UpToDate
Official reprint from UpToDate®
www.uptodate.com ©2016 UpToDate®

Prevention and treatment of neonatal pain

Author
Kanwaljeet JS Anand, MBBS, DPhil, FAAP, FCCM, FRCPCH
Section Editor
Richard Martin, MD
Deputy Editor
Melanie S Kim, MD

INTRODUCTION

Varying degrees of neonatal discomfort, stress, or pain may be associated with routine patient care and is associated with moderate to more severe invasive procedures. Care providers are expected to prevent any infant from experiencing pain.

This topic will address the prevention, control, and treatment of neonatal pain. The assessment of neonatal pain is discussed separately. (See "Assessment of neonatal pain".)

BACKGROUND

Advances in neonatal research demonstrate that newborns experience pain and that controlling newborn pain has short- and long-term benefits [1]. Professional bodies and parent groups expect health care providers to prevent infants from experiencing pain [2-4]. Varying degrees of neonatal discomfort or pain may occur during routine patient care (eg, gavage tube placement, bladder catheterization, or physical examination) [5], moderately invasive procedures (eg, suctioning, phlebotomy, or peripheral intravenous [IV] line placement), or more invasive procedures (eg, chest tube placement, circumcision, or central venous line placement). Pain is most common and intense in infants admitted to the neonatal intensive care unit (NICU). Infants admitted to the NICU frequently experience acute pain from skin-breaking procedures, established pain following surgery, and prolonged (chronic) pain from diseases like necrotizing enterocolitis (NEC) or meningitis. (See "Assessment of neonatal pain".)

APPROACH

To ensure that neonates receive adequate pain control, a pain control program should be established for each health care facility that treats newborns and should include the following [2,6-8]:

Routinely assess the infant for detection of neonatal pain. (See "Assessment of neonatal pain", section on 'Pain assessment'.)

                                                    

Subscribers log in here

To continue reading this article, you must log in with your personal, hospital, or group practice subscription. For more information or to purchase a personal subscription, click below on the option that best describes you:
Literature review current through: Nov 2016. | This topic last updated: Thu Nov 17 00:00:00 GMT 2016.
The content on the UpToDate website is not intended nor recommended as a substitute for medical advice, diagnosis, or treatment. Always seek the advice of your own physician or other qualified health care professional regarding any medical questions or conditions. The use of this website is governed by the UpToDate Terms of Use ©2016 UpToDate, Inc.
References
Top
  1. Anand KJ, Aranda JV, Berde CB, et al. Summary proceedings from the neonatal pain-control group. Pediatrics 2006; 117:S9.
  2. COMMITTEE ON FETUS AND NEWBORN and SECTION ON ANESTHESIOLOGY AND PAIN MEDICINE. Prevention and Management of Procedural Pain in the Neonate: An Update. Pediatrics 2016; 137:e20154271.
  3. Franck LS, Allen A, Cox S, Winter I. Parents' views about infant pain in neonatal intensive care. Clin J Pain 2005; 21:133.
  4. Franck LS, Cox S, Allen A, Winter I. Parental concern and distress about infant pain. Arch Dis Child Fetal Neonatal Ed 2004; 89:F71.
  5. Pereira-Da-Silva L, Bergmans KI, van Kerkhoven LA, et al. Reducing discomfort while measuring crown-heel length in neonates. Acta Paediatr 2006; 95:742.
  6. Sharek PJ, Powers R, Koehn A, Anand KJ. Evaluation and development of potentially better practices to improve pain management of neonates. Pediatrics 2006; 118 Suppl 2:S78.
  7. Anand KJ, International Evidence-Based Group for Neonatal Pain. Consensus statement for the prevention and management of pain in the newborn. Arch Pediatr Adolesc Med 2001; 155:173.
  8. Bellieni CV, Buonocore G. Neonatal pain treatment: ethical to be effective. J Perinatol 2008; 28:87.
  9. Anand KJ, Hall RW. Pharmacological therapy for analgesia and sedation in the newborn. Arch Dis Child Fetal Neonatal Ed 2006; 91:F448.
  10. Lago P, Garetti E, Merazzi D, et al. Guidelines for procedural pain in the newborn. Acta Paediatr 2009; 98:932.
  11. Anand KJ. Analgesia for skin-breaking procedures in newborns and children: what works best? CMAJ 2008; 179:11.
  12. Allegaert K, Naulaers G. Gabapentin as part of multimodal analgesia in a newborn with epidermolysis bullosa. Paediatr Anaesth 2010; 20:972.
  13. Behm MO, Kearns GL. Treatment of pain with gabapentin in a neonate. Pediatrics 2001; 108:482.
  14. Pillai Riddell RR, Racine NM, Turcotte K, et al. Non-pharmacological management of infant and young child procedural pain. Cochrane Database Syst Rev 2011; :CD006275.
  15. Bellieni CV, Cordelli DM, Marchi S, et al. Sensorial saturation for neonatal analgesia. Clin J Pain 2007; 23:219.
  16. Golianu B, Krane E, Seybold J, et al. Non-pharmacological techniques for pain management in neonates. Semin Perinatol 2007; 31:318.
  17. Taddio A, Pollock N, Gilbert-MacLeod C, et al. Combined analgesia and local anesthesia to minimize pain during circumcision. Arch Pediatr Adolesc Med 2000; 154:620.
  18. Chermont AG, Falcão LF, de Souza Silva EH, et al. Skin-to-skin contact and/or oral 25% dextrose for procedural pain relief for term newborn infants. Pediatrics 2009; 124:e1101.
  19. O'Sullivan A, O'Connor M, Brosnahan D, et al. Sweeten, soother and swaddle for retinopathy of prematurity screening: a randomised placebo controlled trial. Arch Dis Child Fetal Neonatal Ed 2010; 95:F419.
  20. Marín Gabriel MÁ, del Rey Hurtado de Mendoza B, Jiménez Figueroa L, et al. Analgesia with breastfeeding in addition to skin-to-skin contact during heel prick. Arch Dis Child Fetal Neonatal Ed 2013; 98:F499.
  21. Okan F, Coban A, Ince Z, et al. Analgesia in preterm newborns: the comparative effects of sucrose and glucose. Eur J Pediatr 2007; 166:1017.
  22. Weissman A, Aranovitch M, Blazer S, Zimmer EZ. Heel-lancing in newborns: behavioral and spectral analysis assessment of pain control methods. Pediatrics 2009; 124:e921.
  23. Shendurnikar N, Gandhi K. Analgesic effects of breastfeeding on heel lancing. Indian Pediatr 2005; 42:730.
  24. Shah PS, Herbozo C, Aliwalas LL, Shah VS. Breastfeeding or breast milk for procedural pain in neonates. Cochrane Database Syst Rev 2012; 12:CD004950.
  25. Abdulkader HM, Freer Y, Fleetwood-Walker SM, McIntosh N. Effect of suckling on the peripheral sensitivity of full-term newborn infants. Arch Dis Child Fetal Neonatal Ed 2007; 92:F130.
  26. Shann F. Suckling and sugar reduce pain in babies. Lancet 2007; 369:721.
  27. Brovedani P, Montico M, Shardlow A, et al. Suckling and sugar for pain reduction in babies. Lancet 2007; 369:1429.
  28. Stevens B, Johnston C, Franck L, et al. The efficacy of developmentally sensitive interventions and sucrose for relieving procedural pain in very low birth weight neonates. Nurs Res 1999; 48:35.
  29. Campos RG. Soothing pain-elicited distress in infants with swaddling and pacifiers. Child Dev 1989; 60:781.
  30. Campos RG. Rocking and pacifiers: two comforting interventions for heelstick pain. Res Nurs Health 1994; 17:321.
  31. Geyer J, Ellsbury D, Kleiber C, et al. An evidence-based multidisciplinary protocol for neonatal circumcision pain management. J Obstet Gynecol Neonatal Nurs 2002; 31:403.
  32. Cignacco E, Hamers JP, Stoffel L, et al. The efficacy of non-pharmacological interventions in the management of procedural pain in preterm and term neonates. A systematic literature review. Eur J Pain 2007; 11:139.
  33. Corff KE, Seideman R, Venkataraman PS, et al. Facilitated tucking: a nonpharmacologic comfort measure for pain in preterm neonates. J Obstet Gynecol Neonatal Nurs 1995; 24:143.
  34. Axelin A, Salanterä S, Lehtonen L. 'Facilitated tucking by parents' in pain management of preterm infants-a randomized crossover trial. Early Hum Dev 2006; 82:241.
  35. Fearon I, Kisilevsky BS, Hains SM, et al. Swaddling after heel lance: age-specific effects on behavioral recovery in preterm infants. J Dev Behav Pediatr 1997; 18:222.
  36. Huang CM, Tung WS, Kuo LL, Ying-Ju C. Comparison of pain responses of premature infants to the heelstick between containment and swaddling. J Nurs Res 2004; 12:31.
  37. Ward-Larson C, Horn RA, Gosnell F. The efficacy of facilitated tucking for relieving procedural pain of endotracheal suctioning in very low birthweight infants. MCN Am J Matern Child Nurs 2004; 29:151.
  38. Cignacco EL, Sellam G, Stoffel L, et al. Oral sucrose and "facilitated tucking" for repeated pain relief in preterms: a randomized controlled trial. Pediatrics 2012; 129:299.
  39. Alinejad-Naeini M, Mohagheghi P, Peyrovi H, Mehran A. The effect of facilitated tucking during endotracheal suctioning on procedural pain in preterm neonates: a randomized controlled crossover study. Glob J Health Sci 2014; 6:278.
  40. Gray L, Watt L, Blass EM. Skin-to-skin contact is analgesic in healthy newborns. Pediatrics 2000; 105:e14.
  41. Johnston CC, Stevens B, Pinelli J, et al. Kangaroo care is effective in diminishing pain response in preterm neonates. Arch Pediatr Adolesc Med 2003; 157:1084.
  42. Ludington-Hoe SM, Hosseini R, Torowicz DL. Skin-to-skin contact (Kangaroo Care) analgesia for preterm infant heel stick. AACN Clin Issues 2005; 16:373.
  43. Ferber SG, Makhoul IR. Neurobehavioural assessment of skin-to-skin effects on reaction to pain in preterm infants: a randomized, controlled within-subject trial. Acta Paediatr 2008; 97:171.
  44. Freire NB, Garcia JB, Lamy ZC. Evaluation of analgesic effect of skin-to-skin contact compared to oral glucose in preterm neonates. Pain 2008; 139:28.
  45. Johnston C, Campbell-Yeo M, Fernandes A, et al. Skin-to-skin care for procedural pain in neonates. Cochrane Database Syst Rev 2014; :CD008435.
  46. Bellieni CV, Bagnoli F, Perrone S, et al. Effect of multisensory stimulation on analgesia in term neonates: a randomized controlled trial. Pediatr Res 2002; 51:460.
  47. Bellieni CV, Buonocore G, Nenci A, et al. Sensorial saturation: an effective analgesic tool for heel-prick in preterm infants: a prospective randomized trial. Biol Neonate 2001; 80:15.
  48. Gray L, Garza E, Zageris D, et al. Sucrose and warmth for analgesia in healthy newborns: an RCT. Pediatrics 2015; 135:e607.
  49. Sadathosseini AS, Negarandeh R, Movahedi Z. The effect of a familiar scent on the behavioral and physiological pain responses in neonates. Pain Manag Nurs 2013; 14:e196.
  50. Harrison D, Bueno M, Yamada J, et al. Analgesic effects of sweet-tasting solutions for infants: current state of equipoise. Pediatrics 2010; 126:894.
  51. Stevens B, Yamada J, Ohlsson A, et al. Sucrose for analgesia in newborn infants undergoing painful procedures. Cochrane Database Syst Rev 2016; 7:CD001069.
  52. Bueno M, Yamada J, Harrison D, et al. A systematic review and meta-analyses of nonsucrose sweet solutions for pain relief in neonates. Pain Res Manag 2013; 18:153.
  53. Slater R, Cornelissen L, Fabrizi L, et al. Oral sucrose as an analgesic drug for procedural pain in newborn infants: a randomised controlled trial. Lancet 2010; 376:1225.
  54. Vanhatalo S. Oral sucrose for procedural pain in infants. Lancet 2011; 377:26; author reply 27.
  55. Linhares MB, Gaspardo CM, Martinez FE. Oral sucrose for procedural pain in infants. Lancet 2011; 377:26.
  56. Stevens B, Craig K, Johnston C, et al. Oral sucrose for procedural pain in infants. Lancet 2011; 377:25.
  57. Steed D, Port L, Connell TG, et al. Oral sucrose for procedural pain in infants. Lancet 2011; 377:25; author reply 27.
  58. Heaton PA, Fernando AM, Herd D. Oral sucrose for procedural pain in infants. Lancet 2011; 377:25; author reply 27.
  59. Fernandez M, Blass EM, Hernandez-Reif M, et al. Sucrose attenuates a negative electroencephalographic response to an aversive stimulus for newborns. J Dev Behav Pediatr 2003; 24:261.
  60. Blass EM, Shah A. Pain-reducing properties of sucrose in human newborns. Chem Senses 1995; 20:29.
  61. Blass EM, Shide DJ. Endogenous cholecystokinin reduces vocalization in isolated 10-day-old rats. Behav Neurosci 1993; 107:488.
  62. Ren K, Blass EM, Zhou Q, Dubner R. Suckling and sucrose ingestion suppress persistent hyperalgesia and spinal Fos expression after forepaw inflammation in infant rats. Proc Natl Acad Sci U S A 1997; 94:1471.
  63. Gradin M, Schollin J. The role of endogenous opioids in mediating pain reduction by orally administered glucose among newborns. Pediatrics 2005; 115:1004.
  64. Taddio A, Shah V, Shah P, Katz J. Beta-endorphin concentration after administration of sucrose in preterm infants. Arch Pediatr Adolesc Med 2003; 157:1071.
  65. Stevens B, Yamada J, Ohlsson A. Sucrose for analgesia in newborn infants undergoing painful procedures. Cochrane Database Syst Rev 2004; :CD001069.
  66. Johnston CC, Stremler R, Horton L, Friedman A. Effect of repeated doses of sucrose during heel stick procedure in preterm neonates. Biol Neonate 1999; 75:160.
  67. Johnston CC, Filion F, Snider L, et al. Routine sucrose analgesia during the first week of life in neonates younger than 31 weeks' postconceptional age. Pediatrics 2002; 110:523.
  68. Stevens B, Yamada J, Beyene J, et al. Consistent management of repeated procedural pain with sucrose in preterm neonates: Is it effective and safe for repeated use over time? Clin J Pain 2005; 21:543.
  69. Johnston CC, Filion F, Snider L, et al. How much sucrose is too much sucrose? Pediatrics 2007; 119:226.
  70. Holsti L, Grunau RE. Considerations for using sucrose to reduce procedural pain in preterm infants. Pediatrics 2010; 125:1042.
  71. Taddio A, Ohlsson K, Ohlsson A. Lidocaine-prilocaine cream for analgesia during circumcision in newborn boys. Cochrane Database Syst Rev 2000; :CD000496.
  72. Taddio A, Ohlsson A, Einarson TR, et al. A systematic review of lidocaine-prilocaine cream (EMLA) in the treatment of acute pain in neonates. Pediatrics 1998; 101:E1.
  73. Kaur G, Gupta P, Kumar A. A randomized trial of eutectic mixture of local anesthetics during lumbar puncture in newborns. Arch Pediatr Adolesc Med 2003; 157:1065.
  74. Biran V, Gourrier E, Cimerman P, et al. Analgesic effects of EMLA cream and oral sucrose during venipuncture in preterm infants. Pediatrics 2011; 128:e63.
  75. Bishai R, Taddio A, Bar-Oz B, et al. Relative efficacy of amethocaine gel and lidocaine-prilocaine cream for Port-a-Cath puncture in children. Pediatrics 1999; 104:e31.
  76. O'Brien L, Taddio A, Lyszkiewicz DA, Koren G. A critical review of the topical local anesthetic amethocaine (Ametop) for pediatric pain. Paediatr Drugs 2005; 7:41.
  77. Ferayorni A, Yniguez R, Bryson M, Bulloch B. Needle-free jet injection of lidocaine for local anesthesia during lumbar puncture: a randomized controlled trial. Pediatr Emerg Care 2012; 28:687.
  78. Roman-Rodriguez CF, Toussaint T, Sherlock DJ, et al. Pre-emptive penile ring block with sucrose analgesia reduces pain response to neonatal circumcision. Urology 2014; 83:893.
  79. Carbajal R, Eriksson M, Courtois E, et al. Sedation and analgesia practices in neonatal intensive care units (EUROPAIN): results from a prospective cohort study. Lancet Respir Med 2015; 3:796.
  80. Howard CR, Howard FM, Weitzman ML. Acetaminophen analgesia in neonatal circumcision: the effect on pain. Pediatrics 1994; 93:641.
  81. Shah V, Taddio A, Ohlsson A. Randomised controlled trial of paracetamol for heel prick pain in neonates. Arch Dis Child Fetal Neonatal Ed 1998; 79:F209.
  82. Ohlsson A, Shah PS. Paracetamol (acetaminophen) for prevention or treatment of pain in newborns. Cochrane Database Syst Rev 2016; 10:CD011219.
  83. Ceelie I, de Wildt SN, van Dijk M, et al. Effect of intravenous paracetamol on postoperative morphine requirements in neonates and infants undergoing major noncardiac surgery: a randomized controlled trial. JAMA 2013; 309:149.
  84. Härmä A, Aikio O, Hallman M, Saarela T. Intravenous Paracetamol Decreases Requirements of Morphine in Very Preterm Infants. J Pediatr 2016; 168:36.
  85. Anand KJ. Pain panacea for opiophobia in infants? JAMA 2013; 309:183.
  86. Anderson BJ, van Lingen RA, Hansen TG, et al. Acetaminophen developmental pharmacokinetics in premature neonates and infants: a pooled population analysis. Anesthesiology 2002; 96:1336.
  87. van Lingen RA, Deinum HT, Quak CM, et al. Multiple-dose pharmacokinetics of rectally administered acetaminophen in term infants. Clin Pharmacol Ther 1999; 66:509.
  88. van Lingen RA, Deinum JT, Quak JM, et al. Pharmacokinetics and metabolism of rectally administered paracetamol in preterm neonates. Arch Dis Child Fetal Neonatal Ed 1999; 80:F59.
  89. Anderson BJ, Pons G, Autret-Leca E, et al. Pediatric intravenous paracetamol (propacetamol) pharmacokinetics: a population analysis. Paediatr Anaesth 2005; 15:282.
  90. Arana A, Morton NS, Hansen TG. Treatment with paracetamol in infants. Acta Anaesthesiol Scand 2001; 45:20.
  91. Anderson BJ, Woollard GA, Holford NH. A model for size and age changes in the pharmacokinetics of paracetamol in neonates, infants and children. Br J Clin Pharmacol 2000; 50:125.
  92. Allegaert K, Palmer GM, Anderson BJ. The pharmacokinetics of intravenous paracetamol in neonates: size matters most. Arch Dis Child 2011; 96:575.
  93. Cuzzolin L, Antonucci R, Fanos V. Paracetamol (acetaminophen) efficacy and safety in the newborn. Curr Drug Metab 2013; 14:178.
  94. Truog R, Anand KJ. Management of pain in the postoperative neonate. Clin Perinatol 1989; 16:61.
  95. Anderson BJ, Holford NH, Armishaw JC, Aicken R. Predicting concentrations in children presenting with acetaminophen overdose. J Pediatr 1999; 135:290.
  96. Hopchet L, Kulo A, Rayyan M, et al. Does intravenous paracetamol administration affect body temperature in neonates? Arch Dis Child 2011; 96:301.
  97. Zenker M, Klinge J, Krüger C, et al. Severe pulmonary hypertension in a neonate caused by premature closure of the ductus arteriosus following maternal treatment with diclofenac: a case report. J Perinat Med 1998; 26:231.
  98. Aldrink JH, Ma M, Wang W, et al. Safety of ketorolac in surgical neonates and infants 0 to 3 months old. J Pediatr Surg 2011; 46:1081.
  99. Alano MA, Ngougmna E, Ostrea EM Jr, Konduri GG. Analysis of nonsteroidal antiinflammatory drugs in meconium and its relation to persistent pulmonary hypertension of the newborn. Pediatrics 2001; 107:519.
  100. Schmidt B, Adelmann C, Stützer H, et al. Comparison of sufentanil versus fentanyl in ventilated term neonates. Klin Padiatr 2010; 222:62.
  101. Penney CL, Gauldie J, Evelegh M, et al. Polycarbonate membranes: a novel surface for solid-phase determinations with utility in field format serological assays. J Immunol Methods 1989; 123:185.
  102. Dyke MP, Kohan R, Evans S. Morphine increases synchronous ventilation in preterm infants. J Paediatr Child Health 1995; 31:176.
  103. Quinn MW, Wild J, Dean HG, et al. Randomised double-blind controlled trial of effect of morphine on catecholamine concentrations in ventilated pre-term babies. Lancet 1993; 342:324.
  104. Wood CM, Rushforth JA, Hartley R, et al. Randomised double blind trial of morphine versus diamorphine for sedation of preterm neonates. Arch Dis Child Fetal Neonatal Ed 1998; 79:F34.
  105. Anand KJ, Hall RW, Desai N, et al. Effects of morphine analgesia in ventilated preterm neonates: primary outcomes from the NEOPAIN randomised trial. Lancet 2004; 363:1673.
  106. Menon G, Boyle EM, Bergqvist LL, et al. Morphine analgesia and gastrointestinal morbidity in preterm infants: secondary results from the NEOPAIN trial. Arch Dis Child Fetal Neonatal Ed 2008; 93:F362.
  107. Hall RW, Kronsberg SS, Barton BA, et al. Morphine, hypotension, and adverse outcomes among preterm neonates: who's to blame? Secondary results from the NEOPAIN trial. Pediatrics 2005; 115:1351.
  108. 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.
  109. Bellù R, de Waal K, Zanini R. Opioids for neonates receiving mechanical ventilation: a systematic review and meta-analysis. Arch Dis Child Fetal Neonatal Ed 2010; 95:F241.
  110. El Sayed MF, Taddio A, Fallah S, et al. Safety profile of morphine following surgery in neonates. J Perinatol 2007; 27:444.
  111. Black AM, Pandya S, Clark D, et al. Effect of caffeine and morphine on the developing pre-mature brain. Brain Res 2008; 1219:136.
  112. MacGregor R, Evans D, Sugden D, et al. Outcome at 5-6 years of prematurely born children who received morphine as neonates. Arch Dis Child Fetal Neonatal Ed 1998; 79:F40.
  113. Krekels EH, Tibboel D, de Wildt SN, et al. Evidence-based morphine dosing for postoperative neonates and infants. Clin Pharmacokinet 2014; 53:553.
  114. Fleishman R, Zhou C, Gleason C, et al. Standardizing morphine use for ventilated preterm neonates with a nursing-driven comfort protocol. J Perinatol 2015; 35:46.
  115. Czarnecki ML, Hainsworth K, Simpson PM, et al. Is there an alternative to continuous opioid infusion for neonatal pain control? A preliminary report of parent/nurse-controlled analgesia in the neonatal intensive care unit. Paediatr Anaesth 2014; 24:377.
  116. Matic M, Simons SH, van Lingen RA, et al. Rescue morphine in mechanically ventilated newborns associated with combined OPRM1 and COMT genotype. Pharmacogenomics 2014; 15:1287.
  117. Ancora G, Lago P, Garetti E, et al. Efficacy and safety of continuous infusion of fentanyl for pain control in preterm newborns on mechanical ventilation. J Pediatr 2013; 163:645.
  118. Orsini AJ, Leef KH, Costarino A, et al. Routine use of fentanyl infusions for pain and stress reduction in infants with respiratory distress syndrome. J Pediatr 1996; 129:140.
  119. Guinsburg R, Kopelman BI, Anand KJ, et al. Physiological, hormonal, and behavioral responses to a single fentanyl dose in intubated and ventilated preterm neonates. J Pediatr 1998; 132:954.
  120. Lago P, Benini F, Agosto C, Zacchello F. Randomised controlled trial of low dose fentanyl infusion in preterm infants with hyaline membrane disease. Arch Dis Child Fetal Neonatal Ed 1998; 79:F194.
  121. Pereira e Silva Y, Gomez RS, Marcatto Jde O, et al. Morphine versus remifentanil for intubating preterm neonates. Arch Dis Child Fetal Neonatal Ed 2007; 92:F293.
  122. Roberts KD, Leone TA, Edwards WH, et al. Premedication for nonemergent neonatal intubations: a randomized, controlled trial comparing atropine and fentanyl to atropine, fentanyl, and mivacurium. Pediatrics 2006; 118:1583.
  123. Pokela ML, Koivisto M. Physiological changes, plasma beta-endorphin and cortisol responses to tracheal intubation in neonates. Acta Paediatr 1994; 83:151.
  124. Kim JH, Kim KH, Woo HY, Shim JY. Maternal cytokine production during pregnancy and the development of childhood wheezing and allergic disease in offspring three years of age. J Asthma 2008; 45:948.
  125. Avino D, Zhang WH, De Villé A, Johansson AB. Remifentanil versus morphine-midazolam premedication on the quality of endotracheal intubation in neonates: a noninferiority randomized trial. J Pediatr 2014; 164:1032.
  126. Carbajal R, Lenclen R, Jugie M, et al. Morphine does not provide adequate analgesia for acute procedural pain among preterm neonates. Pediatrics 2005; 115:1494.
  127. Saarenmaa E, Huttunen P, Leppäluoto J, et al. Advantages of fentanyl over morphine in analgesia for ventilated newborn infants after birth: A randomized trial. J Pediatr 1999; 134:144.
  128. Ionides SP, Weiss MG, Angelopoulos M, et al. Plasma beta-endorphin concentrations and analgesia-muscle relaxation in the newborn infant supported by mechanical ventilation. J Pediatr 1994; 125:113.
  129. Franck LS, Vilardi J, Durand D, Powers R. Opioid withdrawal in neonates after continuous infusions of morphine or fentanyl during extracorporeal membrane oxygenation. Am J Crit Care 1998; 7:364.
  130. Anand KJ, Willson DF, Berger J, et al. Tolerance and withdrawal from prolonged opioid use in critically ill children. Pediatrics 2010; 125:e1208.
  131. Örge FH, Lee TJ, Walsh M, Gordon K. Comparison of fentanyl and morphine in laser surgery for retinopathy of prematurity. J AAPOS 2013; 17:135.
  132. Alencar AJ, Sanudo A, Sampaio VM, et al. Efficacy of tramadol versus fentanyl for postoperative analgesia in neonates. Arch Dis Child Fetal Neonatal Ed 2012; 97:F24.
  133. Hall RW, Boyle E, Young T. Do ventilated neonates require pain management? Semin Perinatol 2007; 31:289.
  134. Bouwmeester NJ, Hop WC, van Dijk M, et al. Postoperative pain in the neonate: age-related differences in morphine requirements and metabolism. Intensive Care Med 2003; 29:2009.
  135. van Dijk M, Bouwmeester NJ, Duivenvoorden HJ, et al. Efficacy of continuous versus intermittent morphine administration after major surgery in 0-3-year-old infants; a double-blind randomized controlled trial. Pain 2002; 98:305.
  136. Rouss K, Gerber A, Albisetti M, et al. Long-term subcutaneous morphine administration after surgery in newborns. J Perinat Med 2007; 35:79.
  137. van der Marel CD, Peters JW, Bouwmeester NJ, et al. Rectal acetaminophen does not reduce morphine consumption after major surgery in young infants. Br J Anaesth 2007; 98:372.
  138. Lynn AM, Nespeca MK, Bratton SL, Shen DD. Intravenous morphine in postoperative infants: intermittent bolus dosing versus targeted continuous infusions. Pain 2000; 88:89.
  139. Taddio A, Lee C, Yip A, et al. Intravenous morphine and topical tetracaine for treatment of pain in [corrected] neonates undergoing central line placement. JAMA 2006; 295:793.
  140. Anand KJ, Anderson BJ, Holford NH, et al. Morphine pharmacokinetics and pharmacodynamics in preterm and term neonates: secondary results from the NEOPAIN trial. Br J Anaesth 2008; 101:680.
  141. Angeles DM, Wycliffe N, Michelson D, et al. Use of opioids in asphyxiated term neonates: effects on neuroimaging and clinical outcome. Pediatr Res 2005; 57:873.
  142. Róka A, Melinda KT, Vásárhelyi B, et al. Elevated morphine concentrations in neonates treated with morphine and prolonged hypothermia for hypoxic ischemic encephalopathy. Pediatrics 2008; 121:e844.
  143. Zimmerman KO, Hornik CP, Ku L, et al. Sedatives and Analgesics Given to Infants in Neonatal Intensive Care Units at the End of Life. J Pediatr 2015; 167:299.
  144. Harlos MS, Stenekes S, Lambert D, et al. Intranasal fentanyl in the palliative care of newborns and infants. J Pain Symptom Manage 2013; 46:265.
  145. Hall RW, Shbarou RM. Drugs of choice for sedation and analgesia in the neonatal ICU. Clin Perinatol 2009; 36:215.
  146. Barois J, Tourneux P. Ketamine and atropine decrease pain for preterm newborn tracheal intubation in the delivery room: an observational pilot study. Acta Paediatr 2013; 102:e534.
  147. Bétrémieux P, Carré P, Pladys P, et al. Doppler ultrasound assessment of the effects of ketamine on neonatal cerebral circulation. Dev Pharmacol Ther 1993; 20:9.
  148. Saarenmaa E, Neuvonen PJ, Huttunen P, Fellman V. Ketamine for procedural pain relief in newborn infants. Arch Dis Child Fetal Neonatal Ed 2001; 85:F53.
  149. 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.
  150. Arya V, Ramji S. Midazolam sedation in mechanically ventilated newborns: a double blind randomized placebo controlled trial. Indian Pediatr 2001; 38:967.
  151. Jacqz-Aigrain E, Daoud P, Burtin P, et al. Placebo-controlled trial of midazolam sedation in mechanically ventilated newborn babies. Lancet 1994; 344:646.
  152. Ng E, Taddio A, Ohlsson A. Intravenous midazolam infusion for sedation of infants in the neonatal intensive care unit. Cochrane Database Syst Rev 2003; :CD002052.
  153. Attardi DM, Paul DA, Tuttle DJ, Greenspan JS. Premedication for intubation in neonates. Arch Dis Child Fetal Neonatal Ed 2000; 83:F161.
  154. Stevens MF, Werdehausen R, Gaza N, et al. Midazolam activates the intrinsic pathway of apoptosis independent of benzodiazepine and death receptor signaling. Reg Anesth Pain Med 2011; 36:343.
  155. Chrysostomou C, Schulman SR, Herrera Castellanos M, et al. A phase II/III, multicenter, safety, efficacy, and pharmacokinetic study of dexmedetomidine in preterm and term neonates. J Pediatr 2014; 164:276.
  156. Díaz SM, Rodarte A, Foley J, Capparelli EV. Pharmacokinetics of dexmedetomidine in postsurgical pediatric intensive care unit patients: preliminary study. Pediatr Crit Care Med 2007; 8:419.
  157. Potts AL, Anderson BJ, Warman GR, et al. Dexmedetomidine pharmacokinetics in pediatric intensive care--a pooled analysis. Paediatr Anaesth 2009; 19:1119.
  158. Su F, Nicolson SC, Gastonguay MR, et al. Population pharmacokinetics of dexmedetomidine in infants after open heart surgery. Anesth Analg 2010; 110:1383.
  159. Vilo S, Rautiainen P, Kaisti K, et al. Pharmacokinetics of intravenous dexmedetomidine in children under 11 yr of age. Br J Anaesth 2008; 100:697.
  160. Kubota T, Fukasawa T, Kitamura E, et al. Epileptic seizures induced by dexmedetomidine in a neonate. Brain Dev 2013; 35:360.
  161. Finkel JC, Quezado ZM. Hypothermia-induced bradycardia in a neonate receiving dexmedetomidine. J Clin Anesth 2007; 19:290.
  162. Berkenbosch JW, Tobias JD. Development of bradycardia during sedation with dexmedetomidine in an infant concurrently receiving digoxin. Pediatr Crit Care Med 2003; 4:203.
  163. Cogen MS, Parker JS, Sleep TE, et al. Masked trial of topical anesthesia for retinopathy of prematurity eye examinations. J AAPOS 2011; 15:45.
  164. Marsh VA, Young WO, Dunaway KK, et al. Efficacy of topical anesthetics to reduce pain in premature infants during eye examinations for retinopathy of prematurity. Ann Pharmacother 2005; 39:829.
  165. Olsson E, Eriksson M. Oral glucose for pain relief during eye examinations for retinopathy of prematurity. J Clin Nurs 2011; 20:1054.
  166. Rush R, Rush S, Ighani F, et al. The effects of comfort care on the pain response in preterm infants undergoing screening for retinopathy of prematurity. Retina 2005; 25:59.
  167. Sammartino M, Bocci MG, Ferro G, et al. Efficacy and safety of continuous intravenous infusion of remifentanil in preterm infants undergoing laser therapy in retinopathy of prematurity: clinical experience. Paediatr Anaesth 2003; 13:596.
  168. Rozé JC, Denizot S, Carbajal R, et al. Prolonged sedation and/or analgesia and 5-year neurodevelopment outcome in very preterm infants: results from the EPIPAGE cohort. Arch Pediatr Adolesc Med 2008; 162:728.
  169. de Graaf J, van Lingen RA, Simons SH, et al. Long-term effects of routine morphine infusion in mechanically ventilated neonates on children's functioning: five-year follow-up of a randomized controlled trial. Pain 2011; 152:1391.
  170. Ferguson SA, Ward WL, Paule MG, et al. A pilot study of preemptive morphine analgesia in preterm neonates: effects on head circumference, social behavior, and response latencies in early childhood. Neurotoxicol Teratol 2012; 34:47.
  171. Steinhorn R, McPherson C, Anderson PJ, et al. Neonatal morphine exposure in very preterm infants-cerebral development and outcomes. J Pediatr 2015; 166:1200.
  172. de Graaf J, van Lingen RA, Valkenburg AJ, et al. Does neonatal morphine use affect neuropsychological outcomes at 8 to 9 years of age? Pain 2013; 154:449.
  173. van den Bosch GE, White T, El Marroun H, et al. Prematurity, Opioid Exposure and Neonatal Pain: Do They Affect the Developing Brain? Neonatology 2015; 108:8.
  174. Zwicker JG, Miller SP, Grunau RE, et al. Smaller Cerebellar Growth and Poorer Neurodevelopmental Outcomes in Very Preterm Infants Exposed to Neonatal Morphine. J Pediatr 2016; 172:81.
  175. Grunau RE, Haley DW, Whitfield MF, et al. Altered basal cortisol levels at 3, 6, 8 and 18 months in infants born at extremely low gestational age. J Pediatr 2007; 150:151.
  176. Grunau RE, Holsti L, Haley DW, et al. Neonatal procedural pain exposure predicts lower cortisol and behavioral reactivity in preterm infants in the NICU. Pain 2005; 113:293.
  177. Tu MT, Grunau RE, Petrie-Thomas J, et al. Maternal stress and behavior modulate relationships between neonatal stress, attention, and basal cortisol at 8 months in preterm infants. Dev Psychobiol 2007; 49:150.
  178. Oberlander TF, Weinberg J, Papsdorf M, et al. Prenatal exposure to maternal depression, neonatal methylation of human glucocorticoid receptor gene (NR3C1) and infant cortisol stress responses. Epigenetics 2008; 3:97.