Evaluation and Treatment of Pain in Fetuses, Neonates and Children

The perception of pain is individual and differs between children and adults. The structures required to feel pain are developed at 24 weeks of gestation. However, pain assessment is complicated, especially in neonates, infants and preschool-age children. Clinical scales adapted to age are the most used methods for assessing and monitoring the degree of pain in children. They evaluate several behavioral and/or physiological parameters related to pain. Some monitors detect the physiological changes that occur in association with painful stimuli, but they do not yet have a clear clinical use. Multimodal analgesia is recommended for pain treatment with non-pharmacological and pharmacological interventions. It is necessary to establish pharmacotherapeutic protocols for analgesia adjusted to the acute or chronic, type and intensity of pain, as well as age. The most used analgesics in children are paracetamol, ibuprofen, dipyrone, opioids (morphine and fentanyl) and local anesthetics. Patient-controlled analgesia is an adequate alternative for adolescent and older children in specific situations, such as after surgery. In patients with severe or persistent pain, it is very important to consult with specific pain services.


Introduction
Pain can be defined as "an unpleasant sensory and emotional experience associated with actual or potential tissue damage or described in terms of such damage" [1]. Pain consists of two features: nociception and emotional reaction.
Perception of pain is individual and differs between children and adults. The sensation of pain is not only influenced by neurophysiological mechanisms but also by both psychological aspects and the environment [2]. These aspects affect and modulate the nociceptive sensation so that the same pathological situation may cause very different painful perceptions depending on the individual. In general, children pay maximum attention to pain, which could lead increased anxiety and fear of the painful sensation, magnifying the sensory experience [3,4].
Therefore, different pain management strategies are required in children than in adults, highlighting the importance of prior preparation and non-pharmacological interventions before performing any painful procedure in a child [5,6] (Table 1).

Fetal Pain
Pain is a conscious and subjective experience and not just a response to noxious stimuli. For human beings to be able to experience pain, a series of physiologically mature neurological structures is needed. On the other hand, for the experience of pain to occur, other cognitive processes related to the state of consciousness and memory must be developed, which, in turn, allow an event to be discriminated as painful [7][8][9][10][11].
The development of neural pathways involved in pain pathophysiology begins early in fetal life, around the seventh week of gestation, followed by the development of the thalamus and neural connections in the cerebral cortex [7][8][9]. Therefore, some authors suggest that fetal pain does not occur before 24 weeks of gestation because the structures of the central nervous system (CNS) required for pain perception. such as the cortex, spinal cord and thalamus are not fully developed [10]. However, other authors argue that pain perception can occur, mediated by developmental structures, such as the subplate, between 12 and 20 weeks of gestation [11][12][13][14]. Additionally, behavioral changes associated with pain, such as simple motor responses, including crying and facial expressions, are described in fetuses and very premature neonates [15,16].

Fetal Pain Evaluation
Several physiological reactions in fetuses, such as crying, avoidance or changes in the levels of stress hormones, can be interpreted as signals of pain.
Ultrasound investigation has enabled the acquisition of behavioral characteristics in fetuses, such as crying [20,21], as well as fetal facial expressions of acute pain in surgery [22], as well as fetal movement in response to contact with an amniocentesis needle [23].
Fetuses exposed to a prolonged painful invasive procedures have increased concentrations of cortisol and beta endorphins in plasma [24,25].

Treatment of Fetal Pain in Fetal Surgery
Treatment of fetal pain is especially significant in fetal surgery. There are three main administration routes of fetal anesthesia and analgesia: uteroplacental transfer; intravenous, usually by the umbilical line; or intramuscularly [26]. Volatile anesthetics and opioids limit the fetal stress response, although they can produce cardiovascular fetal depression, although likely without side effects for short procedures [27].
Most authors use deep general maternal anesthesia in ex-utero intrapartum therapy surgery to anesthetic the mother and the fetus and in fetoscopies the preferences are administrate the anesthesia and analgesia directly to the fetus, usually applying an intramuscular route or umbilical line [28][29][30][31][32][33][34][35][36].

Neonatal Pain
After painful stimulus, newborns have demonstrated in MRI scans that brain regions encoding sensory and affective components of pain responses are similar to those in adults [37].
Excessive or maintained pain exposure can be detrimental, causing adverse physiological effects and even long-term consequences [38][39][40]. Preterm infants, after experiencing pain, were reported to suffer hyperalgesia and allodynia, producing prolonged stress [41].
Infants born very preterm (<32 weeks), have received many pain-related insults in a vulnerable cerebral period, require special attention [38]. Repeated pain-related stress in very premature newborns is associated with alteration of brain development during the neonatal period, [42] as well as later functional cortical activity impairment with thinning of the brain cortex, white matter microstructure alterations and cognitive outcome at school age [43,44].

Pain in Children
Children usually feel pain differently than adults. The American Academy of Pediatrics (AAP) and the American Pain Society provided a general definition of pediatric pain: "the concept of pain and suffering goes far beyond a simple sensory experience. There are emotional, cognitive and behavioral components, along with developmental, environmental and sociocultural aspects" [45]. This definition underlines the importance of the subjectivity of pain [46]. Fear and anxiety produce suffering and increase the perception of pain in children, especially the fear of separation from their parents. An important goal of pain management is to eliminate the suffering associated with pain.

Concepts
The first step in the treatment of pain is its detection; several circumstances must first be taken into account: -The characteristics of the child: age, sex, sociocultural level and mood. - The characteristics of the pain: form of onset, intensity, evolution, duration, etiology and consequences that may be triggered [47].
The assessment of pain in children is complex, specifically in neonates, infants and preschool-aged children, because the expression of pain is undifferentiated, so it is often not possible to distinguish between pain, irritability and anxiety. Because they are not verbal, pain assessment tools rely on surrogated measures of physiologic, behavioral and biobehavioral responses to pain.
The most frequent physiologic indicators of pain are changes in heart and respiratory rate, blood pressure and oxygen saturation. The use of vital signs alone is not adequate because neonates and infants cannot maintain an autonomic response to pain and other factors, such a mechanical ventilation and drugs [48]. These indicators are also affected by other physiological stimuli, such a hypovolemia or fever.
The most used indicators are crying, facial activity, body movements, resting positions, agitation, consolability and sleeplessness. The assessment of these behavioral indicators depends on gestational age, mechanical ventilation and pharmacological treatment, and neurologic impairment and neuromuscular blockade may also decrease or alter responses to pain in critically ill children.

Neonatal Pain Assessment Tools
Several neonatal pain assessment tools are available [49][50][51]. Only three pain scales, PIPP-R, N-PASS and BPSN, are adapted to premature infants. The most commonly used pain scales are summarized in Table 2 [48,52]. Pain assessment tools should be selected with consideration of the population (full-term vs. preterm), context and type of pain (procedural vs. postoperative) [51,52].  Most tools adequately assess acute pain but not persistent or prolonged pain. Only two scales are adequate for prolonged pain (N-PASS and EDIN) [53]. The COMFORTneo scale was reported to be useful for evaluation of prolonged pain in [48].
Most parameters evaluated by these tools are subjective and require observation and recording in real time.
Other tools, such as neuroimaging (functional magnetic resonance imaging and nearinfrared spectroscopy) and neurophysiologic techniques (amplitude-integrated electroencephalography, changes in skin conductance and heart rate variability) during acute or prolonged pain, were studied in [44,51]. Hormonal markers of stress, such as cortisol and parameters of oxidative stress, increase with pain stimuli, but they are not used in clinical settings at this time.

Clinical Scales
Clinical scales are the most commonly used instruments for pain assessment and monitoring [54]. The most frequently used are numerical, visual analogue or graphic scales adapted to the patient's age. Through these scales, the patient can indicate the intensity of pain or the observer estimates the pain intensity based on the child's behavior.
In the preverbal stage (1 month to 3 years), the scales mainly use facial expression and motor and physiological responses, such as crying. In the verbal stage (3 to 8 years) self-report can be tested using photographs and drawings of faces. From the age of 8 years onwards, verbal scale, numerical scale and graphic scales, as well as the visual analogue scale, can be used [55][56][57].
The most commonly used scales for the assessment of pain in child who are able to communicate are: The visual analogue scale (VAS), which is represented on a 10 cm line between 0 (no pain) and 10 (worst pain imaginable). VAS < 4 indicates mild or mild-moderate pain, 4-6 indicates moderate-severe pain and >6 indicates severe pain.

2.
The verbal numeric scale (VNS): the child expresses their perception of pain from 0 (no pain) to 10 (worst pain imaginable).

3.
Graphic scales, which may consist of drawings of happy faces that change to sad according to the degree of pain, columns or thermometers that are more or less filled in, color ranges, etc.
In most children admitted to pediatric intensive care units (PICUs), it is not possible to use such scales, as many of the patients are sedated and unable to communicate. The same applies to children under 3 years of age in the preverbal stage. In such cases, the identification of pain requires tools based on changes in physiological parameters, facial expression or motor response to estimate the degree of pain [54,58].
Two scales have been validated for use in critically ill children: 1.
The FLACC scale (face, leg, activity, cry, consolability) (Table 3), which considers facial expression, leg attitude, spontaneous activity, the presence and characteristics of crying and the ability to comfort or consolability, with scores ranging between 0 and 2 points for each item. A value of 0 indicates no pain, and scores of 9-10 indicate unbearable pain.

2.
MAPS scale (multidimensional assessment pain scale) ( Table 4). This scale is based on the observation of body movements and facial expression. It is a multidimensional scale that also includes physiological parameters, such as breathing, changes in blood pressure (BP) and heart rate (HR). Similar to the FLACC scale, it classifies pain on a scale from 0 (no pain) to 9-10 (unbearable pain) [59].

Objective Pain Monitoring
Some monitors detect physiological changes that occur in association with painful stimuli and stress based on electromyograms, plethysmography, electrocardiograms, skin conductance or measurement of the diameter of the pupil. Such monitors can quantify the intensity of pain and the response to treatment. These parameters are objective, noninvasive, relatively easy to use and can be used at the patient's bedside. However, they are unspecific (other non-pain stimulus, such as agitation, fear and stress, produce the same response) and are expensive. Therefore, they have not yet been applied in clinical settings [60,61]. Such monitors include: Conductance skin impedance monitor (Medstorm Innovations, Oslo, Norway), which assesses the stress response through changes in skin conductance produced by sympathetic stimulation. It is non-invasive with rapid response but does not differentiate between agitation and pain and it is not able to measure baseline stress [62].
The analgesia nociception index (ANI), which is based on the RR variability of ECG intervals. This is a continuous line measurement of parasympathetic tone, which is part of the autonomic nervous system that assesses nociception [63,64].
The pain pupillary index (PPI) measurement, which provides real-time information from a video camera and infrared pupillary diameter [65].

Treatment
In the 2010 Montreal Declaration, access to pain treatment was declared a fundamental human right, constituting a violation of human rights not to treat pain [66][67][68][69][70][71].
It is important to develop treatment protocols to prevent procedural pain by combining pharmacological and non-pharmacological strategies. The intensity of analgesia should be adjusted to the intensity of the potential pain and ensure adequate supervision and monitoring [72,73].

Non-Pharmacological Analgesia
The aim of non-pharmacological analgesia is to increase patient comfort and reduce stress related to diagnostic or therapeutic procedures [74,75]. It should not be used as a substitute for pharmacological treatment but should be combined with pharmacological treatment [76][77][78].
Mechanisms of action are not yet well explained, but such interventions likely reduce the sensitivity of the nociceptive system. Some such measures release endogenous endorphins, activating opioid-enhancing neuropeptides inducing distraction from pain.
Such measures can be classified based on the mechanism of action [79]. Environmental strategies: low noise and lighting, soothing smells or clustering procedures to avoid over handling by modifying the environment to reduce sensibility to pain.
Cognitive strategies, including distraction methods, particularly used in older children. Behavioral strategies, including direct (rocking) or indirect (non-nutritive sucking) manipulation of the infant's body. These techniques produce relaxing tactile stimuli before, during and/or after the painful procedure to reduce pain [80,81].
The main non-pharmacological strategies used in neonates and children are: Posture and mobilization: Mobilizations are applied using pillows or devices to help increase well-being [79]. This strategy is effective in term and preterm babies.
Breastfeeding or expressed breast milk: breastfeeding [82] is one of the most effective non-pharmacological strategies. Supplemental breast milk is less effective than breastfeeding and sucrose [83,84].
Oral sucrose and glucose [85]: It remains unclear whether sucrose suppresses the responses to pain. It should be administered 2 min before the procedure, and the effect lasts approximately 4 min [86].
Non-nutritive sucking [79], which can be achieved with a pacifier, breastfeeding after extraction or with the finger. It is effective in term and preterm babies.
Skin-to-skin contact (kangaroo care) [87], which is effective for pain relief in neonates.
Cognitive reformulation: in older children, recognize thoughts that increase pain and replace them with positive thoughts.
Music therapy [90]: it can improve heart rate, feeding and sucking in preterm infants.
Mother's voice: some studies have demonstrated analgesic qualities in neonates that resulting from exposure to the mother's voice [91].
The main advantages of non-pharmacological treatments include ease of learning and performance, as well as safety and feasibility. However, no studies have been conducted to date analyzing the long-term effects of these techniques [81].

Concepts
The responsible physician must establish the treatment, depending on the age, type and intensity of the pain (Figures 1 and 2), as well as the underlying disease, and assess the following aspects: • Patient's age and associated pathology (cardiorespiratory, renal and hepatic function); • Check for interactions of analgesics with other medications the patient is receiving; and • Prevent and treat the most common side effects of analgesics [97].     [96]. Figure 2. The analgesic ladder proposed by the World Health Organization (WHO) for children [96].
An analgesic regimen and analgesic rescue should be prescribed according to the intensity of pain [98] (Figure 2). Pharmacotherapeutic protocols for pediatric pain need to be established according to intensity, age and the form of drug administration [99][100][101][102].

Pharmacological Analgesia in Neonates
The most used pharmacological analgesia in neonates are paracetamol, opioids and local anesthetics [44,103]. The doses and effects of most frequent drugs used in neonates are summarized in Table 5 [104][105][106][107][108][109][110][111][112].  Pharmacological pain management also involves risks of adverse effects, such as respiratory depression or neurotoxicity. This association is particularly evident for prolonged or repeated exposure to analgosedative drugs [38,104].
Opioids should not be administered routinely in neonates with mechanical ventilation, owing to the possible neurotoxicity of opioids in the developing brain [38,[104][105][106]. Opioid administration should be based on clinical evaluation and scales [107]. The use of combined analgesic regimens permits a reduction in the dose of opioids by maintaining adequate analgesia with reduced frequency of side effects [107,108].

Other Methods
Patients with severe pain that is not well controlled despite powerful opioids at full dosages can become candidates for special anesthesia and regional analgesia techniques [94]. Patients with high tolerance to opioids, severe adverse effects, chest pain with respiratory compromise or chronic pain may also be candidates for these techniques.

PCA Pumps
From the age of 6-7 years, well-educated children with adequate cognitive abilities are able to self-administer analgesics by means of a PCA-programmed device [128]. The most commonly used modality in pediatrics is the mixed mode, whereby the pump administers a minimal basal continuous infusion, and if this is not sufficient, the patient can self-administer boluses until pain is eliminated or reduced. The system has important psychological advantages, especially for adolescents, by improving the perception of control over their own pain and reducing unnecessary analgesic consumption and side effects of opioid drugs. The most commonly used opioids in pediatrics are morphine, fentanyl, hydromorphone, oxycodone and tramadol. In pediatric patients under 6 years of age or without adequate cognitive capacity, the "PCA by proxy" modality can be used, whereby the nurse administers the analgesic rescue boluses ("nurse PCA") or even selected parents ("parent PCA"). 6.4.2. Regional and Interventional Analgesia Techniques Regional techniques have been applied in children with satisfactory results [129][130][131]. The most common technique is epidural analgesia, which can be given at any level of the neuroaxis and which, by insertion of a catheter, allows analgesia to be maintained for several days or even weeks if necessary. In such cases, the catheter must be tunneled. Other catheter-based analgesia techniques, such as paravertebral, fascial and incisional analgesia use, have increased in popularity in pediatric patients [128] (Table 9). In all such techniques, local anesthetics are administered alone or in combination with adjuvants, such as opioids, clonidine, dexmedetomidine or corticosteroids, which enhance their duration and effect. Regional and invasive techniques provide pain elimination without causing CNS side effects, such as those produced by opioids.

Pain Assessment and Treatment Algorithm
The objective of the evaluation of pain and stress is to detect pain and determine the appropriate analgesic dose for each patient without side effects of treatment.
The first step to individualize the treatment of each patient is to implement a validated pain assessment tool, usually clinical scales (the fifth vital sign).
The second step is to evaluate other indicators of the patient, environment and therapies. To establish the treatment of pain, the assessment of pain, the environment, the individual characteristics of the patient, the underlying disease and other treatments must be taken into account.
It is not helpful to implement pain assessment as a stand-alone procedure. Therefore, pain assessment must be followed by a stepped treatment protocol adapted to the patient, as well as a structured follow-up and with multidisciplinary responsibility.
It is recommended to perform multimodal analgesia with non-pharmacological and/or pharmacological interventions. Subsequently, the patient must be re-evaluated to check the response and adjust the medications at the lowest dose necessary at each moment. Figures 1 and 2 summarize the algorithm for the assessment and treatment of pain in neonates and children.

Conclusions
Pain assessment is complicated, especially in neonates, infants and preschool-aged children. We recommend using clinical scales adapted to the age of the patient to assess and monitor the degree of pain in children.
We recommend multimodal analgesia with non-pharmacological and pharmacological interventions for pain treatment and the establishment of pharmacotherapeutic protocols for analgesia adjusted to the acute or chronic, type and intensity of pain, as well as the age of the patient. Patient-controlled analgesia is an adequate alternative for adolescents and older children in specific situations, such as after surgery. Patients with severe or persistent pain should be treated in consultation with specific pain services.
The follow-up of structured protocols will enable early diagnosis of pain and treatment adapted to the intensity and characteristics of the pain and of the child, which can reduce suffering and contribute improved prognosis.
Author Contributions: All authors contributed to the conceptualization and writing. All authors have read and agreed to the published version of the manuscript.

Conflicts of Interest:
The authors declare no conflict of interest.