Management and prevention of pain in neonates

INTRODUCTION — Neonates, especially those cared for in the neonatal intensive care unit (NICU) setting, frequently experience painful procedures. Pain assessment and management is a routine part of neonatal care.

The management and prevention of pain in neonates will be reviewed here. Assessment of pain in neonates is discussed separately. (See "Assessment of pain in neonates".)

MISCONCEPTIONS ABOUT NEONATAL PAIN — Historically, treatment and prevention of pain in neonates have been underemphasized because of the following misconceptions:

●Neural pathways in neonates are unmyelinated or otherwise immature and cannot transmit painful stimuli to the brain.

●There is no alternative for verbal self-report, which remains the "gold standard" for conveying a subjective experience like pain.

●Pain perception is located only in the cortex, and thalamocortical connections must be fully developed in order to allow pain perception.

●The human infant does not have the psychological context necessary to identify experiences as painful; this ability does not develop until the age of two years or later.

●Analgesic or sedative drugs cannot be used in neonates because the risk of adverse effects is too high.

These misconceptions are not supported by scientific evidence. Instead, there is increasing evidence that neonates experience pain and stress, as discussed separately. (See "Assessment of pain in neonates", section on 'Neonatal responses to pain'.)

GOALS OF PAIN MANAGEMENT — Accumulating evidence suggests that repeated exposure to pain during the neonatal period, especially when undertreated, may have long-term adverse effects. These data are discussed separately. (See "Assessment of pain in neonates", section on 'Long-term effects of neonatal pain'.)

Management and prevention of pain in this vulnerable population is therefore a fundamental part of neonatal practice [1].

The goals of an effective pain management program are to:

●Anticipate and recognize pain in neonates (eg, using validated pain assessment tools (table 1)). (See "Assessment of pain in neonates", section on 'Pain assessment'.)

●Eliminate or minimize the neonate's exposure to unnecessary painful or stressful procedures and limit the duration of interventions that cause prolonged or continuous pain and stress.

●When painful procedures or interventions are necessary, ensure adequate analgesia while minimizing adverse side effects. Achieving an optimal balance between these two aims can be challenging and requires a team-based approach.

Healthcare facilities caring for neonates and young infants should establish standardized practices for pain assessment and management to ensure that neonates receive adequate pain control [1-3].

MULTIMODAL APPROACH — A multimodal approach to neonatal pain management includes:

●Nonpharmacologic measures (eg, skin-to-skin contact, breastfeeding, non-nutritive sucking, swaddling) (see 'Nonpharmacologic measures' below)

●Topical or local anesthetics (see 'Topical anesthetics' below and 'Local anesthesia' below)

●Systemic analgesic medications (see 'Acetaminophen' below and 'Opioids' below)

In some cases, nonpharmacologic measures alone may be sufficient. The need for specific analgesic drug therapy depends on the degree of anticipated procedural pain (when managing pain proactively) and/or the severity of pain demonstrated by the neonate (when managing pain reactively).

Multimodal approaches are generally more effective than a single intervention alone [4-7]. Combinations of nonpharmacologic measures (eg, skin-to-skin contact plus non-nutritive sucking) have additive or synergistic effects [5,7]. This can be further enhanced with the addition of oral sucrose. For example, for heel lance, the combination of oral sucrose plus skin-to-skin contact is usually sufficient. (See 'Oral sucrose and other sweet liquids' below and 'Nonpharmacologic measures' below.)

In many cases, combinations of nonpharmacologic interventions may eliminate or minimize the need for analgesic therapy thereby reducing the risk of associated side effects. (See 'Opioid-sparing strategies' below.)

PROCEDURAL ANALGESIA — The following sections outline the approach to providing analgesia and sedation for painful procedures in neonates. Details of specific pain management interventions are provided below. (See 'Specific interventions for pain management' below.)

Simple procedures

Mildly painful (heel lance, venipuncture, etc)

●Example procedures – Examples of minor simple procedures that are typically associated with mild pain include (table 2):

•Heel lance or finger stick

•Venipuncture or peripheral venous catheter insertion

•Intramuscular (IM) or subcutaneous injection

•Nasogastric (NG) tube insertion

•Bladder catheterization

•Dressing change/tape removal

●Appropriate measures — For neonates undergoing brief mildly painful minor procedures, we use oral sucrose in combination with nonpharmacologic measures (eg, skin-to-skin contact, non-nutritive sucking) (table 2). (See 'Nonpharmacologic measures' below and 'Oral sucrose and other sweet liquids' below.)

A topical anesthetic (eg, eutectic mixture of local anesthetics [EMLA]) can also be used for some procedures in this category (eg, intravenous [IV] catheter insertion, IM, or subcutaneous injection) but not others (eg, NG tube insertion, bladder catheterization, dressing change). EMLA is not routinely used for heel lance since it appears to be ineffective in this setting. (See 'Topical anesthetics' below.)

Moderately painful (lumbar puncture, arterial puncture, etc)

●Example procedures – Examples of minor procedures that are associated with moderate pain include (table 2):

•Lumbar puncture (LP)

•Peripheral arterial puncture or catheterization

•Umbilical venous or arterial catheterization

•Intraosseous (IO) cannulation

●Appropriate measures – For neonates undergoing minor procedures associated with moderate pain, we use nonpharmacologic measures, oral sucrose, plus a topical anesthetic (eg, EMLA) when appropriate (table 2). (See 'Nonpharmacologic measures' below and 'Oral sucrose and other sweet liquids' below and 'Topical anesthetics' below.)

In our experience, the combination of these measures usually permits successful completion of the procedure. Rarely, a low dose of a short-acting opioid (eg, fentanyl, sufentanil) may be required. Caution should be used when using opioids for these procedures in nonintubated patients given the risk of respiratory depression. (See 'Opioids' below.)

More complex procedures — More complex procedures are those that not only cause moderate pain, but also require that the neonate remain relatively still during the procedure.

Examples of such procedures include (table 2):

●Percutaneous central venous catheter (CVC) placement

●Placement of a peripherally inserted central catheter (PICC)

●Chest tube placement

This category also includes the following procedures, which are discussed in greater detail below:

●Circumcision (see 'Circumcision' below)

●Endotracheal intubation (see 'Endotracheal intubation' below)

●Retinopathy of prematurity (ROP) examination (see 'ROP screening examination' below)

General approach — For neonates undergoing more complex procedures (ie, CVC or PICC placement, chest tube insertion), we use multimodal analgesia, including all of the following (table 2):

●Nonpharmacologic measures (eg, non-nutritive sucking, facilitated tucking) (see 'Nonpharmacologic measures' below)

●Oral sucrose (see 'Oral sucrose and other sweet liquids' below)

●Topical and/or local anesthetic when appropriate (see 'Topical anesthetics' below and 'Local anesthesia' below)

●Acetaminophen (see 'Acetaminophen' below)

●A short-acting sedative or opioid agent (eg, ketamine, fentanyl, sufentanil), if needed (see 'Ketamine' below and 'Fentanyl' below and 'Sufentanil' below)

When opioids are used for these procedures, we prefer short-acting over longer-acting agents (ie, fentanyl or sufentanil rather than morphine) because these procedures are usually brief. The amount of opioid required can be reduced by using a local anesthetic and acetaminophen. In our experience, this combination often allows for a successful procedure. Opioids can cause respiratory depression in neonates, especially in preterm neonates, and these agents should be used with caution in nonintubated patients. (See 'Adverse effects' below.)

The efficacy and safety of opioids for procedural analgesia/sedation in neonates has been studied in randomized trials and meta-analyses [8,9]. In a meta-analysis of three trials (199 neonates) comparing opioids (morphine, fentanyl, or remifentanil) versus placebo, opioids reduced pain scores during the procedure by a mean 2.6 points on the premature infant pain profile (PIPP) score, which ranges from 0 to 21 points (table 3). Episodes of apnea occurred more often in the opioid group (10 versus 3 percent), but the analysis did not detect a significant difference in desaturation episodes (11 versus 6 percent). There were no episodes of hypotension in either group and only one episode of bradycardia (in a patient receiving morphine).

In a trial not included in the above meta-analysis, intubated preterm neonates undergoing CVC placement were randomly assigned to topical anesthesia alone, morphine alone, topical anesthesia plus morphine, or no specific analgesic therapy [8]. Patients treated with morphine (either alone or in combination with topical anesthesia) had lower pain scores compared with those in the topical anesthesia alone or no treatment groups. However, patients who received morphine more often required an increase in the ventilator rate for the first 12 hours following the procedure.

Specific procedures

Circumcision — Multimodal analgesia for neonatal circumcision includes oral sucrose, non-nutritive sucking, facilitated tucking, local anesthesia (eg, ring block or dorsal penile nerve block), and acetaminophen for postprocedure pain. Analgesia for neonatal circumcision is discussed in greater detail separately. (See "Neonatal circumcision: Techniques", section on 'Pain control'.)

ROP screening examination — For most neonates undergoing screening or follow-up ROP examination, we suggest the following measures [10]:

●Nonpharmacologic measures (eg, non-nutritive sucking, facilitated tucking) (see 'Nonpharmacologic measures' below)

●Oral sucrose (see 'Oral sucrose and other sweet liquids' below)

●Topical anesthetic (eg, proparacaine), depending on ophthalmologist preference [11]

Topical anesthesia (eg, proparacaine) reduces pain at speculum insertion, but this intervention alone may not provide sufficient analgesia for the procedure in some cases. In a meta-analysis of two trials (124 neonates), pretreatment with topical proparacaine reduced pain scores compared with no anesthesia, but a substantial subset of neonates in both groups had unacceptably high pain scores (29 versus 52 percent, respectively) [12].

For this reason, other adjunctive interventions (ie, oral sucrose and nonpharmacologic measures such as non-nutritive sucking and/or facilitated tucking) are used in addition to topical anesthesia to reduce pain during ROP examination [13-16]. (See 'Nonpharmacologic measures' below and 'Oral sucrose and other sweet liquids' below.)

Additional analgesia/sedation is required when ROP treatment is administered during the procedure (eg, laser therapy or intravitreal injection). We typically use a short-acting agent (eg, ketamine, fentanyl, sufentanil) for this purpose. (See 'Ketamine' below and 'Fentanyl' below and 'Sufentanil' below.)

In a small clinical trial, intranasal fentanyl reduced pain scores during ROP examination [17]; however, additional studies are needed before routinely adopting this approach.

Endotracheal intubation — Commonly used agents for neonates undergoing elective tracheal intubation include [18-20]:

●Ketamine (the preferred agent at the author's institution) (see 'Ketamine' below)

●Fentanyl or other short-acting opioid (eg, sufentanil, remifentanil) (see 'Fentanyl' below and 'Sufentanil' below)

Though propofol is used in some centers for endotracheal intubation in neonates, it is not used at the author's institution given the high incidence of adverse hemodynamic effects. (See 'Propofol' below.)

The combination of an opioid plus a benzodiazepine (eg, midazolam) is another alternative; however, this is associated with increased risk of adverse events and does not appear to improve the likelihood of successful intubation compared with an opioid alone [21,22]. (See 'Midazolam' below.)

In a multicenter observational study describing intubation premedication practices across 16 neonatal intensive care units (NICUs) in France, sedative/analgesic drugs were administered for approximately one-half of all neonatal intubations (including elective and emergency procedures) [20]. The most commonly used agents were propofol, sufentanil, and ketamine. Factors associated with receiving premedication included type of procedure (elective versus emergency; those undergoing elective intubation were five times more likely to receive sedation) and whether the NICU had a written protocol for procedural sedation.

In an observational study of 57 preterm infants requiring intubation in the delivery room, neonates who received ketamine (1 to 2 mg/kg) 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 [23]. In addition, the ketamine group was less likely to require vasopressor support during the NICU stay compared with the no analgesia group (8 versus 33 percent). However, given the observational nature of these data, causality cannot be inferred (in other words, it is unclear if administration of ketamine resulted in better hemodynamic stability or if the finding merely reflects that stable infants were more likely to be selected for ketamine sedation).

A randomized controlled trial involving 20 preterm newborns found that the intubating conditions were better in those receiving remifentanil compared with morphine; neither group experienced complications from the medication [18]. In a separate trial of 71 neonates undergoing elective or semi-elective intubation who were randomly assigned to remifentanil or morphine plus midazolam, both groups had similar success rates on first attempt (75 versus 69 percent, respectively) [21]. Pain scores were modestly lower in the morphine/midazolam group (0.5 versus 2 points on a 10-point pain scale).

POSTOPERATIVE PAIN — For postoperative pain, management is tailored to the specific surgical procedure. For most neonates undergoing major surgery, we use a multimodal approach to postoperative pain management including all of the following:

●Nonpharmacologic measures (eg, breastfeeding, skin-to-skin contact) (see 'Nonpharmacologic measures' below)

●Regularly scheduled acetaminophen, which reduces the need for opioid therapy (see 'Acetaminophen' below)

●Intermittent opioids as needed (see 'Opioids' below)

The available observational and clinical trial data suggest that intermittent opioid therapy is safe and effective for reducing postoperative pain in neonates and is equally effective when compared with continuous dosing [24-26]. Higher doses of opioids, particularly when administered via continuous infusion, carry an increased risk of adverse effects (eg, apnea, increased ventilator requirement, hypotension) [27]. (See 'Adverse effects' below.)

A more detailed discussion of postoperative pain management in infants and children is provided separately. (See "Approach to the management of acute perioperative pain in infants and children" and "Pharmacologic management of acute perioperative pain in infants and children".)

PROLONGED OR CHRONIC PAIN — Examples of conditions or circumstances that may cause prolonged pain and discomfort in neonates include:

●Indwelling chest tube

●Ongoing medical condition associated with moderate to severe pain (eg, necrotizing enterocolitis, bacterial meningitis)

●Mechanical ventilation (see 'Mechanical ventilation' below)

The distinction between the terms "prolonged" and "chronic" pain is not always clear. Despite ongoing efforts, consistent definitions for these terms in neonates have not been established [28-30]. We generally use the term "prolonged pain" when referring to pain that persists beyond a simple one-time procedure but that has a limited course (eg, pain associated with an indwelling chest tube or endotracheal tube); whereas we use "chronic pain" when referring to pain that is expected to last well beyond the neonatal period (eg, epidermolysis bullosa). (See "Overview of the management of epidermolysis bullosa", section on 'Pain and itch management'.)

General approach — For neonates with ongoing painful medical conditions and those who are receiving interventions that cause prolonged pain or discomfort, we use a multimodal approach to pain control that typically includes all of the following:

●Nonpharmacologic measures (eg, breastfeeding, skin-to-skin contact) (see 'Nonpharmacologic measures' below)

●Acetaminophen as needed (see 'Acetaminophen' below)

●Intermittent as-needed opioids (eg, morphine, fentanyl) (see 'Opioids' below)

Most neonates are adequately managed with these measures. However, neonates with poorly controlled pain may require a continuous opioid infusion. (See 'Opioids' below.)

We generally prefer intermittent rather than continuous dosing of opioids since intermittent dosing tends to result in a lower cumulative dose and lower risk of apnea and other adverse effects. Another advantage of intermittent dosing is that it necessitates regular pain assessments for these neonates. (See "Assessment of pain in neonates", section on 'Pain assessment'.)

Other agents that are sometimes used in the management of infants with chronic pain include methadone, ketamine, or gabapentin [31]. Consultation with a pain specialist is often helpful for management of these patients.

Specific scenarios

Mechanical ventilation

●Approach – For intubated neonates receiving ongoing invasive mechanical ventilation, we use a multimodal approach to pain and sedation management, including all of the following:

•Intermittent doses of an opioid (eg, morphine, fentanyl, sufentanil) (see 'Opioids' below)

•Acetaminophen as needed (see 'Acetaminophen' below)

•Nonpharmacologic measures (see 'Nonpharmacologic measures' below)

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 'Opioids' below and 'Midazolam' below and 'Dexmedetomidine' below.)

●Monitoring and titration – Opioid therapy for mechanical ventilation in neonates should be guided by routine pain/sedation assessments using a validated tool. In our practice, we use either the neonatal pain, agitation, and sedation scale (N-PASS) or COMFORTneo score for this purpose [32]. (See "Assessment of pain in neonates", section on 'Pain assessment tools'.)

Pain/sedation scores should be assessed and recorded every four to eight hours and after any intervention. A target level of sedation should be specified by the care team and opioid therapy should target the desired score. For example, a typical initial target for intubated neonates is light sedation (ie, a score of -2 to -5 on the N-PASS sedation score or a score of 11 to 13 if using COMFORTneo). However, the target sedation score should be individualized according to the infant's condition, phase of illness, and clinical stability. For stable neonates who are weaning from the ventilator, it is reasonable to target a comfortably awake state (ie, N-PASS score of -1 to +3). For neonates with significant clinical instability (eg, severe pulmonary hypertension) and/or ventilator dyssynchrony, it may be appropriate to target deeper sedation (eg, N-PASS score of -6 to -10). Use of an institutional pain and sedation protocol can help ensure that intubated patients receive adequate sedation and analgesia while minimizing adverse effects of opioid therapy [33,34].

●Intermittent or continuous dosing – In our practice, we generally use a stepwise approach to opioid dosing, beginning with intermittent as-needed doses and only escalating to a continuous infusion if the neonate has poorly controlled pain or agitation despite multiple intermittent doses.

Although data comparing the two approaches are scarce, we generally prefer intermittent rather than continuous opioid dosing, when possible, for the following reasons:

•Intermittent dosing tends to result in a lower cumulative dose and lower risk of hypotension and other adverse effects. (See 'Adverse effects' below.)

•Intermittent dosing necessitates regular pain/sedation assessments. (See "Assessment of pain in neonates", section on 'Pain assessment'.)

•For neonates requiring prolonged therapy, the risk of experiencing severe opioid withdrawal after discontinuing therapy is generally lower with intermittent dosing.

In a multicenter observational study that included 1589 intubated neonates receiving opioid analgesia for mechanical ventilation, 41 percent received both intermittent and continuous dosing, 34 percent received only continuous infusion, and 25 percent received only intermittent doses [35].

●Supporting evidence – The efficacy and safety of opioid analgesia for mechanical ventilation in neonates has been studied in clinical trials and meta-analyses [36-39]. In a meta-analysis of seven trials involving 1259 intubated neonates, the duration of mechanical ventilation was similar in patients managed with or without opioids [37]. In most trials, pain scores during the first 48 hours were lower in the opioid group, though one trial failed to detect a difference in pain scores during endotracheal suctioning. Infants in the opioid group took slightly longer to reach full enteral feeds (mean difference 1.7 days). The incidence of intraventricular hemorrhage was modestly lower in the opioid group (28 versus 34 percent), but the difference was not statistically significant (relative risk [RR] 0.84, 95% CI 0.65-1.09). Rates of other neonatal morbidities (necrotizing enterocolitis, bronchopulmonary dysplasia) were similar in both groups, as was the duration of hospitalization and 28-day mortality rate. Only two trials (n = 173) reported rates of long-term neurodevelopmental impairment, which were similar in both groups. The trials included in the meta-analysis varied considerably in the population studied (most trials enrolled only preterm neonates with various gestational age ranges; two trials enrolled preterm and term neonates), the opioid agent used (approximately half of the trials used morphine, the other half used fentanyl), dosing regimens (most trials used continuous dosing), and the outcomes assessed.

The safety of opioid analgesia for mechanical ventilation in neonates is also supported by observational studies [35,40]. In a multicenter observational study that included 2142 intubated neonates managed at >200 neonatal intensive care units (NICUs) in Europe, 74 percent of patients received opioid analgesia during their mechanical ventilation course [35]. The most common agents were morphine (used in 58 percent of cases), fentanyl (40 percent), and sufentanil (14 percent); some patients received more than one agent.

●Long-term effects – It remains uncertain whether prolonged exposure to analgesic and/or sedative medications in the neonatal period has any long-term impact on neurologic and behavioral outcomes. This issue is discussed separately. (See "Assessment of pain in neonates", section on 'Impact of analgesic and sedative therapy'.)

Hypoxic-ischemic encephalopathy — Opioid analgesia is often used to treat pain and stress in term newborns with hypoxic-ischemic encephalopathy (HIE) resulting from perinatal asphyxia. Most affected infants are managed with therapeutic hypothermia, as discussed separately. (See "Clinical features, diagnosis, and treatment of neonatal encephalopathy", section on 'Therapeutic hypothermia'.)

While data are limited, it is common practice to provide analgesia and sedation for neonates with HIE. The rationale is to reduce the discomfort and stress associated with therapeutic hypothermia and to compliment the general neuroprotective measures provided to these neonates.

At our institution, we use a continuous intravenous (IV) morphine infusion for most neonates with HIE. Other centers may use other agents (eg, fentanyl, dexmedetomidine) [41-43]. (See 'Morphine' below and 'Fentanyl' below and 'Dexmedetomidine' below.)

Newborns with HIE often have other end-organ damage, including acute kidney injury, which may result in reduced morphine clearance [44,45]. Care should be taken to titrate morphine to effect and avoid oversedation.

It is unclear if opioids or other sedating medications improve outcomes for neonates with HIE. Clinical trials are lacking and the available observational studies have reached different conclusions [46-50]. One study reported that neonates with HIE who received opioids had less severe findings on magnetic resonance imaging (MRI) and/or higher scores on neurodevelopmental testing compared with those who did not receive opioid therapy [47]. However, another study did not detect a difference in neurodevelopmental outcomes between those who did and did not receive preemptive opioid therapy [48]. A third study found that both inadequate and excessive sedation (as measured by clinical pain/sedation scores) during therapeutic hypothermia were associated with increased risk of adverse neurologic outcome at NICU discharge [49]. An ongoing clinical trial is evaluating opioid versus dexmedetomidine sedation/analgesia in neonates with HIE [51].

End of life care — Opioids are the most commonly used agents for providing comfort care at the end of life [52]. Benzodiazepines are also commonly used in this setting [52]. (See 'Opioids' below and 'Midazolam' below.)

In a retrospective study that analyzed data from nearly 20,000 neonates admitted to the NICU who died during the birth hospitalization, 31 percent received sedative and/or analgesic medications on the day of death [52]. Of these, 87 percent received opioids and 50 percent received benzodiazepines.

Palliative care in infants and children is discussed in greater detail separately. (See "Pediatric palliative care".)

SPECIFIC INTERVENTIONS FOR PAIN MANAGEMENT — The following sections describe some of interventions that are used for pain control in neonates. The approach to determining which interventions are appropriate in different clinical scenarios is described above. (See 'Procedural analgesia' above and 'Postoperative pain' above and 'Prolonged or chronic pain' above.)

Nonpharmacologic measures — The following nonpharmacologic approaches can effectively reduce pain and discomfort from routine care measures and minor procedures (eg, heel lance) in both preterm and term neonates [53].

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 [54]. 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. However, breastfeeding may not be possible in some situations (eg, an intubated preterm neonate undergoing a painful procedure) . (See 'Oral sucrose and other sweet liquids' below.)

The efficacy of breastfeeding for neonates undergoing painful procedures is supported by randomized trials and meta-analyses [54-56]. 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 [54]. Patients in the breastfeeding group had lower pain scores during the procedure. A separate systematic review found that breastfeeding was more effective for reducing pain scores in full-term or preterm infants than maternal holding, maternal skin-to-skin contact, topical anesthetics, oral sucrose, or music therapy, whereas expressed breast milk did not consistently reduce pain responses [56]. 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 [1,53]. Clinical trial have shown that infants offered pacifiers during painful stimuli have less intense pain responses (less crying , lower heart rate) compared with those who received no intervention or swaddling or rocking alone [53,57]. Infants who received pacifiers dipped in sucrose had greater pain relief compared with those who received a pacifier alone. (See 'Oral sucrose and other sweet liquids' 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 [53].

●Swaddling or facilitated tucking – In term and preterm infants, swaddling or facilitated tucking (defined as gently maintaining the arms and legs in a flexed position) is more effective than no intervention in reducing pain responses to invasive procedures (eg, endotracheal suctioning and heel stick) [53,58]. A multicenter randomized trial showed that facilitated tucking in combination with oral sucrose was more effective in relieving pain from repeated heel sticks compared with either intervention alone [59]. 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 should be avoided as this 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 [60-62]. A systematic review reported that skin-to-skin contact was effective and safe in reducing neonatal pain due to a single painful procedure (eg, heel lance or venipuncture) [63].

●Sensorial saturation – Sensorial saturation refers to providing multimodal sensory inputs (eg, touch, massage, voice, smell) during a painful procedure. Several studies have shown pain reduction in infants receiving sensorial saturation (eg, radiant warmth or exposure to familiar scent) plus oral sucrose during painful procedures compared with oral sucrose alone [4,64-66]. However, this approach is labor-intensive, and it can be challenging to define the right 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 [67]. A subsequent randomized, controlled, blinded crossover clinical trial in neonates >32 weeks gestation found that 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 [68].

●Massage – Several studies have shown that massage has therapeutic benefits for acute pain (eg, heel lance, venipuncture) in term and preterm neonates [69-74].

●Unproven measures – We suggest not routinely using the following modalities for treatment of acute pain in neonates since the available studies have not consistently demonstrated a benefit [75-80].

•Therapeutic touch

•Warming

•Osteopathic manipulation

•Medical acupuncture

Oral sucrose and other sweet liquids — Oral sucrose and other sweet-tasting liquids, such as glucose or dextrose, are effective analgesics in both term and preterm infants [81-83].

●Clinical uses – At our institution, we use oral sucrose solution in combination with nonpharmacologic measures (eg, skin-to-skin contact, non-nutritive sucking) to reduce minor acute episodic procedural pain (eg, venipuncture, intramuscular [IM] injection) [81,83]. Sucrose may also be combined with local anesthesia and/or opioid agents as part of multimodal analgesia for more painful, prolonged and/or invasive procedures (eg, lumbar puncture [LP], circumcision, chest tube insertion, percutaneous central venous catheter insertion, or intraosseous access) (table 2).

●Dosing and administration – We use a 24 percent sucrose solution with weight-based dosing as follows:

•≤1000 g: 0.05 to 0.1 mL (one to two drops)

•>1000 to 1500 g: 0.15 to 0.2 mL (three to four drops)

•>1500 to 2000 g: 0.25 to 0.35 mL (five to seven drops)

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

However, the optimal dose for oral sucrose has not been established and reported dosing regimens range from 0.05 to 1 mL of a 24 percent sucrose solution [1,81,84-86].

Sucrose 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 prescribe and track sucrose as a medication [1].

●Timing – We administer oral sucrose one to two minutes before a painful procedure, and repeat the dose as needed for pain relief. Multiple resources recommend an interval of two minutes after sucrose therapy before performing the procedure [87], although one randomized trial suggested that it may not be necessary to wait after sucrose administration [88].

●Repeat doses – If needed, we repeat sucrose doses during the procedure rather than waiting until after the procedure. In our experience, we have found that additional doses given during the procedure are beneficial [85,89], though one study found little difference in pain scores between infants who received one dose two minutes before a heel stick and those who received a dose before and after the procedure [90].

●Adverse effects – Short-term adverse effects appear to be negligible [91]. It is uncertain if there are any long-term adverse effects of repeated oral sucrose on neurodevelopment. A systematic review identified three trials that reported long-term neurodevelopmental outcomes for infants enrolled in trials of oral sucrose for neonatal procedural pain control [91]. Two trials found that repeated sucrose therapy was not associated with adverse neurodevelopmental outcome, while one trial involving preterm neonates <31 weeks gestation found that receiving >10 doses of oral sucrose per day during the first week of life was associated with increased risk of adverse neurodevelopmental outcome [86,91]. However, this observation has been questioned, and there has not been subsequent supportive evidence confirming this finding [92].

●Efficacy – The efficacy of sucrose and other sweet-tasting liquids for preventing and reducing pain in neonates has been demonstrated in randomized trials and meta-analyses including infants with gestational ages (GA) from 25 to 42 weeks [81-83]. In meta-analyses that included >100 clinical trials involving neonates undergoing painful procedures (eg, heel lance, venipuncture, intramuscular [IM] injection), oral sucrose reduced crying time and pain scores during and after the procedure [81,82]. For example, in a trial using the premature infant pain profile (PIPP) which ranges from 0 to 21 points (table 3), oral sucrose reduced the PIPP score on average by one to three points [93].

●Mode of action – The mode of action for sucrose remains unclear. It is thought that the analgesic effects of sucrose are mediated by endogenous opioid and endorphin pathways triggered by the sweet taste. However, data supporting this theory are scant [94,95].

Topical anesthetics — Topical anesthetics are safe and effective for reducing procedural pain in neonates [96].

●Clinical uses – Topical anesthetics are appropriate for use prior to minor dermal procedures (eg, venipuncture, IM injection, lumbar puncture [LP], circumcision) (table 2). (See 'Simple procedures' above.)

The use of topical anesthetics for neonatal circumcision is discussed in detail separately. (See "Neonatal circumcision: Techniques", section on 'Local topical anesthetics'.)

●Agents – Commonly used topical anesthetics include lidocaine-prilocaine (eg, EMLA [an acronym for "eutectic mixture of local anesthetics"]) and tetracaine (amethocaine) gel (eg, Ametop). EMLA is the topical anesthetic of choice in our center. It is the agent most widely used most extensively studied in neonates. Tetracaine gel is not available in the United States.

•Lidocaine-prilocaine cream (eg, EMLA) – EMLA is a mixture of 2.5% lidocaine and 2.5% prilocaine in a cream base. 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.

EMLA is administered by applying 0.5 to 1 g to the site one hour prior to the procedure and covering with an occlusive dressing [97,98]. The lower end of this dose range is appropriate for preterm neonates <37 weeks gestation. The maximum dose per 24-hour period should not exceed 1 g, and the application time should not exceed one hour.

•Tetracaine (amethocaine) gel – A 4% tetracaine (amethocaine) gel (eg, Ametop), where available, is a reasonable alternative to EMLA cream. Tetracaine gel produces anesthesia within 30 minutes of application, and the effect lasts for four to six hours.

It is administered by applying 0.5 g to the site 30 minutes before the procedure and covering with an occlusive dressing.

Tetracaine gel should not be used in extremely preterm neonates since rare systemic side effects (eg, arrhythmia) have been reported [99].

●Supporting evidence – The evidence supporting EMLA and tetracaine (amethocaine) gel for minor dermal procedures in neonates comes from observational studies and several small randomized trials, which reached variable conclusions [96-98,100-103]. A systematic review identified seven small trials (n = 574 neonates) comparing either EMLA or tetracaine gel to placebo [96]. For EMLA, two trials reported reduced pain scores during venipuncture or LP, whereas three trials found little to no difference in pain scores during heel lance [96]. For tetracaine gel, one trial reported reduced pain scores during venipuncture, whereas a second trial found little to no difference in pain scores during intramuscular injection [96].

●Adverse effects – Topical anesthetics are generally well tolerated in neonates when used at appropriate doses. The most common adverse effects reported in the available trials were minor local skin reactions; no serious adverse events were reported [96]. Repeated or frequent doses should be avoided as this increases the risk for systemic absorption and toxicity. In addition, topical anesthetics should not be applied on open wounds or lacerations. A potential rare adverse effect of topical anesthetics is methemoglobinemia, which is discussed separately. (See "Methemoglobinemia", section on 'Topical anesthetics'.)

The use of topical anesthetics in older children is reviewed in greater detail separately. (See "Clinical use of topical anesthetics in children".)

Local anesthesia — Lidocaine is the agent most commonly used for local anesthesia in neonates.

●Clinical uses – Lidocaine is injected locally to reduce the pain associated with arterial puncture, percutaneous central venous catheter (CVC) placement, LP, chest tube insertion, and circumcision (table 2). Lidocaine infiltration is also commonly used during surgical procedures. (See 'Moderately painful (lumbar puncture, arterial puncture, etc)' above and 'More complex procedures' above.)

The use of topical anesthetics for neonatal circumcision is discussed in detail separately. (See "Neonatal circumcision: Techniques", section on 'Local topical anesthetics'.)

●Dosing and administration – 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. The maximum dose is 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 [104].

Acetaminophen

●Clinical uses – Acetaminophen (paracetamol) is a weak analgesic which is not effective enough to treat acute severe pain if used without other agents [105-108]. In our center, we use acetaminophen in the following settings:

•For postoperative or postprocedural pain – We use acetaminophen in combination with opioids (table 2), since this reduces the amount of opioids required (ie, opioid-sparing effect) [109,110].

•For mild to moderate inflammatory pain (eg, enteropathy or necrotizing enterocolitis, skin wounds, bedsores, or nasal trauma due to noninvasive ventilation).

•For musculoskeletal pain (eg, limb bruises, clavicle fractures, cephalohematoma following birth trauma).

●Dosing and administration – Oral, intravenous (IV), and rectal formulations of acetaminophen are available for use in neonates [111-114]. We generally use oral dosing for neonates who can tolerate oral medication and IV dosing for those who cannot. We do not routinely use rectal acetaminophen at our center.

•Oral acetaminophen – Oral dosing varies by 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 [111,115,116].

•IV acetaminophen – Data are limited for IV dosing of acetaminophen in neonates [117]. 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 [118].

•Rectal acetaminophen – When acetaminophen is administered rectally, it is generally given at the same dose as for oral administration, though the optimal dosing is not established in neonates. As previously mentioned, we do not use rectal acetaminophen at our center. Other centers may use rectal acetaminophen for adjunctive analgesia in neonates who cannot receive oral therapy [119,120]. We generally prefer IV acetaminophen for this purpose. In one study, rectal acetaminophen showed minimal opioid-sparing effects on postoperative pain in neonates and infants, possibly due to inadequate rectal absorption [119].

•Total daily dose – Recommended total daily doses are based on GA and postnatal age [121]:

-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

●Opioid-sparing effect – For patients with postoperative pain, acetaminophen reduces the overall amount of opioid required (ie, it has an opioid-sparing effect) [120,122-125]. In a randomized trial involving 71 neonates who underwent noncardiac thoracic or abdominal surgery, those who received regularly scheduled IV acetaminophen required less total morphine during the first 48 hours (median cumulative dose 121 versus 357 micrograms/kg) [122].

●Adverse effects – Acetaminophen is generally well-tolerated in neonates. Rare adverse events include hepatic or kidney toxicity [126,127]. While acetaminophen is effective for temperature reduction in febrile infants, the available evidence suggests it does not increase the risk of hypothermia in neonates who are normothermic [128].

The long-term safety of IV acetaminophen was demonstrated in a five-year follow-up study of infants who required neonatal intensive care [129]. Rates of various childhood health conditions (eg, asthma, atopic dermatitis, inflammatory bowel disease, autism, speech disorders, or cerebral palsy) were similar in children exposed to IV acetaminophen in the neonatal period compared with those who were not exposed.

Nonsteroidal anti-inflammatory drugs (not recommended) — Nonsteroidal anti-inflammatory drugs (NSAIDs; eg, ibuprofen, ketorolac, indomethacin) are not routinely used in the management of pain in neonates since safer and effective alternative agents are available. In infants <3 months old, NSAIDs have an unacceptably high risk of adverse effects (eg, gastrointestinal bleeding, platelet dysfunction, postoperative bleeding, acute kidney injury) that precludes using these agents routinely for neonatal analgesia [130,131].

Use of NSAIDs in neonates is largely limited to treatment of patent ductus arteriosus, as discussed separately. (See "Patent ductus arteriosus (PDA) in preterm infants: Management and outcome", section on 'Pharmacologic therapy'.)

Opioids — Opioids are highly effective for treating moderate to severe pain in patients of all ages. 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 against the risk of serious adverse effects, including respiratory depression, hypotension, urinary retention, and reduced gastrointestinal motility [37,132].

In neonates, opioids are most commonly used for postoperative pain control following major surgery, to facilitate mechanical ventilation, or for sedation/analgesia in neonates with hypoxic-ischemic encephalopathy. Opioids are also used for procedural sedation and analgesia for invasive procedures such as CVC placement, tracheal intubation, or chest tube placement. (See 'Mechanical ventilation' above and 'Postoperative pain' above and 'Hypoxic-ischemic encephalopathy' above and 'More complex procedures' above.)

In most situations, we use intermittent dosing of 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 [1].

Opioid-sparing strategies — Because neonates are at increased risk of experiencing adverse effects from opioids, especially respiratory depression, the pain management approach should utilize multimodal interventions aimed at minimizing the amount of opioid required. This includes:

●Concomitant use of acetaminophen. (See 'Acetaminophen' above.)

●Use of oral sucrose and nonpharmacologic measures to address pain and discomfort (eg, non-nutritive sucking, swaddling). (See 'Nonpharmacologic measures' above and 'Oral sucrose and other sweet liquids' above.)

●Use of standardized pain management protocols that include routine pain assessments and nursing-driven protocols [109,133]. (See "Assessment of pain in neonates", section on 'Routine standardized approach'.)

Limited data suggested that for neonates with postoperative pain, nurse-controlled analgesia may reduce opioid requirements compared with a continuous opioid infusion [134,135]. (See "Pharmacologic management of acute perioperative pain in infants and children", section on 'Patient-controlled analgesia in children'.)

Agents — Morphine and fentanyl are the most commonly used opioids in neonates [35]. More potent (eg, sufentanil) and shorter-acting (eg, remifentanil) agents are also being used with increasing frequency [35,136].

Morphine — Morphine is the prototypical opioid and is widely used for pain management in infants, children, and adults. The onset of analgesia after a single IV dose of morphine is rapid (within five minutes) with the peak effect occurring within 10 to 20 minutes. The analgesic effect lasts for approximately four hours. The half-life of morphine is longer in neonates compared with older infants and children due to reduced protein binding.

●Single or intermittent doses – We start at the minimum dose possible and increase the dose, if needed, based on serial pain assessments. Initial dosing is based on GA, as follows:

•<32 weeks GA: 5 micrograms (mcg)/kg per dose IV every four to eight hours, as needed based on pain assessment

•≥32 weeks GA: 10 mcg/kg per dose every four to eight hours, as needed based on pain assessment

●Continuous infusion – We start at the minimum dose and increase the dose, if needed, based on serial pain assessments. The initial dose for continuous IV morphine is based on GA is as follows:

•GA <32 weeks: 5 mcg/kg per hour IV

•GA ≥32 weeks: 10 mcg/kg per hour IV

Fentanyl — Fentanyl is a synthetic opioid that is 50 to 100 times more potent than morphine. It has rapid onset (within two to three minutes) and relatively short duration of action (30 to 45 minutes), making it an attractive option for procedural sedation/analgesia.

●Single or intermittent doses – Fentanyl is given via slow IV push every two to four hours as needed based on pain assessment. Dosing is based on GA, as follows:

•GA <28 weeks – 1 to 2 mcg/kg per dose

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

•GA >32 weeks – 3 to 4 mcg/kg per dose

When using fentanyl for procedural sedation/analgesia, the procedurist should wait one to three minutes after administration prior to starting the procedure.

●Continuous infusion – Fentanyl infusion is started at 0.5 to 1 mcg/kg per hour IV. The same dose is used for preterm and term neonates. We typically start at the lower dose and increase the dose if needed based on serial pain assessments.

Sufentanil — Like fentanyl, sufentanil is a synthetic opioid that is substantially more potent than morphine. Sufentanil is approximately 10 times more potent than fentanyl. It has rapid onset (within two to three minutes) and short duration of action (20 to 30 minutes), making it an attractive option for procedural sedation/analgesia.

●Single or intermittent doses – Sufentanil is given via slow IV push every two to four hours as needed based on pain assessment. Dosing is based on GA, as follows:

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

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

When using sufentanil for procedural sedation/analgesia, the procedurist should wait one to three minutes after administration prior to starting the procedure.

●Continuous infusion – Sufentanil infusion is started at 0.05 to 0.1 mcg/kg per hour IV. The same dose is used for preterm and term neonates. We typically start at the lower dose and increase the dose if needed based on serial pain assessments.

Supporting evidence — The evidence supporting use of opioids in neonates in different clinical circumstances is summarized above:

●Procedural sedation/analgesia (see 'General approach' above)

●Elective endotracheal intubation (see 'Endotracheal intubation' above)

●Ongoing invasive mechanical ventilation (see 'Mechanical ventilation' above)

●Hypoxic-ischemic encephalopathy (see 'Hypoxic-ischemic encephalopathy' above)

Comparison of agents — Most of the comparative studies on different opioid agents in neonates have compared morphine versus fentanyl. There are few data comparing these agents to other opioids (eg, sufentanil, remifentanil).

●Analgesic effects – In the available clinical trials, morphine and fentanyl were equally effective in reducing pain scores in intubated patients and in patients undergoing invasive procedures [9,37,137].

●Risk of adverse effects – Some studies suggest that the risk of adverse effects (eg, apnea, hypotension, gastrointestinal dysmotility) is higher with morphine compared with fentanyl [137,138]. (See 'Adverse effects' below.)

●Risk of withdrawal – In studies of neonates exposed to morphine or fentanyl for prolonged periods (eg, patients managed on extracorporeal membrane oxygenation), the risk of clinically significant opioid withdrawal was lower with morphine [139,140].

Adverse effects — Adverse effects associated with opioids include respiratory depression, hypotension, reduced gastrointestinal motility (which can delay establishment of enteral feeding), and urinary retention [132]. The risk of experiencing adverse effects increases with decreasing gestational age. Extremely preterm neonates <26 weeks gestation are at particularly high risk of developing hypotension from opioid therapy [141].

●Respiratory depression – When used for procedural sedation/analgesia, opioids can cause respiratory depression and apnea, particularly in preterm neonates [9]. In mechanically ventilated neonates, use of continuous opioid infusions (eg, morphine, fentanyl) modestly prolongs duration of mechanical ventilation compared with no opioid analgesia [37].

●Hypotension – All opioids can cause hypotension, particularly in at-risk neonates. However, synthetic opioids (fentanyl, sufentanil) cause less histamine release and therefore tend to cause less hemodynamic instability when compared with morphine [137]. Caution must be exercised if using opioid therapy (intermittent or continuous) in patients with hypotension at baseline and in extremely preterm neonates <26 weeks gestation, since these neonates are prone to low blood pressure, which can be exacerbated by opioids [141]. (See "Assessment and management of low blood pressure in extremely preterm infants".)

●Feeding difficulties – In mechanically ventilated neonates, use of continuous opioid infusions (eg, morphine, fentanyl) is associated with delayed establishment of full enteral feeding compared with no opioid analgesia [37].

●Dependence and withdrawal – With prolonged exposure to opioids (≥5 to 7 days), patients begin to develop tolerance and chemical dependence, which can cause withdrawal symptoms upon discontinuation of therapy [140].

●Chest wall rigidity (rare) – Chest wall rigidity is a rare life-threatening complication of synthetic opioids (eg, fentanyl, sufentanil, remifentanil) [142]. (See "Pediatric procedural sedation: Pharmacologic agents", section on 'Fentanyl'.)

●Long-term effects – It is unclear if exposure to opioids in the neonatal period has any long-term effects of neurodevelopment. This issue is discussed separately. (See "Assessment of pain in neonates", section on 'Impact of analgesic and sedative therapy'.)

Sedatives — Sedative drugs (eg, benzodiazepines, dexmedetomidine, ketamine, propofol) play a limited role in NICU practice.

Midazolam — While midazolam is generally considered a short-acting benzodiazepine, its sedating effects tend to be prolonged in neonates, particularly critically ill preterm neonates.

●Clinical uses – Use of midazolam in the NICU setting is generally limited to the following circumstances:

•Mechanically ventilated neonates with severe agitation that is refractory to other measures (eg, significant ventilator dyssynchrony not controlled by opioids). (See 'Mechanical ventilation' above.)

•Mechanically ventilated neonates with severe pulmonary hypertension (eg, persistent pulmonary hypertension of the newborn [PPHN], congenital diaphragmatic hernia [CDH]). (See "Persistent pulmonary hypertension of the newborn (PPHN): Management and outcome", section on 'Sedation and neuromuscular blockade' and "Congenital diaphragmatic hernia in the neonate", section on 'Sedation and neuromuscular blockade'.)

Midazolam is not used for procedural sedation in nonintubated neonates because the risk of apnea and/or desaturation is unacceptably high [22].

●Dosing – We generally administer midazolam via continuous IV infusion. The initial dose is 5 to 10 mcg/kg per hour. We start at the lower end of the dose range and increase if necessary to control agitation.

●Data on efficacy and safety – Midazolam is an effective sedative agent for mechanically ventilated neonates; data are mixed regarding its safety in this setting [40,143-146].

Two small trials involving preterm neonates demonstrated that midazolam effectively increased sedation levels compared with placebo [144,145]. There were no serious adverse hemodynamic or respiratory events noted in either trial, though the trials were likely underpowered to detect a difference. In a separate trial that randomly assigned 67 intubated preterm neonates to continuous midazolam infusion, continuous morphine infusion, or placebo, patients in the midazolam and morphine groups had similar comfort scores during drug infusion [143]. However, at 28 days, more infants in the midazolam group had poor neurologic outcome (defined as death, severe intraventricular hemorrhage [IVH], or periventricular leukomalacia) compared with those in the morphine or placebo groups (32 versus 4 and 24 percent, respectively). While this study suggests that midazolam may adversely impact neurologic outcome, the small number of events (3 deaths and 8 severe IVHs in total) precludes drawing firm conclusions.

By contrast, in an observational study that included 922 intubated preterm neonates receiving sedation with continuous opioid and/or midazolam infusions during the initial episode of mechanical ventilation was associated with improved survival with similar rates of moderate or severe sensorimotor impairments at age two years compared with not receiving midazolam or opioids [40].

Accumulating data in newborn animal models suggests that midazolam induces apoptosis and/or necrosis of neurons and other brain cells in the developing brain [147]. These data add to our concerns regarding the long-terms effects of routinely using midazolam for sedation in term and preterm newborns in NICU.

Ketamine — Ketamine is widely used for procedural, operative, and postoperative analgesia and sedation in infants and children. It is an N-methyl-D-aspartate receptor antagonist, sometimes described as a "dissociative sedative". It has sedative, analgesic, and amnestic properties. A unique property of ketamine that distinguishes it from other sedatives and opioids is that it usually does not cause respiratory depression or hypotension. It also has bronchodilating effects. When given in the usual dosing range (1 to 2 mg/kg), ketamine produces mild increases in heart rate and blood pressure [148]. However, higher doses can because reduced heart rate and/or low blood pressure [149,150].

Because of its favorable cardiorespiratory side effect profile, ketamine is an attractive alternative to opioids for procedural sedation, particularly in neonates with hemodynamic instability.

●Clinical uses – At our institution, we use ketamine for neonates undergoing:

•Elective endotracheal intubation (see 'Endotracheal intubation' above)

•CVC placement (see 'More complex procedures' above)

●Dosing – Ketamine is given at a dose of 1 to 2 mg/kg per dose IV.

●Data on efficacy and safety – The safety and efficacy of ketamine in neonates is largely supported by observational data [20,23,151]; there are limited clinical trial data [152,153]. A single small randomized trial compared ketamine versus fentanyl in infants undergoing laser therapy for retinopathy of prematurity (ROP) [152]. However, the drug regimens provided insufficient analgesia for most infants in both arms, prompting the investigators to change the study protocol midway through the trial. Thus, it is difficult to interpret the results. Infants in the ketamine group less frequently experienced apnea during or after the procedure (4 versus 10 percent) and less frequently required supplemental oxygen during or after the procedure (11 versus 20 percent).

In a single-center retrospective study of 72 infants (mean gestational age 32 weeks; mean postnatal age 7 weeks) who received ketamine (0.5 to 2 mg/kg) plus fentanyl (2 mcg/kg) for sedation for ultrasound-guided CVC placement, the procedural success rate was 100 percent [151]. Respiratory complications were uncommon and included need for supplemental oxygen (15 percent) and apnea (3 percent). Of the 35 infants who were breathing spontaneously during the procedure, none required intubation. No infants experienced hypotension or other adverse hemodynamic effects.

Dexmedetomidine — Dexmedetomidine is a selective alpha-2 adrenergic receptor agonist that provides sedative and mild analgesic effects. Like ketamine, but unlike most other sedatives, it causes minimal respiratory depression. Unlike ketamine, it can cause clinically significant hemodynamic effects, especially bradycardia [154,155]. The risk of bradycardia is highest in extremely low birthweight (<1000 g) infants [156].

●Clinical uses – We use dexmedetomidine as a second-line option for intubated neonates with the same clinical indications as for midazolam (ie, refractory agitation, ventilator dyssynchrony, PPHN, CDH). (See 'Mechanical ventilation' above and 'Midazolam' above.)

Adjunctive dexmedetomidine is particularly advantageous in neonates requiring prolonged mechanical ventilation, as it may help reduce opioid withdrawal and facilitate extubation in this setting [157,158].

●Dosing – Dexmedetomidine is administered as a continuous IV infusion. Our suggested dosing for continuous infusion depends on GA:

•GA <37 weeks: Starting dose of 0.2 mcg/kg per hour IV (maximum dose 1.4 mcg/kg per hour).

•GA ≥37 weeks: Starting dose of 0.4 mcg/kg per hour IV (maximum dose 1.4 mcg/kg per hour).

We typically do not administer a loading dose since it can cause bradycardia. However, other centers do start with a loading dose (0.05 to 0.2 mcg/kg); the risk of bradycardia can be reduced by administering the loading dose slowly (over 20 to 30 minutes). Rapid IV boluses should be avoided, as this can cause severe bradycardia.

●Data on efficacy and safety – There are limited data on the safety and efficacy of dexmedetomidine in neonates [156,158-160]. In a small multicenter dose-finding clinical trial involving 42 intubated preterm and term infants randomly assigned to different dosing regimens of dexmedetomidine, 10 percent of patients required additional midazolam while on dexmedetomidine and 40 percent required additional analgesic medications (fentanyl or morphine) [159]. Serious adverse events related to dexmedetomidine occurred in 5 percent of patients; none required discontinuation of the drug.

A systematic review identified six studies (the clinical trial described above, a small placebo-controlled trial, plus four observational studies) describing the use of dexmedetomidine in 252 neonates [158]. All six studies reported that dexmedetomidine provided adequate sedation in most neonates. Dexmedetomidine was associated with shorter duration of mechanical ventilation and lower requirement for adjunctive sedation compared with control or opioid analgesia alone. Three studies reported no major adverse events; one study reported bradycardia as an uncommon occurrence (5 percent of patients); while one study reported that up to 40 percent of patients treated with dexmedetomidine experienced bradycardia and/or hypotension. The differences in rates of adverse events in these studies may be explained by differences in the populations studied (bradycardia is more likely in more preterm neonates) and dosing regimens used (bradycardia is more likely with higher doses, particularly if a loading dose is given).

Propofol — Propofol is a sedative hypnotic agent that produces deep sedation/anesthesia with amnesia. It does not provide analgesia. Thus, patients undergoing painful procedures under propofol sedation generally require additional medication(s) for pain control.

In older infants and children, propofol is widely used by anesthesiologists as an induction agent for general anesthesia. It is also sometimes used by nonanesthesiologists (eg, emergency medicine specialists) for procedural sedation in children. (See "Pediatric procedural sedation: Pharmacologic agents", section on 'Propofol'.)

Propofol is used in some centers for elective endotracheal intubation in neonates [20,161,162], though it is not used for this purpose at the author's center. Otherwise, propofol is not commonly used for procedural sedation in neonates due to the unfavorable side effect profile in this population. It almost universally causes apnea, and it frequently causes hypotension and/or bradycardia [163,164].

SUMMARY AND RECOMMENDATIONS

●Multimodal approach – A multimodal approach to neonatal pain management includes the following (see 'Multimodal approach' above):

•Nonpharmacologic measures (eg, skin-to-skin contact, breastfeeding, non-nutritive sucking, swaddling) – In some cases, these measures alone may be sufficient. (See 'Nonpharmacologic measures' above.)

•Topical or local anesthetics. (See 'Topical anesthetics' above and 'Local anesthesia' above.)

•Systemic analgesic medications. (See 'Acetaminophen' above and 'Opioids' above.)

●Procedural analgesia – The need for specific analgesic drug therapy depends on the degree of anticipated procedural pain (table 2). (See 'Procedural analgesia' above.)

•Simple procedures associated with mild pain – For neonates undergoing brief painful procedures (table 2), we suggest oral sucrose (or other sweet tasting liquid) in combination with nonpharmacologic measures rather than nonpharmacologic measures alone (Grade 2B). We use weight-based dosing for sucrose and prescribe and track it as a medication. (See 'Mildly painful (heel lance, venipuncture, etc)' above and 'Oral sucrose and other sweet liquids' above and 'Nonpharmacologic measures' above.)

•Simple procedures associated with moderate pain – For neonates undergoing procedures associated with moderate pain (table 2), 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, sufentanil) may be required. (See 'Moderately painful (lumbar puncture, arterial puncture, etc)' above and 'Topical anesthetics' above.)

•More complex procedures – For neonates undergoing more complex procedures associated with moderate pain and which require the neonate to remain still (eg, central venous catheter [CVC] placement, chest tube insertion) (table 2), we suggest local anesthesia plus a short-acting sedative/analgesic (eg, ketamine, fentanyl, or sufentanil) rather than other agents or combinations (Grade 2C). These measures are used in addition to acetaminophen and nonpharmacologic measures. (See 'More complex procedures' above and 'Opioids' above and 'Ketamine' above.)

•Sedation/analgesia for elective intubation – For neonates undergoing elective endotracheal intubation, we suggest premedication with ketamine rather than other agents or drug combinations (Grade 2C). A short-acting opioid (eg, fentanyl, sufentanil) is a reasonable alternative. (See 'Endotracheal intubation' above and 'Ketamine' above and 'Opioids' above.)

●Postoperative pain – Postoperative pain management is tailored to the specific surgical procedure. For most neonates undergoing major surgery, we suggest regularly scheduled acetaminophen (Grade 2B) since it reduces the need for opioid therapy. Nonpharmacologic measures should also be used to reduce pain. Intermittent doses of an opioid (eg, morphine, fentanyl) may be required depending on the specific surgical procedure. (See 'Postoperative pain' above and 'Acetaminophen' above and 'Opioids' above.)

●Prolonged pain/discomfort

•Sedation/analgesia for mechanical ventilation – For intubated neonates receiving ongoing mechanical ventilation, the typical sedation/analgesia regimen includes nonpharmacologic measures, as-needed acetaminophen, and intermittent doses of an opioid (eg, morphine, fentanyl, sufentanil). For patients receiving opioids, we suggest starting with intermittent dosing rather than a continuous opioid infusion or a combined opioid/benzodiazepine regimen (Grade 2C). 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 'Mechanical ventilation' above and 'Opioids' above and 'Sedatives' above.)

•Other painful conditions – Acutely ill neonates with conditions associated with moderate to severe pain (eg, necrotizing enterocolitis, meningitis, indwelling chest tube) (table 2) may require intermittent doses of an opioid (eg, morphine, fentanyl) in addition to acetaminophen, sucrose, and nonpharmacologic measures. (See 'General approach' above and 'Opioids' above and 'Acetaminophen' above.)

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