Opioids in daily practice - bapanaesth.be€¦ · Opioids in daily practice B el gi an P aed i atr...

Opioidsin daily practice

Belgian Paediatric Pain Association

Dr Frédéric Lebrun Soins intensifs et urgences pédiatriques

Unité pédiatrique de prise en charge de la douleur, CHC-Liège

Fear of morphine and opioids !

Opioid Crisis in the US

Opioids restrictions

Restricting the use of codeine in children and breastfeeding women (2013)

Restricting the use of tramadol in children and breastfeeding women (2017)

Adverse opioids reactions

• Respiratory depression

• Loss of consciousness

• ConstipationNausea and vomiting

• Dry mouth

• Drowsiness

• Pruritus

• Withdrawal

• Tolerance

• Dependence

• Addiction

• Serotonergicsyndrome and convulsion

Serotonic effect :

Chronic opioid abuse :

Opioids in my daily practice ?

Awareness of the possible sides effects

should not lead to underuse of opioids !

Serious ADRs ADRs veryunlikely when opioidsare titrated carefully !

Good practice guidelines

• Multimodal approach :

Non-phramacological Pharmacological

• Best suited treatment to patient situation

• Favor oral route (moderate pain)

• Give at regular interval

• Prevent procedural pain

• Quickly adapt therapy according to resudal pain

• Monitor and prevent adverse drug reactions (ADRs)

• Use protocols

Mecanism ?

Intensity ?

Duration ?

Fast onset ?

Route ?

Setting of care ?

Type of pain

Age ?

Patient’s condition

Cormorbidities ?

Co-adminstrations ?

Past-experience?

Which analgesic medication ?

Hospital ?

Home ?

• Paracétamol

• AINS

• Morphiniques

• Benzodiazépines

• Spasmolytiques

• Kétamine

• MEOPA

• Anesthésiques locaux

• Clonidine

• Dexmédétomidine

• Tricycliques

• Antiépileptiques

• Antimigraineux

• Stéroïdes

Which analgesic medication ?

Douleur diminue

Douleur augmente

Douleur légère

Douleur modérée à sévère

Non-opioïdes

Opioïdes

WHO guidelines 2012

+ non-opioïdes

WHO Guidelines 2012

WHO Guidelines 2012

Weak or strong opioids ?

• Opioids for moderate pain :– Oral or IN routes : fast and usually well tolerated,

if not contraindicated (e.g. fasting, nasal trauma).

– IN route : quicker onset (procedural pain)

• Opioids for severe pain :– IV route more rapid pain relief

Need for rapid titration ?

Krauss, Lancet 2016

Douleur légère

Douleur modérée

Paracétamol PO (IV)

Ibuprofène PO

Morphine POFentanyl INTramadol PO/IVHydromorphone POOxycodone PO

Douleur sévère

Morphine IVFentanyl IV and derivatesHydromorphone IV

Kétorolac IV

Rapid IV titration

Need for rapid titration?

Molécule

Voie Délaid’action Duréed’action

Paracétamol PO 30-60min 4-6h

IV 30-60min 4-6hIbuprofene PO 30min 4-8h

Ketorolac IV 30min 4-6hTramadol PO 30-60min 3-6h

IV30min >30min 3-6hMorphine PO 30-60min 4-6h

IV 10-20min 4-6h

Fentanyl IN 5min 30-45minIV <5min 30-45min

Time of onset ?

Time of administration ?

Pain management practices in paediatric emergency departments in Australia and New Zealand: Emerg Med Austral (2009) 21, 210–221

Délai R/ PO: 70-100min (moyenne)

Time before first anagesia !?

Sills; Emergency department crowding is associated with decreased quality of analgesiadelivery for children with pain related, isolated, long-bone fractures. Aced Emerg Med 2011; 18 (12): 1330-8:

• n 1229

• Respect délai (< 1 h) 47 7% si affluence P10 P90

• Taux d’enfant ne recevant pas d’antalgique: 3 17%

Time before first anagesia !?

Joel A. Fein, William T. Zempsky, Joseph P. Cravero and THE COMMITTEE ON PEDIATRIC EMERGENCY MEDICINE AND SECTION ON ANESTHESIOLOGY AND PAIN MEDICINE Relief of Pain and Anxiety in Pediatric Patients in Emergency Medical

Systems: Pediatrics 2012;130;e1391

Triage oral analgesia to reduce time of

administration and accelerate pain relief !

BCFI-CBIPSolutionorale

Gélule Immed. Rel.

GéluleSlow rel.

Solutioninjectable

DiqspostifTransderm.

Morphine (X) X X

Fentanyl X X

Sufentanyl X

Alfentanyl X

Remifentanyl X

Piripramide X

Tramadol X X X X

Oxycodone X X

Tilidine/naloxone X X

Hydromorphone X X X

Buprenorphine Sublingual X X

Tapentadol X X X

Méthadone (X) X


• !

What about pharmacology of

opioids ?

Why so high variabilityin dosing requirements

and in tolerabilityprofiles ?

Is there a beterchoice ?

Absorption

Distribution

Metabolism

Excretion

Receptor binding

• Hepatic first pass metabolism• Transporters activity

• Liposolubility

• Liposolubility• Influx and exflus transporters Influx SLC (tramadol, morphine)

Exlux ABC (fentanyl, morphine, oxycodone)

• Affinity for opioids receptor• NMDA : methadone• NA, Serotonine: tramadol

• CYP2D6 (codeine, tramadol, oxycodone)• CYP3A4/A5 (fentanyl)• UGT2B7 (morphine)

• Fat/muscle content• Plasma protein binding• Fluid balance (TB and EC water)• Changes in blood flow, capillary leak (sepsis)

BBB

Pharmacology of opioids

Opioids PK and PD variability

• High variability in dosing requirements and in tolerability profiles ! – from one patient to another for the same drug

– from one drug to another for the same person

• Effects of each opioids depend on :

1) Organ maturation

2) Genetic polymorphism

3) Drug–drug interactions

4) Comorbidities

The right drugfor the right patientat the right dose !





1) Organ maturation



4) Comorbidities

Titration monitorefficiency AND

adverse reactions !

1) Organ maturation (< 1 year)

• Post-op increased opioid sensitivity in younginfants, in particular preterm, due to organimmaturity require lower doses !

Bouwmeester, Intensive Care Med 2003

• Limited P-gp expression at the BBB greateropioid penetration and accumulation in newborns and young infants.

Lam, Curr. Opin. Anaesthesiol 2016

• Most of the metabolic pathways for the metabolismand elimination of morphine mature rapidly, usuallyreaching adult values by 6 months to 1 year

1) Organ maturation (< 1 year)

Genetic variation in genes coding for metabolizingenzymes, transporters and targets (receptors)


Metabolism

Transpoters

(ABC, SLC)

Receptor

(MOR)

CYP2D6

• Highly polymorphic gene and the mostfrequently addressed in pain literatur

• Liver enzyme involved in transformation

– codeinemorphine

– tramadol O-desmethyltramadol (M1)

– oxycodone oxymorphone

• Individual difference in metabolism result inunpredictable clinical responses

Eur J Pharmacol 2015

CYP2D6 gene

• Highly polymorphic (>100 allelic variants identified)

• 4 metabolizer phenotypes (Zhou, 2009) :

1) Normal activity: EM (extensive metabolizers) • 60–70% caucasia

2) Increased activity: UM (ultra-rapid metabolizers) • 2–6% caucasians• 30% of northern african and arabian population !

3) Low activity : IM (intermediate metabolizers) • 10–15% caucasians• 50% of asians !

4) No or little activity : PM (poor metabolizers) • 5–10% caucasians• <3% other ethnic population

• PM + UM ∼40% of the US population (St Sauver, 2017)

Restricting the use of codeine in childrenand breastfeeding women (2013)

Contraindication :

• < 12 years

• < 18 years

– after surgery to remove the tonsils and/or adenoids

– obstructive sleep apnoea

– patients are more susceptible to respiratory problems

• Any age :

– Known to be ultra-rapid metabolisers (UM)

– Breastfeeding mothers risk for breastfed infants

« The prescribing information should include information for healthcare professionals, patients and carers on the risk of sideseffects and how to recognise them ! »

(Active)

(Inactive)

Tramadol

(More active ?)

(Almost inactive)

Oxycodone

CYP2D6

CYP3A4/A5

• Inactivation of fentanyl, sufentanil, alfentanil

– CYP3A5*1 allele : expected to have an increased elimination of fentanyl/sufentanyl and might require higher doses (not

demonstrated in meta-analysis on postoperative pain)

Pain Physician 2015

• Inactivation M1 metabolites of tramadol and oxycodone

Drug transporters• In the gastrointestinal tract, kidneys, hepatocytes and in the CNS (BBB)

• 2 main families of drug transporters

SLC influx transporters [e.g OCT1] : facilitate the passage

ABC efflux transporters [e.g. P-gp] : restrict the passage

Tranporters genetic polymorphism

• SLC 22A1 : transporter responsible for uptake of morphine and active M1 metabolite of tramadol in the hepatocytes– 205 adult postoperative patients with 2 inactive SLC22A1 alleles

had higher M1 concentration and lower tramadol consumptionduring the first 24 h Pain 2016

• ABC B1 (fentanyl, morphine, oxycodone) : efflux pump in the intestine and at the BBB– 3435TT genotyped individuals : higher morphine concentrations

in cerebrospinal fluid after IV injection lower doses might beneeded Br J Clin Pharmacol 2002

– SNP rs9282564 (11% in white individuals) : increased risk for respiratory depression and prolonged hospital stay in a study on 263 children Pharmacogenomics Journal 2015

Journal of Pain Research 2017:10 1225–1239


• Antibiotiques• Antimycotiques• Antiviraux • …

Copyrights apply


• Antidepresseurs• Antiepileptiques• Pscyhotropes• …

We need software support !e.g. LEXICOMP ® : Drug Interactions

4) Comorbidities

a) Concomitant risk of respiratory depression– Obstructive sleep apnea– Otolaryngologic surgery– Respiratory and neurological dysfunction– Obesity– Concomitant sedative administration

b) Alteration of PK paramaters– Clearence : renal insufficiency– Metabolism : hepatic dysfonction– Absorption : gastric emptying, …– Distribution : fat/muscle content, plasma protein, fluid

balance, changes in blood flow and capillary leak (sepsis), BBB permeability (menengitis)





1) Organ maturation



4) Comorbidities

Titration monitorefficiency AND

adverse reactions !


• !

What are the best options according to the

litterature ?

Opioids should titratesaim for optimal efficacywith minimal toxicity !

Personalized approachesshould include- age-adapted dosing- drug-drug interaction- comorbidities- genetic polmorphism

polymorphism in the near futur …


Gélule Immed. Rel.

GéluleSlow rel.

Solutioninjectable


Morphine (X) X X

Fentanyl X X

Sufentanyl X

Alfentanyl X

Remifentanyl X

Piripramide X

Tramadol X X X X

Oxycodone X X


Hydromorphone X X X


Tapentadol X X X

Méthadone (X) X

Morphine

• Pure agonist (μ > K receptors)

• Standard by which all are compared• Accumulated knowledge

• Low cost and wide availability• Various routes of administration : PO and IV• Low liposoluble • IV : slow onset of action (<20 min) • Oral : bioavailability 19-47%• Prolonged duration of action (4-6h)

Copyrights apply

Morphine

Slow onset time to peak effect (~80% effect at 15 min, but peak

analgesic effect at ~90 min)Prolonged effect

Morphine

• Histamine release (vasidilation, pruritus, diaphoresis)

Unsuitable if hemodynamic instability

• Glucuronidation UGT2B7 > UGT1A1, UGT1A8 : inactive M3G and active M6G (9/1)

• Renal excretion of metabolites (water soluble)

Unsuitable if renal insufficiency due to M6G accumulation

More adverse reactions ?

Risk of respiratory depression ?

REVI EW ARTI CLES

Opioid-induced respiratory depression in paediat rics: a

review of case reports

M. Niesters1, F. Overdyk2, T. Smith1, L. Aarts1 and A. Dahan1*1 Department of Anesthesiology, Leiden University Medical Center, 2300 RC Leiden, The Netherlands2 Department of Anesthesiology, Hofstra University School of Medicine, Hempstead, NY, USA

* Corresponding author. E-mail: [email protected]

Editor’s key points

† Not much has been

published on opioid-

induced respiratory

depression in children.

† The authors undertook

an unusual approach of

reviewing case reports.

† Importantly, this review

has identified some

predisposing patterns and

clinical conditions.

† These conditions are renal

failure, patients

undergoing

adenotonsillectomy, and

those having CYP2D6

gene polymorphism.

Summary. Opioids remain the cornerstone of modern-day pain treatment, also in the

paediatric population. Opioid treatment is potentially life-threatening, although there are

no numbers available on the incidence of opioid-induced respiratory depression (OIRD) in

paediatrics. To get an indication of specific patterns in the development/causes of OIRD,

we searched PubMed (May 2012) for all available case reports on OIRD in paediatrics,

including patients 12 yr of age or younger who developed OIRD from an opioid given to

them for a medical indication or due to transfer of an opioid from their mother in the

perinatal setting, requiring naloxone, tracheal intubation, and/or resuscitation. Twenty-

seven cases are described in 24 reports; of which, seven cases were fatal. In eight cases,

OIRD was due to an iatrogenic overdose. Three distinct patterns in the remaining data

set specifically related to OIRD include: (i) morphine administ ration in patients with renal

impairment, causing accumulation of the active metabolite of morphine; (ii) codeine use

in patients with CYP2D6 gene polymorphism associated with the ultra-rapid metabolizer

phenotype, causing enhanced production of the morphine; and (iii) opioid use in patients

after adenotonsillectomy for recurrent tonsillit is and/or obstructive sleep apnoea, where

OIRD may be related to hypoxia-induced enhancement of OIRD. Despite the restrictions

of this approach, our analysis does yield an important insight in the development of

OIRD, with specific risk factors clearly present in the data.

Keywords: case reports; codeine; opioid; opioid-induced respiratory depression; paediatrics

Most physicians would agree that moderate-to-severe pain

deserves an aggressive treatment approach. Most effective

treatment of pain is with opioid analgesics. Opioids act

through activation of endogenous opioid pathways and

produce relief of pain perception and various side-effects.

Opioid-induced respiratory depression (OIRD) is among the

most serious of these side-effects as it is potentially life-

threatening.1 Most (if not all) prospective studies on the

effect of opioids on the ventilatory control system are per-

formed in adults (mostly men). Litt le information is available

on the occurrence of OIRD in the paediatric population, and

no comparative data on the effect of different opioids on

breathing are available in children. Since we believe that

knowledge on the occurrence of OIRD is important to physi-

cians and opioid manufacturers alike, and no randomized

(case) controlled trials are available on OIRD in the paediatric

population, we performed, as part of a much larger system-

atic review of the literature, a search of case reports that de-

scribe OIRD in children aged 12 yr or younger. Our aims were

to review these cases and assess whether we could find

obvious risk factors for OIRD in the paediatric population.

We focus on OIRD induced by opioid taken by or given to

patients for a medical indication (pain, sedation, and

cough) or OIRD due to transfer of an opioid from mother to

child when the opioid is prescribed or given to the mother

in the perinatal setting.

Methods

In May 2012, we searched the electronic database PubMed

(www.ncbi.nlm.nih.gov) for ‘case reports’ on OIRD related to

opioid intake for a medical indication in the patient (e.g.

pain, sedation, cough) or perinatal OIRD due to transfer of

an opioid from mother to child (see Appendix for the

PubMed search strategy). Also case reports mentioned in

the retrieved papers were taken into account, and we

retrieved case reports on OIRD by systematically scanning

several case report journals (Case Reports in Anesthesiology,

BMJ Case Reports, Journal of Medical Case Reports, Inter-

national Medical Case Reports Journal). Finally, case reports

in our local literature databases were searched for additional

British Journal of Anaesthesia 110 (2): 175–82 (2013)

Advance Access publication 17 December 2012 . doi:10.1093/bja/aes447

& The Author [2012]. Published by Oxford University Press on behalf of the British Journal of Anaesthesia. All rights reserved.

For Permissions, please email: [email protected]

• All available case reports on opioid-induced respiratorydepression (OIRD) in paediatrics : from 1981 to 2012

• Respiratory depression requiring naloxone, tracheal intubation, and/or resuscitation

• Patients < 12 yr who developed OIRD o from an opioid given to them for a medical indication o or due to transfer from their mother in the perinatal setting

• 27 cases from which 7 cases were fatal• 8 cases : iatrogenic overdose• 3 distinct patterns in the remaining data

1) morphine administration in patients with renalimpairment, causing accumulation of the active metabolite of morphine

2) codeine use in patients with ultra-rapid metabolizerCYP2D6 phenotype, causing enhanced production of the morphine

3) opioid use after adenotonsillectomy and/or obstructive sleep apnoea, where OIRD may be related to hypoxia-induced enhancement of OIRD.

Risk of respiratory depression ?

(1) Category paediatrics (< 12 years )

14 cases (6 fatals):

• 8 codeine (4 fatal)– 5 adeno-tonsillectomy 3 ultra-rapid or extended

metabolizer with CYP2D6 gene– 3 upper airway infection and < 1 year old

• 4 morphine (1 fatal)– 3 renal renal failure

• 1 fentanyl (not fatal) :– midazolam – fentany IV for BMA (14 months)

• 1 hydrocodone (fatal):– Poor metabolizer CYP2D6 phenotype + Clarithromycine :

reduced metabolic capacity due to impaired CYP2D6 allele

(2) Category perinatal (maternal intake)

5 cases (1 fatal : codeine)

• 2 use of opioids by a breastfeeding mother

– Methadone and hydrocodone (5 weeks)

– Codeine (13 days) mother ultra-rapid metabolizer(CYP2D6)

• 2 use of epidural labour analgesia :

– Fentanyl

• 1 use of Iv opioids during a caesarean section

– Fentanyl

Morphine

• No more respiratory depression withmorphine !

• ADRs very unlikely when morphine is titratedcarefully !

• Risk factors as for other opioids

– Age < 1 year

– Comorbidity (renal failure)

– Drug–drug interaction

– Genetic polymorphisms


Gélule Immed. Rel.

GéluleSlow rel.

Solutioninjectable


Morphine (X) X X

Fentanyl X X

Sufentanyl X

Alfentanyl X

Remifentanyl X

Piripramide X

Tramadol X X X X

Oxycodone X X


Hydromorphone X X X


Tapentadol X X X

Méthadone (X) X

Fentanyl and derivatives

• More potency (procedural pain, surgery, ICU)

• Rapid onset and low duration of action

• No histamine-release and minimal hemodynamic effect

• PK and PD not affected by renal fonction

Fentanyl :

– More used and more PD/PK data (even if insufficients)

– Various routes of administration

– Cheaper

Remifentanil :

– Rapidly metabolised esterases in blood and tissue despiteprolonged administration and affected hepatic fonction

Fentanyl

• Highly lipophilic rapid distribution to highly perfused tissues (eg, brain, heart, kidney, and GI tract) and slower redistribution to muscle and fat stores in muscle and fat

• Rapid onset (< 5 min)• IV bolus : short duration of action (30-45 min) • IVC infusion : prolonged half time ( for short duration

surgery)

• No histamine-release minimal effect on hemodynamic function

• Metabolisation in the liver CYP3A4 : inactivate metabolite (norfentanyl) excreted in the urine not affected by renal insufficiency

Copyrights apply

Fentanyl

Fentanyl

• Fentanyl’s lipophilicity

– Intranasal route (> 1 year)

• Procedural pain

• No need of IV access

• Faster onset (< 5min) and lower duration (45min) then oral morphine and tramadol

– sublingual or transdermal (> 4-8 years)

• Palliative care and chronic pain settings

Cochrane Databaseof SystematicReviews

Intranasal fentanyl for the management of acute pain in

children (Review)

Murphy A, O’Sullivan R, Wakai A, Grant TS, Barrett MJ, Cronin J, McCoy SC, Hom J, Kandamany N

Murphy A, O’Sullivan R, Wakai A, Grant TS, Barrett MJ, Cronin J, McCoy SC, Hom J, Kandamany N.

Intranasal fentanyl for the management of acute pain in children.

CochraneDatabaseof SystematicReviews 2014, Issue 10. Art. No.: CD009942.

DOI: 10.1002/14651858.CD009942.pub2.

www.cochranelibrary.com

Intranasal fentanyl for the management of acute pain in children (Review)

Copyright © 2014 The CochraneCollaboration. Published by John Wiley & Sons, Ltd.

CochraneDatabaseof SystematicReviews

Intranasal fentanyl for themanagement of acutepainin

children(Review)

MurphyA, O’Sullivan R, Wakai A, Grant TS, Barrett MJ, Cronin J, McCoySC, Hom J, Kandamany N

Murphy A, O’Sullivan R, Wakai A, Grant TS,Barrett MJ, Cronin J, McCoy SC, Hom J, KandamanyN.

Intranasal fentanyl for themanagement of acutepain in children.

CochraneDatabaseof SystematicReviews 2014, Issue10. Art.No.: CD009942.

DOI: 10.1002/14651858.CD009942.pub2.


Intranasal fentanyl for themanagement of acutepain in children (Review)

Copyright © 2014TheCochraneCollaboration. Published by John Wiley &Sons, Ltd.


Intranasal fentanyl for the management of acute pain in

children (Review)

Murphy A, O’Sullivan R, Wakai A, Grant TS, Barrett MJ, Cronin J, McCoy SC, Hom J, Kandamany N

Murphy A, O’Sullivan R, Wakai A, Grant TS, Barrett MJ, Cronin J, McCoy SC, Hom J, Kandamany N.

Intranasal fentanyl for the management of acute pain in children.

CochraneDatabaseof SystematicReviews 2014, Issue 10. Art. No.: CD009942.

DOI: 10.1002/14651858.CD009942.pub2.


Intranasal fentanyl for the management of acute pain in children (Review)

Copyright © 2014 The CochraneCollaboration. Published by John Wiley & Sons, Ltd.

• Efficacité antalgique comparable à la morphine• Plus rapidement efficace et durée d’action plus courte • Pas d’effet secondaire important (parfois mauvais gout et vomissement) • Pas de réelle possibilité de titration• Très peu données pour enfants < 3 ans !

Intranasal fentanyl


Gélule Immed. Rel.

GéluleSlow rel.

Solutioninjectable


Morphine (X) X X

Fentanyl X X

Sufentanyl X

Alfentanyl X

Remifentanyl X

Piripramide X

Tramadol X X X X

Oxycodone X X


Hydromorphone X X X


Tapentadol X X X

Méthadone (X) X

• Frequently used in Germany and AustraliaOften first-line opioid for post-Op management in Germany with no evidence for it ! Hinrichs, 2017

• Lack of published datas in children !

• Only IV !

• PK/PD comparable to morphine (long pain relief)

• Side effect profile comparable to morphine

• Metabolized in the liver to inactive metabolite

no risk in patients with renal failure

Piripramide


Gélule Immed. Rel.

GéluleSlow rel.

Solutioninjectable


Morphine (X) X X

Fentanyl X X

Sufentanyl X

Alfentanyl X

Remifentanyl X

Piripramide X

Tramadol X X X X

Oxycodone X X


Hydromorphone X X X


Tapentadol X X X

Méthadone (X) X

Tramadol

• 2 complementary mechanisms

1) Opioid : M1 metabolite μ-receptor (MOR) agonist

2) Monoaminergic : tramadol parent drug inhibition of norepinephrine and serotonin reuptake(predominant effect ?)

• Fewer side-effets ?

– Less respiratory and gastrointestinal symptoms ??

– Can favorate seizures and serotonin syndrome (interaction with drugs that inhibit serotonin and noradrenaline reuptake centrally)

Tramadol

• Frequently used in Belgium

• One of the only oral solution commercially available

• Oral : bioavailability 75%

• Slow onset (>30 min) and long duration

• No adventage of IV route (IV 30min to diminish digetive SE)

• Metabolized in the liver : – CYP2D6 active M1 metabolite (O-desmethyltramadol)

• UGT2B7, UGT1A8 : M1 inactivation by glucuronidation

– CYP3A4 : inactive M2 metabolite

• Renaly excreted

Tramadol

Active M1

Restricting the use of tramadol in childrenand breastfeeding women (2017)

Contraindication :

• < 12 years

• < 18 years

– after surgery to remove the tonsils and/or adenoids

Warning :

• 12-18 years in conditions which may increase the risk of seriousbreathing problems

– obese

– obstructive sleep apnea

– severe lung disease

• Breastfeeding women risk for breastfed infants

Tramadol

– Do not list tramadol as contraindicated

– Recommend limiting its use to acute postoperative pain in a monitored setting

Paediatr Anaesth. 2017 Aug;27(8)

Brian J. Anderson1 , Jane Thomas2 , Kaye Ottaway1 , George A. Chalkiadis3

1Department of Anaesthesiology, Faculty of Medicine and Health Science, University of Auckland, Auckland, New Zealand 2Department of Anaesthesia, Starship Children’s Hospital, Auckland, New Zealand 3Department of Paediatric Anaesthesia and Pain Management, Royal Children’s Hospital, Parkville, Vic, Australia

Front in Pharmacol : 2018 Mar 5;9:148


Tramadol for postoperative pain treatment in children

(Review)

Schnabel A, Reichl SU, Meyer-Frießem C, Zahn PK, Pogatzki-Zahn E

Schnabel A, Reichl SU, Meyer-Frießem C, Zahn PK, Pogatzki-Zahn E.

Tramadol for postoperativepain treatment in children.

CochraneDatabaseof SystematicReviews 2015, Issue3. Art. No.: CD009574.

DOI: 10.1002/14651858.CD009574.pub2.


Tramadol for postoperativepain treatment in children (Review)

Copyright © 2017The CochraneCollaboration. Published by John Wiley &Sons, Ltd.


Tramadol for postoperative pain treatment in children

(Review)

Schnabel A, Reichl SU, Meyer-Frießem C, Zahn PK, Pogatzki-Zahn E

Schnabel A, Reichl SU, Meyer-Frießem C, Zahn PK, Pogatzki-Zahn E.



DOI: 10.1002/14651858.CD009574.pub2.



Copyright © 2017The CochraneCollaboration. Published by John Wiley & Sons, Ltd.

CochraneDatabaseof SystematicReviews

Tramadol for postoperativepaintreatment inchildren

(Review)

Schnabel A, Reichl SU, Meyer-FrießemC, Zahn PK, Pogatzki-Zahn E

Schnabel A, Reichl SU, Meyer-Frießem C, Zahn PK,Pogatzki-ZahnE.



DOI: 10.1002/14651858.CD009574.pub2.



Copyright © 2017TheCochraneCollaboration. Published by John Wiley &Sons, Ltd.

• 20 randomized controled studies essais randomisés contrôlés (n=1170)• Low level of evidence (small studies and methodological problems)

Efficency• Appropriate analgesia when compared to placebo (8 studies)• Uncertain evidence regarding the comparison with other opioids (4 studies)

Tolerability• Adverse events were only poorly reported an accurate risk-benefit analysis

was not possible.

Tramadol safety ?

Reports of respiratory depression suspected to beattributed to tramadol :

• WHO pharmacovigilance database (1992 – 2016) : – 15 cases suspected to be attributed to tramadol– 9 adolescents and 3 deaths (15-17 years)– Overdoses (majority accidental or intentional) and

other drugs involved

• In the literature (Orliaguet et al., 2015) :– 1 case report of a 5-year-old boy who developed

respiratory depression after tonsillectomy

Pediatrics. 2015 Mar;135(3):e753-5

• 1 case report of a 5-year-old boy • after tonsillectomy for obstructive sleep apnea• respiratory depression 8 h after discharge home• Standard dose • fully recovered after naloxone• Genotyping showed an UM for CYP2D6

Tramadol safety

Perspective with tramadol ?

1) Clinical tolerance testing !

– Close monitoring should allow adapting the treatment in case of inefficacy or adverce reaction

– Information to caregivers about the risks

– Outside hosptal > 3 years after tolerability testing ?

2) Assess the activity of CYP2D6 !?

– Identify patients at risk for “over or under response”

– Need of government agencies and insurance support

3) Choose an alternative molecule ?

Rodieux, Frontiers in Pharmacology 2018

Prise en charge médicamenteuse de la douleur chez l’enfant : alternatives à la codéine | 1

Janvier 2016

Prise en charge médicamenteuse de la

douleur chez l’enfant : alternatives à la codéine

Fiche Mémo

Éducation des prescripteurs, des pharmaciens et des familles sur la douleur et ses traitements

Elle est primordiale afin de garantir des conditions optimales de prise en charge de la douleur (sous-

dosage fréquent des antalgiques en termes de posologie et de nombre de prises prescrites, faible nombre

d’administrations par les familles malgré la douleur, plus rarement risque de surdosage, fausses croyances, etc.).

Des documents d’information (sur les antalgiques, leur posologie, la durée et la fréquence d’administration, les précautions d’emploi, la surveillance à domicile et les moyens non médicamenteux) doivent être mis à disposition des prescripteurs, des pharmaciens et des familles. Le médecin traitant doit assurer le suivi de la prise en charge

de la douleur.

Il est rappelé que des moyens non médicamenteux, tels que l’information de l’enfant et de sa famille, la distraction, la relaxation, l’hypnose, etc., contribuent à la diminution de la douleur. La présence des parents

est un facteur essentiel du soulagement et du sentiment de sécurité.

Préambule

La codéine, antalgique de palier 2, était indiquée chez l’enfant à partir de 1 an dans les douleurs d’intensité modérée à intense ou ne répondant pas à l’utilisation d’antalgiques de palier 1 utilisés seuls. Les décès et événements indésirables graves rapportés après son administration, principalement en post-amygdalectomie, ont conduit l’ANSM à recommander en avril 2013 :

- de n’utiliser la codéine chez l’enfant de plus de 12 ans qu’après échec du paracétamol et/ou d’un anti-inflammatoire non stéroïdien (AINS) ;

- de ne plus utiliser ce produit chez les enfants de moins de 12 ans ;

- de ne plus utiliser ce produit après amygdalectomie ou adénoïdectomie ;

- de ne plus utiliser ce produit chez la femme qui allaite.

La codéine est transformée en plusieurs métabolites : le principal métabolite actif est la morphine, produite par acti-vité du cytochrome P450 2D6 (CYP2D6). Du fait du polymorphisme génétique du CYP2D6 chez l’être humain, la métabolisation de la codéine produit une quantité variable de morphine, de trop faible chez les « métaboliseurs lents » à trop importante chez les « métaboliseurs rapides ou ultra-métaboliseurs ». La plupart des décès, liés à une dépression respiratoire, sont survenus chez des enfants ayant cette dernière particularité.

Objectif

Le but de cette fiche mémo est de proposer des alternatives médicamenteuses à l’utilisation de la codéine dans la prise en charge de la douleur aiguë et prolongée chez l’enfant, dans les situations cliniques problématiques les plus fréquentes.

Ces recommandations n’abordent pas l’évaluation de la douleur en pédiatrie, les thérapies non

médicamenteuses et la prise en charge de la douleur du nouveau-né.


Gélule Immed. Rel.

GéluleSlow rel.

Solutioninjectable


Morphine (X) X X

Fentanyl X X

Sufentanyl X

Alfentanyl X

Remifentanyl X

Piripramide X

Tramadol X X X X

Oxycodone X X


Hydromorphone X X X


Tapentadol X X X

Méthadone (X) X

Oxycodone

• Pharmacologically relatively similar to morphine• opioid receptor agonist (κ > μ)• Immediate-release formulation :

– Faster action and higher bioavailability (60-85%)– Low lipid solubility (not suitable for sublingual administration) – Same duration of action (slightly longer half-life)

• Lower incidence of nausea and hallucinations ?• Marked interindividual variation in PK specially < 6 months• Hepatically metabolized

– CYP2D6 active oxymorphone– CYP3A4 inactive noroxycodone

(Active)

(Inactive)

Tramadol

(More active ?)

(Almost inactive)

Oxycodone

CYP2D6

Oxycodone and CYP2D6

• Concerns with PM !?– Impaired formation of active oxymorphone action

contribution still unclear, but may be substantial Eur J Drug Metab PK 2019

– Accumulation of parent drug increased risk of adverse effects• Higher prevalance of PM in oxycodone-related deaths compared with a

control group J Anal Toxicol 2002

• Concerns with UM !?– Overproduction of oxymorphone, potent active metabolite

• 2 cases reported in which CYP2D6 UM developed adverse drug reactions(anxiety, insomnia, lightheadedness, lack of control, and dysphoria) J Clin Psychopharmacol 2003

Don’t use in UM and PM, or lower the dose !?

We need more data !

Tilidine + Naloxone

CYP3A4

CYP3A4

Active

Inactive

Inactive

• Frequently prescribed in Germany (acute and chronic pain)

• Lower sides effect ?• Low potency and ceiling effect !• Oral bioavailability : 33%• Prodrug : sequencial metabolisation

CYP2C19 and CYP3A4 active nortilidine inactive bisnortilidine

• Drug-drug intercation : strong CYP3A4 and CYP2C19 inhibitors (voriconazole) almost completely inhibit nortilidineformation

Hydromorphone

• A hold drug derivative of morphine but less frequently used– mainly surgery and cancer pain in older children and adolecents

• Liposubility : > morphine but < fentanyl • IV rapid onset like fentanyl ( IV 5-10 min) • Prolonged effect like morphine (4-6h)• Oral bioavaibility : 60%• Low adverse reaction a(low or no histamine release)

• nausea/vomiting or prurit in cancer patients on morphine ?

• Metabolisation : active H3G (hydromorphone-3-glucuronide) potentially neurotoxic Caution with use in patients with renal insuffisancy Cautious use in patients with seizures

Copyrights apply

Hydromorphone

Comparative clinical effects of hydromorphone and morphine: a meta-analysis; Felden, British Journal of Anaesth, 2011

• Randomized, controlled trials or observational

• Meta-analysis of 8 studies (494/510 patients) : suggeste hydromorphone provides slightly betterclinical analgesia than morphine patients disappeared when 1 study was removed !

• Side-effects were similar (e.g. nausea 9 studies, 456/460 patients, vomiting 6 studies 246/239 , or itching 8 studies 405/410).

• Small evidence of safety advantages in renal failure or during acute analgesia titration ??


Gélule Immed. Rel.

GéluleSlow rel.

Solutioninjectable


Morphine (X) X X

Fentanyl X X

Sufentanyl X

Alfentanyl X

Remifentanyl X

Piripramide X

Tramadol X X X X

Oxycodone X X


Hydromorphone X X X


Tapentadol X X X

Méthadone (X) X

Buprenorphine

• Not approved in children! PK/PD data are lacking ! • Partial μ agonist

– analgesic effects at lower plasma concentr. via interaction with MOR– anti-analgesic effects at high doses via interactions with KOR and NOR

• Lower potential for respiratory depression• Ceiling effect !• Very low oral bioavailability (extensive first-pass

metabolism)– Sublingual and transcutaneous formulations not

appropriate in a young child– Transcutaneous route not for acute pain

Tapentadol

• Not approved in children ! PK/PD data are lacking ! • Recently released for use in moderate to severe acute pain

and as a prolonged-release preparation for chronic pain. • Double effect : μ agonist + monoaminoaminergic

(noradrenaline reuptake inhibitor properties) • Advantage > < tramadol :

– hepatic metabolism does not involve CYP2D6 but mainlyglucuronidation

– no active metabolites


Gélule Immed. Rel.

GéluleSlow rel.

Solutioninjectable


Morphine (X) X X

Fentanyl X X

Sufentanyl X

Alfentanyl X

Remifentanyl X

Piripramide X

Tramadol X X X X

Oxycodone X X


Hydromorphone X X X


Tapentadol X X X

Méthadone (X) X

Methadone

• Long duration of action

• High bioavailability (limited first-pass metabolism)

• More limited potential to induce euphoria

• Indications :– withdrawal syndrome

– Sometimes used for treatment of chronic pain • postulated antagonistic activity at the N-methyl-d-aspartate

(NMDA) receptor may account for some of its effectiveness in neuropathic pain states

– adolecents and adults addicted to opioids.


Gélule Immed. Rel.

GéluleSlow rel.

Solutioninjectable


Morphine (X) X X

Fentanyl X X

Sufentanyl X

Alfentanyl X

Remifentanyl X

Piripramide X

Tramadol X X X X

Oxycodone X X


Hydromorphone X X X


Tapentadol X X X

Méthadone (X) X

Conclusion

• Serious ADR are very uncommon when opioids are titrated carefully !

• Healthcare providers and parents should be clearlyinformed of the potential ADRs for a quickerdetection and increased safety

• Awareness of the possible ADRs is important but should not lead to underuse of opioids !

• Outside the hospital, physicians should limit opioidprescriptions.

Conclusions

• Personalized approaches should include choice of age-adapted dosing formulation, search for drug-druginteraction, comorbities and genetic polymorphism in the near futur.

• Morphine may be safer than uncertainty associated withtramadol

• Renal failure and hemodynamic instability: avoidmorphine and prefer fentanyl or derivates

• Tramadol : CYP2D6 activity assessment should allowsafer use in the near future. In the meantime, close monitoring of effectiveness and ADRs is necessary beforeusing outside hospital.

6th of february 2020

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