Tramadol

Generic name
Tramadol
Brand name
ATC Code
N02AX02
Dosages
Side effects in children
Warnings & precautions in children
Contra-indications in children

Interactions
PK
Renal impairment
References

Pharmacokinetics in children

Tramadol is metabolized into the active metabolite O-desmethyltramadol (M1) by CYP2D6 and into N-desmethyltramadol (M2) by CYP2D6 and CYP3A4.

Neonates and Infants (< 1 years)

The formation rate of O-desmethyltramadol via CYP2D6 increase over the neonatal period, reaches adult CYP2D6 activity levels around 1 year of age. In addition, the immature glucuronidation (e.g. UGT2B7) and renal function may result in slower elimination and accumulation of O-desmethyltramadol in children less than 1 year of age, especially in the first week of postnatal life. 

A population-PK-study by Allegaert et. al. 2005 the following age-related PK parameters were predicted with based on the covariate models (Allegaert 2005):

Age (weight (kg)1)

25 wks PCA (0.6 kg)

30 wks PCA (1.3 kg)

35 wks PCA (2.5 kg)

40 wks PCA (3.3 kg)

45 wks PCA (4.5 kg)

50 wks PCA (5.5 kg)

60 wks PCA (7,5kg)

1 yr PNA (10kg)

3 yrs PNA (14kg)

Adult (70kg)

Cl (ml/min/kg)

4.32

7.08

8.12

8.96

9.19

9.4

9.32

9.22

8.54

5.71

Central Vd (L/kg)

3.66

3.51

3.38

3.26

3.15

3.05

2.88

2.54

2.18

2.13

Peripheral Vd (L/kg)

0.57

0.57

0.57

0.57

0.57

0.57

0.57

0.57

0.57

0.57

1. Weight is estimated within each age group, based on weight of participants within studies until 50 wks PCA.  
PCA= postconceptional age
PNA = postnatal age

1 year to 16 years

The pharmacokinetics of tramadol and O-desmethyltramadol after single and multiple oral dosing were generally similar to those in adults when dose-adjusted based on body weight, but with a higher inter-subject correlation variability in children aged ≤8 years  (SmPC Tramal Injection fluid 01/2022)

Reference

Route of administration

 

Dose

Population

 

CL (ml/min/kg)

Tramadol

Vd  (l/kg)

Tramadol

active O-desmethyl-metabolite

Cmax (ng/ml)

(mean+SD)

Tmax (h)

(mean+SD)

T ½ (h)

 

Cmax (ng/ml)

(mean+SD)

Tmax (h)

(mean+SD)

T ½ (h)

 

Vandenbosche et al. 2015 

Oral  (immediate release tablets)

mean 1.5mg/kg/dose every 6 hours for 3 days

7-11 years (n=6)

8,2±1,0

 

 

362±94

1,7±0,5

 

89±40

1,8±0,8

 

12-16 years (n=11)

9,7±3,3

 

 

242±116

1,9±0,8

 

89±33

2,1±1,0

 

 

Payne et al. 2002

oral (single administration, drops)

1.5 mg/kg

4-7 years

(n=24)

5,6±2,7

4,1±1,2

 

< 0,5

3,6±1,1

37,5±5,2

4,5±1,5

5,8±1,7

Zwaveling et al. 2004 1

Rectal (single administration)

1-1.9 mg/kg

1-6 years (n=12)

15.5

6.1

200±60

2,4±1,0

4,3±0,22

35±15

3,9±1,1

 

1. The age-related PK parameters were predicted in population-PK study.
2. (mean±SEM)

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

Pain
  • Intravenous
    • Term neonates and 1 month up to 1 year
      • 1 - 2 mg/kg/dose as needed depending on clinical efficacy, safety and tolerability. Max: 8 mg/kg/day.  .

      • Alternative: 1-2 mg/kg over 30 min, then 0.1 - 0.2 mg/kg/h as continuous infusion. Max. 8 mg/kg/day

    • Preterm neonates Gestational age < 34 weeks
      • 1 - 2 mg/kg/dose as needed depending on clinical efficacy, safety and tolerability. Max: 8 mg/kg/day.  .

      • Alternative: 1-2 mg/kg over 30 min, then 0.1 - 0.15 mg/kg/h as continuous infusion. Max. 8 mg/kg/day

    • Preterm neonates Gestational age ≥ 34 weeks
      • 1 - 2 mg/kg/dose as needed depending on clinical efficacy, safety and tolerability. Max: 8 mg/kg/day.

      • Alternative: 1-2 mg/kg over 30 min, then 0.1 - 0.2mg/kg/h as continuous infusion. Max. 8 mg/kg/day.

    • Normal preparation (immediate release)
      • 1 year up to 12 years
        • 1 - 2 mg/kg/dose As required based on effect and tolerance.. Max: 8mg/kg/day, but not exceeding 400 mg/day.  .

        • Alternative: continuous infusion: 0,5-1 mg/kg as a bolus, then 0.1-0.25 mg/kg/hour as a continuous infusion, max 400 mg/day

    • Regulated release
      • 12 years up to 18 years
        • 50 - 100 mg/dose As required based on effect and tolerance. Max: 400 mg/day.  .

        • Alternative: continuous infusion: 0,5-1 mg/kg as a bolus, then 0.1-0.25 mg/kg/hour as a continuous infusion, max 400 mg/day

  • Oral
    • Normal preparation (immediate release)
      • 1 year up to 12 years
        • 1 - 2 mg/kg/dose as required based on effect and tolerance max 4 times daily. Max: 8mg/kg/day, but not exceeding 400 mg/day. Max single dose: 100 mg/dose.
      • 12 years up to 18 years
        • 50 - 100 mg/dose as required based on effect and tolerance max 4 times daily.. Max: 400 mg/day.
    • Regulated release
      • 12 years up to 18 years
        • 50 - 100 mg/dose as required increase dose gradually based on effect and tolerance to 150-200 mg 2 dd. Max: 400 mg/day.

        • The "once daily" tablets: 200 mg 1dd, increase gradually based on effect and tolerance to max 400 mg/day

  • Rectal
    • 1 year up to 12 years
      • 1 - 2 mg/kg/dose, as required, max. 4x daily. Max single dose: 100 mg/dose.
    • Regulated release
      • 12 years up to 18 years
        • 100 mg/dose As required based on effect and tolerance up to 4 times daily.

Renal impaiment in children > 3 months

Adjustment in renal impairment as specified:

GFR 50-80 ml/min/1.73 m2
Dose adjustment is not required
GFR 30-50 ml/min/1.73 m2
Dose adjustment is not required
GFR 10-30 ml/min/1.73 m2
100 percentage of single dose and dosing interval : 12 uur
GFR < 10 ml/min/1.73 m2
Generalized recommendations cannot be given.

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

Nausea, vomiting, headache.

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

Contra-indications in children

  • The effervescent tablet should not be used in children with phenylketonuria at doses of > 200 mg.
  • Post-operative pain relief in the home situation after tonsillectomy and adenoidectomy.

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

Children are more likely to suffer respiratory depression when using tramadol in all procedures/conditions in which the airway could be obstructed in any way (FDA safety announcement 20-Apr-2017, Anderson et al. 2017).

Oral administration
Careful with dosing the droplet solution, as some preparations have a very high concentrations (e.g. 100 mg/ml, 1 droplet contains 2.5 mg tramadol). 

In chronic pain, always prescribe in combination with a laxative.

Pharmacogenetics.
The occurrence of serious adverse reactions or lack of effect may be due to abnormal drug metabolism. CYP2D6 may determine the variation in response. Genotyping may be considered.

Interactions

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

OPIOIDS

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

Natural opium alkaloids
N02AA03
N02AA01
N02AA05
N02AA59
Phenylpiperidine derivatives
N02AB03
N02AB03
N02AB02
Diphenylpropylamine derivatives
N02AC06
N02AC03
Oripavine derivatives
N02AE01
Morphinan derivatives
N02AF02
Other opioids
N02AX06
N02AX01
Opioids in combination with non-opioid analgesics
N02AJ13

References

  1. Nederlandse Vereniging voor Anesthesie (NVA), Richtlijn postoperatieve pijn, 2012
  2. Grünenthal BV, SPC Tramal (RVG 15513/15511/15510) 26-01-2020, www.geneesmiddeleninformatiebank.nl
  3. FDA, FDA restricts use of prescription codeine pain and cough medicines and tramadol pain medicines in children; recommends against use in breastfeeding women, https://www.fda.gov, 2017
  4. Anderson BJ et al., Tramadol: keep calm and carry on, Paediatr Anaesth, 2017, Aug;27(8), 785-788
  5. Libra-Pharm, SmPC LIBRAPHARM ® Zäpfchen, 100 mg (13144.00.00), 06/2016
  6. Libra-Pharm, SmPC LIBRAPHARM® 50 mg/100 mg, Injektionslösung (13144.00.03/ 13144.01.03), 06/2016
  7. Mylan dura, SmPC Tramadol Mylan Lösung zum Einnehmen (6006921.00.00), 02/2017
  8. ratiopharm, SmPC Tramadol-ratiopharm® 50 mg Hartkapseln/- 50 mg Brausetabletten Tramadol-ratiopharm® 100 mg/ml Tropfen (31518.00.00/ 31375.00.00/ 31467.00.00), 09/2013
  9. ratiopharm, SmPC Tramadol-ratiopharm® 50 mg / 150 mg / 200 mg Retardkapseln (54390.00.00/ 54390.02.00/ 54390.03.00), 03/2017
  10. MEDA, SmPC Travex® one (46414.00.00/46414.01.00/46414.02.00/46414.03.00), 03/2017
  11. ALIUD PHARMA®, SmPC Tramadol AL Retardtabletten (53804.00.00/ 53804.01.00/ 53804.02.00), 06/2016
  12. Grünenthal, SmPC Tramal long (60444.00.00/ 37294.00.00/ 37294.01.00/ 37294.02.00), 06/2016
  13. AbZ Pharma, SmPC Tramadol AbZ 100 mg / 150 mg / 200 mg Retardkapseln (54390.01.00/ 62758.01.00/ 62758.02.00), 03/2017
  14. Hexal, SmPC Tramadol Sandoz® 100 mg Brausetabletten (39935.00.00), 03/2017
  15. STADApharm, SmPC Tramadol STADA® 50 mg Tabs (37814.00.00), 11/2014
  16. Hexal, SmPC Tramadolor 100 mg Brause (37201.01.00), 03/2017
  17. Libra-Pharm, SmPC LIBRAPHARM® Kapseln, 50 mg, Hartkapseln (13144.00.01), 06/2016
  18. AbZ-Pharma, SmPC Tramadol-CT (25527.00.01/ 25527.00.00/ 25527.00.02), 03/2017
  19. Grünenthal, SmPC Tramal® Kapseln, 50 mg, Hartkapseln (1116.00.00), 06/2016
  20. Mundipharma, SmPC Tramundin® 50 mg Filmtabletten (6391213.00.00), 08/2016
  21. Hexal, SmPC Tramadolor tabs (6584337.00.00), 02/2017
  22. Krewel Meuselbach, SmPC Tramagit® Tabletten (6140209.00.00), 06/2016
  23. Grünenthal, SmPC Tramal Tabletten, 50 mg (28705.00.00), 06/2016
  24. Mundipharma, SmPC Tramundin® 100 mg/ml Lösung zum Einnehmen (25526.00.00), 06/2017
  25. STADApharm, SmPC Tramadol STADA® 100 mg Zäpfchen (25037.00.00), 05/2017
  26. Ratiopharm, SmPC Tramadol-ratiopharm® 50 mg/ml, 100 mg/2 ml Injektionslösung (32305.00.00/ 6025891.00.00), 03/2017
  27. Grünenthal, SmPC Tramal® Zäpfchen, 100 mg (13143.00.00), 06/2016
  28. Grünenthal, SmPC Tramal 50 mg, 100 mg Injektionslösung (1116.01.02/ 1116.00.02), 01/2022
  29. Hexal, SmPC Tramadolor® long (42433.00.00/ 42433.01.00/ 42433.02.00/ 42433.03.00), 05/2017
  30. Grünenthal, SmPC Tramal® 100 mg/ml, Lösung zum Einnehmen (1116.00.01), 06/2016
  31. Mundipharma Pharmaceuticals B.V., SmPC Tramagetic (RVG 22232/22233/22234/22235) 13-04-2018, www.geneesmiddeleninformatiebank.nl
  32. Zwaveling, J., et al., Pharmacokinetics of rectal tramadol in postoperative paediatric patients, Br J Anaesth, 2004, 93 (2), 224-7
  33. Griessinger, N., et al., Tramadol infusion for pain therapy following bladder exstrophy surgery in pediatric wards, Urologe A, 1997, 36 (6), 552-6
  34. Grünenthal B.V., SmPC Tramal retard (RVG 22361/22362/22363) 16-01-2020, www.geneesmiddeleninformatiebank.nl
  35. Vandenbossche, J., et al., Single- and multiple-dose pharmacokinetic studies of tramadol immediate-release tablets in children and adolescents., Clin Pharmacol Drug Dev, 2015, 4 (3), 184-92
  36. Payne, K. A., et al., Pharmacokinetics of oral tramadol drops for postoperative pain relief in children aged 4 to 7 years--a pilot study, 2002, Anesth Prog, 49 (4), 109-12
  37. Chiaretti, A., et al., Preemptive analgesia with tramadol and fentanyl in pediatric neurosurgery., Childs Nerv Syst, 2000, 16 (2), 93-9; discussion 100
  38. Moyao-García, D., et al., A pilot study of nalbuphine versus tramadol administered through continuous intravenous infusion for postoperative pain control in children, 2009, Acta Biomed, 80 (2), 124-30
  39. Olischar M, et al. , The addition of tramadol to the standard of i.v. acetaminophen and morphine infusion for postoperative analgesia in neonates offers no clinical benefit: a randomized placebo-controlled trial. , Paediatr Anaesth, 2014, 24(11), 1149-57
  40. Alencar AJ, et al., Efficacy of tramadol versus fentanyl for postoperative analgesia in neonates. , Arch Dis Child Fetal Neonatal Ed., 2012, 97(1), F24-9
  41. Werkgroep Neonatale Farmacologie NVK sectie Neonatologie., Expert opinion on the bases of extrapolation of data from other age groups. , 17 June 2024
  42. Allegaert K, et al., Tramadol disposition in the very young: an attempt to assess in vivo cytochrome P-450 2D6 activity., Br J Anaesth, 2005, 95(2), 231-9
  43. Olischar M, et al., The addition of tramadol to the standard of i.v. acetaminophen and morphine infusion for postoperative analgesia in neonates offers no clinical benefit: a randomized placebo-controlled trial., Paediatr Anaesth, 2014, 24(11), 1149-57
  44. Werkgroep Neonatale Farmacologie NVK sectie Neonatologie., Expert opinion on the bases of extrapolation of data from other age groups., 17 June 2024
  45. Alencar AJ, et al., Efficacy of tramadol versus fentanyl for postoperative analgesia in neonates., Arch Dis Child Fetal Neonatal Ed., 2012, 97(1), F24-9

Changes

Therapeutic Drug Monitoring


Overdose