Neonatal Pain Management

The International Association for the Study of Pain defines pain as an unpleasant sensory and emotional experience arising from actual or potential tissue damage or described in terms of such damage. Pain is further defined as an emotion that is learned through experience.

Unfortunately the history of pain management in infant care has included decades of inadequate analgesia for a wide range of medical problems, including major surgery. This was justified in part on the fear of drug and analgesic risks to the infant, as well as the commonly held belief that infants do not respond to, or remember painful experiences. Before the late 1970’s, clinical and empirical research on pain and pain management focused entirely on adults. Pain management for infants and young children was non existant; surgery was performed on infants and young children with only paralysis. No analgesics or anesthetics were used because of several long-standing medical myths:

• That they would complicate the surgical course;
• That infant pain could not be measured;
• That infants did not process pain neurologically and/or recall it;
• That analgesia could lead to addiction;
• That delivery of analgesia was itself painful;
• That there were no long-term sequelae to infants’ suffering.

The traditional view that infants were relatively insensitive to pain and would not recall it was refuted more than a decade ago. It is now known that the structures required for long-term memory are adequately developed in the newborn and have potential to affect long-term outcomes. Many researchers today believe that pain in early infancy can actually have profound and lasting consequences and may exaggerate affective and behavioral responses during subsequent painful events.

Evidence suggests that newborns react with distress behaviors to actions that have preceded painful interventions in the past. Newborns are as sensitive to pain as adults, and preterm infants are more sensitive to pain. Neonatal positron emission tomography (PET) scans have identified somatosensory areas as the most active sites in the developing infant brain. These neurotransmitters in the dorsal horn of the spinal cord are associated with nociception and increased somatosensory excitability in the preterm infant. On the other hand, neurotransmitters in descending inhibitory nerve fibers are only present at term. Pain perception in neonates is based on nociception, defined as detection and transmission of information about the presence and quality of a painful stimulus to the brain. Nociceptive neural pathways are fully developed and in place by 22 to 23 weeks gestation. Both term and preterm newborns have fully developed pain transmission pathways but lack fully developed inhibitory systems. There is diminished inhibition of pain in premature infants. They may feel even more pain than older child in similar situations. Untreated pain has physical effects and can increase morbidity and mortality. Pain from procedures, surgery, trauma, and disease must be anticipated, assessed, and alleviated in young infants. Analgesia, sedation, and anesthesia can be safely provided to newborns in most circumstances.

Newborn infants, particularly those born preterm, areregularly subjected to diagnostic and therapeutic procedures that are painful but necessary to their care. It has been reported that the frequency with which invasive procedures are performed is inversely related to an infant’s gestational age and acuity of illness. The smaller and sicker infants are subjected to the greatest number of painful procedures. Infant pain is encoded into observable manifestations through which an infant communicates behavioral and physiological changes such as altered vital signs, characteristic cries, and facial expressions.

The current definition of pain excludes individuals who cannot verbalize pain. Therefore, behavioral, physiological, and biochemical responses to pain should be considered as forms of self report and efforts should be made by healthcare professionals to understand these behaviors in order to manage pain effectively. The following table demonstrates the key pain responses:

Aggressive treatment and life-sustaining measures, including intubation, heel sticks, venipuncture, line insertions, lumbar punctures, patent ductus arteriousus repairs, chest tube placement, and chest physiotherapy, can all be necessary procedures, yet can cause an infant great pain and suffering if pharmacologic and/or non-pharmacologic measures are not used. During acute pain, stress hormones such as cortisol and catecholamine promote tissue breakdown, energy metabolism, fluid retention, decreased peristalsis, immune impairment, and cardiovascular responses such as tachycardia, hypertension, ischemia, and ventricular arrhythmias. These physiologic responses can adversely affect an infant with unmanaged pain and stress. Neonates in the NICU experience many painful procedures aimed at improving their immediate and long-term outcomes. On average, neonates born between 27 to 31 weeks gestation receive 134 procedures within the first two weeks of life and approximately 10 percent of the youngest and/or sickest neonates receive over 300 painful procedures. Barker and Rutter observed 488 painful and intrusive procedures performed on one 23-week gestation infant. The most commonly performed procedures in NICU include heel lances, venipunctures, IV attempts, intubations, and tape removals. Most are performed without adequate pain management.

Immediate response to pain can be protective. The response allows the individual to mobilize energy and resources to the site of injury and activate autonomic nervous system to serve as a warning signal for potentially damaging stimuli. Multiple lines of evidence suggest that the cumulative effects on the developing brain of repeated painful medical procedures may be of greater biological and clinical importance than has been recognized. Pain can place increased demands on the cardiorespiratory system. Pain can cause elevation in intracranial pressure which increases the risk of intraventricular hemorrhage. Pain can result in adverse long-term outcomes, such as decreased sensitivity to common childhood pains, a higher incidence of somatic complaints, and long-term structural changes in the brain and spinal cord. The long-term consequences of multiple, repeated, painful procedures on preterm infants remain unclear, but preliminary research indicates that permanent, behavioral, and physical changes may result. Emerging research suggests that repeated pain in preterm infants affects future responses. Babies who experience frequent painful procedures have decreased pain thresholds to future pain and increased physical complaints, such as stomach aches compared to infants who did not experience frequent, painful procedures. It is therefore essential to provide these high risk neonates with safe, effective, and timely pain management. Developmental effect of unrelieved pain can be summarized:

• Increased behavioral and physiologic responses to pain
• Altered temperaments
• More somatization – emotional problems expressed as physical symptoms
• More distress behaviors
• Possible altered development of the pain conduction system
• Increased vulnerability to stress disorders, addictive behavior, and anxiety states
• Lowered pain threshold

Transduction begins at periphery (skin, subcutaneous tissue, visceral structures) and ends at the spinal cord where substances that move pain impulses are released from damaged cells. Substances include prostaglandins, bradykinin, serotonin, substance P and histamine. Many pharmacologic agents used to manage pain work by blocking the release of these substances.

Transmission of pain impulses begins at the level of spinal cord where pain substances are released and continues to the brain stem, thalamus, and ultimately to the cortex for interpretation by two types of pain fibers each responsible for a different type of pain. C-fibers are unmyelinated, small diameter fibers that transmit pain impulses slowly. The pain being carried is dull aching. A-fibers are myelinated, large diameter, fibers that transmit pain impulses quickly, resulting in sharp pain perception.

Perception of pain is meaning and conscious interpretation of the sensation. There is no single pain center responsible for the meaning of pain, but probably several systems that work in parallel.

Modulation of pain is the final process in the movement of pain impulses. Descending pathways from the brain stem to the dorsal horn of the spinal cord release substances that bind to opioid receptors and inhibit transmission of pain impulses. The substances include endogenous opioids and norepenipherine.

Pain is subjective. Each individual learns the application of the word through experiences related to injury in early life. Applying this definition to infants is difficult. Infants are incapable of self-report and may not have yet encountered noxious events. The pain perception is an inherent quality of life that occurs early in development. Accordingly, newborns use physical and behavioral cues to signal when tissue damage has occurred. Caregivers can use these response cues as objective and valid indicator of pain in infants.

The inability to communicate in no way negates the possibility that an individual is experiencing pain and is in need of appropriate pain-relieving treatment. This is especially important for preterm neonates and other infants with limited ability to communicate pain robustly due to immaturity or severe medical illness. In determining appropriate pain management strategies, it is important to interpret an infant’s physiologic and behavioral pain cues in the context of infant’s risk factors for pain. Important behavioral responses include facial expression (grimacing, brow bulge, deepened nasolabial furrows, quivering chin, open or pursed lips); reflexive limb withdrawal; body posturing (squirming, kicking, trunk arching); and a whimper to a high pitch, harsh, intense cry. Facial expressions are a key method of assessing pain in a preverbal infant. Different cry responses have also been observed in infants experiencing pain; findings suggest that a distinguishable pain cry exists.

Physiologic responses to pain include skin color changes, palmar sweating (in infants > 37 weeks gestation), decreased oxygen saturation, alterations in stress hormone production, and increased heart rate, blood pressure, respirations and intracranial pressure. An infant’s heart rate initially decreases and then increases in response to short, sharp pain. Oxygen saturation decreases during painful procedures such as circumcision, lumbar punctures, and intubations. It is important to remember that absence of objective signs of pain does not mean that pain is not present.

Tools to assess infant pain and relief from pain have been developed and should be used in every practice setting. These tools use a combination of behavioral and physiological indicators of pain to diagnose and differentiate pain levels and takes into account attempts to console the infants during evaluation. The choice of tool may be based on neonatal age, setting, ease of use, and institutional preference. Using the pain scale improves communication and consistency between caregivers. The following are commonly used in clinical practice and have demonstrated reliability and validity:

• Neonatal Infant Pain Scale (NIPS) - measures intensity of infant responses to pain or painful stress and the infant’s ability to be consoled. NIPS scoring guidelines:
  • Facial expression – relaxed muscles or grimace
  • Cry – no cry, whimper or vigorous
  • Breathing pattern – relaxed or change in breathing
  • Arms & legs – relaxed/restrained or flexed/extended
  • State of arousal – sleeping/awake or fussy
• Premature Infant Pain Profile (PIPP) – measures pain in premature infants. PIPP scoring guidelines:
  • Score corrected gestational age before beginning
  • Assess baseline heart rate and oxygen saturation
    • For procedural pain, assess before the event
    • If pain is already present, review the chart for earlier baseline
  • Score behavioral state by observing the infant for 15 seconds immediately before the event
  • Observe the infant for 30 seconds immediately after the event.
• CRIES - 10-point scale similar to APGAR score which measures five physiological and behavioral variables previously shown to be associated with neonatal pain.
  • C - crying - no cry, cry but consolable or inconsolable
  • R - requires increased oxygen administration for saturation >95% - no requirement from baseline, <30% from baseline or >30% from baseline
  • I - increased vital signs – heart rate and blood pressure both unchanged or less than baseline, heart rate or blood pressure increased by <20%, or heart rate or blood pressure increased by >20%
  • E – expression – no grimace, grimace present, grimace and non-audible grunt present
  • S-sleeplessness – continuously asleep, awakens at frequent intervals, or awake constantly
• Neonatal Pain, Agitation and Sedation Scale (N-PASS) *has not been published in professional literature, reliability and validity have been demonstrated in abstracts

The following table compares the specifics of these tools:

Despite the fact that alleviating infant pain has become a significant care-giving concern, no standard of care exists for achieving this goal during many procedures. Pain management strategies continue to vary considerably among neonatal and infant care nurses, advanced practice nurses, and other health care professionals, and pain management protocols vary among neonatal intensive care units, as do pain assessment tools. Some professionals do nothing to reduce pain for the infant undergoing a minor procedure. Some use comfort measures only. Others offer a variety of medications, depending on the procedure.

In 2001, the International Evidenced-Based Group for Neonatal Pain published an evidenced-based practice consensus statement for the prevention and management of pain in the newborn. Suggested approaches for alleviating neonatal pain include implementing measures to modify pain response for specific procedures. For most painful procedures, the group recommended at least offering a pacifier, administering sucrose, and containing the infant by swaddling or facilitated tucking. The group also proposed that combining pain-modifying interventions may have an additive or synergistic clinical effect.

Guidelines for assessing pain include the following:

• Assess and document pain with vital signs every four to six hours or as indicated by pain scores or the clinical condition of the infant.
• Use standardized pain assessment methods with evidence of validity, reliability, and clinical utility.
• Use sensitive pain assessment tools that are specific for infants of different gestational ages and/or with acute, recurrent or continuous pain. (i.e. postoperative pain or inflammatory conditions)
• Use comprehensive and multidimensional pain assessment tools, including contextual, behavioral, and physiologic indicators.
• Assess pain after each potentially painful clinical intervention and to evaluate the efficacy of behavioral, environmental, and pharmacologic agents.

Guidelines for managing pain in the newborn include the following:

• Use strategies to prevent pain, particularly by avoiding recurrent painful stimuli.
• Use environmental interventions to reduce stress in the NICU.
• Use behavioral methods, including sucrose and nonnutritive sucking.
• Use pharmacologic agents for preemptive analgesia
• Use pharmacologic therapy for ongoing pain

The American Academy of Pediatrics also published a policy statement on preventing and managing pain and stress in the neonate. Its objectives were to:

• Increase awareness
• Provide a physiologic basis for assessment and management
• Make recommendations for reducing noxious stimuli
• Recommend safe and effective pain interventions

The National Association of Neonatal Nurses published Pain Assessment and Management: Guideline for Practice, in 2001. Its intention was to help standardize neonatal pain management.

Children’s Hospital of Illinois developed an agitation/pain algorithm for the nursing staff:

Agitation/Pain

Untreated pain is known to cause irritability, exhaustion, and slow healing. Infant pain is managed most effectively by preventing, limiting, or avoiding noxious stimuli and by promoting the use of anesthetics and analgesia when appropriate. There are two approaches to pain management in neonates: harmacological and nonpharmacological interventions. Several researchers have suggested that healthcare professionals use the correct terminology (such as environmental, behavioral, or integration approaches) for the type of intervention employed. They believe that the use of the terms pharmacological and nonpharmacological implies that clinicians must choose between two different treatment options. They further argue that choosing only one treatment contributes to suboptimal pain management in neonates. Both pharmacological and nonpharmacological methods should be used together and infants should be continually assessed for pain and comfort.

Pharmacological interventions are drugs or chemicals that are most commonly reserved for moderate to severe pain. The goal of pharmacological pain management is to select drugs that are safe and effective for neonates. While all of the medications most commonly used for infant analgesia and sedation are potentially dangerous, they can be administered safely when titrated carefully.

The number of analgesic drugs approved and available for infants is limited. Opioids are the most flexible and widely used narcotic analgesics; morphine and fentanyl are the most common opioids used to relieve moderate and severe neonatal/infant pain. They are used primarily for pain from invasive procedures. For infants undergoing surgery in which moderate to severe postoperative pain is expected, continuous administration of an opioid is appropriate, and is most effective if plasma level concentrations are consistently maintained. It is essential that pain be managed effectively when a premature or term infant undergoes multiple invasive procedures and ventilatory support because these procedures can cause marked fluctuations in intracranial pressure and subsequent damage to the brain. Studies have shown that low does morphine reduced intraventricular hemorrhage and periventricular leukimalacia, giving providers another reason to assure that appropriate pain relief is administered.

Mild pain relief is usually achieved with acetaminophen which remains the most commonly used analgesic for mild infant pain, for it is considered safe and effective in all age groups including newborns. Codeine is not commonly used in neonates, but is used in older infants and is often given in combination with acetaminophen. It is not known if nonsteroidal anti-inflammatory agents such as ibuprofen are safe for neonates.

Benzodiazepines (e.g., diazepam, lorazepam, midazolam) are also used as sedatives and amnesiacs during painful procedures. However, they have no analgesic properties, and in some cases may even increase pain sensations. Opioids and benzodiazepines used together are more effective and may necessitate a decrease in the total does of either drug used alone. Decisions regarding the type of pharmacologic interventions used to control pain should be made based on the needs of each individual infant. If sedation alone is ordered for infants undergoing invasive procedures, the nurse should remember that sedation alone does not provide pain control and that an analgesic order should be obtained. Regional, local and topical anesthetics should be used for procedural pain relief when procedures such as circumcision are performed. Studies have demonstrated the positive effects of local anesthesia for circumcision. Circumcision pain can be effectively treated with the use of eutectic mixture of local anesthetic (EMLA), dorsal penile nerve block (DPNB) or subcutaneous penile ring block (SQRB).

The goal of pain management is to keep the infant within a therapeutic range by providing enough medication to reduce pain without causing unwanted side effects. The potential for adverse side effects such as respiratory depression or hypotension are real especially wit infants who are premature. The risks can be reduced by knowledge of the pharmacokinetics and proper dosing of these drugs. The incidence of apnea and respiratory depression in infants and children as a reaction to pain medications is dose and route related. Adverse effects of opioid medications can be reversed with opioid antagonists such as naloxone. The first concern should be treatment of stress or pain and then later management of the consequences related to the pain treatment.

Non-pharmacologic – interventions refer to therapies (such as environmental or behavioral) that do not include pharmacological agents. These methods of pain control are most effective as coping strategies to make pain more tolerable, but they may also reduce pain. Environmental stimuli may contribute to increased pain responses. Bright lights, excessive noise and frequent handling may cause physiological instability to high risk neonates, making their ability to respond to additional stress ineffective. Touching or positioning can be used for brief or simple procedures. Sensorimotor stimulation enables the infant to gain better control over movements thus conserving energy and helping to alleviate pain. Simple comfort measures such as swaddling, nonnutritive sucking (pacifier) and positioning have been shown effective and should be used as adjunct therapy whenever possible for minor procedures. Sucrose via oral syringe, NG-tube, dropper or pacifier has been shown to be an effective pain management strategy for single events such as heel sticks and venipunctures. Oral sucrose was shown to be superior to EMLA cream as pain control during venipuncture. Non-pharmacologic interventions should be used with caution in earlier gestational age and sicker infants since excessive stimulation could actually worsen the procedural effects in these infants. Recommended non-pharmacologic interventions for pain relief in neonates:

• Modification of environmental stimuli
  • Shading infant’s eyes
  • Cover isolette/crib with blankets
  • Close doors gently
  • Avoid loud noises/voices
  • Set telephone ring at lowest volume possible
  • Decrease amount of noise from radios, tape players, etc.
  • Cluster nursing care activities
  • Allow periods of undisturbed rest
  • Gentle manipulation of tubes and lines
  • Careful removal of tape from skin
• Positioning
  • Swaddling to limit excessive immature motor responses
  • Nesting using blanket rolls to tuck around sides/back/feet and head to promote boundaries
  • Hugging
  • Holding – kangaroo care (skin-to-skin)
  • Proper body alignment
• Touch
  • Stroking, rocking, caressing, cuddling and massaging
  • Simple massage or rubbing of painful areas can relieve pain and spasm and mobilize contracted muscles through measures that assist the return flow and circulation of blood.

CAUTION: simply stroking the skin of premature infants can cause an intense physiologic response or damage the skin’s integrity.

• Heat
• A warm blanket can be used to improve circulation
• Heat can facilitate relaxation and promote pain relief
• Pacifier/sucrose
• Give sucrose via pacifier 2 minutes before painful procedures
• Distraction
• Use materials that have auditory and visual stimulation such as music, colored objects and mobiles.
• Rhythmic rocking

Sucrose is a disaccharide consisting of fructose and glucose, sucrose was used as early as 325BC by the soldiers of Alexander the Great and introduced to the new world by Columbus in 1493 and is widely used as a household sweetener today. Compared to the other sweet substitutes sucrose is sweeter than glucose, maltose and lactose. It is believed that current medical uses include the sweet taste of sucrose in suspensions for oral medications to conceal the bitter taste of the pharmacological agent.

Sucrose is the most frequently studied non-pharmacological intervention for neonatal pain. It has been shown to reduce the physiological and behavioral responses to painful procedural pain as well as promote calming behaviors in preterm and term neonates. Two systematic reviews and one meta-analysis have examined the safety and efficacy of sucrose – 2 ml of 25% weight/volume sucrose given orally by syringe or pacifier two minutes prior to painful procedures was most effective in reducing the amount of crying. There was no clinical benefit to administering greater doses.

Taste induced analgesia in newborns is rapid, enduring and dependant on the ability to detect sweet taste. Nasogastric administration infants continued to demonstrate pain. Infants allowed to taste sucrose had decreased pain behaviors. Taste mediates the pain response. Taste receptors that detect sweetness are found in the anterior tip of the tongue when sucrose is administered. Taste receptors are present by the end of the eighth week of gestation and sensory nerve fibers from the tongue to the brain stem are established by 26 – 28 weeks. Taste fibers unite in the medulla oblongata, where they synapse with fibers for touch, pain and temperature. Impulses are then relayed to the cerebral cortex for interpretation.

The sweet taste of sucrose is proposed to promote analgesia through activation of endogenous opioids that work on the descending pain pathways. Similarities between oral sucrose and morphine injection have been demonstrated. The combination of sucrose and nonnutritive sucking on a pacifier is more effective in reducing pain than either intervention alone. Sucrose is not hyperosmolar as a 25% is 476 mosmols/L. Dosage is 0.1 to 0.5 ml of 25% sucrose place on the tip of the tongue. It is absorbed by mucus membranes not ingested. Wait 2 minutes for absorption. A total of 2 ml may be given. If pain continues proceed to pharmacologic interventions.

Non-nutritive sucking is the provision of a pacifier or non-lactating nipple into a neonate’s mouth to promote sucking behavior without the provision of breast milk or formula for nutrition. NNS has been used by generations of families to soothe and comfort distressed neonates. Although NNS has historically been used by family members as well as healthcare professionals very little rigorous research exists in relation to procedural pain relief. Pinelle and Synington (1988) suggested that NNS reduces length of hospitalization in NICU’s by encouraging more effective feeding. NNS alone was not found to be effective in reducing infant pain. Combination of sucrose and NNS as pain relieving interventions have been shown effective for a variety of painful procedures such as venipunctures, heel sticks and immunizations. Combination of two therapies reduces crying time as well as physiological and behavioral pain responses in preterm and term infants.

Safety - The mechanisms of NNS as an analgesic are unclear but probably involve stimulation of orotactile and mechano-receptors when a pacifier or non-lactating nipple is introduced into the infant’s mouth. Unlike the mechanisms of sucrose the orotactile induced analgesia associated with NNS does not appear to be mediated through opioid pathways; it is not affected by the administration of naltexone and its efficacy is terminated once sucking has ceased. Non-nutritive sucking has faster quicker up and down chin movements. Nutritive sucking is slow and rhythmic with deep chin movements. NNS has no physiological disturbances. There is no tachycardia or bradycardia, tachypnea, dyspnea or oxygen desaturation. Sucrose and NNS are safe and effective for reducing procedural pain. They can be given as early as 9 hours after birth and 5 – 10 minutes after painful stimulus. It has been shown effective for immunizations for neonates and older infants up to 18 months of age. Indications for use of sucrose and NNS:

The interpretation of pain is subjective. Each person forms an internal construct of pain through encountered injury. The neonate’s expression of pain does not fit within the strict definition of pain because of the requirement for self-report. This lack of the ability to report pain contributes to the failure of health care professionals to recognize and treat pain aggressively during infancy and early childhood. Because neonates cannot verbalize their pain, they depend on others to recognize, assess and manage their pain. Healthcare professionals can diagnose neonatal pain only by recognizing the neonate’s associated behavioral and physiological responses. These responses can be specific to a 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. The American Pain Society suggests that documenting pain assessment with the vital signs raises awareness of the problem of pain.

American Academy of Pediatrics, Prevention and Management of Pain and Stress in the Neonate, Pediatrics Vol. 105 No. 2 February 2000, pp. 454-461.

Byers, Jacqueline Fowler, Cueing Into Infant Pain, MCN Vol. 29 No. 2 March/April 2004. pp. 84-89.

Franck, L. & Lawhon, G., (2000) Environmental & Behavioral Strategies to Prevent & Manage Neonatal Pain in K.S. Anand & B.J. Stevens Pain in the Neonate 2nd Ed. 203-216.

Gibbins, S., Dougherty, D., and Luther, M., (2004) Sucrose & Nonnutritive Sucking, Children’s Medical Ventures.

International Association for the Study of Pain Subcommittee on Taxonomy (1979) Pain terms. A list with definitions and notes on usage. Pain Vol. 6 No. 3, pp. 249-252.

Neu, J. & Koldovsky, O., (1996) Nutrient Absorption in the Preterm Neonate, Clinics in Perinatology, Vol. 23 No. 2, pp. 229-241.

Prince, W.L., Horns, K.M., Latta, T.M. & Gerstmann, D., (2004) Treatment of Neonatal Pain without a Gold Standard: The Case for Caregiving Interventions and Sucrose Administration, Neonatal Network Vol. 23, No. 4, July/August.

Stevens, B., Yamada, J., & Ohlsson, A., (2001) Sucrose for analgesia in newborn infants undergoing painful procedures. Cochrane Database Systematic Reviews, 4, CD001069.

Tiejen, Suzanne D., (2001) Consistent Pain Assessment in the Neonatal Intensive Care Unit, Abstract presented at The Physical and Developmental Environment of the High-Risk Neonate Conference, St. Petersburg Beach, Fl.

Walden, Marlene, (2001) Pain Assessment and Management – Guidelines for Practice, National Association of Neonatal Nurses (Document 1222) Glenview, IL.