Neonatal analgesia: A neglected issue in the tropics.

Pain 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 many quarters, howbeit erroneously, there is compelling evidence that newborns do indeed feel pain. Supportive care, comprising of use of sucrose, glucose, breastfeeding, kangaroo mother care are worthwhile measures in ameliorating pain in the newborn. Novel therapies (such as sensorial saturation and swaddling) have been evaluated and proven useful. The use of sedation did not show any beneficial results.

INTRODUCTION

Pain is defined as an unpleasant sensory and/or emotional experience associated with possible tissue damage.1 It is also defined as localised physical suffering associated with a bodily disorder (disease or injury) or as a basic bodily sensation induced by a noxious stimulus, received by naked nerve endings, characterised by physical discomfort (as pricking, throbbing, or aching), and typically leading to evasive action (Merriam-Webster's English Dictionary, Merriam-Webster Inc, 2013).

Verbalisation of nociceptive sensation is the gold standard for assessment of pain.1 Since neonates cannot verbalise their pain, the recognition and management of pain in this category of children has left much to be desired, both in hospital settings, including neonatal intensive care units, and in the general population. It is often felt, and most erroneously so, that newborns do not feel pain or have not yet developed the capacity to feel pain and as a result are exposed to a variety of painful procedures both in hospital settings and in the community without any form of analgesia. These procedures include ear piercing, circumcision, ligation of extra digits, heel lancing, venepuncture, lumbar puncture, chest tube insertions, intravenous catheter insertion, endotracheal tube suctioning, surgery, etc. Some of these procedures are repeated severally, especially for sick neonates and preterm babies. Indeed, a longitudinal study showed that the youngest pre-term neonates had an average of 750 procedures during their hospital stay.2 It is noted that premature infants in Canadian neonatal intensive care units (NICUs) were subjected to an average of two and up to eight painful procedures per day. For these infants, analgesic agents were provided in only 6.8% of all procedures.3 Moreover, a recent cohort study showed that less than 10% of the sickest NICU infants received opioids compared with 22-33% of those at lesser risk for neurologic impairment.3

There is increasing evidence that newborns indeed experience pain and that these early pain experiences may have long-term consequences. Following extensive work in the 1980s and 1990s, the fact that neonates experience pain and mount a stress response was established and appreciated. Even premature neonates undergoing surgery can mount a clinically significant stress response, as measured by hormonal and metabolic indicators. Stress indicators include plasma adrenaline, noradrenaline, glucagon, insulin and cortisol levels as well as blood glucose, lactate, pyruvate and alanine concentrations.1 The mounting of a stress response results in catabolic responses, including glycogenolysis, gluconeogenesis and lipolysis. These catabolic responses, when un-modulated by medical intervention, may have a detrimental effect on the clinical course of a neonatal surgical patient.1

Before the late nineteenth century, babies were considered to be more sensitive to pain than adults. Doris Cope quotes paediatric surgeon Felix Wόrtz of Basel, writing in 1656: If a new skin in old people be tender, what is it you think in a newborn Babe? Doth a small thing pain you so much on a finger, how painful is it then to a Child, which is tormented all the body over, which hath but a tender new grown flesh?.4,5

PATHOPHYSIOLOGY OF PAIN

There have been several recent consensus statements concerning neonatal pain.6 These evidences show that: Anatomical maturation of nociceptive pathways is complete by mid-to-late second trimester;6,7 and physiological responses in behavioural, cardiovascular, respiratory, endocrine and metabolic systems are similar to that of pain experienced by adults and older children.7 It is now known that these physiological and behavioural responses to painful stimuli can be reduced by analgesia.1

The impact of pain may have short (physiological and behavioural) and long-term consequences (increased or decreased behavioural responses to pain),2 even if not expressed as conscious memory.8,9,10 Memories of pain may be recorded biologically and alter brain development and subsequent behaviour.10

Other mechanism involved in the prevention and management of pain in newborns1,2 include: neuroanatomical components and neuroendocrine systems. These are sufficiently developed to allow transmission of painful stimuli in the term neonate.

It is important to note here that four basic concepts explain the physiology of pain. These include transduction, transmission, modulation and perception. Although still complex, the science of pain reveals a much more ambiguous process, and theories are still continuing to evolve. New receptors, pathways and hypotheses are being investigated every day. Genetic variations at the receptor level have been implicated.11

Pain in newborns is often unrecognised and under treated. If a procedure is painful in adults it should be considered painful in newborns, even if they are pre-term. Compared with older age groups, newborns may experience a greater sensitivity to pain and are more susceptible to the long-term effects of painful stimulation. Adequate treatment of pain may be associated with decreased clinical complications and decreased mortality.11

Tissue injury during the early neonatal period may result in similar enhancement of somatosensory responses. This was buttressed in a study in neonates born at 27-32 weeks, where heel lancing was restricted to one side; periodic flexor reflex threshold testing showed a consistently reduced threshold for the affected heel compared with the non-injured heel, indicating increased pain sensitivity on the side of heel lancing. Compared with untreated and placebo controls, when a group of infants was treated regularly with a topical anaesthetic beginning 3 days after heel lancing was initiated, flexor reflex thresholds between the injured and non-injured side became equivalent.12 These findings show that the human neonate is capable of mounting an inflammatory response with persisting hyperalgesia, or increased sensitivity to pain, due to early painful experiences - a response that can be ameliorated by local anaesthetic application.

Additional studies in humans have supported the suggestion that tissue injury at a young age may have long-lasting somatosensory sequelae. First, Andrews et al.,13 showed that the indicator of the excitability of the neonatal spinal cord — a mechanically evoked flexion reflex threshold to stimuli applied to the foot and leg — increased with age in normal infants of post conception age of 28-42 weeks. However, similar infants with a substantial leg injury did not exhibit the normal age-related increase in threshold, even when the non-injured leg was tested. This absent development of normally increasing thresholds contralateral to the injury reflects substantial ‘secondary’ changes in the spinal cord itself and not merely to the injured leg.13

Finally, studies reveal that lasting changes in pain sensitivity with the early experience of pain have been found in full-term infants as well. Using a prospective cohort design in males, one study found that facial pain-score coding from videotape recordings at 4- or 6-month routine vaccination was related to circumcision status as well as pain treatment for the procedure.14 In particular, a significant linear trend of increasing facial pain scores during immunisation emerged from uncircumcised (lowest) to circumcised infants with topical lidocaine-prilocaine cream (mid) to those who were circumcised with placebo (highest).

DIAGNOSIS OF PAIN

Most of the signs of pain in babies are quite straight forward, requiring no special equipment or training. Here, the baby cries and remains restless when awake, develops a disturbed sleep pattern, feeds poorly and shows a fearful, distrustful reaction towards mothers.

The cry response is indispensable and researchers are now able to differentiate between different kinds of cry: classified as ‘hungry’, ‘angry’ and ‘fearful or in pain’.15 Interpretation is difficult, however, depending on the sensitivity of the listener, and varies significantly between observers.16

Combinations of crying with facial expressions, posture and movements, aided by physiological measurements, have been tested and found to be reliable indicators.9A number of such observational scales have been published and verified. Even with noticeable responses from an infant, the underlying problem may be hidden. Due to the inability to speak or the side effects of the illness, it may be difficult to receive a proper diagnosis, causing infant diagnosis to be one of the hardest to do in the medical field.9

Children and Infants' Post-operative Pain Scale17

The Children and Infants Post-operative Pain Scale (ChIPPS) is often used in the assessment of hospitalised newborns. The scale requires no special measurements, and is therefore applicable across a wide range of circumstances.17

Described in 2000, the scale uses a measurement of five items, each rated as 0, 1 or 2 based on the following parameters: [Table 1].

Table 1

Showing pain scale

0-3: No requirement for treating pain,

4-10: Progressively greater need for analgesia.

All observations, both movement and physiological, tend to decrease when pain is persistent, thus rendering the scale unreliable in acute or prolonged cases.

MANAGEMENT

Non-pharmacological agents

There are several approaches in management of pain in neonates. For instance, acute pain that are meted out from several procedures can be minimised by using indwelling catheters for blood sampling or by using mechanical devices such as spring-loaded lancets for heel sticks. Procedures must be limited to those absolutely necessary for the diagnostic or therapeutic management of neonates.11

Swaddling, which includes wrapping infants to restrict movements, have modest effects on pain-elicited distress during and after heel sticks in neonates.18 It is pertinent to note that in pre-term infants at 32 weeks, prone positioning was not a sufficient intervention for comfort during heel sticks although gentle massage appeared to have analgesic effects.19,20 Furthermore, inadequate treatment of pain may have implications that extend beyond the neonatal period, including hypersensitivity to noxious stimuli later in life.

Some studies have identified the pacifying effects of non-nutritive sucking, which decreases crying, lowers heart rates and increases oxygenation in term and pre-term neonates during painful procedures like heel sticks and venopuncture.21,22

Furthermore, the analgesic effect of sucrose, first reported by Blass et al., cannot be downplayed.23A systematic Cochrane review in 2010 including 44 studies and 3496 infants concluded that sucrose is safe and effective for reducing procedural pain in neonates.23,24

In addition, it was found that oral glucose or other sweet solutions also reduce acute pain in neonates during minor procedures; 30% glucose was effective in term neonates during heel sticks and venipunctures, and in pre-term neonates during subcutaneous injections.24 Administration of a sweet solution with a pacifier was synergistic, providing stronger analgesic effects.23 Gray et al. found that 10-15 min of kangaroo care between mothers and their term newborns reduced crying, grimacing and heart rate during heel-stick procedures.24

Similarly Johnston et al., showed that kangaroo care significantly reduced the acute pain responses of pre-term neonates at 32-36 weeks' and 28-32 weeks' gestation.25

Breastfeeding maintained throughout a procedure relieved procedural pain in term neonates more effectively than swaddling.26 In another study, Carbajal et al., found that breastfeeding effectively reduced venepuncture-associated pain in term neonates.27

Sensorial saturation (SS) is a procedure in which touch, massage, taste, voice, smell and sight compete with pain, producing almost complete analgesia during heel prick in neonates. SS is an apparently verbose manoeuvre, but when correctly demonstrated, it is easily learnt. In a work published by Bellieni et al., they studied its feasibility, assessing whether a long training is really needed to achieve good results.28 They enrolled 66 consecutive babies and divided them randomly into three groups each of which received the following forms of analgesia: glucose plus sucking (A), SS performed by nurses (B), SS performed by mothers (C). They did not use perfume on the caregivers' hands, so that babies could perceive the natural aroma of 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 difference whether SS was performed by mothers who applied it for the first time or experienced nurses. SS is rapid to learn and any caregiver (mother, paediatrician or nurse) can effectively use it.28

Pharmacological agents

A variety of topical anaesthetic creams have been developed, ranging from single agents with good skin penetration, to several mixtures of agents and technologically modern formulations of lignocaine in microspheres. They are effective in suitable procedures, if correctly and timely applied.29 Local infiltration and general anaesthesia can also be used to reduce the pain of the initial injection.

As the site of pain in babies is difficult to confirm, analgesics are often advised against until a proper diagnosis has been performed. For all analgesic drugs, the immaturity of the baby's nervous system and metabolic pathways, the different ways in which the drugs are distributed, and the 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 the same for babies as they are for adults and are both well known and manageable.30

There are three forms of analgesia suitable for the treatment of pain in babies: paracetamol (acetaminophen), the non-steroidal anti-inflammatory drugs and the opiates. Paracetamol is safe and effective if given in the correct dosage.31 The same is true of the non-steroidal anti-inflammatory drugs, such as ibuprofen (aspirin is seldom used). Of the opiates, morphine and fentanyl are most often used in a hospital setting, while codeine is effective for use at home.

Other pharmacological agents used to reduce pain in neonates are sedatives. Some work had been executed using sedatives to relieve pain in neonates, for instance, Eloisa et al. evaluated the analgesic activity of melatonin during endotracheal intubation of the newborn by using the Neonatal Infant Pain Scale (NIPS) and Premature Infant Pain Profile (PIPP) score. Secondary outcome was an evaluation of melatonin as inflammatory responses.32 This was performed by measuring the levels of pro- and anti-inflammatory cytokines implicated in the pain. Sixty pre-term infants were enrolled in the study and were randomly divided into two groups: 30 infants treated with melatonin plus common sedation and analgesia recommended by Italian Society of Neonatology (group 1) and 30 infants treated with only common sedation and analgesia. The sedative and analgesic drugs included atropine, fentanyl and vecuronium. The reduction in pain score (NIPS) was similar in both groups at an early phase, while it (PIPP score) was lower in melatonin-treated group of infants than the other newborns at a late phase, during intubation and mechanical ventilation.32 Notwithstanding, sedation does not provide pain relief and may mask the neonate's response to pain.

CONCLUSION

Newborns do indeed feel pain. Supportive care, comprising of use of sucrose, glucose, breastfeeding, kangaroo mother care are worthwhile means of ameliorating pain in newborns.

Novel therapies (such as SS and swaddling) have been evaluated and proven useful. Suitable analgesic and anaesthetic agents in various forms are available for pain control in newborns. The use of sedation did not show any beneficial results.