Estimation of the minimum effective dose of tramadol for postoperative analgesia in infants using the continual reassessment method
Estimation of the minimum effective dose of tramadol for postoperative analgesia in infants using the continual reassessment method
Yue’e Dai1,2, Dongxu Lei1, Zhenghua Huang1, Yan Yin1, G. Allen Finley3, Yunxia Zuo1()
1. Department of Anesthesiology and Translational Neuroscience Center, West China Hospital, Sichuan University, Chengdu 610041, China; 2. Department of Anesthesiology, Sichuan Academy of Medical Sciences & Sichuan Provincial People’s Hospital, Chengdu 610041, China; 3. Department of Anesthesia and Psychology, IWK Health Centre, Dalhousie University, 5850 University Avenue, Halifax, NS, B3K 6R8, Canada
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.
. Estimation of the minimum effective dose of tramadol for postoperative analgesia in infants using the continual reassessment method[J]. Frontiers of Medicine, 2012, 6(3): 288-295.
Yue’e Dai, Dongxu Lei, Zhenghua Huang, Yan Yin, G. Allen Finley, Yunxia Zuo. Estimation of the minimum effective dose of tramadol for postoperative analgesia in infants using the continual reassessment method. Front Med, 2012, 6(3): 288-295.
McGrath PJ, Allen Finley G. Pediatric acute pain is different from adult acute pain. Acute Pain 2000; 3(1): 5–6 doi: 10.1016/S1366-0071(00)80001-7
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 Pharmacol 2010; 50(12): 1377–1387 doi: 10.1177/0091270009360533 pmid:20150527
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? Pain 2005; 114(3): 444–454 doi: 10.1016/j.pain.2005.01.014 pmid:15777869
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 Pain 2010; 14(3): 321–326 doi: 10.1016/j.ejpain.2009.05.005 pmid:19481484
5
Cummings EA, Reid GJ, Finley GA, McGrath PJ, Ritchie JA. Prevalence and source of pain in pediatric inpatients. Pain 1996; 68(1): 25–31 doi: 10.1016/S0304-3959(96)03163-6 pmid:9251995
6
Filitz J, Ihmsen H, Günther W, Tr?ster A, Schwilden H, Schüttler J, Koppert W. Supra-additive effects of tramadol and acetaminophen in a human pain model. Pain 2008; 136(3): 262–270 doi: 10.1016/j.pain.2007.06.036 pmid:17709207
7
Allegaert K, Rochette A, Veyckemans F. Developmental pharmacology of tramadol during infancy: ontogeny, pharmacogenetics and elimination clearance. Paediatr Anaesth 2011; 21(3): 266–273 doi: 10.1111/j.1460-9592.2010.03389.x pmid:20723094
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. Pain 1995; 62(3): 313–320 doi: 10.1016/0304-3959(94)00274-I pmid:8657431
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 Analg 2006; 102(6): 1668–1673 doi: 10.1213/01.ANE.0000219587.02263.A0 pmid:16717306
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 Anaesth 2008; 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. Biometrics 1990; 46(1): 33–48 doi: 10.2307/2531628 pmid:2350571
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 Analg 2008; 106(2): 622–627 doi: 10.1213/ane.0b013e31816053aa pmid:18227324
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 Ther 2005; 30(5): 479–485 doi: 10.1111/j.1365-2710.2005.00678.x pmid:16164495
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 Ther 2005; 30(2): 121–132 doi: 10.1111/j.1365-2710.2005.00630.x pmid:15811164
15
Barker N, Lim J, Amari E, Malherbe S, Ansermino JM. Relationship between age and spontaneous ventilation during intravenous anesthesia in children. Paediatr Anaesth 2007; 17(10): 948–955 doi: 10.1111/j.1460-9592.2007.02301.x pmid:17767630
16
Schmidlin D, Hager P, Schmid ER. Monitoring level of sedation with bispectral EEG analysis: comparison between hypothermic and normothermic cardiopulmonary bypass. Br J Anaesth 2001; 86(6): 769–776 doi: 10.1093/bja/86.6.769 pmid:11573582
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 Pract 2008; 14(4): 273–278 doi: 10.1111/j.1440-172X.2008.00693.x pmid:18715388
18
Bensadon M, O’Quigley J. Integral evaluation for continual reassessment method. Comput Methods Programs Biomed 1994; 42(4): 271–273 doi: 10.1016/0169-2607(94)90099-X pmid:7924273
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 Biomed 2003; 72(2): 117–125 doi: 10.1016/S0169-2607(02)00120-7 pmid:12941516
20
Bland JM, Altman DG. Measuring agreement in method comparison studies. Stat Methods Med Res 1999; 8(2): 135–160 doi: 10.1191/096228099673819272 pmid:10501650
21
Bunce C. Correlation, agreement, and Bland-Altman analysis: statistical analysis of method comparison studies. Am J Ophthalmol 2009; 148(1): 4–6 doi: 10.1016/j.ajo.2008.09.032 pmid:19540984
22
Mantha S, Roizen MF, Fleisher LA, Thisted R, Foss J. Comparing methods of clinical measurement: reporting standards for bland and altman analysis. Anesth Analg 2000; 90(3): 593–602 doi: 10.1097/00000539-200003000-00018 pmid:10702443
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 Med 2001; 26(2): 118–124 doi: 10.1053/rapm.2001.21437 pmid:11251134
24
?zalevli M, Unlügen? H, Tuncer U, Güne? Y, ?zcengiz D. Comparison of morphine and tramadol by patient-controlled analgesia for postoperative analgesia after tonsillectomy in children. Paediatr Anaesth 2005; 15(11): 979–984 doi: 10.1111/j.1460-9592.2005.01591.x pmid:16238560
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. Pain 2004; 109(3): 250–257 doi: 10.1016/j.pain.2004.01.004 pmid:15157685
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 Manage 2002; 23(2): 121–130 doi: 10.1016/S0885-3924(01)00404-3 pmid:11844632
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 Pain 2003; 5(1): 3–9 doi: 10.1016/S1366-0071(03)00025-1
Cortínez LI, Brandes V, Mu?oz HR, Guerrero ME, Mur M. No clinical evidence of acute opioid tolerance after remifentanil-based anaesthesia. Br J Anaesth 2001; 87(6): 866–869 doi: 10.1093/bja/87.6.866 pmid:11878688
30
De Witte JL, Schoenmaekers B, Sessler DI, Deloof T. The analgesic efficacy of tramadol is impaired by concurrent administration of ondansetron. Anesth Analg 2001; 92(5): 1319–1321 doi: 10.1097/00000539-200105000-00045 pmid:11323369
31
Stamer UM, Lehnen K, H?thker F, Bayerer B, Wolf S, Hoeft A, Stuber F. Impact of CYP2D6 genotype on postoperative tramadol analgesia. Pain 2003; 105(1-2): 231–238 doi: 10.1016/S0304-3959(03)00212-4 pmid:14499440
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. Pharmacogenomics 2010; 11(1): 43–53 doi: 10.2217/pgs.09.133 pmid:20017671
33
Gan SH, Ismail R, Wan Adnan WA, Zulmi W. Impact of CYP2D6 genetic polymorphism on tramadol pharmacokinetics and pharmacodynamics. Mol Diagn Ther 2007; 11(3): 171–181 pmid:17570739
34
Walker SM, Fitzgerald M. Pain in children: recent advances and ongoing challenges. Br J Anaesth 2008; 101(1): 101–110 doi: 10.1093/bja/aen097
35
Merkel S, Voepel-Lewis T, Malviya S. Pain assessment in infants and young children: the FLACC scale. Am J Nurs 2002; 102(10): 55–58 doi: 10.1097/00000446-200210000-00024 pmid:12394307
36
Paoletti X, Baron B, Sch?ffski 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 Cancer 2006; 42(10): 1362–1368 doi: 10.1016/j.ejca.2006.01.051 pmid:16740385
37
Deng XM, Xiao WJ, Tang GZ, Luo MP, Xu KL. The minimum local anesthetic concentration of ropivacaine for caudal analgesia in children. Anesth Analg 2002; 94(6): 1465–1468 pmid:12032008
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 Analg 2007; 105(1): 57–61 doi: 10.1213/01.ane.0000266447.23037.e4 pmid:17578957
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. Anaesthesia 2008; 63(9): 954–958 doi: 10.1111/j.1365-2044.2008.05544.x pmid:18557970
40
Paoletti X, O'Quigley J, Maccario J. Design efficiency in dose finding studies. Comput Stat Data Anal 2004; 45(2): 197–214 doi: 10.1016/S0167-9473(02)00323-7
41
Pang WW, Mok MS, Huang S, Hung CP, Huang MH. Intraoperative loading attenuates nausea and vomiting of tramadol patient-controlled analgesia. Can J Anaesth 2000; 47(10): 968–973 doi: 10.1007/BF03024867 pmid:11032271
