Version May 2024
INTRODUCTION — Neonates, especially those cared for in the neonatal intensive care unit (NICU) setting, frequently experience painful procedures.
Pain assessment is a vital part of neonatal care. An accurate assessment of pain is necessary to determine if intervention is warranted and to assess the response to intervention.
The assessment of pain in neonates will be reviewed here. Management and prevention pain in neonates are discussed separately. (See "Management and prevention of pain in neonates".)
MISCONCEPTIONS ABOUT NEONATAL PAIN — Historically, treatment and prevention of pain in neonates have been underemphasized because of the following misconceptions:
●Neural pathways in neonates are unmyelinated or otherwise immature and cannot transmit painful stimuli to the brain.
●There is no alternative for verbal self-report, which remains the "gold standard" for conveying a subjective experience like pain.
●Pain perception is located only in the cortex, and thalamocortical connections must be fully developed in order to allow pain perception.
●The human infant does not have the psychological context necessary to identify experiences as painful; this ability does not develop until the age of two years or later.
●Analgesic or sedative drugs cannot be used in neonates because the risk of adverse effects is too high.
These misconceptions are not supported by scientific evidence. Instead, there is substantial evidence that neonates experience pain and stress, as discussed in the following sections.
NEONATAL RESPONSES TO PAIN — Both preterm and term infants experience pain and stress in response to noxious stimuli. By the middle of the second trimester, the human fetus has a highly differentiated and functional sensory system [1-3].
Neonates respond to pain with autonomic responses (increases in heart rate and blood pressure), hormonal changes (release of cortisol and catecholamines), and behavioral changes (eg, facial grimace, crying, hand and body movements) [4-11]. These responses form the basis of pain assessment tools used in neonates [6,12-15]. (See 'Parameters evaluated' below.)
Studies using functional magnetic resonance imaging (fMRI) and neurophysiological testing (eg, near infrared spectroscopy [NIRS], electroencephalography [EEG]) have demonstrated that the brain's responses to painful stimuli are similar in preterm and term infants [16-22]. For example, studies using NIRS in preterm and term neonates have demonstrated increased cortical activation in the somatosensory areas of the brain in response to painful stimuli (eg, heel lance, venipuncture) [16,17].
FREQUENCY OF PAINFUL PROCEDURES — Infants cared for in the neonatal intensive care unit (NICU) setting frequently experience painful procedures. Despite our improved understanding of how neonates experience pain, pain is still often underrecognized and undertreated in this population [23-26].
In a systematic review that included six observational studies involving 1122 neonates managed in the NICU setting, neonates on average experienced 8 to 20 painful procedures per day during the first two weeks of their NICU hospitalization [26]. The most common painful procedures were heel lance, nasal or endotracheal suctioning, venipuncture, and vascular catheter placement. In the largest study, specific analgesic therapy was provided for approximately 20 percent of procedures [24].
Studies evaluating changes in practice patterns since the early 2000s have noted increasing attention to pain assessment in NICU practice, a decline in the frequency of painful procedures, and increased use of analgesic medications for hospitalized neonates [25,27].
LONG-TERM EFFECTS OF NEONATAL PAIN
Consequences of undertreated pain — Accumulating evidence suggests that repeated exposure to pain during the neonatal period, especially when undertreated, may have long-term adverse effects [28,29]. These effects include altered brain development [30-35], dysregulation of the hypothalamic-pituitary-adrenal axis [36-38], and changes in how pain is experienced later in life [36,39-47].
The detrimental impact of cumulative procedural pain on neonatal brain development highlights the importance of recognizing and effectively managing pain in neonates. (See 'Pain assessment' below and "Management and prevention of pain in neonates".)
Structural changes in the brain — A systematic review of nine studies involving preterm neonates who underwent neuroimaging in infancy and/or at school age demonstrated structural brain changes in infants with higher exposure to pain compared with individuals without significant neonatal pain exposure [35]:
●Short term effects – Brain changes in the neonatal period included decreased total brain volume, decreased white matter, and decreased thalamic and basal ganglia volume and metabolism.
●Long-term effects – At school age, changes in the brain included decreased cortical thickness, decreased white matter maturation, and decreased volume of the amygdala, hippocampus, cerebellum, thalamus, and basal ganglia.
Altered pain response — Several studies have reported that infants who are exposed to repetitive pain the neonatal period are at risk of subsequently developing increased pain sensitivity and/or chronic pain syndromes [36,39-47].
Examples include:
●Infants of mothers with diabetes often require repeated heel sticks in the newborn period. In one study, affected infants exhibited more intense pain responses (facial grimacing and crying) during later venipuncture compared with healthy infants [46].
●In another study, infants who experienced pain from circumcision in the newborn period demonstrated higher levels of pain during routine immunizations four to six months later [48].
●In a separate study, neonates who exposed to pain from gastric suctioning at birth had threefold greater odds of developing irritable bowel syndrome during adolescence and adulthood [49].
●Adolescents born preterm also display higher somatic pain sensitivity than adolescents born at term [50].
These findings and data from animal studies suggest that repeated exposure to pain in the neonatal period permanently changes how pain is processed [39].
Impact of analgesic and sedative therapy — It remains uncertain whether prolonged exposure to analgesic and/or sedative medications in the neonatal period has any long-term impact on neurologic and behavioral outcomes [51-60]. The available studies have reached variable conclusions. A few small studies suggested that exposure to morphine and other opioids during the neonatal intensive care unit (NICU) hospitalization may be associated with increased risk of certain adverse neurologic outcomes (eg, reduced cerebellar growth, delayed short-term recall, challenges in social functioning) [54,58]. However, larger studies have generally found that exposure to opioid analgesia/sedation in early infancy is not independently associated with poor neurologic outcome after controlling for other confounding factors (eg, gestational age, comorbidities) [51,52,55-57,60]. In fact, some studies suggest that appropriate use of opioid analgesia may even have beneficial effects on survival and long-term neurologic status [56,60].
One of the largest studies to explore this question was a prospective observational study of 922 preterm neonates (<32 weeks gestation) requiring early invasive mechanical ventilation who were followed to age two years [60]. The study compared outcomes in neonates who did versus did not receive continuous opioid and/or midazolam infusions during the first week after birth and used propensity score analysis to adjust for confounding variables. After adjusting for other variables, infants who received opioid and/or midazolam infusions were more likely to survive to age two years without moderate or severe disability compared with those who did not receive sedation (87 versus 81 percent, respectively), although the difference did not achieve statistical significance (adjusted risk difference 5.3 percent, 95% CI -0.3 to 11 percent).
PAIN ASSESSMENT
Routine standardized approach — Pain assessment is a routine part of neonatal care. Healthcare facilities caring for neonates and young infants should establish standardized practices for pain assessment and management [61-63]. This includes:
●Selecting pain assessment tools that are appropriate for the facility's neonatal population. (See 'Pain assessment tools' below.)
●Ensuring that clinical staff are adequately trained to recognize pain in neonates, including correct use of the selected assessment tool(s). (See 'Staff training' below.)
Staff training — It is critical that staff caring for neonates are adequately trained to recognize neonatal pain in order to ensure that neonates receive appropriate treatment of pain [64,65]. Effective use of the clinical assessment tools discussed in the following sections requires that all staff receive specific education and training on the correct use of the institution's selected tool(s) [66,67]. Staff should also be trained in the pitfalls and limitations of these tools. Appropriate staff training reduces interobserver variability in pain assessments [68]. (See 'Challenges and limitations' below.)
Frequency of assessment — For hospitalized neonates, pain assessments are performed using a validated tool at the following intervals:
●Routinely, at least every four hours. The pain score is measured and documented at the same time as routine vital sign measurements.
●After any painful procedure or intervention.
●Any time there is clinical concern for pain or if pain is likely to occur. As a general rule, anything that causes pain in older children also causes pain in neonates, regardless of gestational age (GA). Parental/caregiver concern that the neonate is experiencing pain should also prompt an assessment of the pain score.
Pain assessment tools
Commonly used tools — The pain assessment tools that are commonly used in the neonatal intensive care unit (NICU) include (table 1) [61,69]:
●BIIP (Behavioral Indicators of Infant Pain) [70]
●BPSN (Bernese Pain Scale for Neonates) [71]
●COMFORTneo [72,73]
●COVERS (Crying, Oxygen requirement, Vital signs, Expression, Resting, Signaling distress) [74]
●CRIES (Crying, Requires increased oxygen administration, Increased vital signs, Expression, Sleeplessness) [14]
●DAN (Douleur Aiguë Nouveau-né) scale (table 2) [75,76]
●EDIN (Echelle de Douleur et d'Inconfort du Nouveau-né) [77]
●NFCS (Neonatal Facial Coding System) [78]
●NIPS (Neonatal Infant Pain Scale) [79]
●N-PASS (Neonatal Pain Agitation and Sedation Scale) [80-82]
●PAT (Pain Assessment Tool) [83]
●PIPP-R (Premature Infant Pain Profile-Revised) (table 3) [84]
Among these, the five that have been subjected to the most rigorous validation testing include BIIP, CRIES, DAN, N-PASS, and PIPP-R [61,69].
Several of these tools were initially developed for preterm infants. For example, the PIPP was originally developed for preterm neonates, but later revised (PIPP-R) such that it can be used in neonates with GA from 25 to 41 weeks [85]. By contrast, the COMFORT score was initially developed for older infants and was subsequently revised (COMFORTneo) to better assess neonates (preterm and term) [72].
Parameters evaluated — Neonatal pain assessment tools assess the neonate's physiologic and behavioral responses to pain or noxious stimuli:
●Physiologic parameters – The most common physiologic parameters in neonatal pain assessment tools include changes or variability in heart rate, blood pressure, respiratory rate, and oxygen saturation. Other physiologic parameters that are occasionally considered include pupillary size, palmar sweating, and skin color. Some studies have used alteration in physiologic electroencephalographic (EEG) or electromyographic (EMG) patterns to assess pain; however, these methods are not widely available and their validity and reliability for assessing pain are not well established [86,87].
●Behavioral responses – These include crying patterns, facial expressions, hand and body movements, muscle tone, sleep patterns, behavioral state changes, and consolability. In neonates, assessing for certain specific facial findings (brow bulge, eye squeeze, nasolabial furrow, and open mouth) helps to recognize acute and postoperative pain [6,12-15,78,88].
Some neonatal assessment tools are unidimensional, meaning they are based solely on one category of parameters (physiologic or behavioral); whereas others are multidimensional and consider both physiologic and behavioral parameters as well as contextual factors (eg, GA) (table 1) [61,89-91].
Research efforts are ongoing to improve the objectivity and accuracy of pain assessment tools for neonates. Methods that have been studied in the research setting include neuroimaging modalities (eg, functional magnetic resonance imaging [fMRI]), neurophysiologic monitoring (eg, amplitude-integrated electroencephalography [EEG], near-infrared spectroscopy [NIRS]), and other physiologic measurements (eg, changes in skin conductance, measures of heart rate variability) [10,11,16,17,61,68]. Studies are also in progress to evaluate sensor-fusion and machine-learning algorithms aimed at providing patient-centered, context-dependent, observer-independent, and objective pain measures [92-94].
Choice of tool(s) — A single pain assessment tool is generally not sufficient to meet the needs of all neonates cared for within a given institution. The different tools were developed and validated for use in somewhat distinct populations and clinical settings. The choice of the pain assessment tool should be tailored to the neonatal population being cared for and the different types of pain that will be evaluated [95].
At the author's center, we use the following tools:
●For acute pain, including procedural or postoperative pain [12,88]:
•NFCS [78,96]
•N-PASS [81]
●For prolonged pain (eg, intubated neonates, prolonged pain after major surgery, indwelling chest tubes, painful chronic medical conditions [eg, necrotizing enterocolitis]):
•N-PASS [80]
•COMFORTneo [73]
Additional considerations for the choice of tool in specific neonatal populations and clinical circumstances are discussed below. (See 'Specific populations and circumstances' below.)
There is a wide range of pain assessment tools used in NICUs, as demonstrated in multicenter observational studies [62,65]. For example, in one study describing practices of postoperative pain assessment, eight different assessment tools were used across the 10 study sites [65].
Specific populations and circumstances — The availability of validated pain assessment tools for the following populations and clinical settings is more limited [95]:
Preterm or critically ill infants — Many of the available pain scales were developed and validated in studies that included relatively healthy infants. Very preterm (VPT) infants, a neonatal population typically exposed to many painful procedures, often demonstrate muted responses to pain and therefor pain may be underestimated by some assessment tools [7,78,97-99]. In addition, critically ill infants at any GA will have limited vigor or energy to mount a robust response to acute pain. For these reasons, some neonatal pain scales (eg, PIPP-R and N-PASS) add points for increasing levels of prematurity to compensate for the limited ability of VPT infants to behaviorally or physiologically demonstrate pain.
Persistent or prolonged pain — Many pain scores were developed to evaluate acute or postoperative pain and do not perform as well for assessing persistent or prolonged pain (eg, prolonged pain after major surgery or painful chronic medical conditions [eg, necrotizing enterocolitis]) [84].
The COMFORTneo and EDIN scales were developed specifically for assessing prolonged neonatal pain [72,73,77]. These tools are widely used, though they have not been extensively validated. In addition, the N-PASS has been validated in neonates with prolonged pain, though it was not specifically developed for this purpose [80].
Neonates with persistent or prolonged pain may enter a passive state, with limited or no body movements, an expressionless face, reduced variability in heart rate and respiratory rate, and decreased oxygen consumption [61,68]. Thus, assessment tools based solely on these indicators may not adequately detect and measure pain intensity in this setting [68,97]. However, some neonatal pain scales attempt to account for this passive pain state in the scoring rubric. For example, N-PASS assigns a high score for the behavior state domain if there is an inappropriate lack of movement or arousal in patients not receiving sedation [82].
Intubated patients — Tools that have been studied in intubated neonates include COMFORTneo, NFCS, and N-PASS [61,80,95].
Caregiver involvement — If parents/caregivers are available, we ask for their opinion: Do they feel that their baby is in pain? If so, their perception of pain prompts us to reassess the infant with a validated assessment tool and administer pain control measures to prevent or reduce pain due to known noxious stimuli [62,63]. Developmental care programs and family-centered care practices help to involve the parents/caregivers in the assessment and management of their baby's pain.
Challenges and limitations — Challenges and limitations of the available tools for neonatal pain assessment include [100]:
●Subjectivity and interobserver variability – Neonatal pain assessment tools require subjective evaluation by an observer. As a result, there can be significant interobserver variability in the evaluation of behavioral responses [73,101-103]. As previously discussed, interobserver variability can be reduced by providing sufficient multidisciplinary training of staff. (See 'Staff training' above.)
●Complexity of pain score measurements – Many tools require that the bedside nurse observe the neonate for a period of time, record up to 10 different parameters, and then make mental calculations in real time. Often, the clinician performing the procedure is also tasked with observing the infant's pain responses at the same time.
●Differences between physiologic versus behavioral pain responses – Multimodal assessment tools can be limited by dissociations in the response characteristics of physiologic versus behavioral parameters [104,105]. These response characteristics include the reactivity, trigger threshold, onset, and offset of changes in these parameters. Differences in response characteristics between physiologic and behavioral parameter can impact the overall pain score.
●Factors not accounted for – There are many factors that impact the neonate's response to pain which are not consistently accounted for in the available pain assessment tools. Examples include:
•Neurologic impairment – Behavioral responses to pain such as body movements and changes in facial expression may be blunted or altered in neonates with neurologic impairment [79,99]. Some tools attempt to account for this by assessing changes in behavior relative to the baseline behavioral state. For example, PIPP-R assigns additional points to the pain score if the neonate's baseline behavioral state is quiet and asleep (table 3) [84].
•Neuromuscular blockade – Motor responses to pain are and absent in patients receiving neuromuscular blocking agents (NMBAs). Thus, pain scores based upon these responses are not a valid method for assessing pain in patients receiving NMBAs [106].
•Type and location of pain – Pain assessment tools generally do not take into account the type of the painful stimulus (eg, incisional versus visceral) or the part(s) of the body affected. For example, limited data are available on how neonatal pain assessment tools perform in infants with visceral pain or bone pain.
Given these challenges and limitations, some experts have questioned the utility of pain scores in neonates [107,108]. Instead, some in the field have proposed a "pain detection method," which would simplify pain assessment, taking into account the type of the noxious stimulus and the affected part(s) of the body [108]. This method would aim simply to characterize pain as present or absent rather than attempting to quantify pain intensity. The clinical utility of this approach has not been sufficiently investigated. In our practice, we routinely monitor for pain in hospitalized neonates using the validated pain assessment tools discussed above. (See 'Pain assessment tools' above.)
SUMMARY AND RECOMMENDATIONS
●Misconceptions about neonatal pain – Historically, treatment and prevention of pain in neonates have been underemphasized because of unsupported misconceptions about neonates' inability to experience pain. In fact, neonates experience pain from the same interventions or clinical conditions that cause pain in older children and adults. (See 'Misconceptions about neonatal pain' above and 'Neonatal responses to pain' above.)
●Frequency of painful procedures – Painful and/or stressful procedures are common in hospitalized neonates, especially those in the neonatal intensive care unit (NICU). Neonatal pain is often underrecognized and undertreated, although awareness is improving. (See 'Frequency of painful procedures' above.)
●Consequences of undertreated pain – Accumulating evidence suggests that repeated exposure to pain during the neonatal period, especially when undertreated, may have long-term adverse effects. These may include altered brain development, dysregulation of the hypothalamic-pituitary-adrenal axis, and changes in how pain is experienced later in life. (See 'Long-term effects of neonatal pain' above.)
●Routine assessment of neonatal pain – Pain assessment is a routine part of neonatal care. Healthcare facilities caring for neonates and young infants should establish standardized practices for pain assessment and management. (See 'Pain assessment' above.)
•Frequency of assessments – For hospitalized neonates, pain assessments are performed using a validated tool at the following intervals (see 'Frequency of assessment' above):
-Routinely, at least every four hours; the pain score is measured and documented at the same time as routine vital sign measurements
-After any painful procedure or intervention
-Any time there is clinical concern for pain or if pain is likely to occur
•Assessment tools – The table summarizes some of the pain assessment tools that are commonly used in NICU practice (table 1). The choice of pain assessment tool should be tailored to the neonatal population being cared for and the different types of pain that will be evaluated. (See 'Pain assessment tools' above.)
At the author's center, we use the following tools:
-For acute pain, (eg, procedural or acute postoperative pain), we use the PIPP-R (Premature Infant Pain Profile-Revised (table 3)), the NFCS (Neonatal Facial Coding System), the DAN scale (Douleur Aiguë Nouveau-né (table 2)), or N-PASS (Neonatal Pain Agitation and Sedation Scale). (See 'Commonly used tools' above.)
-For prolonged pain (eg, intubated neonates, indwelling chest tubes, prolonged pain after major surgery), we use the N-PASS or COMFORTNeo. Other centers may use the EDIN (Echelle de Douleur et d'Inconfort du Nouveau-né) scale. (See 'Persistent or prolonged pain' above.)
●Limitations – The available neonatal pain assessment tools have certain limitations (see 'Challenges and limitations' above):
•Some scores rely on subjective observations and are prone to interobserver variability.
•Determining pain scores in real time can be complex and burdensome especially when the clinician performing the procedure is also tasked with observing the infant's response and determining the score.
•Multimodal assessment tools can be limited by dissociations between physiologic versus behavioral responses to pain.
•Pain assessment tools generally do not take into account the type of the painful stimulus (eg, incisional versus visceral), the part(s) of the body affected, and whether the infant is neurologically impaired.
•Scores based upon motor responses to pain are not valid for assessing pain in patients receiving neuromuscular blocking agents.
ACKNOWLEDGMENT — The UpToDate editorial staff acknowledges Kanwaljeet JS Anand, MBBS, DPhil, FAAP, FCCM, FRCPCH, who contributed to an earlier version of this topic review.
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