Use of Tramadol in Children R3. Introduction Availability of potent analgesics for children is limited Paracetamol, NSAIDs, opioids Paracetamol and regional.

Use of Tramadol in Children

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Introduction

Availability of potent analgesics for children is limited

Paracetamol, NSAIDs, opioids Paracetamol and regional techniques Proper dosing and be effective in relieving moder

ate 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

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 recep

tors Central analgesic effects are partially reversed by nalo

xone Monoaminergic mechanism

(+) enantiomer : inhibits serotonin uptake and has direct serotonin-releasing action

(-) enantiomer : more effective inhibitor of norepinephrine reuptake and increases its release

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

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 fo

r dependence or abuse, reduced postoperative shivering

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

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

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, 4-7 세 )

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

Pharmacokinetic profile Rectal route (1-6 세 )

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. (1-12 세 )

Mean serum conc. of tramadol and metabolite after single dose IV were slightly higher than adults

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

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

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

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 af

ter minor surgery

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 avoide

d whenever possible

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

1-3 세 , 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

The parenteral route (I.V.) Tonsillectomy, 2-9 세

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 inciden

ce of adverse effects Preop. tramadol and nerve block

Unilateral hernia repair Preop. IV tramadol 1.5 mg/kg compared with ilioinguin

al-iliohypogastric nerve block with 0.5% bupivacaine (0.25 mg/kg)

The parenteral route (I.V.) Tramadol provided at least the same analgesic effect a

s 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

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 benzodiazepin

es or barbiturates are coadministered 0.1-0.2 mg/kg/h combined with boluses of 1-2 mg/kg prov

ided sufficient postop. analgesia in 13 newborns after medium-traumatic op.

80% of neonates : Dose-dependent hypercapnia Indicates tramadol affects respiratory center during the neo

natal period Monitor constantly respiratory functions during and after tra

madol therapy

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 t

o morphine infusion or PCA in infants

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)

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

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, 1-6 세 Equal analgesic effect through subincisional injection o

f 2 mg/kg of tramadol and 0.2 ml/kg 0.25% bupivacaine

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 y

ears for 7-30 days Very good or excellent by 69% of parents Adverse events (NV, abdominal pain, dizziness, h

eadache, somnolence, fatigue, pruritis) were rated mild to moderate

Only 12 patients discontinued the therapy

Summary Tramadol seems a very promising drug in pediatr

ic 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