Pain Management in Newborns
All neonates in the Neonatal Intensive Care Unit (NICU) or during the first days of life undergo painful and stressful procedures. Epidemiologic studies have shown that pain induced by these procedures is not effectively prevented or is inadequately treated. Pain experienced during the neonatal period may lead to negative outcomes, especially in preterm neonates. Prevention is the first step of pain management, and practical guidelines should be used in the NICU. Assessment must be done with adequate tools that take into account the infant’s pathology and gestational age. Distinguishing between acute and prolonged pain is important for both assessment and treatment. The most common drugs that have been studied for the treatment of pain and stress are opioids, hypnosedatives, and NMDA receptor antagonists. Morphine and fentanyl are most frequently used for acute or prolonged pain in the NICU. They have potent analgesic effects and few immediate or long-term adverse effects. Midazolam is a commonly used hypnosedative, but its adverse effects limit its use. Drugs such as propofol and ketamine have been used for acute painful procedures; however, further research is needed to assess their long-term effects. Use of non-pharmacologic pain management techniques has increased in recent years. These methods are easy, inexpensive, and effective in helping newborns recover from painful procedures. Sweet solutions and non-nutritive sucking, breastfeeding, skin-to-skin mother care, swaddling, and facilitated tucking are the most commonly employed and evaluated non-pharmacologic methods. Hospitals should promote and improve parent involvement in pain management. In-service education and well organized hospital teams are crucial for successful implementation of pain protocols in newborns.
1. Pain in Neonates: Where do we Stand?
According to the International Association for the Study of Pain (IASP), pain is “an unpleasant sensory and emotional experience, associated with actual or potential tissue damage, or described in terms of such damage. Pain is always subjective.” Such a definition is difficult to apply to a pre-verbal neonate who has no previous experience. Furthermore, prior to the study by Anand and Hickey in the late 1980s, it was assumed that neonates were unable to feel pain and, even if they could feel pain, this was not considered important because they would not remember it anyway. The fact that newborns experience pain has now been well established for many years, as is demonstrated by the large body of scientific literature focused on the assessment, treatment, and consequences of pain in this population.
Even the healthiest of neonates will face painful experiences during the first hours or days of life. The intramuscular vitamin K injection and the third-day screening test are unavoidable painful stimuli that occur during the first week. Neonates who are small for gestational age and infants born to diabetic mothers undergo heel lancing to monitor their blood glucose concentrations. Sick neonates requiring intensive care receive a multitude of painful stimuli. Although effective pain relief is usually provided for newborns during and after surgical procedures, pain-reduction therapies are still under-used for the numerous ‘minor’ procedures that are part of routine neonatal medical and nursing care.
Two studies in two different countries provide evidence for these statements.[5,6] To assess how frequently analgesics were used for invasive procedures, Simons et al. prospectively recorded all painful procedures and analgesic therapy used during the first 14 days of Neonatal Intensive Care Unit (NICU) admission in 151 neonates. Each neonate was subjected to a mean of 14 procedures per day. Whereas many procedures (26 of 31 listed) were estimated to be painful, <35% of neonates per study day received preventive analgesic therapy, and 39.7% of the neonates did not receive any analgesic therapy in the NICU. A recent prospective, multicenter study documented the epidemiology and management of painful and stressful neonatal procedures during the first 14 days of hospitalization in 430 neonates admitted to the NICU. The newborns experienced a median of 75 painful procedures during the study period and 10 painful procedures per day of hospitalization. Of all painful procedures performed, 2.1% were performed with pharmacologic-only therapy, 18.2% with non-pharmacologic-only interventions, 20.8% with pharmacologic, non-pharmacologic or both types of therapy, and 79.2% without specific analgesia; 34.2% were performed while the neonate was receiving concurrent analgesia or anesthesia for other reasons. In both of the aforementioned studies, more than 20 different painful, stressful, or uncomfortable procedures were performed. Nasal aspiration, tracheal suctioning, and heel sticks were the most frequent painful procedures.
Noxious stimuli cause immediate hormonal, physiologic, and behavioral responses,[2,7, 8, 9] which are diminished or eliminated by adequate analgesia. In premature babies, a lower pain threshold associated with the immaturity of the descending inhibitory pathways contributes to hypersensitivity after repeated painful procedures.[11,12] Pain in neonates occurs in the context of a developing brain with high plasticity, modifying the normal development of the somatosensory system and, subsequently, the pain processing system that depends upon sensory activity in early life. Many factors may contribute to the type and extent of the long-term effects of pain: developmental maturity of the infant at the time pain occurred (gestational and postnatal age), illness severity, length and extent of exposure to pain, and environmental and contextual factors at the time and after the pain exposure.[10,14] Both singular (e.g. circumcision) and repetitive (e.g. heel lances) painful procedures may have long-term consequences in full-term or prematurely born neonates.[15, 16, 17, 18] Recently, Walker et al. showed a generalized decreased sensitivity to all thermal modalities but not in mechanical sensitivity in 43 children at 11 years of age recruited from the UK EPICure cohort (born at <26 weeks’ gestation in 1995) compared with 43 full-term controls. This suggests centrally mediated alterations in the modulation of C-fiber nociceptive pathways, which may have an impact on the child’s response to future pain or surgery.
Thus, despite tremendous progress in recent years, effective pain management in early life remains challenging. Assessing pain is difficult for caregivers of this non-verbal population and requires adequate tools. While acute pain is well recognized, further research is needed to recognize, assess, and treat chronic pain in this pediatric population. The choice of treatment must be made by balancing the benefits and risks because many analgesics are still under-evaluated in neonates, and non-pharmacologic treatments can often be as effective as drugs for some interventions.
2. Pain Assessment
The main goal of pain assessment is to identify an infant’s potentially painful condition, quantify the pain level, and predict the need for an intervention.
Pain can be assessed by unidimensional or multidimensional approaches. Most available pediatric pain scales are multidimensional, including both behavioral (facial expression, crying, gross motor movement, changes in behavioral state, and functioning) and physiologic indicators (heart rate, blood pressure, etc.). These two methods for assessing pain have not been shown to be highly correlated (r = 0.3), but within each type the associations are stronger. Despite the availability of over 40 pain assessment tools, there is still no consensus on the best method for measuring and treating pain in newborns. Table I summarizes some of the commonly used and validated pain scales in neonates.
Many factors, such as age (gestational and postnatal), neurobehavioral state, and prior experience in the NICU can affect the newborn’s responsiveness to pain.[19,28] Infants who were awake before acute pain stimulation displayed more robust behavioral and physiologic reactivity compared with those in a quiet sleep state. It seems useful to establish whether clinical pain scores, calculated on the basis of the infant’s behavior during a painful procedure, correlate with the magnitude of cortical activation, as measured by near-infrared spectroscopy. The relationship between the total Premature Infant Pain Profile score and the hemodynamic response has been evaluated; there is a strong correlation between the magnitude of the hemodynamic response and change in facial expression, and a weaker correlation with change in heart rate and oxygen saturation. Nevertheless, such findings must be interpreted cautiously, as facial expression alone cannot be used as the sole indicator of pain, and some infants exhibited a clear cortical response following a painful procedure without any change in facial expression. Further research is needed to develop a truly validated behavioral pain scale, combining the accuracy of cortical measurements with the ease of behavioral observations.
There remains a paucity of measures for the assessment of prolonged or chronic pain, as well as for acute pain in infants who may be neurologically, developmentally, or physically compromised. Chronic pain, defined as continuous or recurrent pain that persists past the normal time of healing, most commonly about 3 months’ duration, is difficult to define and assess in the newborn, and the 3-month timeframe is not appropriate to use in the context of the newborn. Because of their limited energy reserves, preterm infants cannot manage the psycho-physiologic challenge of skin-breaking procedures if the pain becomes persistent. Many situations can lead to persistent or chronic pain, such as prolonged intubation and ventilation, restraint, surgical operations, and inflammatory conditions (tissue infiltration of intravenous infusions, necrotizing enterocolitis, osteomyelitis, and meningitis). Some other congenital or neonatal conditions such as limb amputation, birth lesions of the brachial plexus, and medullary lesions can also lead to neuropathic pain that is difficult to assess in the neonate. Nevertheless, later maturation of injured fibers and CNS plasticity may help to prevent long-term chronic pain following central or peripheral nervous system injury. Acute neuropathic pain in newborns poses a challenge, and techniques for its evaluation and treatment are often extrapolated from adults or older children. In situations associated with persistent pain or discomfort, an attempt should be made to assess its intensity and the effectiveness of analgesic treatment using a validated measure for pain assessment such as the Echelle Douleur Inconfort Nouveau-né (EDIN) or the Neonatal Pain Agitation and Sedation Scale. These latter scales have been developed for prolonged pain in neonates; however, construct validity has not yet been established for the EDIN. A recent study showed that EDIN scores were positively associated with gestational age, and that postnatal age, sepsis, and presence of respiratory support also influenced the EDIN score.
Neonatal pain should always be assessed systematically. Pain assessment should be performed every 4–6 hours or as indicated by the pain scores or clinical condition. It is best to choose a multidimensional scale that includes contextual, behavioral, and physiologic indicators. Healthcare providers should be aware of age, pathology, and prior NICU experience in order to better interpret the attributed pain score. Evaluation should be performed before and after each potentially painful procedure and to assess any use of pain-relieving interventions, including behavioral, environmental, and/or pharmacologic strategies. Special attention should be given to situations associated with persistent or chronic pain.
3. Pain Management
The goals of pain management in neonates are to minimize the experience of pain and its physiologic cost, and to maximize the newborn’s capacity to cope with and recover from the painful experience, while maintaining a balance between pain relief and adverse effects of analgesics. Optimal pain management should include a combination of prevention, pharmacologic strategies, and non-pharmacologic approaches, or some combination of these techniques. Tables II and III summarize management strategies for different painful procedures and clinical situations in neonates.
Prevention is the best way to avoid pain. Painful procedures are performed too often in the NICU, as shown by multiple epidemiologic studies.[5,6] Recent recommendations have emphasized the need for developing strategies to minimize the number of minor painful and stressful procedures in the NICU. Systematic procedures carried out for basic care or surveillance should be avoided and, when necessary, procedural techniques should be modified. Painful procedures should be planned so that pre-emptive analgesia can be administered, central lines, if available, should be used to obtain blood rather than peripheral blood sampling, venepuncture should be used instead of heel lance, and appropriate materials should be used (e.g. mechanical lancets for heel pricks rather than manual lancets).[7,10] At a minimum, procedural pain guidelines should be written and applied in all units that care for newborns. These recommendations also apply for the prevention of prolonged or chronic pain, together with reductions in all other factors that may contribute to this outcome by causing heightened activity in nociceptive pathways (noise, light, handling, examination, etc.).
Well organized management is critical for the successful implementation of such practices because pain management in newborns is often heterogeneous.[39,40] There are several key steps to implementing pain protocols effectively. First is having the basic information in written format: indications and contraindications for use (patients and procedures), precautions, potential adverse effects, and personnel who should administer medications. Next, in-service training must be provided for staff. Keeping best practice in the forefront and reinforcing the need for this to staff is critical. Another important step is following up to ensure that staff maintain pain protocols. Interpersonal factors among staff may also influence pain management; nurse-physician collaboration and nurses’ work assignments are more predictive of the use of evidence-based care than infant and other nurse factors.
3.2 Pharmacologic Management of Pain
Whereas stress is not painful, pain is always stressful and its relief most often requires analgesia and sometimes sedation. Many analgesics and hypnosedatives are available, but few of them have been studied in neonates. Furthermore, recent studies have underlined the possibility of short- and long-term adverse effects of these therapeutic agents in neonates. Choosing a suitable medication requires a delicate balance between benefits and risks. The most common analgesics and hypnosedatives used in neonates are described in this section. Recommended or typical doses are summarized in table IV.
Opioids are widely used for analgesia and sedation in neonates. They have potent analgesic effects, sedative but no amnesic or hypnotic effects, weak to moderate effects on hemodynamic stability, and reversible adverse effects. Their adverse effects include respiratory depression, bronchospasm, reduced gastrointestinal motility, urinary retention, and pruritus. After a few days of use, tolerance and pharmacologic dependence will develop. Morphine and fentanyl are the most commonly used opioids in the NICU. Others such as sufentanil are less common and will not be examined in this review.
Morphine is the gold standard of all the opioids. It has a slow onset of analgesia due to lower lipid solubility, especially in premature infants. The onset of action is 5 minutes and the peak effect occurs at 15 minutes. Morphine causes histamine release and may lead to hypotension, bradycardia, and bronchospasm, especially in infants with chronic lung disease (CLD).[10,32,45] Compared with fentanyl, morphine is less likely to cause dependence or withdrawal but more likely to have adverse effects on the gastrointestinal tract. Morphine is widely used for sedation in ventilated neonates and for analgesia when alleviation of severe to intense pain is required. Titration to the desired analgesic effect is essential and efficacy must be evaluated regularly using an adequate pain scale.
The analgesic effect of morphine on acute pain caused by invasive procedures in preterm neonates remains controversial. Although initial studies showed promising results, other recent studies have found non-significant analgesic efficacy.[47,48] Other effective analgesic approaches must be considered for acute painful procedures, such as other potent and short-acting drug and/or brief non-pharmacologic techniques.
Potential adverse effects of morphine therapy include effects on the gastrointestinal tract and possibly on the neurologic system. Morphine analgesia delays the initiation and attainment of full enteral feeding in preterm infants, but does not increase the risk of acquired gastrointestinal pathologies.[49,50] In the NEOPAIN (Neurological Outcomes and Pre-emptive Analgesia in Neonates) trial, which was designed to evaluate neurologic outcomes in ventilated preterm neonates treated with a morphine infusion compared with placebo, continuous morphine did not alter the neurologic outcomes of preterm neonates. A subsequent study evaluated neurobehavioral outcomes at 36 weeks’ postconceptional age (PCA) in the neonates enrolled in the NEOPAIN trial. The Neurobehavioral Assessment of the Preterm Infant instrument was used to evaluate 572 of 793 survivors at 36 weeks’ PCA. The results of this study suggest that morphine analgesia may result in subtle neurobehavioral differences in premature infants. Recent results from the EPIPAGE (Etude EPIdémiologique sur les Petits Ages GEstationnels [Epidemiological Study on Small Gestational Ages]) cohort showed that prolonged sedation and/or analgesia is not associated with a poor 5-year neurologic outcome. This analysis involved 1572 premature infants who received mechanical ventilation for whom information about exposure to prolonged sedation and/or analgesia in the neonatal period was available. Very early preterm infants who were exposed to morphine had significantly severe or moderate disability at 5 years (41/97 [42%]) more often than those who were not exposed (324/1248 [26%]). After adjustment for gestational age and propensity score, this association was no longer significant.
Fentanyl has a faster onset (3 minutes) and shorter duration of action (30 minutes) than morphine. It causes less histamine release than morphine and is therefore more suitable for neonates with hypovolemia, hemodynamic instability, congenital heart disease, or CLD. Fentanyl also reduces pulmonary vascular resistance and is useful for infants with persistent pulmonary hypertension. Attention must be given to the risk of chest wall rigidity after rapid bolus doses. This can be managed by the administration of a neuromuscular relaxant or naloxone. Tolerance and withdrawal are more problematic with fentanyl than with morphine.[45,53]
Alfentanil is a derivative of fentanyl that has lower lipid solubility and causes less histamine release than fentanyl. It has a faster onset of action and a shorter duration of action than fentanyl.[10,54] This may make alfentanil an appropriate treatment for procedural analgesia in newborns.
Methadone is currently being studied as a viable drug to reduce pain in neonates. It is equipotent with morphine, but has additional mechanisms of action that may be advantageous in the preterm neonate population. Methadone activates the μ-opioid receptors in the same way that morphine does, but also causes a desensitization of δ-opioid receptors and an antagonism of the NMDA receptors involved in pain sensitization. The action on the δ-opioid receptors reverses the tolerance that occurs with morphine and, as an NMDA receptor antagonist, methadone produces additive analgesia and delayed development of tolerance. Methadone has a slow onset of action (20 minutes intravenously, 30–60 minutes orally), good oral bioavailability, and a prolonged (15–55 hours) elimination half-life. Further research is needed to assess doses, efficacy, and eventual long-term adverse effects of this NMDA receptor antagonist in neonates.
Doubt persists about the adverse neurologic effects of opioids and, according to the recent work of the Cochrane collaboration group, these agents should be used selectively in neonates when indicated by clinical judgment and evaluation of pain. However, if sedation is needed, morphine is safer than midazolam as it has fewer adverse effects (hypotension, need for cardiac resuscitation).[55,56] Future studies should examine only newborns who express indicators of pain (and not neurologic problems) when on mechanical ventilation. Medium- and long-term follow-up is necessary to assess the neurodevelopmental consequences of opioid treatment during the neonatal period.
3.2.2 Non-Opioid Analgesics
Non-opioid analgesics can be used alone for mild to moderate pain, for procedural pain in combination with non-pharmacologic analgesia, and in combination with opioid analgesics to improve their efficacy and decrease the risk of adverse effects in neonates with severe pain. The non-opioid analgesics often used are acetaminophen (paracetamol), ketamine, and nitrous oxide. NSAIDs are widely used in older children for their analgesic effects. In neonates, large randomized controlled trials of ibuprofen and indometacin have been conducted for closure of patent ductus arteriosus in preterm neonates[57,58] with high incidences of renal and gastrointestinal adverse effects reported. These agents are thus not recommended in neonates (term or preterm), as clinical guidelines and tolerability have not been established.
Acetaminophen has analgesic and antipyretic efficacy and a low incidence of adverse effects. When given in combination with opioids, the analgesic effect is additive and allows opioid doses to be decreased. Acetaminophen can be administered intravenously, orally, or rectally. Acetaminophen is safe and effective in term and preterm neonates with continuous mild to moderate pain but is ineffective for acute procedural pain.[10,60] The use of acetaminophen in the first year of life seems to be associated with an increased risk of asthma, rhinoconjunctivitis and eczema at age 6–7 years, and further studies are needed to confirm these long-term adverse effects.
Ketamine is widely used for anesthesia and analgesia in neonates and children. It produces a dissociative state by blocking NMDA receptors, resulting in sedation, analgesia, and amnesia, and has a short duration of action, supporting hemodynamic and respiratory stability. Adverse effects include emergence phenomena, laryngospasm, and increased production of upper respiratory and salivary secretions. Its use should be preceded by an injection of atropine. Adverse effects such as increased intracranial pressure (ICP) and neurotoxicity on the immature brain have limited its use. However, these observations should be interpreted with caution. ICP does not appear to be modified by ketamine. Apoptosis described in animal models appeared with doses up to 10–100 times those used in clinical practice, and these data may not apply to human neonates receiving clinical doses.[45,62] Recently, in animal models exposed to repetitive inflammatory pain, ketamine was shown to have neuroprotective effects. The use of ketamine should continue while respecting the recommended doses but further research is needed to determine its long-term effects.
Nitrous oxide is an equal mixture of nitrous oxide and oxygen. It produces rapid, short duration analgesia without complete loss of consciousness, and appears to be a weak anesthetic but a strong analgesic. Its mechanism of action is not fully understood. Nitrous oxide is not widely used in neonates. It has moderate efficacy for alleviating pain in neonates or infants before injection of palivizumab or tracheal intubation; however, results from the latter study are controversial. The high oxygen concentration of the mixture makes it unsuitable for preterm neonates because of potential toxicity to the retina and other developing organs. Nitrous oxide could nevertheless be a useful treatment prior to painful procedures, although further studies in term neonates are needed to evaluate the effects of this agent before its routine use can be recommended in this population.
Despite the ability of hypnosedatives to suppress behavioral responses to pain, they should not replace analgesics because they have no actual analgesic effects. Hypnosedatives can be used as an adjunct to analgesia but, according to the recent Cochrane review, opioids are preferred when sedation is required in ventilated neonates.
Midazolam is the most frequently used hypnosedative in neonates. However, adverse effects (hypotension, alterations in cerebral blood flow, need for cardiac resuscitation, etc.) have been reported when midazolam is administered as a continuous infusion or in bolus doses.[56,67] A Cochrane review concluded that data are insufficient to promote the use of intravenous midazolam infusion as a hypnosedative in neonates due to uncertainty about its safety.
Propofol is used for the induction of general anesthesia in neonates and children. It is safe for procedural sedation in children, and its use before procedures such as tracheal intubation seems to be safe in neonates.[69,70] Because propofol has no analgesic effect but a potent amnestic effect, the concomitant use of an analgesic should be considered depending on the procedure and the time available. Large randomized studies would be of interest to confirm the efficacy of propofol and to assess its short- and long-term safety with continuous infusion in children, particularly in relation to cardiac failure, metabolic acidosis, and death.
3.2.4 Local Anesthesia and Analgesia
Local anesthetics are useful for the management of procedure-related acute pain. They can be injected subcutaneously or applied topically on intact skin. Lidocaine (lignocaine) is currently used before painful procedures. However, administration of lidocaine is itself painful, and strategies must therefore be utilized to prevent this induced pain.
Two topical anesthetics are used in neonates: the eutectic mixture of lidocaine/prilocaine 5% cream (Eutectic Mixture of Local Anesthesia [EMLA®]) and tetracaine 4% gel (Ametop®). EMLA® needs approximately 1 hour to achieve clinical effect, with a depth of penetration of approximately 2–3 mm. Recommended doses of EMLA® are 0.5–2 g, according to prematurity severity and the infant’s age, under an occlusive dressing between 1–2 hours before the procedure. In premature babies older than 30 weeks’ gestational age, a single application of 0.5 g of EMLA® for 60 minutes per day appears to be safe and effective. Repeated application during the first week of life in term and premature babies should be undertaken with caution. There are no existing recommendations for neonates under 30 weeks’ gestational age. To avoid pain from the removal of the adhesive, local strategies can be applied (such as non-adhesive plastic film around the hand or foot). EMLA® can cause methemoglobinemia in susceptible infants, especially if its use is associated with other risk factors. In cases of methemoglobinemia, intravenous injection of methylene blue (methylthioninium chloride) 1% (1–2 mg/kg) must be used. Ametop® has a faster onset time than EMLA® (30–40 minutes), and does not lead to methemoglobinemia. However, its effectiveness is controversial in the neonate.[75,76]
Both EMLA® and Ametop® have shown efficacy in acute painful procedures (lumbar puncture, venous cannulation, circumcision, etc.), but they are less effective for intramuscular injections such as immunizations or vitamin K. They are not effective for heel lance.[72,77] For this painful procedure, other strategies such as non-pharmacologic approaches must be used.
3.3 Non-Pharmacologic Techniques
Non-pharmacologic interventions include environmental and behavioral strategies. They reduce neonatal pain directly by blocking nociceptive transduction or transmission or by activating descending inhibitory pathways, and indirectly by reducing the total amount of noxious stimuli to which infants are exposed. Unlike medications that are often used off-label or are unlicensed in neonates, non-pharmacologic methods have short-term efficacy, good tolerability, and are widely recommended for preventing and managing pain.[23,78] They can be implemented easily by nurses as they rarely require a medical prescription, and should be used systematically before painful or stressful procedures to preserve the well-being of the neonate. These interventions are not substitutes or alternatives but are complementary to pharmacologic interventions that must be used if needed.
3.3.1 Environmental Strategies
The purpose of environmental interventions is to decrease the external stress to which newborns are subjected in the NICU. Reducing lights, noises, and frequent handling, and allowing day and night alternation, all have beneficial effects on the subsequent behavior of the neonate and decrease the severity of the illness. Furthermore, reducing other noxious stimuli after a painful stimulus avoids heightening of activity in the nociceptive pathways, which can be perceived as a chronic noxious stimulation (also classified as chronic pain or discomfort).
3.3.2 Behavioral Strategies
Behavioral strategies include non-nutritive sucking (NNS), sweet solutions, kangaroo-mother-care (KMC)/skin-to-skin contact, breastfeeding, facilitated tucking, swaddling, and others such as multisensorial stimulation.
NNS is the placement of a pacifier in the infant’s mouth to promote sucking behaviors. This reduces crying during heel stick and venepuncture in term and preterm neonates, and helps infants to be more calm and attentive.[80,81]
Sucrose 12–24% and glucose 20–30% are sweet solutions that effectively reduce pain in neonates.[82,83] According to the Cochrane review recently actualized, the optimal dose of sucrose has not been established. The dose range of sucrose for reducing pain in neonates is 0.012–0.12 g (0.05–0.5 mL of 24% solution), while larger doses (0.24–0.50 g) were more efficient in term neonates. Doses above 0.50 g confer no additional benefit over lower doses. A recent study from the Vermont Oxford group recommended doses of 0.5, 1 and 2 mL (24% sucrose solution) for infants aged 27–31 weeks’ gestational age, 32–36 weeks’ gestational age, and >37 weeks’ gestational age, respectively. Sweet solutions must be administered at least 1–2 minutes before any painful procedure directly by mouth via a pacifier or oral syringe application because intragastric administration is not effective.[41,84,86] Sweet solutions are recommended to alleviate pain caused by minor procedures (heel stick, venepuncture, etc.), but they seem to be truly effective only for venepuncture and not for heel sticks or intramuscular injection of vitamin K. Because oral sucrose reduces but does not eliminate pain in neonates it should be used with other non-pharmacologic measures to enhance its effectiveness.[4,78] Administering a sweet solution with NNS improves both physiologic and behavioral indicators of pain.[81,88] This may be due to their additive effects on pain pathways, but the underlying mechanisms remain unclear.
To date, with the exception of minor problems such as choking and oxygen desaturation, no serious adverse effects have been reported with sucrose. Nevertheless, attention must be focused on a possible relationship between an increased number of sucrose doses and poorer neurobehavioral developmental outcomes. It seems reasonable to use the lowest possible dose that provides pain relief and to avoid exceeding 8–10 administrations per day.[41,91] Sucrose can be included in pain management protocols, with documentation of the doses administered and any adverse effects.
KMC, first initiated in Colombia in the 1970s, involves holding the infant skin-to-skin against the bare skin of the mother or father. KMC has been found to reduce hypothalamus-pituitary-adrenal activity in response to pain, and diminishes pain responses (measured by crying and grimacing or using a validated pain assessment tool) from heel lancing in healthy neonates from 28 weeks’ gestational age to term.[94, 95, 96, 97] In a recent randomized, single-blind study involving 95 healthy preterm neonates, the analgesic effect of KMC appeared to be at least as effective as glucose 25% during heel lancing. KMC for a duration of 15 minutes prior to heel lancing seems effective in reducing the infant pain response.[96,97] Since neonates <28 weeks’ gestational age were not able to maintain their temperature during KMC, evaluation of KMC for pain control in infants <28 weeks’ gestational age is not suggested at this time. Further studies are needed to assess the effectiveness of KMC for painful or repetitive procedures other than heel stick.
Breastfeeding can also be used to alleviate procedural pain in neonates.[100, 101, 102] In a Cochrane review, breastfeeding, compared with swaddling or pacifiers, was found to reduce crying time during procedural pain, and was as effective as sucrose. In two other studies,[101,102] breastfeeding was more effective than sucrose for relieving pain induced by heel lance or venepuncture in term neonates. It must be noted that breast milk alone does not have any analgesic effect. However, in a recent study, the odor of the mother’s milk was shown to reduce pain from heel stick in term neonates, compared with another mother’s milk, formula, or control (saline serum). Multimodal stimulation such as skin-to-skin contact, positioning, touch, and smell of the mother are probably involved in the ability of breastfeeding to soothe pain.
Facilitated Tucking and Swaddling
Facilitated tucking is the containment of the infant’s arms and legs in flexion in the midline position close to the infant’s trunk. In a recent systematic review of the literature, facilitated tucking was found to achieve significant pain relief during endotracheal suctioning or heel stick.
In the same review, swaddling also demonstrated a pain-relieving effect in preterm neonates, despite some studies showing contradictory results. This technique should be used with caution because of the risk of increasing the infant’s temperature if the swaddling is not done correctly.
Other non-pharmacologic techniques, such as positioning, music, multimodal stimulation, massage, and, recently, acupuncture, seem to be effective in helping neonates recover from painful procedures.[78,104,105]
Many non-pharmacologic techniques, such as KMC and breastfeeding, involve parental presence. Parents, especially the mother, can greatly assist the neonate in being calm during a painful procedure and in recovering more quickly, simply through use of her voice, smell, etc. Furthermore, parental presence is associated with increased use of specific pre-procedural analgesia. Some studies have revealed that parents desire more information and involvement in their infant’s pain management. Parents also need help developing coping strategies to reduce distress related to their infant’s pain.[106,107] This may contribute to an improved mother-child interaction during and after the stay in the NICU. Biologic processes, psychological factors, and social/environmental factors influence the overall experience and consequences of chronic pain. To avoid the development of chronic pain in later childhood and to allow these children to have a better quality of life, all aspects of pain during the neonatal period must be managed effectively.
Despite huge progress in the management of pain in neonates, several problems persist. Repetitive painful stimuli may alter pain processing, and the first goal is to decrease the number of painful procedures, in particular in the NICU. Better evaluation of pain, especially chronic pain and pain in the smallest premature babies, remains a challenge. Non-pharmacologic analgesia should be considered when moderate pain is expected, but further research is necessary to evaluate the real analgesic effect of these strategies.[108, 109, 110] The risk/benefit balance should be carefully addressed when considering analgesic or sedative treatment in a neonate, using currently available data and keeping in mind the major knowledge gaps remaining in this field. Long-term follow up of infants included in large prospective studies on pain control would be very helpful.
No sources of funding were used to prepare this review. The authors have no conflicts of interest that are directly relevant to the content of this review. The authors thank Rachel Gooze for editing the manuscript with respect to language.
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