Atlas of Procedures in Neonatology, 4th Edition

Preparation and Support


Analgesia and Sedation in the Newborn

Nicholas J. Marsh

  1. Introduction

Pain management is an integral part of compassionate neonatal medical care. Historically, barriers to adequate pain management in neonates have been related to the question of pain perception in the newborn. This question is no longer debated, and the use of analgesics for these patients is well established (1,2,3,4 and 5). However, pain management and sedation practices continue to vary among practitioners (6,7). Safe care requires careful choice and dosing of medications, appropriate monitoring, and preparedness to manage complications (4,8). This chapter offers general guidelines for the management of analgesia and sedation in newborn infants.

  1. Definitions
  2. Analgesia: A condition in which nociceptive stimuli are perceived but are not interpreted as pain; usually accompanied by sedation without loss of consciousness (9)
  3. Conscious sedation: A medically controlled state of depressed consciousness that allows protective reflexes to be maintained, retains the ability to maintain a patent airway independently and continuously, and permits appropriate responses by the patient (8)
  4. Deep sedation: A medically controlled state of depressed consciousness or unconsciousness from which the patient is not easily aroused. It may be accompanied by a partial or complete loss of protective reflexes and includes the inability to maintain a patent airway independently and respond purposefully to stimulation (8).
  5. Tolerance: The ability to resist the action of a drug or the requirement for increasing doses of a drug, with time, to achieve a desired effect (10)
  6. Withdrawal: The development of a substance-specific syndrome that follows the cessation of, or reduction in, intake of a psychoactive substance previously used or administered regularly (11)
  7. Neonatal abstinence syndrome: Onset of withdrawal symptoms in neonates upon cessation of an agent associated with physical dependence (11)
  8. General Indications
  9. Any condition or procedure known to be painful (4,12) (see E)
  10. Physiologic indications consistent with perception of pain (1,13)
  11. Tachycardia
  12. Tachypnea
  13. Elevated blood pressure (with secondary increase in intracranial pressure)
  14. Decreased arterial oxygen saturation
  15. Hyperglycemia secondary to hormonal and metabolic stress responses
  16. Behavioral indications consistent with perception of pain (4,5,13,14,16)
  17. Simple motor responses (i.e., withdrawal of an extremity from a noxious stimulus)
  18. Facial expressions (i.e., grimace)
  19. Altered cry (primary method of communicating painful stimuli in infancy)
  20. Agitation
  21. Specific Indications
  22. Analgesia

In general, the potency of analgesic treatment selected should be related directly to the anticipated or assessed level of pain (1).

  1. Mild pain
  2. Nonpharmacologic approaches (see H)
  3. Local and/or topical anesthesia
  4. Nonopioid analgesics (e.g., acetaminophen)
  5. Moderate and severe pain
  6. Intravenous opioid analgesics (see E)
  7. Local and/or topical anesthesia
  8. Benzodiazepines (in combination with D2a; see E)
  9. Sedation

Sedatives may be co-administered with analgesics to enhance the anticipated benefits. Because of the escalated risks associated with deep sedation, conscious sedation should be the usual clinical endpoint.


  1. Benzodiazepines (see E)
  2. Chloral hydrate (see E)
  3. Nonpharmacologic approaches (see H)
  4. Precautions
  5. Be aware, when assessing patients, that:
  6. The clinical assessment of pain in the newborn is imprecise.
  7. Physiologic and behavioral indicators of pain are nonspecific and may be related to many other factors.
  8. Intubated neonates receiving muscle relaxants may have altered physiologic indicators and completely ablated behavioral indicators.
  9. A high index of suspicion is required to identify newborn infants in pain (13).
  10. Be aware, when medicating patients, that:
  11. There are numerous potential complications associated with analgesic and sedative agents (Table 5.1) (17,18).
  12. Large inter- and intraindividual variations in response may occur (19).
  13. Medications must always be titrated slowly (4).
  14. Co-administration of opioids, benzodiazepines, and other sedatives may result in greatly exaggerated respiratory depressant effects, including apnea (20,21).
  15. Resuscitation equipment and medications should be immediately available. Be prepared to support ventilation and perform tracheal intubation if needed; respiratory depression is a common side effect of a number of analgesic agents.
  16. Be aware that:
  17. Newborn infants who have developed tolerance to a sedative or analgesic agent, by either direct or in utero exposure, may exhibit symptoms of the neonatal abstinence syndrome upon abrupt cessation or reversal of the administered agent (20,21). For example, naloxone administered to opioid-dependent neonates may precipitate acute, severe withdrawal symptoms (11).
  18. Chronic analgesic therapy with agents known to induce tolerance should be weaned gradually, with close monitoring for evidence of withdrawal symptoms (4,20,21).
  19. When using analgesics for a painful procedure:
  20. Consider both the duration and the anticipated pain when selecting medications and methods. For example, short procedures with mild to moderate discomfort, such as lumbar puncture, may be best managed with topical and local anesthetics (22,23 and 24).
  21. Minimize the number of painful episodes. Multiple procedures performed at the same time may avoid the need for repeated administration of analgesics (2,15).
  22. Ensure that oxygen, suction, airway, resuscitation equipment, and reversal agents are readily available.
  23. Follow nothing-by-mouth (NPO) guidelines for ambulatory surgery.
  24. Have a nurse, or other professional not involved in the procedure, constantly monitor respirations, pulse oximetry, heart rate, and level of consciousness.
  25. Chloral hydrate, previously regarded as a highly safe sedative, should be used with caution in neonates (particularly premature neonates) owing to the risk of hyperbilirubinemia and accumulation of toxic metabolites (25,26 and 27). For these reasons, a single dose only is recommended.
  26. Advantages and Disadvantages of Commonly Used Agents in the Newborn

See Table 5.1.

  1. Complications

See Table 5.1.

  1. Nonpharmacologic Approaches
  2. Swaddling during heel-stick procedures has been shown to reduce behavioral pain responses (28).
  3. Non-nutritive sucking has been demonstrated to significantly reduce crying in response to painful stimuli (29,30).
  4. Sucrose
  5. Infants who drank 2 mL of a 12% sucrose solution prior to blood collection via heel stick cried 50% less than control infants during the same procedure (30).
  6. Infants who received sucrose on a pacifier prior to and during circumcision cried significantly less than control infants (30).
  7. 2 mL of 12% to 50% sucrose administered orally 2 minutes prior to the procedure is an effective neonatal analgesic with few adverse effects (31,32).
  8. Contraindications
  9. There are no absolute contraindications to using analgesia and/or sedation when deemed clinically appropriate.





  1. Be aware of the potential side effects associated with the specific agent selected and take the proper precautions.

TABLE 5.1 Sedative and Analgesic Agents Commonly Used in the Newborn



Mechanism of Action



Recommended Dose



Oral analgesic

Inhibition of peripheral afferent pain signals

No respiratoy depression

Mild analgesia

10–20 mg/kg p.o., p.r.


Fentanyl (Sublimaze)

Synthetic narcotic analgesic

Opioid receptor agonist

Rapid onset of action (3–5 min)
More potent than morphine
Reversible with narcotic antagonist

Short duration (30–60 min)
Respiratory depression
Risk of seizures
Chest wall rigidity with rapid infusion
Tolerance and withdrawal

1–5 µg/kg i.v. bolus
0.5–1.5 µg/kg/h continuous infusion (analgesia)



Narcotic analgesic

Opioid receptor agonist

Longer duration than fentanyl (4 h)
Reversible with narcotic antagonist

Slower onset of action than fentanyl (10–15 min)
Respiratory depression
More adverse cardiovascular side effects than fentanyl
Tolerance and withdrawal

20 µg/kg/h (ventilated patients)


Meperidine (Demerol)

Narcotic analgesic

Opioid receptor agonist

Longer duration than fentanyl (2–4 h)
Reversible with narcotic antagonist
Less respiratory depression than morphine

Slower onset of action than fentanyl (10 min)
Tolerance and withdrawal

0.5–1.5 mg/kg i.v. or i.m.



Benzodiazepine sedative/hypnotic

Brainstem reticular formation depressant

Music relaxation
Rapid onset (1–2 min)

No analgesic effect
Respiratory depression
Withdrawal symptoms may occur

0.1–0.2 mg/kg i.v.



Benzodiazepine sedative/hypnotic

Brainstem reticular formation depressant

Longer duration than diazepam (8–12 h)

No analgesic effect
Respiratory depression
Withdrawal symptoms may occur

0.05–0.1 mg/kg i.v.



Benzodiazepine sedative/hypnotic

Brainstem reticular formation depressant

Rapid onset of action (2–5 min)

No analgesic effect
Respiratory depression
Withdrawal symptoms may occur

0.05–0.15 mg/kg i.v. loading dose
0.16–1 µg/kg/min continuous infusion



Barbiturate sedative

Nonspecific CNS depressant

Long half-life
Serum levels easily monitored
Reduces serum bilirubin levels

No analgesic effect
Slower onset of action than other barbiturates (5 min)
No specific antagonist
Respiratory depression

2–10 mg/kg i.v. i.m., p.o.


Chloral hydrate


Central depressant effect

Minimal cardiorespiratory side effects

No analgesic effects
Gastrointestinal irritant
May accumulate in neonates
May cause myocardial depression
Associated with hyperbilirubinemia
Toxic metabolites may accumulate with repeated dosing

25–50 mg/kg p.o., p.r.
One administration only—repeated doses increase risk of accumulation and toxicity


EMLA cream (lidocaine 2.5%, prilocaine 2.5% cream)

Topical anesthetic

Delivery of local anesthetic to dermal and epidermal tissue

Painless administration, direct application to intact skin

Not recommended in neonates <1 mo old, contraindicated in patients with congenital or idiopathic methemoglobinemia or those receiving methemoglobininducing agents
Systemic absorption of active ingredients with formation of methemoglobinemia

Age 0–3 mo: maximum 1 g, 10 cm2, ≤ 1 h
Age 3–12 mo: maximum 2 g, 20 cm2, ≤ 4 h

Hepatic, renal

Data from refs. 1,2,4,5,13,19,21,26
CNS, central nervous system.
aLimited data available in newborns.


  1. Vitali SH, Camerota AJ, Arnold JH.Anaesthesia and analgesia in the newborn. In: Macdonald MG, Mullett MD, Sechia MMK, eds.Neonatology: Pathophysiology and Management of the Newborn. 6th ed. Philadelphia: Lippincott Williams & Wilkins; 2005:1557.
  2. Larsson BA.Pain management in neonates. Acta Paediatr. 1999;88:1301.
  3. Anand KJS.Clinical importance of pain and stress in preterm neonates. Biol Neonate. 1998;73:1.
  4. Menon G, Anand KJ, McIntosh N.Practical approach to analgesia and sedation in the neonatal intensive care unit. Semin Perinatol.1998;22:417.
  5. Stevens B.Management of painful procedures in the newborn. Curr Opin Pediatr. 1996;8:102.
  6. Porter FL, Wolf CM, Gold J, et al. Pain and pain management in newborn infants: a survey of physicians and nurses. Pediatrics.1997;100:626.
  7. McLaughlin CK, Hull JG, Edwards WH, et al. Neonatal pain: a comprehensive survey of attitudes and practices. J Pain Symp Manage.1993;8:7
  8. Committee on Drugs, American Academy of Pediatrics.Guidelines for monitoring and management of pediatric patients during and after sedation for diagnostic and therapeutic procedures. Pediatrics. 1992;89:1110.
  9. Stedman's Medical Dictionary.27th ed. Baltimore: Williams & Wilkins; 2000.
  10. American Psychiatric Association.Diagnostic and Statistical Manual of Mental Disorders. 4th ed. rev. Washington, DC: American Psychiatric Press; 1994.
  11. Franck L, Vilardi J.Assessment and management of opioid withdrawal in ill neonates. Neonatal Networks. 1995;14:39.
  12. Anand KJ, Barton BA, McIntosh N, et al. Analgesia and sedation in preterm neonates who require ventilatory support: results of the NOPAIN trial. Neonatal Outcome and Prolonged Analgesia In Neonates. Arch Pediatr Adolesc Med.1999; 153:331.
  13. Mathew PJ, Mathew JL.Assessment and management of pain in infants. Postgrad Med J. 2003;79:438.
  14. McRae ME, Rourke DA, Imperial-Perez FA, et al. Development of a research-based standard for assessment, intervention, and evaluation of pain after neonatal and pediatric cardiac surgery. Pediatr Nurs.1997;23:263.
  15. Weisman SJ, Schechter NL.The management of pain in children. Pediatr Rev. 1991;12:237.
  16. Marshall RE.Neonatal pain associated with caregiving procedures. Pediatr Clin North Am. 1989;36:885.
  17. Cote CJ, Karl HW, Notterman DA, et al. Adverse sedation events in pediatrics: analysis of medications used for sedation.Pediatrics.2000;106:633.
  18. Cote CJ, Notterman DA, Karl HW, et al. Adverse sedation events in pediatrics: a critical incident analysis of contributing factors.Pediatrics.2000;105:805.
  19. Jacqz-Aigrain E, Burtin P.Clinical pharmacokinetics of sedatives in neonates. Clin Pharmacokinet. 1997;36:449.
  20. Caron E, Maguire DP.Current management of pain, sedation, and narcotic physical dependency of the infant on ECMO. J Perinat Neonat Nurs. 1990;4:63.
  21. Notterman DA.Sedation with intravenous midazolam in the pediatric intensive care unit. Clin Pediatr. 1997;36:449.
  22. Porter FL, Miller JP, Sessions CF, et al. A controlled clinical trial of local anesthesia for lumbar punctures in newborns. Pediatrics.1991;88:663.
  23. Essink-Tjebbes CM, Hekster YA, Liem KD, et al. Topical use of local anesthesia in neonates. Pharm World Sci.1999;21: 173.
  24. Taddio A, Stevens B, Craig K, et al. Efficacy and safety of lidocaine–prilocaine cream for pain during circumcision. N Engl J Med.1997;24:1197.
  25. Lambert GH, Muraskas J, Anderson CL, et al. Direct hyperbilirubinemia associated with chloral hydrate administration in the newborn. Pediatrics.1990;86:277.
  26. Reimche LD, Sankaran K, Hindmarsh KW, et al. Chloral hydrate sedation in neonates and infants—clinical and pharmacologic considerations. Dev Pharmacol Ther.1989;12:57.
  27. Mayers DJ, Hindmarsh KW, Sankaran K, et al. Chloral hydrate disposition following single-dose administration to critically ill neonates and children. Dev Pharmacol Ther.1991;16:71.
  28. Campos R.Soothing pain-elicited distress with swaddling and pacifiers in early infancy. Presented at Sixth International Conference on Infant Studies, Washington, DC, April 1988.
  29. Carbajal R, Chauvet X, Coudec S, et al. Randomized trial of analgesic effects of sucrose, glucose and pacifiers in term neonates. Br Med J.1999;319:1393.
  30. Blass EM, Watt LB.Suckling and sucrose-induced analgesia in human newborns. Pain. 1999;88:611.
  31. Carbajal R, Lenclen R, Gajdos V, et al. Crossover trial of analgesic efficacy of glucose and pacifier in very preterm neonates during subcutaneous injections. Pediatrics.2002;110:389.
  32. Horwitz N.Does oral sucrose reduce the pain of neonatal procedures? Arch Dis Child. 2002;87:80.