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

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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 • Effects of each opioids depend on : 1) Organ maturation Titration monitor 2) Genetic polymorphism efficiency AND 3) Drug–drug interactions adverse reactions ! 4) Comorbidities 1) Organ maturation (< 1 year) 1) Organ maturation (< 1 year) • 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),
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