Farmacoriflessioni
Tramadolo: valida alternativa alla codeina?
Tramadol: an effective alternative to codeine?
Anna Di Sessa1, Pierluigi Marzuillo1, Lorenzo Calligaris2, Ingrid Rabach2, Stefano Furlan2, Egidio Barbi2
1Dipartimento della Donna, del Bambino e di Chirurgia Generale e Specialistica, Seconda Università di Napoli
2IRCCS Materno-Infantile “Burlo Garofolo”, Trieste
Gennaio 2016 - pagg. 41 -45
Abstract
In June 2013, the European Medicine Agency (EMA) prohibited the use of medicines
containing codeine for patients under 12 years of age. The EMA recommendations impose
a change in the management of moderate-severe pain in children. Tramadol, an
opioid-related analgesic with an intermediate analgesic potency between NSAIDs and
major opioids, is a possible substitute for codeine in children. It shows less respiratory
depression and sedation as well as other adverse effects of opioids and also has no clinically
relevant effects on heart rate and blood pressure. It acts like a weak or partial
agonist with no affinity for δ e κ opioid receptors and its central analgesic effects are
partially reversed by naloxone. According to the available evidence, tramadol appears
to be efficacious in the management of moderate-severe pain in children and safe both
in inpatients and outpatients with no case of paediatric respiratory depression at therapeutic
dosage being currently reported in the literature. Nevertheless, it may be appropriate
to limit the use of tramadol to monitored settings for children with specific risk factors
(adeno-tonsillectomy, sleep apnoea, obesity, renal impairments and the neonatal
period), subject to further safety evidence. This review takes into consideration the available
evidence on the pharmacokinetic and pharmacodynamic efficacy and safety profile
of tramadol.
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Bibliografia
1. European Medicines Agency (EMA). Review
of codeine-containing medicines started.
2012. http://www.ema.europa.eu/docs/
en_GB/document_library/Referrals_document/
Codeine_containing_medicinal_products/
Procedure_started/WC500133297.pdf.
2. Panizon F, Barbi E. Il dolore: le vie, i segni,
i tempi, le cure. Alcune specificità del dolore
in pediatria. Riassunto e revisione delle
conoscenze e della pratica. Medico e Bambino
2010;29(5):289-301.
3. Leppert W. Tramadol as an analgesic for
mild to moderate cancer pain. Pharmacol
Rep 2009;61:978-92.
4. Marzuillo P, Calligaris L, Barbi E. Tramadol
can selectively manage moderate pain in
children following European advice limiting
codeine use. Acta Paediatr 2014;103(11):
1110-6.
5. Lee CR, McTavish D, Sorkin EM. Tramadol.
A preliminary review of its pharmacodynamic
and pharmacokinetic properties, and
therapeutic potential in acute and chronic
pain states. Drugs 1993;46:313-40.
6. Lintz W, Barth H, Becker R, Frankus E,
Schmidt-Böthelt E. Pharmacokinetics of tramadol
and bioavailability of enteral tramadol
formulations. 2nd communication: Drops
with ethanol. Arzneimittelforschung 1998;
48:436-45.
7. Lintz W, Barth H, Osterloh G, Schmidt-
Böthelt E. Bioavailability of enteral tramadol formulations. 1st Communication: capsules.
Arzneimittelforschung 1986;36:1278-83.
8. Scott LJ, Perry CM. Tramadol: a review of
its use in perioperative pain. Drugs 2000;60:
139-76.
9. Neri E, Maestro A, Minen F, et al. Sublingual
ketorolac versus sublingual tramadol for
moderate to severe post-traumatic bone pain
in children: a double-blind, randomised, controlled
trial. Arch Dis Child 2013;98:721-4.
10. Lintz W, Barth H, Osterloh G, Schmidt-
Böthelt E. Pharmacokinetics of tramadol and
bioavailability of enteral tramadol formulations.
3rd Communication: suppositories.
Arzneimittelforschung 1998;48:889-99.
11. Zwaveling J, Bubbers S, van Meurs AH,
et al. Pharmacokinetics of rectal tramadol in
postoperative paediatric patients. Br J Anaesth
2004;93:224-7.
12. Lintz W, Beier H, Gerloff J. Bioavailability
of tramadol after i.m. injection in comparison
to i.v. infusion. Int J Clin Pharmacol Ther
1999;37:175-83.
13. Chao CK, Yu LL, Su LL, Liu CM, Yang
TH, Chen CM. Bioequivalence study of tramadol
by intramuscular administration in
healthy volunteers. Arzneimittelforschung
2000;50:636-40.
14. Allegaert K, Anderson BJ, Verbesselt R,
et al. Tramadol disposition in the very young:
an attempt to assess in vivo cytochrome P-
450 2D6 activity. Br J Anaesth 2005;95:231-9.
15. Tao Q, Stone DJ, Borenstein MR, et al.
Differential tramadol and O-desmethyl metabolite
levels in brain vs. plasma of mice and
rats administered tramadol hydrochloride
orally. J Clin Pharm Ther 2002;27:99-106.
16. Husslein P, Kubista E, Egarter C. Obstetrical
analgesia with tramadol-results of a prospective
randomized comparative study with
pethidine. Z Geburtshilfe Perinatol 1987;
191:234-7.
17. Grond S, Sablotzki A. Clinical pharmacology
of tramadol. Clin Pharmacokinet 2004;
43:879-923.
18. Lintz W, Erlacin S, Frankus E, Uragg H.
Biotransformation of tramadol in man and animal.
Arzneimittelforschung 1981;31:1932-43.
19. Raffa RB, Nayak RK, Liao S. The mechanism
of action and pharmacokinetics of tramadol
hydrochloride. Rev Contemp Pharmacother
1995;6:458-97.
20. Wu WN, McKown LA, Liao S. Metabolism
of the analgesic drug ULTRAM (tramadol
hydrochloride) in humans: API-MS and
MS/MS characterization of metabolites. Xenobiotica
2002;32:411-25.
21. Paar WD, Frankus P, Dengler HJ. The
metabolism of tramadol by human liver microsomes.
Clin Investig 1992;70:708-10.
22. Lledo P. Variations in drug metabolism
due to genetic polymorphisms: a review of
the debrisoquinidine/sparteine type. Drug
Invest 1993;5:19-34.
23. Abdel-Rahman SM, Leeder JS, Wilson JT,
et al. Concordance between tramadol and
dextromethorphan parent/metabolite ratios:
the influence of CYP2D6 and non-CYP2D6
pathways on biotransformation. J Clin Pharmacol
2002;42:24-9.
24. Collart L, Luthy C, Favario-Constantin C,
Dayer P. Duality of the analgesic effect of tramadol
in humans. Schweiz Med Wochenschr
1993;123:2241-3.
25. Poulsen L, Arendt-Nielsen L, Brøsen K,
Sindrup SH. The hypoalgesic effect of tramadol
in relation to CYP2D6. Clin Pharmacol
Ther 1996;60:636-44.
26. Halfpenny DM, Callado LF, Hopwood SE,
Bamigbade TA, Langford RM, Stamford JA.
Effects of tramadol stereoisomers on norepinephrine
efflux and uptake in the rat locus
coeruleus measured by real time voltammetry.
Br J Anaesth 1999;83:909-15.
27. Kapral S, Gollmann G, Waltl B, et al. Tramadol
added to mepivacaine prolongs the
duration of an axillary brachial plexus
blockade. Anesth Analg 1999;88:853-6.
28. Prosser DP, Davis A, Booker PD, Murray
A. Caudal tramadol for postoperative analgesia
in pediatric hypospadias surgery. Br J
Anaesth 1997;79:293-6.
29. Duthie DJR. Remifentanil and tramadol.
Br J Anaesth 1998;81:51-7.
30. Courtney MJ, Cabraal D. Tramadol vs. diclofenac
for post tonsillectomy analgesia. Arch
Otolaryngol Head Neck Surg 2001;127:
385-8.
31. Putland AJ, McCluskey A. The analgesic
efficacy of tramadol versus ketorolac in daycase
laparoscopic sterilization. Anaesthesia
1999;54:382-5.
32. Umuroglu T, Eti Z, Ciftci H, Yilmaz Gö üs
F. Analgesia for adenotonsillectomy in children:
a comparison of morphine, ketamine and
tramadol. Paediatr Anaesth 2004;14:568-73.
33. Bosenberg AT, Ratcliffe S. The respiratory
effects of tramadol in children under halothane
anaesthesia. Anaesthesia 1998;53:
960-4.
34. Close BR. Tramadol: does it have a role
in emergency medicine? Emerg Med Australas
2005;17:73-83.
35. Kralinski K, Dluholucki S, Laho L. Treatment
of pain with tramal in children above
one year of age. Cs Pediat 1994;49:169-71.
36. Finkel JC, Rose JB, Schmitz ML, et al. An
evaluation of the efficacy and tolerability of
oral tramadol hydrochloride tablets for the
treatment of postsurgical pain in children.
Anesth Analg 2002;94:1469-73.
37. Radbruch L, Grond S, Lehmann KA. A risk–
benefit assessment of tramadol in the management
of pain. Drug Saf 1996;15:8-29.
38. Gibson TP. Pharmacokinetics, efficacy,
and safety of analgesia with a focus on tramadol
HCl. Am J Med 1996;101(Suppl 1A):47-
53.
39. Houmes RJ, Voets MA, Verkaaik A, Erdmann
W, Lachmann B. Efficacy and safety of
tramadol versus morphine for moderate and
severe post-operative pain with special regard
to respiratory depression. Anesth Analg
1992;74:510-4.
40. Hullett BJ, Chambers NA, Pascoe EM,
Johnson C. Tramadol vs morphine during
adenotonsillectomy for obstructive sleep
apnea in children. Paediatr Anaesth 2006;
16:648-53.
41. Stamer UM, Stüber F, Muders T, Musshoff
F. Respiratory depression with tramadol
in a patient with renal impairment and
CYP2D6 gene. Anesth Analg 2008;107:926-9.
42. Tantry TP, Kadam D, Shetty P, Adappa
KK. Tramadol-induced respiratory depression
in a morbidly obese patient with normal renal
function. Indian J Anaesth 2011;55:318-20.
43. Pandey R, Elakkumanan LB, Garg R,
Gupta P, Darlong V, Punj J. Prolonged apnea
after small single dose of intravenous tramadol.
AANA J 2010;78:110-2.
44. Bilgili B, Bozkurt I, Bozkurt P, Metin F.
Prolonged apnea and sedation in premature
babies with the use of oral tramadol. J Clin
Case Rep 2012;2:163.
45. Mikhel’son VA, Zhirkova IuV, Beliaeva
ID, Stepanenko SM, Manerova AF, Butyleva
Olu. Postoperative analgesia with 392 tramadol
in newborn children using the method of
continuous intravenous infusion. Anesteziol
Reanimatol 2003;1:24-8.
46. Bamigbade TA, Langford RM. The clinical
use of tramadol hydrochloride. Pain Rev
1998;5:155-82.
47. Shipton EA. Tramadol - Present and future.
Anaesth Intensive Care 2000;28:363-74.
48. Farajidana H, Hassanian-Moghaddam H,
Zamani N, Sanaei-Zadeh H. Tramadol-induced
seizures and trauma. Eur Rev Med Pharmacol
Sci 2012;16(Suppl 1):34-7.
49. Bozkurt P. Use of tramadol in children.
Paediatr Anaesth 2005;15:1041-7.
50. Desmeules JA. The tramadol option. Eur
J Pain 2000;4(Suppl A):15-21.
51. Engelhardt T, Steel E, Johnston G, Veitch
DY. Tramadol for pain relief in children undergoing
tonsillectomy: a comparison with
morphine. Paediatr Anaesth 2003;13:249-52.
52. Ozalevli M, Unlügenç H, Tuncer U, Günes
Y, Ozcengiz D. Comparison of morphine
and tramadol by patient-controlled analgesia
for postoperative analgesia after tonsillectomy
in children. Paediatr Anaesth 2005;15:
979-84.
53. Viitanen H, Annila P. Analgesic efficacy of
tramadol 2 mg kg (-1) for paediatric day-case
adenoidectomy. Br J Anaesth 2001;86:572-5.
54. Akbay BK, Yildizbas S, Guclu E, Yilmaz
S, Iskender A, Ozturk O. Analgesic efficacy
of topical tramadol in the control of postoperative
pain in children after tonsillectomy. J
Anesth 2010;24:705-8.
55. Mahadevan M, Graff L. Prospective randomized
study of analgesic use for ED patients
with right lower quadrant abdominal
pain. Am J Emerg Med 2000;18:753-6.
56. Eray O, Cete Y, Oktay C, et al. Intravenous
single-dose tramadol versus meperidine
for pain relief in renal colic. Eur J Anaesthesiol
2002;19:368-70.
57. Rose JB, Finkel JC, Arquedas-Mohs A,
Himelstein BP, Schreiner M, Medve RA.
Oral tramadol for the treatment of pain of 7-
30 days’ duration in children. Anesth Analg
2003;96:78-81.
58. Kirchheiner J, Keulen JT, Bauer S, Roots
I, Brockmöller J. Effects of the CYP2D6 gene
duplication on the pharmacokinetics and
pharmacodynamics of tramadol. J Clin Psychopharmacol
2008;28:78-83.
Corrispondenza: anna.disessa@libero.it