Published online November 1, 2004
PEDIATRICS Vol. 114 No. 5 November 2004, pp. 1335-1337 (doi:10.1542/10.1542/peds.2004-0621)
This Article
Right arrow Extract Freely available
Right arrow Full Text (PDF)
Right arrow Submit a response
Right arrow Alert me when this article is cited
Right arrow Alert me when eLetters are posted
Right arrow Alert me if a correction is posted
Services
Right arrow E-mail this article to a friend
Right arrow Similar articles in this journal
Right arrow Similar articles in ISI Web of Science
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Add to My File Cabinet
Right arrow Download to citation manager
Right arrowRequest Permissions
Citing Articles
Right arrow Citing Articles via HighWire
Right arrow Citing Articles via CrossRef
Right arrow Citing Articles via ISI Web of Science (2)
Right arrow Citing Articles via Google Scholar
Google Scholar
Right arrow Articles by Aly, H.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Aly, H.
Related Collections
Right arrow Premature & Newborn
Social Bookmarking
Add to CiteULike   Add to Connotea   Add to Del.icio.us   Add to Digg   Add to Facebook   Add to Reddit   Add to Technorati   Add to Twitter  
What's this?

COMMENTARY

Preemptive Strike in the War on Pain: Is It a Safe Strategy for Our Vulnerable Infants?

Hany Aly, MD

Department of Neonatology, George Washington University and Children's National Medical Center, Washington, DC 20037

Abbreviations: NICU, neonatal intensive care unit

Among the remedies which it has pleased Almighty God to give to man to relieve his sufferings, none is so universal and so efficacious as opium.

Dr Thomas Sydenham (1624–1689)

What a great medicine to relieve pain and emotional stress. With no side effects known at that time, opium was perceived as almost miraculous and became very popular for relieving the suffering of patients with a wide variety of diseases, such as insomnia, headaches, and epilepsy (among many others). Overworked parents also used opium as a pacifying remedy for their harassed infants. Morphine was later extracted from opium and named after Morpheus, the Greek god of dreams.2

The perception of opium changed to the opposite extreme after recognition of its addictive nature. In his remarks about the suffering of the world from opium destruction, Dr John Witherspoon, president of the American Medical Association early in the 20th century, urged the medical community to "save our people from the clutches of this hydra-headed monster which stalks abroad throughout the civilized world, wrecking lives and happy homes, filling our jails and lunatic asylums, and taking from these unfortunates the precious promise of eternal life."3

The ancient Egyptian pharaohs discovered opiates almost 5000 years ago, but their physicians were versed in its medical use. They opted to use other remedies, such as salicyl compounds for relief of rheumatic pain and local cryoanalgesia for male circumcision, a surgical procedure that was routinely performed for young men just before marriage.4

Pain can complicate the illnesses of infants in general and premature infants in particular. Repetitive noxious stimuli may lead to impaired attention, learning disabilities, and decreased thresholds for future painful stimuli.5–7 It is inhumane to let infants suffer from pain without appropriate intervention. It is a challenge, however, to diagnose pain confidently in this vulnerable population. Many clinical scales have been advocated for objective quantification of pain among premature infants. These scales are generally based on recognition of the infant's responses to pain, ie, either physiologic changes in heart rate, blood pressure, and oxygen saturation or behavioral responses in the form of facial expressions, body movements, and cries. Pain causes systemic stress that increases the release of cortisol and catecholamines8 and, unfortunately, the proposed clinical pain scales do not correlate well with increased concentrations of biochemical markers.9 Therefore, the validity of current clinical scales is not certain, and the question of which infants are in need of analgesia remains largely unanswered.

To overcome any doubt about letting an infant suffer from pain, some neonatal intensive care units (NICUs) advocate a strategy of preemptive continuous infusion of opiates and/or benzodiazepines for all critically ill infants and infants undergoing mechanical ventilation. Such a strategy may not be safe, however. Infants receiving opiates or benzodiazepines continuously are at significantly increased risk of medication tolerance and respiratory depression. Consequently, the duration of mechanical ventilation is increased and hospitalization is prolonged.10 In addition, the drug may accumulate with time, and infants may easily become oversedated. The advantages of preemptive continuous infusion of analgesics, compared with intermittent administration, are not clear.11

The safety of sedation among neonates generally remains to be established. Hypotension is often observed among premature infants receiving morphine.12 Despite the hemodynamic stability of fentanyl,13 it may lead to hypothermia and chest wall rigidity.14 Weaning from fentanyl is often associated with withdrawal symptoms, and hospitalization then becomes significantly prolonged. Neonates who receive continuous fentanyl infusions have an average 9.6-day delay in hospital discharge, compared with those who receive morphine infusions.15 Benzodiazepines are also not benign. A randomized trial showed increased risks of death, severe intraventricular hemorrhage, or periventricular leukomalacia when premature infants received midazolam, compared with control subjects.12

Opiates can compromise developmental outcomes among premature infants. Infants born to addicted mothers represent a model for the exposure of premature infants to opiates. Although it is not a perfect model, it may be helpful in pinpointing possible, long-term, developmental deficiencies. Before the safety of opioid use in the NICU is declared, premature infants must be carefully monitored for these long-term deficiencies. Learning disabilities, memory impairments, altered responses to new environments and stressors,16 developmental delays,17 and weaknesses in visual-motor and perceptual abilities were observed during follow-up monitoring of morphine-exposed infants.18,19 Animal studies showed that rats exposed to opiates during gestation significantly tended to self-administer opiates when opiates were made available after delivery. The long-term risk of addiction among NICU graduates has not yet been calculated. Finally, it is important to recognize that the brain may react differently when exposed to opiates in the absence of pain, compared with exposure in the presence of pain. Volunteer adults demonstrated behavioral changes toward addiction after the administration of a single dose of fentanyl.20 Therefore, it is important to distinguish whether infants are suffering from stress or from pain.5

The developing brains of premature infants are very vulnerable. Mean IQ scores are consistently lower among premature infants than among term control subjects, even in the absence of intraventricular hemorrhage or periventricular leukomalacia and after controlling for social and demographic differences. Deficiencies in IQ among formerly premature infants persisted through follow-up evaluations at the age of 20 years.21 The observed cognitive deficiencies among formerly premature infants were correlated with measurable reductions in brain volume, which could not be explained on the basis of known factors such as hypoxia or hemorrhage.22 Therefore, the mechanism of such organic neuronal loss in the developing brains of premature infants remains speculative. Endogenously secreted opioids are known to play morphogenic roles in normal brain development. Exposure of pregnant rats to morphine resulted in decreased dendritic arborization and axonal branching in the developing brains of their offspring and overall decreased neuronal density in the cortex. Fetuses exposed to naloxone (a morphine antagonist) experienced significant increases in neuronal packing in the cortex.23,24 Whether the neuronal loss among premature infants is related to overwhelming stress in the NICU environment or to excessive use of opiates and other sedative agents needs to be clarified.

Exposure of the developing brain to narcotics may be linked to the development of autism. This concept was developed through compilation of available studies on autism. Infants with autism have long been described clinically as resembling infants receiving narcotic medications.25 In a way, adults with opioid addictions represent a model of what happens when there are exogenous increases in opiate concentrations among human subjects. Morphine users are known to display aloofness and reduced socialization. At the cellular level, autistic children are thought to have underlying disturbances in endogenous morphine release in their brains.26 A study on drug exposure during pregnancy reported substantially increased incidences of autism (11.4%) and language delays (94%) among drug-exposed infants. The mothers reported addiction to cocaine, but most of them also used morphine.27 Morphine, when administered to newborn guinea pigs, resulted in significant decreases in the proximity maintenance time with their mothers.28

Our knowledge regarding analgesia and sedation among neonates is far from adequate. Dosing and pharmacokinetic features in relation to gestational and postnatal ages must be established. A standard tool for clinical diagnosis of pain that correlates well with biochemical markers of pain should be established. Cumulative doses and the type of sedative agent should be examined with respect to short-term and long-term neurodevelopmental outcomes of NICU graduates. Until these assessments are performed, claims of safety of sedative narcotic agents are inaccurate, and use of such drugs should be more conservative. We should weigh the risks and benefits of narcotic use in evidence-based practice29 (Table 1). In addition, the efficacy of alternative environmental and behavioral strategies should be scientifically studied.30


View this table:
[in this window]
[in a new window]
  		TABLE 1. Scale for Possible Risks Associated With the Use of Sedation Among Neonates

 
Finally, our memory has not yet healed from our experience with the liberal postnatal use of corticosteroids among premature infants.31 Let us try to learn from our past to better fulfill the oath of Hippocrates, "to relieve pain and suffering" without forgetting "to do no harm."


   FOOTNOTES
 
Accepted Apr 2, 2004.

Address correspondence to Hany Aly, MD, 900 23rd St NW, Suite G-2092, Washington, DC 20037. E-mail: haly{at}mfa.gwu.edu


   REFERENCES
TOP
 REFERENCES
 

  1. Wong KC. Anesthesia: past, present and future. J Chin Med Assoc. 2003;66 :135 –139[Medline]
  2. Hamilton GR, Baskett TF. In the arms of Morpheus: the development of morphine for postoperative pain relief. Can J Anaesth. 2000;47 :367 –374[Web of Science][Medline]
  3. Witherspoon JA. A protest against some of the evils in the profession of medicine. JAMA. 1900;34 :1589 –1592
  4. El Ansary M, Steigerwald I, Esser S. Egypt: over 5000 years of pain management: cultural and historic aspects. Pain Pract. 2003;3 :84 –87[CrossRef]
  5. Whitfield MF, Grunau RE. Behavior, pain perception, and the extremely low-birth-weight survivors. Clin Perinatol. 2000;27 :363 –379[CrossRef][Web of Science][Medline]
  6. Guy ER, Abbott FV. The behavioral response to formalin pain in preweanling rats. Pain. 1992;51 :81 –90[CrossRef][Web of Science][Medline]
  7. McLaughlin CR, Lichtman AH, Fanselow MS, et al. Tonic nociception in neonatal rats. Pharmacol Biochem Behav. 1990;36 :859 –862[CrossRef][Web of Science][Medline]
  8. 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 postoperative period: a pilot study. J Clin Pain. 2000;16 :95 –104
  9. Ambalavanan N, Carlo WA. Analgesia for ventilated neonates: where do we stand? J Pediatr. 1999;135 :403 –405[CrossRef][Web of Science][Medline]
  10. Yaster N, Kost-Byerly S, Berde C, Billet C. The management of opioid and benzodiazipine dependence in infants, children, and adolescents. Pediatrics. 1996;98 :135 –140[Abstract/Free Full Text]
  11. 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 –313[CrossRef][Web of Science][Medline]
  12. 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
  13. Saaremaa E, Huttunen P, Leppaluoto J, Meretoja O, Fellman V. Advantages of fentanyl over morphine in analgesia for ventilated newborn infants after birth: a randomized trial. J Pediatr. 1999;134 :144 –150[CrossRef][Web of Science][Medline]
  14. Okada Y, Powis M, McEwan A, Pierro A. Fentanyl analgesia increases the incidence of postoperative hypothermia in neonates. Pediatr Surg Int. 1998;13 :508 –511[CrossRef][Web of Science][Medline]
  15. 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 –369
  16. Slamberova R. Drugs during pregnancy: effects on the mother and next generation. Cesk Fysiol. 2003;52 :15 –21[Medline]
  17. Johnson HL, Rosen TS. Prenatal methadone exposure: effects on behavior in early infancy. Pediatr Pharmacol. 1982;2 :113 –120
  18. Moe V. Foster-placed and adopted children exposed in utero to opiates and other substances: prediction and outcome at four and half years. J Dev Behav Pediatr. 2002;23 :330 –339[Web of Science][Medline]
  19. Gill AC, Oei J, Lewis NL, Younan N, Kennedy L, Lui K. Strabismus in infants of opiate-dependant mothers. Acta Paediatr. 2003;92 :379 –385[CrossRef][Web of Science][Medline]
  20. Zacny JP, Lichtor JL, Zaragoza JG, de Wit H. Subjective and behavioral responses to intravenous fentanyl in healthy volunteers. Psychopharmacology (Berl). 1992;107 :319 –326[CrossRef][Medline]
  21. Hack M, Flannery DJ, Schluchter M, Carter Lborawski E, Klein N. Outcomes in young adulthood for very-low-birth-weight infants. N Engl J Med. 2002;346 :149 –157[Abstract/Free Full Text]
  22. Peterson B, Vohr B, Staib L, et al. Regional brain volume abnormalities and long-term cognitive outcome in premature infants. JAMA. 2000;284 :1939 –1947[Abstract/Free Full Text]
  23. Hauser KF, McLaughlin PJ, Zagon IS. Endogenous opioids regulate dendritic growth and spine formation in developing rat brain. Brain Res. 1987;416 :157 –161[CrossRef][Web of Science][Medline]
  24. Zagon IS, McLaughlin PJ. Opioid antagonist-induced modulation of cerebral and hippocampal development: histological and morphometric studies. Dev Brain Res. 1986;26 :233 –246
  25. Kalat JW. Speculations on similarities between autism and opiate addiction. J Autism Child Schizophr. 1978;8 :477 –479[CrossRef][Web of Science][Medline]
  26. Gillberg C. Endogenous opioids and opiate antagonists in autism: brief review of empirical findings and implications for clinicians. Dev Med Child Neurol. 1995;37 :239 –245[Web of Science][Medline]
  27. Davis E, Fennoy I, Laraque D, Kanem N, Brown G, Mitchell J. Autism and developmental abnormalities in children with perinatal cocaine exposure. J Natl Med Assoc. 1992;84 :315 –319[Medline]
  28. Herman BH, Panksepp J. Effects of morphine and naloxone in infant guinea pigs. Pharmacol Biochem Behav. 1978;9 :213 –220[CrossRef][Web of Science][Medline]
  29. Sinclair JC. Weighing risks and benefits in treating the individual patient. Clin Perinatol. 2003;30 :251 –268[CrossRef][Web of Science][Medline]
  30. Fleisher BE, VendenBerg K, Constantinou J, et al. Individualized developmental care for very-low-birth-weight premature infants. Clin Pediatr. 1995;34 :523 –529
  31. Shinwell ES, Karplus M, Reich D, et al. Early postnatal dexamethasone treatment and increased incidence of cerebral palsy. Arch Dis Child Fetal Neonatal Ed. 2000;83 :F177 –F181
PEDIATRICS (ISSN 1098-4275). ©2004 by the American Academy of Pediatrics

Add to CiteULike CiteULike   Add to Connotea Connotea   Add to Del.icio.us Del.icio.us   Add to Digg Digg   Add to Facebook Facebook   Add to Reddit Reddit   Add to Technorati Technorati   Add to Twitter Twitter    What's this?


This article has been cited by other articles:


Home page
 PediatricsHome page
H. Aly
Mechanical Ventilation and Cerebral Palsy
Pediatrics, June 1, 2005; 115(6): 1765 - 1767.
[Full Text] [PDF]

This Article
Right arrow Extract Freely available
Right arrow Full Text (PDF)
Right arrow Submit a response
Right arrow Alert me when this article is cited
Right arrow Alert me when eLetters are posted
Right arrow Alert me if a correction is posted
Services
Right arrow E-mail this article to a friend
Right arrow Similar articles in this journal
Right arrow Similar articles in ISI Web of Science
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Add to My File Cabinet
Right arrow Download to citation manager
Right arrowRequest Permissions
Citing Articles
Right arrow Citing Articles via HighWire
Right arrow Citing Articles via CrossRef
Right arrow Citing Articles via ISI Web of Science (2)
Right arrow Citing Articles via Google Scholar
Google Scholar
Right arrow Articles by Aly, H.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Aly, H.
Related Collections
Right arrow Premature & Newborn
Social Bookmarking
Add to CiteULike   Add to Connotea   Add to Del.icio.us   Add to Digg   Add to Facebook   Add to Reddit   Add to Technorati   Add to Twitter  
What's this?