Background: Short-acting opioids like remifentanil are suspected of an increased risk for tolerance, withdrawal and opioid-induced hyperalgesia (OIH). These potential adverse effects have never been investigated in neonates. Objectives: To compare remifentanil and fentanyl concerning the incidence of tolerance, withdrawal and OIH. Methods: 23 mechanically ventilated infants received up to 96 h either a remifentanil- or fentanyl-based analgesia and sedation regimen with low-dose midazolam. We compared the required opioid doses and the number of opioid dose adjustments. Following extubation, withdrawal symptoms were assessed by a modification of the Finnegan score. OIH was evaluated by the CHIPPS scale and by testing the threshold of the flexion withdrawal reflex with calibrated von Frey filaments. Results: Remifentanil had to be increased by 24% and fentanyl by 47% to keep the infants adequately sedated during mechanical ventilation. Following extubation, infants revealed no pronounced opioid withdrawal and low average Finnegan scores in both groups. Only 1 infant of the fentanyl group and 1 infant of the remifentanil group required methadone for treatment of withdrawal symptoms. Infants also revealed no signs of OIH and low CHIPPS scores in both groups. The median threshold of the flexion withdrawal reflex was 4.5 g (IQR = 2.3) in the fentanyl group and 2.7 g (IQR = 3.3) in the remifentanil group (p = 0.312), which is within the physiologic range of healthy infants. Conclusions: Remifentanil does not seem to be associated with an increased risk for tolerance, withdrawal or OIH.

Duhrsen L, Simons SH, Dzietko M, Genz K, Bendix I, Boos V, Sifringer M, Tibboel D, Felderhoff-Mueser U: Effects of repetitive exposure to pain and morphine treatment on the neonatal rat brain. Neonatology 2013;103:35-43.
Jenkins IA, Playfor SD, Bevan C, Davies G, Wolf AR: Current United Kingdom sedation practice in pediatric intensive care. Paediatr Anesth 2007;17:675-683.
Glass PS, Hardman D, Kamiyama Y, Quill TJ, Marton G, Donn KH, Grosse CM, Hermann D: Preliminary pharmacokinetics and pharmacodynamics of an ultra-short-acting opioid: remifentanil. Anesth Analg 1993;77:1031-1040.
Ross AK, Davis PJ, Dear Gd GL, Ginsberg B, McGowan FX, Stiller RD, Henson LG, Huffman C, Muir KT: Pharmacokinetics of remifentanil in anesthetized pediatric patients undergoing elective surgery or diagnostic procedures. Anesth Analg 2001;93:1393-1401.
Anand KJ, Willson DF, Berger J, Harrison R, Meert KL, Zimmerman J, Carcillo J, Newth CJ, Prodhan P, Dean JM, Nicholson C: Tolerance and withdrawal from prolonged opioid use in critically ill children. Pediatrics 2010;125:e1208-e1225.
Sammartino M, Garra R, Sbaraglia F, De Riso M, Continolo N: Remifentanil in children. Paediatr Anaesth 2010;20:246-255.
Welzing L, Oberthuer A, Junghaenel S, Harnischmacher U, Stützer H, Roth B: Remifentanil/midazolam versus fentanyl/midazolam for analgesia and sedation of mechanically ventilated neonates and young infants: a randomized controlled trial. Intensive Care Med 2012;38:1017-1024.
Breen D, Karabinis A, Malbrain M, Morais R, Albrecht S, Jarnvig IL, Parkinson P, Kirkham AJ: Decreased duration of mechanical ventilation when comparing analgesia-based sedation using remifentanil with standard hypnotic-based sedation for up to 10 days in intensive care unit patients: a randomised trial. Crit Care 2005;9:R200-R210.
Hunseler C, Merkt V, Gerloff M, Eifinger F, Kribs A, Roth B: Assessing pain in ventilated newborns and infants: validation of the Hartwig score. Eur J Pediatr 2010.
Finnegan LP, Connaughton JF Jr, Kron RE, Emich JP: Neonatal abstinence syndrome: assessment and management. Addict Dis 1975;2:141-158.
Katz R, Kelly HW, Hsi A: Prospective study on the occurrence of withdrawal in critically ill children who receive fentanyl by continuous infusion. Crit Care Med 1994;22:763-767.
Buttner W, Finke W: Analysis of behavioural and physiological parameters for the assessment of postoperative analgesic demand in newborns, infants and young children: a comprehensive report on seven consecutive studies. Paediatr Anaesth 2000;10:303-318.
Abdulkader HM, Freer Y, Garry EM, Fleetwood-Walker SM, McIntosh N: Prematurity and neonatal noxious events exert lasting effects on infant pain behaviour. Early Hum Dev 2008;84:351-355.
Osborn DA, Jeffery HE, Cole MJ: Opiate treatment for opiate withdrawal in newborn infants. Cochrane Database Syst Rev 2010;10:CD002059.
Lee M, Silverman S, Hansen H, Patel V, Manchikanti L: A comprehensive review of opioid-induced hyperalgesia. Pain Physician 2011;14:145-161.
Anand KJ, Clark AE, Wilson DF, Berger J: Opioid analgesia in mechanically ventilated children: results from the multicenter Measuring Opioid Tolerance Induced by Fentanyl study. Pediatr Crit Care Med 2013;14:27-36.
Tobias JD: Tolerance, withdrawal, and physical dependency after long-term sedation and analgesia of children in the pediatric intensive care unit. Crit Care Med 2000;28:2122-2132.
Arnold JH, Truog RD, Orav EJ, Scavone JM, Hershenson MB: Tolerance and dependence in neonates sedated with fentanyl during extracorporeal membrane oxygenation. Anesthesiology 1990;73:1136-1140.
Delvaux B, Ryckwaert Y, Van Boven M, De Kock M, Capdevila X: Remifentanil in the intensive care unit: tolerance and acute withdrawal syndrome after prolonged sedation. Anesthesiology 2005;102:1281-1282.
Ceger P, Kuhn CM: Opiate withdrawal in the neonatal rat: relationship to duration of treatment and naloxone dose. Psychopharmacology (Berl) 2000;150:253-259.
Angst MS, Clark JD: Opioid-induced hyperalgesia - a qualitative systematic review. Anesthesiology 2006;104:570-587.
Fishbain DA, Cole B, Lewis JE, Gao JR, Rosomoff RS: Do opioids induce hyperalgesia in humans? An evidence-based structured review. Pain Med 2009;10:829-839.
Angst MS, Koppert W, Pahl I, Clark DJ, Schmelz M: Short-term infusion of the μ-opioid agonist remifentanil in humans causes hyperalgesia during withdrawal. Pain 2003;106:49-57.
Cortinez LI, Brandes V, Munoz HR, Guerrero ME, Mur M: No clinical evidence of acute opioid tolerance after remifentanil-based anaesthesia. Br J Anaesth 2001;87:866-869.
Crawford MW, Hickey C, Zaarour C, Howard A, Naser B: Development of acute opioid tolerance during infusion of remifentanil for pediatric scoliosis surgery. Anesth Analg 2006;102:1662-1667.
Roulleau P, Gall O, Desjeux L, Dagher C, Murat I: Remifentanil infusion for cleft palate surgery in young infants. Paediatr Anaesth 2003;13:701-707.
Steinmetz J, Holm-Knudsen R, Sorensen MK, Eriksen K, Rasmussen LS: Hemodynamic differences between propofol-remifentanil and sevoflurane anesthesia for repair of cleft lip and palate in infants. Paediatr Anaesth 2007;17:32-37.
Joly V, Richebe P, Guignard B, Fletcher D, Maurette P, Sessler DI, Chauvin M: Remifentanil-induced postoperative hyperalgesia and its prevention with small-dose ketamine. Anesthesiology 2005;103:147-155.
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