over sedation => good analgesia? Over sedation => poor analgesia?

11 Case Example [Conversion IV:IV] PCA Continuous Infusion (Basal Rate): 1.3 mg/hr (= 1300 mcg/hr) [M:F = 40:1] 1300 mcg/hr 65 mcg/kg/hr / mcg/hr 1.6 mcg/kg/hr 0% reduction 32 mcg PCA Bolus Lockout 5-10 min, max 4-6/hr 33 % reduction 21 mcg/hr 1 mcg/kg/hr 21 mcg PCA Bolus Lockout 5-10 min, max 4-6/hr... reduction...? Clinical Context Incomplete Cross Tolerance: Decrease dose by (0-33% -) 50% (or more?)...it depends... Case Example [Conversion IV:IV] PCA Continuous Infusion (Basal Rate): 1.3 mg/hr (= 1300 mcg/hr) Hydromorphone [M:H = 7:1] 1.3 mg/hr 65 mcg/kg/hr / mg/hr Hydromorphone 9 mcg/kg/hr 0% reduction 0.19 mg PCA Bolus Lockout 7 min, max 6/hr 50 % reduction 0.1 mg/hr Hydromorphone 4.5 mcg/kg/hr 0.1 mg PCA Bolus Lockout 7 min, max 6/hr

12 Case Example [Conversion IV:PO] Andrea is comfortable (VAS 1/10) on her PCA and would like to go home without being hooked up to an infusion pump. Current settings: Hydromorphone PCA Basal Rate: 0.45 mg/hr [22 mcg/kg/hr] PCA bolus: 0.45 mg [18 boluses in last 24 hours] Total drug use: 0.45mg/hr x 24 hr = 10.8 mg/day 0.45mg x 18 boluses = 8.1 mg/day = 18.9 mg/day Case Example [Conversion IV:PO] 19 mg/day IV Hydromorphone => PO Hydromorphone Hydromorphone [IV:PO = 1:3.5] 19 mg/day IV Hydromorphone x mg/day PO Hydromorphone Rescue = 10% 50 % Reduction?? 33 mg/day PO Hydromorphone (not including PCA doses?) 11 mg PO Q4h 6.6 mg PO Q1-2qh PRN Case Example [Conversion IV:PO] 19 mg/day IV Hydromorphone => PO Oxycodone 19 mg/day IV Hydromorphone x 5 95 mg/day IV 190 mg/day PO Oxycodone x mg/day PO / % reduction 95 mg/day PO Oxycodone Rescue = 10% 22.5 mg PO Q6h Oxycodon [or 50 mg Q12h extendedrelease] 10 mg PO Q1-2h PRN Oxycodon immediate release

13 Case Example [Conversion IV:Transmucosal] 19 mg/day IV Hydromorphone => Patch 19 mg/day IV Hydromorphone x 5 95 mg/day IV 99 mcg/hr IV / mcg/day IV / % reduction 50 mcg/hr transdermal Q48-72h 50 mcg/hr IV Rescue = 10% Hydromorphone 6.5 mg PO Q1-2h PRN or lozenge? Andrea would like to thank you for your excellent opioid analgesia management. Spinal Opioids Epidural: IV Opioid Ratios: 1:10 [0.1 mg/hr epidural = 1 mg/hr IV] 1:3 [10 mcg/hr epidural = 30 mcg/hr IV] Hydromorphone 1:3 [0.1 mg/hr epidural = 0.3 mg/hr IV] Intrathecal: IV Opioid Ratios: 1:100 [0.01 mg/hr intrathecal = 1 mg/hr IV] 1:30 [1 mcg/hr intrathecal = 30 mcg/hr IV] Hydromorphone 1:30 [0.01 mg/hr intrathecal = 0.3 mg/hr IV] (Edmonton, Alberta, Canada)

14 Questions? Comments? Your cases, please! Online Narcotic Converter Appropriate for pediatrics? NOT for fentanyl! narcoticonv.htm Conclusions Children usually sleep well... once pain is finally well controlled prepare parents & bed-side nurses (but rule out over sedation) If medium-severe opioid-induced side effects: Opioid rotation at equianalgesic doses [minus reduction for incomplete crosstolerance] Don t manage severe opioidinduced side effects with medications rather rotate the opioid instead (if feasible) IV opioid administration is usually not better than oral administration (only faster) switch to oral administration once pain well controlled and child is eating and drinking Special Report on Children s Health Care in US Explaining Increased Need for Pediatric Pain Specialists

15 Further Training: 9th Annual Pediatric Pain Master Class Minneapolis, MN June 11-17, 2016 Education in Palliative & End-of-life Care [EPEC]: Become an EPEC- Pediatrics Trainer 8th Conference: Montevideo, Uruguay Sept 5, th Conference: Chicago, IL March 12-13, 2016 Stefan J. Friedrichsdorf, MD, FAAP Associate Professor of Pediatrics, University of Minnesota Medical School Medical Director, Department of Pain Medicine, Palliative Care & Integrative Medicine Children's Hospitals and Clinics of Minnesota 2525 Chicago Ave S Minneapolis, MN USA phone fax stefan.friedrichsdorf@childrensmn.org Blog: