Acute pain management

Introduction

The treatment and alleviation of pain is a basic human right that exists regardless of age. The old “wisdom” that young children neither respond to nor remember painful experiences to the same degree that adults do is simply untrue ( ; ; ). Many, if not all, of the nerve pathways essential for the transmission and perception of pain are present and functioning by 24 weeks’ gestation ( ; ). Furthermore, research in newborn animals reveals that the failure to provide analgesia for pain results in a “rewiring” of nerve pathways responsible for pain transmission and increased pain perception with future painful insults ( ; ; ; ).

Because pain is recognized as a “major, yet avoidable, health problem” ( ), many professional guidelines and regulatory agencies set standards for its assessment and treatment, frequently focusing on care of adult patients. However, providing effective analgesia to infants, preverbal children, adolescents, and the mentally and physically disabled poses unique challenges to those who practice pediatric medicine and surgery.

Studies in the 1990s showed that physicians, nurses, and parents underestimated the amount of pain experienced by children ( ; ). Subsequent research documented that clinically relevant pediatric pain is common. Reviews of pain prevalence and demographics in hospitalized pediatric populations between 2010 and 2015 reported that between 27% and 40% of patients experienced moderate or severe pain at some point during hospitalization ( ; ).

Furthermore, pediatric pain may be undertreated. Physicians are taught throughout their training to do no harm ( primum non nocere ), and they have legitimate concerns that children may be harmed by the use of analgesics. For example, nonsteroidal antiinflammatory drugs (NSAIDs) can cause problems such as bleeding, liver dysfunction, coagulopathies, and impaired wound and bone healing. Further, opioids, the analgesics most commonly prescribed to treat moderate to severe pain, can cause respiratory depression, cardiovascular collapse, depressed levels of consciousness, constipation, nausea, vomiting, and—with repeated use—tolerance. In addition, newer evidence has contradicted the long-held belief that opioids are rarely addictive when used to treat acute pain ( ; ; ). The United States is currently in the midst of an opioid epidemic, and societal fears of opioid addiction have had a significant influence on analgesic prescribing ( ; ).

All of these concerns may at times lead physicians to ignore the adverse effects of inadequate pain treatment and prescribe insufficiently potent analgesics or recommend inadequate doses. However, this practice is unwise. In addition to its effect on neurodevelopment, unrelieved pain interferes with sleep, leads to fatigue and a sense of helplessness, exacerbates the stress and inflammatory response, and may lead to increased morbidity or mortality ( ; ).

Fortunately, the past four decades have seen an increase in research and interest in pediatric pain management and the development of pediatric pain services, often directed by pediatric anesthesiologists ( ). Pediatric pain service teams manage acute, postoperative, neuropathic, chronic, and terminal pain. Provision of this care requires an understanding of the developmental and genetic aspects of pain as well as the ability to assess pain and the effects of analgesic therapy. A multimodal approach to pain management requires an understanding of pharmacologic and nonpharmacologic interventions, familiarity with analgesic side effect management, and consideration of both the risks and benefits of therapy. Moving forward, acute pain practitioners together with surgical colleagues will need to develop regimens that optimize pain management and patient recovery after surgery and provide evidence-based guidance for outpatient analgesic prescribing. Finally, our role requires that we remain cognizant of new directions in analgesic management as they unfold. This chapter provides a brief overview of these topics.

Neurophysiology of pain

Acute pain serves a critical, immediate protective purpose. However, pain is more than simply the physiologic transmission of nociceptive input from a site of injury to the brain and its modulation within the central nervous system (CNS). Rather, it is a complex sensation that is integrated and given value at higher, conscious brain centers. No two people experience it the same way. It is similar to symphonic music: despite the fact that the physiology of sound transmission is the same in everyone, symphonic music to some is simply awful and to others it is glorious. As individuals integrate neural transmissions, they give them personal, subjective value based on age, culture, genes, previous experience, education, values, and state of mind. The same is true for pain. Indeed, we now know that there is no primary pain cortex analogous to the somatosensory or visual cortex. Instead, there is a diffuse distributed network of brain activity, none of which is unique to pain. However, when the activity is coordinated or synchronized, it results in the sensory, emotional, motivational, and cognitive experience that is pain ( ; ). These areas include the primary (SI) and secondary (SII) somatosensory cortices, anterior cingulate and midcingulate cortices, insular cortex, amygdala, and regions of the prefrontal cortex and are referred to collectively as the “dynamic pain connectome” ( ).

Sensory afferent neurons that respond to noxious stimulation (nociceptors) have a unipolar cell body located in the dorsal root ganglion and are classified by fiber size into three major groups (A, B, C) ( Table 23.1 ). Group A is further subclassified into four subgroups. These neurons include small-caliber myelinated (Aδ) or fine unmyelinated C fibers. Sensory afferents originate as free nerve endings and arise from epidermal and internal receptive fields, including the periosteum, joints, and viscera. Their terminal axonal membranes include ionophores that enable transduction of specific noxious signals such as pressure, heat, and chemical irritants. For example, heat is often mediated by channels of the transient receptor potential cation channel superfamily (e.g., TRPV1 and TRPM8); heat and mechanical pressure are transduced by potassium channel subfamily K member 2 (KCNK2 or TREK-1); and acid or chemical stimulus is mediated by proton-activated, acid-sensing ion channels (ASIC). However, these classes of thermoreceptors, chemoreceptors, and mechanoreceptors have clear overlap.

After an acute injury such as surgical or accidental trauma, activated nociceptors transmit information via glutamate, an excitatory neurotransmitter ( ). Inflammatory mediators are also released at the site of injury and act to lower the pain threshold at the site of injury (primary hyperalgesia) and in the surrounding uninjured tissue (secondary hyperalgesia) ( ). These inflammatory mediators, which include hydrogen and potassium ions, histamine, leukotrienes, prostaglandins, cytokines, serotonin (5-HT), bradykinins, substance P, calcitonin gene-related peptide (CGRP), and nerve-growth factors make a “sensitizing soup,” which, together with repeated stimuli of the nociceptive fibers, decrease excitatory thresholds and result in peripheral sensitization, vasodilation, and edema. These mediators are also targets of therapeutic intervention ( Fig. 23.1 ).

The Aδ nociceptors transmit “first pain,” which is well localized, sharp, and lasts only as long as the original stimulus. The C-fiber polymodal nociceptors display a slow conduction velocity and respond to mechanothermal and chemical stimuli. This “second pain” is diffuse, persistent, burning, slow to be perceived, and lasts well beyond the termination of the stimulus. Secondary effects of peripheral sensitization include hyperalgesia, the increased response to a noxious stimulus, and allodynia, whereby nonnociceptive fibers transmit noxious stimuli, resulting in the sensation of pain from previously nonpainful stimuli.

As the primary afferent neurons enter the spinal cord, they segregate and occupy a lateral position in the dorsal horn ( Fig. 23.2 ). The Aδ fibers terminate in laminae I, II (substantia gelatinosa), V (nucleus proprius), and X (central canal). The C fibers terminate in laminae I, II, and V, and some enter the dorsal horn through the ventral root. These afferent neurons release one or more excitatory amino acids (e.g., glutamate and aspartate) or peptide neurotransmitters (e.g., substance P, neurokinin A, CGRP, cholecystokinin, and somatostatin). Second-order neurons that receive these chemical signals integrate the afferent input with facilitatory and inhibitory influences of interneurons and descending neuronal projections. It is this convergence within the dorsal horn that is responsible for much of the processing, amplification, and modulation of pain. Furthermore, the ability to simultaneously process noxious and innocuous stimuli underlies the gate-control theory of pain described by Melzack and Wall ( ; ).

Second-order neurons are of two types: nociceptive specific neurons, which respond exclusively to nociceptive impulses from Aδ and C fibers, and wide dynamic range (WDR) neurons, which respond to both noxious and nonpainful stimuli. At a given dermatomal level, WDR neurons receive afferent input from the skin, muscle, and visceral nociceptors. Low-frequency stimulation of C fibers leads to a gradual increase in WDR neuronal discharge until it reaches a state of near-continuous discharge called central sensitization or wind-up. Occupancy of the N-methyl-D-aspartic acid (NMDA) receptor by glutamate in the presence of glycine and the removal of the calcium channel’s magnesium plug are crucial in the development of wind-up. In combination with peripheral sensitization, these two processes contribute to the postinjury hypersensitivity state that is responsible for a decrease in the pain threshold, both at the site of injury and in the surrounding uninjured tissue. It is largely as a result of this mechanism that pain may be prolonged beyond the duration normally expected after an acute insult. Prolonged central sensitization has the capacity to lead to permanent alterations in the CNS, including the death of inhibitory neurons, replacement with new afferent excitatory neurons, and establishment of aberrant excitatory synaptic connections. These alterations can result in intractable pain that is poorly responsive to many analgesics.

Nociceptive activity in the spinal cord and the ascending spinothalamic, spinoreticular, and spinomesencephalic tracts carries messages to supraspinal centers (e.g., periaqueductal gray, locus coeruleus, hypothalamus, thalamus, and cerebral cortex), where they are modulated and integrated with autonomic, homeostatic, and arousal processes. This modulation, particularly by endogenous opioids, γ-aminobutyric acid (GABA), and norepinephrine, can either facilitate pain transmission or inhibit it ( ). Modulating pain at peripheral, spinal, and supraspinal sites helps to achieve better pain management than targeting only one site and is one of the underlying principles of treating pain in a multimodal fashion ( Fig. 23.1 ).

Developmental maturity is also important in pain processing. Although pain pathways are present at birth, they are often immature ( ). Nevertheless, although neural transmission in peripheral nerves is slower in neonates because myelination is incomplete, many if not all of the nerve pathways essential for the transmission, perception, and modulation of pain are present and functioning by 20 to 24 weeks of gestation ( Fig. 23.3 ) ( ; ). Peripheral sensory receptors synapse with spinal cord neurons during the first trimester, whereas spinal cord axons project to the thalamus, sending afferents to the cerebral cortex during the second trimester. It is not until the third trimester, however, that the thalamocortical connections required for the conscious perception of pain are clearly present ( ; ). At birth, peripheral innervation is already sensitive to tissue injury, but inhibitory mechanisms in the dorsal horn are immature, and inhibition of nociceptive input is less than that seen in adults. Furthermore, nociceptive reflex pathways are diffuse and poorly tuned. Dorsal horn neurons in the newborn have wider receptive fields and lower excitatory thresholds than those in older children ( ; ; ). In addition, primary hyperalgesia develops before secondary hyperalgesia, and descending controls via the brainstem are unbalanced. Because of the immaturity of synaptic connections and neural circuits in the newborn, the infant pain experience tends to be more diffuse and less spatially focused.

How and when the complex dynamic pain connectome develops to encode noxious stimuli and create the experience of pain is an important area of current research. For instance, sensory systems and their associated perceptive abilities are established during specific developmental time windows called “critical periods,” during which deprivation of normal external inputs or disruption of physiologic neuronal activity causes long-lasting breakdown of sensory cortical maps and sensory impairment ( ). Importantly, research in newborn animals and humans has revealed that the failure to provide analgesia for pain results in a “rewiring” of the nerve pathways responsible for pain transmission in the dorsal horn and increased pain perception for future painful insults ( ; ; ). This finding confirms human newborn research in which the failure to provide anesthesia or analgesia for newborn circumcision resulted not only in short-term physiologic perturbations but also in longer term behavioral changes, particularly during immunization ( ; ).

Genetics of pain

Variations in pain sensitivity, analgesic response, and opioid-related adverse effects are regularly observed in clinical practice and research. A patient’s individualized response to a painful stimulus is thought to be multifactorial in origin, owing to genetic and environmental factors ( ; ; ; ), and modulated by age, gender, race, ethnicity, education, mood and behavior, expectations and drug choice ( ; ; ; ; ).

Functional pain genomics is the study of the genetic basis of the pain experience. The discipline encompasses the genetics of nociception, including heritable pain conditions, as well as pharmacogenetics, which can affect pain medication responses and treatment efficacy through effects on both pharmacokinetics (drug metabolism) and pharmacodynamics (site of drug action).

More than 400 genes have been reported to regulate pain pathways ( ), and these genes can be modulated by genetic mutations, single nucleotide polymorphisms (SNPs), and epigenetic changes. Mutations permanently alter the DNA code, creating a sequence that differs from that found in most people. The magnitude of mutations can range from a single base pair substitution to the transposition of a large chromosomal segment that encompasses multiple genes. Mutations are rare, but SNPs, which involve a single nucleotide substitution at a specific position in the genome, occur more commonly—on average almost once in every 1000 nucleotides. Hence, each individual’s genome has roughly 4 million to 5 million SNPs.

Unlike mutations and SNPs, epigenetic changes do not alter DNA sequence but may still alter gene expression. DNA methylation, a common epigenetic mechanism, involves the addition of a methyl group to the 5′ position of a cytosine nucleotide followed by a guanine nucleotide. These CpG dinucleotides often cluster in “islands” in gene promoter regions and can influence promoter binding and gene expression. DNA methylation is a dynamic process that can be influenced by injury ( ), and some evidence suggests a role for epigenetic modification in the development of chronic postsurgical pain ( ).

Variable inherited predispositions exist for diverse types of pain including migraine, menstrual, pelvic, neck, back, abdominal, and chronic postsurgical pain ( ; ; ). Depending on pain modality, heredity can also explain between 12% and 70% of observed variability in pain intensity ( ). Twin studies suggest that genetic variability can account for differences in sensitivity to painful thermal, mechanical, and chemical stimuli ( ; ). In addition, these studies support a role for genetic variability in opioid efficacy ( ; ).

Mutations, polymorphisms, and epigenetic changes have been identified in multiple pain-related genes, including genes that influence acute postoperative pain, experimental pain, and opioid responsiveness ( ). Research suggests that some of this genetic variability may be clinically relevant. Genes that have been investigated include those that affect opioid and other receptors (e.g., mu-1 opioid receptor [ OPRM1 ], delta 1 opioid receptor [ OPRD1 ], beta-arrestin 2 [ ARRB2 ], signal transducer and activator of transcription 6 [ STAT6 ], melanocortin 1 receptor [ MC1R ], transient receptor potential ankyrin 1 [ TRPA1 ], transient receptor potential vanilloid 1 [ TRPV1 ], neurotrophic tyrosine kinase receptor type 1 [ NTRK1 ]); catecholamines (e.g., catechol-O-methyl transferase [ COMT ], dopamine receptor D3 [ DRD3 ], adrenoceptor alpha 2A [ ADRA2a ]); sodium and potassium channels (e.g., sodium voltage-gated channel alpha subunit 9 [ SCN9A ] and potassium inwardly rectifying channel subfamily J member 2 [ KCNJ2 ]); drug transport (e.g., ATC binding cassette subfamily B member 1 [ ABCB1 ], ATP binding cassette subfamily C member 3 [ ABCC3 ], solute carrier family 6 members 2 and 4 [ SLC6A2 and SLC6A4 ]); endorphin and endocannabinoid metabolism (e.g., proopiomelanocortin [ POMC ], fatty acid amide hydrolase [ FAAH ]); drug metabolism (e.g., cytochrome P450 family member genes [ CYP2D6 and CYP34A ], UDT glucuronosyltransferase family 2 member B7 [ UGT2B7 ]); and inflammatory mediators (e.g., IL-1 receptor antagonist gene [ IL-1Ra ]) ( ; ; ; ).

Many of these genes were initially chosen for study via a candidate gene approach because of their relevance in pain-mediating pathways and opioid pharmacokinetics ( ; ). Genome-wide association studies, on the other hand, have been used to facilitate exploration of disease risk and drug effects beyond candidate genes and pathways, thus allowing for the identification of novel genes. For example, one such gene, TAOK3 —a serine/threonine protein kinase gene located approximately 300 KB upstream from the OPRM1 transcription site—has variant SNPs associated with increased acute postoperative pain and morphine requirements in opioid-naïve African American children ( ) as well as high opioid requirements in adults with advanced cancer ( ). Although the relevance of TAOK3 to pain sensitivity is currently unknown, the protein regulates multiple protein kinase signaling cascades and is speculated to be a pharmacogene that affects opioid responsiveness ( ).

It is beyond the scope of this chapter to discuss all of the candidate genes listed above. However, we will highlight a few. Some have been associated with profound, clearly demonstrable effects, and others have been the subject of numerous studies. One example of a gene with profound pain sensory effects is SCN9A, which encodes the peripherally expressed Nav1.7 sodium channel. This protein belongs to a family of voltage-gated sodium channels that control sodium ion influx during the rising phase of action potentials that underlie neuronal transmission. The Nav1.7 channel boosts small stimuli to initiate firing of pain-signaling dorsal root ganglia neurons and facilitates neurotransmitter release at the first synapse within the spinal cord. Mutations in SCN9A channels are associated with resistance to lidocaine ( ) and produce distinct human pain syndromes. Gain-of-function mutations underlie painful inherited diseases like erythromelalgia and paroxysmal extreme pain disorder. Conversely, patients with loss-of-function mutations, which are also associated with upregulation of endogenous opioids, can exhibit congenital insensitivity to pain ( ; ). Mutations in approximately 20 other voltage-gated sodium channel genes are also associated with sensory and autonomic neuropathies and pain hypersensitivity or insensitivity. In these instances, pain insensitivity is attributed to effects on anatomic structure, signal transduction, and ion transport ( ).

Another recently described causative mutation for a pain insensitivity disorder involves the coinheritance of a common functional SNP in the fatty-acid amide hydrolase gene FAAH . This mutation confers reduced expression and activity coupled with a microdeletion in FAAH-OUT, a pseudogene located in the FAAH chromosomal region. FAAH is the major catabolic enzyme for a range of bioactive lipids called fatty-acid amides, which include anandamide, an endogenous endocannabinoid that plays a role in nociception, fear extinction, memory, anxiety, and depression ( ). Interestingly, studies of the endocannabinoid pathway have also shown that genetic variability in FAAH can influence the response to placebo analgesics ( ; ). One of the most commonly studied pharmacodynamic genes is OPRM1, which encodes the mu-opioid receptor (MOR-1), the primary receptor for endogenous opioid peptides ( ). Whole-genome sequencing has identified over 3000 polymorphisms in OPRM1 ( ), including a rare, inactivating mutation at position 181 (ARG181CYS) that has been associated with poor or no effect of high opioid doses in adult cancer patients ( ). However, most pharmacogenetic studies of OPRM1 have analyzed the effect of the more commonly occurring SNP located at position 118 (A118G). This SNP, which is generally associated with milder clinical effects, causes an amino acid substitution from asparagine to aspartate at position 40 in the N-terminal region of the protein, leading to the loss of an N-glycosylation site in the extracellular region of the receptor ( ). Although study conclusions have varied ( ; ), some researchers have shown the less frequent G-allele to be associated with reduced levels of OPRM1 mRNA and protein relative to the A-allele ( ), lower cell surface morphine receptor binding site availability, less efficient agonist-induced receptor signaling ( ), and increased thermal pain in females ( ). Conversely, homozygous A-allele carriers are reported to require less analgesic medication after surgery ( ) and to have an increased risk of morphine-induced respiratory depression ( ; ). While OPRM1 has shown moderately consistent associations with acute postoperative pain and opioid analgesia, the SNP effect size is generally small ( ).

In addition to SNP-related effects, methylation of a number of CpG sites in the OPRM1 promoter region affects binding of multiple transcription factors and represses gene transcription ( ; ). It has been associated with chronic postsurgical pain after spinal fusion in healthy adolescents ( ) and worse neonatal abstinence syndrome outcomes in infants exposed to opioids in utero ( ; ).

COMT, the gene that encodes catechol-O-methyltransferase, is another frequently studied gene. COMT inactivates dopamine, epinephrine, and norepinephrine, which play important roles in pain transmission and modulation ( ). Decreased COMT activity results in higher catecholamine levels and increased sensitivity to pain. Multiple SNPs within the COMT gene are associated with pain sensitivity and opioid efficacy ( ; ). Genetic variants have been found to affect enkephalin levels, which inversely regulate mu-opioid receptor expression ( ). Individuals genotyped with the 472G>A MET158MET SNP exhibited lower than normal met-enkephalin concentrations ( ), decreased release of endogenous opioid in response to sustained experimental pain, and an increased concentration of mu-opioid receptors ( ). COMT SNPs were also shown to contribute to postsurgical pain ( ) and postoperative usage of patient-controlled analgesia (PCA) morphine ( ). In addition, by focusing on a group of four SNPs, Diatchenko et al. identified three functional haplotypes: one associated with low, one with average, and one with high pain intensity ( ).

Though no one candidate gene or combination of gene variants can fully explain the heritable aspects of the pain experience and opioid response, evidence does support a polygenic susceptibility to pain ( ). Studies have revealed an interaction between OPRM1 and COMT polymorphisms in placebo analgesic responses, opioid consumption, and postoperative pain in adult patients ( ). In pediatric patients, higher thermal pain sensitivity was seen in children who had the OPRM1 118AA genotype and also carried the COMT 472A allele ( ), whereas the combined OPRM1 118A>G and COMT 472G>A genotype was significantly associated with need for morphine rescue in newborns on mechanical ventilation ( ).

Pharmacokinetic research has included study of the ATP binding cassette subfamily B member 1, a membrane-bound P-glycoprotein and important CNS efflux transporter of exogenous opioids ( ), and UGT2B7, the hepatic enzyme involved in the conversion of morphine to its active and inactive glucuronidated metabolites. However, even more work has focused on cytochrome P450 genes, especially CYP2D6, which encodes the isoenzyme critical for endogenous morphine biosynthesis and the metabolism of many opioids including codeine ( ). Other CYP enzymes that have been studied include CYP2B6, which metabolizes methadone to its inactive metabolite and is highly polymorphic; and CYP3A4 and CYP3A5, which are relevant for inactivation of fentanyl, sufentanil, and alfentanil ( ; ; ; ).

As pharmacogenetic testing has become more efficient and less expensive, testing for variants in a patient’s CYP450 enzyme profile has become increasingly commonplace, though by no means routine. However, when utilized, this testing can provide useful information when prescribing opioids and, at times, tricyclic antidepressants (TCAs). The Pharmacogenomics Knowledge Base (PharmGKB) (www.pharmgkb.org), a publicly available Internet-based research tool, can provide clinical information in terms of dosing guidelines and drug selection using information about patient alleles. And taking into account available evidence, the Clinical Pharmacogenetic Implementation Consortium has published clinical recommendations for codeine and tramadol dosing based on CYP2D6 genotype ( ).

Pain assessment

Pain is a multidimensional phenomenon that includes sensory, cognitive, developmental, behavioral, emotional, spiritual, and cultural components. The International Association for the Study of Pain defines pain as “an unpleasant sensory and emotional experience associated with actual or potential tissue damage, or described in terms of such damage” ( ). Operationally, pain can be defined as “what the patient says hurts” and exists “when the patient says it does hurt.” However, because infants, preverbal children, and children between the ages of 2 and 7 (Piaget’s Preoperational Thought stage) may be unable to describe their pain or their subjective experiences, in the past many concluded incorrectly that these children did not experience pain in the same way that adults did. Clearly, children do not have to know (or be able to express) the meaning of an experience in order to have the experience ( ). On the other hand, because pain is essentially a subjective experience, focusing on the child’s perspective of pain remains an indispensable facet of pediatric pain management and an essential element in the specialized study of childhood pain.

As it is difficult to effectively treat that which cannot be measured, pain assessment and management must be viewed as interdependent, with one essentially useless without the other. The goal of pain assessment is to provide accurate data about the location, qualities, and intensity of pain. Ongoing assessment can also help physicians determine the effect of pain on function; the effectiveness of interventions; and whether cultural, language and cognitive issues, and misconceptions are influencing pain management ( ).

Multiple validated instruments exist to measure and assess pain in children of all ages ( ; ; ). The most commonly used instruments that measure the quality and intensity of pain are “self-report measures.” In older children and adults, the most commonly used self-report instruments are the visual analog scale (VAS) and numerical rating scale (NRS; 0 = no pain; 10 = worst pain). NRS is valid for use in children 8 years of age and older who can comprehend numeric order and quantify their degree of pain ( ).

Pain intensity or severity can also be measured in children as young as 3 years of age by using pictures or word descriptors to describe pain. Two common examples are the Oucher Scale (developed by Dr. Judy Beyer), a two-part scale with a vertical numerical scale (0–100) on one side and six photographs of a young child on the other, and the Six-Face Pain Scale (FPS), first developed by Dr. Donna Wong and later revised by Bieri et al. (FPS-R; Fig. 23.4 ) ( ; ). This scale is recommended for school-aged children (4 to 12 years old) because it has better success rates than the Oucher, NRS, and VAS scales and is preferred by patients ( ). Strong correlations have been demonstrated between the NRS, VAS and FPS-R, though children tend to provide higher ratings with the NRS ( ; ). Accurately defining the location of pain is also helpful and can be accomplished by using dolls or action figures or by using drawings of body outlines, both front and back. Not surprisingly, with improved technology, electronic scales are becoming increasingly available, with good agreement demonstrated between electronic and paper versions but preference in some studies for the electronic format ( ; ).

One obvious limitation of self-report measures is their inability to be used in infants, newborns, the cognitively impaired, and intubated, sedated, and paralyzed patients. In those patients pain can be assessed by measuring physiologic responses to nociceptive stimuli, such as blood pressure and heart rate changes (observational pain scales [OPSs]), or by measuring levels of adrenal stress hormones rather than using nursing or physician assessment ( ). Alternatively, behavioral approaches have used facial expression, body movements, and the intensity and quality of crying as indices of response to nociceptive stimuli. The most appropriate are the Crying, Requires oxygen, Increased vital signs, Expression, and Sleepless (CRIES) score for newborns and the revised Face, Legs, Activity, Cry, and Consolability (FLACC) pain tool for older infants, young children, and those with developmental delay who have difficulty verbalizing pain ( Tables 23.2 and 23.3 ) ( ; ; ).

Another pain and sedation tool that incorporates both behaviors and physiologic parameters is the COMFORT scale, which relies on the measurement of five behavioral variables (alertness, facial tension, muscle tone, agitation, and movement) and three physiologic variables (heart rate, respiration, and blood pressure) ( Table 23.4 ) ( ; ). Each is assigned a score ranging from 1 to 5 to give a total score that extends from 8 (deep sedation) to 40 (alert and agitated). A modified COMFORT scale that eliminates physiologic parameters has also been developed ( ).

It should also be understood that pain management in children is often dependent on the ability of parents to recognize and assess pain and on their decision to treat or not treat it ( ; ). Even in hospitalized patients, most of the pain experienced by children is managed by their parents ( ; ). Parental education is, therefore, essential if children are to be adequately treated for pain. Because parents are primarily responsible for treatment of their children’s pain at home, the Parents’ Postoperative Pain Measure (PPPM) was developed. An observational checklist measure of pain intensity ( ), the tool was designed for use by parents to support research and clinical postoperative care of children at home. Studies have shown that it is a reliable and valid measure of postoperative pain for children 2 through 12 years of age ( ).

With any of these objective scales, however, clinicians must always maintain concern that pain may be underestimated. Studies have shown that healthcare professionals frequently underestimate pain in children, and that reported pain scores are lower in developmentally delayed children who are unable to self-report ( ; ). In addition, behavioral instruments may not be able to differentiate between pain distress and distress from other sources ( ). Hence, interpretation of these scores should include consideration of situational context ( ).

In addition, critically ill children commonly experience pain and agitation due to trauma, medical procedures, invasive devices, and illness-induced discomfort. They often require therapy to provide pain relief and sedation, but they can also experience medication-related side effects, including delirium. Efforts to standardize pain assessment by using objective, noninvasive monitoring such as bispectral index (BIS) or cutaneous conductance have not been successful ( ; ). However, sedation scales have been validated for use in children, specifically the Richmond Agitation Sedation Scale (RASS) and the Pediatric Sedation State Scale (PSSS). The RASS is a scoring system that incorporates both agitation and sedation. It is unique because of its ability to assess awareness, which is important in the recognition of hypoactive and hyperactive delirium. The PSSS is a 6-point scale developed to measure the effectiveness and quality of procedural sedation, including control of pain, anxiety, movement, and adverse side effects. This scoring system allows for analysis of procedural conditions even in the absence of sedation.

Finally, research tools such as functional magnetic resonance imaging and functional near-infrared spectroscopy have been used to objectively assess cortical pain responses and map pain pathways throughout the CNS ( ; ; ). Similarly, electroencephalography has been used to measure event-related cortical activity in a study of needle puncture pain in newborns and infants ( ). Another noninvasive technique that has the potential to provide an objective pain assessment involves analysis of respiratory fluctuations of heart rate to provide a real-time index of parasympathetic tone ( ). In addition, the variation coefficient of pupillary diameter has been shown to correlate with pain in obstetric patients and is under study in children ( ; ; ).

Pharmacologic management of pain: The conundrum of “off-label” drug use

Unfortunately, few studies have evaluated the pharmacokinetic and pharmacodynamic properties of drugs in children ( ; ; ). Most pharmacokinetic studies have been carried out in healthy adult volunteers, adult patients who are only minimally ill, or adult patients in a stable phase of a chronic disease. These data have then been extrapolated to infants, children, and adolescents. As a result, approximately 80% of drugs administered to children in the United States, and over 50% of those administered to children in Europe are prescribed “off-label” ( ). In a 2011 study of medication use in the pediatric intensive care unit (PICU) setting, the authors observed that over two-thirds of the medications prescribed were either not approved for use in any pediatric age group or approved for only limited age groups ( ). These medications included many commonly used to treat pain.

Because historically so little pharmacokinetic and pharmacodynamic testing has been carried out in children, they are often considered “therapeutic orphans” ( ). To address this issue, governmental programs have been enacted over the past two decades to promote pediatric labeling of safe and effective medications for children, including the Best Pharmaceuticals for Children Act, the Pediatric Research Equity Act and the Food and Drug Administration (FDA) Amendments Act. Although these programs have resulted in over 800 labeling changes, analgesic drugs remain underrepresented. For example, no analgesic drugs with a pediatric label have been approved for children less than 6 months of age ( ).

In contrast to acute pain clinical trials in adults, pediatric studies can present unique challenges. Sources of pain often vary with age and pain systems. Pain assessment and relevant metabolic pathways are age-dependent as well. Moreover, placebo-controlled trials, the standard in adult research, may be unethical in those too young to provide consent or assent ( ). As a result of these challenges, the Analgesic, Anesthetic, and Addiction Clinical Trial Translations, Innovations, Opportunities and Networks (ACTTION) Pediatric Pain Research Consortium, in partnership with the US FDA, convened a consensus meeting in 2013 to develop and disseminate recommendations regarding trial designs for acute pain in children. The meeting focused on relevant pain models, methods, and age cohorts in an effort to improve the study of analgesic medications in pediatric populations ( ; ).

Multimodal analgesia

Multimodal analgesia involves the use of a variety of analgesic medications and techniques that target different mechanisms of action in the peripheral nervous system and CNS in an attempt to have additive or synergist effects and provide more effective pain relief than that provided by single-modality interventions ( ). Over the past decade, both adult and pediatric acute pain management have become increasingly characterized by a “balanced” approach in which smaller doses of multiple opioid and nonopioid analgesics are combined in an attempt to maximize pain control and minimize adverse drug-induced side effects ( Fig. 23.5 ) ( ; ; ; ). Additionally, multimodal analgesia can incorporate nonpharmacologic complementary and alternative medicine therapies to reduce anxiety and induce rest and sleep ( ; ).

Multimodal therapy has gained popularity because of its potential to improve postoperative recovery characteristics as well as the desire to reduce opioid use in light of the ongoing opioid epidemic. As a result, we will focus on the numerous components of multimodal analgesia in the setting of pediatric acute pain management below.

Nonpharmacologic management of pain

Recently increased focus has been placed on incorporating nonpharmacologic complementary and alternative medicine therapies to reduce pain and anxiety and induce rest and sleep. As of January 2018, the Joint Commission has required accredited hospitals and facilities to provide nonpharmacologic therapies for pain as a scorable element of performance ( ). Such therapies include, but are not limited to, acupuncture, massage and physical therapy, and cognitive behavioral therapy ( ). A child’s neurodevelopmental stage will affect the way he or she perceives and copes with pain. Therefore, when nonpharmacologic interventions are used, they should be tailored to patient age and developmental stage.

In neonates, nonnutritive sucking, breastfeeding, and sucrose administration have all been used to help with pain relief ( ; ; ). A meta-analysis by provided evidence that sucrose, with or without nonnutritive sucking, could reduce procedural pain from single events such as heel lance, venipuncture, and intramuscular injection in both preterm and term infants. However, sucrose was ineffective at reducing pain from circumcision, and its effectiveness for reducing pain and stress from other interventions such as arterial puncture, subcutaneous injection, insertion of nasogastric or orogastric tubes, bladder catheterization, eye examinations, and echocardiography examinations was inconclusive.

In the Chinese medical model of acupuncture, blockage of the flow of energy, or qi, in the body can result in pain and disease, and placement of acupuncture needles at identifiable points in the body can help restore this flow. An alternative biomedical explanation of acupuncture asserts that placing acupuncture needles at specific points releases endogenous opioids and perhaps other neurotransmitters and neurohormones in the brain ( ). Multiple systematic reviews have shown that, compared with sham acupuncture, controls, and standard care, acupuncture effectively reduces postsurgical pain, the need for opioids, and the incidence of opioid-related side effects ( ; ). Safe use of acupuncture has been established in children ( ). Acupuncture has been shown to be both acceptable and feasible as an adjunct in the management of acute postoperative pain in PICU patients after spinal fusion and other surgeries ( ). As a supplement to conventional analgesia, acupuncture is effective and well tolerated for the treatment of posttonsillectomy pain, and its use reduced postoperative pain and emergence agitation in children after myringotomy tube insertion ( b; ).

Massage therapy involves the manipulation of soft tissues to prevent or alleviate pain, muscle spasms, tension, or stress. Systematic review has shown that a single session of massage therapy significantly improves postoperative pain in adults ( ). In a study of children and adolescents, massage did not affect pain or anxiety scores in the early postoperative period after cardiac surgery. However, compared with controls, children who received massage therapy had significantly lower total benzodiazepine exposure in the 3 days after surgery and lower anxiety scores at discharge ( ).

Cognitive behavioral therapy (CBT) is a brief, goal-oriented form of psychotherapy that includes a combination of cognitive and behavioral techniques, such as reframing, cognitive distraction, and positive self-talk statements. It also utilizes behavioral strategies, such as relaxation, exposure and desensitization, and modeling. Using CBT, therapists can teach children strategies to identify and restructure maladaptive pain-related thoughts and address behaviors that may be contributing to pain-related symptoms. Often employed in the management of chronic pain, CBT has shown efficacy in reducing procedural pain as well ( ; ; ).

Distraction techniques also have been well studied and reported to have large effect sizes, particularly as an intervention for procedural pain ( ; ). In a systematic review of randomized controlled trials of psychological interventions for children and adolescents undergoing needle-related procedures, the largest effect sizes were found for distraction combined with cognitive-behavioral interventions and hypnosis. One type of distraction technique involves the use of virtual reality. Virtual reality technology enables users to become immersed in a computer-simulated three-dimensional environment as a distraction from pain ( ). Coupled with standard analgesia, virtual reality is beneficial for reducing pain related to burn wound care in children and lessening procedural pain and distress caused by intravenous line placement ( ; ).

Additionally, though they have not gained a place in guidelines for pediatric surgery, music interventions are widely used. Music therapy has been shown to reduce postoperative pain, anxiety, and distress in children after orthopedic, cardiac, and day surgery ( ). Moreover, parents, child life specialists, and play therapists can all be helpful in reducing pain and anxiety ( ; ). Of note, decreased parental attention to pain and discomfort and encouragement of positive coping skills have been shown to reduce pain and distress for both procedural and chronic pain ( ).

Though not all of the therapies described here are feasible at all times or in all institutions, it is nonetheless helpful to identify and develop clinical models that integrate nonpharmacologic therapies for pain and deliver evidence-based training to healthcare providers so that they can better incorporate these treatments into patient care paradigms.

Pharmacologic management of pain

Nonsteroidal analgesics (or weaker analgesics with antipyretic activity)

When nonpharmacologic therapy is insufficient, pharmacologic interventions are required. NSAIDs are often the first choice in the treatment of mild pain. The weaker or milder analgesics with antipyretic activity, of which acetaminophen (paracetamol), salicylate (aspirin), ibuprofen, naproxen, ketoprofen, diclofenac, and celecoxib ( ) are examples, are a heterogenous group of NSAIDs and nonopioid analgesics ( Table 23.5 ). See also Chapter 14 (Anesthetic Adjuncts). They produce their analgesic, antiinflammatory, antiplatelet, and antipyretic effects primarily by inhibiting cyclooxygenase (COX) types 1, 2 and 3, thereby blocking peripheral and central prostaglandin and thromboxane production ( Fig. 23.6 ). These metabolites of COX sensitize peripheral nerve endings and dilate blood vessels, causing pain, erythema, and inflammation.

TABLE 23.5

Dosage Guidelines for Commonly Used Nonsteroidal Antiinflammatory Drugs (NSAIDs)

Generic Name	Brand Name	Dose (mg/kg) Frequency	Maximum ADULT Daily Dose (mg)	Comments
Acetaminophen (paracetamol)	Many brand names, including Tylenol, “aspirin-free,” Panadol, Tempra, Ofirmev	10–15 PO q 4–6 hours 20–40 PR q 6–8 hours 12.5–15 IV q 4–6 hours	4000 60 mg/kg per day preterm 80 mg/kg per day term 90 mg/kg per day older	Lacks antiinflammatory activity No platelet effects Hepatic failure with overdose IV form available but expensive
Acetylsalicylic acid (aspirin)	Many brand names, including Bayer, Bufferin, Anacin, Alka-Seltzer	10–15 PO/PR q 4 hours	4000	Inhibits platelet aggregation GI irritability Reye’s syndrome Contraindicated in children
Ibuprofen	Many brand names, including Motrin, Advil IV form: Caldolor, NeoProfen	5–10 PO, IV q 6–8 hours	3200	Available as an oral suspension Renal dysfunction GI irritability Inhibits platelet aggregation 10 mg/kg dose used in newborns to close a patent ductus arteriosus (PDA)
Indomethacin	Indocin	0.3–1.0 PO q 6 hours	150	Commonly used IV to close PDA See Ibuprofen
Naproxen	Naprosyn	5–10 PO q 12 hours	1500	See Ibuprofen
Ketorolac	Toradol	IV or IM Load: 0.5 Maintenance: IV 0.2–0.5 q 6 hours PO 0.25 q 6 hours	120	May be given orally Maximum dose 30 mg Can cause GI upset and ulcers, discontinue after 5 days Expensive See Ibuprofen
Diclofenac	Cambia, Cataflam, Voltaren, Voltaren-XR, Zipsor	0.5–1 PO BID 0.5 PR BID	150	Similar to other NSAIDs Extended-release formulation available Better absorbed rectally than orally IV formulation available
Celecoxib	Celebrex	10–25 kg: 50 mg PO BID (TOTAL DOSE) >25 kg: 100–200 mg PO BID (TOTAL DOSE)	400	Selective COX-2 inhibitor Less GI distress, less antiplatelet effect Risk of MI in adults with chronic administration Indicated for juvenile rheumatoid arthritis Dosing in children under 2 years of age (10 kg) unclear
Choline magnesium trisalicylate	Trilisate	7.5–15 mg PO BID-TID	3000 50 mg/kg per day (max)	Aspirin compound, does not affect platelets No longer commercially available

NSAIDs are administered enterally via the oral or, on occasion, the rectal route and are particularly useful for inflammatory, bony, or rheumatic pain. Parenterally administered agents, including ketorolac, acetaminophen, ibuprofen, and diclofenac, are available for use when the oral or rectal routes of administration are not appropriate ( ; ; ). In addition, ketorolac has been shown to achieve clinically effective plasma concentrations in adolescents after intranasal administration ( ). Although intranasal ketorolac is commercially available (Sprix, Egalet US Inc., Wayne, PA), it is not widely utilized in pediatric patients and is contraindicated for children less than 2 years of age.

Multiple studies and systematic reviews have shown that acetaminophen and NSAIDs are associated with opioid sparing and decreased pain, are cost-effective, and might reduce the risk of opioid-related adverse events ( ; ; ; ; ; ). However, use of these analgesics as single-agent therapy is limited to the treatment of mild-to-moderate pain because they have a “ceiling effect” above which they cannot sufficiently relieve pain when used alone. As a result, these weaker analgesics are often administered in oral combination forms with opioids.

Although studies have not shown major differences in analgesic efficacy when appropriate doses of each drug are used, NSAIDs have at times been shown to be more effective than acetaminophen. In addition, intravenous acetaminophen is generally more effective than the rectal formulation, and coadministration of acetaminophen and an NSAID does at times provide an additive effect ( ).

The commonly used NSAIDs, such as ketorolac, diclofenac, and ibuprofen, have reversible antiplatelet adhesion and aggregation effects that are attributable to the inhibition of thromboxane synthesis ( ). As a result, bleeding times are usually slightly prolonged, but in most instances they remain within normal limits in children who have normal coagulation systems. Nonetheless, this side effect is of significant concern, particularly when used after surgical procedures in which even a small amount of postoperative bleeding can be catastrophic. Hence, for many years clinicians did not prescribe NSAIDs after tonsillectomy even though the evidence supporting increased bleeding was equivocal ( ). However, a 2005 Cochrane review assessing the effects of NSAIDs after pediatric tonsillectomy surgery did not find any increase in bleeding that required surgical intervention ( ). Subsequently, the American Academy of Otolaryngology–Head and Neck Surgery recommended ibuprofen as a safe method of postoperative pain control for children after tonsillectomy ( ).

Care with NSAID therapy should also be taken in dehydrated patients, as dehydration increases the risk of developing acute kidney injury ( ). Finally, for years, many orthopedic surgeons strictly avoided NSAIDs postoperatively out of concern for a negative impact on bone growth and healing, especially after spinal fusion surgery ( ; ). However, an association between nonunion and NSAID use was not statistically significant in an analysis of higher quality studies and was not observed in children ( ; ). In keeping with these findings, the use of NSAIDs has liberalized somewhat in recent years, and some pediatric orthopedic programs now routinely use ketorolac as part of multimodal therapy after spine surgery ( ).

The discovery of at least three COX isoenzymes (COX-1, COX-2, and COX-3) enhanced our knowledge of NSAIDs ( ; ; ). The COX isoenzymes share structural and enzymatic similarities, but they are specifically regulated at the molecular level and may be distinguished by their functions. Protective prostaglandins, which preserve the integrity of the stomach lining and maintain normal renal function in a compromised kidney, are synthesized by COX-1 ( ). The COX-2 isoenzyme is inducible by proinflammatory cytokines and growth factors, implying a role in both inflammation and control of cell growth. In addition to its induction in inflammatory lesions, COX-2 is expressed constitutively in the brain and spinal cord, where it may be involved in nerve transmission, particularly for pain and fever. Prostaglandins made by COX-2 are also important in ovulation and the birth process.

The discovery of COX-2 led to the design of drugs that reduce inflammation without reducing the protective prostaglandins in the stomach and kidneys made by COX-1. Though developing a more specific COX-2 inhibitor was a “holy grail” of drug research for years, adverse cardiovascular risks associated with prolonged use of COX-2 inhibitors identified in postmarket analysis limited the availability of this class of drugs and led to the withdrawal of several compounds from the market ( ). Celecoxib remains available for enteral dosing, and parecoxib, which can be administered parenterally, can be prescribed for use outside of the United States ( ).

Because selective COX-2 inhibitors are less likely than COX-1 inhibitors to induce gastrointestinal ulcers or inhibit platelet aggregation, they are a reasonable option in specific circumstances, such as when an NSAID lacking antiplatelet effects is desirable. Pediatric dosing and pharmacokinetic data are available for celecoxib, which has shown efficacy and good tolerance when used in the management of juvenile rheumatoid arthritis pain ( ; ).

Aspirin

Aspirin, one of the oldest and most effective nonopioid analgesics, has been largely abandoned as a pediatric analgesic because of its possible role in Reye’s syndrome, its effects on platelet function, and its gastric irritant properties. In certain circumstances, however, its antiplatelet effects remain desirable, such as in patients who need to maintain shunt patency after cardiac surgery. Conversely, aspirin’s “sister” compound, choline-magnesium trisalicylate, is a unique aspirin-like compound that does not bind to platelets and therefore has minimal, if any, effects on platelet function. As a result, it was used for years in patients who had low platelet counts (e.g., cancer patients). Unfortunately, it is no longer commercially available for use.

Acetaminophen

One of the most commonly used nonopioid analgesics in pediatric practice remains acetaminophen ( ). Unlike aspirin and other NSAIDs, acetaminophen produces analgesia centrally as a COX-3 inhibitor and via activation of descending serotonergic pathways ( ; ). It is also thought to produce analgesia as a cannabinoid agonist and by antagonizing NMDA and substance P in the spinal cord ( ). Acetaminophen is an antipyretic analgesic with minimal, if any, antiinflammatory and antiplatelet activity. It provides effective analgesia in approximately 30 minutes when administered orally in standard doses (10 to 15 mg/kg every 4 to 6 hours), is extremely safe and effective, and has few serious side effects. When administered rectally, higher doses of 25 to 40 mg/kg are required ( ). Because of its known association with fulminant hepatic necrosis, the daily maximum acetaminophen dose, regardless of formulation or route of delivery, is 60 mg/kg in the preterm infant, 80 mg/kg in the full-term infant, and 90 mg/kg in older children ( Table 23.5 ). Thus, when administering acetaminophen rectally it should be given every 8 hours rather than every 4 hours.

Finally, intravenous acetaminophen can be used for patients in whom the enteral route is unavailable. This formulation bypasses first-pass metabolism in the liver and reaches peak cerebrospinal fluid levels at a significantly faster rate than after oral administration ( ). It has been associated with better analgesia than oral acetaminophen in clinical trials of adult patients. In one study of adolescents undergoing posterior spinal fusion surgery, intravenous acetaminophen use was associated with earlier oral intake and hospital discharge that was thought to be due to decreased opioid consumption ( ). Though questions remain regarding the analgesic efficacy of oral acetaminophen in newborns, intravenous acetaminophen has been shown to be effective as monotherapy for the treatment of moderate pain in neonates and to be opioid sparing in infants and toddlers ( ; ; ). The primary limitation to the use of intravenous acetaminophen is its cost, which for many healthcare delivery systems is prohibitive. However, its use may be justified when associated with reduced postoperative length of stay.

Opioids

Overview

Over the past 30 years, multiple opioid receptors and subtypes have been identified and classified, and six major categories have been described: mu (µ; for morphine), kappa (κ), delta (δ), nociception (NOR), sigma (σ), and epsilon (ε). These receptors bind multiple endogenous and exogenous ligands that elicit physiologic and pharmacologic effects. See also Chapter 12 (Opioids). They are primarily located in the brain and spinal cord but are also present on peripheral nerve cells, immune cells, and other cells (e.g., oocytes) ( ; ; ; ). The mu receptor is further subdivided into several subtypes such as the mu ₁ (supraspinal analgesia), mu ₂ (respiratory depression, inhibition of gastrointestinal motility), and mu ₃ (antiinflammation, leukocytes), which affect the pharmacologic profiles of different opioids ( ). Activation of mu and delta opioid receptors results in rewarding effects and analgesia, whereas the kappa opioid receptor is involved in aversion and dysphoria.

The differentiation of agonists and antagonists is fundamental to pharmacology. A neurotransmitter is defined as having agonist activity, whereas a drug that blocks the action of a neurotransmitter is an antagonist. By definition, receptor recognition of an agonist is “translated” into other cellular alterations (i.e., the agonist initiates a pharmacologic effect), whereas an antagonist occupies the receptor without initiating a transduction step (i.e., it has no intrinsic activity or efficacy). The intrinsic activity of a drug defines the ability of the drug-receptor complex to initiate a pharmacologic effect. Drugs that produce a less-than-maximal response have a lowered intrinsic activity and are called partial agonists. Partial agonists also have antagonistic properties because, by binding the receptor site, they block access of full agonists to the site. Morphine and related opioids are mu agonists, whereas drugs that block the effects of opioids at the mu-opioid receptor, such as naloxone, are designated antagonists. The opioids most commonly used in anesthetic practice and in the management of pain are mu agonists. These include morphine, the fentanyls (fentanyl, alfentanil, sufentanil, remifentanil), hydromorphone, hydrocodone, oxycodone, methadone, and meperidine (pethidine). Mixed agonist-antagonist drugs act as agonists or partial agonists at one receptor and antagonists at another receptor, and include the drugs pentazocine, butorphanol, buprenorphine, nalorphine, and nalbuphine. Most of these drugs are agonists or partial agonists at the kappa and sigma receptors and antagonists at the mu receptor. Naloxone and its oral equivalent, naltrexone, are nonspecific opioid antagonists.

Opioid receptors are anchored to the plasma membrane both presynaptically and postsynaptically, and belong to the steroid superfamily of G-protein-coupled receptors. Their protein structure contains seven transmembrane regions with extracellular loops that confer subtype specificity and intracellular loops that mediate subreceptor phenomena ( ; ). Differences in the extracellular N-terminus determine which ligands bind to the receptor. Intracellularly, receptors couple to guanine nucleotide (GTP)-binding regulatory proteins (G-proteins) and regulate transmembrane signaling by regulating adenylate cyclase (and therefore cyclic adenosine monophosphate [cAMP] levels), various ion channels (K ⁺ , Ca ²⁺ , and Na ⁺ ) and transport proteins, neuronal nitric oxide synthase, and phospholipase C and A2 ( Fig. 23.7 ). Differences in intracellular regions at the C-terminus allow for specificity of downstream signaling and account for the activation of these different pathways by the receptor subtypes ( ).

Opioid signal transduction pathways can produce both inhibitory and excitatory effects. Inhibitory signaling confers analgesia via activation of the inhibitory G-coupled proteins G _i and G _o . Analgesic effects are mediated by a decrease in neuronal excitability from an inwardly rectifying K ⁺ current, which hyperpolarizes the neuronal membrane, reduces action potential duration, decreases cAMP production, increases nitric oxide synthesis, decreases neurotransmitter release, and increases the production of 12-lipoxygenase metabolites. Indeed, synergism between opioids and NSAIDs occurs because the blockade of prostaglandin production by NSAIDs increases the availability of arachidonic acid for metabolism by the 12-lipooxygenase pathway ( ; ).

In addition to inhibitory effects, some opioid agonists elicit excitatory effects by causing receptor coupling with stimulatory G-proteins (G _s ), which stimulate adenylate cyclase, thereby increasing intracellular cAMP and activating protein kinase A. Excitatory signaling can result in transduction of pronociceptive signals ( ), as well as some of the unwanted side effects of opioids, such as pruritus. The nociceptive pathway is activated at much lower ligand concentrations than inhibitory signaling, and for this reason it may be antagonized by low-dose infusions of naloxone ( Fig. 23.7 ) ( ; ). In addition, a strong interaction appears to exist between this excitatory pathway and NMDA receptors. Such an interaction may explain the observation that subanesthetic doses of ketamine can lower opioid requirements in opioid-dependent patients ( ).

Pharmacokinetics

For opioids to effectively relieve or prevent most pain, the agonist must reach the receptor in the CNS. There are essentially two ways that this occurs. See also Chapter 12 (Opioids). Opioids can reach the CNS via the bloodstream (after intravenous, intramuscular, oral, nasal, transdermal, or mucosal administration) or by direct application into the cerebrospinal fluid (intrathecal or epidural dosing). Agonists administered via the bloodstream must cross the blood-brain barrier—a lipid membrane interface between the endothelial cells of the brain vasculature and the extracellular fluid of the brain—to reach the receptor. Normally, highly lipid-soluble agonists, such as fentanyl, rapidly diffuse across the blood-brain barrier, whereas agonists with low lipid solubility, such as morphine, have limited brain uptake. This rule, however, does not hold true for patients of all ages. The blood-brain barrier is immature at birth and known to be more permeable to morphine in neonates. Indeed, Kupferberg and Way demonstrated in a classic paper that morphine concentrations were two to four times greater in the brains of younger rats than in those of older rats despite equal blood concentrations ( ) (see Fig. 12.2 ). Spinal administration, either intrathecally (subarachnoid) or epidurally, bypasses the blood and places an agonist directly into the cerebrospinal fluid, which bathes the receptor sites in the spinal cord (substantia gelatinosa) and brain. This “back door” to the receptor significantly reduces the amount of agonist needed to relieve pain or induce opioid side effects ( ; ). After spinal administration, opioids are absorbed by the epidural veins and redistributed to the systemic circulation, where they are metabolized and excreted. Hydrophilic agents such as morphine cross the dura more slowly than more lipid-soluble agents such as fentanyl. This physicochemical property is responsible for the more prolonged duration of action of spinal morphine and its very slow onset of action after epidural administration ( ; ).

Biotransformation

Effects of age and disease.

Morphine, meperidine, methadone, codeine, and fentanyl are biotransformed in the liver before excretion by the kidneys. Many of these reactions are catalyzed in the liver by glucuronidation or microsomal mixed-function oxidases that require the cytochrome P450 system, nicotinamide adenine dinucleotide phosphate (NADPH), and oxygen. The cytochrome P450 system is immature at birth and does not reach adult levels of activity until the first month or two of life. The immaturity of this hepatic enzyme system may explain the prolonged clearance or elimination of some opioids in the first few days to weeks of life ( ). On the other hand, the P450 system can be induced by various drugs (such as phenobarbital) and substrates, and once the infant is born, the system matures regardless of gestational age. Thus it is the age from birth and not the duration of gestation that generally determines how premature and full-term infants metabolize drugs.

Morphine is primarily glucuronidated into two forms: the inactive morphine-3-glucuronide and the active morphine-6-glucuronide, which has analgesic properties. Both forms are excreted by the kidney. In patients with renal failure, morphine-6-glucuronide can accumulate and cause toxic side effects including respiratory depression ( ; ). Conversely, accumulation of the analgesically inactive 3-glucuronide can produce neuroexcitation, jitteriness, and insomnia. These effects are important to consider not only when prescribing morphine but when administering other opioids that are metabolized into morphine, such as codeine.

The pharmacokinetics of opioids in patients with liver disease and in critically ill patients requires special attention. Many disease states common in the critically ill may alter the metabolism and elimination of morphine and other drugs. Severe cirrhosis, septic shock, and renal failure decrease the clearance of morphine and its metabolites, resulting in increased accumulation, prolonged duration of action, and possible toxicity. Oxidation of opioids is reduced in patients with hepatic cirrhosis, resulting in decreased drug clearance and increased oral bioavailability caused by a reduced first-pass metabolism. Although glucuronidation is thought to be less affected by cirrhosis, the clearance of morphine is decreased and oral bioavailability is increased. Thus the consequence of reduced drug metabolism can be increased drug accumulation in the body, especially with repeated administration, which underscores the old adage: “go low and slow” ( Table 23.6 ) ( ; ; ). Lower doses or longer administration intervals should be used to minimize this risk. Although prescribed less frequently nowadays, meperidine poses a special concern because it is metabolized into normeperidine, a toxic metabolite that causes seizures and accumulates in patients with liver disease. On the other hand, inactive drugs (prodrugs), such as codeine, that require hepatic metabolism for conversion into an active form may be ineffective in patients with severe liver disease. Finally, the disposition of a few opioids, such as fentanyl, sufentanil, and remifentanil, appears to be unaffected by liver disease. As a result, these drugs may be preferentially used in managing pain in patients with liver disease.

TABLE 23.6

Opioid Use Guidelines in Hepatic and Renal Dysfunction

Drug	pKa	Protein Binding (%)	Phase 1 Metabolism	Phase 2 Metabolism	Active Metabolite	Biliary Excretion 1 (%)	Renal Excretion 2	Use in Renal Failure
Morphine	8.0	30	None	Glucuronidation	M6G	10	Metabolites	Use with caution a , c
Fentanyl	8.4	80	CYP3A4	None	None		Norfentanyl	Preferred b , e
Hydromorphone	8.2	20	None	Glucuronidation	H6G		H3G & H6G	Use with caution a , d
Meperidine	8.5	75	CYP3A4	None	Normeperidine		Meperidinenormeperidine	No f
Methadone	8.3	90	CYP2B6 CYP3A4, CYP2D6	None	None	20–40	Metabolites	Use with caution b , e
Codeine	8.2	25	CYP2D6	None	Morphine, Hydrocodone M6G		M6G	No b , d
Oxycodone	8.5	45	CYP3A4, CYP2D6	None	Oxymorphone		Noroxycodone	Use with caution f
Oxymorphone	8.2	10	CYP3A4	Glucuronidation	None		Noroxymorphone	Use with caution a , c
Remifentanil	7.1	70	Esterase	None	None		Metabolite	Preferred

1 In setting of hepatic dysfunction, all opioids should be used cautiously (“go low, go slow”). Meperidine (inactive metabolite is associated with seizures) and codeine (cannot be metabolized into active metabolite, morphine) should not be used. Fentanyl may be best opioid to use (in severe liver dysfunction, plasma cholinesterase may not be available to metabolize remifentanil).

2 In setting of renal failure, metabolites of morphine, codeine, hydromorphone, hydrocodone, and meperidine can accumulate producing increased therapeutic and adverse effects.

a Parent drug removed by dialysis; ^b Parent drug not/poorly dialyzed; ^c Metabolites removed by dialysis; ^d Metabolites not/poorly dialyzed; ^e Metabolites inactive; ^f No data.

You're Reading a Preview

Become a Clinical Tree membership for Full access and enjoy Unlimited articles

Become membership

If you are a member. Log in here