INTRODUCTION — Neonatal discomfort, stress, or pain may be associated with routine patient care (eg, physical examination and diaper changes), frequent invasive procedures (eg, suctioning, phlebotomy, and peripheral intravenous line placement), or infrequent but even more invasive procedures (eg, chest tube placement and circumcision).
Although it is challenging to detect and measure the intensity of pain in neonates because of their inability to communicate with care providers, it is important to control pain in neonates to prevent the long-term complications of untreated neonatal pain. Parents/caregivers also expect medical providers to prevent or protect their infant from experiencing pain if at all possible. Therefore, accurate pain assessment is a necessary part of neonatal pain management to determine if therapy should be initiated, as well as for assessing its effectiveness. The need for effective pain management and the assessment of pain in neonates will be reviewed here. Prevention and treatment of neonatal pain are discussed separately. (See "Prevention and treatment of neonatal pain".)
DEFINITIONS — This topic review uses the following terms as defined by the neonatal pain control group of the Newborn Drug Development Initiative [1]:
●Pain – An unpleasant somatic or visceral sensation associated with actual or potential tissue damage.
●Stress – A disturbance of the dynamic equilibrium between an infant and his/her environment that results in a physiologic response by the infant.
●Stress or pain response – The individual's physiologic response to pain or stress that is characterized primarily by changes in four domains (ie, endocrine-metabolic, autonomic, neurophysiological, and/or behavioral responses).
●Analgesia – Absence or reduction of pain in the presence of stimuli that would normally be painful.
●Pain control – Reduction in the intensity, frequency, and/or duration of pain.
MISCONCEPTIONS ABOUT NEONATAL PAIN — Historically, pain prevention and control have been underutilized in neonates because of the following misconceptions:
●The pain 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 in order to identify any experiences as painful and this does not develop until two years or later.
●Newborn infants are at greater risk for the adverse effects of analgesic or sedative agents, or these drugs have adverse long-term effects on brain development and behavior.
These misconceptions are not supported by scientific evidence. Instead, there is increasing evidence that neonates experience pain and stress.
NEONATAL RESPONSES TO PAIN — Since the 1980s, accumulating evidence demonstrates that both preterm and term infants experience pain and stress in response to noxious stimuli [2-4]. By the middle of the second trimester, the human fetus has a highly differentiated and functional sensory system [5-7]. The fetal system appears to work differently from the mature adult system; it transmits different sensory modalities (pain, touch, and vibration) which are mediated by different pathways and loci in sensory processing [5].
Numerous studies have documented neonatal responses to pain, which include autonomic (eg, increases in heart rate, blood pressure), hormonal (eg, cortisol and catecholamine responses), and behavioral changes (eg, facial grimace) [2,8-12]. These responses form the basis of the many pain assessment tools used to evaluate acute pain in the neonate [9,13-16]. (See 'Pain assessment' below.)
Neuroimaging and neurophysiological studies have reported brain responses to painful stimuli in both preterm and term infants; responses in preterm and term neonates are similar [17-22]. However, these measures should only be used in the research setting, as data are limited regarding their accuracy and specificity [22].
●In preterm infants, near infrared spectroscopy (NIRS) has demonstrated increased cortical activation in the somatosensory areas of the brain in response to painful stimuli (eg, heelstick or venipuncture) [17,18]. Simultaneous imaging and physiologic testing using NIRS and electroencephalography (EEG) also confirmed cortical activation with greater temporal and spatial resolution [19].
●In term infants less than seven days old, functional magnetic resonance imaging (fMRI) studies identified brain activation in 18 of the 20 brain regions typically activated in healthy adults following noxious stimulation [20]. There was no activation in the infant amygdala or orbitofrontal cortex. These results demonstrate that sensory and affective components of pain are active in infants and suggest that the infant pain experience closely resembles that of adults.
●EEG has been shown to identify nociceptive brain activity evoked by acute noxious stimuli and sensitive to analgesia [22]. It has low sensitivity and specificity [23]. However, the routine assessment of EEG responses to neonatal pain is not ready for clinical application because of its relatively low sensitivity (64 percent) and specificity (65 percent) and the difficulty of obtaining and interpreting EEG signals from term and preterm neonates [23].
●Although not universally available, measures of neonatal stress (eg, skin conductance activity) may be indicative of pain. Serum or salivary cortisol levels can provide an indication of the level of stress as well as skin conductance activity [24,25]; however, these endocrine tests are generally not clinically useful as results are not available in real-time and may be affected by other factors (such as illness severity).
FREQUENCY OF PAINFUL PROCEDURES — Painful procedures are common in neonates, especially for those in the neonatal intensive care unit (NICU). Analgesic therapy is often not given, despite greater understanding that neonates experience pain [26-28].
The prevalence of untreated neonatal pain was best illustrated by a large prospective French study of 430 neonates admitted to tertiary NICUs during a six-week time period beginning in September 2005 [27]. All painful and stressful procedures were recorded for each participant during the first 14 days following NICU admission. The following findings were noted:
●Neonates experienced a median of 115 procedures during the 14-day study period, of which 75 were painful. Of the 42,413 painful procedures, specific analgesic therapy was provided in 20.8 percent of patients, which included only nonpharmacologic therapy (18 percent), only pharmacologic therapy (2 percent), and both nonpharmacologic and pharmacologic therapy (0.4 percent). An additional 34 percent of patients were receiving concurrent analgesia or anesthetic therapy for other reasons during the procedure [27].
●Factors associated with greater use of specific preprocedural analgesia included prematurity, the type of procedure, parental presence, surgery, daytime, and day of procedure after the first day of admission. In contrast, mechanical and noninvasive ventilation and use of concurrent analgesia were associated with lower use of specific preprocedural analgesia.
Subsequent studies looking at changes in practice patterns over the past decade have noted an increased attention to pain assessment in the NICU, a decline in the numbers of painful procedures performed, and increased use of pain management using analgesic drugs and nonpharmacologic approaches [28,29].
EFFECTS OF INADEQUATELY TREATED PAIN — Accumulating data suggest that untreated or inadequately treated neonatal pain may have long-term deleterious effects on pain response and neurodevelopmental outcome. These data underscore the need to effectively identify, assess, and treat neonatal pain.
Altered pain response — Several studies have reported that exposure to repetitive pain in early life may lead to a greater risk of subsequently developing increased pain sensitivity and/or chronic pain syndromes [30-39].
For example, infants of diabetic mothers, who were exposed to repeated heelsticks just after birth, exhibited more intense pain responses (facial grimacing and crying) during later venipuncture compared with normal infants [37]. Neonates exposed to circumcision pain at birth experienced greater pain at immunization four to six months later [40]. Neonates exposed to gastric suctioning at birth had threefold greater odds of developing irritable bowel syndrome during adolescence or adulthood [41]. Adolescents born preterm also display higher somatic pain sensitivity than adolescents born at term [42]. These findings and other animal studies substantiate the theory that repeated exposure to neonatal pain leads to permanent changes in pain processing [30].
Neurodevelopmental impairment — Frequency of exposure to neonatal pain-related stress has been correlated with subsequent impairments in cognitive development, altered neurocognitive processing, decreased cortical thickness, and dysregulation of the hypothalamic-pituitary-adrenal axis [43-48]. These effects have been seen in both the short-term (ie, in the neonatal period) and the long-term (ie, at school age). A systematic review of nine clinical neuroimaging studies of preterm neonates shortly after birth or at school age revealed changes in the brain associated with higher neonatal pain exposure [49]:
●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 – Brain changes during school age included decreased cortical thickness, decreased white matter maturation, and decreased volume of the amygdala, hippocampus, cerebellum, thalamus, and basal ganglia.
Effects of repetitive neonatal pain on long-term neurodevelopmental outcomes have also been demonstrated in neuroimaging, neuroendocrine, and neurobehavioral studies [43-48].
The detrimental effects of cumulative procedural pain on neonatal brain development highlight the need to identify, assess, and effectively manage neonatal pain in order to minimize its impact on the intermediate- and long-term outcomes of preterm or term newborns [49].
PAIN ASSESSMENT
Establishing an institutional approach — A neonatal pain control program that includes routine pain assessment should be established for each healthcare facility caring for neonates and young infants [50]. Because of our limited ability to detect and quantify pain in neonates, especially preterm infants, we suggest that judicious pain control measures be used to prevent or reduce pain due to known noxious stimuli [51,52]. (See "Prevention and treatment of neonatal pain".)
Effective neonatal pain assessment is an essential prerequisite for optimal pain management and is based on the following:
●Clinical staff training to ensure health care providers can detect neonatal pain using the selected assessment tools.
●Selection of appropriately sensitive and accurate clinical pain assessment tools.
However, multiple challenges limit the ability of available tools for accurate evaluation. Given these challenges and concerns, some authors have questioned whether scoring methods that assess pain intensity are even required for neonates [53,54]. They propose instead a "pain detection method," which takes into account the type of the noxious stimulus, the body region being stimulated, and simplifies the pain assessment to identify whether pain is present or not [54]. Although novel, the validity, feasibility, and clinical utility of this approach have not been investigated. (See 'Challenges' below.)
As a result, we continue to monitor for neonatal pain on a routine basis using validated pain assessment tools, which have been the focus of mandatory training for the clinical staff.
Staff training — Staff recognition of neonatal pain will determine whether or not neonates receive adequate pain control [55,56]. In a multicenter observational study, the documentation of clinician pain assessment was significantly associated with the use of pharmacologic analgesia after surgery [55]. In contrast, the type of surgery (major or minor) was not associated with the administration of pharmacologic therapy. Thus, each facility that cares for infants should adopt an assessment strategy for the detection and documentation of pain.
Institution of a pain management program increases the awareness of the staff that pain occurs routinely in the neonatal intensive care unit (NICU) and that its control is an important clinical goal [1,55-60]. The effective use of a clinical assessment tool requires mandatory training of the staff to improve interobserver reliability and to educate the staff on the limitations of the selected tool [61].
Frequency of assessment — Our approach includes evaluation with a validated neonatal pain assessment tool every four hours when vital signs are measured, and after each painful or therapeutic intervention. We also utilize information from the clinical setting to determine the likelihood of neonatal pain. As a general rule, anything that causes pain in adults or older children will also cause pain in neonates, regardless of their gestational age (GA).
Pain assessment tools — Accurate neonatal pain assessment tools are required because of the inability of the infant to self-report. The scales most commonly used in the NICU for acute pain assessment include the following (table 1) [50]:
●Premature Infant Pain Profile (PIPP) [13]
●Premature Infant Pain Profile-Revised (PIPP-R) [62]
●Neonatal Pain Agitation and Sedation Scale (N-PASS) [63]
●Neonatal Infant Pain Scale (NIPS) [64]
●Crying, Requires Oxygen Saturation, Increased Vital Signs, Expression, Sleeplessness (CRIES) [15]
●Neonatal Facial Coding System (NFCS) [65]
●Douleur Aiguë Nouveau-né scale (DAN) [66,67]
●Behavioral Infant Pain Profile (BIPP) [68]
●Comfort neo scale (COMFORTneo) [69]
Among these numerous pain scales, the following five have been subjected to rigorous psychometric testing (with the patients serving as their own controls): NFCS, PIPP, N-PASS, BIPP, and DAN [50].
Neonatal pain assessment tools rely on surrogate measures of physiologic and behavioral responses to pain or noxious stimuli:
●Physiologic parameters – Changes in heart rate, respiratory rate, blood pressure, vagal tone, heart rate variability, breathing pattern, oxygen saturation, intracranial pressure, palmar sweating, skin color, or pupillary size. Some studies have used alteration in physiologic electroencephalographic (EEG) or electromyographic patterns to assess pain, but these methods are not considered to be valid or reliable, representative of pain perception, or universally available [70,71].
●Behavioral responses – Crying patterns, acoustic features of infant crying, facial expressions, hand and body movements, muscle tone, sleep patterns, behavioral state changes, and consolability. In infants, total facial activity and cluster of specific facial findings (brow bulge, eye squeeze, nasolabial furrow, and open mouth) are associated with acute and postoperative pain [9,13-16,65,72].
Neonatal assessment tools that are used routinely are either unidimensional, meaning they are dependent on either physiologic or behavioral parameters, or multidimensional, including physiologic, behavioral, and contextual parameters (eg, GA) [50,73-75]. Various contextual factors, and other behavioral or physiological indicators suggesting inadequate analgesia can also be used.
Research efforts to improve the objectivity and accuracy of assessment tools are ongoing. These include using neuroimaging (functional magnetic resonance imaging [fMRI] and near-infrared spectroscopy) and neurophysiologic techniques (amplitude-integrated electroencephalography, changes in skin conductance, and heart rate variability) during acute or prolonged pain [17,18,24,25,50,61]. Studies on multimodal pain assessment are also in progress. These studies use sensor-fusion and machine-learning algorithms aiming to provide patient-centered, context-dependent, observer-independent and objective pain measures [76-78].
Choice of assessment tools — The use of a single assessment tool to address all the needs for neonates is not advisable as each tool was developed and validated for selected populations and clinical settings. The choice of the pain assessment tool is dependent upon the neonatal population to be assessed, and the different types of pain that need to be evaluated [79]. In our practice, we assess pain using the following tools:
●PIPP-R [62,80]
●NFCS [65,81]
●DAN [66,67]
●N-PASS [63,82]
For acute or postoperative pain, we use either the PIPP-R, the NFCS, the DAN, or the N-PASS [13,72]. For prolonged pain we use the N-PASS [63].
Several of these scales were initially developed for preterm infants. The PIPP has been revised with simplification of the scoring methods for oxygen saturations, facial expressions, and the baseline behavioral state, while expanding its application for neonates with GA from 25 to 41 weeks [80]. Although initial validation and feasibility of the revised version has been published [62,80], further validation and dissemination are ongoing.
Three multicenter studies illustrate the wide range of pain assessment tools used in NICUs:
●In the first study, 12 sites evaluated by the 2002 Neonatal Intensive Care Quality Improvement Collaborative used five different assessment tools [51].
●In the second study from the Child Health Accountability Initiative (CHAI), 10 sites used eight different assessment tools [55].
Caregiver involvement — If parents/caregivers are available, we ask for their opinion: Do they feel that their baby is in pain? In cases in which there is a likelihood of pain or perceived pain, we suggest that pain control measures be administered pre-emptively to prevent or reduce pain due to known noxious stimuli [51,52]. 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 — The following challenges limit the ability of available tools for accurate evaluation [61]:
●Interobserver variability and subjectivity – Many signs used in these assessment tools require the subjective evaluation by observers. As a result, there is significant interobserver variability in the evaluation of behavioral responses that can be reduced with multidisciplinary training of the staff [57,83].
In addition, many tools require the observation, mental calculations, and recording of 3 to 10 parameters in real time by the bedside nurse. Often, the nurse performing the painful procedure is also tasked with observing the infant's pain responses at the same time.
●Validity of the assessment tool – Since there is no "gold standard" established for pain in the neonate, the concurrent validity of many assessment tools has been questioned:
•Neuroimaging or neurophysiologic approaches used for research have not reached a level of sensitivity or specificity where they can be accepted as "the gold standard" for testing the accuracy of subjective assessment methods.
•Assessment tools that include multi-modal parameters are often limited by dissociations in the response characteristics of physiologic versus behavioral parameters [84,85]. These characteristics include the reactivity, responsivity, trigger threshold, onset, or decay of changes in these parameters and affect the scaling properties of the pain score.
•Pain assessment tools generally do not take into account the type of the nociceptive stimulus or the body region where it occurs. For example, very limited data are available on visceral pain or bone pain in newborn infants.
In addition, pain assessment may be limited by the availability of reliable validated tools for selected populations and clinical settings as follows [79]:
●Preterm or critically ill infants – Most pain scales are developed and validated by studies including relatively healthy infants or late preterm infants. Very preterm infants, the group most likely to undergo many painful procedures, consistently demonstrate muted responses to pain measured by these assessment tools [10,65,86-88]. Also, critically ill infants at any GA will have limited vigor or energy to mount a robust response to acute pain.
●Persistent or prolonged pain – Most tools evaluate acute pain and some evaluate postoperative pain, but do not assess persistent or prolonged pain [62]. The definition of prolonged or chronic pain in newborns remains unclear, which has led to challenges for research in this area [61,89]. As a result, tools for the assessment of persistent or prolonged pain in neonates (due to major surgery, osteomyelitis, or necrotizing enterocolitis) have not been developed or completely validated [63,69,90,91]. During episodes of persistent pain, neonates 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 [50,61]. Thus, assessment tools based on these indicators will not adequately detect and assess the intensity of prolonged neonatal pain [61,86].
The Echelle de Douleur et d'Inconfort du Nouveau-né (EDIN) and COMFORTneo scale were tools developed specifically for assessing prolonged neonatal pain [24,25]. Although they are used widely, these tools have not been extensively validated.
●Mechanically ventilated patients – Most assessment tools were developed for nonventilated infants. However, several have been used in mechanically ventilated infants, including COMFORTneo scale and NFCS [50,79].
●Neurologic impairment including neuromuscular blockade – Responses to pain, including body movement and changes in facial expression, may be decreased or altered in neurologically impaired neonates [64,88] and absent in those who receive paralytic medications.
SUMMARY AND RECOMMENDATIONS
●Misconceptions about neonatal pain – Despite previous unsupported misconceptions about neonates' inability to experience pain, neonates experience pain from the same interventions or clinical conditions as 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 neonates, especially those in the neonatal intensive care unit (NICU). Neonatal pain is likely underrecognized and undertreated, although awareness is improving. (See 'Frequency of painful procedures' above.)
●Effects of inadequately treated pain – Untreated or inadequately treated neonatal pain may have immediate and long-term effects including altered pain sensitivity and reactivity, and neurodevelopmental impairment. (See 'Effects of inadequately treated pain' above.)
●Effective assessment of neonatal pain – Each facility that cares for infants should adopt an assessment strategy for the detection of pain. This includes routine assessment by trained health care workers using standardized pain assessment tools that are appropriate for the neonatal population and clinical setting. However, clinicians need to be aware of limitations of these assessment instruments and altered patient responses due to neurologic impairment, prematurity, or neuromuscular blockade. (See 'Establishing an institutional approach' above and 'Staff training' above and 'Pain assessment tools' above and 'Challenges' above.)
●Our approach – In our practice, we assess pain:
•Every four hours when vital signs are measured
•After each painful or therapeutic intervention
We also administer pain control measures to prevent or control pain due to known or suspected noxious stimuli. (See 'Establishing an institutional approach' above and 'Frequency of assessment' above and "Prevention and treatment of neonatal pain".)
●Assessment tools – We use a validated tool to assess neonatal pain (table 1) because of our limited ability to detect and quantify neonatal pain. Studies have shown that use of an assessment tool to document neonatal pain leads to better recognition and treatment of pain. We use the following assessment tools:
•Premature Infant Pain Profile-Revised (PIPP-R)
•Neonatal Facial Coding System (NFCS)
•Douleur Aiguë Nouveau-né scale (DAN)
•Neonatal Pain Agitation and Sedation Scale (N-PASS)
For acute or postoperative pain, we use either the PIPP-R, the NFCS, the DAN, or the N-PASS. For prolonged pain we use the N-PASS. (See 'Choice of assessment tools' above.)
●Challenges – Assessment of neonatal pain is challenging because of the inability of the infant to communicate with care providers. Assessment tools based on contextual factors (eg, gestational age [GA]), and physiologic and behavioral responses to pain have been developed to detect and measure the intensity of neonatal pain (table 1). However, a single assessment tool has not been universally adopted because each tool was developed and validated for selected populations and clinical settings. (See 'Pain assessment' above.)
ACKNOWLEDGMENT — The UpToDate editorial staff acknowledges Kanwaljeet JS Anand, MBBS, DPhil, FAAP, FCCM, FRCPCH, who contributed to an earlier version of this topic review.
