Estimation of the minimum effective dose of tramadol for postoperative analgesia in infants using the continual reassessment method

Abstract

Tramadol is a potent analgesic. However, the analgesia efficacy of tramadol, particularly its minimum effective dose (MED), is not clear. The aim of this study is to find MED of tramadol for postoperative analgesia in infants. The continual reassessment method (CRM) was performed to find MED. Infants undergoing surgeries were included in the 3 phases of this series. In each phase, 24 participants were allocated a different tramadol dose. Pain intensity was measured by face, legs, activity, cry, consolability (FLACC) measurement at 3-hour intervals. Tramadol was considered ineffective if the FLACC score was higher than 4 in 10 at anytime. In phase 1, seven dose levels were used within the range 0.1–0.4 mg∙kg^-1·h^-1. Phase 1 was insufficient to identify the MED, and we increased the dose to 0.4–0.8 mg∙kg^-1·h^-1 in phase 2. Phase 2 was insufficient to identify the MED. In phase 3, local anesthetic wound infiltration was introduced, and the tramadol dose levels tested were the same as in phase 1. The successful analgesia probability of tramadol 0.4 mg∙kg^-1∙h^-1 was 82.1% (95% CI, 0.742–0.925) in phase 1. In phase 2, it was 84.7% (95% CI, 0.789–0.991) with the dose 0.8 mg∙kg^-1∙h^-1. Phase 1 and phase 2 were insufficient to identify the MED. In phase 3, the successful analgesia probability for dose 0.35 mg∙kg^-1∙h^-1 was 96.7% (95% CI, 0.853–0.997).We have demonstrated that tramadol provides insufficient analgesia for surgeries considered to cause moderate-to-severe postoperative pain in infants if used as the sole analgesic, and that local anesthetic wound infiltration enhances the efficacy of tramadol.

Keywords

tramadol / minimum effective dose / postoperative analgesia / infants / continual reassessment method

References

[1] McGrath PJ, Allen Finley G. Pediatric acute pain is different from adult acute pain. Acute Pain2000; 3(1): 5–6

[2] Leeder JS, Kearns GL, Spielberg SP, van den Anker J. Understanding the relative roles of pharmacogenetics and ontogeny in pediatric drug development and regulatory science. J Clin Pharmacol2010; 50(12): 1377–1387

[3] Peters JWB, Schouw R, Anand KJS, van Dijk M, Duivenvoorden HJ, Tibboel D. Does neonatal surgery lead to increased pain sensitivity in later childhood? Pain2005; 114(3): 444–454

[4] Slater R, Worley A, Fabrizi L, Roberts S, Meek J, Boyd S, Fitzgerald M. Evoked potentials generated by noxious stimulation in the human infant brain. Eur J Pain2010; 14(3): 321–326

[5] Cummings EA, Reid GJ, Finley GA, McGrath PJ, Ritchie JA. Prevalence and source of pain in pediatric inpatients. Pain1996; 68(1): 25–31

[6] Filitz J, Ihmsen H, Günther W, Tröster A, Schwilden H, Schüttler J, Koppert W. Supra-additive effects of tramadol and acetaminophen in a human pain model. Pain2008; 136(3): 262–270

[7] Allegaert K, Rochette A, Veyckemans F. Developmental pharmacology of tramadol during infancy: ontogeny, pharmacogenetics and elimination clearance. Paediatr Anaesth2011; 21(3): 266–273

[8] Grond S, Meuser T, Zech D, Hennig U, Lehmann KA. Analgesic efficacy and safety of tramadol enantiomers in comparison with the racemate: a randomised, double-blind study with gynaecological patients using intravenous patient-controlled analgesia. Pain1995; 62(3): 313–320

[9] Chu YC, Lin SM, Hsieh YC, Chan KH, Tsou MY. Intraoperative administration of tramadol for postoperative nurse-controlled analgesia resulted in earlier awakening and less sedation than morphine in children after cardiac surgery. Anesth Analg2006; 102(6): 1668–1673

[10] Howard R, Carter B, Curry J, Morton N, Rivett K, Rose M, Tyrrell J, Walker S, Williams G; Association of Paediatric Anaesthetists of Great Britain and Ireland. Good Practice in Postoperative and Procedural Pain management. Backgroud. Paediatr Anaesth2008; 18 (Suppl 1): 1–3

[11] O’Quigley J, Pepe M, Fisher L. Continual reassessment method: a practical design for phase 1 clinical trials in cancer. Biometrics1990; 46(1): 33–48

[12] Thévenin A, Beloeil H, Blanie A, Benhamou D, Mazoit JX. The limited efficacy of tramadol in postoperative patients: a study of ED80 using the continual reassessment method. Anesth Analg2008; 106(2): 622–627

[13] Treluyer JM, Zohar S, Rey E, Hubert P, Iserin F, Jugie M, Lenclen R, Chevret S, Pons G. Minimum effective dose of midazolam for sedation of mechanically ventilated neonates. J Clin Pharm Ther2005; 30(5): 479–485

[14] Desfrere L, Zohar S, Morville P, Brunhes A, Chevret S, Pons G, Moriette G, Rey E, Treluyer JM. Dose-finding study of ibuprofen in patent ductus arteriosus using the continual reassessment method. J Clin Pharm Ther2005; 30(2): 121–132

[15] Barker N, Lim J, Amari E, Malherbe S, Ansermino JM. Relationship between age and spontaneous ventilation during intravenous anesthesia in children. Paediatr Anaesth2007; 17(10): 948–955

[16] Schmidlin D, Hager P, Schmid ER. Monitoring level of sedation with bispectral EEG analysis: comparison between hypothermic and normothermic cardiopulmonary bypass. Br J Anaesth2001; 86(6): 769–776

[17] Olaogun A, Ayandiran O, Olalumade O, Obiajunwa P, Adeyemo F. Knowledge and management of infants’ pain by mothers in Ile Ife, Nigeria. Int J Nurs Pract2008; 14(4): 273–278

[18] Bensadon M, O’Quigley J. Integral evaluation for continual reassessment method. Comput Methods Programs Biomed1994; 42(4): 271–273

[19] Zohar S, Latouche A, Taconnet M, Chevret S. Software to compute and conduct sequential Bayesian phase I or II dose-ranging clinical trials with stopping rules. Comput Methods Programs Biomed2003; 72(2): 117–125

[20] Bland JM, Altman DG. Measuring agreement in method comparison studies. Stat Methods Med Res1999; 8(2): 135–160

[21] Bunce C. Correlation, agreement, and Bland-Altman analysis: statistical analysis of method comparison studies. Am J Ophthalmol2009; 148(1): 4–6

[22] Mantha S, Roizen MF, Fleisher LA, Thisted R, Foss J. Comparing methods of clinical measurement: reporting standards for bland and altman analysis. Anesth Analg2000; 90(3): 593–602

[23] Torres LM, Rodríguez MJ, Montero A, Herrera J, Calderón E, Cabrera J, Porres R, de la Torre MR, Martínez T, Gómez JL, Ruiz J, García-Magaz I, Cámara J, Ortiz P. Efficacy and safety of dipyrone versus tramadol in the management of pain after hysterectomy: a randomized, double-blind, multicenter study. Reg Anesth Pain Med2001; 26(2): 118–124

[24] Özalevli M, Unlügenç H, Tuncer U, Güneş Y, Özcengiz D. Comparison of morphine and tramadol by patient-controlled analgesia for postoperative analgesia after tonsillectomy in children. Paediatr Anaesth2005; 15(11): 979–984

[25] Fricke JR Jr, Hewitt DJ, Jordan DM, Fisher A, Rosenthal NR. A double-blind placebo-controlled comparison of tramadol/acetaminophen and tramadol in patients with postoperative dental pain. Pain2004; 109(3): 250–257

[26] Edwards JE, McQuay HJ, Moore RA. Combination analgesic efficacy: individual patient data meta-analysis of single-dose oral tramadol plus acetaminophen in acute postoperative pain. J Pain Symptom Manage2002; 23(2): 121–130

[27] Spacek A, Goraj E, Neiger FX, Jarosz J, Kress HG. Superior postoperative analgesic efficacy of a continuous infusion of tramadol and dipyrone (metamizol) versus tramadol alone. Acute Pain2003; 5(1): 3–9

[28] Guignard B, Bossard AE, Coste C, Sessler DI, Lebrault C, Alfonsi P, Fletcher D, Chauvin M. Acute opioid tolerance: intraoperative remifentanil increases postoperative pain and morphine requirement. Anesthesiology2000; 93(2): 409–417

[29] Cortínez LI, Brandes V, Muñoz HR, Guerrero ME, Mur M. No clinical evidence of acute opioid tolerance after remifentanil-based anaesthesia. Br J Anaesth2001; 87(6): 866–869

[30] De Witte JL, Schoenmaekers B, Sessler DI, Deloof T. The analgesic efficacy of tramadol is impaired by concurrent administration of ondansetron. Anesth Analg2001; 92(5): 1319–1321

[31] Stamer UM, Lehnen K, Höthker F, Bayerer B, Wolf S, Hoeft A, Stuber F. Impact of CYP2D6 genotype on postoperative tramadol analgesia. Pain2003; 105(1-2): 231–238

[32] Gaedigk A, Fuhr U, Johnson C, Bérard LA, Bradford D, Leeder JS. CYP2D7-2D6 hybrid tandems: identification of novel CYP2D6 duplication arrangements and implications for phenotype prediction. Pharmacogenomics2010; 11(1): 43–53

[33] Gan SH, Ismail R, Wan Adnan WA, Zulmi W. Impact of CYP2D6 genetic polymorphism on tramadol pharmacokinetics and pharmacodynamics. Mol Diagn Ther2007; 11(3): 171–181

[34] Walker SM, Fitzgerald M. Pain in children: recent advances and ongoing challenges. Br J Anaesth2008; 101(1): 101–110

[35] Merkel S, Voepel-Lewis T, Malviya S. Pain assessment in infants and young children: the FLACC scale. Am J Nurs2002; 102(10): 55–58

[36] Paoletti X, Baron B, Schöffski P, Fumoleau P, Lacombe D, Marreaud S, Sylvester R. Using the continual reassessment method: lessons learned from an EORTC phase I dose finding study. Eur J Cancer2006; 42(10): 1362–1368

[37] Deng XM, Xiao WJ, Tang GZ, Luo MP, Xu KL. The minimum local anesthetic concentration of ropivacaine for caudal analgesia in children. Anesth Analg2002; 94(6): 1465–1468

[38] Park HJ, Lee JR, Kim CS, Kim SD, Kim HS. Remifentanil halves the EC50 of propofol for successful insertion of the laryngeal mask airway and laryngeal tube in pediatric patients. Anesth Analg2007; 105(1): 57–61

[39] Kwak HJ, Kim JY, Kim YB, Chae YJ, Kim JY. The optimum bolus dose of remifentanil to facilitate laryngeal mask airway insertion with a single standard dose of propofol at induction in children. Anaesthesia2008; 63(9): 954–958

[40] Paoletti X, O'Quigley J, Maccario J. Design efficiency in dose finding studies. Comput Stat Data Anal2004; 45(2): 197–214

[41] Pang WW, Mok MS, Huang S, Hung CP, Huang MH. Intraoperative loading attenuates nausea and vomiting of tramadol patient-controlled analgesia. Can J Anaesth2000; 47(10): 968–973

Acknowledgements

We thank Ke Tan for statistic technical support and Mazoit JX for his generous donation of software BPCT supply.

RIGHTS & PERMISSIONS

2014 Higher Education Press and Springer-Verlag Berlin Heidelberg