Pediatric Acute and Surgical Pain Management: Recent Advances and Future Perspectives

Vidya Chidambaran, MD Senthilkumar Sadhasivam, MD, MPH Departments of Anesthesia and Pediatrics, Cincinnati Children’s Hospital Medical Center, Cincinnati, Ohio

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Objectives

1. To review limitations of currently used analgesic modalities, surgeryspecific analgesia protocols, and available alternative drugs in children. 2. To discuss the effects of developmental pharmacology and neurobiology on pain management. 3. To introduce fundamentals of pharmacogenomics and personalized analgesia.

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Introduction

Children suffer pain similar to adults. Besides developmental differences, they exhibit exaggerated emotional and behavioral components of pain including higher anxiety and altered coping mechanisms compared with adults.1 Although the practice of pediatric pain management has made great progress in the last decade with the development and validation of pain assessment tools specific to children,2 acute pain remains underrecognized and undertreated even in hospitalized children.3 Parental behavior and misconceptions regarding pain medications, including fear of opioid addiction, fear of serious adverse drug effects, difficulties in assessment of pain, and lack of advocacy constitute reasons for this suboptimal alleviation of pain among this population. A national survey of 252 institutions found that REPRINTS: VIDYA CHIDAMBARAN, MD, CINCINNATI CHILDREN’S HOSPITAL MEDICAL CENTER, 3333 BURNET AVE, MLC 2001, CINCINNATI, OH 45229. E-MAIL: [email protected] INTERNATIONAL ANESTHESIOLOGY CLINICS Volume 50, Number 4, 66–82 r 2012, Lippincott Williams & Wilkins

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only 51% had a pediatric pain management service, the practices and supervision of which were influenced by patient characteristics, institutional demographics, and published national guidelines.4 At our institution, a pain management service initiated in the early 1990s has over the years matured into full-fledged divisions encompassing specific inpatient and outpatient services for perioperative pain, medical pain, chronic pain, and palliative care in addition to education of pain in the core pediatric anesthesia fellowship as well as advanced fellowships in chronic medical pain and palliative care. Our perioperative pain service provides 24/7 coverage with an advanced practice nurse and 1 rotating pediatric anesthesia fellow during the day and 1 nurse trained in pain and a cross-covering anesthesia fellow during the night, under the overall supervision of a faculty member. In fiscal year 2011, we performed >4000 consultations including 750 regional analgesia procedures. In this chapter, we will discuss limitations of currently popular modalities including patient-controlled analgesia (PCA), protocols for the management of pain after pectus excavatum, and scoliosis surgeries and the pharmacology of newly available analgesics like intravenous (IV) acetaminophen in children. We will also review current literature regarding developmental neurobiology and pharmacology in relation to neonatal/fetal pain and neurotoxicity of analgesia to the developing brain. Finally, we will introduce concepts related to pain genetics and the effects of genetic variations on pharmacokinetics and pharmacodynamics of analgesics, especially opioids. Limitations of Currently Used Analgesic Modalities

Although there has been a steady increase in regional analgesic techniques including neuraxial and peripheral nerve blocks for pediatric pain management, PCA remains the most common method of providing opioid analgesia in children.5 PCA is controlled by the patient or a proxy (usually the guardian or the nurse). Two main controversies currently exist related to PCA use in children. 1. PCA by proxy: The Joint Commission issued a sentinel alert in 2004 cautioning against this practice, in which the nurse or parent pushes the PCA button to keep the child comfortable (http://www.jointcom mission.org/assets/1/18/SEA_33.PDF), bypassing the safety feature of the PCA, wherein an oversedated patient cannot push the button. Keeping this in mind, it is essential to have criteria for selecting appropriate patients to receive PCA by proxy. Most children are able to play computer games (by age 6 y) and can understand the PCA/ “pain relief button.” At our institution, children less than 6 years of age and those with mental or disability (preventing pushing of the button) often receive PCA by proxy (nurse and/or a responsible www.anesthesiaclinics.com

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parent). The pain management team, recovery room, and inpatient floor nurses educate family members and provide written instructions regarding the proper use of PCA by proxy emphasizing the danger of pressing the button when the child is not awake. Proxycontrolled analgesia has been found to provide effective pain relief in children less than 6 years of age, although 1.7% incidence of significant apnea/desaturation reinforces the need for patient monitoring.6 With the use of modified Ramsay sedation scale monitoring and use of IV acetaminophen and ketorolac in eligible patients, at our institution, the incidence of severe respiratory depression is T) were not associated with racial differences in morphine’s clearance even though the wild-type of the UGT2B7 isozyme is more prevalent in the African Americans.48 Nonopioid Analgesics and Developmental Pharmacogenetics

Acetaminophen (APAP): APAP is bioactivated to the reactive intermediate, N-acetyl-p-benzoquinoneimine (NAPQI) by 3 CYP 450 isoforms: CYP3A4, CYP2E1, and CYP1A2.49 NAPQI then undergoes conjugation with glutathione to form a nontoxic conjugate. Depletion of glutathione stores causes NAPQI to bind with thiols leading to hepatocellular necrosis.50 Developmental pharmacology studies indicate that CYP3A4 and CYP1A2 activity in 12- to 48-month-old children exceed younger and older children, making the 12 to 48 month olds prone to APAP hepatotoxicity. This is offset by an increased capacity to conjugate the drug with sulfates, providing “relative protection” against acute APAP intoxication. Nevertheless, true polymorphisms of glutathione transferase exist and individuals with the poor metabolizer phenotype are at increased risk of APAP-induced hepatotoxicity51 NSAID: Ketorolac does appear to significantly penetrate cerebrospinal fluid in children, unlike adults. The MDR-1 gene has been suggested as the transport factor for ketorolac to cross the blood brain barrier.52 www.anesthesiaclinics.com

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Animal studies have shown that developmental differences in COX-1 expression in the spinal cord explain the lack of efficacy of COX-1 inhibitors in 3 day-old rat pups compared with 21-day-old rat pups.53 Should similar developmental expression of COX-1 occur in humans, COX-1 inhibitors such as NSAID and APAP may exhibit reduced efficacy in neonates.54 The role of pharmacogenetics in drug response has been rapidly evolving. Genetic factors account for 20% to 95% of drug response variability; 59% of drugs having adverse reactions are metabolized by at least 1 enzyme with a variant allele associated with poor metabolism.55 Presently, the FDA has approved pharmacogenetic warnings in the labels of over 100 drugs, including analgesics like codeine, tramadol/ acetaminophen combinations, and celecoxib.56 Table 1 depicts the pharmacological effects of genetic variations on opioid analgesia. OPRM1 118G variations reduces opioid signaling and increases morphine dose requirement. The presence of the V158M variant of the catechol-O-methyl transferase (COMT) coded by the 472G > A SNP leads to a low-function COMT enzyme that fails to degrade dopamine, leading to a depletion of encephalin and compensatory upregulation of opioid receptor expression. Besides, presence of Z2 nonfunctional Melanocortin Receptor (MC1R) variants resulted in impaired G-protein coupling and decreased function of MC1R receptors leading to a sex nonspecific increase in potency of m-opioid agonists. Lotsch and Geisslinger have suggested simple genotype tailored morphine dosing ranging from 0.4 to 2 times the dose of morphine required for equivalent analgesia in those without the gene variant ( 2 for OPRM1 118G,  0.67 for COMT 472A,  0.67 for 2 MC1R nonfunctional SNPs and multiplicative model for multiple SNPs),74 and this has not been validated in different pain phenotypes and populations. Hence, it remains a futuristic challenge to validate genotype-phenotype associations and incorporate them into the decision-making process of drug and dose selection, to make personalized analgesia a practicable reality and not just a distant dream. ’

Summary

Acute surgical pain management in children is best addressed by a dedicated pain management team. Although PCA with opioids forms the main modality of analgesia, regional techniques have gained popularity. PCA by proxy and PCA basal infusions enhance analgesia but carry a risk for respiratory depression and sedation. Efficient prevention of opioid-induced respiratory depression requires the use of appropriate monitoring including pulsoximetry and respiratory rate, clinical sedation scoring system, repeated assessment by the pain team, early www.anesthesiaclinics.com

*6(516G > T, 85A > G) *16, *5 (172H-262K-487C)

Polymorphisms/Alleles

Interleukin 1 Receptor antagonist (IL1Ra) gene (IL1RN)

IL1Ra 86 bp variable number of tandem repeats (VNTR) of 86 base pair (bp) in intron 2

CYP2D6 (phase I metabolism) PM have 2 nonfunctional alleles, IM have Z1 reduced functional allele or 1 active allele (IM), extensive metabolizers have Z1 or 2 functional alleles and UM have multiple functional alleles.*3 -*8, *11-*16, *19-*21, *38, *40, *42 (inactive); *1, *2, *35 (functional/wild-type); *9, *10, *17, *29, *36, *41 (decreased activity) A118G (asparagine to aspartic acid m-opioid receptor leading to reduced receptor affinity) (OPRM1): Gprotein-coupled opioid receptor

CYP2B6 (phase I metabolism)

Gene

Affects inflammatory reaction and hence nociception

(continued)

Postoperative (after knee, abdominal, orthognathic, abdominal surgery) morphine and fentanyl requirement has been found to be higher in patients with the GG genotype, and lower pain scores in the AA genotype64–67 IL1Ra SNP may contribute to variation in postoperative morphine consumption after hysterectomy68; patients homozygous for the IL1RN*1 allele have lower concentrations of IL1Ra and require higher doses of opioids after nephrectomy than patients carrying at least 1 IL1RN*2 allele69

All opioids

Codeine Tramadol Hydrocodone Oxycodone Dihydrocodeine

Increased risk of prolonged QT interval after methadone use in *6/*6 variant because of reduced metabolism57 *6 variant associated with methadonerelated mortality58 Reports of death after codeine therapy in a breast-fed infant of UM phenotype mother and a 2-y-old boy after tonsillectomy59–61 Tramadol requirement after abdominal surgery higher in PM phenotype62,63

Clinical Consequences of Genetic Variations on Opioid Effects

Methadone Meperidine Tramadol Hydromorphone

Opioids

Table 1. Genetic Polymorphisms Affecting the Pharmacokinetics and Pharmacodynamics of Opioids

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rs6269, rs4633, rs4818, rs4680: decrease in COMT activity is associated with higher pain sensitivity

R151C R160W D294H C1236T, C3435T, G2677T/A: reduced pglycoprotein activity results in reduced opioid efflux across blood brain barrier and increased brain concentrations

COMT

Melanocortin receptor (MC1R) Morphine Fentanyl Methadone Sufentanil Alfentanil Morphine-6glucuronide

k-agonists like pentazocine

Affects pain perception

Opioids Low pain, average pain, and high pain sensitivity haplotypes were identified based on the SNPs. rs4680 (Val 158Met) variant was associated with increased pain sensitivity70 Red-haired women with 2 nonfunctional variants had greater analgesia from kagonist, pentazocine71 The diplotype at 2677 and 3435 in ABCB1 was associated with the frequency of vomiting72; patients with ineffective efflux pump (ABCB1/MDR-1 homozygous T/T) and a functional receptor (OPRM1 homozygous A/A) were the best responders to morphine73

Clinical Consequences of Genetic Variations on Opioid Effects

ABCB1 indicates ATP-binding cassette transporter; COMT, catechol-O-methyl transferase; IM, intermediate metabolizers; IL, interleukin; PM, poor metabolizers; UM, ultrarapid metabolizer.

ABCB1 codes for p-glycoprotein

Polymorphisms/Alleles

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Gene

Table 1. (continued)

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intervention protocols, and use of nonopioid adjuncts like IV or oral acetaminophen and ketorolac/NSAIDs. Thalamocortical connections underpinning the neuroanatomy of pain appear between 20 and 30 weeks of gestational age, and the physiological mechanisms for pain perception become established by early second trimester. There are long-lasting effects of pain experienced in early life underscoring the need to treat surgical pain in fetuses, premature infants, and neonates. In contrast, there is a growing body of evidence in animal models implicating opioids in adversely altering neuronal proliferation in the developing brain and clinical studies wherein morphine sedation in the neonatal period was found to decrease visual motor integration in childhood, suggesting a potential for neurocognitive sequelae. Ongoing research provides hope that future integration of pharmacogenetics, metabolomics, and proteomics in clinical decision and analgesic selection/dosing processes will maximize analgesia and minimize adverse effects.

The authors have no conflicts of interest to disclose.

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