Pain Management in the Neonate
1. An obstetrician is about to do a circumcision without using analgesia. When you question this practice, he replies that neonates cannot perceive pain. Is this correct?
This is not correct. The International Association for the Study of Pain defines pain as “an unpleasant sensory and emotional experience associated with actual or potential tissue damage or described in terms of such damage.” The definition further states that although pain is subjective, the inability to communicate verbally does not negate the possibility that an individual is experiencing pain and requires adequate pain-relieving treatment. The issues of pain perception in newborns, its management, and its prevention were neglected for decades. The inability of newborns to “self-report” contributed significantly to the denial of the importance of neonatal pain and the consequences of inadequate treatment. In response to a painful stimulus, all newborns mount acute changes in endocrine, vegetative, immune, and behavioral functions. Multiple lines of evidence show that the pain system is intact and functional in preterm and term neonates, even among the tiniest preterm newborns. Acute pain is processed in the somatosensory cortex, and these responses are altered by the characteristics of neonates, their behavioral state at the time of painful stimulation, the intensity of stimulation, and contextual factors. Such a nuanced response suggests that term and preterm neonates may be capable of conscious sensory perception of acute pain ( Fig. 17-1). 1234567891011
Figure 17-1 Schematic diagram showing the lateral and medial pain systems. Primary afferents from cutaneous, mucosal, visceral, joint and connective tissue, vascular, and other deep-tissue nociceptors enter the spinal cord via A-delta (thinly myelinated)-fibers, C (unmyelinated)-fibers, and sympathetic fibers. These afferents make rich connections in superficial layers of the dorsal horn of the spinal cord (called the substantia gelatinosa). They have direct and indirect links with projection neurons in deeper layers of the dorsal horn that project to the supraspinal pain-processing areas in the brainstem, medial and posterior thalamus, and various areas of the cortex. The lateral pain system mostly transmits somatic and mucosal pain, whereas the medial pain system transmits visceral pain. Cortical areas most closely associated with pain processing include the primary and secondary somatosensory areas, the anterior cingulate cortex, the insula, and parietal association areas. (From Bonaz B. Visceral sensitivity perturbation integration in the brain-gut axis in functional digestive disorders. J Physiol Pharmacol 2003;54[Suppl 4]:27–42.)
If pain is prolonged or repetitive, these physiologic and behavioral responses may be muted, transient, or absent. Neonates, especially preterm neonates, have limited energy reserves and cannot mount a prolonged psychophysiologic activation response to pain. 1213141516171819
The developing nervous system may be permanently modified after prolonged or repetitive pain, resulting in altered pain processing at the spinal and supraspinal levels. In addition, pain is associated with a number of adverse physiologic responses that include alterations in circulatory (tachycardia, hypertension, vasoconstriction), metabolic (increased catabolism, metabolic acidosis), immunologic (impaired immune response), and hemostatic (platelet activation) systems. 2021222324252627
Cutaneous sensory receptors first appear in the perioral area during the eighth week of gestation. They are present in all cutaneous and mucous surfaces by the 18th week of gestation. Synapses between peripheral sensory afferents and dorsal horn neurons in the spinal cord appear early in the first trimester and are mature by 20 weeks of gestation. Pain activates physiologic stress responses, which are associated with the release of catecholamines, cortisol, and other stress hormones. 2829303132333435363738
Stress responses to a painful stimulation are complex, but they can be detected from the 16th week of gestation. Physiologic stress is different from the pain felt by the more mature fetus, as this stress is mitigated by a pain medication such as fentanyl by 20 to 24 weeks. There is activation of the hypothalamic–pituitary–adrenal axis, autonomic nervous system, and hemodynamic changes in response to fetal pain. 3 In premature infants exposed to pain, there are significant increases of epinephrine, norepinephrine, and cortisol; hemodynamic changes; motor reflexes; and facial reactions. 39
They certainly are not. Developmentally regulated processes and behavioral studies show that pain thresholds increase progressively during late gestation and in the postnatal period. Preterm neonates have much greater sensitivity to pain than term neonates, and they manifest prolonged periods of hyperalgesia after tissue injury. These phenomena were further substantiated in the newborn and infant rat. Central sensitization and immaturity of the pain inhibitory systems are the main neurobiologic explanations for the increased pain sensitivity in newborns. 4041424344454647
Neonates admitted to a modern-day NICU are often exposed to acute or prolonged pain from a variety of sources. These include acute pain caused by heel sticks, venipunctures, tracheal suctioning, lumbar punctures, or chest tubes; postoperative pain resulting from circumcision, surgery to repair a hernia or ligate a patent ductus arteriosus; and prolonged pain from necrotizing enterocolitis, meningitis, birth trauma, or ventilation. Even routine care such as diaper changes, daily weighing, removal of adhesive tape, burns from transcutaneous probes, and rectal stimulation will cause low-level noxious stimulation and background excitability in the “pain system.” Although there is no definition for chronic pain in newborns, conditions associated with constant prolonged pain may include epidermolysis bullosa, necrotizing enterocolitis, scalded skin syndrome (staphylococcal), septic arthritis, tissue ischemia, and rare congenital conditions such as harlequin-type icthyosis. Identifying chronic pain is clinically relevant because it interferes with the infant’s growth, prolongs hospitalization, alters subsequent pain perception, and impairs cognitive and behavioral development (van Ganzewinkel CJ, et al. Unpublished data, 2012). 484950
Neonatal painful experiences cannot be accessed by conscious recall but may lead to long-term or permanent alterations in brain development that are expressed in unique ways during different stages of development, depending on the type, duration, and severity of neonatal painful stimuli; the neurologic maturity at which pain occurs; and the use of analgesia. Term neonates exposed to acute, short-term pain develop significant degrees of hyperalgesia after tissue injury, which includes the areas where the injury occurred (i.e., primary hyperalgesia) as well as areas adjacent to or remote from the original injury (i.e., secondary hyperalgesia). If pain is prolonged or repetitive, the developing nervous system will be permanently modified, with altered processing at spinal and supraspinal levels. Tissue damage in the early neonatal period causes profound and long-lasting dendritic sprouting of sensory nerve terminals, resulting in hyperinnervation that may continue into childhood and adolescence. Thus repeated heel sticks could lead to gait disorders in childhood, repeated perioral and nasal suctioning may promote oral aversion syndrome, surgical sites may maintain an increased pain sensitivity, and gastric suctioning at birth may increase the likelihood of irritable bowel syndrome or visceral pain in adolescence. 51525354555657585960616263646566676869
Twin pairs who were discordant only for the experience of surgery in infancy showed greater signs of attention-deficit/hyperactivity disorder, impulsivity, and socialization problems during early school years in the twin who was exposed to surgery compared with the other twin. Although it was speculated that these individuals may be at increased risk for developing chronic pain syndromes during adulthood, recent epidemiologic data from former preterm young adults suggest that this is not the case.
Repetitive pain in newborn rats accentuates neuronal excitation and cell death in developmentally regulated cortical and subcortical areas, associated with impaired short-term and long-term memory and altered pain thresholds. Morphine analgesia in newborn rats attenuated the long-term effects of neonatal pain on pain thresholds in adult male rats (but not females), whereas ketamine analgesia mediated similar long-term effects in adult female rats (but not males). 707172737475767778798081828384858687
Neonates need to be comfortable and as free of pain as possible to grow and develop normally. Valid, reliable, and regular pain assessments are a major prerequisite for attaining this goal. Behavioral indicators of pain include facial actions, body movements and tone, cry, behavioral state changes, sleep patterns, and consolability. Physiologic indicators of pain include increased heart rate, respiratory rate, and blood pressure, as well as decreased heart rate variability and oxygen saturations. Pain assessment in neonates is difficult in neurologically compromised, chemically paralyzed, or nonresponsive infants.
Many methods for measuring the intensity of acute pain in neonates have been validated, but other aspects of painful experiences (e.g., character, location, rhythmicity, duration of pain) have not been routinely assessed in neonates. Very few methods have been validated for the assessment of postoperative pain or chronic pain. The most commonly used methods include the Premature Infant Pain Profile (PIPP), the Neonatal Infant Pain Scale (NIPS), the CRIES score, the Neonatal Pain, Agitation, and Sedation Scale (NPASS), the Neonatal Facial Coding System (NFCS), and the Douleur Aiguë du Nouveau-né (DAN) scale. For acute procedural pain, results using the the NIPS, NFCS, and DAN scales were comparable. A challenge facing clinicians is to develop and validate objective measures of prolonged pain in preterm and term neonates ( Table 17-1). 888990919293949596979899100101102103104105106107108109110111112113114115116117118119120
TABLE 17-1
9. What are the clinical effects of continuous morphine or fentanyl infusions in ventilated preterm neonates?
In infants receiving morphine infusions, randomized controlled trials showed lower pain scores but no significant differences in intraventricular hemorrhage (IVH) (relative risk [RR] 1.13; 95% confidence interval [CI], 0.80-1.61), periventricular leukomalacia (RR, 0.81; 95% CI, 0.51-1.29), or mortality (RR, 1.14; 95% CI, 0.81-1.60) between the morphine and placebo groups. Intermittent bolus doses of open-label morphine, however, were associated with hypotension and increased rates of IVH and mortality. Morphine infusions did not improve short-term pulmonary outcomes among ventilated preterm neonates, whereas additional morphine doses were associated with worse respiratory outcomes among preterm neonates with respiratory distress syndrome. Infants receiving morphine spent more days on mechanical ventilation (weighted mean difference [WMD], 0.24 days; 95% CI, 0.11-0.36). 121122123124125126127128129130131132
Opiates have numerous side effects, including respiratory depression, nausea, vomiting, urinary retention, decreased gut motility, and histamine release causing hypotension or bronchospasm. Histamine release occurs more commonly with morphine than with fentanyl. In addition, morphine is associated with greater effects on gut motility, and very high doses may cause biliary spasm or even seizures. Chest wall rigidity or laryngospasm occur more commonly with fentanyl, with the rapid administration of intravenous doses. Fentanyl produces less sedation than morphine but has been associated with greater opioid tolerance because of its shorter duration of action. 133134135136137138139140141142143144145146147
Many of these signs were included in scoring systems designed to quantify opioid withdrawal in neonates born from heroin-addicted mothers. Their applicability to iatrogenic opioid tolerance and withdrawal resulting from prolonged use in the NICU has not been proved. Previous methods included the Neonatal Abstinence Score (NAS) by Finnegan et al. or the Neonatal Narcotic Withdrawal Index (NNWI) by Green and Suffet, but newer methods include the Withdrawal Assessment Tool (WAT-1) and the Sophia Observation Scale (SOS). Signs of opioid withdrawal include the following ( Box 17-1):
Neurologic: high-pitched crying, irritability, increased wakefulness, hyperactive deep tendon reflexes, increased muscle tone, tremors, exaggerated Moro reflex, generalized seizures
Gastrointestinal: poor feeding, uncoordinated and constant sucking, vomiting, diarrhea, dehydration
Autonomic signs: increased sweating, nasal congestion, fever, mottling
Other: poor weight gain, disorganized sleep states, skin excoriation 148149150151152153154
Concomitant infusion of opioid agonists and N-methyl-D-aspartate (NMDA) antagonists such as low-dose ketamine (0.2-0.3 mg/kg/h) can delay the development of opioid tolerance. Opioid drugs such as ketobemidone and methadone also block NMDA receptors and produce less tolerance than morphine or fentanyl.
Procedural changes in adult or pediatric ICU patients such as the daily interruption of sedatives, nurse-controlled sedation, sequential rotation of analgesics, or the use of neuraxial opioids may also decrease the incidence of opioid tolerance and withdrawal. 155156157158159160
Methadone: This opioid agonist and NMDA antagonist has a long half-life (25 to 44 hours in neonates), can be given enterally (oral bioavailability, 80% to 90%), and reverses the tolerance produced by morphine or other opioid drugs. In one clinical study a methadone dose equivalent to 2.5 times the total daily fentanyl dose was effective in minimizing symptoms of opioid withdrawal.
