Prevention and treatment of neonatal pain

INTRODUCTION — Varying degrees of neonatal discomfort, stress, or pain resulting from moderate to more severe invasive procedures may occur during routine patient care. Care providers are expected to prevent or treat any infant experiencing pain.

This topic will address the prevention, control, and treatment of neonatal pain. The assessment of neonatal pain is discussed separately. (See "Assessment of neonatal pain".)

BACKGROUND — Advances in neonatal research demonstrate that newborns experience pain, and that controlling pain has short- and long-term benefits for all newborns [1-3]. Professional bodies and parent/caregiver groups appropriately expect health care providers to prevent or protect infants from experiencing pain [4-6]. Varying degrees of neonatal discomfort or pain may occur during routine patient care (eg, gastric tube insertion, bladder catheterization, or physical examination) [7], moderately invasive procedures (eg, suctioning, phlebotomy, or peripheral intravenous [IV] access), or more invasive procedures (eg, chest tube placement, circumcision, or central venous access).

Pain is most frequent and intense in infants admitted to the neonatal intensive care unit (NICU). Infants admitted to the NICU experience acute pain from skin-breaking procedures, short-term pain following surgery, and prolonged (chronic) pain from diseases like necrotizing enterocolitis or epidermolysis bullosa. Despite ongoing efforts, consistent definitions for prolonged or chronic pain in newborn infants have not been developed [8-10]. In part due to the lack of consensus regarding the definition of prolonged neonatal pain, it appears that only 10 percent of neonates received daily assessments for prolonged continuous pain in the NICU [11]. A scientific framework may allow clearer definition of the pain terms used for nonacute pain in neonates and aid in improved assessments of prolonged, persistent, or chronic pain [12]. (See "Assessment of neonatal pain".)

APPROACH — The objective for neonatal pain prevention and treatment is to find a good balance between analgesia and potential side effects. However, there is wide variation in practice across institutions, likely because there are few guidelines to direct care. This topic reflects the approach of the author, which is based on the available evidence and expert opinion. There is a need for additional guidelines to direct management of pain prevention and treatment in neonates.

To ensure that neonates receive adequate pain control, a pain control program should be established for each health care facility that treats newborns and should include the following [4,13-15]:

General principles

●Routinely assess the infant for detection of acute and/or prolonged pain. (See "Assessment of neonatal pain", section on 'Pain assessment'.)

●Reduce the number of painful procedures and unnecessary noxious stimuli.

●Prevent/reduce acute pain by providing pre-emptive analgesia for any anticipated painful procedure.

●Anticipate and treat postoperative pain following surgery.

●Avoid, ameliorate, or limit the duration of prolonged continuous pain/stress.

●Monitor patient responses to analgesic intervention using validated assessment tools. Provide additional analgesia if needed.

Combination of measures — Analgesia begins with nonpharmacologic measures. Pharmacologic measures are added as needed depending on the degree of anticipated procedural pain. In our practice, we use combinations of nonpharmacologic and pharmacologic measures depending upon the clinical setting (table 1). Nonpharmacologic approaches are generally more effective when used in combination with other nonpharmacologic measures and/or with analgesics than when used alone [16-21]. Combinations of nonpharmacologic measures (eg, skin-to-skin contact plus non-nutritive sucking) have additive or synergistic effects [19,21]. This can be further enhanced with the addition of oral sucrose. For example, for a heelstick, a combination of measures may be used, such as oral sucrose and skin-to-skin contact. Sucrose may also be combined with other analgesic agents for painful procedures that are more prolonged or invasive, such as lumbar puncture (LP), circumcision, chest tube insertion, percutaneous central venous catheter insertion, or intraosseous access.

In some settings, these combinations may eliminate pharmacologic use, or reduce drug dosage or the frequency of doses required, and consequently, the risk of pharmacologic side effects [16-18,22]. (See 'Oral sucrose or glucose' below and 'Combination with opioid therapy' below.)

NON-DRUG MEASURES (FOR MOST PROCEDURES) — The following nonpharmacologic approaches can effectively reduce pain and discomfort from routine care measures and minor procedures (eg, heelstick) in both preterm and term neonates (table 1) [23]:

●Breastfeeding

●Non-nutritive sucking

●Swaddling or facilitated tucking (defined as gently maintaining the arms and legs in a flexed position)

●Skin-to-skin contact (eg, kangaroo care)

●Sensorial saturation (use of touch, massage, voice, and smell)

Breastfeeding or breast milk — Breastfeeding is an effective analgesic measure. Supplemental breast milk is a reasonable option for providing neonatal analgesia, but less effective than breastfeeding or sucrose/glucose [24,25]. Breastfeeding is a developmentally superior alternative to oral sucrose or glucose for pain control in infants. Benefits of breastfeeding include maternal proximity and ventral skin-to-skin contact, which increase beta endorphin and oxytocin levels in newborns, and the effects of sugars, fats, and other nutrients in breast milk combined with nutritive sucking to reduce pain and divert the infant's attention away from the painful stimulus [26,27]. However, breastfeeding may not be applicable to intubated or very preterm neonates undergoing painful procedures [28]. (See 'Oral sucrose or glucose' below.)

The efficacy of breastfeeding for neonates undergoing painful procedures is supported by randomized trials and meta-analyses [25,28-32]. In one systematic review, infants who were breastfed or received breast milk were compared with control groups receiving placebo or no intervention, or interventions such as sucrose, holding by mother, non-nutritive sucking, or swaddling [25]. Validated pain scores such as the Premature Infant Pain Profile (PIPP), Douleur Aiguë Nouveau-né (DAN), Neonatal Infant Pain Scale (NIPS), or Neonatal Facial Coding System (NFCS) were lower in the breastfeeding group (table 2). In a second systematic review, direct breastfeeding was more effective than maternal holding, maternal skin-to-skin contact, topical anesthetics, and music therapy, and was as or more effective than sweet solutions, whereas expressed breast milk did not consistently reduce pain responses in full-term or preterm infants [29]. One limitation of the evidence has been the significant variability in study design among trials.

Non-nutritive sucking — Although breastfeeding or oral sucrose are preferred to non-nutritive sucking for infants undergoing minor painful procedures, non-nutritive sucking is effective in reducing pain-related distress in both preterm and term infants [4,23]. Crying decreased and heart rate increased less in infants offered pacifiers during painful stimuli compared with those who received no intervention, swaddling alone, rocking alone, or sensory stimulation [32-35]. Poorer pain relief occurred in infants who received pacifiers only as compared with those receiving sucrose-dipped pacifiers [30-33]. (See 'Oral sucrose or glucose' below.)

Other measures — The use of the following measures alone or in combination with non-nutritive sucking or oral sucrose is beneficial in reducing procedural pain [23].

●Swaddling or facilitated tucking – In term and preterm infants, facilitated tucking or swaddling is more effective than no intervention in reducing pain responses to invasive procedures (eg, endotracheal suctioning and heelstick) [23,36,37]. A multicenter randomized trial showed that facilitated tucking alone was significantly less effective in relieving repeated heelstick stick pain than sucrose, but in combination with sucrose it had additive effects compared with either treatment given alone [38]. Gently keeping the infant's limbs flexed activates proprioceptive, tactile, and thermal systems; facilitates self-soothing behaviors (eg, hand-to-mouth movement, non-nutritive sucking) and is developmentally supportive. This can be achieved manually (facilitated tucking) or by swaddling in a blanket.

Of note, tight swaddling has been associated with an increased risk of developmental dysplasia of the hip. (See "Developmental dysplasia of the hip: Epidemiology and pathogenesis", section on 'Swaddling'.)

●Skin-to-skin contact (kangaroo care) – Skin-to-skin contact, which includes kangaroo care (with infant resting between the mother's breasts) stimulates ventral tactile and proprioceptive systems and reduces neonatal pain responses [39-43]. A systematic review reported that skin-to-skin contact was effective and safe in reducing neonatal pain due to a single painful procedure (eg, heelstick or venipuncture) [44].

●Sensorial saturation – Sensorial saturation results from multi-modal sensory inputs (eg, touch, massage, taste, voice, and smell) during a painful procedure. Several reports have shown pain reduction in infants who received a combination of sensorial saturation (eg, radiant warmth or exposure to familiar scent) and oral sucrose during painful procedures compared with oral sucrose alone [16,45-48]. However, this approach is labor-intensive, and it is difficult to define the proper amount of stimulation (too much stimulation can cause distress and sensitize the infant to pain, too little stimulation may not be effective); this fine line changes across gestational ages.

●Music – Music reduces pain responses and increases physiological stability during neonatal pain, although a systematic review found that the interventions and their therapeutic effects were inconsistent [49]. A subsequent randomized, controlled, blinded crossover clinical trial in neonates >32 weeks gestation found that PIPP pain scores were significantly reduced at all time points when music was combined with sucrose compared with groups given music or sucrose alone, but there were no differences in scores between the music and sucrose groups [50].

●Massage – Massage therapy has been shown in multiple randomized trials and systematic reviews to have therapeutic effects for acute neonatal pain (eg, heel lance, venipuncture) among term and preterm neonates [51-56]. Another study reported the feasibility, safety, and beneficial effects of teaching parents/caregivers to use massage for their infants in the neonatal intensive care unit (NICU) [57].

●Unproven measures – The following modalities should not be used for routine treatment of acute pain in neonates due to inconsistent trial results [58-63].

•Therapeutic touch

•Warming

•Osteopathic manipulation

•Medical acupuncture

SIMPLE PROCEDURES ASSOCIATED WITH MILD PAIN

Example procedures — Examples of such procedures include (table 1):

●Heelstick

●Finger stick

●Venipuncture

●Intramuscular or subcutaneous injection

●Venous catheterization

●Nasogastric tube insertion

●Bladder catheterization

●Dressing change

●Tape removal

●Removal of intravenous catheter

●Bladder compression

●Tracheal extubation

Appropriate measures — For neonates undergoing brief painful procedures, we use oral sucrose or glucose in combination with nonpharmacologic measures (table 1). We do not use acetaminophen for these procedures. (See 'Non-drug measures (for most procedures)' above and 'Oral sucrose or glucose' below.)

Oral sucrose or glucose

Dosing and administration — Oral sucrose and other sweet-tasting liquids, such as glucose or dextrose, are effective analgesics in both term and preterm infants [22,38,64-66].

At our institution, we use a 24 percent sucrose solution in combination with nonpharmacologic measures to reduce acute, episodic pain for procedures [65,67]. We administer oral sucrose one to two minutes before a painful procedure, and repeat the dose as needed for pain relief. It can be administered orally via a syringe or onto the tongue by allowing the infant to suck on a pacifier that has been previously dipped in a sucrose solution. For intubated infants, we place sucrose directly on the infant's tongue.

We repeat sucrose doses during a painful procedure, rather than after the procedure, as our clinical experience suggests that additional doses given during the procedure are beneficial. The evidence also supports the administration of repeated dosing during a painful procedure [68,69], despite one study that found no difference in pain perception between infants who received one dose two minutes before a heelstick and those who received a dose before and after the procedure [70]. We also monitor for changes in vital signs as well as any clinical signs of choking or gagging. In addition, we prescribe and track sucrose as a medication [4].

The optimal dose for oral sucrose has not been established. Dosing ranges from 0.012 to 0.12 g (0.05 to 0.5 mL of a 24 percent sucrose solution) [4,65,68,71,72].

We use a 24 percent sucrose solution with weight-based dosing as follows:

●≤1,000 g: 0.05 to 0.1 mL (one to two drops)

●>1,000 to 1,500 g: 0.15 to 0.2 mL (three to four drops)

●>1,500 to 2,000 g: 0.25 to 0.35 mL (five to seven drops)

●>2000 g: 0.4 to 0.5 mL (8 to 10 drops)

Multiple studies and reviews recommend an interval of two minutes after sucrose therapy before performing the procedure, although one randomized trial found that there is no need to wait after sucrose administration [73,74].

Adverse effects appear to be negligible. A systematic review of the efficacy and safety of repeated sucrose use for procedural pain in neonates found limited evidence for the long-term effects of sucrose on subsequent neurodevelopment and recommended additional studies [75]. One study reported adverse neurodevelopmental effects in preterm infants less than 32 weeks gestation who received more than 10 doses over a 24-hour time period [72,76]. However, this observation has been questioned, and there has not been subsequent supportive evidence confirming this finding [77].

Efficacy — The efficacy of sweet-tasting liquids (most commonly sucrose) as analgesics has been illustrated in systematic reviews of randomized controlled trials that included infants with gestational ages (GA) from 25 to 42 weeks [65-67]. A meta-analysis of premature neonates undergoing skin-breaking procedures (eg, heelstick or venipuncture) found that 24 percent sucrose decreased the premature infant pain profile (PIPP) score by one to three points out of 21 [65]. In addition, use of sucrose or glucose was associated with the following findings:

●Reduced total crying time

●Dampened physiologic responses for heart rate, oxygen saturation, or increased vagal tone

●Reduced facial expressions specific for pain

●Lower pain assessment scores (see "Assessment of neonatal pain", section on 'Choice of assessment tools')

Proposed mode of action — The mode of action for sucrose remains unclear, as the available results are contradictory. One study showed no changes in plasma beta-endorphin levels with sucrose analgesia, while another study demonstrated that intravenous (IV) naloxone appeared to potentiate the analgesic effects of sucrose [78,79].

It also remains unclear whether sucrose suppresses the neurophysiologic responses to pain and whether electroencephalographic (EEG) and electromyographic (EMG) responses are relevant for the study of neonatal pain.

●In a randomized trial of 59 term infants, sucrose therapy reduced pain scores (using the PIPP) following a heelstick, but no differences were noted in brain or spinal cord activity using brief EEG and EMG recordings [80]. However, there were many limitations to the study, and these data were obtained from healthy term neonates and therefore may not apply to preterm neonates [81-85]. The clinical applicability of these findings remains questionable [86].

●In contrast, sucrose suppressed right frontal lobe EEG changes occurring after heelsticks, reducing the patterns that typify negative affect, as compared with control infants who received water [87].

SIMPLE PROCEDURES ASSOCIATED WITH MODERATE PAIN

Example procedures — Examples of such procedures include (table 1):

●Arterial puncture

●Arterial or venous line placement

●Lumbar puncture

●Retinopathy of prematurity (ROP) assessment

●Obtaining intraosseous access

●Umbilical catheterization

Appropriate measures — For neonates undergoing procedures associated with moderate pain, we use a topical anesthetic (eg, eutectic mixture of local anesthetics [EMLA]) in addition to oral sucrose and nonpharmacologic measures (table 1). If the neonate does not achieve adequate analgesia from these measures, a low dose of a short-acting opioid (eg, fentanyl) may be required. (See 'Non-drug measures (for most procedures)' above and 'Oral sucrose or glucose' above and 'Topical anesthetics' below and 'Intermittent fentanyl and sufentanil' below.)

Topical anesthetics — Accumulating data suggest that topical anesthetics are safe and effective for reducing procedural pain in neonates [88]. The use of topical anesthetics in neonates is discussed here. Use in older children is reviewed in greater detail separately (see "Clinical use of topical anesthetics in children"):

The following topical anesthetics are appropriate for use in neonates:

●Lidocaine-prilocaine mixture (EMLA)

●4% tetracaine, also known as amethocaine, in a cream or gel base

At our institution, we use EMLA in addition to the administration of oral sucrose to reduce pain associated with venous, arterial, or lumbar punctures, and peripheral venous or arterial catheter insertion. In contrast, neither EMLA nor tetracaine gel is effective in reducing pain from heelsticks [88,89].

Other countries may use tetracaine (amethocaine), which is less ideal due to rare potential side effects [90].

●EMLA – A lidocaine-prilocaine mixture often referred to as EMLA (eutectic mixture of local anesthetics) is the topical anesthetic of choice in our center. This mixture of 2.5% lidocaine and 2.5% prilocaine in a cream base is the most widely used preparation and the one most extensively studied. It produces anesthesia within 40 to 60 minutes of its application, and the effects last for one to two hours. The term "eutectic" refers to a mixture of substances with a lower melting point than any of the individual constituents alone.

●Tetracaine – 4% tetracaine in a cream or gel base is an alternative to EMLA. It produces anesthesia within 30 minutes of application, which lasts for four to six hours.

Evidence for the efficacy of EMLA and tetracaine for needlestick pain in neonates includes randomized trials and meta-analyses with mixed results [88,89,91-93]. In a meta-analysis evaluating both agents in newborns, there were both positive and negative studies [88]. The investigators concluded that there were insufficient data to make recommendations. A subsequent meta-analysis, which included infants up to three months old and only evaluated EMLA, found little to no benefit [92].

MORE COMPLEX PROCEDURES

Example procedures — More complex procedures are those that not only cause significant pain, but also require that the neonate remain as still as possible. Examples of such procedures include (table 1):

●Central line placement

●Peripheral insertion of central catheter (PICC line placement)

●Chest tube placement

●Circumcision

●Suprapubic bladder aspiration

●Tracheal intubation

Appropriate measures — For neonates undergoing more complex procedures (ie, PICC placement, chest tube insertion), we use local anesthesia plus a short-acting opioid (eg, fentanyl, sufentanil) in addition to acetaminophen and nonpharmacologic measures (table 1). For neonates undergoing elective tracheal intubation, we prefer ketamine.

Our preference for this combination of measures is based upon physiologic principles rather than data. We prefer short-acting opioids rather than longer-acting opioids because these procedures generally do not take a lot of time, and we add a local anesthetic to minimize opioid use. In our experience, this combination often allows for a successful procedure.

Local anesthesia — Lidocaine is injected locally to reduce the pain associated with venous or arterial puncture, percutaneous venous or arterial catheter placement, lumbar puncture (LP), and circumcision. Lidocaine infiltration is also used during surgical operations to reduce the postoperative hyperalgesia and the need for postoperative analgesia.

Lidocaine is usually administered as either a 0.5 mL/kg subcutaneous infiltration of a 1 percent (10 mg/mL) solution or 0.25 mL/kg infiltration of a 2 percent (20 mg/mL) solution to a maximum dose of 3 to 5 mg/kg. In neonates, the combination of lidocaine with epinephrine should be avoided to minimize the risk of tissue necrosis and tachyarrhythmias. Needle-free devices are available to inject lidocaine subcutaneously in infants younger than three months of age [94].

●Circumcision – For male neonatal circumcision, in addition to oral sucrose, pacifier, and facilitated tucking, a ring block or dorsal penile nerve block is used before the procedure and oral acetaminophen is administered immediately after the procedure. For circumcisions, 1 percent lidocaine is administered either as a dorsal penile nerve block or circumferential subcutaneous local anesthesia (ring block) as the most effective therapy to reduce circumcision pain [95]. Infants should also receive oral sucrose prior and during the circumcision, and acetaminophen for postprocedure pain.

Pain control for circumcision is reviewed in greater detail separately. (See "Neonatal circumcision: Techniques", section on 'Pain control'.)

Acetaminophen — Acetaminophen (paracetamol) is the only antipyretic available for use in neonates. It is also a weak analgesic, which if administered alone, is not effective enough to reduce acute severe pain [96-99]. However, it can be combined with opioids in the setting of postoperative pain to reduce the amount of opioids needed [100,101]. In our center, it is also used alone for mild to moderate inflammatory pain (eg, enteropathy or necrotizing enterocolitis, skin wounds, bedsores, or nasal trauma due to nasal ventilation) or limb pain (eg, limb bruises, clavicle fracturs, or cephalohematoma or caput succedaneum following birth trauma).

Formulation and dosing — In infants, oral, rectal, and intravenous (IV) formulations of acetaminophen are available [102-105].

●Total daily dose – Recommended total daily doses are based on gestational age (GA) and postnatal age [106]:

•24 to 30 weeks GA – 20 to 30 mg/kg/day

•31 to 36 weeks GA – 35 to 50 mg/kg/day

•37 to 42 weeks GA – 50 to 60 mg/kg/day

•1 to 3 months postnatal age– 60 to 75 mg/kg/day

●Oral acetaminophen – We give oral doses based on GA:

•<32 weeks gestation – 15 mg/kg/dose every 12 hours

•32 to 36 weeks gestation – 15 mg/kg/dose every eight hours

•Term infants – 15 mg/kg/dose every six hours

These doses and dosing intervals were primarily based upon antipyretic dose-response studies. In both preterm and term infants, the clearance of acetaminophen is slower than in older children, so repeat dosing is required less frequently [102,107,108].

●IV acetaminophen – Data are limited for IV dosing of acetaminophen in neonates [109]. We use the following dosing schedule for IV acetaminophen for infants with postmenstrual age (PMA) between 32 and 44 weeks:

•Loading dose of 20 mg/kg

•Maintenance doses of 10 mg/kg starting six hours after the loading dose, and every six hours thereafter

For neonates with PMA between 28 to 31 weeks, the dosing interval for maintenance doses is increased to 12 hours [110].

●Rectal acetaminophen – Rectal acetaminophen showed minimal opioid-sparing effects on postoperative pain in neonates and infants, possibly due to inadequate rectal absorption or inadequate dosing. The optimal dose for rectal acetaminophen is not known and we do not use it at our center. Despite this, it is occasionally used as adjunctive analgesia in neonates who cannot receive oral therapy [111,112].

Combination with opioid therapy — Data suggest that IV acetaminophen may be useful in combination with other analgesic agents to reduce the overall amount of administered opioid [112-115]. (See 'Efforts to reduce opioid doses' below.)

●In an opioid-sparing randomized trial design, use of IV acetaminophen reduced the cumulative morphine dose following noncardiac thoracic or abdominal surgery [113]. On average, postoperative morphine requirements were reduced by 66 percent in infants, with no differences in their postoperative pain scores or adverse effects [113,116].

●Opioid-sparing effects were also observed in a retrospective cohort study on postoperative morphine consumption in very preterm infants (GA <32 weeks) before and after introduction of IV acetaminophen [114].

Adverse effects — Adverse effects of acetaminophen are rare in infants, but caution should be used in infants with malnutrition and hypoalbuminemia [116]. In contrast to its use in older children and adults, acetaminophen rarely causes hepatic or renal toxicity in neonates [117,118]. In addition, IV administration of acetaminophen does not increase the risk of hypothermia in neonates [119].

Among neonates who received IV acetaminophen during neonatal intensive care unit (NICU) care, a follow-up study at five years of age reported no increase in the likelihood of childhood disorders, including asthma, atopic dermatitis, inflammatory bowel disease, autism, speech disorders, or cerebral palsy [120].

No role for nonsteroidal anti-inflammatory drugs — Nonsteroidal anti-inflammatory drugs are not routinely used for neonatal analgesia because effective and safer agents are available. Adverse effects include gastrointestinal bleeding, platelet dysfunction, and decreased glomerular filtration rate in preterm neonates, as well as increased postoperative bleeding risk in preterm neonates and term neonates less than 21 days of life [121,122].

Intermittent opioids — Opioids are the most effective therapy for moderate to severe pain in patients of all ages. However, because of the multiple adverse effects, particularly respiratory depression, we reserve opioid therapy for ventilated neonates who are undergoing invasive procedures such as central line placement, or for postoperative analgesia. In most situations, we use intermittently-dosed opioids, rather than continuous IV infusions. This approach is in accordance with the American Academy of Pediatrics (AAP) and the Canadian Pediatric Society (CPS) guidelines on pain in neonates [4]. (See 'Continuous opioids' below.)

Opioids provide both analgesia and sedation, have a wide therapeutic window, and attenuate physiologic stress responses. However, the benefits of opioid therapy need to be balanced by the significant adverse effects, including respiratory depression, hypotension, urinary retention, and reduced gut motility [123,124].

Morphine and fentanyl are the most commonly used opioids in neonates [125]. Morphine or fentanyl may be useful as a single analgesic agent in ventilated neonates following surgery or birth asphyxia, or in those requiring moderately invasive procedures such as central venous catheterization, tracheal intubation, or chest tube placement. More potent (eg, sufentanil), shorter-acting (eg, alfentanil, remifentanil), or mixed opioids (eg, tramadol) are also being used with increasing frequency [125,126]. The use of opioid therapy is dependent on the clinical setting, as discussed in this section. (See 'Opioid use in specific situations' below.)

Efforts to reduce opioid doses — The concomitant use of acetaminophen with opioids may allow for lower doses of opioid therapy, which may decrease the risk of adverse opioid effects. Protocols using regular pain assessment, pharmacokinetic models for morphine dosing, and nursing-driven comfort care standards can reduce opioid dosing and decrease the incidence of morphine side effects [113,127,128]. Parent/caregiver/nurse-controlled analgesia can also reduce opioid dosing compared with continuous opioid infusions [129]. In the future, pharmacogenetic data may be incorporated into personalized morphine dosing for individual patients to further improve safety and efficacy [130]. (See 'Combination with opioid therapy' above.)

Intermittent morphine — We use intermittently dosed morphine as a single analgesic agent in ventilated neonates who are undergoing a painful and invasive procedure or after major surgery. We avoid using intermittent morphine in nonventilated infants due to the risk of respiratory depression [123]. We use continuous morphine infusion if necessary in nonventilated infants in situations previously described. (See 'Efforts to reduce opioid doses' above.)

Dosing and administration — We give morphine IV at the following doses based on GA, as follows:

●Very preterm infants (<32 weeks GA):

•Intermittent dosing – 5 micrograms (mcg)/kg per dose every four to eight hours, as needed based on pain assessment

●Later preterm and term infants (≥32 weeks GA):

•Intermittent dosing – 10 mcg/kg per dose every four to eight hours, as needed based on pain assessment

We start at the minimum dose possible based on repeated pain assessment and increase the dose if needed.

Side effects — In preterm and term neonates, morphine analgesia is associated with significant side effects, including respiratory depression, hypotension, delayed feeding, or urinary retention [123]. It remains unclear whether morphine may alter long-term outcomes in children who received morphine as neonates [131-133].

Intermittent fentanyl and sufentanil — In neonates, fentanyl is used in preference to other agents because of its ability to provide rapid analgesia with minimal hemodynamic effects. We reserve the use of fentanyl or a derivative (sufentanil) when a rapidly acting opioid is required for analgesia in a controlled setting (eg, elective intubation) that can adequately address any associated potential side effects (eg, bradycardia, chest wall rigidity). Other indications include fentanyl analgesia for postoperative pain (particularly following cardiac surgery), or for patients with pulmonary hypertension (primary, or secondary to meconium aspiration, diaphragmatic hernia, or congenital heart disease [CHD]). (See 'Continuous fentanyl and sufentanil' below.)

Dosing and administration — At our institution, we give intermittent fentanyl and sufentanil via slow IV push every two to four hours as needed based on pain assessment. Dosing is based on GA, as follows:

●Intermittent fentanyl:

•<28 weeks GA – 1-2 mcg/kg per dose

•28 to 32 weeks GA – 2-3 mcg/kg per dose

•>32 weeks GA – 3-4 mcg/kg per dose

●Intermittent sufentanil:

•<28 weeks GA – 0.1 – 0.2 mcg/kg per dose

•≥28 weeks GA – 0.2 – 0.3 mcg/kg per dose

We wait one to three minutes after administration of intermittent fentanyl or sufentanil prior to starting a procedure.

A multicenter trial of mechanically ventilated preterm infants (GA ≤32 weeks, n = 131) reported lower pain scores for both ongoing pain and episodic pain in the group that was randomly selected to receive fentanyl compared with those who received placebo [134]. Randomized controlled trials with smaller sample size have reported lower stress hormone levels (eg, catecholamines and glucocorticoids), fewer episodes of hypoxia, and lower behavioral stress scores in ventilated infants treated with fentanyl compared with controls, but there were no differences in short-term outcomes between the fentanyl- and placebo-treated groups [135-137].

Side effects — In preterm and term neonates, fentanyl has been associated with respiratory depression and delayed meconium passage. In a trial of ventilated preterm infants receiving fentanyl versus placebo, respiratory depression with prolongation of the initial ventilation course was longer in the fentanyl group versus controls (152 versus 110 hours), resulting in more infants assigned to fentanyl remaining on the ventilator at one week after birth (42 versus 25 percent) [134]. However, there was no difference in the duration of mechanical ventilation between the two groups (10 versus 7 days). Infants receiving fentanyl also had delayed meconium passage (55 versus 41.5 hours).

Fentanyl compared with other opioids — Compared with morphine, fentanyl analgesia is associated with less sedation or hypotension and reduced effects on gastrointestinal motility or urinary retention, but greater opioid tolerance and withdrawal [138-141].

●In one randomized trial comparing infusions of fentanyl (1.5 mcg/kg per hour) versus morphine (20 mcg/kg per hour) in ventilated neonates, similar pain scores, catecholamine responses, and vital signs were reported in the two groups. There were no adverse respiratory effects or difficulties in weaning from ventilation in either group, but lower beta-endorphin levels and decreased incidence of gastrointestinal dysmotility occurred in the fentanyl group [138].

●Another retrospective study comparing fentanyl and morphine for retinopathy of prematurity (ROP) therapy found that worsening ventilation status, temperature instability (outside the 36.5 to 37.4°C range), apneic and bradycardic events occurred more commonly in the morphine group [142].

Opioid use in specific situations — Opioids are used for procedural pain control, although data are conflicting regarding efficacy [131,143-145]. We do not use opioids or opioid derivatives (ie, fentanyl or sufentanil) for routine procedural pain. We generally only use fentanyl or sufentanil for invasive procedures (ie, chest tube insertion) or for comfort measures at the end of life.

Opioids are effective for the following situations:

●Elective tracheal intubation – Although we prefer ketamine for elective tracheal intubation (see 'Ketamine' below), fentanyl or its shorter-acting derivatives (eg, sufentanil, remifentanil) are often used for achieving analgesia prior to tracheal intubation in preterm and term newborns [146-149].

A randomized controlled trial in 20 preterm newborns found that the overall intubating conditions were significantly improved in those receiving remifentanil rather than morphine prior to endotracheal intubation. There were no complications observed following either intravenous morphine or remifentanil use [146]. A larger non-inferiority trial of 71 neonates requiring elective or semi-elective intubation showed similar intubation outcomes in the group assigned to remifentanil versus those assigned to a combination of morphine plus midazolam [150].

●Ventilated term neonates – For neonates receiving ongoing mechanical ventilation, we use intermittent doses of an opioid (eg, morphine, fentanyl, sufentanil) in addition to acetaminophen and nonpharmacologic measures. Most neonates are adequately managed with these measures. However, neonates with poorly controlled pain or severe agitation may require continuous opioid infusion and/or the addition of a sedative agent (eg, midazolam or dexmedetomidine). (See 'Prolonged pain/discomfort' below.)

A meta-analysis of the use of opioids (morphine or fentanyl) in ventilated term and preterm neonates found reduced pain scores in the group of patients who received opioids compared with controls in the first 12 hours (mean difference [MD] -5.74 [95% CI -6.88 to -4.59]) and between 12 and 48 hours of life (MD -0.98, [95% CI -1.35 to -0.61]) [124]. Rates of mortality, duration of mechanical ventilation, and neurodevelopmental outcomes evaluated at 18 to 24 months were similar between the two groups. Rates of secondary outcomes (eg, necrotizing enterocolitis, bronchopulmonary dysplasia, intraventricular hemorrhage (IVH), periventricular leukomalacia (PVL), and hypotension requiring medical intervention) were also similar for both groups. Patients in the morphine group took longer to reach full enteral feeds, especially very preterm infants [151]. There was, however, significant variability of study design resulting in differences in the quality of the included studies.

●Central line placement – In one study, ventilated preterm neonates who required central venous line placement were randomly assigned topical anesthesia alone (tetracaine), morphine alone, both tetracaine and morphine, or no treatment [144]. Morphine alone and morphine plus tetracaine groups had lower pain scores than the no treatment or tetracaine alone groups. However, patients who received morphine required increased ventilatory support within the first 12 hours following the procedure.

●Comfort measures at the end of life – Opioids are the most commonly used sedatives at the end of life [152]. In a retrospective study of almost 20,000 infants, 31 percent received sedative and/or analgesic medications on the day of death. Of these, 87 percent received opioids, whereas 50 percent received a benzodiazepine drug [152]. Intranasal fentanyl is an alternative approach for dying infants who do not have intravenous access [153].

Opioids may be effective for the following situations:

●Ventilated preterm neonates – Data are mixed on whether routine continuous morphine infusions in ventilated preterm infants provide clinical benefits compared with placebo [154-156]. We do not recommend the routine use of continuous infusions of opioids in ventilated preterm neonates. Moreover, extreme caution must be exercised if using opioid therapy in ventilated preterm neonates born at 23 to 26 weeks gestation or in those with pre-existing hypotension at baseline because of the increased risk for associated adverse events [157,158].

A multicenter, blinded prospective trial (the NEOPAIN trial) evaluated the outcomes of 898 ventilated very preterm infants (GA ≤32 weeks) who were randomly assigned to continuous infusion of morphine or placebo [131,157,159]. Neonates in the morphine group had lower pain scores (as assessed by the premature infant pain profile [PIPP]) and smaller increases in heart rate and respiratory rate. Rates of mortality, severe IVH, PVL, and gastrointestinal complications were similar between the two groups. However, infants treated with morphine were more likely to develop hypotension, required longer duration of mechanical ventilation, and took longer to tolerate full-volume nasogastric feeds.

An observational study of very preterm neonates during their initial episode of mechanical ventilation found that treatment with continuous opioid and/or midazolam infusions was associated with improved survival with similar rates of moderate or severe sensorimotor impairments at age two years [160].

●Retinopathy of prematurity screening – Randomized trials show minimal or no effects of topical anesthetic (proparacaine) [161,162], oral sucrose or glucose [163], or comfort care [164] in reducing the pain and distress associated with ROP screening. One trial suggested that intranasal fentanyl was more effective than intranasal saline in reducing pain associated with ROP screening [165]. However, further studies are needed to confirm this finding. Therefore, we recommend deep sedation with short-acting drugs like ketamine and remifentanil, or low-dose fentanyl infusion for this procedure [166,167]. The management of newborns requiring ROP screening and laser surgery is still evolving. (See "Retinopathy of prematurity: Pathogenesis, epidemiology, classification, and screening", section on 'Screening'.)

●Birth asphyxia – Opioid analgesia is often used to treat pain and stress in term neonates following birth asphyxia, although data are limited. At our institution, we use morphine at a loading dose of 10 mcg/kg for ventilated newborns followed by continuous infusion of 5-10 mcg/kg per hour. We do not use a loading dose for nonventilated newborns. However, some patients might need a higher dose to achieve the desired effect. This dose is supported by a pharmacokinetics study of morphine in 244 term and near-term encephalopathic neonates with therapeutic hypothermia [168]. Reduced morphine clearance was reported in newborn infants with hypoxic ischemic encephalopathy and treated with therapeutic hypothermia [168,169].

Potential benefits of opioid analgesia following birth hypoxia were illustrated in an observational study of 52 term infants with hypoxic-ischemic insults at birth who underwent magnetic resonance imaging (MRI) within two weeks after birth and neurological testing at one to two years of age [170]. Thirty three percent of these infants received opioids (morphine or fentanyl) in the first week of NICU care. MRI demonstrated less brain injury in infants who were treated with opioids than in those who did not receive opioid therapy. Opioid-treated infants also had higher scores in their neuromotor function and in the Pediatric Cerebral Performance Category (PCPC) scales.

Opioids are not effective for the following situations:

●Heelstick – In a study of preterm neonates who were undergoing heelstick, neonates were randomly assigned to continuous morphine infusion or placebo therapy [145]. Responses to pain using assessment tools based upon behavioral and physiologic indicators demonstrated no difference in pain scores between the two groups.

●Tracheal suctioning – A trial of ventilated preterm neonates assigned to either morphine or placebo therapy found no difference in the responses to tracheal suctioning between the two groups using multiple methods for pain assessment [143]. A detailed analysis of morphine pharmacodynamics in ventilated preterm neonates also found no relationship between measured plasma morphine levels and the responses to tracheal suctioning [171].

Ketamine — Ketamine, an N-methyl-D-aspartate receptor antagonist, was introduced as a "dissociative anesthetic," but is widely used for procedural, operative, or postoperative analgesia and sedation in neonates and small infants. Ketamine is the only analgesic that produces intense sedation and amnesia, while maintaining respiratory drive, producing bronchodilation, and improving hemodynamic function with mild increases in heart rate and blood pressure [172]. Thus, it is a reasonable alternative to opioids for procedural sedation, particularly in neonates with hemodynamic instability.

At our institution, we use ketamine as a single agent given intravenously at a dose of 1 to 2 mg/kg per dose for neonates for the following clinical situations:

●Tracheal intubation

●Central line placement

We also use ketamine for procedural sedation in neonates with hemodynamic instability due to the following conditions:

●Pulmonary hypertension (primary, or secondary to meconium aspiration, congenital diaphragmatic hernia, or congenital heart disease [CHD])

●Congenital diaphragmatic hernia

In preterm neonates undergoing central venous catheterization, no significant hemodynamic changes were associated with use of ketamine during the procedure [173]. High doses of 2 mg/kg of ketamine were associated with reduced heart rate, and even higher doses of 5 mg/kg reduced blood pressure without impairing cardiac output [173,174].

In a pilot observational study of 57 preterm infants requiring intubation for delivery room resuscitation, neonates who received ketamine (1 mg/kg with an additional dose of 1 mg/kg if required) in combination with atropine had lower pain scores and were less likely to develop vagal bradycardia during intubation compared with neonates who received no analgesia [175]. In addition, the ketamine group was less likely to receive vasopressor support during the NICU stay compared with the no analgesia group (8 versus 33 percent). However, these pilot data are not sufficient to change clinical management of neonates in the delivery room.

Further research is needed to establish the safety and efficacy of ketamine analgesia/sedation for ventilated neonates or for other clinical indications.

PROLONGED PAIN/DISCOMFORT

Example situations — Examples of such situations include (table 1):

●Mechanical ventilation

●Chest tube in place

●Arterial or central venous line in place

●Meningitis

●Necrotizing enterocolitis

Appropriate measures — For neonates in situations that cause prolonged pain or discomfort (ie, receiving ongoing mechanical ventilation) (table 1), we use intermittent, as-needed doses of an opioid (eg, morphine, fentanyl, sufentanil) rather than a continuous opioid infusion or a combined opioid/benzodiazepine regimen. Opioid therapy is used in addition to acetaminophen and nonpharmacologic measures. Most neonates are adequately managed with these measures. However, neonates with poorly controlled pain or severe agitation may require a continuous opioid infusion and/or the addition of a sedative agent (eg, midazolam or dexmedetomidine). (See 'Intermittent opioids' above and 'Sedatives' below.)

Our preference for this combination of measures is based largely on physiologic principles rather than data comparing this combination to other combinations or different measures. We prefer intermittent opioids to continuous opioids because we aim to minimize opioid use while providing adequate analgesia. Intermittent dosing also necessitates regular pain assessment for these neonates. We also use acetaminophen and, if necessary, sedatives to minimize opioid doses.

Continuous opioids — Although we use intermittently-dosed opioids rather than continuous intravenously (IV) infusions in most situations, short duration continuous IV infusions of opioids may be warranted for some neonates (eg, those with prolonged or chronic pain, and those who are post-operative). These neonates require regular pain assessment. If intermittent opioid dosing is not adequately controlling their pain, continuous opioid infusions should be used. Examples of such situations include neonates who are mechanically ventilated, have a chest tube in place, or who have a condition causing ongoing pain (ie, epidermolysis bullosa). These situations are discussed in more detail below. (See 'Opioid use in specific situations' above and 'Prolonged pain/discomfort' above and 'Chronic pain' below and 'Post-operative pain' below.)

Continuous morphine — We give continuous morphine IV at the following doses based on gestational age (GA), as follows:

●For very preterm infants (<32 weeks GA), 5 mcg/kg per hour

●For later preterm and term infants (≥32 weeks GA), 10 mcg/kg per hour

We start at the minimum dose possible based on repeated pain assessment and increase the dose if needed.

In ventilated term neonates, continuous morphine analgesia may cause an increased duration of ventilation. A retrospective study of 62 ventilated term newborns found that postoperative morphine infusion prolonged the need for mechanical ventilation, but was not associated with apnea, hypotension, or other complications [176]. In another study of 68 post-surgical term newborns, higher plasma morphine levels were associated with an increased need for mechanical ventilation beyond 24 hours after surgery [143].

Continuous fentanyl and sufentanil — For continuous fentanyl and sufentanil, we use the same starting dose for term and preterm infants:

●For continuous fentanyl, 0.5 – 1 mcg/kg per hour

●For continuous sufentanil, 0.05-0.1 mcg/kg per hour

We start at the minimum dose possible based on repeated pain assessment and increase the dose if needed.

Sedatives — Benzodiazepines, barbiturates, dexmedetomidine, and chloral hydrate provide sedation, anxiolysis, muscle relaxation, and amnesia. We do not routinely use sedatives in term and preterm neonates due to a lack of data regarding their safety and efficacy in this population. Moreover, these sedatives do not provide significant analgesia and may even mask the clinical signs of pain in some neonates. We do use sedatives such as midazolam and dexmedetomidine on a case-by-case basis to control severe agitation in neonates.

For severe agitation in mechanically ventilated newborns, low-dose continuous infusions of clonidine/dexmedetomidine or fentanyl/sufentanil may be justified, with the goal being to limit opioid exposure, convert to oral agents, and prevent tolerance. We do not routinely use continuous midazolam infusions for sedation of ventilated newborns except when required for agitation (eg, associated with patient-ventilator asynchrony) [160].

Midazolam — Midazolam is a short-acting benzodiazepine, but may cause prolonged sedative effects in sick preterm neonates. Based on the following data, we do not routinely use midazolam in term and preterm neonates. However, we do use continuous midazolam infusions for sedation of ventilated newborns when required for severe agitation (ie, with ventilator asynchrony uncontrolled by opioids [160]) or specific conditions (eg, neonatal pulmonary hypertension, congenital diaphragmatic hernia).

We use the following dosing for continuous midazolam. We start at the lowest dose and increase as necessary to control agitation.

●Continuous midazolam: 5 to 10 mcg/kg per hour intravenously

Data are mixed regarding the safety of midazolam in ventilated preterm neonates [160,177-180]. One trial of ventilated preterm neonates randomized to continuous infusions of midazolam, morphine, or placebo found an increase in poor neurologic outcomes among preterm neonates receiving midazolam [177]. However, an observational study of very preterm neonates during their initial episode of mechanical ventilation found that treatment with continuous opioid and/or midazolam infusions was associated with improved survival with similar rates of moderate or severe sensorimotor impairments at age two years [160].

Two trials of preterm neonates randomized to midazolam or placebo reported increased sedation with midazolam [178,179]. In addition, a randomized trial evaluating midazolam as premedication for endotracheal intubation was terminated early because of significant oxygen desaturations in treated versus control infants (86 versus 0 percent) [181].

Accumulating data in newborn animal models suggests that midazolam induces apoptosis and/or necrosis of neurons and other brain cells, independent of the benzodiazepine receptor, in the developing brain [182]. These data add to our concerns regarding the long-terms effects of using midazolam for sedation in term and preterm newborns in the neonatal intensive care unit (NICU).

Dexmedetomidine — Dexmedetomidine is a selective alpha-2 adrenergic receptor agonist that offers potent sedative and mild analgesic effects. Like ketamine, but unlike most other sedatives, it causes minimal respiratory depression. We use dexmedetomidine as a second-line treatment for agitation in infants who require prolonged mechanical ventilation and continuous opioids and/or sedatives (ie, neonates with persistent pulmonary hypertension of the newborn, congenital diaphragmatic hernia). Dexmedetomidine may also help to prevent withdrawal from opioids and facilitate extubation [183].

We use dexmedetomidine only as a continuous infusion at the following doses based on GA:

●For preterm infants (<37 weeks GA): Starting dose of 0.2 mcg/kg per hour

●For term infants (≥37 weeks GA): Starting dose of 0.4 mcg/kg per hour

●Doses can be increased at the same rate for preterm and term infants:

•Minimum 0.05 mcg/kg per hour

•Maximum 1.4 mcg/kg per hour

For severe agitation not controlled with nonpharmacologic approaches or sucrose, a low-dose continuous infusion of dexmedetomidine may be used.

Although used in adults, experience with use in neonates is limited. Research is being conducted on its dosing, pharmacokinetics, and efficacy in preterm and term infants [184]. A small multicenter dose-finding clinical trial studied preterm neonates (28 to 36 weeks gestation; n = 18) and term neonates (36 to 44 weeks gestation; n = 24). Within each age group, neonates were randomized to receive loading doses of 0.05, or 0.1, or 0.2 mcg/kg intravenously, followed by continuous infusions of 0.05, or 0.1, or 0.2 mcg/kg per hour respectively. Dexmedetomidine provided adequate sedation for most patients based on pain assessment scores. Four patients (10 percent) required more sedation with midazolam and 17 patients (40 percent) required more analgesia with fentanyl or morphine, or both drugs [184].

Clinicians using this drug should also note that plasma levels producing sedation (0.4 to 0.8 mcg/L) are lower than those producing analgesia (0.6 to 1.25 mcg/L) in older children [185-188]. In neonates, case reports of seizures [189] or bradycardia [190,191] associated with the use of dexmedetomidine raise concern.

CHRONIC PAIN

Example conditions — One example of such a condition is epidermolysis bullosa (table 1).

Appropriate measures — For neonates with chronic pain, we use intermittent opioids or opioid infusions (ie, morphine) (table 1). Methadone or ketamine can also be used to treat the hyperalgesia associated with persistent pain of this magnitude. Consultation with a neonatal pain service is often helpful for management of these patients [192,193]. (See 'Intermittent opioids' above and 'Ketamine' above.)

POST-OPERATIVE PAIN — For post-operative pain, management is tailored to the specific surgical procedure (table 1). In most cases, we use regularly scheduled acetaminophen since it may reduce the need for opioid therapy. At our institution, we use a combination of nonpharmacologic approaches and scheduled acetaminophen after surgery, and add intermittent opioids as needed. (See 'Non-drug measures (for most procedures)' above and 'Acetaminophen' above and 'Intermittent opioids' above.)

Observational studies and trials suggest that both intermittent bolus and continuous morphine administration are safe and effective in reducing postoperative pain in neonates [111,194-197]. A retrospective study of 62 ventilated term newborns found that postoperative morphine infusions prolonged the need for mechanical ventilation, but were not associated with apnea, hypotension, or other complications [176]. In another study of 68 post-surgical term newborns, higher plasma morphine levels were associated with an increased need for mechanical ventilation beyond 24 hours after surgery [143].

LONG-TERM OUTCOMES — Neonatal pain and stress may alter the regulation of cortisol secretion in preterm infants with elevated basal cortisol levels and dampened stress reactivity until at least 18 months of age [198,199]. In these infants, high cortisol levels during infancy may contribute to greater risks of impaired neurodevelopment and poorer attention, modulated to some extent by maternal mood and caregiving [199-201]. However, it remains uncertain whether prolonged use of neonatal sedative and/or analgesic drugs has clinical long-term neurological and behavioral sequelae [133,202-208]. Further follow-up studies are needed to determine if there are significant long-term effects of neonatal sedative and/or analgesic drugs.

SUMMARY AND RECOMMENDATIONS

●Approach – The objective for neonatal pain prevention and treatment is to find a good balance between analgesia and potential side effects. Analgesia begins with nonpharmacologic measures. Combinations of nonpharmacologic measures have additive or synergistic effects. Pharmacologic measures are added as needed depending on the degree of anticipated procedural pain (table 1). (See 'Approach' above.)

●Non-drug measures – Non-pharmacologic approaches can effectively reduce pain in both preterm and term neonates. Breastfeeding is an effective analgesic measure. Other effective measures include: non-nutritive sucking, swaddling or facilitated sucking, skin-to-skin contact, and sensorial saturation. (See 'Non-drug measures (for most procedures)' above.)

●Simple procedures associated with mild pain – For neonates undergoing brief painful procedures (table 1), we suggest oral sucrose or glucose in combination with nonpharmacologic measures rather than nonpharmacologic measures alone (Grade 2B). We use a weight-based dose and prescribe and track sucrose as a medication. (See 'Oral sucrose or glucose' above.)

●Simple procedures associated with moderate pain – For neonates undergoing procedures associated with moderate pain (table 1), we suggest a topical anesthetic in addition to oral sucrose and nonpharmacologic measures (Grade 2C). If the neonate does not achieve adequate analgesia from these measures, a low dose of a short-acting opioid (eg, fentanyl) may be required. (See 'Simple procedures associated with moderate pain' above.)

●More complex procedures – For neonates undergoing more complex procedures associated with moderate pain and/or which require the neonate to remain still (ie, peripheral insertion of central catheter [PICC] placement, chest tube insertion) (table 1), we suggest local anesthesia plus a short-acting opioid (eg, fentanyl, sufentanil) rather than other agents or combinations (Grade 2C). Ketamine is a reasonable alternative to an opioid, particularly in hemodynamically unstable neonates. These measures are used in addition to acetaminophen and nonpharmacologic measures. (See 'More complex procedures' above.)

•Sedation/analgesia for elective intubation – For neonates undergoing elective tracheal intubation (table 1), we suggest ketamine as a single agent rather than other agents or drug combinations (Grade 2C). (See 'Ketamine' above.)

●Prolonged pain/discomfort

•Sedation/analgesia for mechanical ventilation – For neonates receiving ongoing mechanical ventilation (table 1), we suggest intermittent as needed doses of an opioid (eg, morphine, fentanyl, sufentanil) rather than a continuous opioid infusion or a combined opioid/benzodiazepine regimen (Grade 2C). Opioid therapy is used in addition to acetaminophen and nonpharmacologic measures. Most neonates are adequately managed with these measures. However, neonates with poorly controlled pain or severe agitation may require a continuous opioid infusion and/or the addition of a sedative agent (eg, midazolam or dexmedetomidine). (See 'Intermittent opioids' above and 'Sedatives' above.)

•Other painful conditions – Acutely ill neonates who have conditions that are associated with moderate to severe pain (eg, necrotizing enterocolitis, meningitis, indwelling chest tube) (table 1) may require intermittent doses of an opioid (eg, morphine, fentanyl) in addition to acetaminophen, sucrose, and nonpharmacologic measures.

●Chronic pain – For neonates with conditions associated with chronic pain (ie, epidermolysis bullosa), management often involves use of long-acting opioids (eg, methadone) and other adjunctive therapies (table 1). Consultation with a neonatal pain service is often helpful for these patients. (See 'Chronic pain' above.)

●Post-operative pain – For post-operative pain (table 1), management is tailored to the specific surgical procedure. In most cases, we suggest regularly scheduled acetaminophen (Grade 2C) since it may reduce the need for opioid therapy. Nonpharmacologic measures should also be used to reduce pain. Intermittent doses of an opioid (eg, morphine, fentanyl, sufentanil) may be required depending on the specific surgical procedure. (See 'Post-operative pain' above.)

ACKNOWLEDGMENT — The UpToDate editorial staff acknowledges Kanwaljeet Anand, MBBS, DPhil, FAAP, FCCM, FRCPCH, who contributed to earlier versions of this topic review.