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

Introduction

Infants are sensitive to pain stimulation [1]. Failure to provide adequate postoperative analgesia not only delays rehabilitation, but also negatively affects the development of the nervous system, and exaggerates responses to painful stimuli well into later life [2-4]. However, postoperative pain in infants is, to a large extent, either ignored or under treated in China, mainly because of the fear of the severe adverse effects of traditional analgesics. For example, opioids carry the risk of respiratory depression and nonsteroidal anti-inflammatory drugs (NSAIDs) may cause a bleeding tendency and renal impairment [5]. In some developing countries, infants stay in a ward following surgery, without routine monitors such as SpO₂. Therefore, analgesics with less respiratory depression are preferred. Tramadol is one of these analgesics. It acts as both a weak opioid agonist, with selectivity for the μ-receptor, and as an effective inhibitor of 5-HT and noradrenaline reuptake [6]. O-desmethyl-tramadol (M1) is one of the active metabolites of tramadol which takes an important part in the analgesia effect because M1 binding affinity to the mu receptor is about 500 times the tramadol affinity [7]. And tramadol has been proven to be an effective analgesic in treating moderate-to-severe postoperative pain in adult and pediatric patients and no severe adverse effects have been reported [8,9]. However, the dose regimen for effective and safe treatment is a key issue and seldom adequate evaluation has been reported. Recommendations for the dosage of tramadol intravenous infusions in infants are not well defined and with a relative wide dosage 0.1-0.4 mg∙kg^-1∙h^-1, according to the Association of Pediatric Anaesthetists of Great Britain and Ireland (APA) [10]. In clinical practice, the effect of using the recommended dosage of tramadol varied among infants. It appeared necessary to establish the relationship between dose and analgesia efficacy.

An effective dose finding study in infants faces distinct ethical, statistical and practical problems. A new approach developed by O’Quigley et al., called the continual reassessment method (CRM), was designed for dose finding studies, minimum effective dose (MED) or maximum tolerated dose (MTD) in particular, and may overcome some of the ethical and recruitment issues [11]. Using CRM, Thevenin et al. [12] found that tramadol had a limited efficacy and that the effective dose in 80% of patients was 260 mg, which is much larger than the usual dose of 100 mg, when used as the sole analgesic to relieve postoperative pain in only 24 adults. CRM has also been used in dose finding in infants, because of the potential advantages to pediatric patients: fewer patients are needed to estimate the MED, a placebo group is not necessary, and double-blind evaluation is possible [13,14]. Therefore, we conducted this investigation using CRM to find the MED (sufficient analgesia dose in 95% of patients) of tramadol intravenous (IV) parent-controlled analgesia (PCA) when it was used as a sole analgesic following surgeries considered to cause moderate-to-severe postoperative pain in infants, as well as when it is combined with local anesthetic wound infiltration.

Materials and methods

Patient selection

The study was approved by the local ethics committee (West China Hospital, Sichuan University, China) and written informed consent was obtained from the parents of each infant. Infants with American Society of Anesthesiologists (ASA) physical status I or II, aged from 1 to 12 months, who were undergoing surgery using general anesthesia alone and considered to cause moderate-to-severe postoperative pain, were enrolled. Exclusion criteria were as follows: (1) risk of hypersensitivity to tramadol (history of seizures, increased intracranial pressure, or being treated with monoamine oxidase inhibitors); (2) the parents have difficulties in pain assessment.

Anesthetic protocol and analgesic protocol

All infants were induced with midazolam 0.1 mg·kg^-1, propofol 1-2 mg∙kg^-1, vecuronium 0.1 mg∙kg^-1 and fentanyl 2-3 µg∙kg^-1. Anesthesia was maintained with sevoflurane 2%-3% and remifentanil 0.1-0.2 µg∙kg^-1.min^-1. Fentanyl 0.5-1 µg∙kg^-1 was administered intravenously before remifentanil infusion was stopped at the skin closure. All infants were transferred to the post anesthesia care unit (PACU) after the extubation.

Infants were allocated a dose level of tramadol by 3-patient cohorts in PACU. To ensure blinding, the electronic pump (DDB-150, APOLLO Scientific Apparatus Company, Ltd. Tongli, Wujiang, Jiangsu 25217, China) was prepared by an anesthesiologist who was not involved in any other part of the study. Infants were administered an initial loading dose of 2 mg∙kg^-1 tramadol (Zieglerstrasse 6, 52079 Aachen, Germany) intravenously, followed by continuous IV PCA (basal infusion rate, 2 ml∙h^-1; PCA bolus, 1 ml; lockout interval, 10 min). The solution in the pump had varying dose levels of tramadol together with granisetron 50 µg∙kg^-1∙d^-1 in 100 ml normal saline solution. The FLACC scores and the adverse effects of seizure, nausea, vomiting, respiratory depression, over-sedation and sweating were documented on arrival in the PACU, and at 3-h intervals thereafter, until the pump ran out. Respiratory depression [15] was defined as a respiratory rate≤10 br∙min^-1. Sedation was scored with the Ramsay scale [16].

Pain assessment

The parents of the infants were trained preoperatively to use the FLACC measurement [8], which includes 5 categories of behavior, to assess pain intensity. Each of the 5 categories, including (F) face, (L) legs, (A) activity, (C) cry, (C) consolability, is scored from 0 to 2, which results in a total score between 0 and 10. Both the investigator and the parents of the infants used FLACC to assess the pain intensity immediately after the infants arrived in the PACU and recorded FLACC scores at 3-h intervals thereafter. The analgesia was considered effective if the FLACC score was less than 4 and ineffective if≥4 at any time point. A bolus dose was given by the parents if the infants could not be comforted by psychological and physical treatments such as hugs, music therapy, comfort, and a soother dipped in sugar solution [17]. Morphine 0.1 mg∙kg^-1 intravenous injection was performed as rescue analgesia if the FLACC score remained higher than 4, after30 min.

Dose-finding statistical analysis

CRM was performed to identify MED of tramadol for postoperative analgesia in this investigation. MED was defined as sufficient tramadol dose to provide analgesia in 95% of infants for postoperative pain in this investigation. It is an iterative Bayesian method based on a one-parameter model, designed to estimate the target percentile of response among distinct dose levels [18]. The experimenter gives a guess of the prior probability according to previous animal studies or clinical experience from the same type of medications and chooses a target rate, then updates the posterior probability after each cohort’s result (success or failure), using BPCT (Bayesian Phase I or II Clinical Trials) software. After each reassessment following a cohort (usually 1-4 individuals), the dose level with the posterior probability closest to the target rate is chosen as the recommended dose for the next cohort and the dose level with the final probability closest to the target rate was defined as the MED. In study 1, the recommended dose of tramadol IV PCA in infants was 0.1-0.4 mg∙kg^-1∙h^-1 according to APA, seven dose levels were chosen with the arithmetic growth dose 0.05 mg∙kg^-1∙h^-1 (the prior successful analgesia probability shown in parentheses): 0.1 (30%), 0.15 (80%), 0.2 (93%), 0.25 (95%), 0.3(97%), 0.35(98%), 0.4 mg∙kg^-1∙h^-1 (99%). The dose 0.25 mg∙kg^-1∙h^-1 with an initial probability closest to the target rate of sufficient analgesia dose in 95% of infants was administered to the first cohort of infants (each cohort containing 3 individuals). Following a group of the infants (η = 3), the posterior successful analgesia probabilities of each dose level were calculated with BPCT for Windows NT 4 software. The dose level with updated posterior analgesia probability closest to an adequate analgesia dose in 95% of infants was allocated to each new cohort. We considered stopping each study in this investigation after the analysis of the stopping criteria that were provided by BPCT software [19]. The first decision to stop was made when the predetermined fixed sample size (24 infants) was reached. The second decision to stop was “no change in administered dose level” made among the next cohort of infants. The third decision to stop was through identification of tramadol MED or by gaining sufficient levels of reliability.

Phase 1 was insufficient to identify the MED, because the highest dose level tested (0.4 mg∙kg^-1∙h^-1) had an estimation of successful analgesia probability of 82.1%, less than the target analgesia probability of 95%, so we made an amendment to the protocol and enrolled infants to estimate the MED by increasing the dose levels of tramadol according to our previous experience with tramadol in infants. In phase 2, five dose levels of tramadol were chosen, with the prior estimates of successful analgesia probability associated with each: 0.4 (80%), 0.5(95%), 0.6 (97%), 0.7(98%) and 0.8 mg∙kg^-1∙h^-1 (99%). Phase 2 was insufficient to identify the MED, because the highest dose level tested (0.8 mg∙kg^-1∙h^-1) had an estimation of successful analgesia probability of 84.7%, less than the target analgesia probability of 95% and insufficient analgesia was found within the first few hours following surgery. Therefore, we decided to enroll infants (phase 3) to estimate the MED of tramadol with an additional local anesthetic wound infiltration with 0.125% bupivacaine before skin closure. The volume dose of bupivacaine was calculated according to the length of the wound (1 ml∙cm^-1) with the maximum dose of 2 mg∙kg^-1. The dose levels of tramadol and associated prior successful analgesia probabilities were similar to phase 1.

Statistical analysis

In each of the phases, demographic data such as age, sex and duration of surgery are expressed as the mean±SD; types of surgeries and adverse effects are expressed as number (%). Besides the analysis of MED in each study, FLACC scores within the first 15 h at each dose level were compared by using one-way analysis of variance for repeated measurements and two-way analysis of variance comparisons between phase 1 and phase 3. P<0.05 was considered significant. The pain assessment agreement between the investigator and the parents were compared using the Bland-Altman method [20-22] in phase 1.

Results

Seventy-two infants were recruited in this investigation. The demographic data and clinical features including age, sex ratio, body weight, types and durations of the surgeries in three phases are shown in Table 2.

The final estimated posterior successful analgesia probabilities for the different dose levels are shown in Table 3 and Fig. 1. The highest dose level tested in phase 1 (0.4 mg∙kg^-1∙h^-1) had an estimation of successful analgesia probability of 82.1%. The highest dose level tested in the phase 2 (0.8 mg∙kg^-1∙h^-1) had an estimation of successful analgesia probability of 84.7%. In phase 3, when local anesthetic wound infiltration was combined with tramadol infusion, the dose level 0.35 mg∙kg^-1∙h^-1 reached a successful analgesia probability of 96.7% (95% credibility interval, 0.853-0.997) after 24 infants had been recruited. Six infants in phase 1, three infants in phase 2 and one infant in phase 3 had insufficient pain relief and received rescue analgesia. The mean time at which infants received rescue analgesia was 6.27±2.54 h after arrival in the PACU in the first two phases.

In phase 1, the FLACC scores at T0 measured immediately on arrival in the PACU were significantly greater than those measured at time points within the first 15 h (ANOVA, ﹟P<0.05). In phase 3, the FLACC scores had no significant difference at the time points within the first 15 h compared with T0 (ANOVA, P>0.05). The FLACC scores at the following time points were significantly lower in phase 3 than those in phase 1: T0 (*P = 0.000), T3 (*P = 0.037), and T6 (*P = 0.023), by two-way analysis of variance (Fig. 2).

Neither respiratory depression nor over-sedation was observed in any of the three phases (Table 4). An infant was observed vomiting at 8 h after the initial loading dose given in phase 2. Twenty-two infants sweated obviously during the period of analgesia in this investigation. A seizure was observed when an infant received dose 0.2 mg∙kg^-1∙h^-1 at 16 h after the initial loading dose given in phase 1.

Discussion

The main finding of this investigation is that tramadol, used postoperatively as the sole analgesic for surgeries causing moderate-to-severe postoperative pain in infants, was insufficient even when administered with doubling the recommended dose according to the APA, but the analgesia efficacy of tramadol could be enhanced significantly when immediately combined with local anesthetic wound infiltration.

In phase 1 and phase 2, we failed to identify the MED of tramadol when it was used as the sole analgesic to treat moderate-to-severe postoperative pain in infants. A previous study also reported that the efficacy of tramadol to relieve early pain was not satisfactory when used as the sole analgesic for postoperative analgesia [23].We failed to identify the MED of tramadol in the first two phases, implying that tramadol is not suitable as a sole analgesic for those surgeries which are considered to be moderately to severely painful in infants. This result strongly suggests that tramadol analgesia may reach a ceiling [24] and also supports the APA recommendation of an upper limit of tramadol 0.4 mg∙kg^-1∙h^-1 for pediatric postoperative analgesia.

Additionally, in the first two phases, we found that rescue analgesia was mainly required in the early hours following surgery. This phenomenon suggested that the failure of tramadol postoperative analgesia might be solved if we added additional immediate postoperative analgesia, such as local anesthetic wound infiltration or nerve block. Therefore, we designed the third phase to validate our hypothesis. We were successful in identifying the MED of tramadol in the APA recommended dose range, by adding bupivacaine wound infiltration in phase 3, because the final successful analgesia probability for dose level 0.35 mg∙kg^-1∙h^-1 was 96.7% (95% credible intervals, 0.853-0.997), was closest to the target rate of 95%. Moreover, the low FLACC scores in the early hours following the surgery in phase 3 demonstrated an improvement in early postoperative analgesia. Some other studies have also found that the analgesia efficacy of tramadol could be improved when combined with acetaminophen [25,26] or in multimodal analgesia [27]

There may be a number of reasons for inadequate postoperative analgesia when tramadol is used as the sole analgesia for infants undergoing surgeries considered to be moderately to severely painful.

Firstly, a short acting opioid, remifentanil, was chosen for the maintenance of intraoperative analgesia in this investigation. Remifentanil may result in acute opioid tolerance and hyperalgesia [28], so fentanyl 0.5-1 μg∙kg^-1 was given at skin closure to provide early postoperative analgesia. The dose and duration of remifentanil intravenous infusion was a key factor in acute opioid tolerance [29]. Cortinez et al. [29] found no difference in morphine consumption or pain scores in patients randomized to receive remifentanil (mean infusion rate, 0.23 μg∙kg^-1∙min^-1) or sevoflurane anesthesia for gynecological surgery. These investigators postulated that the lack of development of acute tolerance might be attributed to the relatively short duration of remifentanil infusion (averaging 116 min) in their study. The infusion rate and the duration of remifentanil application that we used in our study were slower and shorter than Cortinez’s study.

Secondly, adding 5-HT antagonist anti-emetic granisetron into the analgesic solution may impair the analgesia effect of tramadol. De Witte JL [30] found the dose of tramadol required for postoperative analgesia was significantly increased (50%) in the earlier hours when ondansetron was administered simultaneously with tramadol. This may imply that 5-HT antagonist anti-emetic may impair the effects of tramadol. However, 5-HT antagonist is the most commonly used anti-emetic medication. In our third study, the adequate analgesia probability was very high when the local wound infiltration was combined with tramadol PCA, although granisetron was added into the analgesic solution in the first two studies. This implies that the impairment of tramadol analgesia by granisetron is limited.

Thirdly, one of the active metabolites of tramadol, O-demethyltramadol (M1), is generated by CYP2D6. Genetic polymorphisms of CYP2D6 would reduce the production of M1 metabolite and therefore impact the analgesia effect of tramadol [31,32]. It has been reported that as high as 50% of Chinese people have CYP2D6 genetic polymorphisms [33]. This potentially limits the external validity or generalizability of the present findings to non-Chinese infants. But the population in the study of Gan SH is just 44, and they cannot conclude the results above. We did not examine whether those infants with inadequate analgesia have CYP2D6 variant alleles. This may be a limitation of our investigation.

Infants who are cognitively and physically unable to report pain may be at a greater risk than others for incomplete pain treatment, due to the difficulty of pain assessment [34]. Behavioral observation is the primary approach for the assessment of pain in infants. We used the behavioral FLACC scale to assess postoperative pain, as it has been validated for infants in clinical practice [35].

CRM was used for this investigation, allowing dose-finding with a relatively small sample size [36]. In phase 1, we input the results of initial tested dose 0.2 mg∙kg^-1∙h^-1 into BPCT software; it showed that the dose 0.4 mg∙kg^-1∙h^-1 was closest to the target successful analgesia probability (0.95). Therefore, we applied this dose level to the next cohort of patients. In the end, no patients received 0.1, 0.15, 0.3, or 0.35 mg∙kg^-1∙h^-1, which would have had relatively lower analgesia efficacy, according to BPCT calculation. The same phenomenon was found in the following studies. Many studies use Dixon’s up-and-down sequential allocation technique to find MED, particularly the 50% effective dose level [37-39]. If CRM is not superior to this technique, it has proven to be at least as powerful as Dixon’s up-and-down, particularly in finding other doses than 50% effective [13,14,40]. The only limitation to using CRM is a weak dose-response curve; the unclear relationship was present between tramadol dose level and efficacy, in this investigation.

In our phases, no severe adverse effects including respiratory depression or over-sedation were observed, except that one infant showed seizure behaviors. The seizure was observed when the infant received dose 0.2 mg∙kg^-1∙h^-1 16 h following the surgery in phase 1. It was unclear whether this was associated with the use of tramadol, because the infant’s temperature was about 39°C at the time of the incidence occurred. The incidence of vomiting was only 4.2% (1/24), which is far lower than the 28% reported in previous literature [41]. This is probably accounted for by the addition of granisetron to the tramadol solution. However, because of the small number of infants studied in each series, we are unable to draw any definite conclusions.

In conclusion, we succeeded in identifying MED of tramadol for postoperative analgesia in infants using CRM. The MED of tramadol is 0.35 mg∙kg^-1∙h^-1 when tramadol IV PCA is combined with local anesthetic wound infiltration. Tramadol should not be used as the sole analgesic in treating surgeries considered to cause moderate-to-severe postoperative pain in infants.

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

RIGHTS & PERMISSIONS

Higher Education Press and Springer-Verlag Berlin Heidelberg