Morphine Does Not Provide Adequate Analgesia for Acute Procedural Pain Among Preterm Neonates
http://www.100md.com
《小儿科》
Neonatal Intensive Care Unit, Poissy Saint Germain Hospital, Poissy, France
Centre National de Ressources de Lutte Contre la Douleur, Hpital 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
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 Aigu 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 Aigu 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
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 Aigu 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 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
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.
DISCUSSION
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.
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, -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.
No conflict of interest declared.
REFERENCES
Johnston CC, Collinge JM, Henderson SJ, Anand KJ. A cross-sectional survey of pain and pharmacological analgesia in Canadian neonatal intensive care units. Clin J Pain. 1997;13 :308 –312
Simons SH, van Dijk M, Anand KS, Roofthooft D, van Lingen RA, Tibboel D. Do we still hurt newborn babies A prospective study of procedural pain and analgesia in neonates. Arch Pediatr Adolesc Med. 2003;157 :1058 –1064
Giannakoulopoulos X, Teixeira J, Fisk N, Glover V. Human fetal and maternal noradrenaline responses to invasive procedures. Pediatr Res. 1999;45 :494 –499
Anand KJ, Carr DB. The neuroanatomy, neurophysiology, and neurochemistry of pain, stress, and analgesia in newborns and children. Pediatr Clin North Am. 1989;36 :795 –822
Andrews K, Fitzgerald M. The cutaneous withdrawal reflex in human neonates: sensitization, receptive fields, and the effects of contralateral stimulation. Pain. 1994;56 :95 –101
Taddio A, Shah V, Gilbert-MacLeod C, Katz J. Conditioning and hyperalgesia in newborns exposed to repeated heel lances. JAMA. 2002;288 :857 –861
Anand KJ, Scalzo FM. Can adverse neonatal experiences alter brain development and subsequent behavior Biol Neonate. 2000;77 :69 –82
Johnston CC, Stevens BJ. Experience in a neonatal intensive care unit affects pain response. Pediatrics. 1996;98 :925 –930
Taddio A, Katz J, Ilersich AL, Koren G. Effect of neonatal circumcision on pain response during subsequent routine vaccination. Lancet. 1997;349 :599 –603
Anand KJ. Consensus statement for the prevention and management of pain in the newborn. Arch Pediatr Adolesc Med. 2001;155 :173 –180
American Academy of Pediatrics, Committee on Fetus and Newborn, Committee on Drugs, Section on Anesthesiology, Section on Surgery, Canadian Paediatric Society, Fetus and Newborn Committee. Prevention and management of pain and stress in the neonate. Pediatrics. 2000;105 :454 –461
Moustogiannis AN, Raju TN, Roohey T, McCulloch KM. Intravenous morphine attenuates pain induced changes in skin blood flow in newborn infants. Neurol Res. 1996;18 :440 –444
Anand KJS, Hall RW, Desai NS, et al. Effects of pre-emptive morphine analgesia in ventilated preterm neonates: primary outcomes from the NEOPAIN Trial. Lancet. 2004;363 :1673 –1682
Simons SH, van Dijk M, van Lingen RA, et al. Routine morphine infusion in preterm newborns who received ventilatory support: a randomized controlled trial. JAMA. 2003;290 :2419 –2427
MacGregor R, Evans D, Sugden D, Gaussen T, Levene M. Outcome at 5–6 years of prematurely born children who received morphine as neonates. Arch Dis Child Fetal Neonatal Ed. 1998;79 :F40 –F43
Anand KJ, Barton BA, McIntosh N, et al. Analgesia and sedation in preterm neonates who require ventilatory support: results from the NOPAIN trial: Neonatal Outcome and Prolonged Analgesia in Neonates. Arch Pediatr Adolesc Med. 1999;153 :331 –338
Scott CS, Riggs KW, Ling EW, et al. Morphine pharmacokinetics and pain assessment in premature newborns. J Pediatr. 1999;135 :423 –429
Prechtl HFR. The neurological examination of the full term newborn infant. In: Prechtl HFR, ed. Clinics in Developmental Medicine. 2nd rev ed. London, United Kingdom: Heinemann; 1977:1 –68
Carbajal R, Paupe A, Hoenn E, Lenclen R, Olivier-Martin M. APN: evaluation behavioral scale of acute pain in newborn infants [in French]. Arch Pediatr. 1997;4 :623 –628
Carbajal R, Veerapen S, Couderc S, Jugie M, Ville Y. Analgesic effect of breast feeding in term neonates: randomised controlled trial. BMJ. 2003;326 :13
Ballantyne M, Stevens B, McAllister M, Dionne K, Jack A. Validation of the Premature Infant Pain Profile in the clinical setting. Clin J Pain. 1999;15 :297 –303
Farrington EA, McGuinness GA, Johnson GF, Erenberg A, Leff RD. Continuous intravenous morphine infusion in postoperative newborn infants. Am J Perinatol. 1993;10 :84 –87
Bouwmeester NJ, Hop WC, van Dijk M, Anand KJ, van den Anker JN, Tibboel D. Postoperative pain in the neonate: age-related differences in morphine requirements and metabolism. Intensive Care Med. 2003;29 :2009 –2015
Bouwmeester NJ, Anand KJ, van Dijk M, Hop WC, Boomsma F, Tibboel D. Hormonal and metabolic stress responses after major surgery in children aged 0–3 years: a double-blind, randomized trial comparing the effects of continuous versus intermittent morphine. Br J Anaesth. 2001;87 :390 –399
Dyke MP, Kohan R, Evans S. Morphine increases synchronous ventilation in preterm infants. J Paediatr Child Health. 1995;31 :176 –179
Wood CM, Rushforth JA, Hartley R, Dean H, Wild J, Levene MI. Randomised double blind trial of morphine versus diamorphine for sedation of preterm neonates. Arch Dis Child Fetal Neonatal Ed. 1998;79 :F34 –F39
Kart T, Christrup LL, Rasmussen M. Recommended use of morphine in neonates, infants and children based on a literature review: part 2: clinical use. Paediatr Anaesth. 1997;7 :93 –101
Bhat R, Abu-Harb M, Chari G, Gulati A. Morphine metabolism in acutely ill preterm newborn infants. J Pediatr. 1992;120 :795 –799
Hartley R, Green M, Quinn M, Levene MI. Pharmacokinetics of morphine infusion in premature neonates. Arch Dis Child. 1993;69 :55 –58
McCulloch KM, Ji SA, Raju TN. Skin blood flow changes during routine nursery procedures. Early Hum Dev. 1995;41 :147 –156
Franck LS, Boyce WT, Gregory GA, Jemerin J, Levine J, Miaskowski C. Plasma norepinephrine levels, vagal tone index, and flexor reflex threshold in premature neonates receiving intravenous morphine during the postoperative period: a pilot study. Clin J Pain. 2000;16 :95 –104
Lee JS, Hobden E, Stiell IG, Wells GA. Clinically important change in the visual analog scale after adequate pain control. Acad Emerg Med. 2003;10 :1128 –1130
Marsh D, Dickenson A, Hatch D, Fitzgerald M. Epidural opioid analgesia in infant rats, I: mechanical and heat responses. Pain. 1999;82 :23 –32
Abbott FV, Guy ER. Effects of morphine, pentobarbital and amphetamine on formalin-induced behaviours in infant rats: sedation versus specific suppression of pain. Pain. 1995;62 :303 –312
McLaughlin CR, Lichtman AH, Fanselow MS, Cramer CP. Tonic nociception in neonatal rats. Pharmacol Biochem Behav. 1990;36 :859 –862
Narsinghani U, Anand KJS. Developmental neurobiology of pain in neonatal rats. Lab Anim (NY). 2000;29 :27 –39
Giordano J, Barr GA. Morphine- and ketocyclazocine-induced analgesia in the developing rat: differences due to type of noxious stimulus and body topography. Brain Res. 1987;429 :247 –253
Rahman W, Dashwood MR, Fitzgerald M, Aynsley-Green A, Dickenson AH. Postnatal development of multiple opioid receptors in the spinal cord and development of spinal morphine analgesia. Brain Res Dev Brain Res. 1998;108 :239 –254
Kinney HC, Ottoson CK, White WF. Three-dimensional distribution of 3H-naloxone binding to opiate receptors in the human fetal and infant brainstem. J Comp Neurol. 1990;291 :55 –78
Osborne R, Thompson P, Joel S, Trew D, Patel N, Slevin M. The analgesic activity of morphine-6-glucuronide. Br J Clin Pharmacol. 1992;34 :130 –138
Smith MT, Watt JA, Cramond T. Morphine-3-glucuronide: a potent antagonist of morphine analgesia. Life Sci. 1990;47 :579 –585
Choonara IA, McKay P, Hain R, Rane A. Morphine metabolism in children. Br J Clin Pharmacol. 1989;28 :599 –604
Chay PC, Duffy BJ, Walker JS. Pharmacokinetic-pharmacodynamic relationships of morphine in neonates. Clin Pharmacol Ther. 1992;51 :334 –342
Barr GA, Paredes W, Erickson KL, Zukin RS. -Opioid receptor-mediated analgesia in the developing rat. Brain Res. 1986;394 :145 –152
Liu JG, Rovnaghi CR, Garg S, Anand KJS. Opioid receptor desensitization contributes to thermal hyperalgesia in infant rats. Eur J Pharmacol. 2004;491 :127 –136
Bacchetti P. Peer review of statistics in medical research: the other problem. BMJ. 2002;324 :1271 –1273(Ricardo Carbajal, MD, Ric)
Centre National de Ressources de Lutte Contre la Douleur, Hpital 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
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 Aigu 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 Aigu 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
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 Aigu 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 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
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.
DISCUSSION
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.
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, -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.
No conflict of interest declared.
REFERENCES
Johnston CC, Collinge JM, Henderson SJ, Anand KJ. A cross-sectional survey of pain and pharmacological analgesia in Canadian neonatal intensive care units. Clin J Pain. 1997;13 :308 –312
Simons SH, van Dijk M, Anand KS, Roofthooft D, van Lingen RA, Tibboel D. Do we still hurt newborn babies A prospective study of procedural pain and analgesia in neonates. Arch Pediatr Adolesc Med. 2003;157 :1058 –1064
Giannakoulopoulos X, Teixeira J, Fisk N, Glover V. Human fetal and maternal noradrenaline responses to invasive procedures. Pediatr Res. 1999;45 :494 –499
Anand KJ, Carr DB. The neuroanatomy, neurophysiology, and neurochemistry of pain, stress, and analgesia in newborns and children. Pediatr Clin North Am. 1989;36 :795 –822
Andrews K, Fitzgerald M. The cutaneous withdrawal reflex in human neonates: sensitization, receptive fields, and the effects of contralateral stimulation. Pain. 1994;56 :95 –101
Taddio A, Shah V, Gilbert-MacLeod C, Katz J. Conditioning and hyperalgesia in newborns exposed to repeated heel lances. JAMA. 2002;288 :857 –861
Anand KJ, Scalzo FM. Can adverse neonatal experiences alter brain development and subsequent behavior Biol Neonate. 2000;77 :69 –82
Johnston CC, Stevens BJ. Experience in a neonatal intensive care unit affects pain response. Pediatrics. 1996;98 :925 –930
Taddio A, Katz J, Ilersich AL, Koren G. Effect of neonatal circumcision on pain response during subsequent routine vaccination. Lancet. 1997;349 :599 –603
Anand KJ. Consensus statement for the prevention and management of pain in the newborn. Arch Pediatr Adolesc Med. 2001;155 :173 –180
American Academy of Pediatrics, Committee on Fetus and Newborn, Committee on Drugs, Section on Anesthesiology, Section on Surgery, Canadian Paediatric Society, Fetus and Newborn Committee. Prevention and management of pain and stress in the neonate. Pediatrics. 2000;105 :454 –461
Moustogiannis AN, Raju TN, Roohey T, McCulloch KM. Intravenous morphine attenuates pain induced changes in skin blood flow in newborn infants. Neurol Res. 1996;18 :440 –444
Anand KJS, Hall RW, Desai NS, et al. Effects of pre-emptive morphine analgesia in ventilated preterm neonates: primary outcomes from the NEOPAIN Trial. Lancet. 2004;363 :1673 –1682
Simons SH, van Dijk M, van Lingen RA, et al. Routine morphine infusion in preterm newborns who received ventilatory support: a randomized controlled trial. JAMA. 2003;290 :2419 –2427
MacGregor R, Evans D, Sugden D, Gaussen T, Levene M. Outcome at 5–6 years of prematurely born children who received morphine as neonates. Arch Dis Child Fetal Neonatal Ed. 1998;79 :F40 –F43
Anand KJ, Barton BA, McIntosh N, et al. Analgesia and sedation in preterm neonates who require ventilatory support: results from the NOPAIN trial: Neonatal Outcome and Prolonged Analgesia in Neonates. Arch Pediatr Adolesc Med. 1999;153 :331 –338
Scott CS, Riggs KW, Ling EW, et al. Morphine pharmacokinetics and pain assessment in premature newborns. J Pediatr. 1999;135 :423 –429
Prechtl HFR. The neurological examination of the full term newborn infant. In: Prechtl HFR, ed. Clinics in Developmental Medicine. 2nd rev ed. London, United Kingdom: Heinemann; 1977:1 –68
Carbajal R, Paupe A, Hoenn E, Lenclen R, Olivier-Martin M. APN: evaluation behavioral scale of acute pain in newborn infants [in French]. Arch Pediatr. 1997;4 :623 –628
Carbajal R, Veerapen S, Couderc S, Jugie M, Ville Y. Analgesic effect of breast feeding in term neonates: randomised controlled trial. BMJ. 2003;326 :13
Ballantyne M, Stevens B, McAllister M, Dionne K, Jack A. Validation of the Premature Infant Pain Profile in the clinical setting. Clin J Pain. 1999;15 :297 –303
Farrington EA, McGuinness GA, Johnson GF, Erenberg A, Leff RD. Continuous intravenous morphine infusion in postoperative newborn infants. Am J Perinatol. 1993;10 :84 –87
Bouwmeester NJ, Hop WC, van Dijk M, Anand KJ, van den Anker JN, Tibboel D. Postoperative pain in the neonate: age-related differences in morphine requirements and metabolism. Intensive Care Med. 2003;29 :2009 –2015
Bouwmeester NJ, Anand KJ, van Dijk M, Hop WC, Boomsma F, Tibboel D. Hormonal and metabolic stress responses after major surgery in children aged 0–3 years: a double-blind, randomized trial comparing the effects of continuous versus intermittent morphine. Br J Anaesth. 2001;87 :390 –399
Dyke MP, Kohan R, Evans S. Morphine increases synchronous ventilation in preterm infants. J Paediatr Child Health. 1995;31 :176 –179
Wood CM, Rushforth JA, Hartley R, Dean H, Wild J, Levene MI. Randomised double blind trial of morphine versus diamorphine for sedation of preterm neonates. Arch Dis Child Fetal Neonatal Ed. 1998;79 :F34 –F39
Kart T, Christrup LL, Rasmussen M. Recommended use of morphine in neonates, infants and children based on a literature review: part 2: clinical use. Paediatr Anaesth. 1997;7 :93 –101
Bhat R, Abu-Harb M, Chari G, Gulati A. Morphine metabolism in acutely ill preterm newborn infants. J Pediatr. 1992;120 :795 –799
Hartley R, Green M, Quinn M, Levene MI. Pharmacokinetics of morphine infusion in premature neonates. Arch Dis Child. 1993;69 :55 –58
McCulloch KM, Ji SA, Raju TN. Skin blood flow changes during routine nursery procedures. Early Hum Dev. 1995;41 :147 –156
Franck LS, Boyce WT, Gregory GA, Jemerin J, Levine J, Miaskowski C. Plasma norepinephrine levels, vagal tone index, and flexor reflex threshold in premature neonates receiving intravenous morphine during the postoperative period: a pilot study. Clin J Pain. 2000;16 :95 –104
Lee JS, Hobden E, Stiell IG, Wells GA. Clinically important change in the visual analog scale after adequate pain control. Acad Emerg Med. 2003;10 :1128 –1130
Marsh D, Dickenson A, Hatch D, Fitzgerald M. Epidural opioid analgesia in infant rats, I: mechanical and heat responses. Pain. 1999;82 :23 –32
Abbott FV, Guy ER. Effects of morphine, pentobarbital and amphetamine on formalin-induced behaviours in infant rats: sedation versus specific suppression of pain. Pain. 1995;62 :303 –312
McLaughlin CR, Lichtman AH, Fanselow MS, Cramer CP. Tonic nociception in neonatal rats. Pharmacol Biochem Behav. 1990;36 :859 –862
Narsinghani U, Anand KJS. Developmental neurobiology of pain in neonatal rats. Lab Anim (NY). 2000;29 :27 –39
Giordano J, Barr GA. Morphine- and ketocyclazocine-induced analgesia in the developing rat: differences due to type of noxious stimulus and body topography. Brain Res. 1987;429 :247 –253
Rahman W, Dashwood MR, Fitzgerald M, Aynsley-Green A, Dickenson AH. Postnatal development of multiple opioid receptors in the spinal cord and development of spinal morphine analgesia. Brain Res Dev Brain Res. 1998;108 :239 –254
Kinney HC, Ottoson CK, White WF. Three-dimensional distribution of 3H-naloxone binding to opiate receptors in the human fetal and infant brainstem. J Comp Neurol. 1990;291 :55 –78
Osborne R, Thompson P, Joel S, Trew D, Patel N, Slevin M. The analgesic activity of morphine-6-glucuronide. Br J Clin Pharmacol. 1992;34 :130 –138
Smith MT, Watt JA, Cramond T. Morphine-3-glucuronide: a potent antagonist of morphine analgesia. Life Sci. 1990;47 :579 –585
Choonara IA, McKay P, Hain R, Rane A. Morphine metabolism in children. Br J Clin Pharmacol. 1989;28 :599 –604
Chay PC, Duffy BJ, Walker JS. Pharmacokinetic-pharmacodynamic relationships of morphine in neonates. Clin Pharmacol Ther. 1992;51 :334 –342
Barr GA, Paredes W, Erickson KL, Zukin RS. -Opioid receptor-mediated analgesia in the developing rat. Brain Res. 1986;394 :145 –152
Liu JG, Rovnaghi CR, Garg S, Anand KJS. Opioid receptor desensitization contributes to thermal hyperalgesia in infant rats. Eur J Pharmacol. 2004;491 :127 –136
Bacchetti P. Peer review of statistics in medical research: the other problem. BMJ. 2002;324 :1271 –1273(Ricardo Carbajal, MD, Ric)