Treatment of Pain and Stress in the Neonate

Abstract

After completing this article, readers should be able to: Neonates are sensitive to pain and vulnerable to both its short- and long-term effects. However, there is a lack of consistency in both attitudes and practices among NICU staff with regard to pain assessment and management in neonates. Recognition of the clinical importance of neonatal pain and stress has been delayed and hampered by the lack of awareness that newborns are capable of experiencing pain, insufficient knowledge about the developing nervous system, difficulty in assessing neonatal pain, lack of evidence for the safety and efficacy of different modalities available for the treatment of pain, and fears about adverse effects associated with analgesic use.Neonatal pain has been of minimal concern until the last 25 years. For example, at one time, neonates were given paralytic drugs without anesthesia for major surgical procedures because physicians believed that neonates were incapable of interpreting or remembering pain. Further, there was no understanding of the consequences of untreated pain. Newer technologies to sustain life have exposed neonates to multiple invasive procedures and prolonged hospital stays that are associated with acute and chronic pain and stress.In 2001, an international evidence-based group for neonatal pain developed guidelines for the assessment, prevention, and treatment of neonatal pain in an effort to standardize practices for physicians and health care facilities. Within the consensus statement, the group defined general principles to prevent and treat pain and listed the most commonly performed diagnostic, therapeutic, and surgical procedures in the NICU. The guidelines also indicated the methods used most commonly by medical professionals to assess pain in the neonate, recommended an evidence-based approach to analgesic therapy, and listed the adverse effects associated with the use of analgesic agents. Recent evidence reveals a need to modify some of those recommendations.Although guidelines and policy statements have reinforced the need for neonatal pain management, strong evidence shows that ongoing pain often is managed poorly in this population, and many painful procedures are performed without regard to pain relief.Several excellent pain assessment tools are available for the term and preterm neonate. Pain assessments should be validated, reliable, easy to administer at the bedside, appropriate for the gestational age, and comprehensive. Although none of the currently available methods fulfill all these requirements, each NICU should use a validated assessment tool and staff become experienced in its use for pain assessment. Pain should be assessed with an appropriate pain scale for each potentially painful procedure and routinely during chronically painful treatments or conditions such as necrotizing enterocolitis. According to the International Association for the Study of Pain, verbal self-report is the gold standard for pain assessment. Obviously, that is not possible in neonates, who may be the most vulnerable to untreated pain. Although the biochemical, physiologic, and behavioral indicators of pain have been labeled as surrogate and imperfect measures of pain, Anand and Craig proposed a few pain-related infant/neonatal behaviors that may be recognized as nonverbal forms of self-report. Multiple methods of infant pain assessment are based on different combinations of physiologic, biochemical, and behavioral indicators of pain to diagnose and define the intensity of neonatal pain (Table 1).Several comprehensive and multidimensional pain assessment tools were designed by incorporating the pain indicators listed in Table 1. Each has advantages and limitations, and no individual tool has emerged as superior. Some limitations of these methods include severity of illness, gestational age, poor correlation between physiologic and behavioral indicators, blunting of behavioral responses by pharmacologic agents, and the opposing effects of homeostatic mechanisms on the physiologic responses to pain. The most commonly used scales are: Premature Infant Pain Profile (PIPP), Neonatal Facial Coding Scale (NFCS), Neonatal Infant Pain Scale (NIPS), CRIES Score, and Neonatal Pain Assessment and Sedation Scale (the N-PASS) (Table 2). The PIPP is a seven-item measure that includes both physiologic (heart rate, oxygen saturation) and behavioral (brow bulge, eye squeeze, nasolabial furrow) pain indicators and incorporates the gestational age and the neonate’s behavioral state, which can modulate pain expression. The PIPP has established reliability, validity, and clinical utility for procedural pain in preterm and term newborns. It is most useful for preterm infants and recently was validated in two large randomized clinical trials assessing pain in that population. The NFCS includes multiple indicators of facial expression in neonates, with established validity, reliability, feasibility, and usefulness at the bedside. The NIPS assesses facial expression, cry, breathing patterns, movements of arms and legs, and state of arousal. It is better suited for term infants because of robust changes in these parameters associated with acute pain. The CRIES Score assesses crying, requirement for increased oxygen administration, increased vital signs, expression, and sleeplessness in both preterm and term infants and, because of its ease of administration, it is used widely by primary care practitioners.Several other pain scales have been designed for the objective assessment of neonatal pain, including the COMFORT (“behavior”) Score, Pain Assessment Tool, Scale for Use in Newborns, Distress Scale for Ventilated Newborns and Infants, and Infant’s Body Coding System. Although these assessments are validated as research tools, the mainstay of appropriate management includes the caregiver’s awareness of the infant’s ability to perceive pain, knowledge of clinical situations wherein pain occurs, and sensitivity to the need for preventing and controlling pain.Newborns undergo numerous painful procedures in the NICU. They may be exposed to 10 to 14 painful procedures daily. The highest exposure occurs during the first few days of admission and in neonates receiving respiratory support. Critically ill and preterm neonates may experience more than 700 painful procedures by the time of discharge from the NICU! Some of the most common painful procedures are heel sticks; endotracheal intubations; and nasal, tracheal, and gastric suctioning for which pain relief seldom is used. Endotracheal suction of mechanically ventilated children and adults is considered to be a painful and unpleasant procedure and usually is performed with premedication in that population. Premedication rarely is provided in the NICU. Unfortunately, the currently available topical anesthetics are ineffective in providing pain relief for heel sticks. Studies have shown that repeated needle pricks in the neonatal period can cause complex and persistent behavioral effects and reduced pain thresholds that outlast the stimulus by hours or days, even possibly persisting into adulthood. Despite the current knowledge and evidence that preterm neonates are sensitive to pain and experience short- and long-term detrimental effects of untreated pain, only one third of neonates receive appropriate analgesic therapy for invasive procedures.The clinical settings for pain in infants are extremely varied and include acute and chronic painful disease conditions as well as diagnostic, therapeutic, and surgical procedures performed for the treatment of these conditions. Even simple noninvasive procedures, such as removal of adhesive tapes, postural changes, and physiotherapy maneuvers, can cause intense pain and stress in critically ill neonates (Table 3).Nonpharmacologic methods of pain intervention refer to therapies such as environmental and behavioral interventions that do not include pharmacologic agents (Table 4). These interventions may enhance endogenous activity in descending inhibitory pathways, thereby modulating the response to pain through changes in attention and decreased transmission of pain. Nonpharmacologic strategies for pain relief have been used for many generations because they are easy to administer at the bedside, have minimal adverse effects, and do not require intensive monitoring. However, these interventions alone may not alleviate acute pain and should be used as complementary strategies to analgesic treatment.Every diagnostic blood test or invasive therapy should be preceded by the question, “Is this really necessary?” There is no better analgesic than the absence of pain. Pain is managed most effectively by preventing, limiting, or avoiding stimuli that may be perceived as noxious. The NICU environment should be as conducive as possible to the well-being of the neonate and the family. Maternal separation from the newborn for procedures and blood sampling, restricted hospital visiting hours, and stressed and overworked nursery staff all contribute to neonatal stress. Constant use of bright lights in the nursery interferes with the development of the circadian rhythm in newborns and may contribute to retinopathy of prematurity. Unnecessary acoustic and tactile stimuli should be avoided. Whenever possible, painful or stressful procedures should be minimized and coordinated with other aspects of the neonate’s care, and efforts should be made to use noninvasive monitoring techniques (eg, pulse oximeter, transcutaneous bilirubinometer) in place of more invasive methods.Other interventions that modulate pain sensations include minimal handling of sick babies, clustering of nursing activities, avoidance of blood sampling and painful procedures during sleep cycles, not sticking adhesive tapes onto hair, moistening tapes before removal, using lubricated gel during nasogastric or orogastric tube insertions, reducing harsh noise and light in treatment areas, and controlling thermal stress. Skilled and trained personnel should be placing peripheral, central, or arterial lines. Infants show fewer physiologic and behavioral signs of pain during heel lance with the use of mechanical lancets than with manual lancets. Furthermore, blood sampling by venipuncture is less painful than heel lancing and can be treated by topical local anesthesia.Routine developmental care should be provided in the NICU to enhance comfort and stability, reduce unnecessary stress and anxiety, and promote optimal neonatal growth. Simple comfort measures, such as swaddling, nonnutritive sucking (NNS) on a pacifier, containment, and facilitated tucking should be used for minor procedures unless contraindicated. Positioning an infant to provide a nest facilitates self-regulatory behavior in infants, and containment reduces pain by providing gentle stimulation. Swaddling infants after heel lance decreases heart rate and crying time and facilitates a quick return to the sleep state. Other techniques, such as kangaroo care (skin-to-skin contact with mother), breastfeeding, massage, music therapy, waterbeds, or rocking, may benefit neonates undergoing painful procedures.NNS on a pacifier or a nonlactating nipple reduces transient pain elicited by invasive procedures by stimulating orotactile and mechanoreceptors when a pacifier is introduced into the infant’s mouth. Active sucking is required to activate this endogenous analgesic pathway in the brain that is mediated by nonopioid mechanisms. Provision of NNS reduces behavioral pain responses during heel lance, circumcisions, and immunizations. Its efficacy is immediate but is terminated instantly on cessation of sucking, and at times there is rebound distress when the pacifier is removed from the infant’s mouth.Sucrose administration is the most widely studied nonpharmacologic intervention for infant pain management. The soothing, calming, and pain-relieving effects of sucrose during painful procedures in neonates are believed to be mediated by the release of endogenous opioid neurotransmitters such as beta-endorphins. Oral sucrose used alone is appropriate only for pain of very short duration (2 to 3 min), such as heel stick and venipuncture. For treatment of moderate-to-severe pain or when pain is expected to last longer than a few minutes, it should be used in combination with other analgesics or local anesthetics.Oral sucrose can be administered with a syringe by dripping solution into the neonate’s mouth or the neonate may suck the solution through a pacifier or from a pacifier that has been dipped in a sucrose solution. Sucrose concentrations of 24% to 50% are recommended; several studies have shown lower concentrations to be less effective. Volumes of 0.1 mL of oral sucrose solution are given to preterm infants of 24 weeks’ gestational age and up to 2 mL to term infants. The dose must be administered 2 to 3 minutes before the painful procedure and may be repeated during the procedure. There are no documented adverse effects of oral sucrose in neonates, although hyperglycemia and necrotizing enterocolitis have been postulated as potential effects of repeated dosing. Sucrose has shown to be efficacious and safe in the most mature neonates compared with very preterm neonates. In one study, repeated use of sucrose analgesia in infants younger than 31 weeks’ gestation was suggested to increase the risk for poor neurobehavioral development and physiologic outcomes in later weeks of life. The age at which oral sucrose no longer produces analgesic effects is unknown; it is believed to be most effective for neonates and not effective for infants older than 6 months. Combining sucrose, oral tactile stimulation, and parental holding is associated with significantly reduced crying in infants receiving multiple immunization injections. Clinical studies also have shown a pain-reducing effect induced by 30% oral glucose and breastfeeding before venipuncture in newborns.Multidimensional therapy is the mainstay of appropriate pain management in neonates to minimize adverse effects and optimize analgesic effectiveness. Pharmacologic interventions (Table 5) usually are reserved for neonates experiencing moderate-to-severe pain. Drugs should be chosen carefully based on accurate assessment of pain, efficacy and safety of the drug, knowledge of pharmacokinetics of the drug, the clinical condition of the neonate, and the physician’s experience and comfort in using the drug. Although many analgesic agents are approved and available for infants, due consideration must be given to differences in the pharmacokinetics and pharmacodynamics between preterm and term neonates. Drug doses should be calculated based on the current or the most appropriate weight of the neonate, and care must be taken never to exceed maximal recommended amounts. Subsequent doses should be modified based on the cause of pain, response to the drug, and drug interactions. Neonates receiving analgesic medications should be monitored to ensure adequate oxygenation, ventilation, and cardiovascular stability.Opioids are the most flexible and widely used medications for the treatment of moderate-to-severe pain. They are used for the pain associated with invasive procedures, as an adjunct to general anesthesia, for postoperative pain, and for the treatment of painful medical conditions. These drugs also have sedative and anxiolytic properties. They can be administered as single or intermittent boluses or as continuous infusions. Rectal administration is not recommended due to irregular and unpredictable absorption. When opioid analgesics are administered, strict vigilance and monitoring must be maintained for potential adverse effects on the respiratory and cardiovascular systems, and personnel experienced in emergent airway management always should be available at the bedside. An opioid antagonist such as naloxone also should be available for emergent use. The primary adverse effects of opioids are decreased intestinal motility, urinary retention, hypotension, bradycardia, convulsions, and respiratory depression. The risk of adverse effects is related directly to the rate of drug administration, total dose, and combination with other medications causing central nervous system depression. When prolonged infusions are necessary, there is an increased possibility of physical dependence and tolerance in neonates. To avoid withdrawal symptoms, the infant should be weaned gradually from the opioid drug.Fentanyl and morphine are the most commonly used opioid analgesics in infants. Other opioids, including codeine, meperidine, methadone, oxycodone, alfentanil, and sufentanil, also are used in the NICU, but little is known about their pharmacokinetics in preterm neonates and critically ill infants. Morphine and fentanyl provide a similar degree of analgesia, but morphine has greater sedative effects and less risk of chest wall rigidity and produces less tolerance than fentanyl. Fentanyl, on the other hand, has a faster onset and shorter duration of action and fewer effects on gut motility, and it causes less hemodynamic instability or urinary retention than morphine. Two recently completed large multicenter trials revealed that preemptive morphine analgesia in ventilated preterm neonates younger than 33 weeks’ gestation was not associated with more or less risk of severe intraventricular hemorrhage, periventricular leukomalacia, or death compared with a randomized placebo group. Further analyses revealed that morphine should not be used in hypotensive preterm neonates or neonates at 23 to 26 weeks’ gestation because hypotension was accentuated in these populations. Further, PIPP scores were not different in treated versus nontreated preterm neonates and were unrelated to morphine levels. Thus, recent data raise concern about the safety and effectiveness of morphine in the preterm population. This was unexpected after a pilot study, the NOPAIN trial, showed clear benefits for preemptive morphine analgesia.Nonopioid analgesics are used to treat pain of lesser intensity and as an adjunct to reduce the total dose of opioids (“opioid-sparing” effect). They are valuable in clinical situations requiring mild or moderate analgesia, particularly for the pain associated with inflammation (eg, for meningitis, thrombophlebitis, cellulitis, necrotizing enterocolitis, or septic arthritis). This class of drugs includes acetaminophen, acetylsalicylic acid, and nonsteroidal anti-inflammatory drugs (NSAIDs) such as ibuprofen and ketorolac. The current availability of intravenous preparations, including ketorolac tromethamine, ibuprofen lysine, and propacetamol, holds promise for clinical utility in critically ill neonates. Unfortunately, limited data are available on the pharmacokinetics and pharmacodynamics for most of these drugs in neonates (with the exception of acetaminophen and ibuprofen). Acetaminophen is considered safe and effective in reducing mild-to-moderate pain in the pediatric population, with limited studies on its efficacy and safety in preterm and severely ill infants. It can be administered safely for a shorter duration of time to relieve mild procedural pain in neonates without the risk of hepatotoxicity. The recommended dose is 10 to 15 mg/kg orally or 20 to 30 mg/kg rectally. Higher doses do not lead to greater analgesic effects. Tolerance is not possible, but repeated dosing may result in cumulative hepatic and renal toxicity, although this problem has not been addressed formally in neonates.Acetylsalicylic acid and NSAIDs act by inhibiting cyclooxygenase, which blocks prostaglandin synthesis. The effect provided is analgesic, anti-inflammatory, and antipyretic. Acetylsalicylic acid is not recommended for use in neonates because it increases the risk of Reye syndrome due to its decreased clearance and prolonged elimination time. NSAIDs are effective analgesics in the management of mild-to-moderate pain in children, but they have not been studied adequately in neonates. They are most useful for postoperative pain management because surgery causes both pain and inflammation. They also are more effective in preventing pain rather than providing relief in established pain. Ibuprofen is used widely in European NICUs for closure of the ductus arteriosus in preterm infants, but it is not yet approved in the United States. It is a more effective antipyretic than acetaminophen. Intravenous use of ketorolac in infants younger than 6 months of age, who underwent abdominal surgery, reduced opioid use and prevented opioid-associated adverse effects. Ibuprofen and ketorolac have not become standard analgesics in the newborn period because of the potential adverse effects of renal toxicity and platelet dysfunction. Ibuprofen also displaces bilirubin from its binding sites and is associated with an increased risk of gastritis, which limit its use in the NICU.Medications used for general anesthesia produce unconsciousness, analgesia, and amnesia during surgical procedures and keep the patient pain-free and relaxed postoperatively. Advances in anesthetic medications, techniques, and monitoring have increased the safety and efficacy of general anesthesia in preterm and term neonates.Regional, local, and topical anesthesia should be used for pain relief during invasive diagnostic or therapeutic procedures and for minor surgeries such as circumcision or inguinal hernia repair. Regional anesthesia provides excellent anesthesia and analgesia both pre- and postoperatively for procedures on the trunk or limbs. A good knowledge of pediatric anatomy and specialized training in the technique is mandatory for using regional anesthesia. Regional techniques, such as central neuroaxis blockade (epidural, spinal, or nerve plexus blocks) and peripheral nerve blocks, are used in addition to general anesthesia and produce minimal respiratory effects. Examples of peripheral nerve blocks include penile block, digital block, and intercostal nerve block. The duration of peripheral nerve blocks can be extended by using epinephrine, a potent vasoconstrictor, which is contraindicated in the penis, digits, and pinnae of the ear. Penile ring block is more effective than other forms of anesthesia for male circumcision.Spinal anesthesia is suitable but often inefficient for complete surgery in newborns. Clonidine 1 mcg/kg with or without fentanyl 1 mcg/kg added to spinal isobaric bupivacaine can increase the duration and effectiveness of the spinal block markedly without significant deleterious hemodynamic or respiratory adverse effects. Compared with general anesthesia, spinal anesthesia in preterm infants undergoing inguinal hernia repair was associated with decreased postoperative respiratory complications (eg, apneic events, prolonged mechanical ventilation). Further, hemodynamic stability is well preserved in neonates receiving spinal anesthesia. Hyperbaric tetracaine and bupivacaine solutions have demonstrated a good safety profile for spinal or epidural anesthesia in neonates.The availability of new local anesthetic drugs such as ropivacaine and levobupivacaine can add safety to regional anesthesia, and the addition of adjuvants such as clonidine, fentanyl, ketamine, or NSAIDs can contribute to reduced risks associated with toxicity. Serious complications following epidural analgesia, such as death and paraplegia, can be avoided if the procedure is performed by experienced pediatric anesthesiologists. Toxic effects due to differences in protein binding and metabolism in preterm and term infants can be prevented by careful calculation of the doses of all local anesthetic agents. Acidosis, hypoxia, hypercapnia, hyponatremia, and hyperkalemia aggravate the toxicity of these agents; alkalosis reduces it. Continuous epidural infusions can be provided for pain relief in chronic medical conditions or for prolonged postoperative pain. Common complications include dural puncture, convulsions, and intravascular migration of the catheter. Continuous epidural infusions should be managed by anesthesiologists trained in the appropriate pharmacology and recognition of these adverse reactions. In neonates, intermittent administration of local anesthetics with adjunctive use of opioids is much safer than using either drug alone.Ketamine is a dissociative anesthetic that is related chemically to phencyclidine. It provides excellent sedation, analgesia, and amnesia with few cardiovascular effects and minimal adverse respiratory effects (primarily apnea, hypoxemia, or laryngospasm). The safety and efficacy of ketamine sedation has been well documented for a variety of pediatric procedures in the operating room as well as for procedural sedation in the emergency department and intensive care unit. Due to its bronchodilating properties, it is emerging as an ideal agent for sedation during airway manipulative procedures such as flexible bronchoscopy. With appropriate monitoring and vigilance, bronchoscopy with ketamine has been found to be safe in infants. A study conducted in neonates to note if ketamine was suitable for procedural pain relief found that administration of 0.5 to 2.0 mg/kg during the first few postnatal days had only moderate analgesic effects on the pain caused by endotracheal suction. Another study documented that preterm neonates given intravenous boluses of ketamine did not manifest any deleterious changes in cerebral blood flow or cerebral perfusion. Although adverse respiratory effects are rare, these events appear to occur more frequently in patients younger than 3 months of age.Topical anesthesia can produce a loss of sensation in specific areas of skin or mucous membranes and is used for treatment of minor-to-moderate pain associated with diagnostic or surgical procedures such as lumbar punctures, chest tube insertions, suturing, circumcisions, peripheral/central arterial or venous catheter placement, and subcutaneous or intramuscular injections. These agents prevent pain impulses from reaching the brain when infiltrated superficially into the epidermal and subcutaneous space. Widely used local anesthetic agents are lidocaine (available as injection, spray, and gel), benzocaine, bupivacaine, ropivacaine, and amethocaine.Topical anesthetic cream, EMLA, is a eutectic mixture of local anesthetics, consisting of a 1:1 oil-in-water emulsion of 2.5% lidocaine and 2.5% prilocaine hydrochloride. The advent of EMLA has made effective topical analgesia of skin feasible without the need for subcutaneous injections or exposure to high doses of local anesthetics. The efficacy of EMLA for the treatment of procedural pain in children and adults is well established. In neonates, EMLA has been shown to decrease pain during circumcision, venipuncture, arterial puncture, lumbar puncture, and percutaneous venous catheter placement, although it is not effective for heel lance procedures. When applied 1 hour before the intended procedure, it penetrates up to a depth of 5 to 10 mm and provides analgesia for 45 to 60 minutes. Drug penetration can be increased by applying occlusive dressings to the designated area. EMLA cannot be used on mucous membranes or abraded skin. One of the metabolites of prilocaine, ortho-toluidine, is a potent inducer of methemoglobin, putting the neonates at increased risk for developing methemoglobinemia when EMLA is administered in conjunction with other agents capable of producing the same condition. However, studies have shown that single doses of EMLA ranging from 0.5 to 2 g do not cause clinically significant methemoglobinemia in neonates. Other drawbacks of EMLA are local redness, blistering, and petechial rash. Another popular topical anesthetic is Ela-max or LMX-4, which is a 4% gel of liposomal lidocaine. Its use is increasing in the United States, primarily as a replacement for EMLA.Sedatives frequently are administered in NICUs to induce sleep for diagnostic and radiologic procedures, calm irritable infants, manage pain-related agitation, and decrease agitation during ventilation. Sedatives do not provide analgesia, but they have been given in combination with analgesics in an attempt to reduce opioid requirements and associated adverse effects. Sedatives have been used to suppress the infant’s central respiratory drive to achieve synchrony with mechanical ventilation. Infants who demonstrate asynchronous breathing patterns or who “fight” the ventilator are at an increased risk for complications such as pneumothorax and intraventricular hemorrhage. The levels of sedation range from conscious sedation, where protective reflexes are maintained, to deep sedation, which is close to general anesthesia. Because these agents may cause respiratory and cardiovascular depression, continuous pulse oximetry and frequent monitoring of vital signs are essential, and clinicians must be prepared to intervene if the infant’s airway or hemodynamic status is compromised. Short-term neurologic complications also have been reported in ventilated preterm neonates treated with prolonged midazolam infusions. Sedatives and hypnotics can produce tolerance, dependency, and withdrawal when used for long periods of time.Chloral hydrate, benzodiazepines, and barbiturates are used to relieve anxiety and for sedation in neonates. Chloral hydrate is a hypnotic drug, generally used in the NICU for radiologic procedures that require the infant to remain still, such as computed tomography or magnetic resonance imaging. Although this drug is clinically effective, it produces two toxic metabolites: trichloroethanol, which competes for glucuronidation and may exacerbate hyperbilirubinemia, and trichloroacetic acid, which is carcinogenic in mice in very high doses. Both metabolites have extremely long half-lives (> 72 h) in neonates and accumulate with repeated doses. A single dose of chloral hydrate may be sufficient to produce sleep, but repeated doses may be associated with adverse effects such as central nervous system depression, gastritis, supraventricular tachycardias, pulmonary edema, and renal failure.Midazolam is a short-acting benzodiazepine that has been used increasingly in the NICU to provide sedation for mechanically ventilated neonates. It has demonstrated sedative and anxiolytic effects. It is preferred over other benzodiazepines (lorazepam and diazepam) because of its water solubility, rapid clearance, and shorter elimination half-life (6.5 h). Recent concern about the safety of midazolam in neonates has been reported owing to the large number of adverse neurologic effects, including severe intraventricular hemorrhage and periventricular leukomalacia, in ventilated preterm neonates. Other adverse effects in neonates include abnormal movements and hemodynamic effects. Although used extensively in newborns, there is little formal evidence for the safety and efficacy of lorazepam. Diazepam is not recommended for neonates because it displaces bilirubin from albumin-binding sites and produces toxic metabolites that have a prolonged half-life.Phenobarbital is a sedative used in combination with other analgesic modalities for procedural pain, although it has antianalgesic effects. Evidence for its safety and efficacy in high-risk infants is lacking. Hypnotics and sedatives must be used with great caution because they may mask the behavioral responses to pain, while allowing the physiologic and neurohormonal stress responses to continue. Moreover, they have additive effects on the respiratory depression and hypotension caused by opioids. Any use of sedation, regardless of the drug, requires close monitoring for the level of sedation to avoid complications. Providing optimal sedation is complicated by the lack of published clinical assessment tools to monitor the level of sedation in neonates. Research is needed to investigate the short- and long-term safety of sedative drugs in critically ill neonates.The best approach to pain management is prevention and limitation of potentially painful situations and administration of appropriate analgesics, with or without adjuvants or sedatives, whenever pain is anticipated in babies (Table 6). The term “preventive analgesia” emphasizes that central sensitization is induced by noxious inputs, and the administration of analgesic drugs before a procedure may prevent the spinal and supraspinal hyperexcitability caused by acute pain, resulting in decreased analgesic use. Preventive analgesia reduces the distress of infants, their parents, and caregivers; makes the diagnostic or therapeutic procedures easier to perform on neonates; and attenuates the short- and long-term detrimental effects of pain. Unfortunately, preemptive analgesia also causes significant hemodynamic effects that, when not counterbalanced by the increased catecholamines and blood pressure triggered by pain, can be associated with adverse hemodynamic and neurologic adverse effects, especially in preterm infants. The art of analgesic use is to match the use and duration of analgesia with the occurrence and intensity of pain expected in specific clinical situations.Only 10% of drugs currently used in the NICU in the United States are approved for use in neonates by the United States Food and Drug Administration. That organization is trying to remedy this problem by encouraging studies in newborns that prove efficacy and safety, but data in preterm neonates remains limited. This area of research is ripe for scientific investigation because of the inability to interpret neonatal pain, the importance of pain relief, the severe adverse effects of some medications, the plasticity of the neonatal brain, and the number of invasive procedures in the NICU.The ideal analgesic agent is far from a reality. It should be effective, have a rapid onset and short duration of action, have minimal adverse effects such as respiratory depression and hypotension, and be unaffected by genetic differences, all of which are disadvantages to currently used drugs. Ketamine shows promise for use in procedural pain, with minimal adverse effects and potent analgesia. Its pharmacology, especially in preterm and hemodynamically unstable neonates, however, remains unclear. Some of the NSAIDs such as ibuprofen show promise for prolonged use in chronic pain and as adjunctive drugs to limit the use of other pain relievers such as morphine. Their primary adverse effects are related to their inhibition of physiologic functions of the cyclooxygenase enzymes, such as protection of gastric mucosa, platelet aggregation, and glomerular filtration. Studies on NSAIDs should concentrate on safety. One new topical anesthetic, L.M.X., which contains 4% to 5% liposomal lidocaine, shows promise as a drug that might be effective for heel lance procedures, one of the most common painful neonatal procedures, because it has a more rapid onset of action than other anesthetic creams.Several instruments are available for pain assessment in the preterm and term neonate, all of which have advantages and disadvantages in particular populations. Numerous painful procedures and illnesses in the NICU result in acute and chronic pain and should require analgesia. Nonpharmacologic approaches are effective for milder forms of pain and as adjunctive relief. Pharmacologic methods are required for more serious acute and chronic neonatal pain in the NICU. However, all approaches, including opioids, the most effective analgesic drugs, are associated with serious adverse effects, and their effectiveness has been called into question. Neonatal pain cries out for more research on the development of safer and more effective methods for pain relief.