I. BACKGROUND. Recognition that both premature and full-term infants experience pain has led to increasing appreciation of the prevalent problem of undertreatment of stress and pain of hospitalized infants. Both humanitarian considerations and scientific principles favor improved management strategies to prevent pain and stress whenever possible and, when discomfort is unavoidable, to provide prompt and appropriate treatment. Optimal pain management should be individualized and requires an understanding of developmental analgesic pharmacology, neonatal physiology, pain assessment, and techniques for providing pain relief.
A. Fetal and neonatal physiologic responses to pain.
There is considerable maturation of peripheral, spinal, and supraspinal neurologic pathways necessary for nociception by late in the second trimester. By 20 weeks’ gestation, cutaneous sensory nerve terminals are present in all body areas and a full complement of cortical neurons is present within the central nervous system. Research using near-infrared spectroscopy (NIRS) shows a specific pattern of activation of the somatosensory cortex in preterm infants after noxious stimulation suggesting that painful stimuli reach the cerebral cortex.
Peripheral sensory fibers have larger, more overlapping receptive fields and inhibitory cortical descending pathways such as the dorsolateral funiculus that modulate pain postnatally, suggesting that neonates and young infants have hyperresponsiveness to pain.
Infants exhibit predictable pain response patterns with respect to stress hormone levels, changes in heart rate, blood pressure, and oxygen saturation. Although the fetus is capable of mounting a stress response beginning at approximately 23 weeks’ gestation, physiologic parameters are nonspecific and are not necessarily reliable indicators of pain, particularly among critically ill neonates who may be hemodynamically unstable, septic, or mechanically ventilated. As a result, pain assessment tools in infants are composite scales that typically combine physiologic parameters with observed distress behaviors. Behavioral and physiologic responses are less reliable among infants exposed to chronic or persistent noxious stimuli.
B. Medical and developmental outcomes
1. Neonatal medical and surgical outcomes. Neonatal responses to pain may worsen compromised physiologic states such as hypoxia, hypercarbia, acidosis, hyperglycemia, respiratory dyssynchrony, and pneumothorax. Changes in intrathoracic pressure due to diaphragmatic splinting and vagal responses produced in response to pain following invasive procedures precipitate hypoxemic events and alterations in oxygen delivery and cerebral blood flow. Early studies of surgical responses showed a more stable intraoperative course and improved postoperative recovery among infants who received perioperative analgesia and anesthesia.
2. Neurodevelopmental outcomes. There is evidence that infants have the ability to form implicit memory of pain and that there are negative behavioral consequences of untreated pain. Behavioral and neurologic studies suggest that preterm infants who experience numerous painful procedures and noxious stimuli are less responsive to painful stimuli at 18 months corrected age. Neonatal males who were circumcised with little or no analgesia showed significantly increased pain responses when immunized at 2, 4, and 6 months of age compared to infant males who were not circumcised or who received adequate analgesia. Evidence suggests that neonatal pain and stress influence neurodevelopment and affect later perceptions of painful stimuli and behavioral responses and that prevention and control of pain are likely to benefit infants. Newborns undergoing cardiac surgery for patent ductus arteriosus (PDA) ligation who receive less opioid analgesia experienced a significantly greater stress response and more postoperative morbidities compared to infants receiving adequate opioid analgesia.
There are few large randomized clinical trials of pain management in neonates. One such trial (NEOPAIN trial) evaluated preemptive analgesia with morphine infusion up to 14 days among ventilated preterm infants and showed no difference overall in the primary composite outcome (i.e., neonatal death, severe intraventricular hemorrhage [IVH], or periventricular leukomalacia) between placebo and preemptive morphine-treated groups. Concerns were raised, however, when post hoc analyses revealed an increased risk of severe IVH among morphine infusion-treated infants in the subgroup born at 27 to 29 weeks of gestation.
Subsequent analyses suggested the adverse outcomes were limited to infants who were hypotensive before morphine therapy was initiated. These data indicate that treatment with prophylactic morphine infusion should be limited to infants who are normotensive. There is limited data on the long-term consequences of opioid analgesia in infants, and preliminary studies show mixed results. The potential risk associated with morphine use as indicated in the NEOPAIN trial must be weighed against the known risk of untreated pain in the neonatal population, including increased sensitivity to subsequent painful stimuli and potential negative effects in neurodevelopment. Animal research suggests morphine may be either neuroprotective or neurotoxic depending on the presence or absence of pain, but how that translates to newborns is unknown. Further research is needed to identify safe and effective options for pain management in term and preterm infants.
II. COMMITTEE ON THE FETUS AND NEWBORN OF THE AMERICAN ACADEMY OF PEDIATRICS PRINCIPLES OF PREVENTION AND MANAGEMENT OF NEONATAL PAIN AND STRESS
A. Neuroanatomic components and neuroendocrine systems of the neonate are sufficiently developed to allow transmission of painful stimuli.
B. Exposure to prolonged or severe pain may increase neonatal morbidity.
C. Infants who have experienced pain during the neonatal period may respond differently to subsequent painful events.
D. Severity of pain and effects of analgesia can be assessed in the neonate using validated instruments.
E. Newborn infants usually are not easily comforted when analgesia is needed.
F. A lack of behavioral responses (including crying and movement) does not necessarily indicate the absence of pain.
G. The pain intensity of the anticipated painful procedure from venipuncture to abdominal surgery differs dramatically. Careful thought and planning help the health care team develop an appropriate pain management plan before a painful event.
III. EVALUATING NEONATAL PAIN AND STRESS. A number of validated and reliable scales of pain assessment are available. Behavioral indicators (e.g., facial expression, crying, and body/extremity movement) as well as physiologic indicators (e.g., tachycardia or bradycardia, hypertension, tachypnea or apnea, oxygen desaturation, palmar sweating, vagal signs) are useful in assessing an infant’s level of comfort or discomfort. Biochemical markers for pain and stress such as plasma cortisol or catecholamine levels are not typically used in the clinical setting but may be useful for research.
Physiologic responses to painful stimuli include release of circulating catecholamines, heart rate acceleration, blood pressure increase, and a rise in intracranial pressure. Because the stress response of the immature fetus or preterm infant is less robust than that of the more mature infant or child, gestational age and postmenstrual age (PMA) must be considered when evaluating the
pain response. Among preterm infants experiencing pain, a change in vital signs associated with the stress response (e.g., tachycardia, hypertension) and agitation are not consistently evident. Even among infants with an intact response to pain, a painful stimulus that persists for hours or days exhausts sympathetic nervous system output and obscures the clinician’s ability to objectively assess the infant’s level of discomfort.
Changes in vital signs are not specific to pain and may be unreliable when used alone to identify pain. Changes in facial activity and heart rate are the most sensitive measures of pain observed in term and preterm infants. By 25 to 26 weeks, the facial expression is the same as for children/adults. Before that, various facial components of a grimace may be observed separately, such as eye squeeze. The Premature Infant Pain Profile (PIPP) scores the facial components separately to capture the premature infant who may be limited in the ability to produce and sustain a full grimace.
A. Assessment of pain and stress in the newborn
1. Newborns should be assessed for pain routinely (at least every 4 to 6 hours and before and after invasive procedures) by caregivers who are trained to assess pain using multidimensional tools. The pain scales used should help guide caregivers to provide effective pain relief. Because small variations in scoring points can result in under- or overtreatment, the proficiency of individual caregivers using the chosen pain scale should be reassessed periodically to maintain reliability in assessing pain.
Selecting the most appropriate tool for evaluating neonatal pain is essential to its management. Physicians, nurses, and parents express different perceptions of pain cues when presented with the same infant pain responses. A caregiver’s bias can influence both judgment and action when they are evaluating and treating pain. A pain scoring tool with appropriate age range, acceptable psychometric properties, clinical utility, and feasibility may reduce bias even though none is perfect. Many tools exist, and a few of the more common ones are shown in Table 70.1
3. Documentation of pain is essential. In general, pain scores that are documented along with vital signs can be monitored most easily for trends and subtle patterns so that pain, unrelieved pain, or opioid tolerance can be identified early.
4. Because no pain tool is completely accurate in identifying all types of pain in every infant, other patient data must be included in the assessment of pain. Pain that is persistent or prolonged, associated with endof-life care, or influenced by medications cannot be reliably measured using current pain instruments.
B. Critically ill infants.
Pain responses are influenced by the PMA and behavioral state of an infant. Most pain scales that have been tested used acute pain for the stimulus (heel stick), and very few tools that measure acute prolonged or chronic pain have been adequately tested. Critically ill infants may not be able to exhibit indicators of pain due to their illness acuity. Few scales include parameters of nonresponse that may be present when an infant is severely ill or extremely premature. A lack of response does not mean an infant is not in pain. The caregiver must base treatment decisions on other data such as type of disease, health status, pain risk factors, maturity, invasive measures (i.e., chest tubes), medications that blunt response, and
scheduled painful procedures. Existing pain instruments do not account for the extremely premature infant whose immature physiologic and behavioral responses are challenging to interpret. Infants with neurologic impairment can mount a similar pain response to healthy term infants, although the intensity of that response may be diminished. The pain response can be increased in individual infants based on prior pain history and handling before a painful event.
Table 70.1. Summary of Neonatal Pain Assessment Tools
Pain Assessment Tool
Gestational Age/Post-conceptional Age
Type of Pain
Adjusts for Prematurity
PIPP (Premature Infant Pain Profile)1
Heart rate, oxygen saturation
Alertness, brow bulge, eye squeeze, nasolabial furrow
Procedural and Postoperative
0 to 21
CRIES (Cries, Requires Oxygen, Increased Viral Signs, Expression, Sleeplessness)2
Blood pressure, heart rate, oxygen saturation
Cry, expression, sleeplessness
0 to 10
NIPS (Neonatal Infant Pain Scale)3
Facial expression, cry, arms, legs, alertness
0 to 7
COMFORT (and COMFORTneo)4,5
0-3 y (COMFORTneo: 24-42 wk)
Respiratory response, blood pressure, heart rate
Alertness, agitation, physical movements, muscle tone, facial tension
Postoperative (COMFORTneo: prolonged)
8 to 40
NFCS (Neonatal Facial Coding System)6
25 wk to Term
Brow bulge, eye squeeze, nasolabial furrow, open lips, stretch mouth (vertical and horizontal), lip purse, taut tongue, chin quiver
0 to 10
N-PASS (Neonatal Pain, Agitation, and Sedation Scale)7
Heart rate, respiratory rate, blood pressure, oxygen saturation
Crying/irritability, behavior state, facial expression, extremities/tone
Acute and prolonged pain
Also assesses sedation
Pain: 0 to 10 Sedation -10 to 0
EDIN (Échelle de la Douleur Inconfort Noveau-Né-Neonatal Pain and Discomfort Scale)8
Facial activity, body movements, quality of sleep, quality of contact with nurses, consolability
0 to 15
BPSN (Bernese Pain Scale for Neonates)9
Respiratory pattern, heart rate, oxygen saturation
Alertness, duration of cry, time to calm, skin color, brow bulge with eye squeeze, posture
0 to 27
1 Stevens B, Johnston C, Petryshen P, et al. Premature infant pain profile: development and initial validation. Clin J Pain 1996;12:13-22.
2 Krechel SW, Bildner J. CRIES: a new neonatal postoperative pain measurement score. Initial testing of validity and reliability. Paediatr Anaesth 1995;5:53-61.
3 Lawrence J, Alcock D, McGrath P, et al. The development of a tool to assess neonatal pain. Neonatal Netw 1993;12:59-66.
4 van Dijk M, Roofthooft DW, Anand KJ, et al. Taking up the challenge of measuring prolonged pain in (premature) neonates: the COMFORTneo scale seems promising. Clin J Pain 2009;25:607-616.
5 van Dijk M, de Boer JB, Koot HM, et al. The reliability and validity of the COMFORT scale as a postoperative pain instrument in 0 to 3-year-old infants. Pain 2000;84:367-377.
6 Grunau RV, Craig KD. Facial activity as a measure of neonatal pain expression. Adv Pain Res Ther 1990;15:147-155.
7 Hummel P, Puchalski M, Creech SD, et al. Clinical reliability and validity of the N-PASS: Neonatal Pain, Agitation and Sedation Scale with prolonged pain. J Perinatol 2008;28:55-60.
8 Debillon T, Zupan V, Ravault N, et al. Development and initial validation of the EDIN scale, a new tool for assessing prolonged pain in preterm infants. Arch Dis Child Fetal Neonatal Ed 2001;85:F36-F41.
9 Cignacco E, Mueller R, Hamers JP, et al. Pain assessment in the neonate using the Bernese Pain Scale for Neonates. Early Hum Dev 2004;78:125-131.
Source: Reprinted with permission from Maxwell LG, Malavolta CP, Fraga MV. Assessment of pain in the neonate. Clin Perinatol 2013;40:457-469.
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