Policy Statement



Volume 105, Number 2

February 2000, pp 454-461

Prevention and Management of Pain and Stress in the Neonate (RE9945)


Committee on Fetus and Newborn
Committee on Drugs
Section on Anesthesiology
Section on Surgery


Fetus and Newborn Committee

ABSTRACT. This statement is intended for health care professionals caring for neonates (preterm to 1 month of age). The objectives of this statement are to:

  1. Increase awareness that neonates experience pain;
  2. Provide a physiological basis for neonatal pain and stress assessment and management by health care professionals;
  3. Make recommendations for reduced exposure of the neonate to noxious stimuli and to minimize associated adverse outcomes; and
  4. Recommend effective and safe interventions that relieve pain and stress.

ABBREVIATION. SaO2, oxygen saturation.

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 The interpretation of pain is subjective. Each person forms an internal construct of pain through encountered injury. Several experts suggest that the neonate's expression of pain does not fit within the strict definition of the International Association for the Study of Pain because of the requirement for self-report.2-4 This lack of ability to report pain contributes to the failure of health care professionals to recognize and treat pain aggressively during infancy and early childhood.5 Because neonates cannot verbalize their pain, they depend on others to recognize, assess, and manage their pain. Therefore, health care professionals can diagnose neonatal pain only by recognizing the neonate's associated behavioral and physiological responses.6

Stress is defined as "a physical, chemical, or emotional factor that causes bodily or mental tension and may be a factor in disease causation."7 These responses can be specific to the stressor or can be generalized and nonspecific. Pain is always stressful, but stress is not necessarily painful; both require assessment, evaluation, and treatment. The signs of pain and stress must be distinguished from signs of life-threatening conditions, such as hypoxemia or carbon dioxide retention, that require other forms of intervention.8

Studies indicate a lack of awareness among health care professionals of pain perception, assessment, and management in neonates.9-11 When analgesics were used in infants, they often were administered based only on the perceptions of health care professionals or family members. Fear of adverse reactions and toxic effects often contributed to the inadequate use of analgesics. In addition, health care professionals often focused on treatment of pain rather than a systematic approach to reduce or prevent pain.12,13 More recent surveys have demonstrated increased awareness among health care professionals of pain in neonates and infants and its assessment and management.14-16 Several textbooks on pain in neonates and infants have been published,17-19 and measures for assessing pain have been developed and validated.20-24 However, despite the advances in pain assessment and management, prevention and treatment of unnecessary pain attributable to anticipated noxious stimuli remain limited.25-27 Several important concepts must be recognized to provide adequate pain management for the preterm and term neonate:


By late gestation, the fetus has developed the anatomic, neurophysiological, and hormonal components necessary to perceive pain.11,28-32 Preterm and term infants demonstrate similar or even exaggerated physiological and hormonal responses to pain compared with those observed in older children and adults.11,33,35 Some studies suggest that pain experienced early in life by term infants may exaggerate affective and behavioral responses during subsequent painful events.37,38 Neonates who were exposed to numerous painful and noxious stimuli between postconceptual weeks 28 and 32 showed different behavioral and physiological responses to pain compared with neonates of a similar postconceptual age who had not had such experiences.40 In addition, toddlers at 18 months corrected age who were of extremely low weight (<1000 g) at birth (and thus exposed to numerous noxious stimuli in the neonatal intensive care unit) were rated by parents as being less sensitive (reactive) to painful stimuli (eg, bumps, cuts, common hurts) and demonstrating more somatic complaints compared with full-term infants.41,48 In another study, children's judgment about pain at age 8 to 10 years were examined using pictures of children in potentially painful situations (medical, recreational, daily living, and psychosocial situations were used as the pain stimuli).39 Two groups of children who had experienced different exposure to nociceptive procedures in the neonatal period were compared. Unlike infants of birth weight >2500 g, for extremely low birth weight infants (<1000 g), medical pain intensity was rated significantly higher than psychosocial pain at 8 to 10 years of age, at P < .004.39 These clinical data support the experimental observations on the long-term effects of neonatal pain and stress.49

Several validated and reliable pain measures exist to assess acute pain in term and preterm neonates.24 Behavioral indicators of pain (eg, facial expression, body movements, crying), and physiological indicators of pain (eg, changes in heart rate, respiratory rate, blood pressure, oxygen saturation [SaO2], vagal tone, palmar sweating, and plasma cortisol or catecholamine levels) can be used to assess and manage stress and pain in neonates. Composite measures of neonatal pain include the following: 1) the Premature Infant Pain Profile (PIPP) that includes facial actions, such as brow bulge, eyes squeezed shut, and nasolabial furrow, and physiological indicators, including heart rate and SaO2 in the context of gestational age and neonatal state22; 2) CRIES that assesses Crying, the Requirement for oxygen supplementation (for SaO2 >95%), Increases in heart rate and blood pressure, facial Expression and Sleeplessness23; and 3) the Neonatal Infant Pain Scale (NIPS), which assesses facial expression, cry, breathing patterns, movements of arms and legs, and state of arousal.21 Other assessment measures are unidimensional but include multiple indicators of facial expression in term and preterm neonates. One such measure is the Neonatal Facial Coding System20 that was developed for use in pain research, but study continues of its clinical usefulness.41 However, there is a paucity of measures to evaluate pain in very low birth weight neonates or those who require mechanical ventilation.43,44 There remains a need to establish the clinical usefulness of existing measures and to develop measures to assess potential pain in pharmacologically paralyzed neonates or neonates with chronic pain.8

Pain is managed most effectively by preventing, limiting, or avoiding noxious stimuli and providing analgesia.13 Modifying the environment and providing anxiolytics for circumstances expected to be stressful also may be useful. The environment should be as conducive as possible to the well-being of the neonate and the family.50,51 Unnecessary noxious stimuli (acoustic, visual, tactile, vestibular) of neonates should be avoided. Simple comfort measures, such as swaddling, nonnutritive sucking (pacifier), and positioning (when not contraindicated because of specific medical or surgical conditions) should be used whenever possible for minor procedures.52,53 Oral administration of sucrose reduces pain associated with painful procedures.54,55 However, these interventions alone may not alleviate moderate to severe pain, and analgesic treatment should be provided as indicated.

Painful or stressful procedures should be minimized and, when appropriate, coordinated with other aspects of the neonate's care. Furthermore, consideration of the least painful method is important. For example, when performed by trained personnel, obtaining blood by venipuncture may be less painful than heel lancing.56-58 Skillful placement of peripheral, central, or arterial lines reduces the need for repeated intravenous punctures or intramuscular injections. Thus, in some such cases, the risk-benefit balance may favor the more invasive indwelling catheters. Whenever possible, validated noninvasive monitoring techniques (eg, pulse oximetry) that are not tissue damaging should replace invasive methods.

The risks and benefits of pain management techniques must be considered on an individual basis within the context of the type and severity of the painful stimulus. 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 for local anesthetics, should be calculated carefully based on the current or most appropriate weight of the neonate, and initial doses should not exceed maximal recommended amounts. Subsequent doses should be modified based on multiple factors, including the cause of the pain, previous response, clinical condition, concomitant drug use, and the known pharmacokinetics and pharmacodynamics of the sedative and analgesic drugs administered. Medications that might result in the loss of protective reflexes or cause cardiorespiratory instability should be used only by appropriately trained persons in an environment equipped to handle emergencies. Monitoring to ensure adequate oxygenation, ventilation, and cardiovascular stability should follow the guidelines of the American Society of Anesthesiologists,59 the Canadian Anaesthetists Society,60 and the American Academy of Pediatrics.61

Studies are lacking on the management of pain in neonatal conditions associated with extensive tissue damage and those resulting in recurrent or chronic pain (eg, necrotizing enterocolitis, meningitis, fractured bones). The effects of the use of analgesics or sedation during the neonatal period on long-term neurodevelopmental and psychological outcomes has not been well studied.49 No differences in intelligence, motor function, or behavior at 5 to 6 years of age were found between neonates who received morphine for sedation during mechanical ventilation and placebo-treated neonates.62

General Anesthesia

Advances in anesthetic medications, techniques, and monitoring by trained personnel have increased the safety and efficacy of general anesthesia for preterm and term neonates. The state of general anesthesia makes the patient pain-free and amnesic during surgery; the same medications and techniques can be used to extend the period of analgesia postoperatively.63

Regional Anesthesia

Regional techniques, such as peripheral nerve blocks and central neuraxis blockade (spinal, epidural), are sometimes used to provide anesthesia and analgesia for procedures on the trunk or limbs, as an adjunct to general anesthesia, and for postoperative analgesia.64-68 Examples of regional nerve blocks include ilioinguinal and iliohypogastric nerve blocks, penile block, digital block, local infiltration, and intercostal nerve blocks. The duration of such blocks can be extended by using vasoconstrictors (contraindicated in areas of end-arterial circulation, such as the penis, digit, and pinna of the ear). The duration of epidural blockade can be extended with the coadministration of opioids, clonidine, or both. Indwelling epidural catheters threaded from the caudal or lumbar region may provide analgesia for procedures above the diaphragm.18,69,70 These techniques should be used carefully by health care professionals trained in their use and with appropriate and careful observation. In neonates, intermittent administration of dilute local anesthetics with low-dose extradural opioids, such as fentanyl, offers less potential for the toxic effects of drugs than continuous infusion techniques with either drug alone. Careful calculation of doses is mandatory to avoid toxic effects for all uses of local anesthetic agents and for all other medications used to provide analgesia, sedation, and relief of anxiety. Accurate calculation is a particular concern in the care of preterm and term neonates in whom differences in protein binding and metabolism can result in local anesthetic drug accumulation and toxic effects.71,72

Continuous caudal or epidural blockade may be administered for several days postoperatively by using a continuous infusion pump. Continuous infusions are best managed by pain specialists trained in appropriate pharmacology, frequent assessment of effects, and the recognition of adverse reactions.

Local Infiltration Anesthesia

Analgesia for procedures in superficial areas (eg, chest tube insertion) usually can be managed with superficial infiltration with local anesthetic agents. Just as with regional nerve blocks, care must be taken to remain within maximal recommended total doses of local anesthetic agents. The addition of bicarbonate to local anesthetics can reduce the pain of local infiltration.73 For topical use, a cream containing lidocaine and prilocaine decreases the pain associated with a variety of minor procedures, although it was not effective for heel-lance procedures.74-76 For the success of topical analgesia, at least 1 hour must have elapsed between application and the time of the procedure; the analgesia may last 1 to 2 hours.76 Single applications of this cream have not been shown to cause clinically important methemoglobinemia in preterm and term neonates.76 However, despite no data demonstrating additive risk, caution should be used when other agents capable of causing methemoglobinemia (eg, acetaminophen) are coadministered.77


A variety of opioids are available for pediatric use.78,79 Although most of these medications have not received formal approval for use in pediatric patients by the Food and Drug Administration, their use in children of all ages is indicated to treat the pain of procedures, as an adjunct to general anesthesia, for postoperative or postprocedural pain, and for the treatment of painful medical conditions. Such medications may be administered as single or intermittent boluses or as a continuous infusion. For prolonged use, continuous infusion is preferred to avoid large variations in plasma concentration. Whenever medications in this category are administered, there must be accompanying vigilance for potential adverse effects on the respiratory and cardiovascular systems. Such observations may be limited with a single administration but must be more intense with repeated doses, when administered by infusion, or when drug combinations are used. Agents known to compromise cardiorespiratory function should be administered only by persons experienced in airway management and in settings with the capacity for continuous monitoring of vital signs (ie, heart rate, blood pressure, respiratory rate, SaO2).59-61 The need for continued treatment with the opioid to manage pain increases the possibility of tolerance that requires dose escalation to maintain analgesia and slow withdrawal of the drug to avoid abstinence syndrome.

The risk of adverse effects is directly related to rate of drug administration, total dose, and combination with other medications capable of central nervous system depression. Intravenous boluses of the synthetic opioids (eg, fentanyl, sufentanil, alfentanil) may be associated with glottic and chest wall rigidity.80 The propensity for these adverse effects is reduced by avoiding rapid bolus injection. Administration should be by frequent small aliquots or by infusion over several minutes. The health care professional who administers opioids should be trained in the recognition and treatment of the adverse complications, including the use of bag-mask ventilation, an opioid antagonist to oppose the respiratory depression, or a muscle relaxant to treat glottic and chest wall rigidity.80 The health care professional must have airway management skills and knowledge of the pharmacodynamics of the administered drugs to manage life-threatening events. When an opioid antagonist is administered, the analgesic effect of opioids also is antagonized. Opioid antagonists must be used with caution in neonates who have received prolonged treatment with opioids (>4 days). In this situation, an antagonist (eg, naloxone) may precipitate acute opioid withdrawal with seizures, hypertension, and other adverse clinical consequences.81

Concomitant use of opioids and benzodiazepines necessitates a decrease in the total dose of opioid and benzodiazepine. However, nonopioid medications should not be used in place of opioids because they do not possess analgesic properties. Moreover, the risk of respiratory depression may be additive or synergistic.

There are insufficient data to recommend one opioid over another. In general, meperidine is not recommended for prolonged administration owing to the possibility of the accumulation of toxic metabolites capable of causing seizures.82 When opioids or other sedating medications, such as benzodiazepines, are administered for a prolonged period, physical dependence and tolerance may develop, thus increasing the opioid or sedative requirements to maintain patient comfort.81,83-85 The long-term effects of opioids and sedatives have not been well established. However, the first concern of the health care professional should be the treatment of stress or pain, which later can be followed by managing the consequences of the stress or pain treatment.33

When stress or pain medications are no longer deemed necessary, slow weaning of the patient from opioids and other sedatives over a prolonged period may be required.81 Such weaning may be a gradual reduction in daily drug dosage with frequent reassessment to ensure that the patient is free of pain and withdrawal symptoms or it may be a change to longer-acting oral medications, such as methadone, that can be tapered.81,83-85 The starting dose of methadone should be calculated to provide a dose equivalent to the dose of opioid the neonate is receiving. Methadone kinetics and dosing requirements for extremely premature neonates have not been studied adequately.

Titration of dose to observed clinical effect and administration of the lowest effective dose help to avoid toxic effects. Rectal administration of opioids has been described but is not generally recommended owing to irregular and unpredictable absorption.77

Nonsteroidal Anti-inflammatory Drugs

Generally, this category of medications is used to treat less intense pain and as an adjunct to reduce the total dose of more potent analgesics, such as opioids. Limited data are available on the pharmacokinetics of acetaminophen (paracetamol) in newborns.86-88 Acetaminophen does not reduce the response to pain due to heel-lance procedures89 but may provide some reduction in pain after circumcision.90 There are no studies in the newborn of the effectiveness and safety of ketorolac or ibuprofen to reduce pain.91


Behaviors associated with pain (eg, crying, grimacing, posturing, sweating, restlessness) also may accompany nonpainful care-giving procedures for low birth weight neonates.45 Additional research is needed to better differentiate pain, stress, and variation in behavioral or sleep and awake states.92 A method to quantitate stress in preterm neonates has been developed to assist neonatal health care professionals to recognize and reduce stress in preterm neonates, although its clinical usefulness requires further evaluation.46

Noxious environmental stimuli should be minimized. Only limited research addresses the short- and long-term efficacy and toxic effects of the pharmacological agents (sedatives and hypnotics) used to manage perceived neonatal anxiety. Thus, health care professionals must individualize decisions about the appropriateness of the use of these drugs based on extrapolation from adult experience and common sense. The following concepts must be kept in mind: 1) Sedatives and anxiolytics do not provide analgesia. If painful procedures are anticipated, analgesics should usually be administered. 2) Long-term use of many sedatives and hypnotics includes the risks of tolerance, dependency, and withdrawal. 3) Long-term outcome (particularly neurodevelopmental) for infants who have received long-term sedation is unknown, although the long-term effects of neonatal pain and stress were the focus of recent research.37-41,48 4) Sedatives and hypnotics may cause respiratory and cardiovascular depression.93-97 Continuous pulse oximetry and frequent monitoring of vital signs is recommended strongly. 5) Use of combined therapy with a sedative or hypnotic and an opioid necessitates a decrease in dosage of each. Failure to reduce dosage when used in combination increases the risk of adverse effects, such as respiratory depression. In addition, certain combinations, such as fentanyl and midazolam, should not be given as rapid infusions because this combination is associated with severe systemic hypotension.93-97

Among older infants, benzodiazepines, barbiturates, chloral hydrate, and phenothiazines have been used for sedation and to relieve anxiety. Of these options, data are available for the use of benzodiazepines, chloral hydrate, and barbiturates in neonates. Of the benzodiazepines, midazolam has been approved for use in neonates, and a randomized, controlled trial has demonstrated sedative effects.97 However, adverse hemodynamic effects and abnormal movements have been associated with its use in neonates.94-98 If used, a continuous infusion or administration of individual doses over at least 10 minutes is recommended to reduce the risk of adverse effects. Data are insufficient to assess the efficacy and safety of lorazepam.99-103 Diazepam is not recommended owing to its long half-life, its long-acting metabolites, and concern about the benzyl alcohol content, although the dose of benzyl alcohol is far less than that associated with toxic effects.104,105 Chloral hydrate has been used extensively as a sedative-hypnotic in neonates106 but it is metabolized to trichloroethanol, which competes for glucuronidation and may exacerbate hyperbilirubinemia.107 In addition, another metabolite (trichloroacetic acid) persists for up to 1 week after a single dose.108 Owing to a long half-life for trichloroacetic acid and trichloroethanol in premature neonates, repeated doses may be associated with adverse effects (eg, central nervous system depression, arrhythmias, and renal failure).109 Thus, repeated doses should not be given. Phenobarbital has a long half-life, and barbiturates may increase the reaction to painful stimuli.110 Evidence of the effectiveness and safety of phenothiazines is lacking; these drugs are not recommended.


James A. Lemons, MD, Chairperson
Lillian R. Blackmon, MD
William P. Kanto, Jr, MD
Hugh M. MacDonald, MD
Carol A. Miller, MD
Lu-Ann Papile, MD
Warren Rosenfeld, MD
Craig T. Shoemaker, MD
Michael E. Speer, MD
Michael F. Greene, MD
    American College of Obstetricians and Gynecologists
Patricia Johnson, RN, MS, NNP
    American Nurses Association, Association of Women's Health,
    Obstetric and Neonatal Nurses, National Association of Neonatal Nurses
Douglas D. McMillan, MD
    Canadian Paediatric Society
Solomon Iyasu, MBBS, MPH
    Centers for Disease Control and Prevention
Linda L. Wright, MD
    National Institutes of Health
Richard Molteni, MD
    Section on Perinatal Pediatrics
Jacob C. Langer, MD
    Section on Surgery
Marilyn Escobedo, MD
Avroy Fanaroff, MD
Robert M. Ward, MD, Chairperson
Brian A. Bates, MD
D. Gail McCarver, MD
Daniel A. Notterman, MD
Philip D. Walson, MD
Douglas N. Weismann, MD
John T. Wilson, MD
Donald R. Bennett, MD, PhD
    American Medical Association/United States Pharmacopeia
Richard Depp III, MD
    American College of Obstetricians and Gynecologists
Therese Dvetkovich, MD
    Food and Drug Administration
Owen R. Hagino, MD
    American Academy of Child and Adolescent Psychiatry
Stuart M. MacLeod, MD, PhD
    Canadian Paediatric Society
Joseph Mulinare, MD, MSPH
    Centers for Disease Control and Prevention
Sumner J. Yaffe, MD
    National Institutes of Health
Charles J. Coté, MD
    Section on Anesthesiology
Stanley J. Szefler, MD
    Section on Allergy and Immunology
Lynda J. Means, MD, Chairperson
Lynne Ferrari, MD, Chairperson-elect
Ann Bailey, MD
Raeford E. Brown, Jr, MD
Patty Davidson, MD
Peter J. Davis, MD
Jayant K. Deshpande, MD
Thomas J. Mancuso, MD
Myron Yaster, MD
John K. Hall, MD
    International Trauma Anesthesia and Critical Care Society
Mark A. Rockoff, MD
    Society for Pediatric Anesthesia
Arnold Coran, MD, Chairperson
Richard Andrassy, MD
Robert M. Arensman, MD
Richard Azizkhan, MD
Ann M. Kosloske, MD
Thomas R. Weber, MD
Arnold G. Coran, MD
    Advisory Council of the American College of Surgeons on Pediatric Surgery
Douglas D. McMillan, MD, Chairperson
Arne Ohlsson, MD, MSc, Co-chairperson
Deborah J. Davis, MD
Daniel J. Faucher, MD
John E. E. Van Aerde, MD
Michael J. Vincer, MD
Robin Walker, MD
James Lemons, MD
    American Academy of Pediatrics
Saroj Saigal, MD
    CPS, Neonatal-Perinatal Medicine Section
Cheryl Levitt, MD
    College of Family Physicians of Canada
Catherine McCourt, MD
    Health Canada
Debbie Fraser-Askin
    Neonatal Nursing
Line Leduc, MD
    Society of Obstetricians and Gynecologists of Canada
Reginald Sauve
    CPS, Neonatal-Perinatal Medicine Section
Anna Taddio, MSc, PhD
Bonnie Stevens, RN, PhD


  1. Merskey H, Albe-Fessard DG, Bonica JJ, et al. Pain terms: a list with definitions and notes on usage: recommended by the IASP Subcommittee on Taxonomy. Pain. 1979;6:249-252
  2. Derbyshire SWG. Comment on editorial by Anand and Craig. Pain. 1996;66:210-211. Letter
  3. Anand KJS, Craig KD. New perspectives on the definition of pain. Pain. 1996;67:3-6. Editorial
  4. Merskey H. Response to editorial: new perspectives on the definition of pain. Pain. 1996;66:209. Letter
  5. Johnston CC, Collinge JM, Henderson SJ, Anand KJ. A cross-sectional survey of pain and pharmacological analgesia in Canadian neonatal intensive care units. Clin J Pain. 1997;13:308-312
  6. Craig KD, Lilley CM, Gilbert CA. Social barriers to optimal pain management in infants and children. Clin J Pain. 1996;12:232-242
  7. Merriam Webster's Collegiate Dictionary. 10th ed. Springfield, MA: Merriam-Webster Inc; 1994:1164
  8. McIntosh N. Pain in the newborn: a possible new starting point. Eur J Pediatr. 1997;156:173-177
  9. Burokas L. Factors affecting nurses' decisions to medicate pediatric patients after surgery. Heart Lung. 1985;14:373-379
  10. Purcell-Jones G, Dormon F, Sumner E. Pediatric anesthetists' perceptions of neonatal and infant pain. Pain. 1988;33:181-187
  11. 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 Paediatr. 1985;23:143-157
  12. Clinical Practice Guideline Number AHCPR Publication No 92-0032: Acute Pain Management: Operative or Medical Procedures and Trauma. Rockville, MD: Agency for Health Care Policy and Research, Public Health Service, US Dept of Health and Human Services; 1992. AHCPR Publication No. 92-0032
  13. Schechter NL, Blankson V, Pachter LM, Sullivan CM, Costa L. The ouchless place: no pain, children's gain. Pediatrics. 1997;99:890-894
  14. de Lima J, Lloyd-Thomas AR, Howard RF, Sumner E, Quinn TM. Infant and neonatal pain: anaesthetists' perceptions and prescribing patterns. Br Med J. 1996;313:787
  15. Goddard JM, Pickup SE. Postoperative pain in children. Anesthesia. 1996;51:588-590
  16. Porter FL, Wolf CM, Gold J, Lotsoff D, Miller JP. Pain and pain management in newborn infants: a survey of physicians and nurses. Pediatrics. 1997;100:626-632
  17. Anand KJS, McGrath PJ, eds. Pain in Neonates. Amsterdam, The Netherlands: Elsevier; 1993
  18. Schechter NL, Berde CB, Yaster M, eds. Pain in Infants, Children, and Adolescents. Baltimore, MD: Williams & Wilkins; 1993
  19. Sparshott M. Pain, Distress and the Newborn Baby. Oxford, England: Blackwell Science; 1997
  20. Grunau RVE, Craig KD. Facial activity as a measure of neonatal pain expression. In: Tyler DC, Krane EJ, eds. Advances in Pain Research Therapy. New York, NY: Raven Press; 1990:147-154. Pediatric Pain, vol 15
  21. Lawrence J, Alcock D, McGrath P, Kay J, MacMurray SB, Dulberg C. The development of a tool to assess neonatal pain. Neonatal Netw. 1993;12:59-66
  22. Stevens B, Johnston C, Petryshen P, Taddio A. Premature infant pain profile: development and initial validation. Clin J Pain. 1996;12:13-22
  23. Krechel SW, Bildner J. CRIES: a new neonatal postoperative pain measurement score: initial testing of validity and reliability. Pediatr Anaesth. 1995;5:53-61
  24. Abu-Saad HH, Bours GJJW, Stevens B, Hamers JPH. Assessment of pain in neonates. Semin Perinatol. 1998;22:402-416
  25. Fernandez CV, Rees EP. Pain management in Canadian level 3 neonatal intensive care units. CMAJ. 1994;150:499-504
  26. Wellington N, Rieder MJ. Attitudes and practices regarding analgesia for newborn circumcision. Pediatrics. 1993;92:541-543
  27. Howard CR, Howard FM, Garfunkel LC, de Blieck EA, Weitzman M. Neonatal circumcision and pain relief: current training practices. Pediatrics. 1998;101:423-428
  28. 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
  29. Giannakoulopoulos X, Sepulveda W, Kourtis P, Glover V, Fisk NM. Fetal plasma cortisol and beta-endorphin response to intrauterine needling. Lancet. 1994;344:77-81
  30. Fitzgerald M, Shaw A, McIntosh N. Postnatal development of the cutaneous flexor reflex: comparative study of preterm infants and newborn rat pups. Dev Med Child Neurol. 1988;30:520-526
  31. Fitzgerald M, Millard C, McIntosh N. Cutaneous hypersensitivity following peripheral tissue damage in newborn infants and its reversal with topical anesthesia. Pain. 1989;39:31-36
  32. Perreault T, Fraser-Askin D, Liston R, et al. Pain in the neonate. Paediatr Child Health. 1997;2:201-209
  33. Anand KJ. Clinical importance of pain and stress in preterm neonates. Biol Neonate. 1998;73:1-9
  34. 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
  35. Anand KJ, Hickey PR. Pain and its effects in the human neonate and fetus. N Engl J Med. 1987;317:1321-1329
  36. Anand KJ, McIntosh N, Lagercrantz H, Pelausa E, Young TE, Vasa R. Analgesia and sedation in preterm neonates who require ventilatory support: results from the Neonatal Outcome and Prolonged Analgesia in Neonates trial. Arch Pediatr Adolesc Med: 1999;153:331-338
  37. Taddio A, Goldbach M, Ipp M, Stevens B, Koren G. Effect of neonatal circumcision on pain response during vaccination in boys. Lancet. 1995;345:291-292
  38. Taddio A, Katz J, Ilersich AL, Koren G. Effect of neonatal circumcision on pain response during subsequent routine vaccination. Lancet. 1997;349:599-603
  39. Grunau RE, Whitfield MF, Petrie J. Children's judgements about pain at age 8-10 years: do extremely low birthweight (<1000 g) children differ from full birthweight peers? J Child Psychol Psychiatry. 1998;39:587-594
  40. Johnston CC, Stevens BJ. Experience in a neonatal intensive care unit affects pain response. Pediatrics. 1996;98:925-930
  41. 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
  42. Izard CE. Maximally Discriminative Facial Coding System (MAX). Newark, DE: University of Delaware Instructional Resource Center; 1979
  43. Grunau RE, Oberlander T, Holsti L, Whitfield MF. Bedside application of the neonatal facial coding system in pain assessment of premature neonates. Pain. 1998;76:277-286
  44. Sparshott MM. The development of a clinical distress scale for ventilated newborn infants: identification of pain and distress based on validated behavioral scores. J Neonatal Nurs. 1996;2:5-11
  45. Evans JC, Vogelpohl DG, Bourguignon CM, Morcott CS. Pain behaviors in LBW infants accompany some "nonpainful" caregiving procedures. Neonatal Netw. 1997;16:33-39
  46. Modrcin-McCarthy MA, McCue S, Walker J. Preterm infants and STRESS: a tool for the neonatal nurse. J Perinat Neonat Nurs. 1997;10:62-71
  47. Pacifiers, passive behavior, and pain. Lancet. 1992;339:275-276
  48. 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
  49. Winberg J. Do neonatal pain and stress program the brain's response to future stimuli? Acta Paediatr. 1998;87:723-725
  50. Sauve R, Saigal S, eds. Optimizing the neonatal intensive care environment. Report of the Tenth Canadian Ross Conference in Pediatrics, GCI Communications; 1995; Abbott Laboratories; Montreal, Canada
  51. American Academy of Pediatrics, Committee on Environmental Health. Noise: a hazard for the fetus and newborn. Pediatrics. 1997;100:724-727
  52. Corff K, Seideman R, Venkataraman P, Lutes L, Yates B. Facilitated tucking: a nonpharmacologic comfort measure for pain in preterm infants. J Obstet Gynecol Neonatal Nurs. 1995;24:143-147
  53. 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
  54. Stevens B, Taddio A, Ohlsson A, Einarson T. The efficacy of sucrose for relieving procedural pain in neonates: a systematic review and meta-analysis. Acta Paediatr. 1997;86:837-842
  55. Stevens B, Ohlsson A. Sucrose for analgesia in newborn infants undergoing painful procedures (Cochrane Review). In: The Cochrane Library, Issue 4, 1999. Oxford: Update Software
  56. 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
  57. Larsson BA, Tannfeldt G, Lagercrantz H, Olsson GL. Venipuncture is more effective and less painful than heel lancing for blood tests in neonates. Pediatrics. 1998;101:882-886
  58. Shah V, Ohlsson A. Venepuncture versus heel lance for blood sampling in term neonates (Cochrane Review). In: The Cochrane Library, Issue 4, 1999. Oxford: Update Software
  59. 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
  60. Canadian Anaesthetists' Society. CAS guidelines to the practice of anesthesia: revised edition 1997. Can J Anaesth. 1997;44S
  61. 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
  62. MacGregor R, Evans D, Sugden D, Gaussen T, Levene M. Outcome at 5-6 years of prematurely born children who received morphine as neonates. Arch Dis Child Fetal Neonatal Ed. 1998;79:F40-F43
  63. American Academy of Pediatrics, Committee on Fetus and Newborn, Committee on Drugs, Section on Anesthesiology, and Section on Surgery. Neonatal anesthesia. Pediatrics. 1987;80:446
  64. Stang HJ, Snellman LW, Condon LM, et al. Beyond dorsal penile nerve block: a more humane circumcision. Pediatrics. 1997;100(2). URL: http://www.pediatrics.org/cgi/content/full/100/2/e3
  65. Yaster M, Maxwell LG, Nicholas EJ. Local anesthetics in the management of acute pain in children: a primer for the non-anesthesiologist. Compr Ther. 1991;17:27-35
  66. Yaster M, Maxwell LG. Pediatric regional anesthesia. Anesthesiology. 1989;70:324-338
  67. Yaster M, Deshpande JK, Maxwell LG. The pharmacologic management of pain in children. Compr Ther. 1989;15:14-26
  68. Yaster M, Krane EJ, Kaplan RF, Coté CJ, Lappe DG, eds. Pediatric Pain Management and Sedation Handbook. St Louis, MO: Mosby-Year Book Inc; 1997
  69. Dalens B. Regional anesthesia in pediatrics. Ann Fr Anesth Reanim. 1989;8:51-66
  70. Strafford MA, Wilder RT, Berde CB. The risk of infection from epidural analgesia in children: a review of 1620 cases. Anesth Analg. 1995;80:234-238
  71. Larsson BA, Lönnqvist PA, Olsson GL. Plasma concentrations of bupivacaine in neonates after continuous epidural infusion. Anesth Analg. 1997;84:501-505
  72. Berde CB. Toxicity of local anesthetics in infants and children. J Pediatr. 1993;122:S14-20
  73. Klein EJ, Shugerman RP, Leigh-Taylor K, Schneider C, Portscheller D, Koepsell T. Buffered lidocaine: analgesia for intravenous line placement in children. Pediatrics. 1995;95:709-712
  74. Taddio A, Stevens B, Craig K, et al. Efficacy and safety of lidocaine: prilocaine cream for pain during circumcision. N Engl J Med. 1997;336:1197-1201
  75. Larsson BA, Jylli L, Lagercrantz H, Olsson GL. Does a local anesthetic cream (EMLA) alleviate pain from heel-lancing in neonates? Acta Anaesthesiol Scand. 1995;23:1028-1031
  76. Taddio A, Ohlsson A, Einarson TR, Stevens B, Koren G. A systematic review of lidocaine-prilocaine cream (EMLA) in the treatment of acute pain in neonates. Pediatrics. 1998;101(2). URL: http://www.pediatrics.org/cgi/content/full/101/2/e1
  77. American Academy of Pediatrics, Committee on Drugs. Alternate routes of drug administration: advantages and disadvantages. Pediatrics. 1997;100:143-152
  78. Jacqz-Aigrain E, Burtin P. Clinical pharmacokinetics of sedatives in neonates. Clin Pharmacokinet. 1996;31:423-443
  79. Olkkola KT, Hamunen K, Maunuksela EL. Clinical pharmacokinetics and pharmacodynamics of opioid analgesics in infants and children. Clin Pharmacokinet. 1995;28:385-404
  80. Huet F, Reiser V, Gouyon JB. Effet secondaire du fentanyl sur la ventilation mécanique de l'enfant prématuré. Arch Fr Pediatr. 1992;49:841
  81. Anand KJ, Arnold JH. Opioid tolerance and dependence in infants and children. Crit Care Med. 1994;22:334-342
  82. Armstrong PJ, Bersten A. Normeperidine toxicity. Anesth Analg. 1986;65:536-538
  83. Bhatt-Mehta V. Current guidelines for the treatment of acute pain in children. Drugs. 1996;51:760-776
  84. van Engelen BG, Gimbrere JS, Booy LH. Benzodiazepine withdrawal reaction in two children following discontinuation of sedation with midazolam. Ann Pharmacother. 1993;27:579-581
  85. Yaster M, Kost-Byerly S, Berde C, Billet C. The management of opioid and benzodiazepine dependence in infants, children and adolescents. Pediatrics. 1996;98:135-140
  86. 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
  87. Birmingham PK, Tobin MJ, Henthorn TK, et al. Twenty-four-hour pharmacokinetics of rectal acetaminophen in children: an old drug with new recommendations. Anesthesiology. 1997;87:244-252
  88. Van Lingen RA, Deinum JT, Quak JM, et al. Pharmacokinetics and metabolism of rectally administered paracetamol in preterm neonates. Arch Dis Child Fetal Neonat Ed. 1999;80:F59-F63
  89. 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
  90. Howard CR, Howard FM, Weitzman ML. Acetaminophen analgesia in neonatal circumcision: the effect on pain. Pediatrics. 1994;93:641-646
  91. Gillis JC, Brogden RN. Ketorolac: a reappraisal of its pharmacodynamic and pharmacokinetic properties and therapeutic use in pain management. Drugs. 1997;53:139-188
  92. Anand KJ, Aynsley-Green A. Measuring the severity of surgical stress in newborn infants. J Pediatr Surg. 1988;23:297-305
  93. Burtin P, Daoud P, Jacqz-Aigrain E, Mussat P, Moriette G. Hypotension with midazolam and fentanyl in the newborn. Lancet. 1991;337:1545-1546
  94. Jacqz-Aigrain E, Wood E, Robieux I. Pharmacokinetics of midazolam in critically ill neonates. Eur J Clin Pharmacol. 1990;39:191-192
  95. Burtin P, Jacqz-Aigrain E, Girard P, et al. Population pharmacokinetics of midazolam in neonates. Clin Pharmacol Ther. 1994;56:615-625
  96. Jacqz-Aigrain E, Daoud P, Burtin P, Maherzi S, Beaufils F. Pharmacokinetics of midazolam during continuous infusion in critically ill neonates. Eur J Clin Pharmacol. 1992;42:329-332
  97. Jacqz-Aigrain E, Daoud P, Burtin P, Desplanques L, Beaufils F. Placebo-controlled trial of midazolam sedation in mechanically ventilated newborn babies. Lancet. 1994;344:646-650
  98. Magny JF, Zupan V, Dehan M, d'Allest AM, Nedelcoux H. Midazolam and myoclonus in neonate. Eur J Pediatr. 1994;153:389-390
  99. Maloley PA, Gal P, Mize R, Weaver RL, Ransom JL. Lorazepam dosing in neonates: application of objective sedation score. DICP. 1990;24:326-327
  100. Sexson WR, Thigpen J, Stajich GV. Stereotypic movements after lorazepam administration in premature neonates: a series and review of the literature. J Perinatol. 1995;15:146-151
  101. Reiter PD, Stiles AD. Lorazepam toxicity in a premature infant. Ann Pharmacother. 1993;27:727-729
  102. McDermott CA, Kowalczyk AL, Schnitzler ER, Mangurten HH, Rodvold KA, Metrick S. Pharmacokinetics of lorazepam in critically ill neonates with seizures. J Pediatr. 1992;120:479-483
  103. Lee DS, Wong HA, Knoppert DC. Myoclonus associated with lorazepam therapy in very-low-birth-weight infants. Biol Neonate. 1994;66:311-315
  104. Jardine DS, Rogers K. Relationship of benzyl alcohol to kernicterus, intraventricular hemorrhage, and mortality in preterm infants. Pediatrics. 1989;83:153-160
  105. Brown WJ, Buist NR, Gipson HT, Huston RK, Kennaway NG. Fatal benzyl alcohol poisoning in a neonatal intensive care unit. Lancet. 1982;1:1250
  106. Reimche LD, Sankaran K, Hindmarsh KW, Kasian GF, Gorecki DK, Tan L. Chloral hydrate sedation in neonates and infants: clinical and pharmacologic considerations. Dev Pharmacol Ther. 1989;12:57-64
  107. Lambert GH, Muraskas J, Anderson CL, Myers TF. Direct hyperbilirubinemia associated with chloral hydrate administration in the newborn. Pediatrics. 1990;86:277-281
  108. Mayers DJ, Hindmarsh KW, Sankaran K, Gorecki DKJ, Kasian GF. Chloral hydrate disposition following single-dose administration to critically ill neonates and children. Dev Pharmacol Ther. 1991;16:71-77
  109. Goldsmith JP. Ventilatory management casebook: chloral hydrate intoxication. J Perinatol. 1994;14:74-76
  110. Hobbs WR, Rall TW, Verdoorn TA. Hypnotics and sedatives; ethanol. In: Goodman LS, Gilman AG, Hardman JG, Gilman AG, Limbird, LE, eds. Goodman & Gilman's The Pharmacological Basis of Therapeutics. 9th ed. New York, NY: McGraw-Hill; 1995:374

The recommendations in this statement do not indicate an exclusive course of treatment or serve as a standard of medical care. Variations, taking into account individual circumstances, may be appropriate.

Copyright © 2000 by the American Academy of Pediatrics. No part of this statement may be reproduced in any form or by any means without prior written permission from the American Academy of Pediatrics except for one copy for personal use.

(Revised 18 March 2003)

Return to CIRP library