Multiple degrees of neonatal discomfort and stress or pain may occur as a result of various low, moderate, or severe invasive procedures routinely applied to patients in neonatal intensive care. The medical staff in neonatal intensive care units is expected to prevent and treat all of these painful experiences that newborns have.
Advanced research in neonatology reveals that newborns experience pain and that control or noncontrol of pain has long-term repercussions during the development of the newborn(1-3). To control the pain of newborns and protect them from painful experiences represent an important therapeutic act in everyday practice(4-6). Different degrees of discomfort, stress and pain may occur during routine maneuvers practiced on newborns. Such maneuvers that produce low-intensity pain are the placement of the gavage probe, bladder catheterization, or even the simple clinical examination(7). A number of other medical acts performed can generate pain of medium intensity, such as aspiration, oropharyngeal, peripheral or arterial venous approach per cutaneous. There are other medical maneuvers that produce high-intensity pain, such as pleural dermal drainage, abdominal dermal drainage, central venous approach, ritual circumcision or other surgeries. Newborns treated in intensive care are the most exposed to such types of maneuvers, in addition many of them suffering from conditions that are pain-generating, such as necrotic ulcer enterocolitis or bullous epidermolysis, osteomyelitis and osteoneonatal arthritis.
Despite the efforts made, the precise and consistent definition of prolonged or chronic pain in the newborn leaves much to be desired(8-10). Due to the lack of consensus on this issue, only 10% of the newborns hospitalized in the neonatal intensive care unit (NICU) receive a daily evaluation for the appreciation of long-term pain and receive appropriate treatment(11).
Another cause that contributes to the underestimation of neonatal pain and its lack of treatment is the lack of consensus on pain assessment scales, the rhythmicity of their use and the association of different scores obtained with targeted and phased therapeutic measures(12).
In order to be sure that in any neonatal intensive care unit there is an adequate control of pain in newborns, a pain assessment and a treatment protocol must be implemented, adapted to the gestational age, the type of pathology treated in that section and the local possibilities regarding personnel resources, equipment and medicines. This protocol must include:
The routine evaluation of newborns to detect the presence of acute pain and/or of long-term pain(4,13-15).
Reducing the number of procedures to a minimum, removing those procedures that are considered not to be essential in the treatment of the newborn.
The prevention/reduction of acute pain by practicing preemptive analgesia for each procedure, which is expected to cause pain to the newborn.
This preemptive analgesia involves a combination of nonpharmacological measures with pharmacological therapeutic measures.
Curative analgesia will be practiced in a staged, gradual manner, depending on the type of maneuver and the intensity of pain that is expected to occur:
the anticipation and treatment of postoperative pain after surgery;
avoiding, improving or limiting the duration of maneuvers generating long-term pain or stress;
monitoring the patient’s response to therapeutic measures with analgesic role, using standardized evaluation methods within a validated protocol;
the use of additional therapeutic measures for analgesia if it is found that the patient’s current analgesia is insufficient.
Analgesia for specific procedures
Preemptive analgesia before as well as curative, during and after elective pain procedures performed electively, should be done in all newborns. This analgesia includes a combination of nonpharmacological measures and pharmacological measures. It is recommended to use it in a standardized way, according to a protocol, for the different pain-generating maneuvers, frequently practiced in neonatal intensive care, in stages, with different analgesic therapeutic associations. These will be gradually increased as the analgesic potency increases with the intensity of the pain expected to be produced by the various therapeutic maneuvers performed on the newborn(14,16).
This attitude is in line with the recommendations of the American Academy of Pediatrics and the practice guidelines recommended in pain therapy and for adults(4,17).
1. Nonpharmacological measures, such as breastfeeding, isolation of the newborn in a noiseless environment, wrapping and wrapping the newborn, skin-to-skin contact, and the administration of 24% desucrosis or concentrated glucose. For many situations, such as stabbing in the heel for blood collection, a combination of these measures can be used successfully, with the exception in the American practice – the administration of sucrose and the skin-to-skin technique.
2. The use of topical anesthetics, such as topical lidocaine, EMLA-lidocaine-prilocaine cream, amethocaine gel, and tetracaine gel.
3. The use in oral administration of acetaminophen (paracetamol) or nonsteroidal analgesic drugs, kerorolac being elective.
4. The use of synthetic opiates such as tramadol, or potent opiates such as morphine or fentanyl, the latter being used only in bolus or in continuous intravenous administration, but only in intubated and mechanically ventilated patients.
5. Subcutaneous infiltration with lidocaine or percutaneous blockade of various peripheral nerves or nerve plexuses.
6. Deep sedation, generally practiced in intubated newborns. In this technique, a combination of opiates and benzodiazepines type midazolam is used.
The application of these analgesic steps and therapeutic measures in neonatal intensive care units depends on the choice of the treating clinician, as well as on the practical experience, policy and protocols existing in the respective intensive care unit.
A frequently recommended practice proposes the following currently used strategy(18):
nonpharmacological measures should be used to improve analgesia for any pain-generating procedure, when possible;
for newborns who will have a skin prick, such as a heel prick for harvesting or a venous puncture, 24% sucrose or concentrated glucose will be given in combination with nonpharmacological measures.
For newborns who are going to have a maneuver generating pain of higher intensity, such as arterial or venous puncture, with the placement of a catheter or lumbar puncture, in addition to oral administration of fructose and nonpharmacological measures, it is indicated the application at the site of puncture of a cream with lidocaine or EMLA type analgesic, as well as the administration of a tramadol type opiate dose.
In newborns who are to undergo ritual circumcision, in addition to the administration of 24% sucrose or concentrated glucose, a circular block, or a dorsal block of the penis is indicated before the procedure, along with the administration of an oral dose of paracetamol after the maneuver.
In combination with EMLA and glucose, the circular block appears to be much more efficient than the dorsal block of the penis.
For more invasive procedures, such as the placement of central venous lines, the combination of nonpharmacological measures, topical local anesthesia and/or general anesthesia are used to ensure a quality analgesia.
A combination of nonpharmacological measures, paracetamol and opioids are used to ensure an adequate postoperative analgesia(22-27).
In mechanically ventilated infants, a combination of opiate-fentanyl or morphine with benzodiazepine, administered in an intermittent bolus or in continuous infusion, both for sedation and for analgesia of the basic or postoperative condition, is frequently used.
Newborns with persistent pain for a long time and high intensity (e.g., necrotic ulcer enterocolitis, meningitis, bullous epidermolysis) may receive adequate analgesia only through the use of opioids, in intermittent administration or continuous infusion with tramadol, fentanyl or morphine, even though they are not mechanically ventilated(19,20).
The following nonpharmacological methods of analgesia can effectively reduce pain and discomfort for pain-generating therapeutic measures performed in newborn therapy:
wrapping or gently holding the limbs in a flexed position;
skin-to-skin contact (kangaroo therapy);
sensory saturation, which involves the use of sensory techniques (gentle-caressing touch, gentle massage, spoken in an equal tone with soft voice, symphonic music, pleasant ambient smell).
The nonpharmacological techniques and measures are generally much more effective when used in combination than when used individually(22-27). The American Society of Pediatrics recommends the use of nonpharmacological techniques in association with each other and in combination with pharmacological ones.
The use of the skin-to-skin technique associated with the administration of 24% fructose or glucose in high concentration has a much better effect than each of the two methods applied individually.
It has been found that the use of these techniques in combination for maneuvers producing low or medium intensity pain sometimes leads to the elimination of the pharmacological techniques to combat pain(22-24,28).
Breastfeeding or oral administration of breast milk is a therapeutic measure with a good analgesic effect. Breastfeeding is a technique that can be used as an alternative to 24% sucrose or high glucose. The benefits of this method include the presence of the mother near the newborn and the association of maternal contact – newborn skin to ventral skin, which increases the release of beta endorphins and oxytocin in the newborn. Also, the effect of carbohydrates in breast milk and fatty acids combined with the sucking gesture of the newborn also increase the level of the aforementioned mediators and have a major analgesic effect. Unfortunately, this technique cannot be applied to newborns intubated. However, it has been found that the simple breastfeeding is beneficial in terms of cutting pain, but less effective than breastfeeding(29,30).
Non-nutritive suction is efficient in reducing pain in both full-term and premature newborns. Newborns who are offered a pacifier have a lower increase in heart rate and a marked decrease in psychomotor agitation through calming cries than those who are not given a pacifier. However, studies have shown that the effect of pacifiers is inferior to that of breastfeeding and skin-to-skin techniques, as well as the administration of 24% sucrose or concentrated glucose(4,21).
Newborn covering, wrapping and soft maintenance in a lightly flexed position of the limbs is a nonpharmacological technique to reduce pain which is more efficient than performing any maneuver, for example for oropharyngeal aspiration and stinging from the heel. However, this technique is not as effective as 24% sucrose or the administration of concentrated glucose orally.
Keeping the limbs slightly flexed activates the proprioceptors, tactile and thermal receptors, and facilitates behavioral movements of the newborn, such as hand-mouth and sucking movements, all these generating increased levels of mediators, such as endorphins and oxytocin and thus having an analgesic effect(21,41).
Skin-to-skin contact (kangaroo therapy), in which the newborn is held between the mother’s breasts, stimulates the system of ventral tactile receptors and proprioceptors of the newborn and reduces his response to pain. Several studies report that skin-to-skin contact is effective and safe in reducing pain caused by a single painful procedure (e.g., stinging from the heel or venous puncture)(44-48).
Sensory saturation results from the simultaneous use of several sensory inputs (gentle touch and caress, gentle massage, soft voice, music, pleasant smell) during a painful procedure. Several studies have revealed a significant decrease in pain when, during a painful maneuver, it was used in combination with the administration of sucrose and sensory saturation. This combination was clearly superior to the simple use of 24% sucrose(25,40-43).
Pharmacological pain therapy
The pharmacological therapy of pain in the newborn includes:
sucrose 24% or concentrated glucose administered orally, as well as other sweet liquids;
local anesthesia, including topical anesthetics and lidocaine.
When drug therapy is used (especially analgesia by systemic drug administration), the benefit and the side effects must be weighed. In particular, the effects of opioid drugs, including respiratory depression, hypotension, urinary retention and ileus, should be considered.
Oral administration of sucrose 24%
or concentrated glucose
Sucrose 24% administered orally, or other sweet liquids such as concentrated glucose or saccharin, have analgesic effects in both full-term and premature newborns(39-41).
The effectiveness of orally administered sweet liquids (most commonly, 24% sucrose) as analgesics has been demonstrated in numerous large randomized studies and trials, which included newborns with gestational ages of 25 to 42 weeks who underwent the skin prick procedure (harvesting from the heel or venous puncture). Sucrose 24% or concentrated glucose administered orally were associated with the following findings(4):
reducing the crying time of the newborn;
blocking the physiological response of heart rate increases, decrease in saturation, increase in vagal tone;
reduction of facial expression characteristic of pain in the newborn;
low pain scores on specific scales for newborns.
However, it remains unclear whether sucrose 24% suppresses the neurophysiological response to pain in the newborn and whether monitoring this response is relevant to the study of pain(39,50).
Animal studies suggest that the analgesic effect of sucrose 24% or concentrated glucose is mediated by the activation of the opioid but also the nonopioid system in the brain. In children, however, the studies are somehow contradictory. One study demonstrates that there is no change in plasma levels of beta endorphins when given sucrose 24%, while another study shows that the concomitant intravenous administration of naloxone would potentiate the analgesic effect of sucrose 24%(42).
In current practice, in many neonatal intensive care centers, sucrose 24% is used by oral administration to reduce pain when performing pain-generating maneuvers such as: heel puncture, venous puncture, nasal drainage insert gastric puncture, arterial puncture, bladder catheterization, intramuscular or subcutaneous injections, eye examination to assess retinopathy, diaper change, or dressing change(43-47).
There is no optimal dose set to treat pain in the newborn. Doses range from 0.012 to 0.12 g, respectively 0.05 ml to 0.5 ml orally and per dose of sucrose 24%. Sucrose can be given orally with a syringe or directly on the tongue, leaving the newborn to suck on a teat or pacifier that has been soaked in a sucrose 24% solution(4,39,40,45,46).
The vast majority of studies recommend a period of 2 minutes from the time of administration of sucrose until the performance of the therapeutic maneuver generating pain and possibly the repetition of the administration during the maneuver or immediately after its performance, in the same manner if necessary.
There are studies that recommend the administration of sucrose 24% or concentrated glucose, including intubated newborns, directly on the tongue.
Local analgesics recommended in neonatal pain therapy include both topically administered analgesics and formulas for injection.
As local anesthetics used as local topics, there are recommended: lidocaine-prilocaine in a mixture, in a concentration of 2.5%, the commercial product being Emla®; 4% tetracaine, known as amethocaine, in the form of cream or gel; lidocaine 4% or 5% in the form of gel, lidocaine-tetracaine mixture, both in percentage of 7%, the commercial product being S-Caine Patch®.
Of these, the most used is Emla®, frequently used for lumbar, venous, arterial punctures or for ritual circumcision. Its disadvantage is the long waiting time to obtain the local analgesic effect, which can vary from 30 minutes to 45-60 minutes. The most common side effects are represented by local irritation and methemoglobinemia, due to prilocaine in the Emla® composition(44).
Lidocaine in a concentration of 1% or 0.5% is frequently used for local injections, for venous and arterial punctures, the insertion of central or arterial venous catheter or for penile block. The analgesia is of good quality, and the adverse effects, such as neurological toxicity, are avoided if a dose of 5 mg/kg body weight is not exceeded(45,46).
A number of drugs are used in the systemic administration to achieve analgesia in newborns. These are acetaminophen (paracetamol), ketamine, nonsteroidal anti-inflammatory drugs such as ketorolac, and a number of opioids such as morphine, fentanyl, oxycodone, tramadol and methadone(45).
Acetaminophen (paracetamol) is used in the management of low and medium intensity pain and for the treatment of postoperative pain or background pain caused by some diseases, such as bullous epidermolysis, meningitis or necrotic ulcer enterocolitis. Acetaminophen should not be given alone to combat high-intensity pain because, as many studies have shown, it is not as effective. Therefore, acetaminophen is recommended for use in combination with local analgesics or opioids(38-49).
Because both in the full-term newborn and especially in the premature, the clearance of acetaminophen is reduced, it is recommended that the doses used orally be 10-15 mg/kg b.w. at 6-8 hours.
For intravenous administration, a dose of 20 mg/kg b.w. loading is recommended followed by doses of 10 mg/kg b.w. at 6-8 hours, with a total daily dose of 50-60 mg/kg b.w.
The side effects are minor, but hepatic toxicity should be considered at doses exceeding 80-90 mg/kg b.w. and per day, the toxicity being increased in newborns with hypoalbuminemia and caloric protein malnutrition(48).
Nonsteroid and anti-inflammatory medicines
Although this class of drugs are widely used in older children and adults, in newborns there are few drugs in this class that can be used for pain therapy. The most important and limiting side effects are the gastrointestinal bleeding, the platelet dysfunction, and decreased glomerular filtration rate(41-49).
The only drug in this class used for pain therapy in newborns is ketorolac. The Food and Drug Administration (FDA) recommended dose for both premature and full-term infants is 0.5 mg/kg b.w. at 8 hours, with a maximum use of three consecutive days(34).
Opioids are the most frequently used analgesic drugs with systemic administration, being utilized to combat pain of medium to high intensity. In addition to analgesia and sedation, they produce a beneficial effect for which they are preferred to be used in intubated and mechanically ventilated newborns.
Morphine, fentanyl and tramadol are the most used opioids in newborns. There are other opioids, such as sufentanil, much more potent than fentanyl, or opioids with a much shorter duration of action than morphine and fentanyl, such as alfentanil and remifentanil. They are less used in practice in newborns due to their important side effects. In general, in opiates their beneficial effect must be balanced with their side effects which include respiratory depression, hypotension, urinary retention and ileus. As such, opioid therapy should be reserved primarily for combating postoperative pain as well as invasive pain-generating maneuvers like thoracic, abdominal tube placement, or arterial or central venous catheter placement per cutaneous.
Morphine is the most widely used opioid in neonatal practice. It is used both in intravenous bolus administration and in continuous infusion, generally in ventilated patients to combat postoperative pain or for sedation. Morphine is not recommended for use in unventilated patients due to its strong central respiratory depressant effect. It is recommended to be used sparingly due to its side effects(46), along with respiratory depression, the most important being hypotension, urinary retention, ileus, and delayed resumption of eating.
The recommended doses are 0.05-0.1 mg/kg b.w./bolus dose, at 4-6 hours, and in continuous i.v. administration in a dose of 0.01 mg/kg b.w./hour, titrated depending on the effect, up to a maximum dose of 0.03 mg/kg b.w./hour.
Fentanyl is used in the newborn due to the rapid onset of the analgesic effect and its much lower hemodynamic effects than morphine. Like morphine, it is recommended to be used only in mechanically intubated and ventilated patients, the doses being 0.5-1 µg/kg b.w. bolus, doses administered every 4-6 hours. The continuous infusion is not a custom in neonatal practice(40-42).
Tramadol, a semisynthetic opiate, recently entered in the neonatal practice, has a much lower ability to depress the respiratory center than morphine and fentanyl, therefore it can be used as a bolus even in unintubated newborns. The dose is 0.5-1 mg/kg b.w., at every 4-6 hours, the administration being very slow, due to the risk of emesis. This is a common side effect with tramadol(46).
Ketamine is an N-methyl D aspartate receptor antagonist (NMDA), introduced in the medical practice as a dissociative anesthetic, but which is used for procedural analgesia and in pediatric and neonatal practice. Ketamine produces a lower degree of analgesia than opiates, but has an intense sedative and amnestic effect, stimulating the respiratory center, with the advantage of maintaining the respiratory function, while producing bronhodilation and maintaining the hemodynamic function with a slight increase in heart rate and blood pressure. At a dose of 1-2 mg/kg b.w. in the bolus, it is indicated for procedural analgesia in newborns with hemodynamic instability, such as those suffering from diaphragmatic hernia, or those who require cannulation for extracorporeal oxygenation (ECMO)(50).
Dexmedetomidine is a selective alpha-2 agonist drug with strong sedative and analgesic effects which, like ketamine, stimulates the respiratory center and maintains spontaneous breathing. It has been approved by the FDA since 2008, with limited but growing neonatal experience. It can be administered in a bolus of 0.05-0.1 µg/kg b.w. or in continuous infusion in the same hourly dose. The side effects at high doses are convulsions and bradycardia(44-46).
The evolution of patients at distance
It is currently unclear whether the neonatal use of analgesics, especially opioids, has far-reaching clinical consequences in terms of the neurological evolution of patients and the occurrence of possible behavioral disorders(48).
A recently published study, NEOPAIN, which looked at a cohort of patients who received neonatal morphine compared to a group of patients who did not receive it, revealed that there were no differences at 5 and 7 years in the somatic and neuropsychiatric development of the children from the two groups. However, the group of children who received morphine compared to the second group, who did not receive it, had a decrease in body weight and head circumference, a tendency to decrease in the ability to socialize and adapt, and short-term memory disorders.
On the other hand, it has been found that neonatal pain can alter the cortisol secretion, especially in premature infants, with an increase in basal cortisol levels and a decrease in the ability to react to stress until the age of 18 months old. In these children, high levels of cortisol can lead to behavioral disorders with decreased attention span and a lower ability to adapt to stressful situations(49).
Conclusions and recommendations
The pain experience of newborns is similar to that of older children and adults. Pain is a reality in newborns who are being treated in neonatal intensive care units(50).
In each neonatal therapy service, there must be a pain control program for this category of patients. This program includes:
1. The routine evaluation of pain in newborns in intensive care using scales validated and adapted to the pathology of patients admitted to the respective ward.
2. Reducing as much as possible the number of pain-generating maneuvers within the therapeutic act practiced in the intensive care unit.
3. Establishing guidelines and practice protocols in order to prevent and reduce the intensity of pain in newborns by using nonpharmacological and pharmacological means of analgesia adapted to pain scores.
Analgesia must be practiced firstly preemptively and then curatively for any maneuver generating pain applied to newborns. Nonpharmacological measures (breastfeeding, non-nutritive suction, semi-flexed limb wrapping and wrapping, skin-to-skin contact) and pharmacological means (oral sucrose, topical EMLA anesthetics, block lidocaine, opioids, acetaminophen, ketorolacid, dexmed) should be used in section pain protocols.
The American Pediatric Society recommends the use of the following staged protocol in neonatal pain:
1. The use of nonpharmacological measures, such as wrapping newborns in the semi-bent position of the limbs or skin-to-skin contact to improve analgesia in any situation in which newborns are subjected to pain-generating maneuvers.
2. For newborns who have a heel prick or venous puncture for harvesting, it is recommended oral sucrose 24% (grade 1B). This can be combined with nonpharmacological measures, such as non-nutritive sucking, wrapping in a semi-flexed position, or skin-to-skin contact. Alternatives to orally administered sucrose are breastfeeding, breast milk or glucose. For these situations, acetaminophen is not recommended (grade 1B).
3. For newborns in which a more laborious puncture maneuver is performed, such as placing an arterial or venous line, or lumbar puncture, in addition to sucrose administration, it is recommended to use a topical EMLA anesthetic (grade 2B).
4. For ritual circumcision in male newborns, in addition to orally administered sucrose 24%, circular penile block or dorsal penile block is recommended rather than the use of local topical EMLA type (grade 2B).
5. For newborns undergoing more invasive pain-generating maneuvers, such as central venous placement, it is recommended that nonpharmacological measures be combined with local or topical anesthesia and/or the administration of systemic anesthetic drugs to produce adequate analgesia (grade 2B).
6. For newborns who have undergone surgery, it is recommended that they receive postoperative analgesia (grade 1B). This recommendation consists of combining nonpharmacological methods with systemically administered drugs, such as acetaminophen and opioids.
7. Morphine or fentanyl in continuous infusion is not recommended for routine sedation or pain control in mechanically ventilated newborns (grade 1B). Analgesia in these patients should be based on the individual assessment of the need for analgesia for each newborn(50).
Conflicts of interests: The authors declare no conflict of interests.