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Options for procedural pain in newborn infants

Judith Meek

Neonatal Unit, Elizabeth Garrett Anderson Wing, University College Hospital, 235 Euston Road, London NW1 2BU, UK; Judith.meek@uclh.nhs.uk Received 17 June 2011 Accepted 3 October 2011 Published Online First 28 October 2011

Neonatologists often feel helpless in the management of procedural pain. While we acknowledge that our patients are more frequently and chronically exposed to tissue damaging procedures than any other hospital population, and that they are more vulnerable both in the short and long term, it is not certain that we have any techniques that are proven to be effective. Although we have developed numerous guidelines1 2 they are not reliably applied in clinical practice.3 It is widely recognised that newborns undergoing intensive care are necessarily subjected to numerous painful procedures.4 Despite the availability of clinical guidelines the majority of painful procedures on neonatal intensive care units (NICUs) are still carried out without any form of analgesia. Even outside the NICU term neonates are subjected to multiple procedures such as blood tests and insertion of nasogastric tubes. Surgical procedures such as circumcision, tendonotomy and division of tongue tie are routinely carried out without analgesia because they are quick. The extra vulnerability of newborns to repeated noxious stimulation, arising from both their clinical instability and their developmental immaturity, makes this a situation that needs urgent solutions. This review will explore the options for managing procedural pain, and the limitations of the clinical evidence for their effectiveness.
Clinical aspects of minimising the frequency and impact of painful procedures
Controlling chronic pain

tissue damage. Although the evidence base for treating these conditions is weak, careful observation and developmental care should also be used to enhance comfort and stability.
Reducing the number of painful procedures

Avoiding painful procedures is an obvious goal. For example, blood sampling can be rationalised in the following ways: 1. By using transcutaneous or end tidal PCO2 monitoring instead of capillary blood gas sampling (especially during minimal handling after extubation). 2. By reviewing the necessity for a daily blood sample on the evening ward round. 3. By using rational guidelines and validated techniques for blood glucose monitoring. This would prevent the use of routine blood tests for well babies who are large or small for dates. 4. By using transcutaneous bilirubinometers. 5. By enforcing a rule that procedures should only be attempted twice by junior staff before deferring to somebody more experienced.
Using venesection rather than heel lance

The newborn may experience both acute procedural pain and chronic pain. It is recognised in adults that uncontrolled chronic pain increases the intensity of additional acute painful experiences. Therefore the first step towards managing procedural pain is to minimise chronic pain, which may be due to intensive care support apparatus, gastro-oesophageal reflux disease or

Venesection is preferable to heel lance in term infants; for every three venepunctures performed instead of heel lances, one extra heel lance is avoided.5 Mechanical lances are preferable to manual lances, which are still used despite evidence that they are more traumatic and lead to repeated punctures to obtain adequate samples of blood. Repeated tissue damaging events lead to hypersensitivity and hyperalgesia. Areas of pre-existing tissue damage or inflammation should be avoided, particularly for premature infants who have a wide receptive field for sensory stimulation.6
Pain assessment The major obstacle in developing a rational approach to managing procedural pain has been the lack of an outcome measure. For

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REVIEW adults and children the effectiveness of analgesics can be assessed by subjective reporting. These reports can be quantified into linear pain scales. A variety of similar scales, based on observations, have been developed for infants and neonates, and these have formed the basis of measuring the experience of pain in babies who cannot speak. Until recently the entire body of work in the field of neonatal pain research has used these scores, which are usually composites of measured behavioural, physiological and stress responses.7 8 However there is no gold standard score, and the only validation studies have been internal comparisons between different scales. They are invaluable clinical tools, ensuring that babies are regularly observed for signs of pain or discomfort, but they have limitations as research tools. Even in children, behavioural observational pain scoring scales may underestimate the severity of persistent pain compared with self report.9
Observational pain scoring is less accurate for preterm infants

Pain scoring is less reliable when used for extremely premature infants, and adjustments for gestational age and sleep state are included in composite scales such as the PIPP (Premature Infant Pain Profile).10 11
Preterm infants have a longer latency for facial responses

Slater et al12 have demonstrated that preterm infants have a delayed facial response up to 25 s after a heel lance, and scales which measure changes over a 30 s period after a procedure may significantly underestimate the size of a preterm infants response.
PIPP correlates with cortical response, but facial changes are not always present

of subcortical and autonomic pathways, and may not be reliably linked to central sensory or emotional processing in the brain. Recent studies using near infrared spectroscopy,13 14 and evoked potentials15 have demonstrated that distinct activation resulting from touch and noxius stimulation can be detected in the newborn sensory cortex. In a study comparing the contralateral haemodynamic cortical response to a single heel lance, with the simultaneously recorded PIPP score, Slater et al16 demonstrated a positive correlation which was largely accounted for by the facial component of the PIPP score (figure 1), with only a weak contribution from the physiological variables. The correlation was weaker when the weighting factors for sleep state and gestational age were included. This was because the youngest and sleeping infants tended to have the smallest cortical responses, but these are the infants whose scores were weighted most heavily. However on 13 of the 33 test occasions there was no change in facial expression and the PIPP score was zero. On 10 of these occasions the infants still mounted a normal cortical response. This response of tuning out when stressed is widely recognised in developmental care practice. The relation of a sensory cortical response to the overall experience of pain is not known for babies, but a sensory response is a prerequisite for more complex cortical processing. This study implies that behavioural pain scoring techniques may underestimate responses to procedural pain. These concerns add to the difficulty in using pain scores as an end point for studying analgesic interventions. They also imply that we should be clincially vigilent, and should not assume that a quiet, expressionless baby is pain free.
Sucrose Sucrose is widely used to decrease the observed responses to procedural pain in neonates and is

Observational pain scoring is based on physiological and behavioural changes that can arise from activation

Figure 1

Relationship of the haemodynamic cortical response to noxious stimulation and facial expression score (Slater et al16)

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Table 1 Summary of relevant Cochrane reviews
Procedure
Ventilation

Intervention
Opiates23

Primary outcome measures

Pain scores Duration of mechanical ventilation Neonatal mortality and mortality to discharge; Neurodevelopmental outcome and quality of life (measured by validated scales) at short, medium and long term

Conclusion
Insufcient evidence to recommend routine use of opioids Should be used selectively according to clinical judgement

Morphine is safer than midazolam for sedation Sucrose17 Heel lance Venepuncture Optimal dose not identied Further research needed in unstable, ventilated and VLBW infants Midazolam29 Intensive care for critically ill neonates Behavioural and physiological assessments of sedation levels Denite conclusions about the effectiveness and safety cannot be made Adverse neurological events more frequently observed in the midazolam-treated infants Not recommended Venesection
5

Pain scores

Sucrose is safe and effective

Venepuncture versus heel lance in term neonates, performed by skilled phlebotomists

Pain scoring scales and cry characteristics

Venepuncture is the method of choice

The study needs to be repeated with a range of practitioners Local anaesthetic37 Neonatal circumcision Pain scores Crying times Physiological changes Cortisol levels Dorsal penile nerve block is more effective than EMLA Both more effective than no analgesia, but neither eliminated response Developmental Care36 Positioning Clustering of nursery care activities Modication of external stimuli NIDCAP interventions Neurobehavioural development Weight gain Length of hospital stay Length of mechanical ventilation Physiological parameters Limited benets to preterm infants

Very limited evidence of the long-term effect of NIDCAP on behaviour and movement at 5 years Some NIDCAP trials showed benets in long term outcome, but some were incompletely blinded EMLA, eutectic mixture of local anaesthetics; NIDCAP, Newborn Individualised Developmental Care and Assessment Program; VLBW, very low birth weight.

recommended as the method of choice by international guidelines. A recent Cochrane review17 included 44 randomised controlled trials and demonstrated a significant decrease in pain scores when sucrose is used. Sucrose is the only agent that has been subjected to a randomised controlled trial using a directly measured cerebral response as an outcome measure. In a trial randomising term infants to 24% sucrose or water, electrophysiological responses were measured as well as the PIPP score.18 Pain specific cortical activity was assessed using event related EEG, and spinal withdrawal activity was measured as electromyogram activity over the ipsilateral biceps femoris. The nociceptive specific brain activity did not differ significantly between the infants who received sucrose and those who received water. There was also no difference in the spinal reflex withdrawal activity, or its latency. The PIPP score, however, as expected, was significantly lower in the sucrose treated group.

The finding that sucrose does not change neural activity suggests that it may not alter underlying nociceptive activity. Its mechanism of action is uncertain, there is evidence both for and against the induction of rapid opiate production.19 It may act as a distraction, which is a valid technique used for painful procedures in the paediatric population. Functional MRI (fMRI) in adult subjects shows that distraction from a painful procedure results in retention of the sensory cortical response, but reduction of activity in other regions of the brain.20 Other techniques that could provide distraction are breastfeeding and sucking a pacifier. This is consistent with observation that sucrose has a similar effect to breastfeeding in term infants.21 Therefore it should be used as an adjunct to other behaviour modifying techniques. The statement that we are no longer in equipoise over the use of sucrose22 may be premature, and sucrose should not replace good nursing care.
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Opiates Designing clinical trials to test the effects of morphine is challenging. It is a commonly used sedative and analgesic in the intensive care setting. All opiates can cause ventilatory depression, hypotension, urinary retention and decreased intestinal motility leading to delayed establishment of enteral feeding.23 Opiate therapy is usually prescribed as a loading dose followed by an infusion. As tolerance develops, the infusion rate may need to be increased. A bolus may be given prior to a procedure. By ethical necessity most studies have observed the effects of infusions of morphine, which provide smaller doses than boluses effective for skin breaking procedures. A meta-analysis of 13 studies of ventilated infants receiving morphine showed a reduction in PIPP scores, but concluded that there is insufficient evidence to recommend routine use of opioids, because of the wide heterogeneity of PIPP scores.23 Carbajal et al24 demonstrated no difference in pain scores after heel lances in 42 babies randomised to receive morphine or dextrose infusions. They did not demonstrate any correlation between serum morphine levels and pain scores. However the range of scores was wide in both groups, ranging from 0 to 10. Several infants had PIPP scores of zero, in both morphine and control groups, reflecting the observations of Slater et al.16 Morphine infusions have been shown to decrease plasma epinephrine levels in ventilated preterm babies,25 but to date there are no studies measuring changes in cortical responses to painful procedures using a pre-emptive bolus of morphine. Fentanyl provides intense analgesia, with a fast onset and offset. Chest wall rigidity is a common side effect. Remifentanil is cleared rapidly and predictably thereby making it an attractive drug for short neonatal surgery when rapid recovery is needed. These are widely used with suxamethonium for tracheal intubation. The NEOPAIN trial26 was designed to test whether opiates improved outcome (severe intraventricular haemorrhage, periventricular leukomalacia or death within 28 days of birth) in 898 ventilated preterm neonates. Babies assigned to the morphine group received a loading dose and then a continuous infusion. No improvement in outcome was seen, but there was an association of morphine use with hypotension. On more detailed analysis morphine was shown to worsen pre-existing hypotension, and should be used with caution for hypotensive infants. Non-opioids Paracetamol is a widely accepted treatment for moderate pain in neonates and can be given orally, rectally or intravenously. It is safe and efficacious for short term use in the newborn. It has additive effects when combined with opioids thereby allowing lower doses and subsequently lower incidence of side effects. Intravenous paracetamol can be used for alleviating pain due to daily medical care (such as endotracheal

tube suctioning), but pharmacokinetics are variable in neonates, with clearance depending on weight. Safety data is limited, particularly for infants less than 32 weeks post menstrual age.27 Ketamine is a centrally acting NMDA receptor antagonist and potent analgesic. It can be given intravenously, rectally, intramuscularly and via the neuroaxial route, but there is evidence that it is directly neurotoxic when given intrathecally to newborn rats at therapeutic doses.28 This raises concerns about its use in babies, and makes a study of neurodevelopmental follow-up imperative.
Adjuvent sedation Pure sedative drugs may have an adjuvant role in the treatment of neonatal pain. In combination with analgesics, they may reduce anxiety and stress, and promote sleep. Morphine, chloral hydrate and benzodiazepines are used as sedatives. However in the preterm developing nervous system midazolam has a paradoxical effect, and there is a large body of experimental work in preterm animals demonstrating potentiation of nociception. A Cochrane review of intravenous midazolam has quoted an increase in adverse neurological effects, and raises concerns about its safety.29 Local anaesthetics Local anaesthetics can block nociceptive transmission at various sites; topically and by local infiltration to the skin, regionally by nerve blocks or neuro-axially via the caudal, lumbar or thoracic epidural route. Single shot administration can provide up to 12 h of analgesia or indwelling catheters can be used for local anaesthetic infusions or repeat bolus. Eutectic mixture of local anaesthetics (EMLA) and Amethocaine are topical anaesthetics that are widely used for older infants. There is evidence that these are safe and effective in neonates as young as 27 weeks.30 31 They are effective 4060 min after application, for 46 h. Neither EMLA nor Amethocaine have been found to be effective for heel lancing pain. Developmental care Developmental care is an umbrella term for a range of approaches to handling preterm infants. By modifying both the physical environment, and care-giving practices, developmental care enables the infant to adapt to the extra-uterine sensory environment. These approaches are used by care givers and family to reduce the dual stresses of separation from the mother and frequent painful procedures. Firstly, by reducing arousal and discomfort from the environment, responses to procedures can be improved. Secondly, specific support can be offered by staff and parents during cares and procedures. Sleep should be protected, and infants should be given time to recover between procedures.32 Developmental support can be used to stabilise babies during procedures such as retinal examinations, and

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REVIEW is often the only option other than opiates for the extremely preterm group. Newborn Individualised Developmental Care and Assessment Program is a more formal and structured approach to assessing a babys individual needs and responses, and provides a personalised guide to supporting each baby through the painful procedures they experience.
Kangaroo mother care Kangaroo mother care (KMC) is widely used to support ventilated and non-ventilated premature newborns. The technique can be used for ventilated or non-ventilated babies. While only wearing a nappy the baby is nursed vertically between the mothers breasts with head and trunk aligned and limbs flexed. Kangaroo care has been shown to be effective in reducing the PIPP score by 2 points after heel lance in babies of 3236 weeks gestation.33 For babies between 28 and 32 weeks gestation the PIPP score was not significantly reduced until 90 s after the lance, and then by a score of less than 2. Recovery time was also more rapid in the KMC group.34 Clearly many procedures cannot be performed during KMC, but whenever possible it is recommended, for example during blood sampling or passing nasogastric tubes. Developmental outcome associated with pain reducing strategies The long term developmental and sensory deficits associated with exposure to procedural pain in the neonatal period are of enormous concern. In the absence of a gold standard test for the effectiveness of analgesics, developmental outcomes may be the most relevant indicators of the balance between pain relief and side effects. Very few randomised controlled trials include long term outcomes as end points. The NEOPAIN trial26 did not demonstrate an increase in early adverse neurological outcomes in the group randomised to morphine, but intermittent boluses of open label morphine were associated with worse outcomes. The babies who received extra morphine boluses may have already been more unwell. Johnston et al35 randomised 281 preterm infants to receive sucrose or water every time they underwent a painful procedure. There was no difference in neurobehavioural outcomes at 2 weeks postnatal age between the sucrose and placebo group. However higher numbers of doses of sucrose predicted a poorer outcome. The more unwell, higher risk babies, were subjected to more procedures, and therefore more sucrose. However this study indicates the importance of careful developmental follow-up, and raises awareness of the potential for giving a neonate up to 125 doses of sucrose per week. Both developmental care and KMC are associated with improved developmental outcomes, but these have not been investigated specifically in the context of managing procedural pain. A Cochrane review of

developmental care did not demonstrate a generalised positive effect on developmental outcomes, but acknowledged the difficulty of blinding randomised controlled trials.36 Therefore we do not have a validated method of measuring the pain experience of newborn babies. All our pain management guidelines are based on pain scoring scales, but these have limitations, especially for the most preterm babies, in whom responses to analgesics are the most unpredictable, and exposure to pain is often protracted over months. There is a paucity of long term outcome data to indicate the safety and effectiveness of different agents. However there is a large body of clinical research which leads to some clear guidelines (see table 1), and urgent questions for further work. The comfort and wellbeing of infants at all times should be ensured, so that their response to painful procedures is reduced, and their recovery is promoted. Developmental care has an important role in decreasing the impact of repeated procedures by enabling parents and staff to provide containment and stability. An increased awareness of the infant as another human being, whether or not a numerical pain scale is used, should lead to a rationalisation of painful procedures and greater care in their conduct. If pain scoring scales are used in clinical practice it should be recognised that expressionless babies may still be in pain. The effectiveness of analgesic agents is an area that requires further research. Although there is evidence that morphine infusions (albeit at relatively small doses) do not affect pain scores, there is still a consensus that morphine should not be withheld if a baby is distressed. Combinations of drugs such as opiates and paracetamol are recommended. Local anaesthetic creams are safe and should be more widely used. However, none of these agents has yet been tested using cortical responses or long term outcomes as end points. Sucrose, widely considered to be a potent analgesic, does not appear to affect the cortical response. This has generated uncertainty about its mode of action, and demonstrated the complexity of testing pain relieving techniques in preverbal, rapidly developing neonates. Further work using cortical responses to measure the effectiveness of analgesics is necessary, although challenging. In conclusion, we should promote good nursing and developmental comfort care as an adjunct to validated analgesics to prevent long term damage due to untreated pain.
Acknowledgements The work of Slater et al has been funded by The Medical Research Council, the Wellcome Trust and Sparks (the Childrens Medical Research Charity). Dr Meek is a member of the UCL/UCLH biomedical research centre. Competing interests None. Provenance and peer review Commissioned;

externally peer reviewed. 27

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Options for procedural pain in newborn infants

Judith Meek Arch Dis Child Educ Pract Ed 2012 97: 23-28 originally published online October 28, 2011

doi: 10.1136/archdischild-2011-300508

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