Managing pain in newborns: A multidimensional approach

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Background

The experience of early, acute pain is commonplace for most newborns, who receive a routine vitamin K injection and heel lance or venipunctures for blood collection in their first hours and days post-birth. Infants requiring neonatal intensive care are reported to undergo between 7 and 17 painful procedures daily^[1], and they may, routinely, go on to receive up to 20 immunizations in their early years^[1]-[4].

Otherwise healthy newborns who are exposed to inadequately treated or repeated pain (or both) in the early years, which is also a critical period for brain development^[5], can experience immediate effects, such as physiological instability, and longer term outcomes such as heightened inflammatory response and altered sensitivity to subsequent pain. For infants delivered very preterm, exposure to repeated pain and related distress is associated with immediate physiological instability and the following long-term outcomes: altered pain processing, cognition, and behaviour^[5][6], including executive function and visual abilities^[7], altered hypothalamic-pituitary-adrenal axis development and cortisol dysregulation^[8], reduced brain growth and structure^[9], altered thalamic development^[10], decreased frontal and parietal brain width, altered diffusion measures and functional connectivity in the temporal lobes, abnormalities in motor behaviour^[11], and reduced cerebellar size^[12]. Alterations in epigenetic programming and telomere length in infants born preterm have also been linked to repeated pain exposure in early life^[13]-[15].

This position statement, which revises and updates a 2007 joint statement on this topic from the Canadian Paediatric Society (CPS) and the American Academy of Pediatrics (AAP)^[16], addresses priority questions regarding the assessment and management of newborn pain, and provides practice recommendations on strategies to improve care, including the engagement of parents in pain prevention and care.

Statement development method

A comprehensive search was conducted from inception to June 2023 that included the Cochrane Central Register of Controlled Trials (CENTRAL 2023, issue 6) in the Cochrane Library; MEDLINE (1950 onward); EMBASE (1974 onward); CINAHL (1982 onward); Web of Science (1980 onward); and PsycINFO (1980 onward). Key terms, developed in collaboration with a health sciences librarian specializing in systematic searches and informed by experts in the field, included: neonate, pain, pain measurement, pain management, procedural pain, and other applicable MeSH terms. Randomized controlled trials (RCTs), including crossover studies, and systematic reviews were specifically sought. Searches were not restricted by language.

Priority questions on neonatal pain management

1.  How should we reduce exposure to pain?

Care providers should incorporate and emphasize infant care practices to minimize the number of painful procedures in care as much as possible (e.g., by eliminating routine blood collections, non-invasive monitoring, and clustering required bloodwork). 

2.  Which are the most sensitive and specific pain assessment tools?

Because infants may express but cannot describe physical experiences, the use of sensitive, reliable tools to assess pain by competent trained care providers is an essential component of optimal pain management^[17]. The choice of what tool to use depends on  purpose, age, and the type of pain being assessed. A tool should be multi-dimensional (Table 1), validated to detect all painful situations (highly sensitive), and able to: discriminate between painful and non-painful situations (highly specific), produce the same results when repeated by different observers (reliable), and help determine whether a pain-relieving intervention was effective (evaluate responsiveness)^[18]. The tools most used in clinical studies are the Premature Infant Pain Profile (PIPP/PIPP-R, at 43.9%) and the Neonatal Infant Pain Scale (NIPS, at 23.9%)^[19]-[27].

Table 1. Multi-dimensional pain assessment
Instrument	Indicators	Validated for pain type and infant age
ALPS-Neo/Astrid Lindgren and Lund Children’s Hospitals Pain and Stress Assessment Scale for Preterm and Sick Newborn Infants[20]	Facial expression, breathing pattern, tone of extremities, hand/food activity, level of activity	Prolonged pain in preterm and term infants
CRIES[21]	Crying, Requires oxygen, Increased vital signs, Expressions, Sleeplessness	Prolonged pain in preterm and term infants and children up to 6 years of age
EDIN – Échelle de Douleur et d'Inconfort du Nouveau-né (EDIN)[22]	Facial activity, body movements, quality of sleep, quality of contact with nurses, consolability	Prolonged pain in preterm infants
NIPS – Neonatal Infant Pain Scale[23]	Facial expression, cry, breathing patterns, arms, legs, state of arousal	Acute procedural pain in preterm and term infants
N-PASS – Neonatal Pain, Agitation and Sedation Scale[24]	Crying/irritability, behavioural state, facial expression, tone in extremities, vital signs	Acute procedural pain, prolonged pain (post-operative and during mechanical ventilation) in both preterm and term infants
PAT – Pain Assessment Tool[25]	Posture/tone, sleep patterns, expression, colour, cry, respirations, heart rate, oxygen saturation, blood pressure, nurse perceptions	Post-operative pain in preterm and term infants
PIPP, PIPP-R – Premature Infant Pain Profile (Revised)[26][27]	Gestational age, behavioural state, heart rate, oxygen saturation, brow bulge, eye squeeze, naso-labial furrow	Acute procedural pain in preterm and term infants

3.  What interventions to reduce infant pain are most effective?

This overview of existing evidence across treatments is based on direct comparison studies and systematic reviews. Routinely performed painful procedures included those involving insertion of a needle (i.e., arterial puncture, heel lance, subcutaneous and intramuscular injections, intravenous insertion, venipuncture, lumbar puncture, peripherally inserted central line, chest tube insertion), and non-needle-related procedures (i.e., endotracheal intubation, endotracheal suctioning, naso/oro gastric tube insertion, and ocular examination in the context of retinopathy of prematurity (ROP) evaluation).

Acute pain associated with routinely performed procedures

Non-pharmacological interventions

Direct breastfeeding and expressed human milk

Evidence of moderate certainty suggests that direct breastfeeding (where the infant latches onto the breast and actively sucks and swallows for at least 2 minutes before a painful procedure) is more effective in preventing pain than placebo or no treatment, swaddling, maternal holding, or skin-to-skin contact, topical anaesthetics, cooling spray, non-nutritive sucking, heel warming, and music therapy^[28][29]. 

Evidence of very low certainty from randomized trials suggests that direct breastfeeding may be more effective than sweet-tasting solutions (i.e., sucrose)^[29]-[31]. Mothers report feeling positive about breastfeeding during their infant’s heel lance procedure ^[30]. Studies assessing  feeding with expressed human milk without maternal contact have shown this strategy to be less effective than direct breastfeeding and use of sweet tasting solutions. However, human milk feeding is still more effective than either placebo or no treatment^[27][29].

Skin-to-skin care 

Skin-to-skin care (SSC) is defined as the diaper-clad upright holding of the infant on the chest, providing maximal skin-to-skin contact between the baby and parent. A 2023 Cochrane review of 36 RCTs, enrolling 3403 term and preterm neonates, demonstrated with moderate certainty that SSC reduces composite pain scores post-procedure and the proportion of infants showing high pain scores during and after procedure. SSC’s effect on physiological parameters were mixed (high to very low certainty evidence), but it likely reduces crying and stabilizes heart rate post-procedure (moderate certainty). There appears to be little or no difference in efficacy of SSC compared with sucrose solutions (moderate-certainty). SSC provided by a birthing parent compared with an alternative provider or parent may result in little or no difference in composite pain scores following a heel lance (high to very low certainty). SSC was shown in one clinical trial with low risk of bias to remain effective over repeated painful procedures across neonatal intensive care unit (NICU) hospitalizations for preterm infants^[33]. A recent CPS statement examines this comfort measure in detail^[34]. 

Non-nutritive sucking (NNS)

A Cochrane systematic review of 63 RCTs enrolling 4905 infants found that non-nutritive sucking (NNS, or pacifier use) improved physiological regulation after painful procedures in term and preterm neonates, and pain response in term neonates^[35]. The combining of NNS with oral sucrose^[32] or ‘containment’ (see below)^[36] may result in greater effectiveness.

Facilitated tucking or ‘containment’

Facilitated tucking involves placing hands on the head and limbs of an infant who is undergoing a painful procedure to comfort and maintain them in a side-lying, flexed position^[37]. In a meta-analysis of 15 clinical trials examining the pain-reducing effects of facilitated tucking, preterm infants who received this intervention during endotracheal suctioning had reduced pain response compared with placebo or control (low certainty evidence). There was no difference in pain response during heel-lance when facilitated tucking was compared with oral glucose or an oral opioid (very low certainty evidence)^[38]. However, facilitated tucking was more beneficial when combined with other interventions, such as sucrose, NNS, or both^[39]-[42]. In a review of 14 trials, authors reported that combining non-pharmacological interventions (e.g., sucrose, containment, NNS, and parent voice), may be more effective than single modalities^[43]. Infant massage prior to the procedure may provide some additional effect, though the evidence for this effect was of very low certainty^[44].

Sweet-tasting solutions

Orally administered sucrose is the most extensively studied treatment for the management of infant procedural pain, with 74 RCTs (n = 7,049)^[45]. While various concentrations of sucrose have been tested, the strongest evidence for their pain-reducing effect is 24% sucrose solution when combined with NNS^[45]. Combining sucrose with other adjuvant interventions, such as swaddling, may provide added pain-reducing benefit^[46].

One recent meta-analysis of 55 trials enrolling 6273 infants (29 included term neonates, 22 included preterms, and 4 included both) reported on the effectiveness of sucrose to reduce pain associated with heel lance. Administering sucrose with or without NNS appears (based on evidence of moderate certainty) to be effective for pain relief following a single heel lance^[47]. Very low to low-certainty evidence was found regarding efficacy of sucrose alone when compared with NNS, facilitated tucking, expressed breast milk, music, sucrose, SSC, or breastfeeding.

Some concern regarding the sedative versus analgesic effect of sucrose has been raised in the literature, based on data derived from neonatal EEG readings. However, the limitations of these studies render the evidence insufficient to support or refute such concerns^[30][47]. Findings from 8 trials provide evidence supporting the safety and efficacy of repeated sucrose administration^[49]. Only minor and self-resolving adverse effects have been documented with sucrose administered for single procedures.

Data around the appropriate dosing of sucrose is limited, but the evidence suggests that smaller volumes (e.g., 0.1 mL or 0.2 mL) repeated throughout a painful procedure provide similar benefit in reducing pain (based on composite pain measures) as larger volumes (e.g., 0.5 mL to 1.0 mL) administered before the painful procedure^[50][51]. Little to no evidence exists regarding isolated or long-term neurodevelopmental effects following sucrose administration during the neonatal period or the safe, efficacious use of sucrose in extremely preterm infants.

Pharmacological interventions

Topical anaesthetic

A 2017 Cochrane review including 8 RCTs (n=506), reported that in term or preterm newborn infants, topical local anesthetics such as a eutectic mixture of 2.5% prilocaine and 2.5% lidocaine applied to the skin did not reduce pain associated with heel lance or frenotomy^[52]. A topical lidocaine and prilocaine mixture may reduce pain associated with lumbar puncture^[53]. However, due to the potential for systemic absorption, topical applications should be used with caution in extremely preterm infants, and smaller doses considered^[53]. 

Topical anaesthetic eye drops reduce pain associated with routine eye examinations for screening of ROP^[54], although their use alone does not provide optimal pain relief. Topical anaesthetic eye drops should be combined  with multi-sensorial interventions such as NNS, containment, sweet taste, parent voice, or touch^[55].

A systematic review of 29 RCTs demonstrated that using topical anesthetics alone during circumcision provided insufficient pain relief. They should always be combined with other interventions, such as regional block^[56].

Acetaminophen/Paracetamol

Acetaminophen (or paracetamol) is one of the most widely used analgesics in the NICU. However, one Cochrane review of 9 trials (n=728) provided only low-certainty evidence that acetaminophen reduced pain from heel lance or eye examination for ROP assessment more effectively than administering water, cherry elixir, or a topical lidocaine/prilocaine mixture^[57].

Opioids

A 2023 Cochrane review evaluating the benefits and harms of opioids in term or preterm neonates exposed to procedural pain included 13 studies (n=823 infants). Seven studies compared opioids with no treatment or placebo (the main comparison in this review), 2 with a sweet-tasting solution (or other non-pharmacological intervention), and 5 with another analgesic or a sedative^[58]. Compared with placebo, opioids probably reduced pain scores assessed using the  PIPP/PIPP-R scale during a medical procedure, may reduce NIPS during the procedure, and may result in little to no difference in DAN (the Douleur Aiguë Nouveau-né scale) 1 to 2 hours post-procedure. Opioids may increase apnea episodes, but the evidence is also very uncertain regarding their effect on episodes of bradycardia or hypotension. The evidence is also very uncertain regarding the effect of opioids on any outcome when compared with non-pharmacological interventions or using other analgesics. No studies have provided head-to-head comparison of different opioids or compared different routes of administration of the same opioid in newborns.

Non-opioid analgesics or sedatives

There is some interest in the possibility that non-opioid analgesics, specifically non-steroidal anti-inflammatory drugs (NSAIDs) and N-Methyl-D-aspartate (NMDA) receptor antagonists, which alleviate pain by inhibiting cellular pathways, could be effective and safe alternatives to opioids for alleviating neonatal pain. However, to date, only two RCTs including 269 neonates have been conducted^[59]. One study compared oral ketamine (10 mg/kg body weight) versus sugar syrup (66.7% w/w at 1 mL/kg body weight) for neonatal circumcision. The other study compared intravenous fentanyl with intravenous ketamine during laser photocoagulation for ROP. In both studies, the evidence was of very low certainty and no recommendations could be made. No studies were found comparing NSAIDs with no treatment, placebo, sweet-tasting solutions, non-pharmacological interventions, or different routes of administration for the same analgesics^[60].

Pain associated with mechanical ventilation

To fulfill the medico-ethical obligation to “do no harm”, care providers must ensure that all infants undergoing non-emergent endotracheal intubation or laryngoscopy receive an effective analgesic beforehand. Endotracheal intubation has been clearly associated with moderate to severe pain and stress, and untreated pain in early life with impeding health outcomes. Providing analgesia increases clinical success rates and reduces adverse effects such as rising intracranial pressure and physiological instability^[61][62]. Details regarding the type and dosage of premedication are provided in a CPS statement on this topic. Infant response to an opioid during invasive mechanical ventilation should be evaluated using a validated pain assessment tool (Table 1)^[63]. Midazolam should be avoided in infants younger than 34 weeks and is not indicated for post-operative pain because it lacks analgesic properties^[64]. Sedative agents should be used with caution in all infants and, if used, should be considered an adjuvant therapy rather than administered as a sole agent^[65].

Major invasive and post-operative pain

Opioids should be used to reduce pain associated with a major invasive procedure (e.g., chest tube insertion) and post-operatively. Limited data exist regarding the benefits and harms of systemic opioid analgesic use in neonates undergoing a major surgery. Most relevent studies did not report on pain scores during invasive procedures or on later patient outcomes (i.e., major neurodevelopmental disability or cognitive or educational impairment) at follow-up. No studies were found comparing opioids with non-pharmacological interventions in acute settings.

Regular-dose acetaminophen used as an adjuvant in treating major pain (e.g., chest tube insertion) and post-operative pain may reduce the total amount of opioid required ^[68][69]. A 2020 consensus statement from the Enhanced Recovery After Surgery (ERAS) Society advised that, barring contraindications, regular dosing of acetaminophen (rather than “as needed” administration) should be used following neonatal intestinal surgery and throughout the early postoperative phase. This approach aims to reduce but not replace opioid use^[70].

Dexmedetomidine, a selective alpha-2 adrenergic receptor agonist, is increasingly being used off-label across NICUs, either as primary therapy or as an adjunct combined with an opioid. In a small cohort study examining the pharmacokinetic (PK) profile of dexmedetomidine, the PK variables for preterm infants (n=18) were different from those for term infants (n=24), and different again from variables reported previously for children and adults. Adverse events (i.e., hypotension, hypertension, extreme agitation) were similar across both gestational age groups (61% and 62.5%, respectively). In one small retrospective study (n=38) of infants receiving dexmedetomidine postoperatively, 67% received less opioid but 89% had at least one adverse event and, despite 80% of infants having a gradual wean, 71% experienced at least one sign of opioid withdrawal^[71][72]. To date, there have been no clinical trials examining the effectiveness, safety, or neurodevelopmental impact of dexmedetomidine use in newborns^[73]. Similarly, there is no evidence to recommend or refute the use of clonidine to prevent or treat procedural or postoperative pain, or pain associated with clinical conditions in neonates^[74].

Whole body hypothermia or selective head hypothermia for infants with hypoxic ischemic encephalopathy

There is limited evidence from RCTs to make any recommendations on optimal pain and sedation management in newborn infants undergoing therapeutic hypothermia^[75][76].

4. How should parents and families be actively engaged in neonatal pain management?

Historically, the role of parents in neonatal pain care has been significantly underappreciated and used, and lack of focus on ensuring that families have the resources needed to manage infant pain sufficiently is an ongoing issue^[77]-[80] in Canada. Parents report that seeing their child in pain is one of the most stressful aspects of required neonatal care^[81][82] and want to be more involved in their infant’s pain care^{[77]-[80][83]}. The important role parents can play in reducing infant pain also strengthens their parenting roles generally^[84]. Parent-led interventions, such as direct breastfeeding and SSC, are among the most effective ways to reduce procedural pain in neonates^[35][85]. While facilitated tucking, parental voice, singing, or music may be less effective as first-line interventions, they are superior to placebo and can be considered as complementary strategies^{[28][29][34][86][87]}. In keeping with recommendations that any painful procedure should always be performed with at least two people present, parents may also be second care providers during procedures. Neonatal health care professionals should empower families through counselling, involvement, and site-specific resources to be both advocates for, and active participants in, their infant’s pain and comfort care^[88][89], as fully engaged members of the neonatal health care team^[90]-[93].

Recommendations

Prevention

• Avoid routine blood sampling. Investigations that require  blood draws should be clustered whenever possible and only performed when required  (i.e., when there is clear justification that testing will alter management based on results). 

Assessement

• Hospital care providers should be trained to assess newborn pain and stress using gestational age-appropriate and validated tools (Table 1).
• Infant pain should be reassessed regularly using the same tool(s): at least once per shift, always before and after a procedure, and with greater frequency when determined by an infant’s condition or a previous assessment.
• To guide provision of pain care, assessment results should be recorded and reported, with responsive care actions and strategies specified in advance for every level of pain.

Parent engagement

• Painful procedures should be performed with at least two care providers present, one of whom  can be a parent.
• Parents should be actively engaged in assessing their child’s pain, decision-making regarding management strategies, and be invited to lead such interventions whenever possible.

Pain management

Needle-related procedures

• Maternal or parent-led interventions such as direct breastfeeding and skin-to-skin care should be considered as first-line pain management before and during needle-related procedures.
• Sweet-tasting solutions combined with non-nutritive sucking may be considered as second-line management steps to reduce procedural pain.
• Combining non-pharmacological interventions as adjuvant therapies should be considered essential comfort care for any painful procedure.
• Topical anesthetics should not routinely be used for heel lance or frenotomy.
• Topical anesthetic eye drops combined with a sweet-tasting solution, non-nutritive sucking, containment, and parental presence or voice should be provided during eye examinations for screening of retinopathy of prematurity.
• Topical anesthetic use may be considered at the needle insertion site for lumbar puncture. Topical anesthetics should be used with caution in extremely preterm infants, who must then be monitored closely for adverse effects.
• Topical anesthetic should be used in combination with a regional anesthetic block during circumcision.  
• Acetaminophen should not be used routinely for treatment of procedural pain.

Surgical, major invasive and post-operative procedures

• Acetaminophen should be considered as post-operative adjuvant therapy.
• All infants undergoing non-emergent laryngoscopy should receive effective analgesic.
• Opioid administration during invasive mechanical ventilation should be guided by a valid pain assessment tool. Continuous infusion or intermittent boluses of opioids should be provided for surgical pain, major invasive procedures, and post-operatively.
• Sedative agents should be used with caution and, if used, should be considered as an adjuvant therapy and not be provided alone as a sole agent. Midazolam should be avoided in infants younger than 34 weeks, and no recommendation can yet be made for the safe use of ketamine.

Acknowledgements

This position statement was reviewed by the Acute Care and Community Paediatrics Committees of the Canadian Paediatric Society.

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CANADIAN PAEDIATRIC SOCIETY FETUS AND NEWBORN COMMITTEE (2023-2024)

Members: Gabriel Altit MD, Anne-Sophie Gervais MD (Resident Member), Heidi Budden MD (Board Representative), Leonora Hendson MD (past member), Souvik Mitra MD, Michael R. Narvey MD (Chair), Eugene Ng MD, Nicole Radziminski MD
Liaisons: Eric Eichenwald MD (Committee on Fetus and Newborn, American Academy of Pediatrics), William Ehman MD (College of Family Physicians of Canada), Isabelle Milette RN (Canadian Association of Neonatal Nurses), Emer Finan MBBCH (CPS Neonatal-Perinatal Medicine Section Executive), Chantal Nelson PhD (Public Health Agency of Canada), Douglas Wilson (The Society of Obstetricians and Gynaecologists of Canada)
Authors: Marsha Campbell-Yeo RN NNP-BC PhD (Dalhousie University, IWK Health), Timothy Disher RN PhD (Eversana Inc.), Souvik Mitra MD, PhD

Funding
There is no funding to declare.

Potential Conflict of Interest
Timothy Disher PhD is an employee of Eversana Inc, which consults for various pharmaceutical and medical device companies.  Other authors have no reported conflicts of interest.

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References

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Disclaimer: The recommendations in this position statement do not indicate an exclusive course of treatment or procedure to be followed. Variations, taking into account individual circumstances, may be appropriate. Internet addresses are current at time of publication.