Procedural pain management in neonates: A Narrative review

ABSTRACT

Over the past three decades, awareness regarding pain management in neonates has risen significantly. It has been very well established that neonates can perceive, feel, and react to stimuli that cause pain and discomfort to them. Neonates admitted to neonatal intensive care units (NICUs) are repeatedly subjected to invasive treatments, most of which are painful. These procedures, nevertheless, are still performed, sometimes without sufficient analgesia. Exposure to frequent traumatic and painful procedures has been associated with several adverse effects such as altered brain growth and signs of internalization. Both inadequate and excessive analgesia during this period of rapid development may lead to profound neurodevelopmental outcomes. Ensuring the avoidance of pain in NICUs is a crucial obligation from both ethical and medical standpoints. Despite established international criteria, there is currently insufficient adherence to this criterion, highlighting the need for additional development in uniformly providing effective pain management to newborns in NICUs.

INTRODUCTION

Pain was infrequently recognized or treated in newborns before 1980 because self-reporting, the gold standard for pain assessment, was not possible in a newborn.[1] Neonates are often subjected to various procedures in neonatal intensive care units (NICUs), which can vary from simple ones like orogastric tube insertion to more intensive ones such as endotracheal intubation and lumbar puncture, however, lack of treatment is reported in approximately 80% of these.[2] Clinical studies showed that most physiologic, behavioral, and cognitive complications result from untreated neonatal pain.[3] On the other hand, some studies have documented that analgesic therapy prolongs the duration of mechanical ventilation, delays feeding, and is associated with impaired and impaired performance in short-term memory tasks.[1] Therefore, striking a balance between zero and excessive analgesia is a necessity. Neonatal pain management is still a challenge for clinicians because a uniform strategy has not yet been established. Hence, appropriate assessments and even, the development of universal guidelines is the need of the hour.

Sedation and analgesic options include nonpharmacological preferences for minor pain to pharmacological ones for more intense pain.

NONPHARMACOLOGIC STRATEGIES

Nonpharmacological techniques relieve mild-to-moderate pain. Nonnutritive sucking (NNS) (with or without sucrose), breastfeeding, swaddling, kangaroo care (skin-to-skin contact), and massage therapy are some of the best nonpharmacological techniques.[1] In neonates undergoing minor procedures, several of these techniques have shown to be effective in delaying the onset of acute pain and reducing its intensity. They are known to be beneficial, carry negligible risk to babies, and have modest running costs.[4]

Skin-to-skin care

Skin-to-skin contact has proven to be a time-tested method of neonatal care, especially preterm and low-birth weight babies. Several studies explored the impact of skin-to-skin care (SSC) on pain management and found promising results. Seo et al. compared skin-to-skin contact with controls during heel pricks and reported 35% decrease in pain and an 88% decrease in the cry duration.[5] Furthermore, de Sousa Freire et al. evaluated the analgesic effect of skin-to-skin contact compared to oral glucose during heel prick and enrolled 95 preterm infants in the study. Infants who were randomized to skin-to-skin contact showed significantly lower heart rate (HR) and oxygen saturation variation than those given glucose or infants in the control group.[6] Johnston et al. performed a systematic review and concluded that SSC does play a pivotal role in reducing pain during and also improves recovery from frequent painful procedures performed on neonates in NICUs.[7]

Breastfeeding

Breastfeeding is shown to have an additive analgesic effect because of parental presence and skin-to-skin contact and is considered to be an effective analgesic measure for procedures such as venipuncture and heel pricks. Erkul and Efe compared the efficacy of breastfeeding with a control group on pain experienced by babies during vaccinations and reported lower pain, lower duration of crying, a lower HR, and higher mean oxygen saturation in the breastfeeding group.[8] In another trial, conducted by Baudesson de Chanville et al., the analgesic effect of maternal human milk odor on premature neonates was studied and concluded that the smell of breast milk in premature infants during venipuncture reduced pain scores by 50% alongside reducing the duration of cry.[9] On the contrary, Simonse et al. compared the analgesic effect of breast milk versus sucrose for analgesia during heel lance in late preterm infants and documented a significant difference between breastfeeding and bottle feeding. Mean COMFORT neo pain score was significantly reduced by bottle feeding (BF: 19.0, bottle feed) but could not find any significant difference in pain scores when comparing the analgesic effect of breastfeeding with sucrose.[10] These results are of importance in settings where breastfeeding is not feasible, like in intensive care.

Nonnutritive sucking

NNS has also been studied as a modality for analgesia during minor neonatal procedures. Sucking reflex activates tactile sensitivity, mechanic receptors, and endogenous analgesic pathway, resulting in diminished pain sensation during procedures such as heel prick, vaccination, and venipuncture. Akbari et al. through their systematic review and meta-analysis concluded that NNS was useful in reducing pain scores (mean difference [MD], −1.05; 95% CI, −1.53 to − 0.57) during heel lance procedures, however, they could not comment on long-term outcomes.[11] Additionally, Lima et al. compared the efficacy of nutritive and non-nutritive sucking in 64 newborns during venipuncture and found a similar efficacy in both modalities [P=0.874] but overall, found that both nutritive and non-nutritive sucking provided significantly more analgesia, as compared to no intervention (P=0.001 and P<0.001, respectively).[12]

Swaddling

Swaddling, a method traditionally used for the bedding of babies, was also assessed in several studies. Erkut and Yildiz studied the efficacy of swaddling on pain, vitals, and crying duration during heel lance in newborns. The authors observed a statistically significant reduction in pain scores during and after the procedure in the swaddling group. Similar observations were made for the duration of the cry, however, no significant difference was observed in SpO₂ levels.[13] In another study conducted by Ho et al., lower pain scores, lower HR, and higher oxygen saturation were recorded in the swaddling group undergoing heel stick procedure, as compared to the control group.[14]

Massage therapy

The results of several previous studies indicated that gentle massage before a heel prick can reduce pain. Two randomized trials done by Chik et al. and Jain et al. reported that during venipuncture, pain responses reduced significantly after upper limb massage, in both preterm and term infants.[15,16] Furthermore, Zargham-Boroujeni et al. performed a clinical trial in 2017, comparing the effects of massage therapy, breastfeeding, and no intervention among 75 infants, and found that mean scores of pain (Neonatal Infant Pain Scale) were 0.92, 4.84, and 6.16 in the massage, breastfeeding, and control respectively, with a statistical significance (F = 437.50, P < 0.01).[17]

Sucrose/glucose solutions

Oral sucrose solution is most commonly used for newborn pain management. Sucrose works by increasing endogenous endorphins.[18] Previous studies have shown conflicting results regarding pain relief. Results of a randomized controlled trial (RCT) done by Lima et al. showed that during immunization, pain scores were reduced by 40% and crying time reduced by 70% in 78 healthy newborns with oral glucose compared to NNS.[12] However, in a double-blind trial done by Gouin et al., subjects were randomized to either sucrose or placebo and a comparison was made regarding the effect of an oral sucrose solution versus placebo on pain, in 1–3 months old children undergoing venipuncture. This trial also documented similar pain scores, crying duration, and HR variation in both groups.[19] The results have been conflicting in various studies. A recent systematic review by Huang et al., which included 4999 neonates, across 31 trials concluded that in sick and healthy preterm and term infants under 28 days of age, sweet solutions reliably lower behavioral responses during routinely occurring painful procedures; however, variations are observed in physiological responses.[20] Another systematic review inferred that sweet solutions were useful in reducing Premature Infant Pain Profile (PIPP) scores (MD = −2.18, 95% CI [−3.86, −0.51], P = 0.01) during orogastric or nasogastric tube insertions in infants from 0 to 12 months of age.[21]

PHARMACOLOGIC STRATEGIES

Pharmacological sedation and analgesia are essential components of neonatal care, especially during medical procedures and surgeries. These strategies run a higher risk of adverse effects and warrant close monitoring due to a neonate’s unique physiological characteristics. What adds to the problem is the lack of established and proven therapies specifically designed for term and preterm infants. There is a paucity of clinical trials evaluating the use of medications in newborns, resulting in a scarcity of reliable data regarding the safety and effectiveness of pharmacological treatments in these patients. Despite that, their use is warranted during procedures associated with significant pain.

Opioids

Opioids are the most efficient treatment for people of all ages who are experiencing moderate-to-severe pain. Along with having a broad therapeutic window, they provide both analgesia and sedation and also lessen the physiological stress reactions of newborns.[1] Their use in neonates is mainly restricted to major surgeries and procedures.

Morphine

There has been conflicting data on whether morphine can serve as an effective analgesic. A RCT by Hartley et al. concluded that morphine was not effective in reducing PIPP-Revised Score after ROP screening.[1]

There is concern about the effectiveness of morphine therapy for treating acute pain in preterm neonates since it may enhance neurological results but worsen pulmonary outcomes and reduce cerebral blood flow.[22] That is why it is the need of the hour that we find potential alternatives to morphine, with similar effects but lesser adverse effect profiles. A systematic review conducted in 2021 concluded that the use of opioids for newborn infants receiving mechanical ventilation does not have a clear impact on pain and neurodevelopmental outcomes at 18–24 months. It also does not reduce the duration of mechanical ventilation and neonatal mortality. The use should be guided mainly by clinical judgment.[23] Another systematic review conducted in 2023, concluded that limited evidence existed to determine the effectiveness of continuous opioid infusion compared to bolus infusion for postoperative pain management in neonates.[24]

Fentanyl

The mu-opioid receptor is involved in the pharmacological action of fentanyl and its derivatives. In comparison to morphine, fentanyl is less histamine-releasing and crosses the blood–brain barrier quickly.[22] Tolerance sets in faster than morphine, necessitating an increase in successive doses, as shown in a study in infants receiving extracorporeal membrane oxygenation (ECMO).[25] Qiu et al. observed fentanyl to be effective in reducing PIPP scores in preterm infants on mechanical ventilation. The effect was most profound at 24 h from the start of the infusion.[26] Another study in Brazil deduced that tramadol and fentanyl, both were effective in the decrease of the CRIES pain score and Neonata Facial activity Coding Scale (NFCS) during the first 72 postoperative hours.[27]

Comparing fentanyl to morphine, a prospective randomized trial conducted by Avino et al. found that there was no statistically significant difference in the median time to successful intubation between the groups receiving remifentanil and morphine as premedication (33 s vs. 36 s; P = 0.359). In addition, there was no difference in the side effect profiles.[28] Another recent study found out that IV fentanyl, intranasal fentanyl, and oral sucrose, all 3, when compared to each other for an ROP examination, were not found to be superior to each other but for laser photocoagulation for ROP, 1% fentanyl (1 mcg/kg/h) was found to be more efficacious than 24% oral sucrose.[29,30] Another recent study, used fentanyl as an analgesic for premedication during surfactant administration by less invasive surfactant administration procedure in neonates with respiratory distress syndrome. The R-PIPP scores were significantly reduced when compared to no premedication, with no complications (P = 0.025).[31]

Benzodiazepines

Despite widespread empirical use and the ability to improve ventilator synchrony, neonatologists face a great deal of concern when it comes to prescribing and administering benzodiazepines.

This is because there are no established rules for their use, and they are frequently combined with opioids, it is challenging to determine their standalone precise effects in real-world situations.[22,32]

Lorazepam

A comparative study for the best sedative agent for procedural sedation found that the use of lorazepam as an alternative to chloral hydrate (CH) may increase the chances of adverse reactions in newborns. CH was found to be a better alternative for procedural sedation than a lot of sedatives and analgesics and also had the least chance of adverse effects.[33]

Midazolam

Midazolam is a short-acting benzodiazepine having a rapid onset of action. It has anxiolytic, muscle relaxant, and anticonvulsant activity, whose main application in the NICUs is to spawn anterograde amnesia.[34] However, benzyl alcohol toxicity in preterm newborns is still a worry because it is a preservative in midazolam preparations and increases mortality and intraventricular hemorrhage (IVH).[35]

A study by Milési et al. concluded that nasal midazolam (nMDZ) had a greater success rate in neonatal intubation in the labor room when compared to ketamine; (88.9% vs. 57.6%; P < 0.01). It also had a lower first-dose to intubation time (mean [standard deviation]; 10 min[6] vs. 16 min[8] P < 0.01).[36] Another cross-sectional study, conducted in 2013, involving 27 neonates, reported that most patients experienced satisfactory comfort during the procedure due to quick intubation which was possible because of the administration of nMDZ to neonates in the delivery room. The primary adverse impact, which necessitated fluid boluses in the more immature infants, was reduced mean arterial blood pressure in the hour after nMDZ, warranting close hemodynamic monitoring.[37] However, an RCT conducted in 2019, probed alternatives for anxiolysis and concluded that melatonin and midazolam were both equally effective in lowering anxiety in the pediatric population undergoing elective surgery, highlighting the importance of nonpharmacological agents for this role and the avoidance of AE’s associated with their counterparts.[38]

Other sedative and analgesics agents

Chloral hydrate

CH in a single dose or for a brief period in newborns is both quite effective and safe but may cause hyperbilirubinemia, especially in premature and sick neonates with impaired hepatic function.[39] The preferred medication for transthoracic echocardiography (TTE) is oral CH, which is also particularly useful in a condition where sedation is useful but analgesia is not needed, particularly imaging procedures. Ganigara et al. reported that oral CH and intranasal dexmedetomidine (DEX) were equally effective for sedating children under the age of 3 years before TTE and also had identical start and recovery times for the sedation.[22,40]

Propofol

Having a quick onset of action and rapid weaning off, along with being easy to use and administer, many NICUs have already implemented propofol to be used in clinical practice for endotracheal intubation.[41] Respiratory depression, hypotension, bradycardia, and upper airway obstruction are some of the detrimental consequences that can ensue. A study by Sgrò et al. concluded that it took less time for the orotracheal intubation procedure using IV propofol rather than sevoflurane, without any compromise in quality.[42] A systematic review conducted by Hayes et al. in 2021, found that combination of propofol and ketamine for procedural sedation and anesthesia in children is related to a slight reduction in hypotension, bradycardia, and apnea.[43]

Ketamine

Ketamine’s use as an analgesic in different procedures or as an adjuvant in surgical and postoperative therapy has drawn some interest in recent years. There is concern about its use, even though it has been shown to cause anxiolysis, analgesia, and incognizance and is still not routinely employed in NICUs. In 2016, the NOPAIN-ROP trial showed that ketamine-based drug routines could only provide analgesia in a small proportion of infants during ROP screening as compared to fentanyl, which was only 4.5% (95% CI: 1.3%–15.1%).[44,45]

Nonsteroidal anti-inflammatory drugs

NSAIDs are associated with a lot of extremely consequential side effects. To list a few, they include gastric erosions, leading to gastrointestinal bleeding. Others are decreased platelet aggregation which can lead to IVH, and reduced glomerular filtration rate leading to renal shutdown.[22,46]

A meta-analysis conducted in 2020, comparing acetaminophen to ibuprofen for controlling pain and fever in children, found that ibuprofen was associated with lesser pain at 4–24 h (95% CI, 0.03–0.37; P = 0.02; I² = 25%; moderate quality evidence). The safety profiles of both medications were also comparable, along with a lower incidence of adverse effects.[47]

Another systematic review conducted in 2022, recommended the use of preprocedure oral paracetamol alongside intraprocedure topical anesthesia with proxymetacaine, along with nonpharmacological measures for pain during ROP screening.[48]

Dexmedetomidine

By activating receptors in the brainstem, DEX, a specific alpha 2-adrenergic agonist, prevents the release of norepinephrine. It performs the functions of a sedative and an analgesic, and because it only slightly depressed breathing, it is also a relatively safe alternative.[49] Its mode of action is the reason that it can be used as a nonbenzodiazepine option for NICU/pediatric intensive care unit sedation since it can provide sufficient sedation with fewer adverse effects than benzodiazepines.[50] DEX is an appealing option for procedural sedation for preterm newborns due to its reduced risk of respiratory side effects and possible neuroprotective characteristics as demonstrated in animal studies.[51]

Mason et al. through their clinical trial, demonstrated that, for kids undergoing computed tomography imaging, hemodynamic indicators such as HR and mean arterial pressure did not change drastically on the infusion of DEX, making it a suitable choice for imaging-related modalities, an area where there already is a paucity for a reliable agent.[52] Another study compared DEX to midazolam for the same procedure and showed that sedation set in quicker in the DEX group. The parents and physician satisfaction score was also higher in the DEX group than in the midazolam group.[53] Another RCT performed by Zhang et al. determined that intranasal DEX can reduce the incidence of peri-operative adverse events in children undergoing cardiac catheterization.[54]

Gabapentin

Gabapentin has been described as advantageous in several painful procedures, such as changing dressings in epidermolysis bullosa, and has been linked to decreased opioid and sedative/anxiolytic usage.[55]

Sacha et al. concluded that gabapentin was a useful alternative for neonates and babies with persistent pain and agitation as it was well tolerated and resulted in reduced pain ratings. Gabapentin was well tolerated in newborns and babies and was linked to lower N-PASS scores after 2 weeks of initiation. Still, there appear to be no standardized guidelines regarding gabapentin use in neonates and further research is warranted as it may serve as an effective alternative to opioids in treating pain.[56,57]

Table 1 summarizes various drugs used for neonatal sedation and analgesia along with their effects, dose, routes of administration and side effects.

Table 1.

Common drugs used for neonatal analgesia and sedation

Drug	Dose	Route	Effect	Side effect/precautions
Morphine	0.025–0.03 mg/kg/dose every 2–4 h	IV	Analgesia, sedation used for postoperative analgesia	Respiratory depression Use in spina bifida/hepatic or renal failure with caution Premature <29 weeks
Fentanyl	10–50 µg/kg	IV	Analgesia, sedation	Chest wall rigidity on fast bolus dose Urinary retention respiratory depression postoperative hypothermia Muscle rigidity
Midazolam	0.03–0.06 mg/kg/h	IV	Used as an adjunct for sedation alongside opioids. Have the added benefit of anxiolysis and relieving agitation	Myoclonic movements (rare) hypotension Irritability methemoglobinemia, due to benzyl alcohol being used as an additive 0.06 mg/kg dose can be used in term infants, whereas 0.03 mg/kg is the dose for preterm infants
CH	25–50 mg/kg	PO/PR	Sedation during outpatient procedures	Respiratory depression hypoxia
Propofol	0.5–4.5 mg/kg	IV	Rapid sedation agent	Respiratory depression hypoxia Bradycardia Upper airway obstruction cardiac monitoring is necessary
Ketamine	0.5–2 mg/kg IV or 2–5 mg/kg PR	IV/PR	Postoperative analgesia anxiolysis	Emergence hypersalivation hypoxemia Atropine use is recommended before administering ketamine
Acetaminophen	20 mg/kg loading dose, followed by 10–15 mg/kg	IV/PR	Analgesia	Gastrointestinal bleed hepatotoxicity at high levels renal impairment
DEX	0.3–0.4 mg/kg	IV	Sedation	Bradycardia Hypotension
Gabapentin	9–22 mg/kg	IV	Analgesia	On abrupt discontinuation, it can cause episodic hypertension, emesis and increased irritability Bradycardia

IV: Intravenous, PO: Per oral, PR: Per rectum, CH: Chloral hydrate, DEX: Dexmedetomidine

Future directions

It is difficult to quantify how pain affects the development of the brain and might be challenging to distinguish the contribution of pain itself from the concomitant illnesses producing painful stimuli given that the severity of the illness can be related to an increased demand for painful therapies.[58] Despite significant advancements in the treatment of newborn pain, several issues still exist.

Recent times are seeing lots of research on combinations of sedatives and analgesics due to more compassionate approaches to neonatal intensive care operations and monitoring, aiming to maximize the efficacy and reduce the adverse effects. Toxicology or drug overdose brought on by repeated use of these medications, or the increased susceptibility of specific groups (such as very preterm babies, sepsis, and renal failure), must be taken into account to assure their safe administration. Clinicians and nurses should undertake a risk–benefit analysis and take into account the long-term side effects of pharmaceutical analgesia, which also calls for the establishment of such protocols. In addition, because nonpharmacological interventions have a lower dose dependence and a lower chance of noticeable side effects than pharmaceutical interventions, they should be used in conjunction with them. Table 2 summarizes some of the options that can be used for various procedures in clinical practice.

Table 2.

Analgesics and sedative options for various procedures in neonatal intensive care units

Summary of procedures and their proposed interventions
Procedure	Proposed interventions	Comments
Heel lancing	Nonpharmacologic measures (breastfeeding or NNS, SSC, holding/swaddling, multisensory stimulation, oral sucrose), use mechanical lance	Consider use of venipuncture as it is less painful, more efficient and requires less sampling May not apply to the care of extremely preterm neonates Local anesthetics, heel warming and acetaminophen are ineffective for heel lancing
Venipuncture or arterial puncture, IV cannulation/removal	Nonpharmacologic measures (breastfeeding or NNS, SSC, multisensory stimulation, holding/swaddling, oral sucrose), use topical and subcutaneous local anesthetics, consider IV fentanyl if ventilated	Arterial puncture is more painful than venipuncture, check dose and duration of anesthetics required
NG/OG tube insertion	Nonpharmacologic measures (NNS, SSC, holding/swaddling, multisensory stimulation, oral sucrose), local anesthetic gel	Use a gentle technique and appropriate lubrication
Umbilical catheterization	Nonpharmacologic measures (oral sucrose, swaddling, or facilitated tucking)	Avoid placement of sutures or hemostat clamps on the skin around the umbilicus
Bladder catheterization	Nonpharmacologic measures (NNS, oral sucrose, swaddling, SSC), IV acetaminophen if prolonged	Inadequate data on pharmacokinetics of acetaminophen at gestational age under 28 weeks to permit calculation of appropriate dosages
Subcutaneous or intramuscular injection	Nonpharmacologic measures (breastfeeding or NNS, SSC, holding/swaddling, multisensory stimulation), and topical local anesthetics	Avoid if possible, give drugs intravenously whenever possible
Peripherally inserted central catheter placement, arterial or venous cut down	Nonpharmacologic measures (NNS, swaddling, multisensory stimulation, oral sucrose), and topical local anesthetics, lidocaine infiltration, consider IV fentanyl or ketamine	Some centers prefer using deep sedation or general anesthesia Most arterial or venous cutdown can be avoided, consider referral to interventional radiology
Lumbar puncture	Nonpharmacologic measures (NNS, holding), and topical local anesthetic, lidocaine infiltration	Use IV analgesia/sedation if patients are intubated and ventilated
Endotracheal intubation	Give fentanyl or morphine, with midazolam, ketamine, use muscle relaxant only if experienced clinician, consider atropine	It should be performed without the use of analgesia or sedation only for resuscitation in the delivery room or for other life threatening situations associated with the unavailability of IV access
Chest tube insertion	Nonpharmacologic measures (NNS/oral sucrose), subcutaneous infiltration of lidocaine, fentanyl (if ventilated: 1–2 µg/kg, if not ventilated: 5–1 µg/kg) or ketamine	Liberal use of local anesthetic with each layer particularly on awake patients Adequately anesthetize the pleural, as it is highly innervated and can be the most uncomfortable portion of the procedure for the patient
Chest physiotherapy	Gentle positioning, IV fentanyl (if chest tube present)	Avoid areas of injured or inflamed skin, areas with indwelling drains or catheters
Eye examination for retinopathy of prematurity	Nonpharmacologic measures (NNS, holding/swaddling), anesthetic eye drops (proparacaine HCl 0.5% or tetracaine)	Best pain reduction measures are unclear
2D - ECHO	Oral sucrose in combination with other nonpharmacological measures such as NNS	Sucrose should be cautiously used in the following circumstances  Intubated neonates  Neonate <27 weeks corrected gestational age  Neonates with cardiac instability

NNS: Nonnutritive sucking, IV: Intravenous, NG: Nasogastric, OG: Orogastric, 2D-ECHO: 2-dimensional echocardiography, SSC: Skin-to-skin care

Despite improvements and advancements in this area of research over the past 20 years, significant gaps in the knowledge still exist, contributing to clinical practice uncertainty and variability. In addition, little is known about the efficacy of treatment, acute toxicity, effects on particular patient populations, or long-term effects of analgesics or sedatives in neonates. Clear therapeutic goals, ongoing physiological monitoring, assessments of side effects or tolerance, and consideration of long-term clinical outcomes must be added to the preliminary findings of various studies/protocols that are being devised.[22] Another important step in the right direction would be a long-term follow-up of infants included in large prospective studies on pain control. All in all, a lot of research is required to devise proper protocols for pain and discomfort faced by neonates in the NICU due to pathology or procedures that are endured by the patients.

Research quality and ethics statement

This project did not require approval by the institutional review board/ethics committee. No applicable EQUATOR Network (http://www.equator-network.org/) guideline is available for narrative reviews.

Conflicts of interest

There are no conflicts of interest.

Funding Statement

Nil