You are here

Article Text

Article menu

Download PDFPDF

Original articles
Efficacy of tramadol versus fentanyl for postoperative analgesia in neonates
  1. Ana Julia Couto Alencar1,
  2. Adriana Sanudo2,
  3. Virginia Maria Ramos Sampaio3,
  4. Rôsicler Pereira Góis3,
  5. Fernando Antônio Barbosa Benevides3,
  6. Ruth Guinsburg2
  1. 1Department of Pediatrics, Federal University of Ceará, Fortaleza, Ceará, Brazil
  2. 2Division of Neonatal Medicine, Department of Pediatrics, Federal University of São Paulo, São Paulo, Brazil
  3. 3Albert Sabin Hospital, Fortaleza, Ceará, Brazil
  1. Correspondence to Professor Ruth Guinsburg, Federal University of São Paulo, Rua Vicente Felix 77 apt 09, São Paulo, SP 01410-020, Brazil; ruthgbr{at}netpoint.com.br

Abstract

Objective To assess, in newborn infants submitted to surgical procedures, the efficacy of two opioids—fentanyl and tramadol—regarding time to extubate, time to achieve 100 ml/kg of enteral feeding and pain in the first 72 h after surgery.

Design Controlled, blind, randomised clinical trial.

Setting Neonatal intensive care unit.

Patients 160 newborn infants up to 28 days of life requiring major or minor surgeries.

Interventions Patients were randomised to receive analgesia with fentanyl (1–2 μg/kg/h intravenously) or tramadol (0.1–0.2 mg/kg/h intravenously) in the first 72 h of the postoperative period, stratified by surgical size and by patient's gender.

Main outcome measures Pain assessed by validated neonatal scales (Crying, Requires oxygen, Increased vital signs, Expression and Sleepless Scale and the Neonatal Facial Coding System), time until extubation and time to reach 100 ml/kg enteral feeding. Statistical analysis included repeated measures analysis of variance adjusted for confounding variables and Kaplan–Meier curve adjusted by a Cox model of proportional risks.

Results Neonatal characteristics were (mean±SD) birth weight of 2924±702 g, gestational age of 37.6±2.2 weeks and age at surgery of 199±63 h. The main indication of surgery was gastrointestinal malformation (85 newborns; 53%). Neonates who received fentanyl or tramadol were similar regarding time until extubation, time to reach 100 ml/kg of enteral feeding and pain scores in the first 72 h after surgery.

Conclusion Tramadol was as effective as fentanyl for postoperative pain relief in neonates but does not appear to offer advantages over fentanyl regarding the duration of mechanical ventilation and time to reach full enteral feeding.

Trial registration NCT00713726

https://doi.org/10.1136/adc.2010.203851

Statistics from Altmetric.com

    Request Permissions

    If you wish to reuse any or all of this article please use the link below which will take you to the Copyright Clearance Center’s RightsLink service. You will be able to get a quick price and instant permission to reuse the content in many different ways.

    Introduction

    Newborn infants experience pain after surgical procedures. The intensity and duration of the pain depend, among several factors, on the type of surgery and the need for vital support and invasive diagnostic procedures during the postoperative period.1

    The opioid µ-agonist fentanyl promotes rapid analgesia and blocks the endocrine-metabolic stress response without haemodynamic instability, making it one of the most used opioids for the relief of pain in critically ill newborn infants.2 Its administration however, is not free of adverse effects including, tolerance (especially when fentanyl is given by continuous intravenous infusion), respiratory depression, urinary retention, ileum and eventually nausea and vomiting. This profile prevents wider neonatal use of the drug because of fears that fentanyl will prolong the need of mechanical ventilation and parenteral nutrition, increasing the risk of morbidity and mortality during neonatal intensive care.1,–,3

    What is already known on this topic

    • ▶ Newborn infants experience pain after surgical procedures.

    • ▶ Fentanyl promotes rapid analgesia in neonates, but it has adverse effects such as tolerance, respiratory depression, urinary retention and ileum.

    • ▶ Tramadol is a weak opioid that leads to less respiratory depression, ileum, tolerance and physical dependence compared with classical opioids, in adults.

    What this study adds

    • ▶ In neonates submitted to major and minor surgical procedures, tramadol is as effective as fentanyl for postoperative pain relief.

    • ▶ Tramadol does not appear to offer advantages over fentanyl regarding the duration of mechanical ventilation and the time to reach full enteral feeding.

    Tramadol is a weak opioid that acts in the central nervous system and has a µ-receptor affinity 6000 times lower than morphine.4 The drug releases serotonin from nervous terminals and increases synaptic reuptake of serotonin and norepinephrine, leading to the activation of cortex–spinal descendent tracts that modulate and inhibit pain afference to subcortical and cortical centres.5 In adults, tramadol has a good analgesic effect with less respiratory depression, ileum, tolerance and physical dependence compared with morphine, meperidine and fentanyl.6 7 Studies on the analgesic efficacy and safety of tramadol in critically ill neonates are scarce.

    Therefore, the aim of this study was to compare the efficacy of two opioids—fentanyl and tramadol—regarding time to extubation, time to achieve 100 ml/kg of enteral feeding and pain in the first 72 h after surgery, in newborn infants submitted to surgical procedures.

    Methods

    This prospective, blind, randomised, controlled trial enrolled outborn neonatesadmitted to Albert Sabin Hospital with indication for surgical procedures. This is a referral paediatric hospital, without a maternity service, that receives patients needing complex care in the state of Ceará (Northeast Brazil). The research protocol was approved by the Albert Sabin Hospital Institutional Review Board (IRB, protocol 02/06), the Federal University of São Paulo IRB (protocol 1386/06) and by the Brazilian National Committee of Ethics in Research (protocol 12962/06). All parents signed an informed written consent prior to the enrolment of their infant, and the study was registered in ClinicalTrials.gov (NCT00713726).

    Patients were included if they were admitted at ages below 28 days of life and required major or minor surgeries, according to the definition of the American College of Cardiology/American Heart Association.8 Infants were excluded if they were discharged, had died or needed a new surgical procedure before completing 72 h after the initial surgery. Also, neonates with chromosomal syndromes or ambiguous genitalia were excluded.

    Patients were randomised to receive fentanyl or tramadol after surgery in blocks of four according to gender (male and female) and the size of the surgery (major and minor). The choice to randomise by gender was due to the growing body of evidence which indicates differences in clinical and experimental pain responses, and some evidence which suggests that pain treatment responses may differ for women versus men.9 For randomisation, four opaque envelopes were prepared (male/female infants with major/minor surgeries). Each envelope contained 10 blocks of four patients randomly ordered as ‘fentanyl’ or ‘tramadol’. The central pharmacy performed the randomisation, prepared the medication and delivered the medication to the neonatal intensive care unit (NICU).

    The necessary sample size was calculated as 160 patients, based on the estimate that tramadol would reduce by 30% the duration of mechanical ventilation by endotracheal tube, considering an α error of 5%, a β error of 20% and the loss of 15% of patients initially enrolled. The choice of 30% reduction in time until tracheal extubation as the end point of power analysis was based on Chu et al10 report. Enrolment was stopped independently for each one of the four study arms (fentanyl male and female and tramadol male and female) as soon as 40 patients had been included.

    The analgesic solution was initiated between 0 and 4 h after surgery, as soon as patients opened their eyes and had some motor activity, as the following:

    • ▶ Fentanyl: administered as a continuous infusion of 2 µg/kg/h for term newborns and 1 µg/kg/h for preterm neonates or for those extubated soon after surgery.

    • ▶ Tramadol: administered as a continuous infusion of 0.2 mg/kg/h for term newborns and 0.1 mg/kg/h for preterm neonates or for those extubated soon after surgery.

    The phials of fentanyl (50 µg/ml) and tramadol (50 mg/ml) were diluted in 9 ml of normal saline. Tramadol solution was further diluted in 9 ml of normal saline. Therefore, 0.2 ml/h of the solution was equivalent to 1 µg/h of fentanyl and 0.1 mg/h of tramadol. These prediluted solutions prepared in the central pharmacy were labelled as ‘postoperative analgesic: use 0.2 ml/kg/h for preterm infants and 0.4 ml/kg/h for term neonates for 24 hours”. Predefined thresholds were used to adapt intravenous administration of analgesics and included the presence of pain detected in two consecutive assessments by two pain scales. If patients required more analgesia, solution infusion was increased by 0.1 ml/h, equivalent to dose increases of 1 µg of fentanyl or 0.1 mg of tramadol. If pain was absent after 48 h of surgery, the infusion rate was decreased by 0.1 ml/h every 12 h. The medical staff was strongly discouraged to increase or decrease analgesic doses or to prescribe sedatives based on their impressions. However, due to ethical constraints, if they felt that changes in analgesic doses were needed, they contacted the main investigator in order to update the prescription or they could prescribe, as a sedative, intermittent midazolam doses. No other sedatives were allowed during the study.

    Primary outcome was the time, in hours, from the end of the surgical procedure until extubation. Secondary outcomes were: hours to reach 100 ml/kg of enteral feeding and pain evaluation during the first 72 h after surgery. The decisions regarding extubation and management of enteral feeding were managed by attending neonatologists who were blind to group allocation of the patients. Pain was evaluated by two validated pain scales: Crying, Requires oxygen, Increased vital signs, Expression and Sleepless (CRIES)11 and the Neonatal Facial Coding System (NFCS).12 These scales were applied every 2 h for the first 24 postoperative hours and every 4 h for the following 48 h by the nursing staff. Pain was considered present if CRIES was >4 and/or NFCS was >3. All NICU medical and nursing staff were trained to apply the pain scales by one of the investigators (AJCdA).

    Patients were continuously monitored regarding body temperature, heart rate (HR), respiratory rate and oxygen saturation by pulse oxymetry. Non-invasive blood pressure and capillary glycaemia were measured every 8 h. Adverse effects possibly associated to pain and/or to opioid administration during the first 72 h after surgery were considered as secondary outcomes, and included: episodes of bradycardia (HR<100 bpm) or tachycardia (HR>160 bpm), thoracic stiffness, number of apnoeas after extubation, need for re-intubation, hypotension or hypertension,13 urinary retention, seizures, need to increase opioid infusion rate, need to switch the infused opioid, tolerance to opioid infusion (defined by the need to the increase opioid infusion rate in three consecutive pain evaluations) and abstinence syndrome (Finnegan scale applied 4 h after each reduction in the opioid infusion rate).14

    Statistical analysis was performed by ‘intention-to-treat’. An interim analysis was blindly made after enrolment of the first 50 patients to verify the safety profile of both opioid infusions. Pain scales during the first 72 postoperative hours were analysed by repeated measures analysis of variance (ANOVA) adjusted for possible confounding variables (birth weight, gender, presurgery clinical severity, according to American Society of Anesthesiologists (ASA)criteria15and hours of life at surgery). Time to extubation and time to reach 100 ml/kg of enteral feeding in the fentanyl and tramadol groups for both major and minor surgeries were compared by Kaplan–Meier survival curves adjusted for confounding variables by a Cox proportional hazards model. In order to facilitate the analysis of the survival curves, the data for both outcomes, collected as hours, were transformed to days with a precision of two decimals. Other end points were compared between groups by ANOVA or Mann–Whitney U test for numerical variables and by χ2 for categorical variables, with significance set at p<0.05.

    Results

    Between July 2006 and June 2008, 201 neonates with surgical problems were admitted to the study hospital. Among these, 13 infants had chromosomal abnormalities, 2 infants had ambiguous genitalia, 10 infants died prior or during surgery, 4 admissions were not communicated to the research team and the parents of 1 neonate refused participation. Therefore, 171 patients were randomised to receive either tramadol or fentanyl. Among these 171 patients, eight died during the first 72 postoperative hours (five from the fentanyl group and three from the tramadol group) and three were re-operated on within 72 h after the first surgery (one from the fentanyl group and two from the tramadol group), leaving 160 infants in the study.

    For the whole group, the main demographic and clinical characteristics were described in mean±SD or number (%): birth weight of 2924±702 g, gestational age of 37.6±2.2 weeks, postnatal age at surgery of 199±163 h and weight at surgery of 2823±699 g. Only six patients (three of each group) had a gestational age less than 32 weeks and four of them were very low birth weight infants (two of each group). Regarding the baseline diseases that indicated the surgical procedure, the most frequent were gastrointestinal malformations (n=85), followed by central nervous system malformations (n=34). Immediately prior to surgery, the severity of illness of these neonates as evaluated by ASA criteria showed 28 (18%) at ASA I, 80 (50%) at ASA II, 47 (29%) at ASA III and 5 (3%) at ASA IV/V. The characteristics of the patients and their surgical procedures in the four studied groups are shown in table 1. Regarding intraoperative anaesthesia, the exclusive use of volatile agents occurred in 92 patients, volatile agents plus opioids were given to 63 neonates and only opioids were administered to 4 infants. None of them received regional anaesthesia.

    View this table:
    Table 1

    General characteristics of neonates at study entry

    The evaluation of pain in the first 72 postoperative hours by validated pain scales is shown in table 2. Repeated measures ANOVA was applied for CRIES and NFCS scores for each size of surgery and were adjusted for birth weight (<1500 g, 1500–2499 g and ≥2500 g), gender, ASA criteria (≤2 and >2) and hours of life (<72 h, 72–167 h and ≥168 h). In all groups, there was a significant decrease of pain scores during the first 72 postoperative hours (p≤0.002). The main effect of ‘medication for analgesia’ was not significant in any comparison (minor surgeries: CRIES, p=0.873 and NFCS, p=0.160; major surgeries: CRIES, p=0.075 and NFCS, p=0.331). Also, the interaction between ‘time’ and ‘medication for analgesia’ was not significant (minor surgeries: CRIES, p=0.705 and NFCS, p=0.773; major surgeries: CRIES, p=0.773 and NFCS, p=0.578). There was a trend towards higher CRIES scores in newborn infants submitted to major surgeries who received tramadol compared with those who received fentanyl.

    View this table:
    Table 2

    CRIES and NFCS pain scores (mean±SD) during the first 72 h after surgery

    The duration of mechanical ventilation by endotracheal tube and the number of intubated newborns after surgery were similar between both the analgesic groups regardless of surgery size (table 3). Kaplan–Meier analysis revealed that, after minor surgeries, the median time that patients remained intubated was 0.08 days (95% CI 0.06 to 0.10) for the fentanyl group and 0.10 days (95% CI 0.07 to 0.14) for the tramadol group (p=0.479). For major surgeries, the median time that patients remained intubated was 4 days (95% CI 3.4 to 4.6) for the fentanyl group and 4 days (95% CI 2.8 to 5.2) for the tramadol group (p=0.476). Cox proportional hazards model adjusted for birth weight, gender, postnatal age at surgery and ASA criteria showed that the risk to be extubated after 168 postoperative hours was similar for fentanyl and tramadol groups submitted to minor or major surgeries.

    View this table:
    Table 3

    Time to extubation and time to reach 100 ml/kg of enteral feeding

    The median time to reach 100 ml/kg of enteral feeding and the number of newborns who reached this amount of enteral feeding was similar between both analgesic groups regardless of surgery size (table 3). Kaplan–Meier analysis showed that, after minor surgeries, the median time to reach 100 ml/kg of enteral feeding was 2 days (95% CI 1.3 to 2.7) for the fentanyl group and 1 day (95% CI 0.8 to 1.2) for the tramadol group (p=0.579). For major surgeries, this time was 13 days (95% CI 10.8 to 15.3) for newborns who received fentanyl and 11 days (95% CI 8.5 to 13.5) for those newborns who received tramadol (p=0.634). The Cox proportional hazards model adjusted for confounding variables did not show differences between the fentanyl and tramadol groups either for minor or major surgeries.

    The adverse effects possibly related to opioid infusion are shown in table 4. The intrahospital mortality rates were similar between groups. The median time until hospital discharge or death was 26 days (95% CI 23 to 29) for minor surgeries and 38 days for major operations (95% CI 34 to 43), without differences between patients who received fentanyl or tramadol in minor (p=0.379) or major (p=0.951) surgeries. The 124 patients who were discharged alive had similar median length of hospital stay regardless of the size of surgery: 21 (IQR 13–29) and 14 (IQR 8–30) days, respectively for fentanyl and tramadol groups (p=0.134). The same occurred with the 36 infants who died postoperatively: 12 (IQR 4–93) and 33 (IQR 9–48) days, respectively for fentanyl and tramadol groups (p=0.230). The baseline diseases of the 36 patients who died were: gastrointestinal malformations in 23 (64%), central nervous system malformations in 5, cardiac malformations in 3, other malformations in 3 and necrotising enterocolitis in 2 neonates. The immediate cause of death was sepsis in 31 (86%) surgical newborn infants.

    View this table:
    Table 4

    Adverse effects related to opioids during the first 168 postoperative hours

    Discussion

    Both fentanyl and tramadol were effective medications for pain relief during the first 3 postoperative days in neonates submitted to major or minor surgeries evaluated by two validated pain scales. However, analgesia with tramadol decreased neither the duration of invasive mechanical ventilation nor the time to reach full enteral feeding. Regarding opioid side effects, tramadol did not show any advantage over fentanyl, except for a lower frequency of bradycardia in newborns who received tramadol after minor surgeries. The bradycardia noted in patients who received fentanyl did not require cardiovascular support.

    Although there are literature reports about fentanyl use after surgical procedures in paediatric patients15,–,17 and in intubated newborn infants,2 we could not find studies designed to verify the efficacy of fentanyl in treating postoperative neonatal pain. Regarding tramadol, its effects were evaluated mainly in adults and children.18,–,20 In newborn infants, Mikhel'son et al21 used tramadol for postoperative analgesia in 20 patients and reported adequate pain control. The analgesic efficacy of tramadol is partly dependent on its CYP2D6-induced-O-desmethyl metabolite that exhibits an age-dependent maturation pattern.22 Therefore, CYP2D6 polymorphisms could possibly interfere in the pharmacological action of tramadol on studied infants, and at least 19 different alleles and 5 allele duplications have been already identified in African and European Brazilians.23 This study indicates that, despite the fact that the maturational pattern is still evolving in neonates and this pattern would vary depending on the molecular diversity at the CYP2D6 locus, tramadol was effective to alleviate the postoperative pain of term and late preterm neonates. Newborns receiving fentanyl for minor surgeries more often needed a decrease in their opioid dose. However, after major surgeries, patients of the tramadol group more frequently needed to increase their analgesic dose. It should be noted that the fentanyl and tramadol doses used were similar to those reported in the literature,4 21 24 25 but a loading dose was not given for either opioid drug based on the fact that perioperative pain control started with the anaesthetic management during surgery and the lack of reliable data about loading doses of tramadol prior to continuous intravenous infusion in surgical neonates. Our results suggest that a smaller fentanyl dose would be effective for analgesia after minor surgeries and that fentanyl allows less variability in neonatal analgesia after major surgeries.

    One of the main concerns related to opioid use in neonates is respiratory depression, with a prolonged need of mechanical ventilation and its complications.26 A meta-analysis of studies that compared fentanyl with placebo in mechanically ventilated neonates showed that those randomised to fentanyl needed higher respiratory support.2 However, one of the advantages of tramadol in adults and children is a lower frequency of respiratory depression compared with traditional opioids,6 10 27 although Mikhel'son et al,21 in the only study of postoperative neonates receiving continuous infusion of tramadol, found hypercapnia in 80% of non-ventilated patients. Our study adds to the knowledgeabout the absence of any advantage of tramadol use for neonatal postoperative pain regarding respiratory depression, irrespective of the surgery size.

    Maybe the difference between neonates and children or adults depends on the maturational stage of pain tracts and neurotransmitters; the development of the endogenous opioid system precedes the maturation of the modulator pain system mediated by epinephrine and serotonin.28 There is evidence that the endogenous opioid system is operative at 28 weeks of gestation, but the inhibitory pain descendent tracts will mature weeks or months after term.28 If this is the case, both fentanyl and tramadol should be equally efficacious regarding their action in the opioid receptors in the neonatal period, but the potential advantage of tramadol should disappear since its effects on releasing neurotransmitters of the cortex–spinal descendent tracts would not occur until weeks after term, after the neonatal period.

    Regarding the time to reach full enteral feeding in the studied groups, there were no differences between patients who received fentanyl or tramadol after major or minor surgeries. Other studies that administered fentanyl in the neonatal period showed decreased gastrointestinal motility.2 29 The use of tramadol in adults, children and in 20 neonates did not affect the progression of enteral feeding.6 21 27 From a pharmacological point of view, opioids decrease intestinal motility due to their interaction with µ-opioid receptors,30 and the lack of an effect of tramadol on this system is attributed to its action at non-opioid receptors sites.31 Maybe the difference in tramadol effects between newborn infants and older patients depends on the maturational stage of pain tracts and neurotransmitters.28

    The side effects of both tramadol and fentanyl were similar, with the exception of the increased frequency of bradycardia in neonates who received fentanyl after minor surgeries. This effect is explained by the vagal stimulus triggered by the fentanyl action on the δ-opioid receptor in the carotid sinus,32 which does not occur with tramadol as it acts exclusively on µ-opioid receptors.4 27 Most likely the bradycardia was not evident in neonates who received fentanyl after major surgeries because the surgical trauma released catecholamines that overcame the vagal effect of the opioid.

    It should be noted that this trial was powered to compare time until extubation of patients who received tramadol versus fentanyl for postsurgery analgesia. Therefore, the absence of differences in the secondary outcomes may be a consequence of the study design. Other limitations were the lack of standardisation of the surgical anaesthesia and the study design that left to the attending neonatologists the decision to extubate and increase enteral feeding of randomised patients. The fact that anaesthesia protocols varied among patients increases the external validity of our results to be extended to postoperative neonatal periods irrespective of intraoperatory anaesthesia. Regarding the lack of predefined thresholds to extubate and feed enrolled patients, the study was designed to compare tramadol versus fentanyl analgesia for postoperative analgesia routinely performed in the context of neonatal intensive care. In the NICU, clinicians consider a body of data in order to decide timing of extubation and nutritional management of postoperative patients, such as sleep/alert state, ventilatory settings, haemodynamic variables, presence of ileum and infections, among others, making it very difficult to standardise these decisions in patients with diverse baseline diseases. The mortalities found in the study reflects the reality of high-risk neonatal care in Brazil, where hospital infections are the main cause of death.33

    This randomised, controlled, blind study is the first one sufficiently powered to compare tramadol and fentanyl in postoperative neonates. Tramadol was as effective as fentanyl for postoperative pain relief, but did not appear to offer advantages over fentanyl regarding the duration of mechanical ventilation and the time to reach full enteral feeding. There is a strong need to study the efficacy and safety profiles of analgesics in age-compatible populations in order to find alternatives to treat pain for critically ill newborn infants.

    References

    1. ↵
      1. Anand KJ,
      2. Aranda JV,
      3. Berde CB,
      4. et al
      . Summary proceedings from the neonatal pain-control group. Pediatrics 2006;117:S9–22.
      OpenUrlAbstract/FREE Full Text
    2. ↵
      1. Aranda JV,
      2. Carlo W,
      3. Hummel P,
      4. et al
      . Analgesia and sedation during mechanical ventilation in neonates. Clin Ther 2005;27:877–99.
      OpenUrlCrossRefPubMedWeb of Science
    3. ↵
      1. Berde CB,
      2. Jaksic T,
      3. Lynn AM,
      4. et al
      . Anesthesia and analgesia during and after surgery in neonates. Clin Ther 2005;27:900–21.
      OpenUrlCrossRefPubMedWeb of Science
    4. ↵
      1. Allegaert K,
      2. Simons SH,
      3. Vanhole C,
      4. et al
      . Developmental pharmacokinetics of opioids in neonates. J Opioid Manag 2007;3:59–64.
      OpenUrlPubMed
    5. ↵
      1. Allegaert K,
      2. van den Anker JN,
      3. de Hoon JN,
      4. et al
      . Covariates of tramadol disposition in the first months of life. Br J Anaesth 2008;100:525–32.
      OpenUrlAbstract/FREE Full Text
    6. ↵
      1. Lee CR,
      2. McTavish D,
      3. 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.
      OpenUrlPubMedWeb of Science
    7. ↵
      1. Scott LJ,
      2. Perry CM
      . Tramadol: a review of its use in perioperative pain. Drugs 2000;60:139–76.
      OpenUrlCrossRefPubMedWeb of Science
    8. ↵
      1. Eagle KA,
      2. Berger PB,
      3. Calkins H,
      4. et al
      . ACC/AHA guideline update for perioperative cardiovascular evaluation for noncardiac surgery—executive summary—a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines (Committee to Update the 1996 Guidelines on Perioperative Cardiovascular Evaluation for Noncardiac Surgery). Circulation 2002;105:1257–67.
      OpenUrlFREE Full Text
    9. ↵
      1. Fillingim RB,
      2. King CD,
      3. Ribeiro-Dasilva MC,
      4. et al
      . Sex, gender, and pain: a review of recent clinical and experimental findings. J Pain 2009;10:447–85.
      OpenUrlCrossRefPubMedWeb of Science
    10. ↵
      1. Chu YC,
      2. Lin SM,
      3. Hsieh YC,
      4. et al
      . 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;102:1668–73.
      OpenUrlCrossRefPubMedWeb of Science
    11. ↵
      1. Krechel SW,
      2. Bildner J
      . CRIES: a new neonatal postoperative pain measurement score. Initial testing of validity and reliability. Paediatr Anaesth 1995;5:53–61.
      OpenUrlPubMedWeb of Science
    12. ↵
      1. Grunau RV,
      2. Craig KD
      . Pain expression in neonates: facial action and cry. Pain 1987;28:395–410.
      OpenUrlCrossRefPubMedWeb of Science
    13. ↵
      1. Park MK,
      2. Menard SM
      . Normative oscillometric blood pressure values in the first 5 years in an office setting. Am J Dis Child 1989;143:860–4.
      OpenUrlCrossRefPubMed
    14. ↵
      1. Finnegan LP
      . Effects of maternal opiate abuse on the newborn. Fed Proc 1985;44:2314–17.
      OpenUrlPubMedWeb of Science
    15. ↵
      1. Anand KJ,
      2. Sippell WG,
      3. Aynsley-Green A
      . Randomised trial of fentanyl anaesthesia in preterm babies undergoing surgery: effects on the stress response. Lancet 1987;1:62–6.
      OpenUrlCrossRefPubMedWeb of Science
    16. ↵
      1. Okada Y,
      2. Powis M,
      3. McEwan A,
      4. et al
      . Fentanyl analgesia increases the incidence of postoperative hypothermia in neonates. Pediatr Surg Int 1998;13:508–11.
      OpenUrlCrossRefPubMedWeb of Science
    17. ↵
      1. Koehntop DE,
      2. Rodman JH,
      3. Brundage DM,
      4. et al
      . Pharmacokinetics of fentanyl in neonates. Anesth Analg 1986;65:227–32.
      OpenUrlCrossRefPubMedWeb of Science
    18. ↵
      1. Houmes RJ,
      2. Voets MA,
      3. Verkaaik A,
      4. et al
      . Efficacy and safety of tramadol versus morphine for moderate and severe postoperative pain with special regard to respiratory depression. Anesth Analg 1992;74:510–14.
      OpenUrlPubMedWeb of Science
    19. ↵
      1. Lehmann KA,
      2. Kratzenberg U,
      3. Schroeder-Bark B,
      4. et al
      . Postoperative patient-controlled analgesia with tramadol: analgesic efficacy and minimum effective concentrations. Clin J Pain 1990;6:212–20.
      OpenUrlPubMedWeb of Science
    20. ↵
      1. Ozköse Z,
      2. Akçabay M,
      3. Kemaloglu YK,
      4. et al
      . Relief of posttonsillectomy pain with low-dose tramadol given at induction of anesthesia in children. Int J Pediatr Otorhinolaryngol 2000;53:207–14.
      OpenUrlCrossRefPubMedWeb of Science
    21. ↵
      1. Mikhel'son VA,
      2. Zhirkova IuV,
      3. Beliaeva ID,
      4. et al
      . Postoperative analgesia with tramal in newborn children using the method of continuous intravenous infusion. Anesteziol Reanimatol 2003;1:24–8.
      OpenUrlPubMed
    22. ↵
      1. Allegaert K,
      2. Rochette A,
      3. Veyckemans F
      . Developmental pharmacology of tramadol during infancy: ontogeny, pharmacogenetics and elimination clearance. Paediatr Anaesth 2010;21:266–73.
      OpenUrlPubMed
    23. ↵
      1. Kohlrausch FB,
      2. Gama CS,
      3. Lobato MI,
      4. et al
      . Molecular diversity at the CYP2D6 locus in healthy and schizophrenic southern Brazilians. Pharmacogenomics 2009;10:1457–66.
      OpenUrlCrossRefPubMedWeb of Science
    24. ↵
      1. Lago P,
      2. Benini F,
      3. Agosto C,
      4. et al
      . Randomised controlled trial of low dose fentanyl infusion in preterm infants with hyaline membrane disease. Arch Dis Child Fetal Neonatal Ed 1998;79:F194–7.
      OpenUrlAbstract/FREE Full Text
    25. ↵
      1. Orsini AJ,
      2. Leef KH,
      3. Costarino A,
      4. et al
      . Routine use of fentanyl infusions for pain and stress reduction in infants with respiratory distress syndrome. J Pediatr 1996;129:140–5.
      OpenUrlCrossRefPubMedWeb of Science
    26. ↵
      1. Bellù R,
      2. de Waal K,
      3. Zanini R
      . Opioids for neonates receiving mechanical ventilation: a systematic review and meta-analysis. Arch Dis Child Fetal Neonatal Ed 2010;95:F241–51.
      OpenUrlAbstract/FREE Full Text
    27. ↵
      1. Bozkurt P
      . Use of tramadol in children. Paediatr Anaesth 2005;15:1041–7.
      OpenUrlPubMed
    28. ↵
      1. Fitzgerald M
      . The development of nociceptive circuits. Nat Rev Neurosci 2005;6:507–20.
      OpenUrlPubMedWeb of Science
    29. ↵
      1. Saarenmaa E,
      2. Huttunen P,
      3. Leppäluoto J,
      4. et al
      . Advantages of fentanyl over morphine in analgesia for ventilated newborn infants after birth: a randomized trial. J Pediatr 1999;134:144–50.
      OpenUrlCrossRefPubMedWeb of Science
    30. ↵
      1. Miaskowski C
      . A review of the incidence, causes, consequences, and management of gastrointestinal effects associated with postoperative opioid administration. J Perianesth Nurs 2009;24:222–8.
      OpenUrlCrossRefPubMed
    31. ↵
      1. Valle M,
      2. Garrido MJ,
      3. Pavón JM,
      4. et al
      . Pharmacokinetic-pharmacodynamic modeling of the antinociceptive effects of main active metabolites of tramadol, (+)-O-desmethyltramadol and (-)-O-desmethyltramadol, in rats. J Pharmacol Exp Ther 2000;293:646–53.
      OpenUrlAbstract/FREE Full Text
    32. ↵
      1. Deo SH,
      2. Barlow MA,
      3. Gonzalez L,
      4. et al
      . Cholinergic location of delta-opioid receptors in canine atria and SA node. Am J Physiol Heart Circ Physiol 2008;294:H829–38.
      OpenUrlAbstract/FREE Full Text
    33. ↵
      1. Couto RC,
      2. Carvalho EA,
      3. Pedrosa TM,
      4. et al
      . A 10-year prospective surveillance of nosocomial infections in neonatal intensive care units. Am J Infect Control 2007;35:183–9.
      OpenUrlCrossRefPubMedWeb of Science

    Footnotes

    • Competing interests The authors declare that they do not have any relationship with other people or organisations that could inappropriately influence this work.

    • Ethics approval Brazilian National Committee of Ethics in Research, Institutional Review Boards from the Federal University of São Paulo and Institutional Review Boards from Albert Sabin Hospital.

    • Provenance and peer review Not commissioned; externally peer reviewed.