Respiratory Depression • • Loss of Consciousness Serotonergic Syndrome and • Constipation Nausea and Vomiting Convulsion

Opioids in daily practice

Dr Frédéric Lebrun Soins intensifs et urgences pédiatriques

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

Belgian Paediatric Pain Association

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

Serotonic effect : • Respiratory depression • • Loss of consciousness Serotonergic syndrome and • Constipation Nausea and vomiting convulsion

• Dry mouth Chronic opioid abuse : • Drowsiness • Tolerance • Pruritus • Dependence • Withdrawal • Addiction Opioids in my daily practice ?

Serious ADRs ADRs very unlikely when opioids are titrated carefully !

Awareness of the possible sides effects should not lead to underuse of opioids ! 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 Which analgesic medication ?

Type of pain Patient’s condition Intensity ? Age ?

Route ? Cormorbidities ?

Fast onset ? Co-adminstrations ?

Duration ? Setting of care ? Past-experience? Mecanism ? Hospital ?

Home ? Which analgesic medication ?

• Paracétamol • Benzodiazépines • AINS • Spasmolytiques • Morphiniques • Clonidine • Dexmédétomidine • Kétamine • Tricycliques • MEOPA • Antiépileptiques • Anesthésiques locaux • Antimigraineux • Stéroïdes WHO Guidelines 2012

Douleur diminue Opioïdes + non-opioïdes

Douleur modérée à sévère Non-opioïdes

Douleur légère

Douleur augmente

WHO guidelines 2012 WHO Guidelines 2012 WeakNeed orfor strong rapid titrationopioids ??

• 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?

Douleur sévère

Morphine IV Douleur modérée Fentanyl IV and derivates Hydromorphone IV Morphine PO Fentanyl IN Tramadol PO/IV Hydromorphone PO Rapid IV titration Douleur légère Oxycodone PO

(IV) Paracétamol PO  Kétorolac IV Ibuprofène PO

Krauss, Lancet 2016 Time of onset ?

Molécule Voie Délai d’action Durée d’action

Paracétamol PO 30-60min 4-6h IV 30-60min 4-6h Ibuprofene PO 30min 4-8h Ketorolac IV 30min 4-6h Tramadol PO 30-60min 3-6h IV 30min >30min 3-6h Morphine PO 30-60min 4-6h IV 10-20min 4-6h Fentanyl IN 5min 30-45min IV <5min 30-45min

Time of administration ? Time before first anagesia !?

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 analgesia delivery 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% Triage oral analgesia to reduce time of administration and accelerate pain relief !

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 BCFI-CBIP

Solution Gélule Gélule Solution Diqspostif orale Immed. Rel. Slow rel. injectable Transderm. 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 Opioids in my daily practice ?

Why so high variability in dosing requirements and in tolerability Is there a beter profiles ? choice ?

• ! What about pharmacology of opioids ? Pharmacology of opioids Absorption Metabolism Receptor binding

• CYP2D6 (codeine, tramadol, oxycodone) • CYP3A4/A5 (fentanyl) • UGT2B7 (morphine) • Hepatic first pass metabolism • Transporters activity BBB • Affinity for opioids receptor Distribution • NMDA : methadone • NA, Serotonine: tramadol

• Liposolubility • Influx and exflus transporters  Influx SLC (tramadol, morphine)  Exlux ABC (fentanyl, morphine, oxycodone)

• Liposolubility Excretion

• Fat/muscle content • Plasma protein binding • Fluid balance (TB and EC water) • Changes in blood flow, capillary leak (sepsis) 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 The right drug 2) Genetic polymorphism for the right patient 3) Drug–drug interactions at the right dose ! 4) Comorbidities 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

• Post-op increased opioid sensitivity in young infants, in particular preterm, due to organ immaturity  require lower doses ! Bouwmeester, Intensive Care Med 2003 • Limited P-gp expression at the BBB  greater opioid penetration and accumulation in newborns and young infants. Lam, Curr. Opin. Anaesthesiol 2016 • Most of the metabolic pathways for the metabolism and elimination of morphine mature rapidly, usually reaching adult values by 6 months to 1 year 2) Genetic polymorphism

Genetic variation in genes coding for metabolizing enzymes, transporters and targets (receptors) Metabolism

Receptor (MOR)

Transpoters (ABC, SLC) CYP2D6

• Highly polymorphic gene and the most frequently addressed in pain literatur • Liver enzyme involved in transformation – codeine  morphine – tramadol  O-desmethyltramadol (M1) – oxycodone  oxymorphone • Individual difference in metabolism result in unpredictable 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 children and 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 sides effects and how to recognise them ! » CYP2D6

Tramadol Oxycodone

(Almost inactive)

(More active ?) (Inactive) (Active) 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 consumption during 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 be needed 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 3) Drug–drug interactions

• Antibiotiques • Antimycotiques • Antiviraux • …

Journal of Pain Research 2017:10 1225–1239 3) Drug–drug interactions

• Antidepresseurs • Antiepileptiques • Pscyhotropes • …

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

Copyrights apply 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) 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 Titration  monitor 2) Genetic polymorphism efficiency AND 3) Drug–drug interactions adverse reactions ! 4) Comorbidities Opioids in my daily practice ? Personalized approaches Opioids should titrates should include aim for optimal efficacy - age-adapted dosing with minimal toxicity ! - drug-drug interaction - comorbidities - genetic polmorphism polymorphism in the near futur …

• !

What are the best options according to the litterature ? BCFI-CBIP

• 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) Morphine

Slow onset time to peak effect (~80% effect at 15 min, but peak analgesic effect at ~90 min) Prolonged effect

Copyrights apply 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 ?

British Journal of Anaesthesia 110 (2): 175–82 (2013) Advance Access publication 17 December 2012 . doi:10.1093/bja/aes447

REVI EW ARTI CLES Opioid-induced respiratory depression in paediatrics: 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 Netherlands 2 Department of Anesthesiology, Hofstra University School of Medicine, Hempstead, NY, USA * Corresponding author. E-mail: [email protected]

Summary. Opioids remain the cornerstone of modern-day pain treatment, also in the •Editor’sAll availablekey points casepaediatri reportsc populatio onn. Opioidopioidtreatment-inducedis potentiallyrespiratorylife-threatening, although there are † Nodepressiont much has been (OIRD)no numbers in paediatricsavailable on the :incidence fromof1981opioid-induced to 2012respiratory depression (OIRD) in published on opioid- paediatrics. To get an indication of speciﬁc patterns in the development/causes of OIRD, • indRespiratoryuced respiratory depressionwe searched requiringPubMed (May 2012)naloxonefor all available, trachealcase reports intubation,on OIRD in paediatri cs, depression in children. 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 † Theand/orauthors unde resuscitationrtook perinatal setting, requiring naloxone, tracheal intubation, and/or resuscitation. Twenty- an unusual approach of • seven cases are described in 24 reports; of which, seven cases were fatal. In eight cases, revPatientsiewing case rep o

Most physicians would agree that moderate-to-severe pain obvious risk factors for OIRD in the paediatric population. deserves an aggressive treatment approach. Most effective We focus on OIRD induced by opioid taken by or given to treatment of pain is with opioid analgesics. Opioids act patients for a medical indication (pain, sedation, and through activation of endogenous opioid pathways and cough) or OIRD due to transfer of an opioid from mother to produce relief of pain perception and various side-effects. child when the opioid is prescribed or given to the mother Opioid-induced respiratory depression (OIRD) is among the in the perinatal setting. most serious of these side-effects as it is potentially life- threatening.1 Most (if not all) prospective studies on the Methods effect of opioids on the ventilatory control system are per- In May 2012, we searched the electronic database PubMed formed in adults (mostly men). Little information is available (www.ncbi.nlm.nih.gov) for ‘case reports’ on OIRD related to on the occurrence of OIRD in the paediatric population, and opioid intake for a medical indication in the patient (e.g. no comparative data on the effect of different opioids on pain, sedation, cough) or perinatal OIRD due to transfer of breathing are available in children. Since we believe that an opioid from mother to child (see Appendix for the knowledge on the occurrence of OIRD is important to physi- PubMed search strategy). Also case reports mentioned in cians and opioid manufacturers alike, and no randomized the retrieved papers were taken into account, and we (case) controlled trials are available on OIRD in the paediatric retrieved case reports on OIRD by systematically scanning population, we performed, as part of a much larger system- several case report journals (Case Reports in Anesthesiology, atic review of the literature, a search of case reports that de- BMJ Case Reports, Journal of Medical Case Reports, Inter- scribe OIRD in children aged 12 yr or younger. Our aims were national Medical Case Reports Journal). Finally, case reports to review these cases and assess whether we could ﬁnd in our local literature databases were searched for additional

& The Author [2012]. Published by Oxford University Pr ess on behalf of the British Journal of Anaesthesia. All rights reserved. For Permissions, please email: [email protected] Risk of respiratory depression ?

• 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 renal impairment, causing accumulation of the active metabolite of morphine 2) codeine use in patients with ultra-rapid metabolizer CYP2D6 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. (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 with morphine ! • ADRs very unlikely when morphine is titrated carefully ! • Risk factors as for other opioids – Age < 1 year – Comorbidity (renal failure) – Drug–drug interaction – Genetic polymorphisms BCFI-CBIP

• 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 despite prolonged 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 Fentanyl

Copyrights apply 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 CochraneDatabaseof SystematicReviews

Intranasal fentanyl for themanagement of acutepainin children (Review)

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

Intranasal fentanyl

Cochrane Database of Systematic Reviews

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, KandamanyN. Intranasal fentanyl for themanagement of acutepain in children. Murphy A, O’Sullivan R, Wakai A, Grant TS, Barrett MJ, Cronin J, McCoy SC, Hom J, Kandamany N InCtorcharnaanesaDal tfaebnatsaenofySlyfsortemtahtiecRemvaienwasg2e0m14e, Insstuofe10a.cAurtt.eNop.a: CinD0i0n9942. chDOilId: 1r0e.1n00(R2/e1v46ie51w85)8.CD009942.pub2. • Efficacité antalgique comparable à la morphine Murphy A, O’Sullivan R, Wakai A, Grant TS, Barrett MJ, Cronin J, McCoy SC, Hom J, Kandamany N •www.Plusco rapidementchranelibrary .efficomcace 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 !

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. Cochrane Databaseof SystematicReviews 2014, Issue 10. Art. No.: CD009942. DOI: 10.1002/14651858.CD009942.pub2.

www.cochranelibrary.com 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. Cochrane Databaseof 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. www.cochranelibrary.com

• Frequently used in Germany and Australia Often 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 BCFI-CBIP

• 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 children and 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 serious breathing 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 Front in Pharmacol : 2018 Mar 5;9:148

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 CochraneDatabaseof SystematicReviews

Tramadol for postoperative paintreatment inchildren (Review)

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

Cochrane Database of SystematicReviews

Cochrane Databaseof SystematicReviews Tramadol for postoperative pain treatment in children (RScehvnieawb)el A, Reichl SU, Meyer-Frießem C, Zahn PK, Pogatzki-ZahnE.

STchrnaambelaAdo, Reilchfol SrUpo, Mesyetro-FperießreamtiCv,eZapahn PiKn, Ptorgeaatztkmi-ZeahnntEin children. Cochrane Databaseof SystematicReviews 2015, Issue3. Art. No.: CD009574. Tramadol for postoperative pain treatment in children (ReDOvieI:w1)0.1002/14651858.CD009574.pub2. • 20 randomized controled studies essais randomisés contrôlés (n=1170) • ScLowhnabe llevelA, Reic hofl SU evidence, Meyer-Frieße (smallm C, Zahn studiesPK, Pogatzk andi-Zahn methodologicalE problems) www.cochranelibrary.com 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 wasTram notado possible.l for postoperativepain treatment in children (Review) Schnabel A, Reichl SU, Meyer-Frießem C, Zahn PK, Pogatzki-ZahnE. TrCamoapdoyl froirgpohstope©ra2tiv0e1pa7in TtrehatemeCntoincchildrraen.eCollaboration. Published by John Wiley &Sons, Ltd. Cochrane Databaseof SystematicReviews 2015, Issue3. Art. No.: CD009574. DOI: 10.1002/14651858.CD009574.pub2.

www.cochranelibrary.com

Schnabel A, Reichl SU, Meyer-Frießem C, Zahn PK, Pogatzki-ZahnE. Tramadol for postoperative pain treatment in children.

CochTrraamneadoDlaftoar bpoasstoepeofrSatiysvteepamianttriceaRetmveienwt ins c2h0il1dr5e,nIs(Rsueevie3w. A) rt. No.: CD009574. DOIC:o1p0y.r1ig0h0t2©/12401675T1h8e5C8o.CchD0ran0e9C5o7ll4a.bpuorabt2io.n. Published by John Wiley & Sons, Ltd.

www.cochranelibrary.com

Reports of respiratory depression suspected to be attributed 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 Tramadol safety

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 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

Fiche Mémo Prise en charge médicamenteuse de la douleur chez l’enfant : alternatives à la codéine

Janvier 2016

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.

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’informati on (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.

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

• 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 CYP2D6

Tramadol Oxycodone

(Almost inactive)

(More active ?) (Inactive) (Active) 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, We need more data ! or lower the dose !? Tilidine + Naloxone

• Frequently prescribed in Germany (acute and chronic pain) • Lower sides effect ? Inactive • Low potency and ceiling effect ! CYP3A4 • Oral bioavailability : 33% • Prodrug : sequencial metabolisation CYP2C19 and CYP3A4  active nortilidine  inactive bisnortilidine Active • Drug-drug intercation : strong CYP3A4 CYP3A4 and CYP2C19 inhibitors (voriconazole) almost completely inhibit nortilidine formation

Inactive 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 Hydromorphone

Copyrights apply 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 better clinical 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 ?? BCFI-CBIP

• 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 mainly glucuronidation – no active metabolites BCFI-CBIP

• 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. BCFI-CBIP

• Serious ADR are very uncommon when opioids are titrated carefully ! • Healthcare providers and parents should be clearly informed of the potential ADRs for a quicker detection and increased safety • Awareness of the possible ADRs is important but should not lead to underuse of opioids ! • Outside the hospital, physicians should limit opioid prescriptions. Conclusions

• Personalized approaches should include choice of age- adapted dosing formulation, search for drug-drug interaction, comorbities and genetic polymorphism in the near futur. • Morphine may be safer than uncertainty associated with tramadol • Renal failure and hemodynamic instability: avoid morphine and prefer fentanyl or derivates • Tramadol : CYP2D6 activity assessment should allow safer use in the near future. In the meantime, close monitoring of effectiveness and ADRs is necessary before using outside hospital.

6th of february 2020

#beppa @BBeppa