Advertisement

Long-Term Effects of Neonatal Morphine Infusion on Pain Sensitivity: Follow-Up of a Randomized Controlled Trial

      Highlights

      • Opioids are commonly used in the NICU and have both beneficial and adverse short-term effects.
      • Long-term follow-up studies on neonatal morphine administration in humans are scarce.
      • Neonatal morphine infusion has no long-term adverse effects on thermal pain thresholds.
      • No effects on neurological functioning or incidence of chronic pain have been observed.

      Abstract

      Short-term and long-term effects of neonatal pain and its analgesic treatment have been topics of translational research over the years. This study aimed to identify the long-term effects of continuous morphine infusion in the neonatal period on thermal pain sensitivity, the incidence of chronic pain, and neurological functioning. Eighty-nine of the 150 participants of a neonatal randomized controlled trial on continuous morphine infusion versus placebo during mechanical ventilation underwent quantitative sensory testing and neurological examination at the age of 8 or 9 years. Forty-three children from the morphine group and 46 children from the placebo group participated in this follow-up study. Thermal detection and pain thresholds were compared with data from 28 healthy controls. Multivariate analyses revealed no statistically significant differences in thermal detection thresholds and pain thresholds between the morphine and placebo groups. The incidence of chronic pain was comparable between both groups. The neurological examination was normal in 29 (76%) of the children in the morphine group and 25 (61%) of the children in the control group (P = .14). We found that neonatal continuous morphine infusion (10 μg/kg/h) has no adverse effects on thermal detection and pain thresholds, the incidence of chronic pain, or overall neurological functioning 8 to 9 years later.

      Perspective

      This unique long-term follow-up study shows that neonatal continuous morphine infusion (10 μg/kg/h) has no long-term adverse effects on thermal detection and pain thresholds or overall neurological functioning. These findings will help clinicians to find the most adequate and safe analgesic dosing regimens for neonates and infants.

      Key words

      To read this article in full you will need to make a payment

      Purchase one-time access:

      Academic & Personal: 24 hour online accessCorporate R&D Professionals: 24 hour online access
      One-time access price info
      • For academic or personal research use, select 'Academic and Personal'
      • For corporate R&D use, select 'Corporate R&D Professionals'

      Subscribe:

      Subscribe to The Journal of Pain
      Already a print subscriber? Claim online access
      Already an online subscriber? Sign in
      Institutional Access: Sign in to ScienceDirect

      References

        • Anand K.J.
        • Hall R.W.
        • Desai N.
        • Shephard B.
        • Bergqvist L.L.
        • Young T.E.
        • Boyle E.M.
        • Carbajal R.
        • Bhutani V.K.
        • Moore M.B.
        • Kronsberg S.S.
        • Barton B.A.
        Effects of morphine analgesia in ventilated preterm neonates: primary outcomes from the NEOPAIN randomised trial.
        Lancet. 2004; 363: 1673-1682
        • Atici S.
        • Cinel L.
        • Cinel I.
        • Doruk N.
        • Aktekin M.
        • Akca A.
        • Camdeviren H.
        • Oral U.
        Opioid neurotoxicity: comparison of morphine and tramadol in an experimental rat model.
        Int J Neurosci. 2004; 114: 1001-1011
        • Bajic D.
        • Proudfit H.K.
        Projections from the rat cuneiform nucleus to the A7, A6 (locus coeruleus), and A5 pontine noradrenergic cell groups.
        J Chem Neuroanat. 2013; 50-51: 11-20
        • Bellu' R.
        • Dewaal K.
        • Zanini R.
        Opioids for neonates receiving mechanical ventilation. a systematic review and meta-analysis.
        Arch Dis Child-Fetal. 2009; 95: 241-251
        • Carbajal R.
        • Lenclen R.
        • Jugie M.
        • Paupe A.
        • Barton B.A.
        • Anand K.J.S.
        Morphine does not provide adequate analgesia for acute procedural pain among preterm neonates.
        Pediatrics. 2005; 115: 1494-1500
        • de Graaf J.
        • Valkenburg A.J.
        • Tibboel D.
        • van Dijk M.
        Thermal detection thresholds in 5-year-old preterm born children.
        Early Hum Dev. 2012; 88: 487-491
        • de Graaf J.
        • van Lingen R.A.
        • Simons S.H.P.
        • Anand K.J.S.
        • Duivenvoorden H.J.
        • Weisglas-Kuperus N.
        • Roofthooft D.W.E.
        • Jebbink L.J.M.G.
        • Veenstra R.R.
        • Tibboel D.
        • van Dijk M.
        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: 1391-1397
        • de Graaf J.
        • van Lingen R.A.
        • Valkenburg A.J.
        • Weisglas-Kuperus N.
        • Groot Jebbink L.
        • Wijnberg-Williams B.
        • Anand K.J.
        • Tibboel D.
        • van Dijk M.
        Does neonatal morphine use affect neuropsychological outcomes at 8 to 9 years of age?.
        Pain. 2013; 154: 449-458
        • Ferguson S.A.
        • Ward W.L.
        • Paule M.G.
        • Hall R.W.
        • Anand K.J.
        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: 47-55
        • Fredriks AM.
        • van Buuren S.
        • Wit J.M.
        • Verloove-Vanhorick S.P.
        Body index measurements in 1996-7 compared with 1980.
        Arch Dis Child. 2000; 82: 107-112
        • Hauser K.F.
        • Gurwell J.A.
        • Turbek C.S.
        Morphine inhibits Purkinje cell survival and dendritic differentiation in organotypic cultures of the mouse cerebellum.
        Exp Neurol. 1994; 130: 95-105
        • Hermann C.
        • Hohmeister J.
        • Demirakça S.
        • Zohsel K.
        • Flor H.
        Long-term alteration of pain sensitivity in school-aged children with early pain experiences.
        Pain. 2006; 125: 278-285
        • Johnston C.C.
        • Fernandes A.M.
        • Campbell-Yeo M.
        Pain in neonates is different.
        Pain. 2011; 152: S65-S73
        • Juul S.E.
        • Beyer R.P.
        • Bammler T.K.
        • Farin F.M.
        • Gleason C.A.
        Effects of neonatal stress and morphine on murine hippocampal gene expression.
        Pediatr Res. 2010; 69: 285-292
        • Kikkert H.K.
        • De Jong C.
        • Hadders-Algra M.
        Minor neurological dysfunction and IQ in 9-year-old children born at term.
        Dev Disabil Res Rev. 2011; 53: e16-25
        • Kort W.
        • Schittekatte M.
        • Dekker P.H.
        • Verhaeghe P.
        • Compaan E.L.
        • Bosmans M.
        • Vermeir G.
        WISC-III NL Wechsler Intelligence Scale for Children.
        in: Derde Editie N.L. Handleiding en Verantwoording. Harcourt Test Publishers/Nederlands Instituut voor Psychologen, Amsterdam2005
        • Manto M.U.
        • Jissendi P.
        Cerebellum: links between development, developmental disorders and motor learning.
        Front Neuroanat. 2012; 6: 1-10
        • Perquin C.W.
        • Hazebroek-Kampschreur A.A.
        • Hunfeld J.A.
        • Bohnen A.M.
        • van Suijlekom-Smit L.W.
        • Passchier J.
        • van der Wouden J.C.
        Pain in children and adolescents: a common experience.
        Pain. 2000; 87: 51-58
        • Schmelzle-Lubiecki B.M.
        • Campbell K.A.
        • Howard R.H.
        • Franck L.
        • Fitzgerald M.
        Long-term consequences of early infant injury and trauma upon somatosensory processing.
        Eur J Pain. 2007; 11: 799-809
        • Simons S.H.
        • van Dijk M.
        • van Lingen R.A.
        • Roofthooft D.
        • Duivenvoorden H.J.
        • Jongeneel N.
        • Bunkers C.
        • Smink E.
        • Anand K.J.S.
        • van den Anker J.N.
        • Tibboel D.
        Routine morphine infusion in preterm newborns who received ventilatory support: a randomized controlled trial.
        JAMA. 2003; 290: 2419-2427
        • Sternberg W.F.
        • Scorr L.
        • Smith L.D.
        • Ridgway C.G.
        • Stout M.
        Long-term effects of neonatal surgery on adulthood pain behavior.
        Pain. 2005; 113: 347-353
        • Taddio A.
        • Shah V.
        • Atenafu E.
        • Katz J.
        Influence of repeated painful procedures and sucrose analgesia on the development of hyperalgesia in newborn infants.
        Pain. 2009; 144: 43-48
        • Tibboel D.
        • Anand K.J.S.
        • van den Anker J.N.
        The pharmacological treatment of neonatal pain.
        Semin Fetal Neonat Med. 2005; 10: 195-205
        • van den Bosch G.E.
        • White T.
        • Tibboel D.
        • van Dijk M.
        Functional MRI pain studies in children? Yes, we (s)can!.
        Pediatr Radiol. 2013; 43: 1235-1236
        • Vien T.N.
        • Gleason C.A.
        • Hays S.L.
        • McPherson R.J.
        • Chavkin C.
        • Juul S.E.
        Effects of neonatal stress and morphine on kappa opioid receptor signaling.
        Neonatology. 2009; 96: 235-243
        • Walker S.M.
        • Franck L.S.
        • Fitzgerald M.
        • Myles J.
        • Stocks J.
        • Marlow N.
        Long-term impact of neonatal intensive care and surgery on somatosensory perception in children born extremely preterm.
        Pain. 2009; 141: 79-87
        • Wright A.A.
        • Zhang B.
        • Ray A.
        • Mack J.W.
        • Trice E.
        • Balboni T.
        • Mitchell S.L.
        • Jackson V.A.
        • Block S.D.
        • Maciejewski P.K.
        • Prigerson H.G.
        Associations between end-of-life discussions, patient mental health, medical care near death, and caregiver bereavement adjustment.
        JAMA. 2008; 300: 1665-1673
        • Yohai V.J.
        • Zamar R.H.
        Optimal locally robust M-estimates of regression.
        J Stat Plan Inference. 1997; 64: 309-323