Managing Procedural Pain in the Neonate Using an Opioid-Sparing Approach

Abstract

Purpose

Pain in the neonate is often challenging to assess but important to control. Physicians often must balance the need for optimal pain control with the need to minimize over-sedation and prolonged opioid use. Both inadequate pain control and over-utilization of opioids can have long-term consequences including poor developmental outcomes. The aim of this review is to introduce a comprehensive approach to pain management for physicians, nurses and surgeons caring for critically ill neonates, focusing on non-opioid alternatives to manage procedural pain.

Findings

Following review, categories of opioid-sparing interventions identified included (1) non-opioid pharmacologics, (2) local and regional anesthesia, and (3) nonpharmacologic alternatives. Non-opioid pharmacologics identified for neonatal use included acetaminophen, non-steroidal anti-inflammatories (NSAIDs), dexmedetomidine, and gabapentin. Local and regional anesthesia included neuraxial blockade (spinals and epidurals), subcutaneous injections and topical anesthesia. Non-pharmacologics uniquely available in the neonatal setting included skin-to-skin care, facilitated tucking, sucrose, breastfeeding, and non-nutritive sucking.

Implications

Utilizing various pharmacologic and interventional treatments for neonatal pain management allow for the incorporation of opioid-sparing techniques in neonates who are already at risk for poor neurodevelopmental outcomes. A multifactorial approach to pain control is paramount to optimize periprocedural comfort and minimize the negative sequelae of uncontrolled pain in the neonate.

Introduction

The balance between the over- and under-treatment of neonatal procedural pain is challenging, as both insufficient pain control and excess opioid use can lead to poor developmental outcomes.¹ Neonatal physiologic and hormonal responses to pain can lead to increased neurologic morbidity and mortality, thus timely and effective pain management is integral to comprehensive neonatal care.^2–4 Opioid analgesics have been historically a first line treatment for procedural and post-operative pain management in neonatal intensive care units (NICU) and surgical units. In a survey of hospitals in the United Kingdom, 93% of hospitals used morphine as a first line medication for post-operative pain management in neonates undergoing elective intubation, sedation for ventilation, and post-operative pain management.⁵ While widespread and commonly used, opioid analgesics in the neonatal and infant population can have profound side effects including tolerance, withdrawal, and adverse neurodevelopmental outcomes.^2,6–9 Furthermore, long term opioid exposure can result in opioid-induced hyperalgesia, tolerance, and withdrawal.¹⁰ Fortunately, non-opioid analgesia provides safe and efficacious pharmacological alternative treatment to neonates and infants who have undergone surgery or a procedure in an intensive care setting. The aim of the paper is to review non-opioid alternatives for procedural pain management in term and preterm neonates.

Physiology of pain

Pain is defined as “an unpleasant sensory and emotional experience associated with actual or potential tissue damage, or described in terms of such damage,” but importantly, “inability to communicate verbally does not negate the possibility that an individual is experiencing pain and needs appropriate pain-relieving treatment.”² The neural pathway of pain begins at sensory receptors that transmit the pain signal to the dorsal horn of spinal cord, then up the spinothalamic tracts to supraspinal centers in brainstem, thalamus, and cerebral cortex.¹¹ Tissues subjected to direct noxious stimuli resulting in damage cause nociceptive pain, whereby the painful response is experienced through pain receptors at the site of injury.¹² Examples include pain following surgery due to iatrogenic tissue violation or acute trauma such as from a sport-related injury.¹² Health care providers rely on physiologic ques (i.e. increased heart rate or facial grimacing) or standardized neonatal pain scales (e.g. NPASS) to assess pain in neonates. However, there is significant variation between practitioners when rating pain levels in neonates, leading to inconsistent delivery and utilization of pain medication.^4,13

Risks of uncontrolled pain

Multiple studies report poor outcomes in neonates with under-treated pain that can have both short and long-term consequences. Short term effects of uncontrolled pain include: 1) changes in physiologic vital signs (e.g. oxygen desaturations and increased heart rate), 2) increased catabolism from these physiologic changes, 3) delayed healing time, and 4) greater postoperative morbidity and mortality.¹⁴ Long term effects of uncontrolled pain include: 1) impaired emotional bonding, 2) developmental delay, and 3) hypo/hyper-active response to pain, and stress.^15,16 Because of the many negative sequelae from uncontrolled pain in the neonate, proper assessment and treatment is imperative.

Traditionally, the most common therapy for moderate and severe pain control in critically ill children is opioid analgesics, providing efficacious and reliable relief for all age groups. Opioids are well-known to produce both analgesia and sedation that can acceptably treat neonates and infants undergoing a variety of procedures. Despite the potential side effects of opioids, morphine for instance, has a wide therapeutic window, and the deleterious effects are often experienced at higher doses or combined with other medications. The benefits of opioids such as morphine are particularly important for neonates subjected to severe pain and physiological stress due to procedures. For the experienced provider and applicable clinical setting, opioids can be an effective therapy for pain control in the neonate.

Risks of opioid overuse

Although opioid analgesics routinely and effectively treat pain resulting from many common ICU procedures, opioid overuse is associated with poor neurodevelopmental outcomes in neonates. Risks from opioid overuse include death, prolonged hospitalization, and risk for future habituation in neonates.^17,18 Moreover, studies in neonates with prenatal opioid exposure report increased cognitive, motor, and behavioral delays compared to population norms.¹⁹ Premature neonates in particular are at substantial risk of increased morbidity associated with opioid exposure. Postnatal studies in preterm neonates exposed to opioids show decreased cerebellar volume and poorer 18-month motor and cognitive scores are associated with increasing morphine exposure.⁸

Two randomized controlled trials have explored the relationship between opioid use and neurologic morbidity in neonates. In the NOPAIN trial, researchers randomized 67 premature neonates who required intubation and ventilatory support to receive a midazolam infusion, morphine infusion or saline (placebo) infusion.²⁰ Infants randomized to the morphine infusion group showed significantly lower rates of death, grade III or IV intraventricular hemorrhage, and periventricular leukomalacia compared to infants randomized to midazolam or saline infusions. Similarly, in the NEOPAIN trial, 898 intubated premature neonates were randomized to either a morphine or saline (placebo) infusion.²¹ Of note, both groups in the NEOPAIN trial were allowed open-label, or as needed, dosing of morphine. Unlike the smaller NOPAIN trial, there was no difference between groups regarding rates of death, intraventricular hemorrhage, or periventricular leukomalacia in the NEOPAIN trial. However, infants in both groups who received additional open-label morphine boluses did exhibit increased rates of death, intraventricular hemorrhage, and periventricular leukomalacia. The morphine group also exhibited increased hypotension, prolonged ventilation, and increased time to reach full enteral nutrition^22–24 Furthermore, long-term clinical characteristics and neurodevelopmental assessments of the morphine infusion group revealed significantly lower weight and head circumference and increased social problems.²

Opioid alternatives

Fortunately, there are many non-opioid pain management strategies appropriate for neonatal and infant use (Table 1). Non-opioid pharmacologic alternatives include acetaminophen, non-steroidal anti-inflammatory drugs (e.g. ketorolac, ibuprofen), dexmedetomidine, and gabapentin. Epidural and spinal blocks are routinely used for inguinal hernia repairs, orchiopexy, and circumcision.^25,26 Furthermore, neonates are a unique population in which nonpharmacologic alternatives such as non-nutritive suck with and without oral sucrose, facilitated tucking, or skin-to-skin care can be broadly applied.²⁷

Table 1:

Summary of non-opioid therapies for neonates and infants

Non-Opioid Pharmacologics	Local & Regional Anestheisa	Non-Pharmacologic Alternatives
Acetaminophen NSAIDs* (ibuprofen, ketorolac) Gabapentin Dexmedetomidine	Neuraxial Blockade (spinal, epidural) Local Anesthetics (lidocaine, bupivacaine) Topical Anesthetics (EMLA®)	Skin-to-Skin Care Facilitated Tucking Oral Sucrose/Glucose Breastfeeding Non-nutritive Sucking

^*Note: Not approved for use in infants <6 months.

NON-OPIOID PHARMACOLOGICS

Various classes of non-opioid pharmacologic agents exist and are emerging as both primary pain control regimens as well as helpful adjuncts that are beneficial when added to opioid pain control regimens. A summary of the below non-opioid pharmacologic alternatives is outlined in Table 2.

Table 2:

Commonly used non-opioid pharmacologic agents for neonates and infants in critical care and periprocedural settings

Non-Opioid Pharmacologic Analgesics	Routes	Advantages	Disadvantages
Acetaminophen	PO, IV, PR	Combined analgesic and antipyretic No respiratory depression PR and IV options for NPO patients Reduction of morphine requirements*	Precluded in patients with compromised liver function Enteral and rectal delivery with variable absorption
Non-Steroidal Anti-Inflammatory Drugs (NSAIDs)	PO, IV	No respiratory depression Anti-inflammatory and analgesic properties	Renal injury Gastrointestinal bleeding Ketorolac not FDA approved for neonates due to demonstrated bleeding risk
Gabapentin	PO	Improves feeding intolerance** Decreases use of benzodiazepines and opioids	Autonomic instability with abrupt withdrawal; symptoms include tachycardia or bradycardia, emesis, and irritability
Dexmedetomidine	IV, IM, intranasal, buccal	Sedative, analgesic, and anti-anxiolytic Rapid onset Limited respiratory depression Does not require intubation for procedural sedation	Currently only off-label use in neonates Requires continuous monitoring Side effects of hypotension and bradycardia

Abbreviations: PO, per os. PR, per rectum. IV, intravenous. IM, intramuscular. NPO, nil per os.

^*For infants receiving IV acetaminophen in major thoracic and abdominal surgery.

^**For infants with visceral hyperalgesia in the setting of neurological impairment and poor gastrointestinal motility.

Acetaminophen

Acetaminophen is one of the most commonly delivered drugs to neonates and young children as both an antipyretic and analgesic. As an alternative to opioids, acetaminophen has been shown to be an effective postprocedural analgesic for neonatal and pediatric populations.^28,29 While the mechanisms of acetaminophen are not fully understood, analgesia results from a variety of proposed mechanisms including potent inhibitor of prostaglandin synthesis acting within the central nervous system, peripherally acting along the serotonergic pathway by blocking chemoreceptors responsible for nociceptive impulses, producing a metabolite that acts as a ligand for a cannabinoid receptor, and has effects on spinal neurotransmitter nitrous oxide.^30–32 In spite of acetaminophen’s widespread use for infants, the mechanisms of hepatotoxicity are well-known and must be judiciously considered in neonates and most certainly avoided in those patients with compromised liver function.

While the multifactorial mechanisms of action probably contribute to acetaminophen’s analgesic effects, one must also consider the neonate’s unique physiology, as their pharmacodynamics and pharmacokinetics differ substantially from older children and adults. If acetaminophen is administered by the oral route, the slow and variable gastric motility of a newborn paired with the immature ability to acidify gastric juices should be considered. Neonatal gastric motility is slower than in older children, taking about 6–8 hours for gastric emptying. Gastric acid secretions start to occur at day 8–10 of life and are less acidic than pediatric and adult populations.³³ As acetaminophen is absorbed in the upper small bowel, slow gastric transit time can affect the bioavailability of acetaminophen as compared to older children. Often enteral feeding and drug administration is not possible or may be delayed for pediatric patients in an ICU or perioperative setting. For these patients, alternative routes such as rectal and intravenous acetaminophen delivery may be more efficacious.

Rectal administration of medication is often appropriate for surgical patients, especially neonates who may be ventilated and unable to tolerate per os intake. The rectum is a well vascularized site, with two distinct venous drainage systems, enterohepatic and systemic, that can have variable implications on drug absorption. If administered high in the rectum, acetaminophen is subject to enterohepatic circulation but if more distal, systemic circulation avoids first pass metabolism. Although variable in absorption site, bioavailability of medication per rectum is still higher in neonates than older patients, most likely due to less mature first pass metabolism in developing hepatic enzymes.³⁴ Limitations of rectal administration include fixed suppository dosing, loss of suppository with defecation, and the immaturity of the porta-rectal venous system contribute to variable absorption. In addition, prolonged absorption seems to occur in preterm neonates as compared to term neonates, with rectal temperature as a possible contribution.³⁵

Several studies have shown that rectal mode of delivery results in less efficient absorption than the oral route, with a single dose unable to achieve a therapeutic plasma concentration for analgesia, thus requiring higher doses than oral route.^35,36 In a randomized trial assessing oral versus rectal acetaminophen administration for children undergoing tonsillectomy, children who received an oral elixir had higher mean plasma concentrations of acetaminophen as well as lower pain scores post-operatively compared to patients receiving a suppository at the equivalent dose of 40 mg/kg.³⁷ Given the variability of acetaminophen absorption, delivery route in newborns can have profoundly inconsistent effects on periprocedural pain control.

Since the advent of intravenous acetaminophen, its use has been increasing in neonates and has favorably augmented post-surgical pain regimens.^38,39 Specifically, where oral or rectal formulations are not appropriate or not adequate for pain control, such as for an infant with ileus, intravenous acetaminophen provides beneficial analgesia. Intravenous acetaminophen is often used in conjunction with opioids for post-operative analgesia, as it can mitigate the cumulative usage of opioid analgesia.³⁸ A randomized study of neonates and infants undergoing major thoracic and abdominal surgery were found to receive 66% less cumulative morphine doses in the first 48 hours after surgery when IV acetaminophen was incorporated into the postoperative pain regimen.⁴⁰ Decreasing cumulative opioid use in neonates undergoing major surgeries is particularly important to minimize the adverse effects of opioids.

Preterm infants are especially susceptible to opioid-related adverse effects. They often experience more painful and stressful procedures in the NICU as compared to their term counterparts. The stress of surgery has been shown to induce greater white matter injury and lower scores on mental developmental index in small preterm infants.⁴¹ In addition to the stress of surgery, opioid related respiratory complications can result in devastating events for this at-risk population. Medications which limit respiratory distress episodes and are not associated with adverse neurodevelopmental outcomes are paramount as these can be devastating insults. Incorporating acetaminophen can have a significant effect on decreasing dosage for opioids, with infants receiving acetaminophen requiring fewer cumulative doses of morphine.⁴² A significant decrease is important, as cumulative opioid dose was associated with worse neurodevelopmental outcomes at two years.⁴³ For preterm neonates subjected to critical procedures, it seems that intravenous acetaminophen is a preferred route of administration, given its predictable absorption and decrease in morphine requirements.

NSAIDs

With the focus of opioid analgesia minimization, non-steroidal anti-inflammatory drugs (NSAIDs) have become a common adjunct in procedural analgesia. NSAIDs are widely used in pediatric and adult populations after surgery, but the safety and efficacy in the neonatal population is only partially understood. NSAIDs are cyclooxygenase (COX) inhibitors that act by constricting prostaglandin synthesis. However, systemic toxicities such as renal injury and gastrointestinal bleeding are particularly worrisome in infants and most NSAIDs are not approved for use in patients under 6 months of age. Historically, the most serious adverse effects of NSAIDs usage are encountered in neonates being treated for patent ductus arteriosus, who require higher doses and longer duration of NSAIDs usage than those for post-operative analgesia.⁴⁴

Among NSAIDs, ketorolac is FDA-approved for intravenous administration. Ketorolac is a potent inhibitor of prostaglandin synthesis and an IV formulation makes it an attractive post-surgical analgesic. In a retrospective study of 18 infants in Italy, a single post-operative dose of 1mg·kg⁻¹ ketorolac was found to achieve near total pain control in almost all patients without any renal, hepatic, or hematologic complications.⁴⁵ Despite this, while ketorolac has been used in the pediatric and adult population, its use in neonatal postoperative management is not currently advised due to bleeding events as a major side effect. In a retrospective cohort study of 57 postsurgical neonates and infants aged 0 to 3 months in the United States, 17.2% of patients experienced a bleeding complication after ketorolac administration.⁴⁶ Complications were more likely in neonates younger than 21 days and less than 37 weeks corrected gestational age. Given the concerns of bleeding and the contrasting findings between small, retrospective studies, extreme caution should be advised with NSAID use for periprocedural pain management in neonatal populations.

Dexmedetomidine

More recently, use of dexmedetomidine in perioperative pain management has gained popularity due to its favorable pharmacologic properties. Dexmedetomidine is a highly selective α2-agonist providing sedation, analgesia, and anti-anxiolytic properties without appreciably compromising respiratory function.⁴⁷ The mechanism of analgesia is by inhibition of release of substance P and shares a potassium channel with opioid receptors.^48,49 Dexmedetomidine was initially used as an off-label sedative for infants undergoing open heart surgery due to its minimal effects on respiratory function at sedative doses. More recently, current indications have evolved, finding efficacy in the critical care setting of dexmedetodine to reduce opioid usage in neonates and pediatric patients as well as to facilitated extubation.^50,51

Dexmedetomidine can be administered intravenously, intramuscularly, orally, buccally, and intranasally. Intranasal and buccal administrations are relatively non-invasive and have high bioavailability, which can be an especially relevant option for pediatric patients undergoing surgery.⁵² In patients undergoing tonsillectomy, premedication with intranasal dexmedetomidine markedly reduced the required dosage of postoperative analgesia.⁵³ Infusions routes are often necessary for surgical patient and for ICU sedation. A metanalysis of randomized controlled trials in adults assessing use of intraoperative dexmedetomidine for postoperative pain control found collectively that patients experienced lower post-operative pain, had lower consumption opioid pain medication in the first 24 hours postoperatively, and had lower opioid related adverse effects.⁵⁴ While safety and efficacy has been validated in adult populations where dexmedetomidine gained FDA-approval, the use of dexmedetomidine in infants is still off-label. Currently, clinical experience with dexmedetomidine in infants is based on off-label limited to case reports and small case series.^55,56 Further studies focused on neonates and infants may validate favorable efficacy for postoperative pain control in children as has been seen in older children and adults.

Gabapentin

Gabapentin is a gamma-aminobutyric acid (GABA) analog that acts by binding the α₂-δ subunit on voltage-gated calcium channels, blocking the release of excitatory neurotransmitters in the central nervous system that cause pain.⁵⁷ The role of gabapentin in neonates and infants has been gaining attention due to its efficacy in treating refractory pain not responding to traditional analgesics and for its relatively safe side effect profile compared to opioids.

Gabapentin is increasingly used to treat multiple conditions in neonates and infants cared for in the NICU. Agitation and refractory pain are often difficult to manage in critically ill infants undergoing procedures in the ICU. A retrospective study found that the addition of gabapentin to relieve pain and agitation in neonates and infants in the ICU was associated with decreased N-PASS scores and reduced requirements for analgesic and sedative medications.⁵⁸ The upregulation of sensory input in visceral hyperalgesia is associated with pain and prolonged feeding intolerance in the neonatal patient population. There is growing retrospective evidence for term and preterm infants with refractory visceral hyperalgesia caused by neurologic and gastrointestinal morbidities suggesting that gabapentin reduces chronic irritability and feeding intolerance, as well as reduces benzodiazepine and opioids use.^59,60 For a certain subset of neonates and infants with either refractory pain or agitation, or the neurodevelopmentally impaired child with enteral feeding compromise gabapentin may be a useful adjunct.

LOCAL ANESTHESIA

Neuraxial blockade

Neuraxial anesthesia is an alternative method to opioid analgesics for procedural and postoperative pain. This includes spinal and epidural blockade via percutaneously administered local anesthetics as a continuous infusion or single injection.⁶¹ Local anesthetic agents such as bupivacaine, lidocaine, or ropivacaine are commonly administered as regional anesthesia.^61–63 These blocks allow for pain relief without the risks of systemic side effects of opioids such as cardiorespiratory impairment.⁶⁴ They allow for earlier extubation, decreased perioperative apnea and respiratory morbidity, decreased exposure to volatile anesthetic agents, lower perioperative response to stress, and better pain relief.⁶² They can also be used as the sole anesthetic in awake patients for minor surgeries (inguinal hernia repair, circumcision, orchidopexy, hydrocele, hypospadias repair, rectal surgery, or lower extremity surgery) or for procedures (chest tubes, proctoscopy, colonoscopy, cystoscopy, or nonsurgical reduction of intussusception).^63,64 Placement of neuraxial blockade requires an experienced provider with good technique for appropriate placement and careful attention to pediatric analgesic dosing to prevent local anesthetic toxicity which may result in seizures or dysrhythmias.^62,63

Topical analgesics

In the setting of procedures such as venipuncture, peripheral arterial puncture, and percutaneous central venous catheter insertion, topical agents such as Eutectic Mixture of Local Anesthetics (EMLA®, Astra Pharmaceuticals, L.P, Wayne, PA) may be used to obtain local anesthesia.⁶⁵ EMLA is a combination of 2.5% prilocaine and 2.5% lidocaine, that upon application to skin, allows for absorption of the two agents into the epidermal and dermal skin layers resulting in anesthesia at the area of application.⁶⁶ It has been shown to reduce pain associated with lumbar puncture at the time of needle insertion and withdrawal as well as for venipuncture, particularly when used in combination with oral sucrose.^67–69 It has also been shown to be efficacious in decreasing pain associated with circumcision when combined with a regional block and/or oral sucrose.^70,71 However, care must be taken with regards to dosing, frequency of use and time of administration especially in preterm infants, as it places the neonate at risk of methemoglobinemia, skin irritation, and toxicity.⁷²

NONPHARMACOLOGIC ALTERNATIVES

Procedural pain can cause neonates significant distress, especially for infants in the NICU where they can average up to 14 procedures per day, often without analgesia.^73–75 As a result, nonpharmacologic interventions such as skin-to-skin care, facilitated tucking, oral sucrose, breastfeeding, and non-nutritive sucking have been introduced as important mediators in managing neonatal distress in the hospital setting.^73,74,76 These nonpharmacologic therapies may be used alone or in combination with other interventions to address mild to moderate pain secondary to heel-sticks, intravenous access, injections, circumcision, oral gastric tube insertion, and lumbar puncture.^18,77

Skin-to-skin care and facilitated tucking

Skin-to-skin care (SSC) involves direct skin-to-skin contact between the neonate and their caregiver. This contact has been shown to increase oxytocin levels and decrease cortisol levels following 60 minutes of SSC.⁷⁸ SSC also decreases pain-related stress in neonates undergoing heel lancing and venipuncture and facilitates physiologic stability.^79–83 Furthermore, safety and feasibility of SSC for surgical infants, including intubated infants,^84–87 has also been established.⁸⁰ A comprehensive systematic review of barriers and enablers of SSC revealed that most barriers are at the hospital and staff level.⁸⁸ For the critically ill infant and their caregivers, multidisciplinary endorsement of SSC from nursing and physician teams is paramount in an effort to minimize procedural pain.

Facilitated tucking involves gently holding the neonate in a flexed position while in a supine, prone, or decubitus position.⁸⁹ It may be used during small procedures resulting in mild pain such as heel sticks, venipuncture, and endotracheal suctioning, especially in premature infants.⁹⁰ Studies show that it can be combined with other interventions such as oral sucrose or non-nutritive sucking for improved efficacy.^89,91,92 However, its use as a sole method of pain management for repeated procedures is discouraged.

Oral sucrose/glucose, breastfeeding, and non-nutritive sucking

Oral feeding and stimulation are simple bedside interventions for pain management in the neonate.⁹³ Both oral feeding and oral stimulation work by increasing endogenous endorphin levels in the neonate and improving pain.⁹⁴ Administration of oral sucrose/glucose has been found to be effective in single event procedures such as heel stick, intramuscular injections, oral gastric tube insertion, and venipuncture as well as echocardiography and retinal exams.⁹⁵ It is also effective in combination with EMLA with and without a local anesthetic block in relieving circumcision-associated pain.⁷⁰ However, it is unclear whether there are adverse outcomes related to dose-response or tolerance.

Breastfeeding and non-nutritive suckling are both evidence based methods for pain relief in neonates undergoing painful procedures such as heel sticks, intramuscular injections, or venipuncture. In comparison to SSC, topical anesthetics, and music therapy, Benoit et al.’s systematic review of the literature found breastfeeding to be more effective than all other therapies and recommended that it be a first-line intervention for the aforementioned procedures.⁹⁶ Non-nutritive sucking also improves neonatal response to pain during minor procedures in the NICU. Most commonly, non-nutritive suckling used in combination with other nonpharmacologic pain management techniques is most effective. Peng et al.’s prospective, randomized control trial of non-nutritive sucking, oral breast milk, and facilitated tucking found that the combined use of these modalities effectively reduced preterm infants’ mild pain and moderate-to-severe pain during heel-stick procedures.⁹⁷ These findings are further underscored in Liu et al.’s systematic review and meta-analysis of oral sucrose in combination with non-nutritive suckling finding that the combined therapies can be an alternative for better prevention and management of procedure pain in NICU newborns.⁷⁴ In summary, most nonpharmacologic pain management techniques are best used in combination with each other in order to optimize infant comfort.

Conclusion

Opioids have historically provided sufficient pain control and sedation for critically ill neonates as well as infants undergoing procedures. Alternatives to opioid analgesics have emerged as both primary and adjunctive therapies with promising applications for neonatal and infants who require critical care interventions. Optimizing pain control with opioid-sparing techniques may reduce the risk of poor neurodevelopmental outcomes in infants and neonates. There is strong evidence to support use of non-opioid pharmacologics, regional anesthesia, and nonpharmacologic interventions in infants and neonates. As outlined in Figure 1, a multimodal approach to pain management is paramount in order to optimize periprocedural discomfort and minimize the negative sequelae of uncontrolled pain in the neonate.

Figure 1.

Managing Pain in Neonates Using an Opioid-Sparing Approach: Highlights

Managing Pain in Neonates Using an Opioid-Sparing Approach: Highlights.

• Critically ill neonates frequently undergo numerous painful procedures. Pain in the neonate is often challenging to assess but important to control.

• Opioid analgesics are beneficial and historically reliable therapies for pain control and sedation, but can be limited by the risk of unwanted side-effects and future dependence.

• Non-opioid pharmacologics can provide primary pain control, replacing traditional opioids and/or provide adjunctive modes of pain control that reduce opioid requirements.

• Local & regional anesthesia such as neuraxial spinal and epidural blockade, local subcutaneous anesthetics, and topical agents provide additional periprocedural pain control.

• Non-pharmacologic alternatives such as skin-to-skin care, sucrose/glucose, facilitated tucking, breastfeeding, and non-nutritive sucking used alone or in combination with other interventions can address mild to moderate pain and decrease neonatal distress during procedures.