PEDIATRICS Vol. 115 No. 4 April 2005, pp. 1073-1075 (doi:10.1542/peds.2005-0204)
COMMENTARY |
Procedural Pain in Neonates: The New Millennium
Center for the Advancement of Perioperative Health and the Departments of Anesthesiology and Pediatrics and Child Psychiatry
Yale University School of Medicine
New Haven, CT 06510
For decades, pain management for infants and neonates was, in essence, nonexistent, and various procedures including surgery were performed in this vulnerable patient population with paralytics and minimal analgesics. This commonly practiced approach was justified by the belief that infants do not feel pain because of immaturity of the central nervous system and that because were no long-term outcomes to infant suffering. Today we know that the neurotransmitters and structures required for pain sensation as well as structures needed for long-term memory are developed adequately in the neonate and thus have the potential to affect long-term outcomes.1
One should note that neonates admitted to an intensive care unit are subjected daily to multiple painful procedures. These critically ill neonates experience procedures such as numerous heel sticks, arterial and venous punctures, endotracheal intubations, and gastric suctioning. Indeed, a recent study conducted in a tertiary neonatal intensive care unit confirmed the need for improved pain relief in neonates.2 The investigators indicated that the number of procedures to which each infant was exposed ranged from 0 to 53 per day. On a scale of 0 to 10, the average pain score in these infants ranged from 1.7 for a diaper change to 8.9 for endotracheal intubation. The investigators indicated also that 
40% of all neonates did not receive any analgesia at all during the intensive care stay. These findings point to the continuous need to educate the medical community regarding the long-term outcomes of pain management in neonates.
Clinical interpretation of neonatal response to noxious stimuli such as single or repeated heel sticks is also complicated because of limited sensitivity of current pain-assessment tools. Unlike older children or adults, neonates must depend on their caregivers to interpret their cues of pain and manage them appropriately. The 7 assessment tools that are frequently used in this patient population incorporate cry, a less-than-specific response.3 Many studies have studied pitch, onset, delay, and duration of cry, etc, yet the sensitivity of this assessment parameter remains to be proven. Similar problems exist with interpreting the cutaneous flexion reflex, oxygen saturation, and the biophysical profile as indicators of pain presence and intensity.4,5 Prematurity, postnatal age, and coexisting disease further confound neonatal pain assessment. Of the existing neonatal composite measures, the Premature Infant Pain Profile has the best construct validity and interrater and intrarater reliability.6 This 7-indicator pain measure includes behavioral, physiologic, and contextual indicators.
The underappreciation of the impact of noxious stimulation is due, in part, to the variable and sometimes conflicting data that have been gathered in the arena of neonatal pain. The response to pain in the neonate is variable because of multiple issues in brain development and function. There are little human data, and research has relied on animal models with the staged development of the rat pup as the accepted model. The ontogeny of opioid receptors and their ligands is not uniform.7 µ and 
receptors appear much earlier than 
receptors, and the endogenous opioid ligands (endorphins, enkephalins, and dynorphins) appear before receptors are present. Additionally, in the rat pup, descending inhibitory pathways are present at birth but are not functional before day 10 of life; a 7-day-old pup is comparable to a term neonate, and a 3-week-old pup is comparable to an adult.8 Thus, the human preterm or even term neonate may have a heightened physiochemical response to noxious stimuli, because the existing endogenous opioids seem incapable of participating in descending inhibitory modulation to diminish the pain response.
There are several conceptual issues that one needs to consider when interpreting the findings of Gradin and Schollin9 (in this issue of Pediatrics) involving the analgesic effect of naloxone. First, one must consider that in the neonate, the degree of endogenous peripheral antinociception depends on the degree of opioid receptor expression. That is, opioid receptor expression in the neonate lags behind the development of endogenous opioids, and thus, whether naloxone is involved in blocking the analgesic effects of sucrose cannot be determined by this present study. Second, Gradin and Schollin brought up the question of analgesic properties related to naloxone. Indeed, naloxone has been shown to have a bidirectional effect, and in adults, low doses of naloxone potentiate analgesia and high doses potentiate hyperalgesia and pain. Also, in patients displaying central sensitization, low-dose naloxone induces analgesia, whereas patients who are pain insensitive experience hyperalgesia.10 The mechanism of action is likely through the opioid receptor and not the µ opioid receptor.11 How this relates to neonatal opioid neurobiology is unclear, because we do not know what is considered a low dose of naloxone in the neonate. Another explanation of the observed findings by Gradin and Schollin may relate to wide dynamic range neurons and wind-up via indirect C-fiber activity. Their observation may not be of a gustatory response to sucrose but a mechanical effect from the act of suckling (orotactile). Orotactile suckling may decrease C-fiber activity, an indirect but major component in the development of hyperalgesia and central sensitization. Recent data suggest that orotactile suckling effectively reduces persistent hyperalgesia and allodynia from inflammatory pain.12 Indeed, repeated heel sticks excite an inflammatory pain response.
Research on the role of central neuroplasticity in the pathophysiology of pain-developmental biology suggests that prolonged changes in the central nervous system from pain may influence later responses to painful stimuli.13 Studies in human neonates consistently show that preemptive analgesia for circumcision decreases the likelihood of a heightened response to subsequent painful procedures (eg, vaccination) occurring months later. Noxious stimuli-induced changes in the central neural function may contribute to continued pain long after the removal of the initial stimulus.14 Thus, poorly controlled acute pain may lead to hyperalgesia, altered pain perception, and possibly a predilection to chronic pain states.
In conclusion, the current research in neonatal pain makes it clear that aggressive pain control in the neonate is desirable not only for the management of current pain but also for protection from pain experiences to come. We strongly suggest that health care providers consider these issues when taking care of neonates.
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ACKNOWLEDGMENTS |
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Z.N.K. is supported by the National Institutes of Health (National Institute of Child Health and Human Development grant R01HD37007-02).
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FOOTNOTES |
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Accepted Feb 4, 2005.
Address correspondence to Zeev N. Kain, MD, MBA, Department of Anesthesiology, Yale University School of Medicine, 333 Cedar St, New Haven, CT 06510. E-mail: zeev.kain{at}yale.edu
No conflict of interest declared.
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PEDIATRICS (ISSN 1098-4275). ©2005 by the American Academy of Pediatrics
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