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).

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).

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).

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).

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 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.

Funding: None.

Competing interests: None declared.

1. Merskey H, Albe-Fessard DG, Bonica JJ, Carmon A, Dubner R, Kerrf WL, et al. Pain terms: A list with definitions and notes on usage: Recommended by the ISAP Sub-committee on Taxonomy. Pain 1979; 6: 249-252.

2. Craig KD, Lilley CM, Gilbert CA. Social barriers to optimal pain management in infants and children. Clin J Pain 1996; 12: 232-242.

3. Anand KJ, Aynsley-Green A. Metabolic and endocrine effects of surgical ligation of patent ductus arteriosus in the human preterm neonate: Are there implications for further improvement of postoperative outcome? Mod Probl Pediatr 1985; 23: 143-157.

4. Anand KJ, Carr DB. The neuroanatomy, neurophysiology and neurochemistry of pain, stress, and analgesia in newborns and children. Pediatr Clin North Am 1989; 36: 795-822.

5. Giannakoulopoulus X, Sepulveda W, Kourtis P, Glover V, Fisk NK. Fetal plasma cortisol and beta-endorphin response to intrauterine needling. Lancet 1994; 344: 77-81.

6. Anand KJ. Clinical importance of pain and stress in preterm neonates. Biol Neonate 1998; 73: 1-9.

7. Anand KJ, Sippell WG, Aynsley-Green A. Randomized trial of fentanyl anesthesia in preterm neonates undergoing surgery: Effects on the stress response. Lancet 1987; 1: 243-248.

8. Taddio A, Golbach M, Ipp M, Stevens B, Koren G. Effect of neonatal circumcision on pain response during vaccination. Lancet 1995; 345: 291-292.

9. Taddio A, Katz J, Ilersich AL, Koren G. Effect of neonatal circumcision on pain response during subsequent routine vaccination. Lancet 1997; 349: 599-603.

10. Johnston CC, Stevens BJ. Experience in a neonatal intensive care unit affects pain response. Pediatrics 1996; 98: 925-930.

11. Grunau RVE, Whitfield MF, Petrie JH. Pain sensitivity and temperament in extremely low-birth-weight premature toddlers and preterm and full-term controls. Pain 1994; 58: 341-346.

12. Grunau RVE, Whitfield MF, Petrie JH, Fryer EL. Early pain experience, child and family factors, as precursors of somatization: A prospective study of extremely premature and full term children. Pain 1994; 56: 353-359.

13. Grunau RE, Whitfield MF, Petrie J. Children’s judgements about pain at age 8-10 years: extremely low birthweight (< 1000 g) children differ from full birthweight peers? J Child Psychol Psychiatry 1998; 39: 587-594.

14. Bero LA, Kuhn CM. Role of serotonin in opiate induced prolactin secretion and antinociception in the developing rat. J Pharmacol Exp Therap 1987; 240(3): 831-836.

15. McVey C. Pain in the very preterm baby: Suffer little children? Ped Rehab 1998; 2: 47-55.

16. Anand KJS. The applied physiology of pain. In: Pain in Neonates. Eds Anand KJS, McGrath PJ. Amsterdam; Elsevier; 1993; pp 39-66.

17. Anand KJS, Hickey P. Halothane-morphine compared with high-dose sufentanil for anesthesia and postoperative analgesia in neonatal cardiac surgery. N Engl J Med 1992; 326: 1-9.

18. Burokas L. Factors affecting nurses’ decisions to mediate pediatric patients after surgery. Heart Lung 1985; 14: 373-379.

19. Purcell-Jones G, Dormon F, Sumner E. Pediatric anesthetists’ perceptions of neonatal and infant pain. Pain 1988; 33: 181-187.

20. Clinical Practice Guideline AHCPR Publication No 92-0032. Acute Pain Manage-ment: Operative or Medical Procedures and Trauma. Rockville, MD: Agency for Health Care Policy and Research, Public Health Service, US Department of Health and Human Services; 1992.

21. Schechter NL, Blankson V, Pachter LM, Sullivan CM, Costa L. The ouchless place: No pain, children’s gain. Pediatrics 1997; 99: 890-894.

22. Sauve R, Saigal S. Optimizing the Neonatal Intensive Care Environment. Report of the Tenth Canadian Ross Conference in Pediatrics, GCI Communications; Abott Laboratories; Montreal, Canada, 1995.

23. American Academy of Pediatrics, Committee on Drugs. Guidelines for monitoring and management of pediatric patients during and after sedation for diagnostic and therapeutic procedures. Pediatrics 1992; 89: 1110-1115.

24. Corff K, Seidemann R, Venkataram P, Lutes L, Yates B. Facilitated tucking: A non-pharmacologic comfort measure for pain in preterm infants. J Obstet Gynecol Neonatal Nurs 1995; 24: 143-147.

25. Gunnar Mr, Fisch RC, Malone S. The effects of pacifying stimulus on behavioral and adrenocortical responses to circumcision in the newborn. J Am Acad Child Psychiatry 1984; 23: 34-38.

26. Shah VS, Taddio A, Bennett S, Speidel BD. Neonatal pain response to heelstick vs venepuncture for routine blood sampling. Arch Dis Child 1997; 77: F143-F144.

27. Larsson BA, Tannfedlt G, Lagercrannk H, Olsson GL. Venepuncture is more effective and less painful than heel lancing for blood tests in neonates. Pediatrics 1998; 101: 882-886.

28. Shah V, Ohlsson A. Venepuncture versus heel lance for blood sampling in term neonates. In: The Cochrane Library, Issue 4, 1999, Oxford Update Software.

29. Practice guidelines for sedation and analgesia by non-anesthesiologists: A report by the American Society of Anesthesiologists Task Force on Sedation and Analgesia by Non-Anesthesiologists. Anesthesiology 1996; 84: 459-471.

30. Canadian Anesthesists’ Society. CAS guide-lines to the practice of anesthesia. Can J Anaesth 1997; 44S: 1.

31. American Academy of Pediatrics, Committee on Environmental Health. Noise: A hazard for the fetus and newborn. Pediatrics 1997; 100: 724-727.

32. Olkkola KT, Hamunen K, Maunuksela EL. Clinical pharmacokinetics and pharmaco-dynamics of opioid analgesics in infants and children. Clin Pharmacokinet 1995; 28: 385-404.

33. Pasternak G, Zhang A, Tecott L. Develop-mental differences between high and low affinity opiate binding sites: Their relationship to analgesia and respiratory depression. Life Sci 1980; 27: 1185-1190.

34. Yaster M, Maxwell L. Opioid agonists and antagonists. In: Pain in Infants, Children and Adolescents. Eds. Schechter N, Berde C, Yaster M. Baltimore, Williams and Wilkins, 1993; pp 145-171.

35. Quinn M, Wild J, Dean H, Hartley R, Rushforth J, Puntis J, et al. Randomized double blind controlled trial of effect of morphine on catecholamine concentrations in ventilated pre-term babies. Lancet 1993; 343: 324-327.

36. Huet F, Reiser V, Gouyon JB. Effect secondaire du fentanyl sur la ventilation mecanique de 1’enfant premature. Arch Fr Pediatr 1992; 49: 841.

37. Chana SK, Anand KJS. Can we use methadone analgesia in neonates? Arch Dis Child Fetal Neonatal Ed 2001; 85: F79-F81.

38. Anand KJ, Arnold JH. Opioid tolerance and dependance in infants and children. Crit Care Med 1994; 22: 334-342.

39. American Academy of Pediatrics, Canadian Pediatric Society. Committee on Fetus and Newborn Committee on Drugs; Section on Anesthesiology; Section on Surgery, Fetus and Newborn Committee. Prevention and manage-ment of pain and stress in the neonate. Pediatrics 2000; 105: 454-461.

40. Larsson BA, Tannfedlt G, Lagercrannk H, Olsson GL. Alleviation of the pain of venepuncture in neonates. Acta Pediatrica 1998; 87: 774-779.

41. Brisman M, Ljung BM. Otterbom I, Andreasson SE. Methemoglobin formation after the use of EMLA cream in term neonates. Acta Pediatrica 1998; 87: 1191-1194.

42. Jain A, Rutler N. Local anesthetic effect of topical amethocaine gel in neonates: Randomized controlled trial. Arch Dis Child Fetal Neonatal Ed 2000; 82: F42-F45.

43. Autret E, Dutertre JP, Breteau M, Jonville AP, Furet Y, Laugier J. Pharmacokinetics of paracetamol in the neonate and infant after administration of propacetamol chlorhydrate. Dev Pharmacol Ther 1993; 20: 129-134.

44. Birmingham PK, Tobin MJ, Henthorn TK, Fisber DM, Berkelmaper MC, Smith FA, et al. Twenty-four hour pharmacokinetics of rectal acetominaophen in children: An old drug with new recommendations. Anesthesiology 1997; 87: 244-252.

45. Van Lingen RA, Deinum JT, Quak JM, Kuirenga AJ, Van Dan JG, Anand KJ, et al. Pharmocokinetics and metabolism of rectally administered paracetamol in preterm neonates. Arch Dis Child Fetal Neonat Ed 1999; 80: F59-F63.

46. Shah V, Taddio A, Ohlsson A. Randomized controlled trial of paracetamol for heel prick pain in neonates. Arch Dis Child Fetal Neonat Ed 1998; 79: F209-F211.

47. Howard CR, Howard FM, Weitzman ML. Acetaminophen analgesia in neonatal circumci-sion: The effect on pain. Pediatrics 1994; 93: 641-646.

48. Gillis JC, Brogden RN. Ketorolac: A reappraisal of its pharmacodynamic and pharmacokinetic properties and therapeutic use in pain management. Drugs 1997; 53: 139-188.

49. Valley R, Bailey A. Caudal morphine for postoperative analgesia in infants and children: A report of 138 cases. Anesth Analg 1991; 72: 120-124.

50. Birmingham P. Recent advances in acute pain management. Curr Probl Pediatr 1995; 25: 99-112.

51. Fontaine P, Dittberner D, Scheltema K. The safety of dorsal penile nerve block for neonatal circumcision. J Fam Pract 1994; 39: 243-248.

52. Carbajal R, Chawet X, Coudre S, Oliver-Martin M. Randomized trial of analgesic effects of sucrose, glucose and pacifiers in term neonates. Br Med J 1999; 319: 1393-1397.

53. Steps to Successful Breastfeeding. Protecting, Promoting and Supporting Breastfeeding. The Special Role of Health Services. A joint WHO/UNICEF Statement. Geneva, World Health Organization, 1989.

54. Shiao SY, Chang YJ, Lannon H, Yarindi H. Meta-analysis of the effects of the non- nutritive sucking on heart rate and peripheral oxygenation: Research from the past 30 years. Iss Comp Pediatr Nurs 1997; 20: 11-24.

55. Schubiger G, Schwarz U, Tonz O. UNICEF/WHO baby-friendly hospital initiative: Does the use of bottles and pacifiers in neonatal nursery prevent successful breastfeeding. Neonatal Study Group. Eur J Pediatr 1997; 156: 874-877.

56. Ors R. Ozek E, Baysoy G, Cebeci D, Bilgen H, Turnkuner et al. Comparison of sucrose and human milk on pain response in newborn. Eur J Pediatr 1999; 158: 63-66.

57. Larsson BA, Tannefedlt G, Langercrannk H, Olsson Gl. Venepuncture is more effective and less painful than heel lancing for blood tests in neonates. Pediatrics 1998; 101: 882-886.

58. Sabrine N, Sinha S. Pain in neonates. Lancet 2000; 355: 932-933.