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.
Benzodiazepines: Benzodiazepines, such as diazepam or lorazepam, may be used for treating the seizures associated with opioid withdrawal, but they are not cross-tolerant with opioids and cannot be used as sole therapy for opioid withdrawal. 161162163164165166167168169170171172173174175176177
Procedural pain should be prevented whenever possible. Procedural pain can be minimized with an appropriate awareness program involving nursing and respiratory therapy staff members; physicians; and, most important, parents. The most common sources of minor procedural pain are heel sticks and tracheal suctioning. Heel sticks can be treated with 25% sucrose, and tracheal suctioning can be treated with facilitated tucking. More pronounced pain should be treated with opiates. Remifentanyl, for example, is a good choice for short-term procedures such as intubation, whereas more prolonged pain should be treated with a longer-acting opiate such as morphine or fentanyl. Anxiolytics such as midazolam can be used as adjuncts, but they do not treat pain. Circumcision should be performed with sucrose and local anesthetic nerve block before the procedure and acetaminophen after the procedure. 178179180181182183184185
EMLA is an acronym for eutectic mixture of local anesthetics, containing lidocaine (2.5%) and prilocaine (2.5%). Prilocaine is metabolized to ortho-toluidine, which can oxidize hemoglobin to methemoglobin in neonates. Preterm newborns are particularly at risk because their stratum corneum is thinner, causing increased absorption and higher serum prilocaine levels. However,this appears mainly to be a theoretical concern because the incidence of clinically significant methemoglobinemia is strikingly low, even among the preterm neonates exposed to repeated daily doses of EMLA (up to four times a day). The use of EMLA and sucrose is effective in reducing venipuncture pain. 186187
Nonpharmacologic interventions are useful for minor pain and as adjunct therapy for severe pain. Sucrose solutions block the nociceptive transmission in the ascending pathways that transmit noxious stimuli to the brain, while activating the descending inhibitory pathways that modulate pain. Additionally, animal studies show that the gustatory receptors stimulated by sucrose lead to an activation of the endogenous opioid systems in the newborn brainstem, with reduced pain transmission to the thalamocortical circuits. These mechanisms are unlikely to lead to increased beta-endorphin levels in peripheral plasma, as noted in preterm newborns. Additional evidence for this mechanism is demonstrated by the fact that naloxone blocks the analgesic effects of sucrose. Until further evidence becomes available, the consensus opinion remains that sucrose induces effective analgesia for acute pain resulting from skin-breaking procedures in term and preterm newborns. Recently, however, safety of the long-term repeated use of sucrose solutions has been called into question, and protocols should be developed to limit sucrose dosing. 188189190191192
The goals of perioperative analgesic approaches are the relief of pain, the maintenance of physiologic stability, and the prevention of adverse events such as hypoventilation or shallow respiration owing to diaphragmatic splinting, paralytic ileus, protein catabolism, and pulmonary hypertension. The management of postoperative pain should ideally start before the operative procedure, with consideration given to the size and alignment of the surgical incision; the choice of anesthetic agents; infiltration of the surgical site with lidocaine or bupivacaine; and, if possible, the placement of an epidural catheter before or after surgery. Use of analgesics may improve postoperative outcomes with fewer adverse events, shorter duration of mechanical ventilation, rapid return of gastrointestinal function, and reduced incidence of postoperative apnea and other complications. Opiates are the mainstay of therapy; however, because of their known side effects, including respiratory depression, other drugs such as ketorolac and acetaminophen are being studied. 193194195
Postoperative analgesia is usually provided with opioids (e.g., morphine, fentanyl, methadone), antipyretic analgesics including acetaminophen or its intravenous analog propacetamol, or the nonspecific cyclooxygenase (COX) inhibitors (e.g., ibuprofen, ketorolac, diclofenac). The newer COX-2 inhibitors (e.g., parecoxib, valdecoxib, celecoxib, meloxicam) have not been studied in or approved for newborns and small children. Other options include epidural or caudal anesthesia with bupivacaine, or bupivacaine mixed with fentanyl infusions continued into the postoperative period. The use of nurse-controlled analgesia using a patient-controlled analgesia pump is also under investigation. 196
19. Are the doses of morphine and fentanyl for postoperative analgesia in neonates similar to the doses used for older children?
Neonates may receive lower morphine infusion rates than older children after surgery, starting as low as 0.005 mg/kg/h for preterm neonates and 0.01 mg/kg/h for term neonates. Neonates with cyanotic congenital heart defects also require lower morphine infusion rates than neonates undergoing noncardiac surgery. Depending on the dose and other patient characteristics, fentanyl and sufentanil provide variable degrees of suppression of autonomic and hormonal/metabolic responses to major surgery in neonates, although fentanyl may increase the risk of postoperative hypothermia. Critically ill neonates, whose vascular tone depends on sympathetic outflow, may become hypotensive after bolus doses of fentanyl or morphine. In preterm neonates undergoing ductal closure, higher fentanyl doses (>10.3 mg/kg) were associated with a decrease in an unstable postoperative respiratory course. Randomized controlled trials show no differences in the postoperative analgesia produced by bolus doses versus continuous infusions of morphine; however, apnea or other complications were greater in the bolus-dosing groups. Intravenous boluses of opioids should be given slowly (over 15 to 30 minutes) to postoperative neonates. 197198199
The majority of preterm neonates are capable of glucuronidating morphine, but birth weight and gestational and postnatal age influence the hepatic capacity for glucuronidation. Term and preterm neonates and older infants produce relatively greater proportions of morphine-3-glucuronide, which acts as an opioid antagonist and has a prolonged half-life. Older children and adults produce morphine-6-glucuronide, which is a potent analgesic, with 20 times the analgesic potency of morphine itself. Morphine-6-glucuronide was not detected in the plasma of any neonate, which may explain why neonates require relatively high plasma concentrations of unchanged morphine for effective analgesia. 200200
A meta-analysis performed from the reported pharmacokinetics parameters showed an increased volume of distribution for morphine, estimated to be 2.8 ± 2.6 L/kg, which seems to be unaffected by age. In contrast, the half-life and plasma clearance rates for morphine are clearly related to age, secondary to maturational changes in hepatic and renal function. Morphine half-life was estimated to be 9.0 ± 3.4 hours in preterm neonates, 6.5 ± 2.8 hours in term neonates ages 0 to 57 days and 2.0 ± 1.8 hours for older infants and children. Clearance was estimated to be 2.2 ± 0.7 mL/min/kg for preterm neonates, 8.1 ± 3.2 mL/min/kg for term neonates ages 0 to 57 days, and 23.6 ± 8.5 mL/min/kg for older infants and children. The prolonged half-life explains why effective analgesia can be maintained, following a loading dose, with very low infusion rates of morphine (5-15 μg/kg/h). Doses must be further decreased for neonates with impaired hepatic or renal functions, and a pharmacist should be consulted for these patients. 201
It is important to remember that preterm neonates are exposed to repeated invasive procedures that induce pain at a time of rapid brain growth and developmental programming of stress responses. In the few experiments that used opioids for surgical or inflammatory pain, no detrimental effects resulting from morphine exposure in infancy could be demonstrated. The long-term outcomes of former preterm children at 5 to 6 years of age who received morphine during their NICU course showed no differences in their cognitive, neuromotor, or behavioral outcomes, but there was a trend toward better performance in those receiving morphine. In children who were 5-years-old, de Graaf found that morphine-exposed neonates (compared with those in the placebo group) rated lower on a visual analysis subset. Other IQ subsets demonstrated no change when adjusted for other covariates using propensity scoring. Pilot data from the NEOPAIN cohort randomized to morphine or placebo groups in the NICU showed no differences in neuropsychologic outcomes at 5 to 7 years of age, but decreased body weight and head circumference, reduced socialization, and adaptive behaviors occurred in the morphine group. These children also had longer choice response latencies and 27% less task completion during a short-term memory task. However, in this same cohort at school age, the authors found a significant benefit of preemptive morphine analgesia compared with placebo controls among ventilated preterm neonates in math skills (8 to 10 years of age). Literacy placement was similar in the morphine and placebo groups. Limited data are available on the long-term developmental outcomes for neonates exposed to fentanyl therapy in the NICU. 202203
KEY POINTS: PAIN MANAGEMENT IN NEONATES
1. All neonates feel pain, and the clinician must effectively deal with the potential for pain during any procedure performed during the neonatal period.
2. Premature infants have a greater sensitivity to pain than do term infants.
3. Although children may not directly recall painful experiences from their NICU stay, they may demonstrate altered behavioral states resulting from painful experiences that were not well managed.
4. Morphine and fentanyl appear to be equally effective for pain relief in neonates and appear to have similar outcomes in short-term follow-up studies.
5. Methadone and some of the newer narcotic agonists (e.g., buprenorphine), as well as a number of other agents, appear to be optimal treatments for narcotic withdrawal in neonates. Paregoric and phenobarbital are no longer drugs of choice.
6. Nonpharmacological approaches, including sucrose, pacifier, swaddling, and breastfeeding, are effective against the acute pain caused by skin or tissue injury.
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