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Is Sucrose Administration a True Non-pharmacological Analgesic during Painful Procedures for Preterm Neonates: The Current State of the Debate

Full article by Megan A. Young

  • Summary
  • Introduction
  • References

Introduction-Historically, infants were rarely given analgesia during painful procedures. A reason for this was the difficulty to discern the causes of infant distress. In the past fifteen years, measures of the effectiveness of non-pharmacological analgesics were developed, including the Preterm Infant Pain Profile (PIPP). The PIPP has been used in several studies to speculate that administration of oral simple sucrose solution provides effective, non-pharmacological analgesia for neonates. However, more recently, the use of sucrose as an analgesic has become scrutinized as there are now more accurate, physiological measures of assessing pain.

This literature review evaluates five recent studies regarding the effectiveness of non-pharmacological analgesia, including sucrose, for premature neonates during routine heel lance.

Method-Using the current protocol for administrating nonpharmacological analgesia in new-born infants during painful procedures was evaluated. A literature review using studies sourced from Cochrane and MEDLINE databases was done to identify and evaluate the current evidence regarding the use of sucrose administration to neonates during painful procedures.Articles from this search were reduced to original research regarding sucrose analgesia in neonates before 2010, and critically appraised randomised control trials comparing sucrose to other topical and oral analgesia with significant results and effects on physiological response to pain that have not been previously observed were evaluated

Discussion- In 2010, Stevens et al. conducted a meta-analysis to evaluate the efficacy of oral sucrose administration for analgesia in 3496 neonates.7 It was found that there was some inconsistency in the effects of sucrose administration affects physiological indicators of pain, such as heart rate and oxygen saturation; this may be due to inconsistency in the amount of sucrose administered across studies.

Slater et al. evaluated the concordance between PIPP score and cortical haemodynamic response in twelve healthy premature neonates over the course of 33 routine heel lance procedures; they found that PIPP score were highly correlated with increased cortical activity.10

Biran et al. conducted a randomised controlled trial comparing the use Eutectic Mixture of Local Anaesthetic (EMLA) cream, a topical analgesic plus oral sucrose to oral sucrose and placebo cream in 76 premature infants during routine venepuncture, and evaluated using PIPP.11The infants in the EMLA group scored significantly better PIPP scores than the placebo group.

Conclusion-The use of sucrose administration to reduce neonatal behavioural and physiological pain response has consistently shown to be effective; however, current research suggests lack of impact on nociceptive pain pathways.6 The recent EEG study analysed in this review suggested that oral
sucrose has no impact on nociceptive pathways to the brain from the affected area during heel lance procedure.6 Since countless well-appraised studies from the past decade have concluded that oral sucrose administration significantly reduces pain response in premature neonates, it should remain an important component of analgesia during painful procedures. However, as the evidence for using concomitant topical, oral or intravenous administration of pharmaceutical analgesia suggests, it is preferable to use it as an add-on to pharmaceutical analgesia where appropriate.12

Abstract

Historically, infants were rarely given analgesia during painful procedures. A reason for this was the difficulty to discern the causes of infant distress. In the past fifteen years, measures of the effectiveness of non-pharmacological analgesics were developed, including the Preterm Infant Pain Profile (PIPP). The PIPP has been used in several studies to speculate that administration of oral simple sucrose solution provides effective, non-pharmacological analgesia for neonates. However, more recently, the use of sucrose as an analgesic has become scrutinized as there are now more accurate, physiological measures of assessing pain.

Previously, reduction of pain response rather than sensitivity was the means of measuring effectiveness of analgesia in infants. It is clear that sucrose reduces pain response in infants; however, it is also important to reduce pain sensation. This is especially important in premature babies, as their neural pathways may not be appropriately developed; really and recurrent exposure to pain is thought to leave potential lasting neurological changes and psychological distress. Although sucrose may not reduce pain sensation, it might be useful as a concomitant agent with pharmaceutical analgesia for reduction of pain sensation. This literature review evaluates five recent studies regarding the effectiveness of non-pharmacological analgesia, including sucrose, for premature neonates during routine heel lance.

Introduction
Until twenty years ago, infants were rarely given analgesia during painful procedures, mainly because it was believed that neonates could not experience pain the way adults do during their early stages of development.1 This belief was rooted in the lack of definitive evidence that neonates experience pain, since early measures to assess pain in neonates had not yet been developed. It wasn’t until the 1980s that a paediatric pain study observed physiological and verbal responses to pain were observed.2 Before this, objective assessment of pain was limited to verbal response; therefore, neonates were widely undertreated for pain if they were unable to express it verbally.3 Infants express most of their needs by crying, making it difficult in ascertaining the exact reason for the infant’s agitation.4Responding to an infant’s crying is often a matter of trial and error, through attempts to feed, change soiled napkins and soothe. Nevertheless, there have been studies that observe infant caregivers’ ability to recognize the pitch, style and volume of their child’s cries and associate them with specific needs- one of these is the need to alleviate pain.4
All neonates experience pain, however, due to differences in development, they may express and respond to it differently. This is especially true for premature infants, who may not have achieved appropriate neurological development, and there may be significant neurological effects of exposure to pain in these infants.6Facial expressions and physiological responses to pain, such as tachycardia, are also useful indications of pain according to the assessment tool, Preterm Infant Pain Profile (PIPP).5The PIPP is now the most prevalent tool for assessing effectiveness of alleviating pain in premature neonates by using behavioural and physiological parameters.5It has been tested for reliability since its development to confirm its appropriateness across international neonatology units Behavioural indicators include high-pitched, harsh crying, specific facial expressions, and increased movement; physiological indicators included tachycardia, hypoxia and increased respiratory rate.5,7More recent studies evaluating physiological measures of pain have found the use of measuring electrical activity in nociceptive pathways.6Further research suggested that PIPP scores and the nociceptive electrical activity may not be related, as there are times when neonates will not engage in pain behaviour, despite increased nociceptive electrical activity.6This suggests that neonates may experience pain without the ability to express it, resulting in widely undertreated pain in neonates.
Non-pharmacological analgesia for neonates include sucking, swaddling and kangaroo care, and oral administration of breast milk or simple sucrose solution.6,7 Administration of a sucrose solution has become a standard of pain protocol for neonates,7 as the reduction of physiological and behavioural pain scores after administering sucrose solution to neonates has been replicated in many studies.6 It was previously hypothesized that oral sucrose may increase endogenous opioid production; however there has been lack of definitive evidence to support this. Meta-analyses of similar studies have consistently resulted in the conclusion that an oral sucrose solution is a cost-effective non-pharmacological analgesic that should be administered during all painful procedures.7 However recent studies evaluating brain activity and electrical nociceptive pathways have shown uncertainty regarding whether sucrose administration truly provides analgesia or simply masks the signs of pain.6 This review of five recent articles on sucrose administration will evaluate the operational definition of analgesia to determine the current rationale for sucrose administration to neonates during painful procedures.
Method
Using the current protocol for administrating nonpharmacological analgesia in new-born infants during painful procedures was evaluated. A literature review using studies sourced from Cochrane and MEDLINE databases was done to identify and evaluate the current evidence regarding the use of sucrose administration to neonates during painful procedures.

Discussion
In 2010, Stevens et al. conducted a meta-analysis to evaluate the efficacy of oral sucrose administration for analgesia in 3496 neonates.7Since different measures of behavioural and physiological pain indicators were used, some studies were excluded from analysis. One study evaluated behaviour indicators of pain, such as total crying time, during venepuncture. There was some inconsistency in the effects of sucrose administration affects physiological indicators of pain, such as heart rate and oxygen saturation; this may be due to inconsistency in the amount of sucrose administered across studies.
Slater et al. evaluated the concordance between PIPP score and cortical haemodynamic response in twelve healthy premature neonates over the course of 33 routine heel lance procedures; they found that PIPP score were highly correlated with increased cortical activity.10 Facial expressions were most correlated with increased cortical activity. There were a few infants did not score high on the PIPP despite increased cortical activity. These findings support the need to effectively block pain pathways using pharmaceutical analgesia to reduce risk of negative impact on neurodevelopment. After the relationship between behavioural and physiological indicators of pain and cortical activity was demonstrated, a double-blind, randomised controlled trial comparing the effect of oral sucrose versus sterile water on nociceptive pathway activity in 59 infants during heel lance.6 Nociceptive cortical activity was measured using electroencephalography (EEG) and PIPP scores.6 The infants in the sucrose group had lower PIPP scores than those given sterile water; however, there was no significant difference in reduction of nociceptive cortical activity on EEG.
Biran et al. conducted a randomised controlled trial comparing the use Eutectic Mixture of Local Anaesthetic (EMLA) cream, a topical analgesic plus oral sucrose to oral sucrose and placebo cream in 76 premature infants during routine venepuncture, and evaluated using PIPP.11The infants in the EMLA group scored significantly better PIPP scores than the placebo group. Although further research must be done to evaluate objective difference in nociceptive activity, this suggests that even behavioural pain response can be improved using concomitant pharmacological analgesia. Furthermore, an Australian study evaluating neonatal pain response to oral sucrose plus an opioid during heel lance found that intravenous morphine, oral codeine or intravenous fentanyl with adjunct oral sucrose significantly reduced physiological and behavioural and physiological pain response in 79 patients with morbidities compared to the 364 healthy patients who were given oral sucrose alone.12

Conclusion
The use of sucrose administration to reduce neonatal behavioural and physiological pain response has consistently shown to be effective; however, current research suggests lack of impact on nociceptive pain pathways.6This could have long-term impact on pain response and psychology in premature neonates, it is also ethically preferable to reduce any distress in patients where possible. Understanding of neonatal pain was previously limited to behavioural and physiological response, such as the PIPP, rather than and neuro-electrical activity and sensation.10 The recent EEG study analysed in this review suggested that oral sucrose has no impact on nociceptive pathways to the brain from the affected area during heel lance procedure.6 Since countless well-appraised studies from the past decade have concluded that oral sucrose administration significantly reduces pain response in premature neonates, it should remain an important component of analgesia during painful procedures. However, as the evidence for using concomitant topical, oral or intravenous administration of pharmaceutical analgesia suggests, it is preferable to use it as an add-on to pharmaceutical analgesia where appropriate.12

Future Research
Most measures of evaluating preterm neonate nociceptive response have been limited to only physiological or behavioural measures; future research should include evaluation of brain activity using EEG or functional Magnetic Resonance Imaging to ensure subjective and objective evaluation of pain sensation. Since the study by Slater et al. is recent and has not been included in most other studies, EEG measurement of nociceptive activity should be replicated to ensure reliability.6
Comparing the cost-effectiveness of using different pharmaceutical analgesia using nociceptive response evaluation may also be beneficial.
The long-term effects of the experience of pain in preterm neonates is not well understood; the potential neurological and psychological effects, including Attention Deficit Hyperactivity Disorder, chronic pain disorders, and hyper and hypo-sensitive pain responses of early pain exposure should be evaluated.6

 

1. Harrison D, Bueno M, Yamada J, Adams-Webber T, Stevens B. Analgesic effects of sweettasting solutions for infants: current state of equipoise. Pediatrics 2010;126(6):894-902.
2. Craig K. Psychology of pain. Postgraduate Med J 1984;60:835-840.
3. Harrison D, Loughnan P, Manias E, Johnston L. Analgesics administered during minor painful procedures in a cohort of hospitalized infants: a prospective clinical audit. J Pain 2009;10(8):715-722.
4. Zeskind P, Marshall T. The Relation between Variations in Pitch and Maternal Perceptions of Infant Crying. Child Dev 1988;59(1):193-196.
5. Stevens BRN, Johnston C, Petryshen P, Taddio A. Premature Infant Pain Profile: Development and Initial Validation. Clin J Pain 1996;12(1):13-22.
6. Slater R, Cornelissen L, Fabrizi L, Patten D, Yoxen J, Worley A, et al. Oral sucrose as an analgesic drug for procedural pain in newborn infants: a randomised controlled trial. Lancet 2010 ;376(9748):1225-1232.
7. Stevens B, Yamada J, Ohlsson A. Sucrose for analgesia in newborn infants undergoing painful procedures. Cochrane Database of Systematic Reviews 2010(1):001069.
8. Codipietro L, Ceccarelli M, Ponzone A. Breastfeeding or oral sucrose solution in term neonates receiving heel lance: a randomized, controlled trial. Pediatrics 2008;122(4):716-21.
9. Liverpool Women’s Hospital. Non-pharmacological analgesia in newborn infants. 2010 (2)-NICU86.
10. Slater R, Cantarella A, Franck L, Meek J, Fitzgerald M. How well do clinical pain assessment tools reflect pain in infants?. PLoS Med 2008;5(7):129.
11. Biran V, Gourrier E, Cimerman P, Walter-Nicolet E, Mitanchez D, Carbajal R. Analgesic effects of EMLA cream and oral sucrose during venipuncture in preterm infants. Pediatrics 2011;128(1):63-70.
12. Harrison D, Loughnan P, Manias E, Smith K, Johnston L. Effect of concomitant opioid analgesics and oral sucrose during heel lancing. Early Hum Dev 2011; 87(3):147-149.
13. Martin EA. Concise Medical Dictionary (Oxford Paperback Reference). 8th ed. Oxford: OUP; 2008.

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