Published online June 1, 2005
PEDIATRICS Vol. 115 No. 6 June 2005, pp. 1494-1500 (doi:10.1542/peds.2004-1425)
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Morphine Does Not Provide Adequate Analgesia for Acute Procedural Pain Among Preterm Neonates

Ricardo Carbajal, MD*,{ddagger}, Richard Lenclen, MD*, Myriam Jugie, MD*, Alain Paupe, MD*, Bruce A. Barton, PhD§ and Kanwaljeet J. S. Anand, MBBS, DPhil||

* Neonatal Intensive Care Unit, Poissy Saint Germain Hospital, Poissy, France
{ddagger} Centre National de Ressources de Lutte Contre la Douleur, Hôpital d’Enfants Armand Trousseau, Paris, France
§ Maryland Medical Research Institute, Baltimore, Maryland
|| University of Arkansas for Medical Sciences, Arkansas Children’s Hospital, Little Rock, Arkansas


   ABSTRACT
TOP
 ABSTRACT
METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
Background. Morphine alleviates prolonged pain, reduces behavioral and hormonal stress responses induced by surgery among term neonates, and improves ventilator synchrony and sedation among ventilated preterm neonates, but its analgesic effects on the acute pain caused by invasive procedures remain unclear.

Objective. To investigate the analgesic efficacy of intravenously administered morphine on heel stick-induced acute pain among preterm neonates.

Design. This study was nested within a prospective, randomized, double-blind, multicenter, placebo-controlled trial (the NEOPAIN Trial).

Setting. A tertiary-care NICU in a teaching hospital.

Participants. Forty-two preterm neonates undergoing ventilation.

Interventions. Neonates were randomized to either the morphine (loading dose of 100 µg/kg, followed by infusions of 10–30 µg/kg per hour according to gestation, N = 21) or placebo (5% dextrose infusions, N = 21) group. Pain responses to 3 heel sticks were evaluated, ie, before the loading dose (T1), 2 to 3 hours after the loading dose (T2), and 20 to 28 hours after the loading dose (T3).

Main Outcomes Measures. Pain was assessed with the Douleur Aiguë Nouveau-né (DAN) scale (behavioral pain scale) and the Premature Infant Pain Profile (PIPP) (multidimensional pain scale); plasma morphine levels were measured at T3.

Results. Infants in the placebo and morphine groups had similar gestational ages (mean ± SD: 27.2 ± 1.7 vs 27.3 ± 1.8 weeks) and birth weights (972 ± 270 vs 947 ± 269 g). Mean ± SD DAN pain scores at T1, T2, and T3 were 4.8 ± 4.0, 4.6 ± 2.9, and 4.7 ± 3.6, respectively, for the placebo group and 4.5 ± 3.8, 4.4 ± 3.7, and 3.1 ± 3.4 for the morphine group. The within-group factor (pain at T1, T2, and T3) was not statistically different over time. The between-group analysis (infants receiving placebo versus those receiving morphine) showed no significant differences. Mean ± SD PIPP pain scores at T1, T2, and T3 were 11.5 ± 4.8, 11.1 ± 3.7, and 9.1 ± 4.0, respectively, for the placebo group and 10.0 ± 3.6, 8.8 ± 4.9, and 7.8 ± 3.6 for the morphine group. The within-group factor was statistically different over time. The between-group analysis showed no significant differences. Mean ± SD plasma morphine levels at T3 were 0.44 ± 1.79 ng/mL and 63.36 ± 33.35 ng/mL for the placebo and morphine groups, respectively. There was no correlation between plasma morphine levels and pain scores at T3 (DAN, R = –0.05; PIPP, R = –0.02).

Conclusions. Despite its routine use in the NICU, morphine given as a loading dose followed by continuous intravenous infusions does not appear to provide adequate analgesia for the acute pain caused by invasive procedures among ventilated preterm neonates.

Key Words: morphine • pain • neonates • analgesia • procedures

Abbreviations: PIPP, Premature Infant Pain Profile • DAN, Douleur Aiguë Nouveau-né • RCT, randomized, controlled trial

Preterm neonates undergo many painful procedures as part of their standard care in the NICU.1,2 Recent data show that preterm infants are able to experience pain3,4 and indeed, as a result of their immature and vulnerable nervous systems, are highly sensitive to pain.5 Painful procedures elicit acute painful reactions among very preterm neonates,6 and increasing evidence indicates that repeated invasive procedures cause hyperalgesia,7 leading to long-term changes in pain processing and development.8–10 Therefore, there is an urgent need to find safe effective treatments to relieve pain among these infants.

Expert opinions have recommended the use of continuous morphine infusions for ongoing analgesia during routine NICU care and invasive procedures among preterm neonates undergoing ventilation,11,12 despite limited data on their efficacy during routine invasive procedures13 or their safety in this population.14,15 Long-term outcomes assessed at 5 to 6 years of age among formerly preterm children who were exposed to continuous morphine infusions in the neonatal period indicated no adverse effects of morphine on intelligence, motor function, or behavior.16

Conflicting evidence exists about the efficacy of continuous morphine infusions to relieve pain from routine procedures among preterm neonates undergoing ventilation. Two studies investigated responses to tracheal suctioning.15,17 Anand et al17 found a reduction in pain scores, whereas Simons et al,15 judging from pain scores obtained with 3 validated scales, found no difference between the morphine and placebo groups. Pain measured with facial expressions was diminished with morphine infusions during heel sticks among preterm and term neonates, but pain measures did not correlate with plasma morphine concentrations.18 Our primary objective was to measure the analgesic efficacy of continuous morphine infusions for relieving heel stick-induced pain among preterm neonates undergoing ventilation.


   METHODS
TOP
 ABSTRACT
 METHODS
RESULTS
 DISCUSSION
 REFERENCES
 
Protocol
A randomized, blinded, multicenter, placebo-controlled trial (the NEOPAIN Trial, ie, NEurological Outcomes and Preemptive Analgesia In Neonates) at 16 participating NICUs was designed to measure the effects of preemptive morphine analgesia on the incidence of early adverse neurologic outcomes among ventilated preterm neonates. Neonates for the present study were enrolled from 1 NICU, to examine the analgesic efficacy of morphine for the acute pain elicited by heel sticks. Neonates born at 23 to 32 weeks of gestation, intubated before 72 hours of age, and ventilated for <8 hours at inclusion were enrolled. Exclusion criteria included congenital anomalies (requiring surgical, medical, or cosmetic interventions within 7 days after birth), birth asphyxia (5-minute Apgar score of ≤3 or cord blood pH of ≤7.00), intrauterine growth retardation (birth weight ≤5th percentile for gestational age), maternal opioid addiction (drug intake within 72 hours before delivery or positive drug test with maternal urine), and participation in other clinical trials. Enrolled infants were expected to undergo heel sticks for blood glucose determinations as part of their standard clinical management. We assessed the efficacy of continuous morphine infusions to relieve pain during heel sticks by comparing the blinded pain assessments of infants receiving continuous intravenous morphine infusions and those receiving placebo.

The study protocol and the letter of permission addressed to parents were approved by the local ethics committee. We obtained written informed consent from both parents of each enrolled infant.

Assignment
Randomization to the morphine and placebo groups occurred with an automated telephone response system located in the United States, followed by faxed confirmation of the coded treatment assignment to the NICU and the hospital pharmacy. Neonates were randomized to 8 study drug codes, with 4 codes each for the morphine and placebo groups. Physicians and nurses in charge of neonates were blinded to the treatments received by the patients. Study drug syringes were dispensed by a research pharmacist who did not participate in the routine care of neonates.

Procedures and Masking
Neonates randomized to the morphine group received a loading dose of morphine (100 µg/kg, infused intravenously in 1 hour), followed by continuous infusions of 10, 20, or 30 µg/kg per hour for preterm neonates at 23 to 26 weeks, 27 to 29 weeks, or 30 to 32 weeks of gestation, respectively. Bolus doses of the study drug and increases in the infusion rate were not allowed. The study drug was stopped if the patient could be weaned from mechanical ventilation within 24 hours, if no spontaneous respirations occurred with low ventilator rates and normal PaCO2 values (5.3–6.7 kPa), or if the clinical condition was deteriorating rapidly. Ethical concerns related to a blinded placebo group necessitated a protocol design with the option of administering additional analgesia, which could be provided to either group through intermittent, open-label, morphine bolus doses, on the basis of pain assessments or specific clinical criteria.

To determine the efficacy of morphine analgesia, pain-related responses to 3 heel sticks were evaluated, at T1 (baseline), ie, the heel stick before the loading dose, T2, ie, the heel stick 2 to 3 hours after the loading dose, and T3, ie, the heel stick after 20 to 28 hours of morphine infusion. Heel stick pain was assessed with 2 validated pain measurement instruments, ie, the Douleur Aiguë Nouveau-né (DAN) scale (behavioral pain scale) and the Premature Infant Pain Profile (PIPP) (multidimensional pain scale). Serum morphine concentrations were measured at T3 with standard gas chromatography-mass spectrometry techniques, with a detection limit of 15 ng/mL. Pain assessments were conducted by an independent observer, who did not participate in the procedure. The observer also assessed the neonate’s arousal state with the observational rating system described by Prechtl,19 as follows: 1, eyes closed, regular respiration, no movements; 2, eyes closed, irregular respiration, gross movements; 3, eyes open, no gross movements; 4, eyes open, continual gross movements, no crying; 5, eyes open or closed, fussing or crying. Assessment of pain started when an automated lancet (Unistick 2 Junior; Owen Mumford, Vernon, France) was inserted and ended when blood collection was complete. Hypotension, which was defined as the need for intravenous vasopressor support or intravenous fluid boluses of ≥20 mL/kg, was evaluated before study drug, after the study drug loading dose, and at 24 ± 4 hours during study drug infusion.

Pain Scales
The DAN scale is a behavioral scale developed to rate acute pain among term and preterm neonates.20 Scores range from 0 (no pain) to 10 (maximal pain), based on evaluations of facial expressions, limb movements, and vocal expression. An English version of this scale is presented elsewhere.21 In the validation study for this scale, it was found to be sensitive and specific, because all possible scores were obtained and it was able to differentiate painful from nonpainful procedures (pain scores of ≥3 for 95% of painful procedures and ≤2 for 88% of sham procedures). There was good internal consistency (Cronbach’s coefficient = .88) and good agreement between raters (Krippendorf’s r = 91.2).

The PIPP scale is a multidimensional measure developed to assess acute pain among preterm and term infants.22 It measures gestational age, behavioral state, heart rate, oxygen saturation, and 3 facial reactions (brow bulge, eye squeeze, and nasolabial furrow). Among preterm infants of <33 weeks’ gestational age, scores range from 1 (no pain) to 21 (maximal pain). Validation of the PIPP score also showed construct validity with an ability to differentiate painful from nonpainful or baseline events (P = .0001), with inter-rater reliability coefficients of 0.93 to 0.96, whereas the intra-rater reliability coefficients for individual events were 0.94 to 0.98.22

Sample-Size Calculation
We tested the hypothesis that continuous intravenous morphine administration would reduce pain scores during heel sticks, compared with placebo infusions. Pain assessment with the DAN scale was the primary outcome. A sample calculation with PASS statistical software (NCSS, Kaysville, UT), with previous data obtained for preterm neonates (25–32 weeks’ gestation and 30.4 weeks’ mean postconceptional age), yielded a sample size of 19 infants in each group to achieve 80% power for detecting a difference of 2 points with a SD of 2.2 between morphine and placebo, with a significance level of 5% (2-tailed). Of note, during the validation study for the DAN scale, the 95% confidence interval for the 2.2 SD was 1.6 to 3.5.

Statistical Analyses
Comparisons of pain scores between the placebo and morphine groups at T1 (baseline), T2, and T3 were conducted with a repeated-measures analysis of variance. The within-subjects factor was the pain score at T1, T2, and T3; the between-subjects factor was the treatment group (placebo versus morphine). Box’s test of equality of covariance matrices and Mauchly’s test of sphericity were verified before interpretation of results. Nominal variables were compared with {chi}2 tests or Fisher’s exact tests (for contingency tables with small cell frequencies). Ordinal variables were compared with the median 2-sample test. The critical P value was set at .05 for all analyses. Statistical analyses were performed with the SAS program (SAS Institute, Cary, NC).


   RESULTS
TOP
 ABSTRACT
 METHODS
 RESULTS
DISCUSSION
 REFERENCES
 
During the study period (February to December 2001), 42 of 121 eligible infants were enrolled in this study (flow diagram in Fig 1). There were no differences in perinatal characteristics between the morphine and placebo groups (Table 1). All DAN and PIPP pain scores for both groups are shown in Figure 2. Table 2 shows mean pain scores induced by heel sticks in the morphine and placebo groups at T1, T2, and T3. Table 3 shows the results of the repeated-measures analysis of variance for the within- and between-groups comparisons of pain scores with the DAN scale. The within-groups factor (pain at T1, T2, and T3) did not differ statistically over time (P = .651) and the interaction between this factor and treatment groups was not statistically significant (P = .663), which indicates that the changes in pain scores over the 3 time periods were the same for infants in the placebo and morphine groups.


Figure 1
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  		Fig 1. Trial profile and participant flow.

 

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  		TABLE 1. Perinatal Characteristics of 42 Preterm Newborns Included in the Study of the Analgesic Efficacy of Morphine for Acute Procedural Pain

 

Figure 2
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  		Fig 2. DAN scale pain scores during heel sticks performed before (T1), 2 to 3 hours after (T2), and 20 to 28 hours after (T3) a loading dose of morphine or placebo, followed by a continuous infusion of morphine or placebo, among preterm neonates.

 

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  		TABLE 2. Pain Scores Induced by Heel Sticks Performed Before (T1), 2 to 3 Hours After (T2), and 20 to 28 Hours After (T3) a Loading Dose of Morphine or Placebo, Followed by a Continuous Infusion of Morphine or Placebo, Among Preterm Neonates

 

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  		TABLE 3. Results of the Repeated-Measures Analysis of Variance for Within- and Between-Groups Factors Comparing DAN Scale Scores During Heel Sticks Performed Before (T1), 2 to 3 Hours After (T2), and 20 to 28 Hours After (T3) a Loading Dose of Morphine or Placebo, Followed by a Continuous Infusion of Morphine or Placebo, Among Preterm Neonates

 
Table 4 shows the results of repeated-measures analysis of variance for within- and between-groups comparisons of pain scores with the PIPP scale. The within-groups factor (pain at T1, T2, and T3) differed statistically over time (P = .044), but the interaction between pain at the 3 time points and treatment groups was not statistically significant (P = .860), which indicates that, as seen with the DAN scale, the changes in pain scores over the 3 time periods were the same for the placebo and morphine groups. No infants received additional open-label morphine in the morphine or placebo groups during the study period. Mean ± SD plasma morphine concentrations measured at T3 were 63.36 ± 33.35 and 0.44 ± 1.79 ng/mL in the morphine and placebo groups, respectively. There was no correlation between plasma morphine concentrations and pain scores (DAN, R = –0.05, P = .16; PIPP, R = –0.02, P = .58). Of the 21 neonates in each group, hypotension was observed for 0 and 2 infants in the placebo and morphine groups, respectively, before study drug (P = .48), 0 and 3 infants after the study drug loading dose (P = .23), and 0 and 1 infant at 24 ± 4 hours during study drug infusion (P > .99).


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  		TABLE 4. Results of the Repeated-Measures Analysis of Variance for Within- and Between-Groups Factors Comparing PIPP Scores During Heel Sticks Performed Before (T1), 2 to 3 Hours After (T2), and 20 to 28 Hours After (T3) a Loading Dose of Morphine or Placebo, Followed by a Continuous Infusion of Morphine or Placebo, Among Preterm Neonates

 

   DISCUSSION
TOP
 ABSTRACT
 METHODS
 RESULTS
 DISCUSSION
REFERENCES
 
In this study, intravenous administration of morphine as a loading dose followed by a continuous infusion did not provide adequate analgesia for heel stick-induced pain among ventilated preterm neonates, as measured with both behavioral and multidimensional pain scales. This finding is worrisome because morphine is used widely for ongoing analgesia during routine NICU care and procedures among ventilated preterm neonates.1,2,11–15,17,18 Among critically ill neonates, it is well known that morphine reduces behavioral and hormonal stress responses induced by surgery among term neonates23–25 and improves ventilator synchrony26 and sedation27 among ventilated preterm neonates, but its analgesic effects on the acute pain caused by invasive procedures remain unclear.

Initial data were in favor of an analgesic effect of morphine for procedural pain among preterm neonates. With the Neonatal Facial Coding System, Scott et al18 evaluated behavioral pain responses during heel sticks among preterm and term neonates who were receiving morphine at steady-state serum concentrations. After a 50 µg/kg bolus, a 20 to 30 µg/kg per hour continuous infusion was administered for at least 60 hours before a painful procedure. Pain measured with the Neonatal Facial Coding System was diminished by morphine during swab and lance procedures, although pain scores did not correlate with serum morphine concentrations. Steady-state serum concentrations were relatively high, with mean ± SD values of 207.1 ± 99.4 ng/mL for neonates at 24 to 27 weeks and 130.2 ± 34.6 ng/mL for neonates at 28 to 31 weeks.18 These morphine concentrations were considerably higher than those reported to be analgesic among older children (ie, 4–65 ng/mL).28 The mean ± SD plasma morphine concentration measured 20 to 28 hours after the start of continuous morphine infusion was 63.36 ± 33.35 ng/mL in our population. The pharmacokinetic data available at the start of the study were used to select the morphine infusion rates for our study.18,29,30 Because no neonate in the placebo group received open-label morphine, the trace mean concentrations found in this group were considered to be below the detection limit. In a pilot, randomized, controlled trial (RCT), pain responses (measured with PIPP scores) during tracheal suctioning were reduced significantly among the ventilated preterm neonates receiving morphine (P < .001) or midazolam (P = .002) infusions, compared with those in the placebo group.17 By using laser Doppler flowmetry to measure changes in skin blood flow related to pain and discomfort, McCulloch et al31 found that skin blood flow in the abdominal wall increased by 27 to 134% during intensive care procedures such as heel sticks, physical handling, tracheal suctioning, or chest physiotherapy, whereas it decreased after intravenous morphine administration. Interestingly, physical handling and chest physiotherapy elicited greater increases in skin blood flow than did heel sticks. Another study by the same authors showed that skin blood flow increased significantly (97%) among neonates undergoing percutaneous central venous catheter placement (N = 19) without analgesia, whereas it remained unchanged among neonates given intravenous morphine treatment before the procedure.13

Recent evidence, however, seems to refute the effectiveness of morphine during acute pain among preterm neonates. An observational study among ventilated preterm neonates showed no significant changes in plasma norepinephrine levels, vagal tone index, or flexor withdrawal reflexes (Von Frey filaments) before, 20 minutes after, or 60 minutes after administration of the first postoperative dose of morphine (0.1 mg/kg).32 More recently, a blinded RCT comparing the effects of morphine or placebo infusions among ventilated preterm neonates showed no analgesic effects of morphine during tracheal tube suctioning, with 3 different pain assessment tools (PIPP scores, Neonatal Infant Pain Scale, and global pain assessment by the bedside nurse with a visual analog scale).15 In our double-blind RCT, acute pain measured with the DAN scale and PIPP scores during heel sticks performed before, 2 to 3 hours after, and 20 to 28 hours after a loading dose of morphine (0.1 mg/kg) or placebo, followed by continuous infusions of morphine or placebo, among ventilated preterm neonates showed no analgesic effects of morphine. In addition, plasma morphine levels were not correlated with pain responses measured with the DAN scale or the PIPP scale. Although pain scores tended to be lower at T2 and T3, compared with T1, the interaction between pain at the 3 time points and treatment group was not statistically significant with either the DAN scale or the PIPP scale, which indicates that the patterns of changes in pain scores over the 3 time periods were the same for infants receiving placebo and those receiving morphine. Furthermore, the nonsignificant P values for the between-groups analyses of DAN and PIPP scores indicated that pain scores collapsed over the 3 time periods were not different for infants with and without morphine. This study was powered to detect a clinically relevant 2-point difference between morphine and placebo groups; this expected difference was greater than the trend observed. Among adult patients, a reduction of 30% of the range in a pain scale represents a clinically important difference, corresponding to a patient’s perception of reduced pain. Defining analgesic efficacy in terms of clinically important differences, rather than minimal detectable changes, may be more appropriate for judging effective treatments for acute pain.33 These accumulating data raise questions about the effectiveness of morphine analgesia for acute pain resulting from invasive procedures among preterm neonates.

The relatively inadequate analgesic effect of morphine during the neonatal period has also been found in animal studies. Indeed, morphine analgesia has been studied among infant rats exposed to mechanical,34 thermal, or inflammatory pain,35,36 because of similarities in the pain systems of newborn rodents and humans.37 Among neonatal rat pups, the efficacy of morphine analgesia increased 40-fold with age from postnatal day 3 to postnatal day 14, as demonstrated with a limb withdrawal test of thermal pain.38 Possible explanations for the lack of analgesic effects of morphine among preterm neonates may include the immaturity of opioid receptors (decreased receptor concentrations and/or receptor affinity) among neonates.28,39,40 Alternatively, morphine metabolism in the immature liver, with decreased production of morphine-6-glucuronide (which has 20-fold greater analgesic potency than morphine41) and increased production of morphine-3-glucuronide (which antagonizes the analgesic effects of both morphine and morphine-6-glucuronide42), may explain the decreased effects of morphine among preterm neonates. Neonates produce both glucuronides less well than older children.43 Preterm neonates (26–34 weeks of gestation) administered single doses29 or continuous infusions30 of morphine achieved higher plasma concentrations of morphine-3-glucuronide than morphine-6-glucuronide. Decreased production of morphine-6-glucuronide may explain why high plasma concentrations of unchanged morphine were necessary in one study to produce adequate sedation and analgesia among preterm and term neonates.44 In rats pups, {kappa}-opioid receptor agonists produced robust analgesia in the tail-flick nociceptive test, whereas µ-opioid receptor agonists had no detectable effect until postnatal day 12, corresponding to the expression of µ-opioid receptors during development.45 Acute pain may also cause an uncoupling of opioid receptors,46 which could explain the relative lack of morphine effects among preterm neonates exposed to acute procedural pain.

This study might have less power than intended during the study design, because the SD of mean pain scores assessed with the DAN scale was 4.0, instead of the 2.2 value used in the sample-size calculations. Because the SD we used for sample-size estimation was based on a small previous sample, its 95% confidence interval was wide (1.6–3.5). Indeed, very accurate sample-size calculations can be performed only for studies based on extensive previous data and are often difficult in exploratory studies.47 Although this loss of power is a limitation, it is worth noting that pain assessment with another scale, ie, PIPP scores, yielded exactly the same results.

Infants in the NICU are subjected repeatedly to painful procedures and may have chronic pain and stress from intensive care itself and from a variety of medical conditions associated with inflammation. Opioid analgesics have been used increasingly to decrease pain and stress for neonates in the NICU. Nevertheless, current evidence does not support the routine use of morphine infusions for all ventilated preterm neonates.14,15 Morphine infusions in this population should be limited to the presence of severe ongoing pain or clinical situations in which morphine provides short-term clinical benefits. On the basis of our results, we conclude that morphine does not provide adequate analgesia for ventilated preterm neonates of <33 weeks’ gestational age who are exposed to acute pain resulting from multiple procedures, such as heel sticks. These conclusions do not apply to continuous severe pain and should not encourage the reduction of analgesic treatment for ventilated preterm neonates in severe pain, who constitute a group at high risk for physiologic instability and long-term effects of pain. In fact, the administration of continuous morphine infusions to preterm neonates does not eliminate the need for other analgesic approaches (eg, sucrose) that are effective against acute procedural pain.


   ACKNOWLEDGMENTS
 
This study was supported by grant funds from the Fondation CNP (Paris, France) (to R.C. and R.L.), and National Institute for Child Health and Human Development grants HD36484 (to K.J.S.A.) and HD36270 (to B.A.B.).

We gratefully acknowledge the contributions of the physicians, nurses, pharmacists, ultrasonographers, and occupational and physical therapists at the participating institutions and the parents who gave consent for this study.


   FOOTNOTES
 
Accepted Nov 16, 2004.

Address correspondence to Ricardo Carbajal, MD, Centre National de Ressources de Lutte Contre la Douleur, Hôpital d’Enfants Armand Trousseau, 26, av du Dr Netter, 75012 Paris, France. E-mail: ricardo.carbajal{at}trs.aphp.fr

No conflict of interest declared.


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 ABSTRACT
 METHODS
 RESULTS
 DISCUSSION
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PEDIATRICS (ISSN 1098-4275). ©2005 by the American Academy of Pediatrics




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