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http://dx.doi.org/10.2147/RRN.S52378

Prevention and management of pain and stress in the neonate

Denise Harrison1,2

Mariana Bueno3

Jessica Reszel2

1School of Nursing, University of Ottawa, Ottawa, ON, Canada; 2Children’s Hospital of eastern Ontario and Children’s Hospital of eastern Ontario Research institute, Ottawa, ON, Canada; 3Department of Maternal Child and Psychiatric Nursing, School of Nursing, University of São Paulo, São Paulo, Brazil

Correspondence: Denise Harrison Children’s Hospital of eastern Ontario, 401 Smyth Road, Ottawa, ON, Canada, K1H 8L1 Tel +1 613 737 7600 ext 4140 Fax +1 613 737 6504 email [email protected]

Abstract: Neonates have blood work for newborn screening in their first days of life, and preterm and sick hospitalized infants often require repeated invasive needle-related procedures

over the duration of their hospitalization. Reducing newborn infants’ pain during such painful

procedures is important and may reduce the risk of negative sequela of poorly treated procedural

pain. High-quality synthesized evidence demonstrates analgesic effects of three pain manage-

ment strategies: breastfeeding; skin-to-skin care, also referred to as kangaroo care; and small

amounts of sweet solutions. These strategies are simple to use, easily accessible, and extremely

cost-effective. Published neonatal and infant pain guidelines include recommendations to use

these strategies prior to and during painful procedures. Yet, despite the robust evidence and

pain management recommendations in guidelines and national and international organizations,

knowledge has not been translated into consistent normalized care in diverse maternal newborn,

neonatal, and pediatric settings where painful procedures for infants take place. There may be

knowledge gaps or barriers impeding consistent use of effective pain management for newborn

infants. This paper will present a brief review of methods used to assess neonatal pain, followed

by a summary of the evidence supporting breastfeeding, skin-to-skin care, and sweet solutions

for procedural pain reduction with a discussion about barriers and facilitators to using these

strategies in the clinical setting. Finally, a review of recommendations included in current neo-

natal pain guidelines will be presented.

Keywords: infant, pain management, breastfeeding, skin-to-skin care, sucrose

Introduction Almost all neonates have blood work for newborn screening in their first days of life,

and preterm or sick hospitalized infants may require repeated invasive needle-related

procedures for medical monitoring over the course of their hospitalization.1–4 The

publication of an increasing number of studies in recent years linking repeated neo-

natal pain exposure with poor neurological outcomes is concerning,5–9 and highlights

the urgent need for health care professionals and parents of healthy, preterm, and sick

neonates, to reduce pain exposure and to advocate for consistent use of effective pain

management strategies.

The encouraging news is that health care providers (HCPs) now have well-validated

means of assessing pain10 and simple, feasible, and effective ways to reduce pain dur-

ing needle-related painful procedures. Breastfeeding (BF),11 skin-to-skin care (SSC),

also referred to as kangaroo mother care,12 and sweet solutions; either sucrose13 or

glucose,14 reduce pain during commonly performed painful procedures compared

to no treatment, water, breast milk, or positioning, swaddling, holding, or cuddling.

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HCPs and parents now have effective pain-reducing strategies

available to use for neonatal pain – the next step is to ensure

that these strategies are consistently used during necessary

painful procedures.

This paper will present an overview of indicators used

to assess pain in the neonate, a review of the evidence sup-

porting BF, SSC, and sweet solutions for procedural pain

reduction, and recommendations included in neonatal pain

management guidelines.

Pain indicators Extensive research by multiple professions including nurs-

ing, psychology, basic science, and medicine, focusing on

neonatal pain measurement has been conducted over the past

20 years.10 The most frequently used indicators of neonatal

pain for clinical care and research purposes are behavioral

indicators – most commonly, facial expressions and crying.

Nearly all composite pain assessment tools developed include

one or both of these behavioral indicators. The first identified

systematic descriptions of infants’ facial expressions during

periods of crying were by Charles Darwin, using a series

of photographs accompanying written explanations of the

facial muscles involved in the formation of expressions of

distress.15 Over a century later, authors of the neonatal facial

coding system categorized ten facial expressions in response

to heel lancing, with the four most frequently occurring facial

expressions of brow bulge, eye squeeze, nasolabial furrow,

and open lips described as the most specific behavioral

indicators of acute procedural pain in infants regardless of

gestational age or severity of illness.16–18 These four facial

expressions form the basis of the majority of the more than

40 composite uni- or multidimensional published pain assess-

ment tools used to quantify the existence and intensity of

pain in neonates.19,20

Crying incidence and duration, although unable to be

assessed in neonates with endotracheal or tracheostomy

tubes, are also frequently used as behavioral indicators of

pain. For example, in the systematic review of sucrose for

neonatal procedural pain, crying duration was used as an out-

come measure in 35 (61%) of the 58 included studies.13 The

acoustic characteristics of a newborn’s cry such as pitch and

amplitude have been studied in the past;21–23 however, they are

rarely used in clinical care or clinical research due to the need

for specialized equipment as well as the lack of specificity

to pain, especially in preterm and sick infants with altered

crying characteristics. Physiological responses to painful

procedures are less sensitive and specific to procedural pain

than behavioral indicators, and are highly influenced by health

status. However, they are also frequently used in studies

evaluating interventions for reducing pain in neonates and

are included in many composite and multi dimensional pain

assessment tools. The most commonly included parameters

are heart rate, oxygen saturation levels, and respiratory rate

and pattern. In the search for reliable objective specific

indicators of pain, numerous other indicators of neonatal

pain have also been explored. These include: heart rate varia-

bility;24 skin conductance, a measure of sympathetic nervous

system activation due to the release of sweat in response to

stress;25–28 stress hormone levels, such as serum, salivary,

urinary, or hair cortisol;29–31 and neural activity such as

electroencephalography (EEG)32,33 or cerebral near-infrared

spectroscopy (NIRS).34 Despite the multitude of indicators

of pain in newborns that have been identified and explored

to various degrees, questions remain about the validity,

reliability, and specificity of these different pain indicators.

A lack of convergence of behavioral, physical, hormonal, and

cortical responses35 further highlight the complex nature of

pain assessment and ongoing research questions to address.

While further research is being planned and conducted to

continue to evaluate neonatal pain assessment methods

and indicators to use in research and clinical care over the

spectrum of neonatal care, in the meantime, clinicians are

faced with decisions about the best pain assessment method

to use. The best answer currently is – use a pain assessment

method that is:

• already developed and tested in the clinical area • suitable for the specific unit/setting/population • feasible to use • acceptable to staff • used consistently • used in ward rounds, handovers, and in clinical care to

make decisions about pain management.

When planning to introduce a new pain assessment

method or composite measurement tool, it is important that

the bedside clinicians are involved in the decision-making

process about which tools are the most suitable for their

patient population. Once the decision has been made, pro-

viding initial and ongoing education to ensure all HCPs are

familiar with the use of the pain assessment tools is vital for

integrating pain assessment into normalized practice.

In addition to the need for further exploration of issues

surrounding the measurement of pain, clinically important

challenges are also to: i) reduce pain exposure, and ii) consis-

tently utilize effective pain reduction strategies in diverse set-

tings where painful procedures take place. Recommendations

aimed at reducing neonatal procedural pain need to start

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Pain and stress in neonates

with minimizing pain exposure. Worryingly, despite the

often quoted study by Barker et al nearly two decades ago

in 1995, which showed that for a cohort of 54 infants in a

neonatal intensive care unit (NICU), over 3,000 procedures

were performed, the large majority being heel lances,36 more

recently published studies continue to report large numbers

of painful procedures with suboptimal use of effective

pain management strategies.1–4,37–47 Such large numbers

of painful procedures continue to occur despite the trend

in the last decade toward use of less invasive respiratory

support.48 Although respiratory support–related procedures

such as endotracheal intubations and airway suctioning have

decreased, Axelin et al reported that the number of heel lances

actually increased.48 This situation highlights the need for

HCPs to balance the need for close monitoring of preterm and

sick neonates’ pathology with efforts to minimize exposure

to painful procedures.

When painful procedures are necessary, however,

evidence-based pain reduction strategies are available. High-

quality synthesized evidence shows that BF, SSC, and sweet

solutions – either sucrose or glucose, effectively reduce

pain during commonly performed needle-related painful

procedures.11–14,49 These three strategies are effective, feasible,

simple to use, and cost-effective. If the mother is able to

participate, BF and SSC during blood collection are free, and

sucrose is inexpensive. Sucrose made by hospital pharmacies

costs approximately 45 cents/dose (R Vaillancourt, personal

communication, 2013) and manufactured sucrose (TootSweet

24%) costs $1/unit (currency in Canadian dollars).

The following section will review the evidence for these

three strategies, facilitators and barriers to using each strategy

in clinical care, and recommendations for practice.

Breastfeeding A Cochrane systematic review of BF or breast milk for pro-

cedural pain management demonstrated analgesic effects of

BF for medically stable newborn infants during heel lance

and venipuncture.11 Twenty trials were included; ten of which

evaluated BF and ten studied analgesic effects of small

volumes of breast milk. Comparators included no treatment,

placebo, sweet solutions, non-nutritive sucking, holding,

and positioning. Overall, findings were that BF effectively

reduced behavioral and physiological responses and com-

posite pain scores during or following painful procedures.

However, small volumes of breast milk were ineffective in

reducing pain. The mechanism of action of BF is considered

to be multifactorial, combining maternal SSC,50 sucking and

slightly sweet taste,51 as well as the presence of endorphins

in the breast milk.52–54 However, lactose, the sugar in breast

milk, is the least sweet of the four sugars,55 and therefore has

minimal sweet taste–mediated analgesic effects when used in

isolation. The conclusions of the systematic review were that

if the mother is available, BF should be used during painful

procedures where feasible.

Facilitators and barriers to implementation BF is a simple and cost-effective method of pain reduction

for neonates during non-urgent procedures such as newborn

screening or routine bloodwork performed by heel lance and

venipuncture. As long as the mother is available, BF requires

no additional resources (ie, cost or equipment) and can thus

be implemented in diverse settings (such as hospitals, clin-

ics, and in the home). Yet, despite the evidence, BF has not

been consistently implemented in clinical practice.38,42 In

a Canadian-wide study of pain management practices in

NICUs, Johnston et al3 showed that of the 582 neonates in

their study, almost half received no pain management during

skin-breaking procedures, and only 0.03% of infants were

breastfed during bloodwork. Barriers to using BF for pain

management, especially in preterm and/or sick neonates in

NICUs may include delayed or impaired sucking reflex,56

separation from the mother,42 as well as the need for further

evidence of effectiveness and feasibility in this population.11

Other barriers include lack of awareness of the benefits,

parents not being aware of the possibility of participating

in pain management, and HCPs’ lack of knowledge of the

evidence and beliefs surrounding BF during painful proce-

dures, such as: the baby will associate feeding with pain and

BF during painful procedures will cause the baby to choke.57

Organizational factors such as the need to schedule non-

urgent blood work around the availability of the mother and

ergonomic factors such as having the nursing or laboratory

staff change positions to accommodate drawing blood during

BF, have also been identified as barriers to implementing

this strategy.38

Skin-to-skin care Johnston et al recently published a Cochrane systematic

review of the effectiveness of SSC for pain management

during painful procedures.12 The systematic review included

19 studies and a total of 1,594 infants. The majority of the

included studies examined heel lance (n=15, 744 infants), and the remaining studied SSC during venipuncture and

heel lance combined, and intramuscular injection. Fifteen

studies included preterm infants and four included full-term

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infants. Eleven of the studies compared SSC with the mother

to a no treatment control group, while the other studies’

comparators included SSC with other family members;

sucrose or other sweet solutions; BF; or enhanced SSC

(rocking, singing, talking, non-nutritive sucking). There

was significant heterogeneity across the studies, including

wide variations in the dose of SSC prior to the procedures,

outcome measures used, and timing of measurement of

outcomes. These factors limited pooling of the results

across the studies. Overall, SSC with the mother had vari-

able effects but in most studies, was more effective than

no treatment. The authors concluded that SSC is safe, and

a potentially beneficial method of reducing physiological

and behavioral responses in neonates during heel lance,

venipuncture, and intramuscular injections.

Facilitators and barriers to implementation Similar to BF, SSC is a cost-effective method for pain man-

agement, requiring only the mother or another caregiver to

hold the infant against their skin, facilitating implementation

in diverse settings. Factors influencing implementation of

SSC during painful procedures have been examined and

include a positive effect of HCPs’ perception of the physi-

ologic stability of the infant58–60 and the level of experience

of the nurse, with more experienced nurses more likely to

implement SSC during painful procedures.58 However, use

of SSC in practice may be hindered by several factors. SSC

requires that the mother or other caregiver be present for the

painful procedure; therefore, non-urgent procedures need

to be scheduled accordingly.38 In addition, there may be the

perception that implementing SSC is not feasible as it takes

additional time to prepare the infant and parent for SSC.38,60

Environmental factors such as dim lighting and lack of

privacy for caregivers, as well as ergonomic factors such as

challenges to drawing blood while the infant is in SSC have

also been identified.38,56,60

Sweet solutions Sweet solutions are the most frequently investigated

strategy for neonatal pain relief. There are now more than

200 published studies reporting calming and analgesic

effects of sweet-tasting solutions in infants, the large major-

ity of which are placebo-controlled trials.49,61,62 Although the

exact mechanism remains uncertain, effects are considered to

be orally mediated through endogenous opioid mechanisms,

with reversal of effects by administration of opioid recep-

tor antagonists.54,63–65 Analgesic effects of sweet solutions

are considered to be taste-dependent, with the sweetest

solutions providing more effective pain relief.55 Sucrose,

a disaccharide (glucose and fructose) is the sweetest of the

sugars (sucrose . fructose . glucose . lactose)55 and the

most effective when compared to less sweet solutions.49

However, glucose, if administered in sufficient concentra-

tions, eg, 20%–30%, is also considered as an effective

alternative.14

Two large systematic reviews, including 57 studies of

sucrose13 and 39 studies of glucose,14 highlight the extensive

and rigorous evidence of sweet taste–induced analgesia

for neonatal pain reduction. The results of both systematic

reviews demonstrated consistent reduction of behavioral

parameters and composite pain scores compared to no treat-

ment groups, water, small volumes of breast milk or formula

milk, and non-nutritive sucking during heel lancing and

venipuncture, as well as less frequently studied painful pro-

cedures such as gastric tube insertions or arterial punctures.

However heterogeneity in outcome measures across stud-

ies included in both systematic reviews precluded broad

pooling of results.13,14 Furthermore, although sucrose or

glucose consistently reduce behavioral responses during

painful procedures compared to no treatment, placebo, or

less sweet solutions, physiological indicators and stress

hormone responses are inconsistently affected by sweet

solutions. In addition, two studies examining the effects

of sweet solutions on cortical responses showed no effects

compared to placebo.32,33,66 Norman et al33 concluded that

EEG was not a useful measure of cortical brain activity in

newborn infants, yet Slater et al concluded that further anal-

gesic studies using cortical measures of pain as outcomes

measures were warranted.32 Weak correlations between

indicators of pain, direction, and degree of responses have

long been reported,67 highlighting challenges in interpreting

and making decisions about the implementation of research

findings. However, the extensive research conducted over

the past 25 years provides indisputable evidence that small

volumes of sweet solutions significantly reduce behavioral

responses and composite pain scores to painful procedures

in newborn and young infants.35 It can therefore be argued

that a condition of clinical equipoise, a requirement for

conducting ethical placebo-controlled trials, has not been

in existence since the publication of the international con-

sensus statement of neonatal pain management in 2001.49,68

In response to this statement, calls have been made to cease

further conduct of placebo-controlled trials of sweet solu-

tions for single episodes of painful procedures for neonatal

pain.49,61,62,69,70

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Pain and stress in neonates

However, uncertainties and important research questions

still remain:

• What are the exact mechanisms of analgesic effects of sweet solutions?

• Does consistent use of sweet solutions as required, during repeated painful procedures, ameliorate negative sequela

of procedural pain exposure?

• Are sweet solutions efficacious when used in the context of exogenous opioids?

• What is the minimal effective volume required for anal- gesic effects?

Addressing these remaining key knowledge gaps need

to be prioritized in future research on sweet solutions for

analgesia.

Facilitators and barriers to implementation Sucrose or glucose solutions are simple to use and cost-

effective, and maximum analgesic effects are rapidly achieved

after delivering the solution onto the tongue (1–2 minutes),35,71

facilitating its use before scheduled and non-scheduled pain-

ful procedures. Ensuring availability and easy accessibility

in diverse postnatal and neonatal settings where bloodwork,

immunizations, and other painful procedures take place is vital

for facilitating consistent use during painful procedures. Many

hospital pharmacies now produce their own sucrose solutions,

and commercially manufactured sucrose solutions are avail-

able for purchase. Glucose is commonly available in clinical

settings for intravenous use and can be orally administered

prior to and during painful procedures.

Remaining knowledge gaps, however, may be acting as

barriers to adoption of sweet solutions into normalized care.

In addition, despite the prolific research conducted to date,

repeated doses of sweet solutions over prolonged periods

have only been investigated in a small number of studies.72–75

Although these studies showed ongoing effectiveness of

sucrose over weeks to months of use, further research in

this area, especially with the aim of exploring if consistently

reducing procedural pain over prolonged hospitalizations

ameliorates negative sequela of untreated pain for preterm

and high-risk neonates, will add valuable information to the

science of neonatal pain management.

Recommendations for practice and clinical practice guidelines Over the past decade, increasing numbers of clinical practice

guidelines (CPG) focusing on, or including neonatal and

infant pain management, have been developed at the level

of individual organizations,40,42,43 as well as at a national and

international level.76–80 In a recent systematic review of CPGs

focusing on pain reduction in neonates, infants, and children,

18 published CPGs were identified, and seven specifically

related to neonates or infants.80 Recommendations for this

age group included minimizing the number of painful pro-

cedures, reducing environmental noise and light, using SSC

or BF during painful procedures, and using sucrose with or

without non-nutritive sucking.

A consistent and coordinated approach to improving neo-

natal pain management and implementing pain management

recommendations included in nationally and internationally

endorsed guidelines is called for. Such a coordinated effort

requires commitment and engagement from all involved

parties, including parents, HCPs from the level of frontline

carers, through to organizational and professional association

leadership, as well as administrators and consumer groups.80

To optimize effectiveness, knowledge translation (KT) efforts

need to target HCPs as well as the parents of healthy, preterm,

and hospitalized term infants. Strategies planned to support

parents to advocate for their infants and participate in their

infants’ pain management during painful procedures need

to include the parents of infants, particularly the mothers, if

BF during routine non-urgent blood draws is to be promoted.

To date, however, very little research has targeted parents of

hospitalized infants as partners in pain management improve-

ment initiatives, despite care being viewed as a partnership

between HCPs and the family,81,82 and parents expressing the

need to be more involved in comforting their infants during

painful procedures.83,84 In addition, in a Canada-wide study,

infants in the NICU whose mothers were present during

painful procedures were more likely to receive effective

pain management strategies than those infants whose moth-

ers were not present,3 highlighting a positive influence of

parents. There is therefore a clear need for developing and

testing acceptable parent-targeted interventions, alongside

HCP-targeted KT interventions, to support parents to be

involved in comforting their infants and to increase use of

BF, SSC, and sucrose during painful procedures. An example

of such an intervention is a publicly accessible YouTube

video, targeted at parents of infants, showing three scenarios;

a mother BF, a mother holding her infant in SSC during heel

lance, and an infant being given sucrose with non-nutritive

sucking during a venipuncture procedure (http://tinyurl.

com/BSweet2newborns). The effectiveness of this YouTube

video and other interventions disseminated via social media

are potentially promising methods to widely disseminate

knowledge. Research is warranted on the reach, impact, and

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effectiveness of using social media avenues such as YouTube

in changing practices.

Conclusion In conclusion, extensive high-quality synthesized evidence

demonstrates the analgesic effects of BF,11 SSC,12 and

sweet-tasting solutions during short-lasting acute painful

procedures.13,14,49 The growing and concerning evidence of

adverse effects of untreated neonatal pain5–9,85 behooves HCPs

in partnership with parents of infants, to strongly advocate for

consistently using suitable effective pain reduction strategies

during necessary painful procedures. Focusing on KT of exist-

ing evidence, while conducting further research to address

remaining key knowledge gaps, will help to ensure that no

infant suffers unnecessary pain during painful procedures.

Acknowledgments The authors wish to thank the Children’s Hospital of Eastern

Ontario Media House, and infants, parents, midwives, nurses,

and physicians who participated in the production of the

BSweet2newborns video.

Author contributions All of the authors have made substantial contribution to the

writing and final editing of this review, and meet all criteria

for authorship as per the author guidelines of this journal.

The authors have all contributed to the production and dis-

semination of the parent-targeted YouTube video (http://

tinyurl.com/BSweet2newborns).

Disclosure The authors report no conflicts of interest in this work.

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