In the neonatal intensive care unit, each preterm neonate experiences about 5 to 15 painful procedures per day. Exposure to pain in preterm infants is multifactorial, and can result from mechanical ventilation, invasive procedures, repeated heel sticks and venipuncture attempts, postoperative pain, and acute medical illnesses such as necrotizing enterocolitis. Neonates were initially thought to have diminished pain perception due to immaturity of their central nervous system (CNS). But evidence shows that sensory receptors and nerve fibers appear in the perioral area as early as the 7th week of gestation, spread to the rest of the face, palms, and soles by the 11th week, to the trunk, arms, and legs by the 15th week, and to all cutaneous surfaces by the 20th week.1 Integrated nociceptive pathways are functional by 24 to 28 weeks of gestation.2 Recent studies using near-infrared spectroscopy and electroencephalogram (EEG) recordings in babies as premature as 25 weeks demonstrate altered cortical activity after noxious stimuli.3 Neonates and particularly preterm infants feel more pain as a result of immaturity of the descending inhibitory pathways that appear only after the 32nd week of gestation. Several studies have shown changes in physiologic and biochemical markers of stress after painful stimuli, even in preterm infants.4 A growing body of evidence supports the necessity and importance of analgesia and sedation in neonates. Opioids are believed to be the most effective sedative analgesics in patients of all ages to effectively control moderate to severe pain, and morphine remains the gold standard for procedural pain management in neonates despite the lack of proven efficacy in preterm neonates and despite having the undesirable side effect of respiratory depression. Evidence from animal and human studies has demonstrated that morphine exposure in prenatal and postnatal periods can have both short- and long-term adverse neurologic effects, such as restricting brain growth, induction of neuronal apoptosis-altering behavior, and pain responses later in life (Figure 1). The goal of the clinician is to minimize the risks of detrimental effects on neurodevelopment from both pain and drugs used for pain.
A schematic representation depicting: (A) the developmental maturation of pain pathway in neonates, (B) the acute and long-term effects of painful stimuli, and (C) the potential harm from the use of morphine. PVL, periventricular leukomalacia.
Impact of Neonatal Pain on the Developing Brain
Effective pain control is not only important to reduce the acute markers of stress that can affect the immediate morbidity in a sick neonate,5 but it is also important to pay attention to the long-term ill effects of repeated painful stimuli that can have a permanent effect on the developing neurologic system. Acute physiologic and biochemical markers of stress that result from noxious stimuli can lead to impaired ventilation, changes in intrathoracic and arterial pressures, and may contribute to intraventricular hemorrhage and periventricular leukomalacia.6 Changing levels of neural activity as a result of painful stimuli can affect the normal development of the CNS in a developing organism. Repetitive painful stimuli may persistently alter pain processing in humans, and can lead to emotional/behavioral problems in childhood such as anxiety, depression, and suicidal tendencies.7 Increased exposure to procedural pain in neonates has been associated with poorer cognitive and motor outcomes, reduced white matter and subcortical grey matter maturation, altered corticospinal tract structure, and growth impairment.8 Functional brain magnetic resonance imaging of former preterm neonates showed greater activation of sensory areas in response to pain compared to former full-term controls.9 As a result of this strong correlation between neonatal pain and adverse neurodevelopmental outcomes, the American Academy of Pediatrics recommends preemptive analgesia for moderate to severe pain and invasive procedures.10 Therefore, analgesia and sedation have become an integral part of neonatal critical care to ensure optimal long-term outcomes in this vulnerable population.
Benefits of Morphine in Neonatal Pain
Sedative-analgesic medications reduce the stress response that results from painful stimuli, provide anxiolysis, facilitate respiratory support by increasing ventilatory synchrony, and thereby optimize pain control. Opiates, specifically morphine, are the mainstay of pain control and sedation protocols in critically ill patients including newborns. Morphine blunts the behavioral and stress hormonal responses that result from pain and is very effective for postoperative pain.11 Morphine improves ventilator synchrony with improved oxygenation12 and effectively sedates ventilated neonates.13 In preterm neonates, morphine therapy may improve neurologic outcomes.14 Under painful conditions, morphine may have protective effects on nerve cell necrosis as demonstrated in newborn rats.15 Morphine has been shown to down-regulate stress-related changes in gene expression, protecting cells against apoptosis.16 A recent randomized control trial demonstrated that lower gestational age, greater neonatal pain, and higher morphine exposure were correlated with smaller brain volumes, but not with cognitive performance.17 This study also reported no difference in cortical thickness; however, the children in this study had a higher median gestational age (31 weeks) as well as lower dose of morphine administered to the morphine group. Preemptive analgesia with morphine may be neuroprotective; however, this is limited to specific conditions of pain and stress.18 The potential neuroprotective effects of morphine likely depend on the severity and duration of stress.
Pharmacokinetics and Immediate Adverse Effects of Morphine
Neonates demonstrate significantly altered opioid pharmacokinetics. Neonates have lower plasma clearance, higher volume of distribution, decreased protein binding, decreased hepatic clearance, decreased renal clearance, and immature blood-brain barrier that increases the respiratory side effects of opiates. Morphine is metabolized in the liver to morphine-3-glucoronide and morphine-6-glucuronide. Morphine-3-glucuronide is an opioid antagonist and morphine-6-glucuronide is a potent opioid agonist. Preterm neonates mainly produce morphine-3-glucuronide compared with 6-glucuronide as a result of immature hepatic glucuronidation, which may explain the tolerance to morphine observed within a week after the initiation of administration.19 Morphine can cause significant apnea in newborns and is associated with seizure activity in newborn infants.20 Prenatal exposure to morphine increases opioid receptors in the substantia nigra, subthalamic nucleus, and the hippocampus, the structures involved in seizures. This corresponds to the increased seizure activity, EEG changes, and increased irritability observed in children of opioid-abusing mothers. The Neurologic Outcomes and Pre-emptive Analgesia in Neonates (NEOPAIN) Trial21 demonstrated that morphine-exposed premature neonates experience side effects such as hypotension, increased duration of ventilation, and increased time to reach full volume nasogastric feeds. Morphine-associated respiratory depression is greater in newborn infants, especially premature infants due to the immaturity of their respiratory center responses to hypoxia and hypercarbia. Despite developmental alterations in pharmacokinetics, the potential to cause seizures and having the undesirable side effect of respiratory depression, morphine is still the most common opioid used to effectively manage painful stimuli in neonates. Sedation and analgesia with morphine can thus affect multiple physiologic variables that could potentially induce or exacerbate neurologic injury in a vulnerable-developing neonate.
Adverse Neuromodulation Effects of Morphine During Development
Opioid receptors are expressed early in the developing brain.22 Opiates such as morphine and fentanyl act on mu, kappa, and delta opioid receptors and activate multiple intracellular signaling pathways that are implicated not only in the analgesic effects but also on the modulation of proliferation, survival, and differentiation of neural stem cells, neurons, and glia that express opioid receptors.23 Exposure to opiates such as morphine during a critical period of neuronal maturation can therefore lead to permanent changes in the formation and function of the CNS. The mechanisms underlying the effect of sedative analgesics on the developing CNS are complex, as the changes can be due to an effect on both the brain and peripheral organ systems.
Prenatal morphine exposure leads to structural and functional changes in the CNS.24 Adult animals that were exposed to morphine prenatally showed increased locomotor activity, impaired memory and learning, and worsened adaptability to stress.25 Prenatal morphine exposure increased the amount of opioid receptors in the nucleus accumbens and in the amygdala—the structures of the CNS associated with the drug-reward system.25 Chronic morphine exposure during prenatal and early postnatal periods induces significant reduction in brain volume, neuronal packing density, and dendritic growth, which leads to long-term alterations in pain threshold, impairments in learning abilities, and locomotor activity.23 Morphine exposure significantly increased apoptosis in both human neuronal and glial cells via a caspase-3 dependent pathway.26 There was significant up-regulation of the proapoptotic receptors and down-regulation of antiapoptotic receptors from chronic exposure to morphine in rats. Repeated morphine exposure modifies the synaptic neuroplasticity in postsynaptic sites of the limbic system, which leads to persistent effects on the reorganization of synaptic connections in areas that regulate motivation, reward, and learning throughout adult life; these changes are permanent and remain even after removal of morphine.27
Both short- (<5–7 days) and long-term (>7 days) exposure to morphine have been implicated in permanent detrimental effects on the developing brain. Short-term exposure to morphine in preterm neonates leads to poor performance on the visual analysis part of the IQ assessment.28 The NEOPAIN trial19 investigated whether preemptive analgesia with morphine decreased the rate of neonatal death, severe intraventricular hemorrhage (IVH), and periventricular leukomalacia (PVL) in premature neonates born at 23 to 32 weeks gestation. Infants in this trial received continuous infusion of morphine as well as intermittent doses as clinically needed for a maximum of 14 days. Infants that received intermittent boluses of morphine had increased rates of IVH, PVL, and neonatal death. Follow-up studies from the same trial at age 5 to 7 years reported morphine-associated adverse effects such as lower body weight and head circumference, increased social problems, and poorer executive function.24 These infants had significantly increased latencies to make a choice response in a memory task, implying that these infants had impaired ability to analyze and match the visual stimuli. This not only leads to decreased task completion, but it also correlates with lower confidence in the accuracy of an answer. Former preterm children and adolescents generally have social problems such as deficits in making and maintaining peer relationships, but preemptive morphine analgesia may have the potential to worsen these problems.
Grunau et al.29 investigated the cumulative effect of procedural pain and morphine exposure on neurodevelopmental outcomes in very preterm infants in comparison to full-term controls. They reported overall poor motor and cognitive function in extremely premature infants at age 8 and 18 months corrected age and concluded that this was multifactorial including more severe illness, more painful procedures, higher morphine exposure, and longer duration of ventilation. But greater morphine exposure correlated with lower psychomotor development index only at age 8 months. Ranger et al.30 proposed to examine whether neonatal pain and morphine exposure was associated with increasing internalizing behaviors at age 7 years in babies born very preterm (24–32 weeks gestation) using the child behavior checklist and parent stress index, and concluded that higher morphine exposure was associated with greater internalizing characteristics such as anxious/depressed, withdrawn/depressed, or somatic problems. This was found to be independent of other neonatal clinical predictors of poor outcomes such as gestational age, Score for Neonatal Acute Physiology, postnatal infections, the number of surgeries, skin breaks, and parental stress.30
Pain management is an important indicator of the quality of care provided to neonates, who are subjected to repeated painful stimuli that may alter nociceptive pathways during a critical period of neurologic development and have adverse neuropsychologic outcomes. The maturation of systems modulating pain in premature infants coincides with the highest frequency of noxious stimuli, thus increasing their long-term sensitivity to pain. Opioid administration is a common practice in neonatal intensive care to effectively manage pain. Effective pain control is based on systematic assessment of pain, decreasing the frequency of painful procedures and environmental stressors, determining the optimal techniques to relieve pain and stress, followed by titrated administration of the most appropriate analgesic with subsequent reassessment to adapt treatment.31 Durrmeyer et al.23 propose a stepwise approach to the management of pain and have developed practical recommendations in different settings such as mechanical ventilation, postoperative analgesia, endotracheal intubation, and other invasive procedures based on randomized controlled trials and large observational studies. The primary goal of optimal pain management is avoidance of painful procedures such as repeated heel sticks/venipuncture, followed by progression to nonpharmacologic techniques such as massage, sucrose and kangaroo care, and finally proceeding to pharmacologic treatment that includes opiates. Neonatal opioid exposure can have long-lasting implications for brain structure and function. As with every clinical decision, the risks and benefits of opioid analgesia should be considered carefully.
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