Methadone

Generic name
Methadone
Brand name
ATC Code
N07BC02
Dosages
Side effects in children
Warnings & precautions in children
Contra-indications in children

Interactions
PK
Renal impairment
References

Pharmacokinetics in children

Methadone is well absorbed with bioavailability in adults of more than 80%. Plasma protein binding is about 89%, also there is tissue binding, especially in the liver, lungs, and kidneys. Accumulation takes place with repeated administration. Methadone is mostly converted in the liver by N-demethylation into inactive metabolites and in addition converted by CYP3A4 and to a lesser extent by CYP2D6 and CYP2B6. Renal excretion of methadone is 15-60%, whereas the other part is mostly excreted with the bile.

Age T1/2 (h) (SD) Vd (L) Cl (L/h) Referentie
R-Methadone S-Methadone R-Methadone S-Methadone
Preterm neonates (GA 32wks (26-36; PNA 3 days (0-15); weight 1,6 kg (0,93-2,7), (N=31))ᶻ unknown 26,9 bd 18 bd 0,24 bd 0,17 bd Van Donge 2019
Neonates (PMA 40(3,6) wks; weight 3,2(0,99) kg, (N=7))a unknown 685 L/70kg cE 438 L/70kg cE 7,25 L/h/70kg cE 8,2 L/h/70kg cE Ward 2014
Neonates (GA 38 wks [37,4-39,5]; birthweight 3 kg [2,6 -3,2], (N=20))ᶰ unknown 177 L/70kg bE 8.94 L/h/70kg  bE Wiles 2015
Neonates (GA 40 wks, weight 2900-3610 g, (N=5)) 41(22) unknown unknown Smiee-Zafarghandy 2021
Children (1-18 years (N=15)) 19.2 (range 3,8-62) 7,1, (range 2,4-12) unknown Berde 1987

ᶰ median [IQR], ᶻ median (min-max),a Mean (SD), b Data derived from popPK models and Vd/F or Cl/F, c Intravenous methadone, d Included GA on clearance by power function and on Vd in a linear relationship, E Standardized to a typical (adult) person of 70kg bodyweight.

The following pharmacokinetic parameters were estimated with a popPK model based on data from children with a median age of 14.74 years (IQR 13.62-15.66 years) who had received methadone for perioperative pain (Aruldhas 2021):

Table: Population estimates of pharmacokinetic parameters (95% CI)

  R-methadone S-methadone
Cmax unknown unknown
Tmax unknown unknown
Vd CC1 176 L (113-225 L) 98,3 L (75,4-126 L)
Bio availability (F) 0,72 (0,54-0,91) 0,61 (0,47-0,81)
T1/2 unknown unknown
Clearance (Cl)2 15.7 L/h/70 kg (7.58-24.3 L/h); 13.0 L/h/70 kg (9.35-17.9 L/h);

1) For a typical child with a serum AAG of 94.76 ng/ml
2) Standardized to  a typical (adult) person of 70 kg bodyweight and a CYP2B6 activity score of 1

dose recommendation of formulary compared to licensed use (on-label versus off-label)

No information is present at this moment.

Available formulations

No information is present at this moment.

Dosages

Chronic moderate to severe pain
  • Oral
    • 1 month up to 18 years
      [1] [31] [33]
      • Initial dose: Opioid naive patients: 0.1 mg/kg/day in 2 doses. Max single dose: 5 mg/dose.
      • Maintenance dose: If needed, increase up to 0.3 mg/kg/day in 3 doses. Max: 15 mg/day. Max single dose: 5 mg/dose. If needed,  increase or decrease dose based on effect and side effects.
Opoid withdrawal
  • Oral
    • 1 month up to 18 years
      [38] [39] [40]

      •  

          < 5 days of opoid use  5-15 days of opoid use  ≥ 15 days of opoid use 

        CALCULATE  STARTING DOSE METHADONE

        Conversion and weaning not needed. Discontinue opiate use.

         
        • Convert morphine to methadon in ratio 1:1
          • Morphine in mcg/kg/hour IV : 1000) x 24 = methadone in mg/kg/day oral in 4 divided doses
          • Convert methadone daily dose to single dose (= initial single dose)
            CALCULATION EXAMPLE: 10 mcg/kg/hour morphine = 0,24 mg/kg/day methadone in 4 divided doses = 0,06 mg/kg/dose(initial single dose)
        • Convert fentanyl to methadone in ratio 1:10
          • Fentanyl in mcg/kg/hour IV : 1000) x 24 x 10 = methadone in mg/kg/day oral in 4 divided doses
          • Convert methadone daily dose to single dose (= initial single dose)
            CALCULATION EXAMPLE: 1 mcg/kg/uur fentanyl = 0,24 mg/kg/day methadone in 4 divided doses = 0,06 mg/kg/dose (initial single dose)
        AFBOUWSCHEMA

        100% of initial single dose every 6 hours during 48 uur 

        100% of initial single dose every 8 hours during 48 uur 

        100% of initial single dose every 12 hours during 48 uur 

        100% of initial single dose every 24 hours during 48 uur 

        Stop 

        100% of initial single dose every 6 hours during 48 uur 

        85% of initial single dose every 6 hours during 48 uur  

        85% of initial single dose every 8 hours during 48 uur 

        70% of initial single dose every 8 hours during 48 uur 

        60% of initial single dose every 8 hours during 48 uur 

        45% of initial single dose every 8 hours during 48 uur 

        45% of initial single dose every 12 hours during 48 uur 

        30% of initial single dose every 12 hours during 48 uur 

        0,3* of initial single dose every 24 hours during 48 uur 

        Stop 
Neonatal abstinence syndrome (NAS)
  • Oral
    • Preterm and Term neonate
      [8] [9]

      • Start dose:  0.4 mg/kg/day in 4 doses.

        Titrate starting dose based on NAS scores:

        • NAS score ≥12: consider dose increase (step 1A) and subsequent reduction according to steps 1B and 1C.
          • Step 1A: 0.6 mg/kg/day in 6 doses for 24 hours
          • Step 1B: 0.3 mg/kg/day in 3 doses over 24 hours
          • Step 1C: 0.2 mg/kg/day in 2 doses for 24 hours
        • NAS score 8-12: pause taper
        • NAS score < 8: continue tapering according to the table below

        Weaning scheme:

        0.15 mg/kg/day in 2 doses during 24 hours
        • Average NAS score <8 for past 24h: wean to the next step.
        • Average  NAS score 8-12: do not wean.
        • Average NAS score ≥12: consider extra dose of methadone at the current step, or return to previous step.
        0.1 mg/kg/day in 2 doses during 24 hours
        0.08 mg/kg/day in 2 doses during 24 hours
        0.06 mg/kg/day in 2 doses during 24 hours
        0.04 mg/kg/day in 2 doses during 24 hours
        0.02 mg/kg/day in 2 doses during 24 hours
        0.01 mg/kg/day in 1 dose during 24 hours

Renal impaiment in children > 3 months

GFR ≥10 ml/min/1.73m2: Dose adjustment not required.

GFR <10 ml/min/1.73m2: A general recommendation on dose adjustment cannot be provided.

The complete list of all undesirable drug reactions can be found in the national Summary of Product Characteristics (SmPC) – click here

Side effects in children

The following side effects have been observed in neonates taking morphine or methadone: bradycardia, lethargy, poor nutritional intake, hypothermia. [Davis 2018] Some of these side effects of methaodone in neonates (preterm and full-term) could also be symptoms of NAS.

The complete list of all contra-indications can be found in the national Summary of Product Characteristics (SmPC) – click here

Contra-indications

No information available on specific contra indications in children.

The complete list of all warnings and precautions can be found in the national Summary of Product Characteristics (SmPC) – click here

Warnings & precautions in children

As with adults, bradycardia can occur in children when methadone is used.

Children are more sensitive to the effects of methadone; intoxications can occur at very low doses.

Overdose problems occur, partly because of a relevant risk of cumulation when used for longer than several days due to large variation in elimination half-life.

Interactions

The complete list of all interactions can be found in the national Summary of Product Characteristics (SmPC) – click here

DRUGS USED IN ADDICTIVE DISORDERS

This pages provides a list of drugs from the same ATC class for comparison. This does not necessarily mean that these drugs are interchangeable.

References

  1. Rademaker C.M.A. et al, Geneesmiddelen-formularium voor Kinderen, 2007
  2. Berde CB, et al, Pharmacokinetics of methadone in children and adolescents in the perioperative period., Anesthesiology, 1987, 67, 519
  3. Seddappa R, Methadon dosage for prevention of opioid withdrawl, Pediatric anesth, 2003, 13(9), 805-810
  4. Wheeler AD et al, Bradycardia during methadone therapy in an infant., Pediatr Crit Care Med, 2006, Jan;7(1), 83-5
  5. Kranzlin S, Abstinentie, preventie en behandeling, 2008 (jan)
  6. Ward RM, et al., The pharmacokinetics of methadone and its metabolites in neonates, infants, and children, Paediatr Anaesth, 2014, 24(6), 591-601
  7. Vipond JM, et al., Shortened Taper Duration after Implementation of a Standardized Protocol for Iatrogenic Benzodiazepine and Opioid Withdrawal in Pediatric Patients: Results of a Cohort Study, Pediatr Qual Saf., 2018, 3(3), e079
  8. Hall ES, et al., Cohort Analysis of a Pharmacokinetic-Modeled Methadone Weaning Optimization for Neonatal Abstinence Syndrome, J Pediatr., 2015, 167(6), 1221-5
  9. Wiles JR, et al., Pharmacokinetics of Oral Methadone in the Treatment of Neonatal Abstinence Syndrome: A Pilot Study., J Pediatr., 2015, 167(6), 1214-20
  10. Davis JM, et al., Comparison of Safety and Efficacy of Methadone vs Morphine for Treatment of Neonatal Abstinence Syndrome: A Randomized Clinical Trial., JAMA Pediatr., 2018, 172(8), 741-8
  11. Brown MS, et al., Methadone versus morphine for treatment of neonatal abstinence syndrome: a prospective randomized clinical trial., J Perinatol, 2015, 35(4), 278-83
  12. van Donge T, et al., Methadone dosing strategies in preterm neonates can be simplified, Br J Clin Pharmacol., 2019, 85(6), 1348-56
  13. Samiee-Zafarghandy S, et al., Pharmacometric Evaluation of Umbilical Cord Blood Concentration-Based Early Initiation of Treatment in Methadone-Exposed Preterm Neonates, Children (Basel)., 2021, 8(3)
  14. Berde CB, et al., PHARMACOKINETICS OF METHADONE IN CHILDREN AND ADOLESCENTS IN THE PERIOPERATIVE PERIOD, Anesthesiology, 1987, 67(3), A519-A
  15. Rosen TS, Pippenger CE., Pharmacologic observations on the neonatal withdrawal syndrome, The Journal of Pediatrics, 1979, 88(6), 1044-8
  16. Gjedsted J, et al, Severe hypoglycemia during methadone escalation in an 8-year-old child., Acta Anaesthesiol Scand, 2015, 59(10), 1394-6
  17. Mack G, et al, Methadone levels and neonatal withdrawal., J Paediatr Child Health, 1991, 27(2), 96-100
  18. Wilson AK, et al., Exposure-Based Methadone and Lorazepam Weaning Protocol Reduces Wean Length in Children., J Pediatr Pharmacol Ther., 2021, 26(1), 42-9
  19. Werkgroep Neonatale Farmacologie NVK sectie Neonatologie,, Expert opinie, 13 november 2018
  20. Amos LB, et al, Severe central sleep apnea in a child with leukemia on chronic methadone therapy., Pediatr Pulmonol., 2013, 48(1), 85-7
  21. Habashy C, et al, Methadone for Pain Management in Children with Cancer. , Paediatr Drugs., 2018, 20(5), 409-16
  22. Solodiuk JC, et al, Effect of a Sedation Weaning Protocol on Safety and Medication Use among Hospitalized Children Post Critical Illness, J Pediatr Nurs, 2019, 49, 18-23
  23. Smith HAB, et al. , Society of Critical Care Medicine Clinical Practice Guidelines on Prevention and Management of Pain, Agitation, Neuromuscular Blockade, and Delirium in Critically Ill Pediatric Patients With Consideration of the ICU Environment and Early Mobility, Pediatr Crit Care Med, 2022, 23(2), e74-e110
  24. Ávila-Alzate JA, , Assessment and treatment of the withdrawal syndrome in paediatric intensive care units: Systematic review., Medicine (Baltimore), 2020, 99(5), e18502
  25. LeBlanc Z, et al., Management of severe chronic pain with methadone in pediatric patients with sickle cell disease, Pediatr Blood Cancer, 2018, 65(8), e27084
  26. Thigpen JC, et al, Opoids: A Review of Pharmacokinetics and Pharmacodynamics in Neonates, Infants, and Children_, Eur J Drug Metab Pharmacokinet., 2019, 44(5), 591-609
  27. Madden K, et al, Very-Low-Dose Methadone To Treat Refractory Neuropathic Pain in Children with Cancer, J Palliat Med, 2017, 20(11), 1280-3
  28. Madden K, et al., The frequency of QTc prolongation among pediatric and young adult patients receiving methadone for cancer pain, Pediatr Blood Cancer., 2017, 64(11)
  29. Mulder DJ, et al , NMDA-receptor Antagonism in Pediatric Pancreatitis: Use of Ketamine and Methadone in a Teenager With Refractory Pain, J Pediatr Gastroenterol Nutr., 2018, 66(5), e134-e6
  30. Robertson RC, et al, Evaluation of an opiate-weaning protocol using methadone in pediatric intensive care unit patients., Pediatr Crit Care Med, 2000, 1(2), 119-23
  31. Madden K, et al, Methadone as the Initial Long-Acting Opioid in Children with Advanced Cancer., J Palliat Med., 2018, 21(9), 1317-21
  32. Walters RA, et al., Iatrogenic Opiate Withdrawal in Pediatric Patients: Implementation of a Standardized Methadone Weaning Protocol and Withdrawal Assessment Tool. , J Pharm Pract., 2021, 34(3), 417-22
  33. Friedrichsdorf SJ., From Tramadol to Methadone: Opioids in the Treatment of Pain and Dyspnea in Pediatric Palliative Care, Clin J Pain, 2019, 35(6), 501-8
  34. Aruldhas BW, et al., Pharmacokinetic modeling of R and S-Methadone and their metabolites to study the effects of various covariates in post-operative children., CPT Pharmacometrics Syst Pharmacol., 2021, 10(10), 1183-94
  35. Johnson PN,et al, Selection of the initial methadone regimen for the management of iatrogenic opioid abstinence syndrome in critically ill children, Pharmacotherapy, 2012, 32(2), 148-57
  36. Hudak ML, et al, Neonatal drug withdrawal, Pediatrics, 2012, 129(2), e540-60
  37. Wiles JR, et al., Pharmacokinetics of Oral Methadone in the Treatment of Neonatal Abstinence Syndrome: A Pilot Study., J Pediatr., 2015, 167(6), 1214-20.e3
  38. Ad hoc Expert Werkgroep Methadon Nederlandse kinder-intensivisten en ziekenhuisapothekers, Expert opinion, Jan 2025
  39. De Hoop M, et al, Simulations PBPK modelling (manuscript in preparation), 2025
  40. Ford J, et al., Implementation of an Opioid Weaning Protocol at a Tertiary Care Children's Hospital. , Hosp Pediatr., 2022, Nov 1;12(11), 945-953

Changes

Therapeutic Drug Monitoring


Overdose