February 2001, Vol 155, No. 2 >

< Previous Article Next Article >

Article | February 2001

Consensus Statement for the Prevention and Management of Pain in the Newborn FREE

K. J. S. Anand, MBBS, DPhil; and the International Evidence-Based Group for Neonatal Pain

[+] Author Affiliations

Participants (listed alphabetically) of the International Evidence-Based Group for Neonatal Pain are the following: Huda Huijer Abu-Saad, Maastricht, the Netherlands; K. J. S. Anand, Little Rock, Ark (chair); Albert Aynsley-Green, London, England; Eduardo Bancalari, Miami, Fla; Franca Benini, Padova, Italy; G. David Champion, Darlinghurst, Australia; Kenneth D. Craig, Vancouver, British Columbia; Tomasz S. Dangel, Warszawa, Poland; Elisabeth Fournier-Charrière, Kremlin-Bicetre, France; Linda S. Franck, London, England; Ruth Eckstein Grunau, Vancouver, British Columbia; Steen A. Hertel, Copenhagen, Denmark; Evelyne Jacqz-Aigrain, Paris, France; Gerhard Jorch, Magdeburg, Germany; Benjamin I. Kopelman, São Paulo, Brazil; Gideon Koren, Toronto, Ontario; Björn Larsson, Stockholm, Sweden; Neil Marlow, Nottingham, England; Neil McIntosh, Edinburgh, Scotland; Arne Ohlsson, Toronto, Ontario; Gunnar Olsson, Stockholm, Sweden; Fran Porter, St Louis, Mo; Renate Richter, Erlangen, Germany; Bonnie Stevens, Toronto, Ontario; and Anna Taddio, Toronto, Ontario.

Arch Pediatr Adolesc Med. 2001;155(2):173-180. doi:10.1001/archpedi.155.2.173.

Text Size: A A A

Published online

Article

Tables

References

Comments

ABSTRACT

Objective To develop evidence-based guidelines for preventing or treating neonatal pain and its adverse consequences. Compared with older children and adults, neonates are more sensitive to pain and vulnerable to its long-term effects. Despite the clinical importance of neonatal pain, current medical practices continue to expose infants to repetitive, acute, or prolonged pain.

Design Experts representing several different countries, professional disciplines, and practice settings used systematic reviews, data synthesis, and open discussion to develop a consensus on clinical practices that were supported by published evidence or were commonly used, the latter based on extrapolation of evidence from older age groups. A practical format was used to describe the analgesic management for specific invasive procedures and for ongoing pain in neonates.

Results Recognition of the sources of pain and routine assessments of neonatal pain should dictate the avoidance of recurrent painful stimuli and the use of specific environmental, behavioral, and pharmacological interventions. Individualized care plans and analgesic protocols for specific clinical situations, patients, and health care settings can be developed from these guidelines. By clearly outlining areas where evidence is not available, these guidelines may also stimulate further research. To use the recommended therapeutic approaches, clinicians must be familiar with their adverse effects and the potential for drug interactions.

Conclusion Management of pain must be considered an important component of the health care provided to all neonates, regardless of their gestational age or severity of illness.

NEWBORNS routinely experience pain associated with invasive procedures such as blood sampling, immunization, vitamin K injection, or circumcision. The sick or preterm infant may experience repetitive or prolonged pain resulting from many diagnostic, surgical, or therapeutic procedures.¹^- 4

Multiple lines of evidence suggest an increased sensitivity to pain in neonates compared with older age groups.⁵^- 6 This pain sensitivity is further accentuated in preterm neonates, and may not be clinically evident.⁵^- 8 Critically ill and preterm neonates do not mount vigorous behavioral responses to pain, and therefore require particularly detailed assessment.⁶^- 8 The pain modulation systems that operate in older children and adults do not appear to be fully functional in newborns⁹^- 11 or may function only during maternal contact in healthy newborns.¹² Even the most immature preterm neonates mount increasing responses to the pain caused by mild, moderate, or highly invasive procedures, and the magnitude of their responses increase with postnatal age.⁶^- 7,13 Compared with older children, neonates exhibit greater hormonal, metabolic, and cardiovascular responses to surgical operations, and may require relatively higher doses of anesthetics and analgesics for adequate pain control.⁵^,14^- 17 The metabolism and clearance rates of most analgesic agents in preterm neonates are slower than in term neonates, but increase rapidly with age.¹⁸^- 19

Management of pain in the newborn is hampered by the lack of awareness among health care professionals that the neonate is capable of experiencing pain, and by fears about the adverse effects associated with analgesic use. Current evidence supports the general principles listed in Table 1 for the routine management of neonates using safe and effective environmental, behavioral, and pharmacological interventions for relieving pain and for preventing its adverse consequences.²⁰

Table 1. General Principles for the Prevention and Management of Pain in Newborns

View Large | Save Table | Download Slide (.ppt) | View in Article Context

METHODS

These guidelines were developed from 2 consensus development meetings (in April 1998 and August 1999). A detailed search of the published literature on neonatal pain was conducted to identify the experts who were invited to these meetings. Databases searched were MEDLINE, Embase, and PubMed using the following terms: pain, nociception, stress, infant-newborn, and infant-premature. Faculty members were selected by the chairman (K.J.S.A.) based on their expertise in specific topics related to neonatal pain, coupled with a concerted effort to include professionals trained in different disciplines and representing different countries and distinct practice settings (eg, children's hospitals, general hospitals, office practices). The disciplines represented were pediatrics, neonatology, child psychology, anesthesiology, neuroscience, endocrinology, neonatal nursing, pharmacy/pharmacology, rehabilitation medicine, critical care medicine, rheumatology/immunology, and others. At the time of these meetings, faculty members were affiliated to academic institutions in Australia, Brazil, Canada, Denmark, France, Germany, Israel, Italy, Poland, Sweden, Switzerland, the Netherlands, United Kingdom, and the United States.

Faculty members performed a systematic review of the published literature on their specific topic, critically evaluated the quality of published data, and synthesized these findings. Data from all relevant studies were presented at these meetings and were discussed by the experts present. Other faculty members were encouraged to present additional data and ample time was allowed for detailed discussion. Guidelines were developed after reaching a consensus on the clinical practices that were prevalent in most countries. As such, these guidelines were based on a combination of published evidence (from randomized controlled trials, systematic reviews, or meta-analyses of trials) and its critical evaluation by the faculty members. Between September 1999 and April 2000, 3 separate draft versions of this statement were circulated and modified by all members of the participating faculty. Approval of all faculty members was obtained for the final version of the consensus statement, which is organized around broad general principles (Table 1) and evidence-based guidelines for neonatal pain management. The pharmacological interventions recommended in these guidelines are not the exclusive products of the pharmaceutical company that funded these meetings, and the representatives of this company have had no input in the format or content of these guidelines.

RESULTS

EVIDENCE-BASED GUIDELINES FOR THE MANAGEMENT OF NEONATAL PAIN

Recognition of the Sources of Pain

Some of the painful procedures commonly performed on neonates in the neonatal intensive care unit (NICU) include heel lancing, venipuncture, venous or arterial catheter insertion, chest tube placement, tracheal intubation or suctioning, lumbar puncture, and subcutaneous or intramuscular injections (see Table 2 for additional procedures).¹^- 4 Other sources of pain may include areas of inflammation and hyperalgesia around previous tissue injury, postoperative pain, localized infection or inflammation, and skin burns or abrasions caused by transcutaneous probes, monitoring leads, or topical agents.

Table 2. Painful Procedures Commonly Performed in the Neonatal Intensive Care Unit

View Large | Save Table | Download Slide (.ppt) | View in Article Context

Assessment of Pain

Concomitantly with the vital signs, assessment of neonatal pain must be undertaken and documented every 4 to 6 hours or as indicated by the pain scores or clinical condition of the neonate.²¹^- 24
Standardized pain assessment methods with evidence of validity, reliability, and clinical utility should be used²⁵^- 32 (Table 3).
Pain assessment instruments should be sensitive and specific for infants of different gestational ages and/or with acute, recurrent, or continuous pain.¹³^,32^- 33 Examples of ongoing, continuous pain may include postoperative pain or inflammatory conditions.¹^,3^,33
Pain assessment should be comprehensive and multidimensional, including contextual, behavioral, and physiological indicators.⁸^,13^,21^- 23
Pain assessment must be performed after each potentially painful clinical intervention and to evaluate the efficacy of behavioral, environmental, and pharmacological agents.²¹^,23^,33^- 34

Table 3. Commonly Used Methods for Assessment of Pain in Newborns

View Large | Save Table | Download Slide (.ppt) | View in Article Context

Management of Pain in the Newborn

Strategies for prevention, particularly by avoiding recurrent painful stimuli.²⁰^,33
Use of environmental interventions to reduce stress in the NICU.³³^,35^- 36
Behavioral methods, including sucrose and nonnutritive sucking.¹²^,20^,37^- 56
Pharmacological agents for preemptive analgesia²⁰^,57^- 76 (Table 4).
Pharmacological therapy for ongoing pain¹⁷^,19^,34^,58^,71^- 80 (Table 4).

Table 4. Recommended Analgesic Doses for Neonates*

View Large | Save Table | Download Slide (.ppt) | View in Article Context

SUGGESTED MANAGEMENT APPROACHES FOR NEONATAL PAIN

In the following sections, an asterisk indicates that evidence from studies in neonates is available to support the proposed intervention. The combined use of multiple interventions may have additive or synergistic clinical effects.

Heel Lance

Consider use of venipuncture instead of heel lance in full-term neonates and more mature preterm neonates* (because it is less painful, more efficient and requires less resampling).⁶²^,81^- 87 This approach may not apply to the care of extremely preterm infants.
Use a pacifier* with sucrose* (concentration 12%-24%) given 2 minutes before the procedure.³⁹^- 48,51^- 55
Use swaddling, containment,* or facilitated tucking.³⁷^- 38
Consider skin-to-skin contact with the mother.*¹²
Use a mechanical spring-loaded lance, eg, Autolance.*⁶²^,85^- 86

EMLA (a eutectic mixture of local anesthetics: lidocaine and prilocaine hydrochloride in an emulsion base), acetaminophen, and warming the heel are ineffective for heel lancing*; squeezing for blood collection is the most painful part of the procedure.⁷⁰^,81^- 85,87

Percutaneous Venous Catheter Insertion

Use a pacifier* with sucrose.*³⁹^,41^,70^,81^- 84
Use swaddling, containment, or facilitated tucking.³⁷^- 38
Apply EMLA* to the proposed site (when nonurgent).⁶⁰^,82^,88^- 89
Consider opioid dose(s),* if intravenous access is available.⁵⁸^,73
Consider a similar approach for venipuncture.⁸⁸^- 89

Percutaneous Arterial Catheter Insertion

Use a pacifier* with sucrose.³⁹^,41
Use swaddling, containment, or facilitated tucking.³⁷^- 38
Apply EMLA to the proposed site.⁶⁰^,70
Consider subcutaneous infiltration of lidocaine.⁵⁸^,70
Consider a similar approach for arterial puncture.

Peripheral Arterial or Venous Cutdown

Use a pacifier with sucrose.³⁹^,41
Use swaddling, containment, or facilitated tucking.³⁷^- 38
Apply EMLA to the proposed site.⁵⁸^,60^,70
Consider subcutaneous infiltration of lidocaine; avoid intravascular injection.⁵⁸^,70
Consider opioid dose(s), if intravenous access is available.¹⁵^,58^,76

Central Venous Line Placement

Use a pacifier* with sucrose.³⁹^,41
Use swaddling, containment, or facilitated tucking.³⁷^- 38
Apply EMLA to the proposed site, if nonurgent.⁶⁰^,90
Consider subcutaneous infiltration of lidocaine.⁵⁸^,70
Consider slow intravenous opioid infusion (morphine sulfate* or fentanyl citrate*).⁷³^,76
Consider using general anesthesia for the procedure.¹⁵^,70^,76^,91

Umbilical Catheter Insertion (Umbilical Arterial/Umbilical Venous)

Consider the use of a pacifier with sucrose.³⁹^,41
Use swaddling, containment, or facilitated tucking.³⁷^- 38
Avoid the placement of sutures or hemostat clamps on the skin around the umbilicus.

Peripherally Inserted Central Catheter Placement

Use a pacifier with sucrose.³⁹^,41
Use swaddling, containment, or facilitated tucking.³⁷^- 38
Apply EMLA* to the proposed site (when nonurgent).⁵⁸^,60^,90
Consider opioid dose(s), if intravenous access is available.⁵⁸^,76^,91

Lumbar Puncture

Use a pacifier* with sucrose.³⁹^,41
Apply EMLA to the proposed site.⁶⁰
Consider subcutaneous infiltration of lidocaine.⁵⁸^,70
Because containment is not possible, careful physical handling is advised.

Subcutaneous or Intramuscular Injection

Avoid subcutaneous and intramuscular injections; give drugs intravenously whenever possible.
If necessary:
Use a pacifier with sucrose.³⁹^,41
Use swaddling, containment, or facilitated tucking.³⁷^- 38
Apply EMLA to the proposed site (evidence for this approach is available from studies in children, but not from studies in neonates).⁹²^- 94

Endotracheal Intubation

Many variations in clinical approach have been noted; the superior efficacy of any one technique is not supported by current evidence³³^,58^,70^,95^- 97:

Use combination of atropine sulfate and ketamine hydrochloride*⁹⁵
Use combination of atropine, thiopental sodium,* and succinylcholine chloride.⁹⁷
Use combination of atropine, morphine, or fentanyl, and nondepolarizing muscle relaxant (pancuronium, vercuronium, rorcuronium).¹⁵^,58
Consider using a topical lidocaine spray, if available.⁹⁸^- 99
Other drug combinations are frequently used.⁵⁸^,70

Tracheal intubation without the use of analgesia or sedation should be performed only for resuscitation in the delivery room or for other life-threatening situations associated with the unavailability of intravenous access.⁹⁵^- 97

Endotracheal Suction

This is considered a stressful procedure and may be associated with the same physiological responses that accompany other painful procedures⁷¹^,100^- 104:

Use a pacifier; may consider giving sucrose.³⁹^,41
Use swaddling, containment, or facilitated tucking.³⁷^- 38
Consider continuous intravenous infusion of opioids (morphine*)⁷¹ or slow injection of intermittent opioid doses (fentanyl,* meperidine,* or alfentanil*).¹⁰⁰^- 104

Nasogastric or Orogastric Tube Insertion

Use a pacifier with sucrose.³⁹^,41
Use swaddling, containment, or facilitated tucking.³⁷^- 38
Use a gentle technique and appropriate lubrication.¹⁰⁵

Chest Tube Insertion

Anticipate the need for intubation and ventilation in neonates breathing spontaneously.⁵⁸
Use a pacifier with sucrose.³⁹^,41
Consider subcutaneous infiltration of lidocaine.⁵⁸^,70
Consider slow intravenous opioid infusion (morphine or fentanyl; see Table 4 for dosages).¹⁵^,58
Other approaches may include the use of short-acting anesthetic agents.¹⁵^,58^,76

The use of intravenous midazolam is not recommended.¹⁰⁶^- 107

Circumcision

If deemed necessary¹⁰⁸^- 109:

Use an appropriate clamp (Mogen clamp preferred over Gomco*).¹¹⁰^- 111
Apply EMLA* to the proposed site.⁵⁷^,60^,111
Place a dorsal penile nerve block,*⁶⁴^,111^- 112 ring block,*⁶⁵^- 66 or caudal block,⁶⁷^- 68,113^- 116 using plain or buffered lidocaine.*¹¹⁷^- 119
Use a pacifier* with sucrose.*³⁹^,41^,56^,111^,118
Consider acetaminophen for postoperative pain.*⁶⁹

Analgesics can be combined for maximum efficacy,⁶⁷^,110^- 111,118 although the addition of sodium bicarbonate to lidocaine does not alter the neonatal responses to lidocaine injection.¹¹⁷^- 119

Ongoing Analgesia for Routine NICU Care and Procedures

Use swaddling, containment, or facilitated tucking.³⁷^- 38
Use a pacifier; may consider giving sucrose.³⁹^,41
Low-dose continuous infusion of morphine* or fentanyl* if patient is ventilated.⁷¹^- 75
There is no evidence to show that neonates can be safely sedated for several weeks or months²⁰^,71^- 72,74^- 75 and the use of midazolam is not recommended.⁷¹^,106^- 107
Consider acetaminophen therapy.
The efficacy and safety of repeated acetaminophen doses is unknown, rectal absorption is variable, and intravenous propacetamol is not available in the United States.⁷⁷^- 80,87
Reduce acoustic, thermal, and other environmental stresses.³³^,35^- 36

COMMENT

Recognition of the clinical importance of neonatal pain and stress has been delayed⁵^,20 by outdated professional attitudes (that newborns are less sensitive to pain),¹²⁰^- 126 lack of education,¹²⁷^- 128 need for accurate assessment methods, and lack of evidence for the safety and efficacy of management approaches that can be applied to the routine care of neonates. This is a preliminary attempt to present the available evidence so that it may be useful to the clinicians at the bedside. We hope to stimulate further research by clearly outlining the areas where current evidence is not available for defining the efficacy of specific therapeutic approaches. Although these management approaches are mainly applicable for established NICUs that provide advanced medical and nursing care for critically ill neonates, they can be adapted for management of neonatal pain in other clinical settings or geographical locations.

Adverse effects that may result from these therapies are listed in Table 5,¹²⁹^- 158 and all clinicians using these guidelines must be familiar with the safe use of analgesic agents in healthy or critically ill, term and preterm neonates. Professionals working with neonates are expected to be knowledgeable about the current assessment and management approaches through participation in ongoing pain education, interaction with pain experts, attention to the most recent research evidence, and adherence to professional standards and clinical guidelines.¹⁵⁹ We strongly support the initiative taken by national professional organizations for the prevention and management of neonatal pain²⁰^,108^- 109 and for the development of standards for health care professionals and institutions. This consensus statement provides evidence-based protocols for developing neonatal pain management guidelines that can be uniquely designed for various clinical situations and diverse practice settings. Adherence to such guidelines will not only improve the clinical care provided to all neonates, but may also have a positive impact on their subsequent health and behaviors during childhood and adolescence.¹⁶⁰

Table 5. Adverse Effects of Analgesic Agents in Neonates

View Large | Save Table | Download Slide (.ppt) | View in Article Context

REFERENCES

Fernandez CVRees EP Pain management in Canadian level 3 neonatal intensive care units. CMAJ. 1994;150499- 504

Barker DPRutter N Exposure to invasive procedures in neonatal intensive care unit admissions. Arch Dis Child Fetal Neonatal Ed. 1995;72F47- F48

Johnston CCCollinge JMHenderson SJAnand KJS A cross-sectional survey of pain and pharmacological analgesia in Canadian neonatal intensive care units. Clin J Pain. 1997;13308- 312

Porter FLAnand KJS Epidemiology of pain in neonates. Res Clin Forums. 1998;209- 18

Anand KJS Clinical importance of pain and stress in preterm newborn infants. Biol Neonate. 1998;731- 9

Johnston CCStevens BJYang FHorton L Differential response to pain by very premature neonates. Pain. 1995;61471- 479

Johnston CCStevens BJFranck LSJack AStremler RPlatt R Factors explaining lack of response to heel stick in preterm newborns. J Obstet Gynecol Neonatal Nurs. 1999;28587- 594

Craig KDWhitfield MFGrunau RVELinton JHadjistavropoulos HD Pain in the pre-term neonate: behavioral and physiological indices. Pain. 1993;52201- 299

Marti EGibson SJPolak JM et al. Ontogeny of peptide and amino-containing neurons in motor, sensory and autonomic regions of rat and human spinal cord. J Comp Neurol. 1987;266332- 359

Jennings EFitzgerald M C-fos can be induced in the neonatal rat spinal cord by both noxious and innocuous peripheral stimulation. Pain. 1996;68301- 306

Boucher TJennings EFitzgerald M The onset of diffuse noxious inhibitory controls in postnatal rat pups: a C-fos study. Neurosci Lett. 1998;2579- 12

Gray LWatt LBlass EM Skin-to-skin contact is analgesic in healthy newborns. Pediatrics [serial online]. 2000;105e14

Porter FLWolf CMMiller JP Procedural pain in newborn infants: the influence of intensity and development. Pediatrics [serial online]. 1999;104e13

Anand KJSBrown MJCauson RC et al. Can the human neonate mount an endocrine and metabolic response to surgery? J Pediatr Surg. 1985;2041- 48

Yaster M The dose response of fentanyl in neonatal anesthesia. Anesthesiology. 1987;56433- 435

Greeley WJde Broijn NP Changes in sufentanil pharmacokinetics within the neonatal period. Anesth Analg. 1988;5786- 90

Chay PCWDuffy BJWalker JS Pharmacokinetic:pharmacodynamic relationships of morphine in neonates. Clin Pharmacol Ther. 1992;51334- 342

Olkkola KTHamunen K Pharmacokinetics and pharmacodynamics of analgesic drugs. Anand KJSStevens BJMcGrath PJeds.Pain in Neonates. 2nd ed. Amsterdam, the Netherlands Elsevier Science2000;135- 158

Scott CSRiggs KWLing EW et al. Morphine pharmacokinetics and pain assessment in premature newborns. J Pediatr. 1999;135423- 429

American Academy of Pediatrics and Canadian Paediatric Society, Prevention and management of pain and stress in the newborn. Pediatrics. 2000;105454- 461Paediatr Child Health. 2000;531- 3839- 47

Chiswick ML Assessment of pain in neonates. Lancet. 2000;3556- 8

Abu-Saad HHBours GJStevens BHamers JP Assessment of pain in the neonate. Semin Perinatol. 1998;22402- 416

Stevens BJohnston CGibbins S Assessment of pain in the neonate. Anand KJSStevens BMcGrath PJeds.Pain in Neonates. 2nd ed. Pain Research and Clinical Management. 10 Amsterdam, the Netherlands Elsevier Science2000;101- 134

Franck LSGreenberg CSStevens B Pain assessment in infants and children. Pediatr Clin North Am. 2000;47487- 512

Krechel SWBildner J CRIES: a new neonatal postoperative pain measurement score: initial testing of validity and reliability. Paediatr Anaesth. 1995;553- 61

Sparshott M The development of a clinical distress scale for ventilated newborn infants: identification of pain and distress based on validated behavioural scores. J Neonatal Nurs. 1996;25- 11

Stevens BJohnston CCPetryshen PTaddio A Premature infant pain profile: development and initial validation. Clin J Pain. 1996;1213- 22

Grunau RVEOberlander TFHolsti L et al. Bedside application of the Neonatal Facial Coding System in pain assessment of premature neonates. Pain. 1998;76277- 286

Lawrence JAlcock DMcGrath PKay JMacMurray SBDulberg C The development of a tool to assess neonatal pain. Neonatal Network. 1993;1259- 66

Blauer TGerstmann D A simultaneous comparison of three neonatal pain scales during common NICU procedures. Clin J Pain. 1998;1439- 47

Ballantyne MStevens BMcAllister M et al. Validation of the Premature Infant Pain Profile in the clinical setting. Clin J Pain. 1999;15297- 303

Guinsburg RBerenguel RCXavier RCAlmeida MFBKopelman BI Are behavioral scales suitable for preterm and term pain assessment? Jensen TSTurner JAWiesenfeld-Hallin Zeds.Proceedings of the 8th World Congress on Pain. Seattle, Wash International Association for the Study of Pain1997;893- 902

McIntosh N Pain in the newborn, a possible new starting point. Eur J Pediatr. 1997;156173- 177

Guinsburg RKopelman BIAnand KJSAlmeida MFBPeres CAMiyoshi MH Physiological, hormonal and behavioral responses to a single fentanyl dose in intubated and ventilated preterm neonates. J Pediatr. 1998;132954- 959

Sauve RedSaigal Sed Optimizing the neonatal intensive care environment. Report of the 10th Canadian Ross Conference in Pediatrics. Montreal, Quebec GCI Communications1995;

American Academy of Pediatrics, Committee on Environmental Health, Noise: a hazard for the fetus and the newborn. Pediatrics. 1997;100724- 727

Corff KE An effective comfort measure for minor pain and stress in preterm infants: facilitated tucking. Neonatal Network. 1993;1274

Corff KSeideman RVenkataraman PLutes LYates B Facilitated tucking: a nonpharmacologic comfort measure for pain in preterm infants. J Obstet Gynecol Neonatal Nurs. 1995;24143- 147

Stevens BOhlsson A Sucrose for analgesia in newborn infants undergoing painful procedures [Cochrane Review on CD-ROM]. Oxford, England Cochrane Library2000;2CD001069

Stevens BJohnston CFranck L et al. The efficiency of developmentally sensitive interventions and sucrose for relieving pain in VLBW neonates. Nurs Res. 1999;4835- 43

Stevens BTaddio AOhlsson AEinarson T The efficacy of sucrose for relieving pain in neonates: a systematic review and meta-analysis. Acta Paediatr. 1997;86837- 842

Abad FDiaz NDomenech ERobayna MRico J Oral sweet solution reduces pain-related behavior in preterm infants. Acta Paediatr. 1996;85854- 858

Barr RGPantel MSYoung SNWright JHHendricks LAGravel R The response of crying newborns to sucrose: is it a "sweetness" effect? Physiol Behav. 1999;66409- 417

Blass EMHoffmeyer LB Sucrose as an analgesic for newborn infants. Pediatrics. 1991;87215- 218

Bucher HUMoser Tvon Siebenthal KKeel MWolf MDuc G Sucrose reduces pain reaction to heel lancing in preterm infants: a placebo-controlled, randomized and masked study. Pediatr Res. 1995;38332- 335

Haouari NWood CGriffiths GLevene M The analgesic effect of sucrose in full term infants: a randomised controlled trial. BMJ. 1995;3101498- 1500

Ramenghi LWood CGriffeth GLevene M Reduction of pain response in premature infants using intraoral sucrose. Arch Dis Child Fetal Neonatal Ed. 1996;74F126- F128

Ramenghi LEvans DJLevene M "Sucrose analgesia": absorptive mechanism or taste perception? Arch Dis Child Fetal Neonatal Ed. 1999;80F146- F147

Gormally SMBarr RGYoung SNAlhawaf RWersheim L Combined sucrose and carrying reduces newborn pain response more than sucrose or carrying alone. Arch Pediatr Adolesc Med. 1996;15047

Johnston CCStremler RStevens RHorton L Effectiveness of oral sucrose and simulated rocking on pain response in preterm neonates. Pain. 1997;72193- 199

Overgaard CKnudsen A Pain-relieving effect of sucrose in newborns during heel prick. Biol Neonate. 1999;75279- 284

Carbajal RChauvet XCouder SOlivier-Martin M Randomised trial of analgesic effects of sucrose, glucose, and pacifiers in term neonates. BMJ. 1999;3191393- 1397

Barker DRutter N Analgesic effect of sucrose: heel pricks were unnecessarily painful. BMJ. 1995;311747

Johnston CCStremler RHorton L et al. Effect of repeated doses of sucrose during heel stick procedure in preterm neonates. Biol Neonate. 1999;75160- 166

Mellah DGourrier EMerbouche S et al. Analgesia with saccharose during heel capillary prick: a randomized study in 37 newborns of over 33 weeks of amenorrhea [French]. Arch Pediatr. 1999;6610- 616

Herschel MKnoshnood BEllman C et al. Neonatal circumcision: randomized trial of a sucrose pacifier for pain control. Arch Pediatr Adolesc Med. 1998;152279- 284

Taddio AStevens BCraig K Efficacy and safety of lidocaine-prilocaine cream for pain during neonatal circumcision. N Engl J Med. 1997;3361197- 1201

Menon GAnand KJSMcIntosh N Practical approach to analgesia and sedation in the neonatal intensive care unit. Semin Perinatol. 1998;22417- 424

Larsson BAJylli LLagercrantz HOlsson GL Does a local anaesthetic cream (EMLA) alleviate pain from heel lancing in neonates? Acta Anaesthesiol Scand. 1995;391028- 1031

Taddio AOhlsson AStevens BEinarson TRKoren G A systematic review of lidocaine-prilocaine cream EMLA in the treatment of acute pain in neonates. Pediatrics [serial online]. 1998;101e1

Brisman MLjung BMOtterbom ILarsson LEAndreasson SE Methaemoglobin formation after the use of EMLA cream in term neonates. Acta Paediatr. 1998;871191- 1194

McIntosh NVan Veen LBrameyer H Alleviation of the pain of heel prick in preterm infants. Arch Dis Child Fetal Neonatal Ed. 1994;70F177- F181

Essink-Tebbes CMWuis EWLiem KD et al. Safety of lidocaine-prilocaine cream application four times a day in premature infants: a pilot study. Eur J Pediatr. 1999;158421- 423

Holliday MAPinckert TLKiernan SC et al. Dorsal penile nerve block vs topical placebo for circumcision in low-birth-weight neonates. Arch Pediatr Adolesc Med. 1999;153476- 480

DeJonge MH Ring block for neonatal circumcision. Obstet Gynecol. 1998;92891- 892

Hardwick-Smith SMastrobattista MWallace PA et al. Ring block for neonatal circumcision. Obstet Gynecol. 1998;91930- 934

Mohan CGRisucci DACasimir MGulrajani-LaCorte M Comparison of analgesics in ameliorating the pain of circumcision. J Perinatol. 1998;1813- 19

Shechet Rabbi JFried SMTanenbaum B et al. Local anesthesia for infants undergoing circumcision. JAMA. 1998;2791170- 1171

Howard CRHoward FMWeitzman ML Acetaminophen analgesia in neonatal circumcision: the effect on pain. Pediatrics. 1994;93641- 646

Larsson BA Strategies to reduce procedural pain in the newborn. Res Clin Forums. 1998;2063- 71

Anand KJSMcIntosh NLagercrantz H et al. Analgesia and sedation in preterm neonates who require ventilatory support: results from the NOPAIN trial. Arch Pediatr Adolesc Med. 1999;153331- 338

Quinn MWWild JDean HG et al. Randomised double-blind controlled trial of effect of morphine on catecholamine concentrations in ventilated preterm babies. Lancet. 1993;342324- 327

Moustogiannis ANRaju TNKRoohey TMcCulloch KM Intravenous morphine attenuates pain induced changes in skin blood flow in newborn infants. Neurol Res. 1996;18440- 444

Dyke MPKohan REvans S Morphine increases synchronous ventilation in preterm infants. J Paediatr Child Health. 1995;31176- 179

Orsini AJLeef KHCostarino ADettorre MDStefano JL Routine use of fentanyl infusions for pain and stress reduction in infants with respiratory distress syndrome. J Pediatr. 1996;129140- 145

Cordero LGardner DKO'Shaughnessy R Analgesia versus sedation during Broviac catheter placement. Am J Perinatol. 1991;8284- 287

van Lingen RADeinum JTQuak JM et al. Pharmacokinetics and metabolism of rectally administered paracetamol in preterm neonates. Arch Dis Child Fetal Neonatal Ed. 1999;80F59- F63

Lin YCSussman HHBenitz WE Plasma concentrations after rectal administration of acetaminophen in preterm neonates. Paediatr Anaesth. 1997;7457- 459

van Lingen RADeinum HTQuak CMOkken ATibboel D Multiple-dose pharmacokinetics of rectally administered acetaminophen in term infants. Clin Pharmacol Ther. 1999;66509- 515

Autret EDutertre JPBreteau MJonville APFuret YLaugier J Pharmacokinetics of paracetamol in the neonate and infant after administration of propacetamol chlorhydrate. Dev Pharmacol Ther. 1993;20129- 134

Larsson BATannfeldt GLagercrantz HOlsson GL Venipuncture is more effective and less painful than heel lancing for blood tests in neonates. Pediatrics. 1998;101882- 886

Larsson BATannfeldt GLagercrantz HOlsson GL Alleviation of the pain of venipuncture in neonates. Acta Paediatr. 1998;87774- 779

Shah VSTaddio ABennett SSpeidel BD Neonatal pain response to heel stick vs venepuncture for routine blood sampling. Arch Dis Child Fetal Neonatal Ed. 1997;77F143- F144

Shah VOhlsson A Venepuncture versus heel lance for blood sampling in term neonates [Cochrane Review on CD-ROM]. Oxford, England Cochrane Library2000;2CD001452

Ohlsson ATaddio AJadad ARStevens BJ Evidence-based decision making, systematic reviews and the Cochrane collaboration: implications for neonatal analgesia. Anand KJSStevens BJMcGrath PJeds.Pain in Neonates. 2nd ed. Pain Research & Clinical Management 10 Amsterdam, the Netherlands Elsevier Science2000;251- 268

Harpin VARutter N Making heel pricks less painful. Arch Dis Child. 1983;58226- 228

Shah VTaddio AOhlsson A Randomised controlled trial of paracetamol for heel prick pain in neonates. Arch Dis Child Fetal Neonatal Ed. 1998;79F209- F211

Gourrier EKaroubi PEl-Hanache A et al. Utilisation de la crème EMLA chez le nouveau-ne a terme et premature: etude d'efficacite et de tolerance. Arch Pediatr. 1995;21041- 1046

Acharya ABBustani PCPhillips JDTaub NABeattie RM Randomised controlled trial of eutectic mixture of local anaesthetics cream for venepuncture in healthy preterm infants. Arch Dis Child Fetal Neonatal Ed. 1998;78F138- F142

Garcia OCReichberg SBrion LPSchulman M Topical anesthesia for line insertion in very low birth weight infants. J Perinatol. 1997;17477- 480

Smith MF Internal jugular venous cannulation in children under 5 years of age. Can J Anaesth. 1990;37 (4 pt 2) S102

Walsh ZBertilson SO Topical anaesthetic cream provides pain relief in tetanus vaccination. Lakartidningen. 1987;84611- 612

Uhari M A eutectic mixture of lidocaine and prilocaine for alleviating vaccination pain in infants. Pediatrics. 1993;92719- 721

Taddio ANulman IGoldbach MIpp MKoren G Use of lidocaine-prilocaine cream for vaccination pain in infants. J Pediatr. 1994;124643- 648

Friesen RHHonda ATThieme RE Changes in anterior fontanel pressure in preterm neonates during tracheal intubation. Anesth Analg. 1987;66874- 878

Pokela MLKoivisto M Physiological changes, plasma beta-endorphin and cortisol responses to tracheal intubation in neonates. Acta Paediatr. 1994;83151- 156

Bhutada ASahni RRastogi SWung JT Randomised controlled trial of thiopental for intubation in neonates. Arch Dis Child Fetal Neonatal Ed. 2000;82F34- F37

Mostafa SMMurthy BVBarrett PJMcHugh P Comparison of the effects of topical lidocaine spray applied before or after induction of anaesthesia on the pressor response to direct laryngoscopy and intubation. Eur J Anaesthesiol. 1999;167- 10

Lehtinen AMHovorka JWidholm O Modification of aspects of the endocrine response to tracheal intubation by lignocaine, halothane and thiopentone. Br J Anaesth. 1984;56239- 246

100

Durand MSangha BCabal LAHoppenbrouwers THodgman JE Cardiopulmonary and intracranial pressure changes related to endotracheal suctioning in preterm infants. Crit Care Med. 1989;17506- 510

101

Greisen GSFrederiksen PSHertel MChristensen NJ Catecholamine response to chest physiotherapy and endotracheal suctioning in preterm infants. Acta Paediatr Scand. 1985;74525- 529

102

Pokela ML Pain relief can reduce hypoxemia in distressed neonates during routine treatment procedures. Pediatrics. 1994;93379- 383

103

Saarenmaa EHuttunen PLeppaluoto JFellman V Alfentanil as procedural pain relief in newborn infants. Arch Dis Child Fetal Neonatal Ed. 1996;75F103- F107

104

Hickey PRHansen DDWessel DLLang PJonas RAElixson EM Blunting of stress responses in the pulmonary circulation of infants by fentanyl. Anesth Analg. 1985;641137- 1142

105

Haxhija EQRosegger HPrechtl HF Vagal response to feeding tube insertion in preterm infants: has the key been found? Early Hum Dev. 1995;4115- 25

106

Ng ETaddio AOhlsson A Intravenous midazolam infusion for sedation of infants in the neonatal intensive care unit. [Cochrane Review on CD-ROM]. Oxford, England Cochrane Library2000;2CD002052

107

Jacqz Aigrain EDaoud PBurtin P et al. Placebo-controlled trial of midazolam sedation in mechanically ventilated newborn infants. Lancet. 1994;344646- 650

108

American Academy of Pediatrics, Task Force on Circumcision, Circumcision policy statement. Pediatrics. 1999;103686- 693

109

Canadian Paediatric Society, Fetus and Newborn Committee, Neonatal circumcision revisited. CMAJ. 1996;154769- 780

110

Kurtis PSDeSilva HNBernstein BAMalakh LSchechter NL A comparison of the Mogen and Gomco clamps in combination with dorsal penile nerve block in minimizing the pain of neonatal circumcision. Pediatrics [serial online]. 1999;103e23

111

Taddio APollock NGilbert-MacLeod COhlsson KKoren G Combined analgesia and local anesthesia to minimize pain during circumcision. Arch Pediatr Adolesc Med. 2000;154620- 623

112

Butler-O'Hara MLeMoine CGuillet R Analgesia for neonatal circumcision: a randomized controlled trial of EMLA cream versus dorsal penile nerve block. Pediatrics [serial online]. 1998;101e5

113

Hassan SZ Caudal anesthesia in infants. Anesth Analg. 1977;56686- 689

114

Lunn JN Postoperative analgesia after circumcision: a randomized comparison between caudal analgesia and intramuscular morphine in boys. Anaesthesia. 1979;34552- 554

115

May AEWandless JJames RH Analgesia for circumcision in children: a comparison of caudal bupivacaine and intramuscular buprenorphine. Acta Anaesth Scand. 1982;6331- 333

116

Spear RM Dose-response in infants receiving caudal anaesthesia with bupivacaine. Paediatr Anaesth. 1991;147- 52

117

Newton CWMulnix NBaer LBovee T Plain and buffered lidocaine for neonatal circumcision. Obstet Gynecol. 1999;93350- 352

118

Stang HJSnellman LWCondon LM et al. Beyond dorsal penile nerve block: a more humane circumcision. Pediatrics [serial online]. 1997;100e3

119

Fatovich DMJacobs IG A randomized controlled trial of buffered lidocaine for local anesthetic infiltration in children and adults with simple lacerations. J Emerg Med. 1999;17223- 228

120

Anand KJSHickey PR Pain and its effects in the human neonate and fetus. N Engl J Med. 1987;3171321- 1329

121

Franck LS A national survey of the assessment and treatment of pain and agitation in the neonatal intensive care unit. J Obstet Gynecol Neonatal Nurs. 1987;16387- 393

122

Purcell-Jones GDormon FSumner E Paediatric anaesthetists' perceptions of neonatal and infant pain. Pain. 1988;33181- 187

123

Wellington NRieder MJ Attitudes and practices regarding analgesia for newborn circumcision. Pediatrics. 1993;92541- 543

124

McLaughlin CRHull JGEdwards WHCramer CPDewey WL Neonatal pain: a comprehensive survey of attitudes and practices. J Pain Symptom Manag. 1993;87- 16

125

Porter FLWolf CMGold JLotsoff DMiller JP Pain and pain management in newborn infants: a survey of physicians and nurses. Pediatrics. 1997;100626- 632

126

Salantera S Finnish nurses' attitudes to pain in children. J Adv Nurs. 1999;29727- 736

127

Howard CRHoward FMGarfunkel LCde Blieck EAWeitzman M Neonatal circumcision and pain relief: current training practices. Pediatrics. 1998;101423- 428

128

Rana SR Pain: a subject ignored. Pediatrics. 1987;79309

129

Kart TChristrup LLRasmussen M Recommended use of morphine in neonates, infants and children based on a literature review, part 2: clinical use. Paediatr Anaesth. 1997;793- 101

130

Barker DPSimpson JPawula MBarrett DAShaw PNRutter N Randomised, double blind trial of two loading dose regimens of diamorphine in ventilated newborn infants. Arch Dis Child Fetal Neonatal Ed. 1995;73F22- F26

131

Campbell NNReynolds GJPerkins G Postoperative analgesia in neonates: an Australia-wide survey. Anaesth Intensive Care. 1989;17487- 491

132

Gill AMCousins ANunn AJChoonara IA Opiate-induced respiratory depression in pediatric patients. Ann Pharmacother. 1996;30125- 129

133

Partridge JCWall SN Analgesia for dying infants whose life support is withdrawn or withheld. Pediatrics. 1997;9976- 79

134

Tholl DAWager MSSajous CHMyers TF Morphine use and adverse effects in a neonatal intensive care unit. Am J Hosp Pharm. 1994;512801- 2803

135

Saarenmaa EHuttunen PLeppaluoto JMeretoja OFellman V Advantages of fentanyl over morphine in analgesia for ventilated newborn infants after birth: a randomized trial. J Pediatr. 1999;134144- 150

136

Sabatino GQuartulli LDi Fabio SRamenghi LA Hemodynamic effects of intravenous morphine infusion in ventilated preterm babies. Early Hum Dev. 1997;47263- 270

137

Goldstein RFBrazy JE Narcotic sedation stabilizes arterial blood pressure fluctuations in sick premature infants. J Perinatol. 1991;11365- 371

138

Farrington EAMcGuinness GAJohnson GFErenberg ALeff RD Continuous intravenous morphine infusion in postoperative newborn infants. Am J Perinatol. 1993;1084- 87

139

Rasch DKWebster DEPollard TGGurkowski MA Lumbar and thoracic epidural analgesia via the caudal approach for postoperative pain relief in infants and children. Can J Anaesth. 1990;37359- 362

140

Vaughn PRTownsend SFThilo EHMcKenzie SMoreland SDenver KK Comparison of continuous infusion of fentanyl to bolus dosing in neonates after surgery. J Pediatr Surg. 1996;311616- 1623

141

Burtin PDaoud PJacqz-Aigrain E et al. Hypotension with midazolam and fentanyl in the newborn. Lancet. 1991;3371545- 1546

142

Irazuzta JPascucci RPerlman NWessel D Effects of fentanyl administration on respiratory system compliance in infants. Crit Care Med. 1993;211001- 1004

143

Lemmen RJSemmekrot BA Muscle rigidity causing life-threatening hypercapnia following fentanyl administration in a premature infant [letter]. Eur J Pediatr. 1996;1551067

144

Lindemann R Respiratory muscle rigidity in a preterm infant after use of fentanyl during caesarean section. Eur J Pediatr. 1998;1571012- 1013

145

Bolisetty SKitchanan SWhitehall J Generalized muscle rigidity in a neonate following intrathecal fentanyl during caesarean delivery [letter]. Intensive Care Med. 1999;251337

146

Pokela MLRyhanen PTKoivisto MEOlkkola KTSaukkonen AL Alfentanil-induced rigidity in newborn infants. Anesth Analgesia. 1992;75252- 257

147

Okada YPowis MMcEwan APierro A Fentanyl analgesia increases the incidence of postoperative hypothermia in neonates. Pediatr Surg Int. 1998;13508- 511

148

Anand KJSSippell WGAynsley-Green A Randomised trial of fentanyl anaesthesia in preterm babies undergoing surgery: effects on the stress response. Lancet. 1987;1243- 248

149

Resar LMHelfaer MA Recurrent seizures in a neonate after lidocaine administration. J Perinatol. 1998;18193- 195

150

Garner LStirt JAFinholt DA Heart block after intravenous lidocaine in an infant. Can Anaesth Soc J. 1985;32425- 428

151

Calobrisi SDDrolet BAEsterly NB Petechial eruption after the application of EMLA cream. Pediatrics. 1998;101471- 473

152

Frey BKehrer B Toxic methaemoglobin concentrations in premature infants after application of a prilocaine-containing cream and peridural prilocaine. Eur J Pediatr. 1999;158785- 788

153

Law RMHalpern SMartins RFReich HInnanen VOhlsson A Measurement of methemoglobin after EMLA analgesia for newborn circumcision. Biol Neonate. 1996;70213- 217

154

Cotsen MRDonaldson JSUejima TMorello FP Efficacy of ketamine hydrochloride sedation in children for interventional radiologic procedures. AJR Am J Roentgenol. 1997;1691019- 1022

155

Tashiro CMatsui YNakano SUeyama HNishimura MOka N Respiratory outcome in extremely premature infants following ketamine anaesthesia. Can J Anaesth. 1991;38287- 291

156

Green SMClark RHostetler MACohen MCarlson DRothrock SG Inadvertent ketamine overdose in children: clinical manifestations and outcome. Ann Emerg Med. 1999;34492- 497

157

Parker RIMahan RAGiugliano DParker MM Efficacy and safety of intravenous midazolam and ketamine as sedation for therapeutic and diagnostic procedures in children. Pediatrics. 1997;99427- 431

158

Goldberg RNMoscoso PBauer CR et al. Use of barbiturate therapy in severe perinatal asphyxia: a randomized controlled trial. J Pediatr. 1986;109851- 856

159

Anand KJSStevens BJMcGrath PJ Pain in neonates. Pain Research and Clinical Management 2nd ed.10 Amsterdam, the Netherlands Elsevier Science2000;

160

Anand KJS Pain, plasticity, and premature birth: a prescription for permanent suffering? Nat Med. 2000;6971- 973

AUTHOR INFORMATION

Accepted for publication October 16, 2000.

These efforts were supported by an unrestricted educational grant from Astra Pharmaceuticals (now AstraZeneca Inc, London, England) and were developed at 2 meetings of the International Evidence-Based Group for Neonatal Pain (Nice, France, April 21-23, 1998, and Baden, Austria, August 20-22, 1999).

The group gratefully acknowledges Jonas Nylander, Nadia Hammouda (AstraZeneca, Inc), Brian Parsons, Anna Welsh (Colwood Healthworld, London, England), Sarah Knott, and Daphne Steptoe (Wells Medical, Royal Tunbridge Wells, Kent, England) for helping in the development of these guidelines.

Corresponding author and reprints: K. J. S. Anand, MD, Arkansas Children's Hospital, S-431, 800 Marshall St, Little Rock, AR 72202 (e-mail: anandsunny@exchange.uams.edu).

Figures

Tables

Table 1. General Principles for the Prevention and Management of Pain in Newborns

View Large | Save Table | Download Slide (.ppt) | View in Article Context

Table 2. Painful Procedures Commonly Performed in the Neonatal Intensive Care Unit

View Large | Save Table | Download Slide (.ppt) | View in Article Context

Table 3. Commonly Used Methods for Assessment of Pain in Newborns

View Large | Save Table | Download Slide (.ppt) | View in Article Context

Table 4. Recommended Analgesic Doses for Neonates*

View Large | Save Table | Download Slide (.ppt) | View in Article Context

Table 5. Adverse Effects of Analgesic Agents in Neonates

View Large | Save Table | Download Slide (.ppt) | View in Article Context

Interactive Graphics

Video

Country-Specific Mortality and Growth Failure in Infancy and Yound Children and Association With Material Stature

Use interactive graphics and maps to view and sort country-specific infant and early dhildhood mortality and growth failure data and their association with maternal