How can we improve pain relief in neonates?

The alleviation of pain is a basic and human right regardless of age. Thus, it seems unbelievable how long it took the medical community to realize that newborns are able to feel pain. In the past, there was an erroneous consensus that the immaturity of the nervous system in neonates was such that it precluded them from feeling pain. However, it has been shown that even premature neonates react purposely to noxious stimulation [1,2]. Furthermore, recent studies have shown that noxious stimuli elicit measurable cortical responses in neonates as young as 25 weeks gestational age [3,4]. Using near-infrared spectroscopy (NIRS) to measure blood and tissue oxygenation in the somatosensory cortex, Slater et al. demonstrated that premature infants, from 25 weeks postmenstrual age, are able to mount a localized hemodynamic cortical response to a noxious heel lance [4]. The specificity of the response was confirmed by comparing the responses to non-noxious tactile stimulation [4].

Bartocci et al. also monitored cerebral hemodynamics by NIRS in preterm neonates at 28–36 weeks gestation undergoing tactile, non-noxious and painful (venipuncture) stimuli, and found that somatosensory cortical activation occurs bilaterally following unilateral stimulation, and that pain related changes are more pronounced in preterm neonates at lower gestational ages and at higher postnatal ages [3]. These results suggest that infants do have the required neuronal connections to experience the affective components of pain and are not simply displaying reflex responses to nociception [5].

Long-term consequences of pain

Multiple lines of evidence suggest that repeated and prolonged pain exposure in neonates alters their subsequent pain processing, long-term development and behavior [6,7]. The type and extent of long-term effects probably depends on the developmental maturity of the infant at the time the pain occurred, other concomitant clinical factors, the length and extent of exposure to pain, and multiple environmental and contextual factors both concurrently at the time of pain exposure and ongoing during development [8]. Repetitive pain leads to altered pain sensitivity [9] with dampened behavioral responses to pain reflecting interrupted development [10,11] or heightened peripheral sensitivity [7,12]. Thus, the prevention of pain in critically ill neonates is not only an ethical obligation, but it also averts immediate and long-term adverse consequences [13].

Burden of procedural pain

Newborns routinely undergo painful invasive procedures, even after uncomplicated birth. For obvious reasons, these invasive procedures that cause pain or distress are more frequently performed on infants admitted to the neonatal intensive care unit (NICU). For sick babies, multiple studies have documented a high frequency of invasive procedures during neonatal intensive care, particularly in preterm neonates [14,15]. The most frequent procedures performed in NICUs are heel sticks, endotracheal suctions, and venous and arterial punctures [15,16].

Notwithstanding an increased awareness among clinicians regarding neonatal pain, management of procedural pain in neonates is not yet optimal. A prospective, multicenter study, conducted in a large geographically defined population, documented the epidemiology and management of neonatal painful and stressful procedures in neonates admitted to ICUs [16]. This study demonstrated that neonates undergo numerous painful and stressful procedures during the first 14 days of intensive care, that the frequency of painful procedures does not markedly decrease during the ICU stay, that some common procedures require four or more attempts to be terminated in almost a fifth of neonates, and that many of the documented painful procedures were not accompanied by analgesia. The mean number of painful and painful plus stressful procedures per day were 12 and 16, respectively; some neonates experiencing as many as 62 procedures per day [16]. Of all painful procedures, 2.1% were performed with specific preprocedural pharmacological-only therapy, 18.2% with nonpharmacological-only interventions, 20.8% with pharmacological, nonpharmacological or both types of therapy and 79.2% without specific analgesia; 34.2% were performed while the neonate was receiving concurrent analgesic or anesthetic infusions for other reasons. Prematurity, category of procedure, parental presence, surgery, daytime and day of procedure after the first day of admission were associated with greater use of specific preprocedural analgesia, whereas mechanical ventilation, noninvasive ventilation and administration of nonspecific concurrent analgesia were associated with lower use of specific preprocedural analgesia [16].

Neonatal pain relief is feasible

Numerous pharmacological and nonpharmacological treatments have been shown to be effective and safe for the alleviation of pain in neonates [17]. Several national [18] and international [17] societies have issued evidence-based guidelines for preventing or treating neonatal pain and its adverse consequences.

The goals of pain management in neonates are to minimize the pain experience and its physiological cost, and to maximize the newborn’s capacity to cope with and recover from the painful experience while maintaining the best benefit/risk ratio of the treatment. Nonpharmacological interventions, which comprise environmental and behavioral interventions, have a wide applicability for neonatal pain management alone or in combination with pharmacological treatments. These interventions are not necessarily substitutes or alternatives for pharmacological interventions, but rather are complementary. Nonpharmacological interventions can reduce neonatal pain indirectly by reducing the total amount of noxious stimuli to which infants are exposed, and directly by blocking nociceptive transduction or transmission, activation of descending inhibitory pathways or by activating attention and arousal systems that modulate pain [19].

One of the first strategies to relieve neonatal pain is to reduce the number of painful procedures performed in neonates. The American Academy of Pediatrics recently emphasized the need to incorporate a principle of minimizing the number of painful disruptions in neonatal care protocols [13]. Such strategies would aim at bundling interventions, eliminating unnecessary laboratory or radiographic procedures, using transcutaneous measurements when possible and minimizing the number of procedures performed after failed attempts [13]. The burden of procedural pain is greatly aggravated by multiple attempts in sick neonates. In the study by Carbajal et al., some common procedures (such as insertions of intravenous cannulas, central catheters or peripheral arterial lines) required four or more attempts in more than 18% of neonates [16]. Procedural techniques should also be modified in order to prevent neonatal pain [20]. Studies must be designed to determine to what extent common painful procedures are necessary, and to what degree it is possible to avoid pain, stress and discomfort while appropriately medically managing the neonates. There is a paucity of research in this area. For example, endotracheal suctioning could be performed on an individual need-basis rather than a routine scheduled-basis. In one study, when suction frequency was changed from every 6 to every 12 h during the initial ventilation of preterm neonates with respiratory distress syndrome, there was no increase in secretions or occluded tubes [21].

Obviously, analgesic treatments should be tailored to the invasiveness or presumed pain intensity of the procedure. For minor procedures, the combination of oral sucrose/glucose with other nonpharmacological pain-reduction methods (e.g., non-nutrive sucking) should be sufficient. For major procedures, while general nonpharmacological measures still apply, systemic analgesia with a rapidly acting opiate such as fentanyl is usually necessary. Topical anesthetics can be used to reduce pain associated with needle punctures but are ineffective for heel-stick pain.

Opioids have been increasingly used for sedation and analgesia in ventilated preterm neonates [22]. The analgesic effect of morphine on the acute pain caused by invasive procedures in preterm neonates remains controversial. While initial studies showed promising results [23], recent studies have found non-significant analgesic efficacy [24,25]. Thus, the administration of continuous morphine infusions to preterm neonates during the first days of life does not eliminate the need for other analgesic approaches (e.g., sucrose) that are effective against acute pain [25]. A recent systematic analysis of published clinical trials stated that more research in mechanically ventilated preterm and full-term neonates is needed before the routine management of analgesia and sedation with opiates and benzodiazepines can be placed on a scientific footing [22]. A great deal of work remains to be done to determine whether ongoing pharmacological treatment is beneficial or harmful to the neurodevelopment of preterm infants in the long run [8].

The administration of analgesic drugs for stressful, nonpainful procedures is not adequate. All analgesic agents have adverse effects that will certainly outweigh benefits in this context. When using opioids, for instance, clinicians should be aware of adverse effects such as respiratory depression, decreased gastrointestinal motility, hypotension, urinary retention and muscle rigidity [17]. Therapeutic but also toxic effects of analgesics and anesthetics in the immature brain [26] must be considered. Long-term effects of analgesic/anesthetic drugs depend on whether they are given in the presence or absence of painful stimulation [26]. Thus, the effects of surgery without anesthesia as well as the effects of anesthesia without surgery may be detrimental for the developing brain [26].

One important reason for the undertreatment of neonatal pain is the large gap that exists between published research results and routine clinical practice. Despite increased knowledge, improved options and available guidelines, pain management of neonates remains inadequate, promoted by the ineffective translation of research data into clinical practice. Recently, efforts have been directed to the use of proven quality improvement methods to develop a process to improve neonatal pain management collaboratively [27]. Sharek et al. reported one experience in which 12 centers formed an exploratory group to improve neonatal pain management. The exploratory group established group and site-specific goals and outcome measures for this project. Group members crafted a list of potentially better practices on the basis of the available literature, encouraged implementation of the potentially evidence-based better practices at individual sites, developed a database for sharing information and measured baseline outcomes. The collaborative use of quality improvement methods resulted in the creation of self-directed, efficient and effective processes to improve neonatal pain management. Group establishment of potentially better practices, collective and site-specific goals, and extensive baseline data resulted in accelerated implementation of clinical practices that would not likely occur outside a collaborative setting [27].

In conclusion, and in line with the American Academy of Pediatrics, the prevention of pain in neonates should be the goal of all caregivers [13]. Every healthcare facility caring for neonates should implement an effective pain-prevention program, which includes regular pain assessment, reduction of the number of painful procedures performed, use of combinations of sucrose/glucose with other nonpharmacological pain reduction methods (non-nutritive sucking, kangaroo care, swaddling and developmental care) for minor painful procedures and the use of topical anesthetics when time permits. Facilities providing neonatal surgery should have clear protocols to assess pain and administer effective and safe analgesia. In this context, opioids are the mainstay for postoperative analgesia. Finally, all major procedures, such as chest tube insertions or tracheal intubations, should include the prevention of pain by using systemic analgesia with a rapidly acting opiate accompanied, if necessary and relevant, by adequate general nonpharmacological measures [13].

Financial & competing interests disclosure

The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

No writing assistance was utilized in the production of this manuscript.