Indian Pediatrics 2002; 39:437-443
Practical Approach to Neonatal Analgesia
The International Association for the Study of Pain has defined pain as an unpleasant sensory and emotional experience associated with actual or potential tissue damage or described in terms of such damage(1).
Evidence of Pain in Neonates
Because, neonates cannot verbalize their pain, they depend on others to recognize, assess and manage their pain. Therefore, healthcare professionals can diagnose neonatal pain only by recognizing neonate’s associated behavioral and physiological responses(2). By late gestation, the fetus has developed the anatomic, neuro-physiological and hormonal components necessary to perceive pain(3-5). Preterm infants demonstrate similar or even exaggerated physiological and hormonal responses to pain as compared to older children and adults(3,6,7).
Some studies suggest that pain experienced early in life by term infants many exaggerate effective behavioral response during subse-quent painful events(8-9).
Neonates who were exposed to numerous, painful and noxious stimuli between post conceptional age of 28-32 weeks, showed different physiological and behavioral responses to pain, compared with neonates of a similar postconceptional age, who had not had such experience(10). In addition, toddlers at 18 months of corrected age, who were extremely low birth weight (<1000 g) at birth (and thus exposed to numerous noxious stimuli in neonatal intensive care) were related by parents as being less sensitive (reactive) to painful stimuli (e.g., bumps, cuts, common hurts) and demonstrating more somatic complaints compared with fullterm infants(11,12).
In another study, children’s judgement about pain at the age of 8-10 years was examined, using pictures of children in potentially painful situations (medical, recreational, daily living and psychosocial situation were used as pain stimuli). Two groups of children who experienced different exposure to nociceptive procedures in the neonatal period were compared. Unlike, infants of birth weight >2500 g, for extremely low birth infants (<1000 g) medical pain intensity was rated significantly higher than psychosocial pain (p <0.004)(13).
Rat pup studies suggest that preterm babies may experience pain more intensely than mature babies(14). Exposure to repetitive pain causes excitotoxic damage to the developing neurons. These changes promote distinct behavioral phenotypes characterized by increased anxiety, altered pain sensitivity, stress disorders and hyperactive attention deficit disorder, leading to impaired social skills and self destructive behavior(15).
There is a speculation that infants may have memory of pain that results in disruption of sleep, feeding patterns and mother infant interaction persisting longer after noxious stimuli has ended(15).
Attitude of Medical Profession to Pain Management in Neonates
Pain management of neonates continues to be inadequate despite convincing evidence supporting infants’ capability to perceive and respond to painful events at birth(16) and despite documentation of detrimental post surgical outcomes following inadequate analgesia(17). Studies indicate a lack of awareness among health care professionals of pain perception, assessment and management in neonates(18,19). When analgesics were used in infants, they often were administered on the basis of perception of health care professionals or family member. Fear of adverse reaction and toxic effect often contributed to inadequate use of analgesics. In addition, health care professionals often focussed on treatment of pain rather than a systemic approach to reduce or prevent pain(20,21). Therefore, the use of reliable and valid measures to minimize pain, maximize coping, minimize infant risk must be developed. Pain measures for infants, both pharmacologic and nonpharmacologic approaches to procedural pain alleviation must be evaluated(21).
Interventions to Manage Neonatal Pain
Pain is managed most effectively by preventing, limiting, or avoiding noxious stimuli(21). Modifying the environment and providing anxiolytics for circumstances expected to be stressful also may be useful. The environment should be as conductive as possible to the well being of the neonate and family(22,23).
Unnecessary noxious stimuli (acoustic, visual, tactile, vestibular) of neonates should be avoided. Simple comfort measures such as swaddling, non-nutritive sucking and positioning should be used whenever possible for minor procedures(24,25). Consideration of least painful method is important(26-28). Skillful placement of peripheral, central or arterial line reduces need of repeated intra-venous puncture or intramuscular injections. In some cases, the risk benefit balance may favor the more invasive indwelling catheter(26-28).
The relationship between drug dose, blood concentration and the effect of develop- ment makes choosing appropriate analgesic complex. The unpredictable drug dose response often results in the avoidance of prescribing or administering analgesics. The risk and benefits of pain management techniques must be considered on an individual basis within the context of the type and severity of painful stimuli. Pharmacological analgesia should be chosen carefully based on comprehensive assessment of the neonate, efficacy and safety of the drug, the clinical setting and experience of the personnel using the drug. Drug doses, including those of local anesthetics, should be calculated carefully based on the current or most appropriate weight of the newborn. An initial dose should not exceed the maximum recommended dose. Monitoring to ensure adequate oxygenation ventilation and cardio-vascular stability should follow appropriate guidelines(29-31).
A variety of opioids are available for pediatric use for the management of moderate to severe postoperative pain or procedural pain(31-32). Such medication may be administered as single or intermittent boluses or as continuous infusion. For prolonged use, continuous infusion is preferred to avoid large variation in plasma concentration. Whenever medication in this category is administered there must be an accompanying vigilance for potential adverse effect on the respiratory and cardio-vascular system. Agents known to compromise cardio-respiratory functions should be administered only by persons experienced in airway management and in settings with the capacity of continuous monitoring of vital signs(29-31). Morphine is the most common opioids used in infants. Newborns are thought to be less sensitive to analgesic effect of morphine but more sensitive to respiratory-depressive effect(33). This sensitivity is most likely due to age related changes in the number and subtypes of µ receptors, the decreased amount of drug bound to the serum protein and known delay in drug clearance(34). Continuous administration of morphine has been safe and effective in reducing procedural pain in ventilated preterm infants(35). Intravenous boluses of synthetic opioid (e.g., fentanyl, sufentanyl, alfentanyl) may be associated with glottic and chest rigidity(36). When an opioid antagonist is administered, the analgesic effect of opioid is also antagonized. Opioid anatagonist must be used with caution in neonates who have received prolonged treatment with opioid (>4 days). In this situation an antagonist (e.g., nalaxon) may precipitate acute opioid withdrawl with seizures, hypertension and other clinical consequences.
In view of physiochemical, pharmaco-logical and therapeutic properties of methadone and its usefulness in adults, it is proposed that there is an urgent need for clinical studies of use of methadone analgesia in newborn. The benefits of methadone include potent analgesic effect, prolonged duration of action, delayed development of opioid tolerance, excellent enteral bio availability and its low cost compared to other opioid analgesics(37). Weaning from opioid may also be achieved by changing to oral methadone, the dose of which may be slowly tapered(38).
Concomitant use of opioids and benzo-diazepines necessitates a decrease in the total dose of opioids and benzodiazepines. However, non-opioid medications should not be used in place of opioid because they do not possess analgesic properties. Moreover, the risk of respiratory depression may be additive or synergistic(39).
Local anesthetics are popular for alleviating pain. One of the most commonly used is eutectic mixture of local anesthetics (EMLA) which is 2.5% lidocaine and 2.5% prilocaine. In some studies EMLA cream appeared safe for heel lancing in pre-term infants and in comparison to placebo EMLA significantly reduced the pain caused by venepuncture on the dorsum of the hand. Its presence does not complicate the puncture of the veins(40), but can cause meth-hemo-globinemia(41). Topical amethocaine gel has an anesthetic effect on neonatal skin, which merits further investigation (42).
Non Steroidal Drugs
Generally this category of medication is used to treat less intense pain and as an adjunct to reduce the total dose of analgesics such as opioids. Limited data are available on the pharmaco-kinetic of paracetamol in new-born(43-45). Paracetamol does not reduce the response of pain due to heel lance procedure(46) but provides some reduction of pain after circumcision(47). There are no studies in newborn of the effectiveness and safety of ketorolac or ibuprofen to reduce pain.
Regional Anesthesia and Analgesia
Regional anesthetic techniques are now being adopted for use beyond their historic role in the operating room. The most common of this is the epidural. Administration of opioids and local anaesthetics (e.g., bupivacaine) via epidural catheter is now feasible in full term and some preterm neonates(48,49). A single dose of an opioid (i.e., morphine or fentany1) or a local anaesthetic (i.e., bupivacaine) may be administered at the end of surgery and the cathether discontinued providing pain relief for 12-24 hours post operatively. The catheter may be left in place during immediate postoperative period. For milder or briefer postoperative pain, a local anesthetic alone may be administered when patient is still anesthetised providing up to 12 hours of pain relief(50).
Dorsal penile nerve block also has been documented as an effective intervention for alleviating pain in newborn undergoing circumcision(51).
A randomized trial showed that the analgesic effect of concentrated glucose or sucrose solution is more effective than placebo. Pacifiers showed a better response than these sweet solutions. The association of sucrose and pacifiers showed the best response of all(52). Though non-nutritive sucking using pacifiers have received disapproval from breast-feeding promoters(53), metanalysis has shown that it can cause significant decrease in distress. Larger effects were noted in preterm infants than in term infants and for longer duration of non-nutritive sucking(54). Further-more, a study has suggested that the use of pacifiers during the first five days of life is not associated with lower frequency or shorter duration of breastfeeding during the first 6 months of life(55). It is believed that the rapid onset of pain relief elicited by sweet solutions is mediated by endogenous opioids. However, the precise mechanism by which pacifiers relieve pain remains to be identified(52). Swaddling as a means of comforting babies during or after a painful procedure proved to be an effective intervention, significantly reducing behavioral disturbances in both term and preterm babies(56). Venepuncture is more effective and less painful than heel lancing for blood test(26-28,57).
Management of pain should be a quality issue in neonatal care just as it is in care of adults(58). Recent attention to pain in infants resulted in better understanding of the underlying anatomy and physiology of pain transmission, the hormonal and metabolic response to pain and the assessment of pain. Investigators have begun to address the safety and efficacy of pharmacologic and non- pharmacologic treatment interventions for procedural pain in infants. A guideline consist-ing of morphine analgesia during moderate to severe painful procedures and sucrose or sucrose and pacifiers for mild painful procedures may be adopted. Venepuncture should be preferred to heel lancing and EMLA cream can be used for single elective venepuncture. Simple comforing measures such as swaddling the baby must be universally adopted after a painful procedure.
Contributors: Both the authors were involved in reviewing the literature and drafting the manuscript and will act as guarantor.
Competing interests: None declared.