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Use of Tramadol in Children

Use of Tramadol in Children. R3 정상우. Introduction. Availability of potent analgesics for children is limited Paracetamol, NSAIDs, opioids Paracetamol and regional techniques Proper dosing and be effective in relieving moderate to severe pain is still needed Tramadol

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Use of Tramadol in Children

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  1. Use of Tramadol in Children R3 정상우

  2. Introduction • Availability of potent analgesics for children is limited • Paracetamol, NSAIDs, opioids • Paracetamol and regional techniques • Proper dosing and be effective in relieving moderate to severe pain is still needed • Tramadol • Launched 30 years ago in Germany • New oral tablet form (paracetamol + tramadol) • Not yet approved for use in children

  3. Pharmacodynamic profile • Synthetic 4-phenyl-piperidine analog of codeine • Racemic mixture of (+) and (-) enantiomers • Mechanisms • Opioid activity • Low affinity binding of (+) enantiomer to μ-opioid receptors • Central analgesic effects are partially reversed by naloxone • Monoaminergic mechanism • (+) enantiomer : inhibits serotonin uptake and has direct serotonin-releasing action • (-) enantiomer : more effective inhibitor of norepinephrine reuptake and increases its release

  4. Pharmacodynamic profile • O-desmethylated metabolite (M1) • 300-fold higher affinity to bind μ-opioid receptors • Analgesic potency : medium • 1/10 of morphine, 1/5 of nalbuphine, equivalent of pethidine, oxycodone • At least the equivalent of ketamine and NSAIDs • Advantages over opioids • Lower incidence of side effects • Ventilatory depression, nausea-vomiting (NV), constipation, sedation • No clinically relevant effects on HR and BP

  5. Pharmacodynamic profile • Adverse effects • Overall : > 15% in adults (higher dose ↑) • No report of respiratory depression and sedation • Kralinsky • 11.7% (n=77), increased by chronic use • Finkel et al. • NV (9-10%), pruritis (7%), rash (4%) • Others • Absence of effect on sphincter of Oddi, low potential for dependence or abuse, reduced postoperative shivering

  6. Pharmacodynamic profile • Does not inhibit PG synthesis • Substitution for NSAIDs • peptic ulcer, asthma, renal impairment • Incidence of seizure < 1% • Exceeding dose • Lethargy, nausea, tachycardia, agitation, seizure, coma, HTN, respiratory depression • Sedation and apnea • Can be reversed in 50% of cases by naloxone • No serious cardiotoxicity

  7. Pharmacokinetic profile • Extensive metabolization in liver (GI route) • CYP2D6 sparteine-oxygenase • Produce O-desmethylated metabolite (M1) • Parent drug and metabolites • Excreted via kidneys (90%) • Ondansetron (5-HT3 antagonist) • May decrease efficacy of tramadol • 5-HT3 receptors play a role in pain transmission at the spinal level

  8. Pharmacokinetic profile • Oral tramadol • Bioavailability • 68% after single dose, 100% after multiple doses • Onset of action : 30 min to 1 h • Peak concentration : 2 h • Tramadol drops (1.5 mg/kg, 4-7세) • Maximum serum conc. at 30 min • Conc. above analgesic level for 7 h • Elimination half-life, serum clearance, conc. of metabolites are similar to healthy young adults

  9. Pharmacokinetic profile • Rectal route (1-6세) • Well-absorbed, low variability in absorption and clearance • Max. serum conc. of tramadol : 2.4 ± 1 h • Max. serum conc. of metabolite : 3.9 ± 1.1 h • I.V. • Max. serum conc. : 0.19 ± 0.06 h • Max. serum conc. of metabolite : around 5 h • Murthy et al. (1-12세) • Mean serum conc. of tramadol and metabolite after single dose IV were slightly higher than adults

  10. Pharmacokinetic profile • Children require similar bodyweight-related doses to adults via the IV route • Allegaert et al. • Total clearance of tramadol reached 84% of adult value by 44 weeks postconceptual age • Documented the presence of CYP2D6 activity in early neonatal life • Caudal administration • Peak conc. of tramadol : 0.5 ± 0.11 h • Murthy et al. • Speculated the analgesic efficacy could be attributed to extensive systemic availability

  11. Clinical Use in Pediatric Anesthesia • Perioperative pain treatment • The gastrointestinal route • The parenteral route • Intramuscular • Intravenous • Novel routes • Caudal epidural • Local infiltration and blocks • Chronic pain treatment

  12. The gastrointestinal route • Payne and Roelofse • 71 children, extraction of six or more teeth • Drops 1.5 or 3 mg/kg with concomitant oral MDZ 0.5 mg/kg 30 min prior to induction • Postop. analgesia superior to that of placebo • Rescue analgesic (paracetamol 120 mg) • tramadol : placebo = 20% : 83-100% • Postop. oral tramadol 1mg/kg vs 2mg/kg • 8 h follow-up : 1 mg/kg group required more supplemental analgesics at an earlier time • Good or excellent in 80% of all cases

  13. The gastrointestinal route • Zwaveling et al. • Suppositories consisting of 25 mg tramadol • 100 mg tramadol are available in some countries • At least 1.5 mg/kg required for pain treatment after minor surgery

  14. The parenteral route • Intramuscular • 0.75-1-2 mg/kg to compare with pethidine 1 mg/kg or nalbuphine 0.15-0.2-0.1 mg/kg on moderate to severe postop. pain • Provided equivalent analgesia • In children, intramuscular route should be avoided whenever possible

  15. The parenteral route • Intravenous • 2 mg/kg was found best for analgesic action with minimal side effects • Slow IV injection decrease adverse effects • When 1 mg/kg used, NSAID should be added • Double-blind placebo-controlled study • 1-3세, adenoidectomy, n=80 • 2 mg/kg of tramadol + preop. rectal ibuprofen 10 mg/kg • No need of rescue analgesic : 45% vs 15% • All pts. required additional analgesia at home

  16. The parenteral route (I.V.) • Tonsillectomy, 2-9세 • 1st group : tramadol 3 mg/kg after induction, rectal tramadol 2.5 mg/kg • 2nd group : proparacetamol 30 mg/kg, rectal paracetamol 15 mg/kg • 3 times for 3 days • Tramadol provided better analgesia with similar incidence of adverse effects • Preop. tramadol and nerve block • Unilateral hernia repair • Preop. IV tramadol 1.5 mg/kg compared with ilioinguinal-iliohypogastric nerve block with 0.5% bupivacaine (0.25 mg/kg)

  17. The parenteral route (I.V.) • Tramadol provided at least the same analgesic effect as that of ilioinguinal-iliohypogastric nerve block, with a superior effect at the time of maximal analgesia (2-3 h after injection) • Incidence of emesis was significantly higher • Preemptive analgesic effect with tramadol • Ozkose et al., Chiaretti et al. • Technical problem • Not enough time elapsed to reach peak effect • Further studies should be performed

  18. The parenteral route (I.V.) • Continous infusion • Kralinski et al. • 0.1-0.25 mg/kg/h to 1-16 year old children • Decrease dose to 0.07-0.15 mg/kg/h when benzodiazepines or barbiturates are coadministered • 0.1-0.2 mg/kg/h combined with boluses of 1-2 mg/kg provided sufficient postop. analgesia in 13 newborns after medium-traumatic op. • 80% of neonates : Dose-dependent hypercapnia • Indicates tramadol affects respiratory center during the neonatal period • Monitor constantly respiratory functions during and after tramadol therapy

  19. The parenteral route (I.V.) • Nurse-controlled analgesia (NCA) • 30 children, mean age 9.5 months, 6 mg/kg/24h • Initial dose : 0.5 mg/kg • Bolus injection : 0.3 mg/kg • Interval : 10 min • Highest dose : 1.2 mg/kg/4h • Recommended for postsurgical pain as an alternative to morphine infusion or PCA in infants

  20. Novel routes • Caudal epidural • Several reports since 1997 • Parallel or contradictory to each other • Koc et al. • Glial cell reaction : 6 ㎍ in 10 ㎕ normal saline intracerebroventricular (rats) • Disruption of membrane fluidity of BBB : 200 ㎍ in 0.2 ml normal saline into intracisternal subarachnoid space (rabbits)

  21. Novel routes • Gursoy et al. • Neurotoxicity : intrathecal tramadol 1-8 mg/kg in 1 ml volume after 24 h (rabbits) • Clarify myoclonus and death 48 h after accidental intrathecal injection of tramadol • Safety and neurotoxicity in the epidural space has not been proved in animal studies • Not licensed for use by this route • Murthy et al. • Equal efficacy and duration between epidural and enteral-parenteral routes • Use by this epidural route should be abandoned

  22. Novel routes • Local infiltration and blocks • Specific analgesic effects of tramadol • Prolongation of analgesic effect of axillary BPB, psoas compartment block, subcutaneous infiltration • Demiraran et al. (unpublished study) • Herniorrhaphy, 1-6세 • Equal analgesic effect through subincisional injection of 2 mg/kg of tramadol and 0.2 ml/kg 0.25% bupivacaine

  23. Chronic pain treatment • Oral tramadol • Effective analgesic in step 2 of WHO’s guidelines for cancer pain • Rose et al. • 1 mg/kg every 4-6 h in 113 children aged 7-16 years for 7-30 days • Very good or excellent by 69% of parents • Adverse events (NV, abdominal pain, dizziness, headache, somnolence, fatigue, pruritis) were rated mild to moderate • Only 12 patients discontinued the therapy

  24. Summary • Tramadol seems a very promising drug in pediatric pain treatment, analgesic potency intermediate between NSAIDs and opioids • Several forms of systemic preparations make its use easier in children • One of the options in multimodal pain treatment approach in postoperative and chronic pain in children • Caudal administration should be stopped

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