REVIEW ARTICLE Neonatal analgesia: A neglected issue in the tropics

Herbert A. Obu, Josephat M. Chinawa

Department of , College of Medicine, University of Nigeria, University of Nigeria Teaching Hospital, Ituku- Ozalla, Enugu, Nigeria

ABSTRACT control in newborns is poorly understood and often neglected in neonatal practice in many settings in our environment. Managing pain among newborns can be quite challenging and the effectiveness of various interventions used to ameliorate pain in this category of patients are either unknown or poorly understood by many a people engaged in the care of newborns in one way or the other. A search for published works on neonatal analgesia was performed using Google and PubMed. The Cochrane Database of Systematic Reviews was also searched. The areas of focus were definition, pathophysiology and management of pain in neonates. Relevant information was extracted and processed. Contrary to what is widely believed in Address for correspondence: many quarters, howbeit erroneously, there is compelling evidence that newborns do indeed Dr. Josephat M. Chinawa, feel pain. Supportive care, comprising of use of sucrose, glucose, , kangaroo Department of Paediatrics, mother care are worthwhile measures in ameliorating pain in the newborn. Novel therapies University of Nigeria Teaching (such as sensorial saturation and ) have been evaluated and proven useful. The use Hospital, Enugu 01129, Nigeria. of sedation did not show any beneficial results. E-mail: josephat.chinawa@ unn.edu.ng Key words: Control, neonates, pain

INTRODUCTION any form of analgesia. These procedures include ear piercing, circumcision, ligation of extra digits, heel Pain is defined as an unpleasant sensory and/or emotional lancing, venepuncture, lumbar puncture, chest tube 1 experience associated with possible tissue damage. It is insertions, intravenous catheter insertion, endotracheal also defined as localised physical suffering associated with tube suctioning, surgery, etc. Some of these procedures a bodily disorder ( or injury) or as a basic bodily are repeated severally, especially for sick neonates and sensation induced by a noxious , received by naked preterm babies. Indeed, a longitudinal study showed that nerve endings, characterised by physical discomfort (as the youngest pre-term neonates had an average of 750 pricking, throbbing, or aching), and typically leading to procedures during their hospital stay.2 It is noted that evasive action (Merriam-Webster’s English Dictionary, premature in Canadian neonatal intensive care units Merriam-Webster Inc, 2013). (NICUs) were subjected to an average of two and up to eight Verbalisation of nociceptive sensation is the gold standard painful procedures per day. For these infants, 3 for assessment of pain.1 Since neonates cannot verbalise agents were provided in only 6.8% of all procedures. their pain, the recognition and management of pain in Moreover, a recent cohort study showed that less than 10% this category of children has left much to be desired, both of the sickest NICU infants received compared with in hospital settings, including neonatal intensive care 22-33% of those at lesser risk for neurologic impairment.3 units, and in the general population. It is often felt, and There is increasing evidence that newborns indeed most erroneously so, that newborns do not feel pain or experience pain and that these early pain experiences may have not yet developed the capacity to feel pain and as have long-term consequences. Following extensive work a result are exposed to a variety of painful procedures in the 1980s and 1990s, the fact that neonates experience both in hospital settings and in the community without pain and mount a stress response was established and appreciated. Even premature neonates undergoing surgery Access this article online can mount a clinically significant stress response, as Quick Response Code: measured by hormonal and metabolic indicators. Stress Website: indicators include plasma adrenaline, noradrenaline, www.nigeriamedj.com glucagon, insulin and cortisol levels as well as blood glucose, lactate, pyruvate and alanine concentrations.1 DOI: The mounting of a stress response results in catabolic 10.4103/0300-1652.132034 responses, including glycogenolysis, gluconeogenesis and lipolysis. These catabolic responses, when un-modulated

Nigerian Medical Journal | Vol. 55 | Issue 3 | May-June | 2014 Page | 183 Obu and Chinawa: Neonatal analgesia: A neglected issue in the tropics by medical intervention, may have a detrimental effect on 27-32 weeks, where heel lancing was restricted to one the clinical course of a neonatal surgical patient.1 side; periodic flexor threshold testing showed a consistently reduced threshold for the affected heel Before the late nineteenth century, babies were considered compared with the non-injured heel, indicating increased to be more sensitive to pain than adults. Doris Cope quotes pain sensitivity on the side of heel lancing. Compared paediatric surgeon Felix Würtz of Basel, writing in 1656: with untreated and placebo controls, when a group of If a new skin in old people be tender, what is it you think in infants was treated regularly with a topical anaesthetic a newborn Babe? Doth a small thing pain you so much on a beginning 3 days after heel lancing was initiated, flexor finger, how painful is it then to a Child, which is tormented all reflex thresholds between the injured and non-injured the body over, which hath but a tender new grown flesh?.4,5 side became equivalent.12 These findings show that the human neonate is capable of mounting an inflammatory PATHOPHYSIOLOGY OF PAIN response with persisting , or increased sensitivity to pain, due to early painful experiences — a There have been several recent consensus statements response that can be ameliorated by local anaesthetic concerning neonatal pain.6 These evidences show that: application. Anatomical maturation of nociceptive pathways is complete by mid-to-late second trimester;6,7 and physiological Additional studies in humans have supported the responses in behavioural, cardiovascular, respiratory, suggestion that tissue injury at a young age may have endocrine and metabolic systems are similar to that of long-lasting somatosensory sequelae. First, Andrews 13 pain experienced by adults and older children.7 It is now et al., showed that the indicator of the excitability of the known that these physiological and behavioural responses neonatal — a mechanically evoked flexion to painful stimuli can be reduced by analgesia.1 reflex threshold to stimuli applied to the foot and leg — increased with age in normal infants of post conception age The impact of pain may have short (physiological and of 28-42 weeks. However, similar infants with a substantial behavioural) and long-term consequences (increased or leg injury did not exhibit the normal age-related increase decreased behavioural responses to pain),2 even if not in threshold, even when the non-injured leg was tested. expressed as conscious .8-10 of pain may This absent development of normally increasing thresholds be recorded biologically and alter development and contralateral to the injury reflects substantial ‘secondary’ subsequent behaviour.10 changes in the spinal cord itself and not merely to the injured leg.13 Other mechanism involved in the prevention and management of pain in newborns1,2 include: neuroanatomical Finally, studies reveal that lasting changes in pain sensitivity components and neuroendocrine systems. These are with the early experience of pain have been found in full- sufficiently developed to allow transmission of painful term infants as well. Using a prospective cohort design in stimuli in the term neonate. males, one study found that facial pain-score coding from videotape recordings at 4- or 6-month routine vaccination It is important to note here that four basic concepts was related to circumcision status as well as pain treatment explain the physiology of pain. These include transduction, for the procedure.14 In particular, a significant linear trend transmission, modulation and perception. Although of increasing facial pain scores during immunisation still complex, the science of pain reveals a much more emerged from uncircumcised (lowest) to circumcised ambiguous process, and theories are still continuing to infants with topical -prilocaine cream (mid) to evolve. New receptors, pathways and hypotheses are being those who were circumcised with placebo (highest). investigated every day. Genetic variations at the receptor level have been implicated.11 DIAGNOSIS OF PAIN

Pain in newborns is often unrecognised and under treated. Most of the signs of pain in babies are quite straight If a procedure is painful in adults it should be considered forward, requiring no special equipment or training. Here, painful in newborns, even if they are pre-term. Compared the baby cries and remains restless when awake, develops with older age groups, newborns may experience a greater a disturbed sleep pattern, feeds poorly and shows a fearful, sensitivity to pain and are more susceptible to the long-term distrustful reaction towards mothers. effects of painful stimulation. Adequate treatment of pain may be associated with decreased clinical complications The cry response is indispensable and researchers are and decreased mortality.11 now able to differentiate between different kinds of cry: classified as ‘hungry’, ‘angry’ and ‘fearful or in pain’.15 Tissue injury during the early neonatal period may result Interpretation is difficult, however, depending on the in similar enhancement of somatosensory responses. sensitivity of the listener, and varies significantly between This was buttressed in a study in neonates born at observers.16

Page | 184 Nigerian Medical Journal | Vol. 55 | Issue 3 | May-June | 2014 Obu and Chinawa: Neonatal analgesia: A neglected issue in the tropics

Combinations of crying with facial expressions, posture Some studies have identified the pacifying effects of non- and movements, aided by physiological measurements, nutritive sucking, which decreases crying, lowers heart have been tested and found to be reliable indicators.9 A rates and increases oxygenation in term and pre-term number of such observational scales have been published neonates during painful procedures like heel sticks and and verified. Even with noticeable responses from an , venopuncture.21,22 the underlying problem may be hidden. Due to the inability to speak or the side effects of the illness, it may be difficult Furthermore, the analgesic effect of sucrose, first reported to receive a proper diagnosis, causing infant diagnosis to by Blass et al., cannot be downplayed.23 A systematic be one of the hardest to do in the medical field.9 Cochrane review in 2010 including 44 studies and 3496 infants concluded that sucrose is safe and effective for Children and Infants’ Post-operative Pain Scale17 reducing procedural pain in neonates.23,24 The Children and Infants Post-operative Pain Scale (ChIPPS) is often used in the assessment of hospitalised newborns. In addition, it was found that oral glucose or other sweet The scale requires no special measurements, and is solutions also reduce acute pain in neonates during minor therefore applicable across a wide range of circumstances.17 procedures; 30% glucose was effective in term neonates during heel sticks and venipunctures, and in pre-term Described in 2000, the scale uses a measurement of neonates during subcutaneous injections.24 Administration five items, each rated as 0, 1 or 2 based on the following of a sweet solution with a pacifier was synergistic, parameters: [Table 1]. providing stronger analgesic effects.23 Gray et al. found that 10-15 min of between mothers and their 0-3: No requirement for treating pain, term newborns reduced crying, grimacing and heart rate 4-10: Progressively greater need for analgesia. during heel-stick procedures.24

All observations, both movement and physiological, tend to Similarly Johnston et al., showed that kangaroo care decrease when pain is persistent, thus rendering the scale significantly reduced the acute pain responses of pre-term unreliable in acute or prolonged cases. neonates at 32-36 weeks’ and 28-32 weeks’ gestation.25 Breastfeeding maintained throughout a procedure relieved MANAGEMENT procedural pain in term neonates more effectively than swaddling.26 In another study, Carbajal et al., found that Non-pharmacological agents breastfeeding effectively reduced venepuncture-associated There are several approaches in management of pain in pain in term neonates.27 neonates. For instance, acute pain that are meted out from several procedures can be minimised by using indwelling Sensorial saturation (SS) is a procedure in which touch, catheters for blood sampling or by using mechanical devices massage, taste, voice, smell and sight compete with pain, such as spring-loaded lancets for heel sticks. Procedures producing almost complete analgesia during heel prick must be limited to those absolutely necessary for the in neonates. SS is an apparently verbose manoeuvre, but 11 diagnostic or therapeutic management of neonates. when correctly demonstrated, it is easily learnt. In a work Swaddling, which includes wrapping infants to restrict published by Bellieni et al., they studied its feasibility, movements, have modest effects on pain-elicited distress assessing whether a long training is really needed to 28 during and after heel sticks in neonates.18 It is pertinent to achieve good results. They enrolled 66 consecutive babies note that in pre-term infants at 32 weeks, prone positioning and divided them randomly into three groups each of which was not a sufficient intervention for comfort during heel received the following forms of analgesia: glucose plus sticks although gentle massage appeared to have analgesic sucking (A), SS performed by nurses (B), SS performed by effects.19,20 Furthermore, inadequate treatment of pain may mothers (C). They did not use perfume on the caregivers’ have implications that extend beyond the neonatal period, hands, so that babies could perceive the natural aroma of including hypersensitivity to noxious stimuli later in life. the palms. Pain level was assessed by the ABC scale. They noted that, even without the use of perfume on the hands, SS was effective as an analgesic manoeuvre. It made no Table 1: Showing pain scale difference whether SS was performed by mothers who Item Score 0 Score 1 Score 2 applied it for the first time or experienced nurses. SS is Crying None Moaning Screaming rapid to learn and any caregiver (mother, paediatrician or Facial expression Relaxed smiling Wry mouth Grimacing nurse) can effectively use it.28 Posture of the trunk Neutral Variable Rear up Posture of the legs Neutral Kicking Tightened Pharmacological agents Motor restlessness None Moderate Restless A variety of topical anaesthetic creams have been developed, Total score indicates how the baby should be managed according to the scale:18 ranging from single agents with good skin penetration, to

Nigerian Medical Journal | Vol. 55 | Issue 3 | May-June | 2014 Page | 185 Obu and Chinawa: Neonatal analgesia: A neglected issue in the tropics several mixtures of agents and technologically modern Novel therapies (such as SS and swaddling) have been evaluated formulations of lignocaine in microspheres. They are and proven useful. Suitable analgesic and anaesthetic agents in effective in suitable procedures, if correctly and timely various forms are available for pain control in newborns. The applied.29 Local infiltration and can use of sedation did not show any beneficial results. also be used to reduce the pain of the initial injection.

As the site of pain in babies is difficult to confirm, ACKNOWLEDGEMENTS are often advised against until a proper diagnosis has All authors contributed to the writing of this manuscript. JMC been performed. For all analgesic drugs, the immaturity and HAO were involved in the conceptualization, formatting and of the baby’s and metabolic pathways, the writing of this article. IEO and PM were involved in data collection different ways in which the drugs are distributed, and the and analysis. reduced ability of the baby to excrete the drugs through the kidneys, etc., make the prescription of dosage important. The potentially harmful side effects of analgesic drugs are REFERENCES the same for babies as they are for adults and are both well 1. Stevens B, McGrath P, Gibbins S, Beyene J, Breau L, Camfield known and manageable.30 C, et al. Procedural pain in newborns at risk for neurology impairment. Pain 2003;105:27-35. There are three forms of analgesia suitable for the 2. Porter FL, Wolf CM, Miller JP. Procedural pain in newborn treatment of pain in babies: (acetaminophen), infants: The influence of intensity and development. Pediatrics 1999;104:e13. the non-steroidal anti-inflammatory drugs and the . 3. Johnston CC, Collinge JM, Henderson SJ, Anand KJ. A Paracetamol is safe and effective if given in the correct cross-sectional survey of pain and pharmacological analgesia dosage.31 The same is true of the non-steroidal anti- in Canadian neonatal intensive care units. Clin J Pain inflammatory drugs, such as ( is seldom 1997;13:308-12. 4. Cope DK. Neonatal Pain: The Evolution of an Idea. The American used). Of the opiates, and are most Association of Anesthesiologists Newsletter, September 1998. often used in a hospital setting, while is effective Available from: www.asahq.org/Newsletters/1998/09_98/ for use at home. Neonatal_0998.html. [Last accessed on 2013 Oct 15]. 5. Chamberlain DB. Babies remember pain. Pre-Peri-natal Other pharmacological agents used to reduce pain in Psychol 1989;3:297-310. Available from Circumcision neonates are sedatives. Some work had been executed Reference Library [Last accessed on 2013 Oct 15]. 6. Shah V, Ohlsson A. Pain in the newborn. In: Moyer VA, using sedatives to relieve pain in neonates, for instance, Elliot E, editors. Evidence Based Pediatrics and Child Health. Eloisa et al. evaluated the analgesic activity of melatonin London: BMJ Books; 2004. p. 509-22. during endotracheal intubation of the newborn by using 7. Puchalski M, Hummel P. The reality of neonatal pain. Adv the Neonatal Infant Pain Scale (NIPS) and Premature Infant Neonatal Care 2002;2:233-44. 8. Whitfield MF, Grunau RE. Behaviour, pain perception, and Pain Profile (PIPP) score. Secondary outcome was an the extremely low-birth weight survivor. Clin Perinatol 32 evaluation of melatonin as inflammatory responses. This 2000;27:363-79. was performed by measuring the levels of pro- and anti- 9. Porter FL, Grunau RE, Anand KJ. Long-term effects of pain in inflammatory cytokines implicated in the pain. Sixty pre- infants. J Dev Behav Pediatr 1999;20:253-61. term infants were enrolled in the study and were randomly 10. Anand KJ, Scalzo FM. Can adverse neonatal experiences alter brain development and subsequent behaviour? Biol Neonate divided into two groups: 30 infants treated with melatonin 2000;77:69-82. plus common sedation and analgesia recommended by 11. Zacharoff KL. Pathophysiology of pain. Northwest Regional Italian Society of Neonatology (group 1) and 30 infants Primary Care Association. Obtainable at http://www.nwrpca. treated with only common sedation and analgesia. The org/health-center-news/156-thepathophysiology-of-pain. html.assessed on 2013. sedative and analgesic drugs included atropine, fentanyl 12. Fitzgerald M, Millard C, McIntosh N. Cutaneous hypersensitivity and vecuronium. The reduction in pain score (NIPS) was following peripheral tissue damage in newborn infants and its similar in both groups at an early phase, while it (PIPP reversal with topical anaesthesia. Pain 1989;39:31-6. score) was lower in melatonin-treated group of infants 13. Andrews K, Fitzgerald M. Cutaneous flexion reflex in human neonates: A quantitative study of threshold and stimulus- than the other newborns at a late phase, during intubation response characteristics after single and repeated stimuli. 32 and mechanical ventilation. Notwithstanding, sedation Dev Med Child Neurol 1999;41:696-703. does not provide pain relief and may mask the neonate’s 14. Andrews KA, Desai D, Dhillon HK, Wilcox DT, Fitzgerald M. response to pain. Abdominal sensitivity in the first year of life: Comparison of infants with and without prenatally diagnosed unilateral hydronephrosis. Pain 2002;100:35-46. CONCLUSION 15. Koeslag J. The human lifecycle, Obtainable at http:// en.wikipedia.org/wiki/Pain_in_babies.Assessed on 18/01/2013 Newborns do indeed feel pain. Supportive care, comprising 16. Zeskind PS. Cross-cultural differences in maternal of use of sucrose, glucose, breastfeeding, kangaroo perceptions of cries of low- and high-risk infants. Child Dev 1983;54:1119-28. mother care are worthwhile means of ameliorating pain 17. Buttner W, Finke W. Analysis of behavioral and physiological in newborns. parameters for the assessment of postoperative analgesic

Page | 186 Nigerian Medical Journal | Vol. 55 | Issue 3 | May-June | 2014 Obu and Chinawa: Neonatal analgesia: A neglected issue in the tropics

demand in newborns, infants and young children: A from heel lance in very preterm neonates: A crossover trial. comprehensive report on seven consecutive studies. Paediatr BMC Pediatr 2008;8:13. Anaesth 2000;10:303-18. 26. Gray L, Miller LW, Philipp BL, Blass EM. Breastfeeding is 18. van Sleuwen BE, Engelberts AC, Boere-Boonekamp MM, analgesic in healthy newborns. Pediatrics 2002;109:590-3. Kuis W, Schulpen TW, L’Hoir MP. Swaddling: A systematic 27. Carbajal R, Veerapen S, Couderc S, Jugie M, Ville Y. Analgesic review. Pediatrics 2007;120:1097-106. effect of breastfeeding in term neonates: Randomised 19. Grunau RE, Linhares MB, Holsti L, Oberlander TF, Whitfield controlled trial. BMJ 2003;326:13. MF. Does prone or supine position influence pain responses 28. Bellieni CV, Cordelli DM, Marchi S, Ceccarelli S, Perrone S, in preterm infants at 32 weeks gestational age? Clin J Pain Maffei M, et al. Sensorial saturation for neonatal analgesia. 2004;20:76-82. Clin J Pain 2007;23:219-21. 20. Jain S, Kumar P, McMillan DD. Prior leg massage decreases 29. Wagner AM. Pain control in the paediatric patient. Dermatol pain responses to heel stick in preterm babies. J Paediatr Clin 1998;16:609-17. Child Health 2006;42:505-8. 21. Golianu B, Krane E, Seybold J, Almgren C, Anand KJ. 30. Mathew PJ, Mathew JL. Assessment and management of Non-pharmacological techniques for in pain in infants. Postgrad Med J 2003;79:438-43. neonates. Semin Perinatol 2007;31:318-22. 31. Walco GA, Cassidy RC, Schechter NL. Pain, hurt and harm. 22. Corbo MG, Mansi G, Stagni A, Romano A, van den Heuvel The ethics of pain control in infants and children. N Engl J J, Capasso L, et al. Nonnutritive sucking during heelstick Med 1994;331:541-4. procedures decreases behavioral distress in the newborn 32. Gitto E, Aversa S, Salpietro CD, Barberi I, Arrigo T, Trimarchi infant. Biol Neonate 2000;77:162-7. G, et al. Pain in neonatal intensive care: Role of melatonin as 23. Blass EM, Hoffmeyer LB. Sucrose as an analgesic for newborn an analgesic antioxidant. J Pineal Res 2012;52:291-5. infants. Pediatrics 1991;87:215-8. 24. Stevens B, Yamada J, Ohlsson A. Sucrose for analgesia in newborn infants undergoing painful procedures. Cochrane How to cite this article: Obu HA, Chinawa JM. Neonatal analgesia: Database Syst Rev 2010;CD001069. A neglected issue in the tropics. Niger Med J 2014;55:183-7. 25. Johnston CC, Filion F, Campbell-Yeo M, Goulet C, Bell L, Source of Support: Nil, Confl ict of Interest: None declared. McNaughton K, et al. Kangaroo mother care diminishes pain

Nigerian Medical Journal | Vol. 55 | Issue 3 | May-June | 2014 Page | 187 Copyright of Nigerian Medical Journal is the property of Medknow Publications & Media Pvt. Ltd. and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use.