43 Acute Pain
THE PRACTICE OF PAIN MANAGEMENT in children continues to advance. Since the early 1980s, clinicians have come to recognize that neonates and infants experience pain and process those learning experiences. Research has demonstrated the adverse long-term consequences of unrelieved pain, including harmful neuroendocrine responses, disrupted eating and sleep cycles, and increased pain perception during subsequent painful experiences.1–3 Disparities in pain treatment led organizations, such as the Agency for Healthcare Research and Quality (AHRQ) and the American Pain Society (APS), to provide guidelines and the Joint Commission (formerly the Joint Commission on Accreditation of Healthcare Organizations [JCAHO]) to issue mandates that further enhanced the practice of pediatric pain management.4–6 The availability of reliable and valid pain assessment tools for children and governmental incentives encouraged the inclusion of children in analgesic drug trials. Sufficient research data regarding children’s pain became available, making it possible to develop pediatric evidence-based pain management guidelines. Many children’s hospitals now have dedicated specialized multidisciplinary pain teams that manage acute and chronic pain. The increasing use of regional analgesia techniques led to the development of the Pediatric Regional Anesthesia Network (PRAN), a registry of practice patterns and complications of regional anesthetics in children. An enormous expansion of the breadth of techniques for acute pain management in children, the establishment of pediatric pain services, and the investigation and introduction of innovative modalities of therapy all attest to the importance accorded to this aspect of perioperative care.
Developmental Neurobiology of Pain
Investigators have examined indices suggestive of cortical activation, including near-infrared spectroscopy7 and electroencephalography,8 in response to noxious events. Using near-infrared spectroscopy, a unilateral heelstick (performed for clinical purposes) produces signal changes suggestive of contralateral cortical activation.7–9
Despite these lines of evidence, the nature of pain in neonates, viewed as conscious suffering, remains unknown. Other investigators have looked for long-term consequences of painful events (with or without treatment) in humans and in animal models. Despite attempts by these investigators to correct for confounding factors, in our view, the interpretation of these studies, especially in humans, should be quite cautious. Neonates who undergo painful procedures are commonly those who are more medically ill. It appears difficult to distinguish consequences of pain per se from the consequences of other factors, such as prematurity, critical illness (including episodes of hypoxia or ischemia), deprivation of tactile and social contact, and nutritional deprivation. Many clinicians and investigators have adopted the view that, in the absence of better information about either the nature of suffering experienced by neonates or the potential adverse consequences of pain in terms of long-term development, caregivers should err on the side of providing, rather than withholding, analgesia. Although this is a compelling perspective, it is important to highlight three concerns: (1) in general, available studies have had difficulty showing effects of routine administration of analgesia (e.g., morphine infusions) on immediate behavioral indices of distress in neonates undergoing intensive care; (2) repeated or prolonged administration of anesthetics and sedatives in animal models have been shown to have deleterious effects on brain development, (the human implications of these animal studies remain unclear at this time [see also Chapters 6 and 23]);10–16 and (3) as will be detailed later, younger organisms develop tolerance to opioids and benzodiazepines more rapidly than older organisms, so that the management of tolerance and withdrawal has now become a nearly universal consequence of prolonged administration of these medications to critically ill neonates, infants, and children.
Pain Assessment
The International Association for the Study of Pain (IASP) has defined pain as an unpleasant sensory and emotional experience associated with actual or potential tissue damage, or described in terms of such damage. The IASP and others have acknowledged that the inability to communicate verbally, as in the preverbal, nonverbal, or the cognitively impaired, does not preclude the possibility that an individual is experiencing pain and is in need of appropriate pain management.17,18 Physicians and nurses have been very creative in developing tools to evaluate pain in children of all ages; most of these tools are discussed below. Table 43-1 summarizes various pain assessment tools in terms of appropriate age, target population, ease of use, and practicality.
TABLE 43-1 Appropriate Pain Assessment Measures by Age-Group: Self Report, Observational/Behavior, and for the Cognitively Impaired
| Self-Report Tools | Appropriate Age-Groups | Comments |
|---|---|---|
| Faces Pain Scale | 3-18 years | Simple and quick to use; extensively validated in healthy schoolchildren with postoperative and cancer pain |
| Oucher | 3-18 years | Photographic for ≥3-year-olds, numeric 0-10 scale for ≥6-year-olds; less clinical utility and feasibility compared to other faces scales |
| Manchester Pain Scale | 3-18 years | Panda bear faces eliminate gender and ethnic bias; tested in emergency department setting |
| Computer Face Scale | 4-18 years | Offers option for continuous rather than categorical format; good construct validity; preferred by children over the Wong Baker Faces Scale; further testing needed |
| Sydney Animated Facial Expression Scale (SAFE) | 4-18 years | Animated version of Faces Pain Scale; rated by children as easiest to use; no psychometric advantage compared to other scales |
| Visual Analog Scale (VAS) | 6-18 years | Simple and quick to use; requires the concepts of order, magnitude, and seriation (the ability to place or visualize in series); widely used across settings; preferred to other self-report tools by children ≥8 years old and adolescents |
| Numeric Rating Scale (NRS) | 7-18 years | Simplest and most commonly used in clinical as well as research settings |
| Observational/Behavioral Measures | ||
| Comfort Scale | 0-18 years | Developed for use in intensive care settings; useful in mechanically ventilated children and in the postoperative setting |
| Face, Legs, Activity, Cry, Consolability (FLACC) | 2 months to 7 years | Excellent pragmatic and psychometric qualities; widely adopted in clinical and research settings; has been translated into several languages other than English |
| Children’s Hospital of Eastern Ontario Pain Scale (CHEOPS) | 1-7 years | Good psychometric properties; lengthy with inconsistent scoring among categories; cumbersome; extensively used both in clinical and research settings |
| Cognitively Impaired Children | ||
| Revised FLACC | All ages | Allows for scoring individualized pain behaviors; good psychometric properties; highest clinical utility compared to the Non-Communicating Children’s Pain Checklist−Postoperative Version (NCCPC-PV) and Nurses’ Assessment of Pain Intensity (NAPI) |
| Non-Communicating Children’s Pain Checklist (NCCPC) | All ages | Requires 5-minute observation period; comprehensive but cumbersome; used in clinical and research setting |
| University of Wisconsin Pain Scale | All ages | Inconsistent scoring style compared to other clinical scoring systems; scoring style may permit flexibility but limits precision |
| The Pain Indicator for Communicatively Impaired Children | All ages | Useful for pain assessment in cognitively impaired children in the home setting. |
Self-Report Measures
Because pain is a subjective experience, self-report measures, in which a patient is asked to quantify the severity of the pain between 0 (no pain) and 10 (maximum pain), are considered to most accurately reflect acute pain. Because many children lack the cognitive skills to use such scales, pain assessment measures that include developmentally appropriate self-report tools, behavioral-observational tools, and physiologic-biologic measures have been developed. Given the multidimensional nature of the individual pain experience, and the complexity and inherent biases associated with self-report, use of unidimensional numeric scales alone to reflect pain is overly simplistic.19–22 Therefore, regardless of the measure used, it must be emphasized that a complete pain assessment is more than just a number attempting to quantify the severity of pain. Estimating the impact of pain on the suffering and the quality of the individual’s life, targeting appropriate therapeutic measures, and evaluating the effectiveness of such measures are additional key components of a global and ongoing pain assessment and treatment strategy.
Faces Pain Scales
Faces pain scales comprise a series of line diagrams of faces with expressions of increasing distress.23–28 Some versions have a smiling face whereas others have a neutral face to represent the “no pain” end of the scale (Fig. 43-1). Unlike the numeric scales, the faces scales do not require the concept of magnitude or seriation and can therefore be used by preschool aged children. The Wong Baker Faces Pain Scale has been extensively studied and its reliability and validity confirmed in children 3 to 18 years of age. Strong correlations have been reported between the Wong Baker Scale scores and other faces scales, the Visual Analog Scale (VAS), as well as nurses’ ratings based on behavior.29–32 Recent data suggest that versions with the smiling face at the no-pain end of the spectrum, such as the Wong Baker Scale, may overestimate pain because children without pain, but with distress from other sources, may be reluctant to choose the smiling face.28 The Wong-Baker scale was preferred by children to the numeric rating scale, the graphic rating scale, and the Color Analog Scale.23,25,30,33 Overall, the Faces Pain Scale–Revised is the faces scale with the largest support for its validity.34
FIGURE 43-1 A, The Wong-Baker Faces Pain Scale. B, The Bieri Faces Pain Scale.
(B modified from Bieri D, Reeve RA, Champion GD, et al. The Faces Pain Scale for the self-assessment of the severity of pain experienced by children: development, initial validation, and preliminary investigation for ratio scale properties. Pain 1990;41:139-50.)
Oucher
The Oucher combines a photographic faces scale with a 0 to 10 vertical numeric scale. Different versions of the Oucher incorporate photographs of Caucasian, African American, Asian, and Hispanic children to minimize biases related to ethnicity (Fig. 43-2 and E-Fig. 43-1, A to C).35,36 Strong correlations have been demonstrated between Oucher scores and those obtained using the Pieces of Hurt tool, faces pain scales, and VAS.37–39 The Oucher also demonstrates responsivity, that is, the ability to detect change in pain intensity before and after surgery and after administration of an analgesic.37 The numerical rating component of the Oucher requires that the child be able to count to 10 and has been used successfully in children older than 6 years.
The Manchester Pain Scale
The Manchester Pain Scale (Fig. 43-3), which was designed to overcome the gender and ethnic biases of the Oucher, is composed of a pain ruler on which panda facial images are superimposed.40 It includes verbal descriptors of the extent of pain and how pain possibly interferes with normal functions. A study of children presenting to an emergency department found a very good correlation between scores assigned using the Manchester Scale and the Oucher.40
Novel Self-Report Tools
These self-report tools use a categorical format and the static faces do not allow for “fine tuning” of the ratings before a final assessment regarding the severity of pain is reached.41 In recent years, there has been interest in developing computer-based self-report assessment tools that use a continuous rather than categorical format.42
The Computer Face Scale allows the child to adjust the shape of the mouth of a cartoon face from smiling to frowning and simultaneously to adjust the eyes from completely open to completely closed
.41,43 The suggested benefits of this scale include increased sensitivity (given the ability to select from a wide range of faces) and computerized storage of the results, with ready access and data display. Preliminary work with this scale has demonstrated its construct validity and it was preferred by children over the Wong Baker Faces Scale.41
The Sydney Animated Facial Expression Scale (SAFE) is an animated version of the Faces Pain Scale44 and comprises of a series of 101 faces (Video 43-1
). To administer this scale, the child pushes the left or right arrow key on a computer causing the expression of the single face to change until it corresponds with the child’s pain intensity (www.usask.ca/childpain/research/safe). At this point, a keystroke records a score between 0 and 100. The SAFE scale was rated to be easiest to use by children aged 4 to 16 years compared with other scales, including the Faces Pain Scale, the Color Analog Scale, and Pieces of Hurt,45 although it offered no psychometric advantage over the other scales. At this time, further research with this tool is needed before its role can be clearly defined.
Numeric Scales
Visual Analog Scale
Several versions of the VAS are available, including horizontal and vertical lines, word anchors representing extremes of pain, and lines with divisions and numeric values (Fig. 43-4). When using the vertical versions of this scale, the severity of the pain increases as one ascends the ladder. Although moderate to strong correlations have been reported between the VAS, faces pain scales, and the Oucher,37,46 the effect of user age on VAS ratings are conflicting.
Numeric Rating Scale
The Numeric Rating Scale (NRS) is the simplest and most commonly used numeric scale in which the child rates the pain from 0 (no pain) to 10 (worst pain). Its validity has been established with good correlations between NRS and Faces Pain Scale-Revised scores in children 7 to 17 years of age and NRS and VAS scores in children 9 to 17 years of age.47 An important caveat when using numeric scales is to be sure of the denominator that the child is using. For example a pain score of 9 on a 0 to 100 scale would reflect mild pain and may not require treatment whereas a score of 9 on a 0 to 10 scale would reflect severe pain that warrants aggressive treatment.
Selection Criteria
Selection of a self-report tool for a child requires careful consideration of the age and cognitive and developmental level. Figure 43-5 depicts the percentages of children of different ages who are able to self-report their pain and the tools most appropriate for various age ranges. Children who are unable to use a self-report tool may be able to report their pain intensity using simple words, such as “small,” “medium,” and “big.” However, self-reports of pain are subject to the modulating influences of a number of factors, including the child’s previous pain experience and response to treatment, psychosocial factors, and parental preferences and influences. In many cases, therefore, it may be necessary to complement self-reported pain scores with behavioral observations, particularly in preschool-aged children. Regardless of the tool selected, assessment of postoperative pain is greatly facilitated by the introduction of the concept of rating pain and of the tool itself during the preoperative preparation of the child.
Observational-Behavioral Measures
Despite several age-appropriate methods for self-reporting, assessing pain in children who are unable or unwilling to self-report depends on observations of their behaviors. Five behaviors that have been shown to be reliable, specific, and sensitive when predicting analgesic requirements are facial expression, vocalization or cry, leg posture, body posture, and motor restlessness.48 Variations in these behaviors have been used in several observational pain tools. Table 43-2 describes the content validity of some of the observational tools that are commonly used in clinical practice. Behavior checklists provide a list of pain behaviors that are marked as present or absent and the extent of pain is estimated on the basis of the number of behaviors present at the time of the assessment.49,50 Behavior rating scales also incorporate a rating of the intensity or frequency and duration of each behavior.51 Global rating scales provide a rating of the observer’s global impression of the child’s pain.
TABLE 43-2 Content Validity of Behavioral Pain Tools: Categories of Behavior in Pain Assessment Tools
Children’s Hospital of Eastern Ontario Pain Scale
The Children’s Hospital of Eastern Ontario Pain Scale (CHEOPS), one of the earliest behavioral rating scales (Table 43-3),52 incorporates six categories of behavior scored individually from 0 to 2 or 1 to 3 and then sums them to provide a pain score ranging from 4 to 13. Scores of 6 or less indicate no pain. Its validity and reliability for brief painful events and for postoperative pain has been well established, with good to excellent correlations with faces pain scales and the VAS.46,53 However, the time required to complete the evaluation and inconsistent scoring among categories of the CHEOPS makes it cumbersome and impractical to use in a busy clinical setting.
Face, Legs, Activity, Cry, Consolability Scale
The Face, Legs, Activity, Cry, Consolability (FLACC) scale was developed in an effort to improve on the pragmatic qualities of the existing behavioral pain tools by providing a simple framework for quantifying pain behaviors in children.51 This tool includes five categories of behaviors previously found to reliably correlate with pain in young children, including: facial expression, leg movement, activity, cry, and consolability (Table 43-4).48 The acronym FLACC facilitates recall of these categories, each of which is scored from 0 to 2 to provide a total pain score ranging from 0 to 10. The FLACC tool has been extensively tested and determined to have good inter-rater reliability and excellent validity based on changes in pain scores from before to after analgesic administration and excellent correlation with the Objective Pain Scale (OPS), the CHEOPS, the Toddler Preschool Preoperative Pain Scale (TPPPS), and good correlation with self-reported pain scores using faces pain scales.51,53–55 The FLACC scale has been translated into several languages, including Chinese, Swedish, French, Italian, Portuguese, Norwegian, and Thai.
Comfort Scale
The Comfort scale (Table 43-5), developed for use in an intensive care setting, consists of six behavioral and two physiologic measures, each of which has five response categories, thereby allowing detection of subtle changes in the child’s distress.56 Initial evaluation of the Comfort scale found acceptable inter-rater reliability and good correlations with VAS scores in 37 mechanically ventilated infants.56 Another study evaluated the reliability and validity of the Comfort scale as a postoperative pain instrument in children after thoracic or abdominal surgery.57 This study found good to excellent inter-rater agreement for all categories except respiratory response, for which there was moderate agreement. Additionally, strong correlations between Comfort and VAS pain scores support the use of the Comfort scale as a postoperative pain measurement instrument in children.
After a systematic review of observational pain measures, the FLACC and the CHEOPS52 scales were recommended for assessment of pain associated with medical procedures, the FLACC for postoperative pain, and the Comfort Scale for pain in children in critical care.19 Despite the extensive science supporting the use of behavioral tools, it may be difficult to separate behaviors caused by pain from those caused by other sources of distress in some children.58 Accurate pain assessment in children, therefore, requires careful consideration of the context of the behaviors. Input from the parents or caregivers may be valuable as proxy measures, although some parents may lose objectivity in such a situation. Similarly, a regular caregiver may best assess older children with significant developmental delay. When in doubt regarding the source of distress, a trial of analgesics is appropriate and may be both diagnostic and therapeutic.
Limitations of PAIN Assessment
It remains unclear whether integration of routine pain assessment into clinical practice significantly improves patient outcomes. A critical review of the studies that addressed this question determined that in 2 of 6 studies, children experienced a reduction in pain intensity when a standardized pain assessment tool was used, in 2 studies there was no change in pain intensity, and in 2 studies pain intensity decreased when pain assessment was combined with pain management interventions.59 Studies that examined sustainability of the benefits over time reported conflicting results, and most studies were identified to have major methodologic problems.60,61 Additional investigation is required to determine whether routine pain assessment has any effect on pain outcomes.
Despite the large body of evidence supporting the psychometric properties of numerous structured pain assessment tools described previously and elsewhere, there remains considerable variability in the interpretation of the clinical relevance of pain scores.22 Attempts have been made to define what range of pain scores is associated with a perceived need for medicine or what magnitude of change in pain score is associated with a perception of better or worse pain.62–64 A survey of 6- to 16-year-old hospitalized children found that a median pain score of 3 on a 0-to-6 Faces Pain Scale was associated with the child’s perceived need for medicine.62 Others have reported that a 10-mm change in a 0-to-100-mm VAS score was the minimum difference whereby children in the emergency department perceived their pain to be slightly better or slightly worse.63 In the postoperative period, children with a median pain score of 6 on a 0-to-10 NRS scale perceived the need for an analgesic whereas those with a score of 3 felt there was “no need” for treatment.64 In addition, children felt “a little better” or “worse” if the NRS scale changed by at least 1. Despite these findings, there was large variability and overlap in scores associated with these outcomes.
It has been suggested that the widespread adoption of a pain score as the fifth vital sign may contribute to the overprescribing of analgesics and sedatives.65 A review of trauma center site surveys reported a fivefold increase in deaths from excessive pain medicines during two time periods (1994 through 1998 and 2000 through 2004). Evaluations of the effectiveness of pain treatment algorithms based on numerical pain scores have yielded conflicting results. One study reported increased prescription for opioid and nonopioid analgesics, an increased administration of nonopioids, and reduced pain scores in children who received postoperative pain treatment based on a pain score–based algorithm.66 Children whose pain management was algorithm-based experienced more nausea, but no other adverse effects. In contrast, hospitalized adults whose pain management was based on a numerical pain treatment algorithm, experienced a twofold increase in episodes of oversedation and a 49% increase in opioid-related adverse drug events.67 This latter study highlights the potential for harm when numeric pain scores alone are used guide decisions regarding pain treatment. A comprehensive approach to pain assessment that includes consideration of the child’s self-reporting (when available), combined with behavioral observation and the overall clinical context, is required to direct treatment decisions.68
Special Considerations for the Cognitively Impaired Child
Children who are cognitively impaired experience pain more frequently than cognitively intact children because of a number of inherent conditions, such as spasticity, muscle spasms, the need for assistive devices for positioning and mobility, and the need for invasive surgical procedures. Indeed, as many as 60% of children with cerebral palsy undergo orthopedic surgery by 8 years of age, and many of them require repeated procedures.69 Yet both children and adults who are cognitively impaired receive fewer analgesics than those who are cognitively intact with similar painful conditions.70,71 Barriers to effective pain management in the cognitively impaired include the complexity of pain assessment in those who cannot verbalize their pain, outdated beliefs that these children have altered or blunted pain perception, limited evidence for the safety and efficacy of analgesic regimens, and an exaggerated concern regarding opioid adverse effects, particularly respiratory depression. Difficulties with pain assessment have led to the virtual exclusion of these children from clinical drug trials, leading to deficits in our knowledge of how to effectively manage their pain. A survey of clinicians who treat children who are cognitively impaired identified inadequate pain assessment tools and inadequate training and knowledge of providers as significant barriers to effective pain management, despite respondents beliefs that children who are cognitively impaired perceive pain to a similar extent as cognitively intact children.72
The University of Wisconsin Pain Scale for Preverbal and Nonverbal Children
This scale is composed of five behavior categories with four descriptors for each (E-Table 43-1).73 The overall rating using this tool is not a sum of scores of individual behaviors but a score assigned on a 0- to 5-scale based on the clinician’s judgment relative to assessment of individual categories. The scoring style of this tool does allow for flexibility, but limits its precision. This scale has been tested in 59 preverbal children and 15 children who were nonverbal because of cognitive impairment. Although these investigators reported good validity and reliability in their overall sample, the reliability and validity of this tool for the subset of children with cognitive impairment was not reported.
The Non-Communicating Children’s Pain Checklist—Postoperative Version
This tool comprises a checklist of 27 pain behaviors across six categories.74 Each of these behaviors (E-Table 43-2) is scored on a 0- to 3-point scale based on the frequency of observation of that behavior over a 10-minute observation period. The scores of all items are summed to provide a total pain score. This tool has been evaluated in 25 children who were cognitively impaired,74 with good inter-rater reliability in four of the six behavior categories and good correlations between the Non-Communicating Children’s Pain Checklist—Postoperative Version (NCCPC-PV) scores and VAS scores. Although this checklist provides a comprehensive pain assessment method for children with cognitive impairment undergoing surgery, it may be cumbersome for frequent and repeated pain assessments in the clinical setting.
E-TABLE 43-2 Noncommunicating Children’s Pain Checklist—Postoperative Version
| Vocal | Social |
| Facial | Activity |
| Body and Limbs | Physiologic Signs |
From Breau LM, Finley GA, McGrath PJ, Camfield CS. Validation of the Non-communicating Children’s Pain Checklist—Postoperative Version. Anesthesiology 2002;96:528-35.
The Pain Indicator for Communicatively Impaired Children
One group of investigators interviewed parents and/or caregivers of 30 communicatively impaired children regarding cues they used to identify pain in their child.75 Six core pain cues were reported by 90% of the caregivers as signs of definite or severe pain in their child (E-Table 43-3). Each of these cues is scored on a 4-point Likert scale (not at all, a little, often, all the time), based on the frequency of occurrence of the behavior over the observation period. Caregivers of children with severe cognitive impairment, who evaluated this scale at home over a 7-day period, reported no significant relationship between crying and the presence of pain. Yet, they found that a “screwed up or distressed looking face” had the strongest relationship with the presence of pain. In fact, they found that facial expression alone correctly identified 71% of children in pain and 93% of those not in pain, with an overall correct classification rate of 87%. This tool provides a simple method of assessing pain in children with cognitive impairment in the home setting. Further testing of this tool is required in the hospital setting, and using shorter observation periods, to determine its feasibility of use by clinicians.
E-TABLE 43-3 Pain Indicator for Communicatively Impaired Children (PICIC)
From Stallard P, Williams L, Velleman R, et al. The development and evaluation of the pain indicator for communicatively impaired children (PICIC). Pain 2002;98:145-9.
Face, Legs, Activity, Cry, Consolability Observational Tool
Initial evaluation of the FLACC tool in children with cognitive impairment found a good correlation between scores assigned independently by different observers and by parent global ratings of pain.76 Although measures of exact agreement between observers were acceptable for the face, cry, and consolability categories, measure of agreement for the legs and activity categories were less acceptable, likely because of coexisting motor impairments such as spasticity. The FLACC tool was therefore revised to incorporate additional descriptors of behaviors most consistently associated with pain in children with cognitive impairment (Table 43-6).77 Inter-rater reliability for the total FLACC scores, as well as for each of the categories, improved when the evaluation included the revised FLACC (r-FLACC) in 52 cognitively impaired children. Also, good correlation between FLACC, parent, and child scores supported its criterion validity. FLACC scores were noted to decrease after an opioid was administered, supporting the construct validity of the tool. The pragmatic attributes of the r-FLACC were compared with those of the Nurses’ Assessment of Pain Intensity (NAPI) and the NCCPC-PV.78 Clinicians using these tools to score pain rated the complexity as less and the relative advantage and overall clinical utility of the FLACC and the NAPI to be greater compared with the NCCPC-PV, suggesting that these tools may be more readily adopted into clinical practice.
Strategies for Pain Management
Pain is a complex phenomenon that occurs because of the transmission of nociceptive stimuli from the peripheral nervous system through the spinal cord to the cerebral cortex. Pain perception is further influenced by emotions, behavior, and previous pain experiences via multiple synapses in the limbic system, frontal cortex, and thalamus. Given the complexity of the pain mechanism, effective treatment of pain requires the use of multimodal therapies that target multiple sites along the pain pathways, as illustrated in Figure 43-6. Analgesics with additive or synergistic activity and different adverse effect profiles should be selected so that adequate analgesia can be provided with fewer adverse consequences. Thus pain can be treated at the peripheral level using local anesthetics, peripheral nerve blockade, nonsteroidal antiinflammatory drugs (NSAIDs), antihistamines, or opioids. At the spinal cord level, pain can be treated with local anesthetics, neuraxial opioids, α2-adrenoceptor agonists, and N-methyl-d-aspartate (NMDA) receptor antagonists. Finally, at the cortical level systemic opioids, α2-agonists, and voltage-gated calcium channel α2δ proteins (targets for anticonvulsants) can be used.79 Most cases of moderate to severe pain are best treated with a combination of analgesic techniques.
FIGURE 43-6 Schematic diagram of the pain pathways and multimodal measures to provide pain relief.
(From http://old.cvm.msu.edu/courses/VM545/Evans/Pain%20Management%20PDA.htm.)
The strategy for postoperative pain management is an integral part of the preanesthetic plan, so that informed consent for procedures, such as placement of peripheral or regional blocks, can be obtained (see Chapters 41 and 42). Additionally, appropriate teaching for techniques, such as patient-controlled analgesia (PCA), should begin in the preoperative period. An honest discussion with the child that, although some discomfort is inevitable, every effort will be made to minimize pain after surgery, decreases the anxiety related to the perioperative experience. This, together with the use of nonpharmacologic techniques, may even reduce the need for opioids and other analgesics. Selection of an analgesic regimen requires careful consideration of a number of factors, including scope and requirements of the surgical procedure, age and cognitive abilities of the child, the child’s previous pain experience and response to treatment, underlying medical conditions that might alter the response to pain medications, and child and family preferences. The goal should be for the child to emerge from anesthesia in reasonable comfort, because it is generally easier to maintain analgesia in a pain-free child than to achieve analgesia in a child with severe pain. Figure 43-7 presents a flowchart describing strategies for assessment and management of acute postoperative pain in a child.
Surgical Considerations
The scope and requirements of the surgical procedure, as well as specific postoperative issues, should be discussed with the surgical team before choosing an analgesic regimen, particularly if a regional technique is planned. For example, the site of placement of an epidural catheter and choice of epidural solution will differ in a child with a vertical midline incision from a child with a transverse suprapubic incision. With certain procedures, an epidural catheter may intrude into the surgical field or access to the catheter site in the postoperative period may be obscured by a cast or dressing. In such cases, the catheter may be tunneled subcutaneously away from the surgical field. Alternatively, one or more epidural catheters may be placed under direct vision by the surgeon at the end of the procedure (e.g., spinal fusion or selective dorsal rhizotomy).80–83 Postoperative pain is managed by the pain service, using infusion of local anesthetic and/or opioid solutions through the catheter.80 Painful muscle spasms after certain procedures are often well managed with continuous epidural analgesia.80,84,85 Refractory spasms of the bladder, which can be quite problematic after some surgeries (e.g., ureteral reimplantation), can also be effectively treated with NSAIDs (e.g., ketorolac) or anticholinergics.86 Intravesical bupivacaine has also been used to manage bladder spasm.87,88 Muscle spasms after orthopedic surgery may be prevented by dense levels of regional blockade, but may also require supplementation with oral or parenteral benzodiazepines if epidural analgesia alone is ineffective. Epidural blockade may favorably alter diaphragmatic mechanics after thoracotomy and upper abdominal surgery. This effect is likely a result of the motor blockade of the intercostal muscles and alteration in the resting length of the diaphragm, and not solely a result of reversal of diaphragmatic inhibition.89–92 However, it remains uncertain whether analgesia alone, achieved by systemic opioids or central neuraxial blockade, is of value in diminishing postoperative diaphragmatic inhibition or significantly improving postoperative pulmonary function.93,94 Effective analgesia, however, does improve child compliance with measures such as deep breathing and early mobilization, thereby reducing the incidence of postoperative complications.95
Child-Related Considerations
Age and Cognitive Abilities
Analgesic techniques, such as infiltration of the wound with local anesthetics, peripheral nerve blocks, or regional blockade that minimize the use of opioids and central respiratory depressants, may be ideal for preterm or very young infants with impaired central respiratory drive.96,97 Acetaminophen can be a useful adjunct, because when used within its recommended dose range it has a large therapeutic window with few untoward effects. Although the judicious use of opioids is not contraindicated, preterm or term infants younger than 1 month of age who receive these medications require careful observation and monitoring to detect respiratory depression.98 The use of local anesthetics in infants also requires more careful attention to dose, to avoid accumulation and toxicity.
Although analgesia for the preterm infant was often neglected in the past, we now understand that these infants have reduced thresholds to painful or noxious stimuli when compared with older children.99 Most of the neural pathways that conduct nociception from the periphery through the central nervous system (CNS) are present and functional at 24 weeks gestational age, although the central connections, particularly in the thalamocortical pathways that are involved in the integration and perception of conscious pain, are not as well developed.100–102 Controversy remains as to the meaning and implications of this neural immaturity. Opioid receptors and responses are present in the spinal cord at the time of birth, although spinal glial inflammatory mechanisms are immature. Because these mechanisms are central to the cyclooxygenase (COX-1 and COX-2) responses, this may imply that there is limited or no analgesic response to NSAIDs and COX inhibitors in preterm infants or neonates, whereas opioid responses are active. GABAergic pathways, which play an important role in the effects of analgesics and anesthetics, can be either excitatory or inhibitory, depending on the stage of development.103 The neuroplasticity that is characteristic of these infants may be a double-edged sword. Animal models and some clinical evidence suggest that repeated noxious stimuli may result in heightened sensitivity to nociceptive input and adverse behavioral sequelae.2,10,104–107 On the other hand, nerve injury in infant animals may result in less pain than it does in older animals.106,107 In humans, the neural injury to the brachial plexus after shoulder dystocia during delivery rarely results in chronic pain.108 It may be that there are both vulnerable periods and periods of greater resiliency during development, so that the consequences of pain in our youngest children may not be easily predictable.
Older infants and toddlers who are expected to experience moderate to severe pain may be adequately treated with oral opioids when oral intake resumes. Alternatively, low-dose continuous opioid infusions, nurse-controlled analgesia,109 or regional blockade may be required in those undergoing extensive surgery. Nonpharmacologic techniques, such as child life therapy and the presence of a comforting parent, can do much to supplement analgesic therapy.
Preschool and school-aged children have greater fears and better understanding of the postoperative experience than do their younger counterparts. Most cognitively intact children 7 years of age or more are able to understand the concept of patient-controlled analgesia (PCA), which may be helpful in giving a sense of control back to the child during a period in which all other aspects of control are removed.110 Such issues of control and dependency assume even greater importance in adolescents; allowing them to participate in decision-making will contribute to the success of any analgesic technique.110 Regional techniques are excellent for providing analgesia in all age groups and are associated with a reduced incidence of adverse effects compared with systemic opioids (e.g., nausea, vomiting, excessive sedation, dysphoria and respiratory depression). Children with significant developmental delay require special consideration of their physical disability, as well as cognitive abilities, although in most cases the pharmacologic actions of the drugs are not altered.
Previous Pain Experience
A detailed history regarding the child’s previous pain experience, analgesic history, response to treatment, and adverse effects from previous analgesic regimens should be carefully considered when selecting a pain management technique. An opioid-naive child undergoing surgery for the first time requires smaller doses of opioids for a smaller duration compared with a child with chronic pain who has developed opioid tolerance as a result of long-term or repeated opioid use. Analgesic selection should also be modified based on the effectiveness of analgesics for that particular child in the past. For example, a child with a history of not responding to codeine may be deficient in the cytochrome P-450 2D6 isoenzyme (see also Chapter 6). These children cannot metabolize codeine (methylmorphine) to morphine (its active moiety) and experience reduced analgesia after codeine. Ineffective conversion of codeine to morphine may be present in up to 7% to 10% of Caucasian children, whereas the incidence of fast metabolizers is 5% in North America. These incidences differ with ethnicity, with a significantly greater incidence of polymorphisms in North African descendants.111–115 On the other hand, another polymorphism, present in about 0.5% of children, results in rapid demethylation of codeine to morphine, producing exaggerated sedation and respiratory depression when codeine is administered.116,117 Overall, we strongly discourage routine use of codeine as a first-line opioid for children. Oxycodone, hydrocodone, hydromorphone, or morphine are superior alternatives to codeine. Alternatively, if pain is of moderate or smaller intensity, another class of analgesics (e.g., NSAIDs) can be substituted.
Pharmacologic Treatment of Pain
Nonopioid Analgesics
Nonopioid analgesics may be used as sole agents for the treatment for mild pain and as important adjuncts for the multimodal treatment of moderate to severe pain. Although most nonopioid analgesics produce dose-dependent responses, they are limited by a ceiling effect in the analgesia achieved, that is, larger doses of the medication provide no additional analgesia. Hence, more severe pain is resistant to therapy from these medications alone.118 Therefore they are frequently prescribed in combination with opioids to reduce both the opioid requirements and the adverse effects (Table 43-7).
Acetaminophen
Acetaminophen is the most common antipyretic and nonopioid analgesic used in children. It exerts its analgesic effects by blocking central and peripheral prostaglandin synthesis, reducing substance P–induced hyperalgesia, and modulating the production of hyperalgesic nitric oxide in the spinal cord.119–121 In addition, it has been suggested that acetaminophen produces analgesia via activation of descending serotonergic pathways.122–124 However, it is likely that its primary site of action may be inhibition of prostaglandin H2 synthetase at the peroxidase site.123 Effective analgesic and antipyretic effects have been described with plasma concentrations of 5 to 20 µg/mL125–129; a target effect-site concentration of 10 µg/mL reduces pain after tonsillectomy by 3.6/10 pain units.130 The total daily dose of acetaminophen via any route is age- and weight-based but should not exceed 75 mg/kg for children; term and preterm infants require further downward dosing adjustment (60 mg/kg and 45 mg/kg, respectively).
The recommended dose for oral administration is 10 to 15 mg/kg every 4 hours. Acetaminophen has a wide margin of safety when administered in the recommended therapeutic dose range. However, hepatotoxicity has been reported with doses only slightly above the recommended 10- to 15-mg/kg/dose orally for a total of five doses or 75 mg/kg/day, suggesting that acetaminophen may have a narrow therapeutic index in some children.131,132 Because of these reports and on the advice of a U.S. Food and Drug Administration panel, the manufacturers have reduced the maximum single dose of oral acetaminophen in adults to 650 mg and the maximum daily dose to 3 grams. Acetaminophen is available in a wide variety of formulations, alone or in combination with decongestants, for oral use in a variety of cold remedies, and with opioids for the treatment of moderate to severe pain. There are currently more than 600 over-the-counter acetaminophen-containing products, increasing the risk of an overdose because children may take more than one formulation that contains the drug. Frequent review of medications and parental education is needed to minimize the risk of overdose. In the past, pediatric liquid formulations of acetaminophen as in infant drops were commonly supplied in larger concentrations than that in elixirs, resulting in dosing errors. The current recommendation is to standardize liquid formulations to a single concentration of 32 mg/mL. Acetaminophen can be given orally before surgery; both gastric fluid volume and pH are unchanged after acetaminophen was administered orally 90 minutes before induction of anesthesia.133
Slow and unpredictable absorption of acetaminophen after rectal administration results in variable blood concentrations, with peak concentrations reached between 60 and 180 minutes after administration.128,134,135 There is a dose-response relationship for rectal acetaminophen. The morphine-sparing effects of 40 mg/kg and 60 mg/kg of rectal acetaminophen were greater than those of 20 mg/kg and placebo in children undergoing ambulatory surgery.136 In children undergoing orthopedic surgery, a loading dose of 40 mg/kg rectal acetaminophen followed by 20 mg/kg every 6 hours yielded serum concentrations of 10 to 20 µg/mL, with no evidence of accumulation over a 24-hour period.134 This dosing scheme is now the one most commonly recommended when the rectal route is employed.
After IV administration of acetaminophen, analgesic onset occurs in 15 minutes and that of antipyresis in 30 minutes.137,138 IV paracetamol rapidly penetrates the blood-brain barrier in children, yielding detectable concentrations in the cerebrospinal fluid (CSF) within 5 minutes of administration, and peak CSF concentrations within 57 minutes after injection (compared with 2 to 3 hours after rectal or oral administration), thus explaining the fast onset of its analgesic and antipyretic effects.139 A large multicenter trial reported that 1 gram of IV paracetamol and 2 grams of IV propacetamol (equivalent to 1 gram acetaminophen) provided superior analgesia with a reduced need for morphine compared with placebo in adults after lower extremity joint replacement.140 The propacetamol group experienced a greater incidence of local skin reactions and pain on injection compared with the IV paracetamol group. A controlled randomized trial reported that both rectal acetaminophen, 40 mg/kg, and IV acetaminophen, 15 mg/kg, administered after induction of anesthesia in children undergoing adenotonsillectomy, provided good analgesia for the first 6 hours after surgery.141 However, children who received acetaminophen rectally had a greater duration of analgesia and did not require rescue analgesia as early as those in the IV group.141 This is attributable to the slow absorption of rectal acetaminophen causing sustained effective concentrations. A prospective randomized trial comparing rectal acetaminophen to IV propacetamol in infants after craniofacial surgery reported that the IV formulation provided superior analgesia,142 in part because of reduced bioavailability of acetaminophen by the rectal route.
Another controlled randomized study compared the analgesic efficacy and side effects of fentanyl-placebo versus fentanyl-acetaminophen administered via PCA in 6- to 24-month-old children undergoing ureteroneocystostomy.143 Children in the acetaminophen group required significantly less fentanyl and demonstrated a reduced incidence of vomiting and excessive sedation compared with those in the placebo group. Lastly, a large retrospective study reported no differences in alanine transaminase and γ-glutamyl transferase concentrations, and a progressive decrease in aspartate aminotransferase levels, in term and preterm neonates before, during and after IV acetaminophen injection.144
Nonsteroidal Antiinflammatory Drugs
NSAIDs provide excellent analgesia for mild to moderate pain resulting from surgery, injury, and disease. Their principle mechanism of action is via inhibition of the enzyme prostaglandin H2 synthetase at the COX site, causing a reduction in the production of prostaglandins at the site of tissue injury, and attenuation of the inflammatory cascade. In addition to their peripheral effects, the NSAIDs have also been shown to exert a direct spinal action by blocking the hyperalgesic response induced by activation of spinal glutamate and substance P receptors.145 Decreased production of leukotrienes, activation of serotonin pathways, and inhibition of excitatory amino acids, NMDA-mediated hyperalgesia, and central inhibition of prostaglandin biosynthesis have been proposed as additional mechanisms of action.146,147 The COX-1 enzyme is present in the brain, gastrointestinal tract, kidneys, and platelets and is expressed constitutively. It preserves gastric mucosal integrity and function, platelet aggregation, and renal perfusion. COX-2 expression is induced by inflammation or tissue injury. Selective COX-2 inhibitors reduce inflammation but have less effect on gastric mucosal function and have fewer effects on platelet aggregation, thereby resulting in fewer adverse effects. Their deleterious effects on renal perfusion, however, are no different than the nonselective COX drugs, because COX-2 is constitutively expressed in renal tissues and may be involved in prostaglandin-dependent renal homeostatic processes.148 The risks of renal toxicity increase in the presence of hypovolemia, cardiac failure, preexisting renal dysfunction, or with the concurrent use of other nephrotoxic drugs. Reports of thrombotic cardiovascular and CNS events after both long-term and short-term use in adults led to withdrawal of two of the COX-2 inhibitors, rofecoxib and valdecoxib from the market.149,150 Similar data are unavailable to date in children; consequently, the risk of these agents causing thrombotic complications in children remains unknown. Most pediatric studies have evaluated the use of nonselective COX medications. In adult studies, COX-2 inhibitors have generally, but not always, produced analgesia roughly equivalent to that of traditional NSAIDs. Ibuprofen, one of the oldest orally administered NSAIDs, has been used extensively for treatment of fever and pain related to surgery, trauma, arthritis, menstrual cramps, and sickle cell disease. A large, controlled, randomized, double-blind study reported a greater decrease in VAS pain scores with ibuprofen than with acetaminophen or codeine in children presenting to the emergency department with acute pain after musculoskeletal trauma.151 Additionally, more children who received ibuprofen had VAS scores less than 30 on a 0-to-100-mm VAS scale than in the other two groups. The recommended dose of ibuprofen is 6 to 10 mg/kg every 6 hours. Like acetaminophen, ibuprofen is available in a variety of formulations and concentrations, placing children at risk for an overdose. For pediatric use, ibuprofen is available as:
Concentrated drops containing 50 mg ibuprofen in 1.25 mL
Oral suspension containing 100 mg of ibuprofen in 5 mL
Junior-strength chewable tablets or caplets containing 100 mg of ibuprofen in each
Diclofenac provides effective analgesia after minor surgical procedures in children. It is available only as an oral tablet in the United States, but it is available as a suppository and in the injectable form in several countries. The pediatric dose of diclofenac is 1 mg/kg every 8 hours orally, 0.5 mg/kg rectally, and 0.3 mg/kg IV.152 The oral and rectal doses reflect bioavailabilities of 0.36, 0.35, and 0.6 for suspension, dispersible tablets, and suppository, respectively. When diclofenac was administered rectally, the relative bioavailability was greater and the peak concentration was reached earlier than after enteric coated tablets administered orally.153 Children who received diclofenac experienced comparable analgesia to those who received caudal bupivacaine or IV ketorolac for inguinal hernia repair.154–156 In children undergoing tonsillectomy and/or adenoidectomy, diclofenac yielded superior analgesia with less supplemental opioid dosing, less nausea and vomiting, and earlier resumption of oral intake compared with acetaminophen.157,158 Although there are occasional reports of increased bleeding and restlessness in the recovery room in children who received diclofenac compared with those who had received papaveretum during tonsillectomy,159 a Cochrane review established that NSAIDs did not cause any increase in bleeding that required a return to the operating room (OR) for children. There was significantly less nausea and vomiting with NSAIDs compared with alternative analgesics, suggesting their benefits outweigh their negative aspects.160
Ketorolac, indomethacin and ibuprofen are the only injectable NSAIDs available in the United States. Indomethacin is the only NSAID used for closure of patent ductus arteriosus in preterm neonates. The IV formulation of ibuprofen is only labeled for adults in the United States. Clinical trials are currently under way in children. Ketoprofen and diclofenac are other injectable NSAIDs that are available outside the United States. A large multicenter study compared the risks of serious adverse events from IV ketorolac, ketoprofen, and diclofenac in more than 11,000 adults undergoing major surgery.161 The results indicated that 1.4% of adults experienced a serious adverse outcome, including surgical site bleeding (1%), death (0.17%), severe allergic reactions (0.12%), renal failure (0.09%), and gastrointestinal bleeding (0.04%), with no differences in outcomes among the groups; similar large-scale studies are not available for children.
Ketorolac has been shown to provide postoperative analgesia similar to opioids, in children of all ages.162–165 Its benefits include lack of opioid adverse effects (respiratory depression, sedation, nausea, and pruritus) making it an attractive choice for the treatment of postoperative pain. However, in common with all NSAIDs, it carries risks of platelet dysfunction, gastrointestinal bleeding, and renal dysfunction. Ketorolac (1 mg/kg) given to 18 preterm and term neonates undergoing painful procedures in the OR or the neonatal intensive care unit,163 revealed reduced pain scores (Neonatal Infant Pain Scale) with no incidents of systemic or local bleeding and no hematologic, hepatic, or renal complications (note that this dose is twice the usually recommended dose of 0.5 mg/kg). Similarly, no adverse effects on surgical drain output, renal or hepatic function tests, or oxygen saturation after major surgery were noted in 37 infants and toddlers between 6 and 18 months of age.166 Children in that study received continuous morphine infusions postoperatively, confounding the evaluation of the analgesic efficacy of ketorolac. Finally, ketorolac has been used to supplement opioid analgesia, with no increase in renal or bleeding complications in infants and children after open heart surgery.167–169 Nevertheless, because ketorolac can reduce renal blood flow, many recommend that its course be limited to 48 to 72 hours, and that renal function be checked if a course of administration greater than 72 hours is required. In single dose studies, the pharmacokinetics (PK) of ketorolac in infants less than 12 months of age appear to be homogeneous, although there was a trend toward reduced clearance in the infants less than 6 months of age.170
In an effort to avoid the respiratory depressant effects of opioids after airway surgery, several studies investigated the safety and benefits of ketorolac in children undergoing tonsillectomy.171–175 These early reports of ketorolac adversely skewed analyses of the adverse effects of NSAIDs after tonsillectomy. All but one of these studies171 found a two- to fivefold increase in bleeding complications, including measured blood loss, ease of achieving hemostasis, and bleeding episodes in the postanesthesia care unit (PACU), necessitating reexploration and hospital admission in some cases. Two of these studies were terminated prematurely, when preliminary data showed an unacceptably greater risk of bleeding in children who had received ketorolac.172,175 In one of these two studies, ketorolac was given at the end of surgery after hemostasis had been achieved.172 The benefits of ketorolac, including adequacy of analgesia, resumption of oral intake, and reduction in nausea, vomiting, and sedation were modest. This issue is further confounded by conflicting results yielded by two meta-analyses that evaluated the related literature. In one of these, the use of aspirin, but not of NSAIDs (diclofenac or ibuprofen), significantly increased the risk of post-tonsillectomy hemorrhage compared with either acetaminophen with codeine or tramadol for postoperative analgesia.176
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