From Coke to Pepsi or a cocktail? Rotating and adding opioids in advanced pediatric pain medicineStefan J. Friedrichsdorf, MD, FAAPAssociate Professor of Pediatrics, University of Minnesota Medical SchoolMedical 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 FFPMANZCAPaediatric Pain Consultant, Monash Children’s Hospital, MelbourneChief Medical Officer, Very Special Kid’s hospice, Melbourne

Stefan.Friedrichsdorf@ChildrensMN.org Twitter: @NoNeedlessPain

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 => good analgesia?

• Over sedation => poor analgesia?

Management of Opioid Adverse Effect “Over Sedation”

• Dose reduction

• If good analgesia

• Opioid rotation

• If poor analgesia and/or medium-severe side effects

• Adverse effect targeted therapy

• If mild side effects or opioid rotation not possible

• What arguments might you hear from parents, patients or colleagues/care team NOT to rotate the opioid?

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 mu-receptor subtypes

• Generated through “alternative splicing”, known to enhance protein diversity

• Binding profiles & resulting pharmacologic effects of opioid receptor subtypes vary among μ-opioids

• 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. 2012 Dec;44(6 Suppl):S15-22.

dimer of μ receptors. Credit: Kobilka lab

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 2014.15(4):8-9

Opioid tolerance: Non-pharmacodynamic 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) Dose Ratios Among Different Opioids. In: Bruera E, Portenoy RK (ed) Topics in Palliative Care Vol 5; Oxford University Press, pp

247-76

Analgesia

Side effects Analgesia

Side effects

Adding and Mixing Opioids

Perceived Efficacy of Analgesic Drug Regimens Used for Koalas (Phascolarctos

cinereus) in AustraliaDe Kauwe T, Kimble B, Govendir M

Journal of Zoo and Wildlife Medicine 2014 Jun;45(2):350-6.

‘Analgesic drug combinations were generally thought efficacious‘

7

8

Morphine

63

O

N

HO OH

CH3

Methadone

C CH2 CH

CH3

NCCH3

CH3

CH3CH2

O

CH2CH2N

CH3CH2CN

O

Fentanyl

63

Heroin

N

O OCCH3

CH3

CH3CO

OO

Morphine 6-Glucuronide

O

N

HO O

CH3

COOH

OHOHHO

O

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 303:557–562, 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 303:557–562, 2002 Vol. 303, No. 2

Comparison of sustained-release morphine with sustained-releaseoxycodone in advanced cancer patients

British Journal of Cancer (2003) 89, 2027 – 2030

& 2003 Cancer Research UK All rights reserved 0007 – 0920/03 $25.00

www.bjcancer.com

Support Care Cancer (2004) 12:762–766DOI 10.1007/s00520-004-0650-1 O R I G I NA L ART I C L E

Sebastiano MercadantePatrizia VillariPatrizia FerreraAlessandra Casuccio

Addition of a second opioidmay improve opioid response in cancer pain:preliminary data

Analgesic Efficacy and Tolerability of Intravenous MorphineVersus Combined Intravenous Morphine and Oxycodone in a2-Center, Randomized, Double-Blind, Pilot Trial of PatientsWith Moderate to Severe Pain After Total Hip Replacement

Robin Joppich, MD1,*; Patricia Richards, MD, PhD2,*; Robin Kelen, MS, RN2;2 4 4 †

Clinical Therapeutics/Volume 34, Number 8, 2012

Analgesic and adverse effects of a fixed-ratio morphine-oxycodonecombination (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

Take Home Messages Combining Opioids

• May cause analgesic synergy

• Unlikely to increase side effects

• Useful manoeuvre to employ as part of a multi-modal therapy

Opioid Rotation (at equi-analgesic doses!) ... “eminence”, not evidence based...

“Gold Standard”: Morphine

Route of administration:

Oral (sublingual, rectal)

Oxycodone

Route of administration:

Intravenous (subcutaneous)

Hydromorphone

Fentanyl

Hydromorphone

MethadoneMethadone

Problems with Equianalgesic Tables?

• 10 mg IV Morphine = 1.5 mg Hydromorphone?• 1.5 mg Hydromorphone = 10 mg IV Morphine?• 50 mcg/hour [0.05mg] IV Fentanyl = 5 mg IV/hour Morphine????

(Real life example)

Relative Potency

• Equianalgesic tables oversimplify, Lawlor P (2001) Dose Ratios Among Different Opioids. In: Bruera

E, Portenoy RK (ed) Topics in Palliative Care Vol 5; Oxford University Press, pp 247-76 e.g.

• Morphine:Hydromorphone 5:1 or 7:1

• M:HM => (median) 5.0 - 5.3

• HM:M => (median) 3.6 - 3.7

Bruera E (1996) Cancer 78:852-7; Lawlor P (1997) Pain 72:79-85

• ...And what is the difference between 1:7 and 7:1....????

Relative Potency

Published experience: Hydromorphone : Morphine Davis MP, McPherson ML. Tabling hydromorphone: do we have it right?J Palliat Med. 2010 Apr;13(4):365-6.

• 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: Dose reduction 25-75% for incomplete cross-tolerance often inadequately portrayed

• Assumption that relative potency ratios remains irrespective of level of opioid

• No account for unidirectional cross-tolerance

• No account for possibility of active metabolite accumulation

Schechter NE, Berde CB, Yaster M (eds) (2003): Pain in Infants, Children, and Adolescents, 2nd ed., Lippincott Williams & Wilkins, p.850

I.V.Morphine

I.V.Morphine

IntravenousMorphine

I.V.Morphine

I.V.Morphine

Morphine PO

Oxycodone PO

Hydromorphone IV

Hydromorphone PO

Oxycodone PO

Morphine PO

Fentanyl IV

Friedrichsdorf SJ: 8th Pediatric Pain Master Class, Minneapolis , MN, June 20-26, 2015

3:13mg PO = 1mg IV

3 : 13mg PO = 1mg IV

1.5 : 13 mg PO Morphine

= 2 mg PO Oxycodone

5 : 15mg PO = 1mg IV

1 : 3.51 mg IV = 3.5 mg PO

1 : 51 mg IV Hydromorphone

= 5 mg IV Morphine

1 : 4025 mcg IV Fentanyl

= 1000 mcg [1mg] IV Morphine

Infants 1 : 13-2025 mcg IV Fentanyl = 325 - 500 mcg

[0.3 - 0.5 mg) IV Morphine

1 : 21mg IV = 2 mg PO

1 : 31mg IV = 3 mg PO

7 : 17 mg IV Morphine =

1 mg IV Hydromorphone Hydro-morphone IV

Fentanyl IV

40 : 11 mg [1000 mcg] IV Morphine

= 25 mcg IV Fentanyl

Clinical ContextIncomplete Cross Tolerance:

Decrease dose by (0 - 33% -) 50% (or more?)

1 : 13 mg PO Oxycodone= 3 mg PO Morphine

5 : 15 mg PO Morphine

= 1 mg PO Hydromorphone

1 : 41 mg PO Hydromorphone

= 4 mg PO Morphine

Suggested Opioid Conversion “The rough (!) guide”

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 Dose: 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?

Morphine PCAContinuous Infusion (Basal Rate): 1.3 mg/hr (= 1300 mcg/hr) Fentanyl [M:F = 40:1]

1300 mcg/hrMorphine65 mcg/kg/hr

/ 4032 mcg/hrFentanyl

1.6 mcg/kg/hr 0% Dose reduction

32 mcg PCA Bolus

Lockout 5-10 min, max 4-6/hr

33 % Dose reduction 21 mcg/hr

Fentanyl1 mcg/kg/hr

21 mcg PCA Bolus

Lockout 5-10 min, max 4-6/hr

Case Example [Conversion IV:IV]

...Dose reduction...?

Clinical ContextIncomplete Cross

Tolerance: Decrease dose by

(0 - 33% -) 50% (or more?)

...it depends...

Morphine PCAContinuous Infusion (Basal Rate): 1.3 mg/hr (= 1300 mcg/hr)

Case Example [Conversion IV:IV]

Hydromorphone [M:H = 7:1]

1.3 mg/hrMorphine65 mcg/kg/hr

/ 70.19 mg/hr

Hydromorphone9 mcg/kg/hr

0% Dose reduction0.19 mg

PCA Bolus Lockout 7 min, max 6/hr

50 % Dose reduction 0.1 mg/hr

Hydromorphone4.5 mcg/kg/hr

0.1 mgPCA Bolus

Lockout 7 min, max 6/hr

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 IVHydromorphone x 3.5

66.5 mg/day POHydromorphone

33 mg/day POHydromorphone

(not including PCA doses?)

11 mgPO Q4h

50 % Dose Reduction??

RescueDose= 10%

6.6 mgPO Q1-2qh PRN

Case Example [Conversion IV:PO] 19 mg/day IV Hydromorphone=> PO Oxycodone

19 mg/day IVHydromorphone x 5

95 mg/day IVMorphine

95 mg/day POOxycodone

50 % Dose reduction

RescueDose= 10%

10 mg PO Q1-2h PRN

Oxycodon immediate release

x 3285 mg/day PO

Morphine

190 mg/day POOxycodone

/ 1.5

22.5 mg PO Q6hOxycodon

[or 50 mg Q12h extended-release]

Case Example [Conversion IV:Transmucosal] 19 mg/day IV Hydromorphone=> Fentanyl Patch

19 mg/day IVHydromorphone x 5

95 mg/day IVMorphine

50 mcg/hr IVFentanyl

50 mcg/hrtransdermal

Fentanyl Q48-72h

50 % Dose reduction

RescueDose= 10%

Hydromorphone 6.5 mg PO Q1-2h PRN

or Fentanyl lozenge?

/ 402375 mcg/day IV

Fentanyl

99 mcg/hr IVFentanyl

/ 24

Andrea would like to thank you for your excellentopioid analgesia management.

Spinal OpioidsEpidural: IV Opioid Ratios:Morphine 1:10 [0.1 mg/hr epidural = 1 mg/hr IV]

Fentanyl 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:Morphine 1:100 [0.01 mg/hr intrathecal = 1 mg/hr IV]

Fentanyl 1:30 [1 mcg/hr intrathecal = 30 mcg/hr IV]

Hydromorphone 1:30 [0.01 mg/hr intrathecal = 0.3 mg/hr IV]

www.Palliative.org (Edmonton, Alberta, Canada)http://www.palliative.org/PC/ClinicalInfo/AssessmentTools/MeanEquivalent%20for%20program%20v3.pdf

Questions? Comments?

• Your cases, please!

• Online Narcotic Converter

• Appropriate for pediatrics? NOT for fentanyl!

• http://www.globalrph.com/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 cross-tolerance]

• Don’t manage severe opioid-induced 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 USExplaining Increased Need for Pediatric Pain Specialists

Twitter: @NoNeedlessPain

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 55404 | USA612.813.6450 phone | 612.813.7199 fax

stefan.friedrichsdorf@childrensMN.org

http://www.childrensmn.org/services/painpalliativeintegrativemed

Further Training: CIPPC@ChildrensMN.org

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, 2015 • 9th Conference: Chicago, IL | March 12-13, 2016

 Blog: http://NoNeedlessPain.org