Tolerance and Withdrawal From Prolonged Opioid Use in Critically Ill Children

AUTHORS: Kanwaljeet J. S. Anand, MBBS, DPhil,a Douglas F. abstract Willson, MD,b John Berger, MD,c Rick Harrison, MD,d Kathleen L. Meert, MD,e Jerry Zimmerman, MD, PhD,f Joseph OBJECTIVE: After prolonged opioid exposure, children develop opioid- Carcillo, MD,g Christopher J. L. Newth, MD, FRCPC,h Parthak induced hyperalgesia, tolerance, and withdrawal. Strategies for pre- Prodhan, MD,i J. Michael Dean, MD,j and Carol Nicholson, vention and management should be based on the mechanisms of opi- MD,k for the Eunice Kennedy Shriver National Institute of oid tolerance and withdrawal. Child Health and Human Development Collaborative Pediatric Critical Care Research Network PATIENTS AND METHODS: Relevant manuscripts published in the En- aDepartment of Pediatrics, Le Bonheur Children’s Hospital and glish language were searched in Medline by using search terms “opi- University of Tennessee Health Science Center, Memphis, oid,” “opiate,” “sedation,” “analgesia,” “child,” “infant-newborn,” “toler- Tennessee; bDepartment of Pediatrics & Anesthesiology, University ance,” “dependency,” “withdrawal,” “analgesic,” “receptor,” and of Virginia Children’s Hospital, Charlottesville, Virginia; cDepartment of Pediatrics, Children’s National Medical Center, Washington, DC; “individual opioid drugs.” Clinical and preclinical studies were re- dDepartment of Pediatrics, University of California at Los Angeles, viewed for data synthesis. Los Angeles, California; eDepartment of Pediatrics, Children’s f RESULTS: Mechanisms of opioid-induced hyperalgesia and tolerance Hospital of Michigan, Detroit, Michigan; Department of Pediatrics, Children’s Hospital and Medical Center, Seattle, Washington; suggest important drug- and patient-related risk factors that lead to gDepartment of Critical Care Medicine, Children’s Hospital of tolerance and withdrawal. Opioid tolerance occurs earlier in the Pittsburgh, Pittsburgh, Pennsylvania; hDepartment of Pediatrics, younger age groups, develops commonly during critical illness, and Children’s Hospital Los Angeles, Los Angeles, California; iDepartment of Pediatrics, University of Arkansas for Medical results more frequently from prolonged intravenous infusions of Sciences, Little Rock, Arkansas; jDepartment of Pediatrics, short-acting opioids. Treatment options include slowly tapering opioid University of Utah School of Medicine, Salt Lake City, Utah; and doses, switching to longer-acting opioids, or specifically treating the kPediatric Critical Care and Rehabilitation Program, National Center for Medical Rehabilitation Research (NCMRR), Eunice symptoms of opioid withdrawal. Novel therapies may also include Kennedy Shriver National Institute of Child Health and Human blocking the mechanisms of opioid tolerance, which would enhance Development, National Institutes of Health, Bethesda, Maryland the safety and effectiveness of opioid analgesia. KEY WORDS CONCLUSIONS: Opioid tolerance and withdrawal occur frequently in tolerance, withdrawal, abstinence, opiate, opioid, narcotic, stress, critical illness critically ill children. Novel insights into opioid receptor physiology and ABBREVIATIONS cellular biochemical changes will inform scientific approaches for the AC—adenylate cyclase use of opioid analgesia and the prevention of opioid tolerance and cAMP—cyclic adenosine monophosphate withdrawal. Pediatrics 2010;125:e1208–e1225 iNOS—inducible nitric oxide synthase PKC—protein kinase C NMDA—N-methyl-D-aspartate COMT—catechol-O-methyltransferase SNP—single-nucleotide polymorphism M6G—morphine-6-glucuronide M3G—morphine-3-glucuronide MNAS—Modified Narcotic Abstinence Scale WAT-1—Withdrawal Assessment Tool 1 www.pediatrics.org/cgi/doi/10.1542/peds.2009-0489 doi:10.1542/peds.2009-0489 Accepted for publication Dec 10, 2009 Address correspondence to Kanwaljeet J. S. Anand, MBBS, DPhil, Le Bonheur Children’s Medical Center, Room 4624, 50 N Dunlap St, Memphis, TN 38103. E-mail: [email protected] PEDIATRICS (ISSN Numbers: Print, 0031-4005; Online, 1098-4275). Copyright © 2010 by the American Academy of Pediatrics FINANCIAL DISCLOSURE: The authors have indicated they have no financial relationships relevant to this article to disclose. Funded by the National Institutes of Health (NIH).

e1208 ANAND et al Downloaded from www.pediatrics.org. Provided by Eccles Health Sciences Lib on May 11, 2010 REVIEW ARTICLES

TABLE 1 Definition of Terms and Underlying Mechanisms Term Definition Primary Mechanism Tolerance Decreasing clinical effects of a drug after prolonged exposure Upregulation of the cAMP pathway; desensitization of opioid to it receptors; other mechanisms Dependence A physiologic and biochemical adaptation of neurons such that Activation of second-messenger protein kinases; changes in removing a drug precipitates withdrawal or an abstinence neurotransmitter levels; changes in neuronal networks syndrome

Withdrawal A clinical syndrome that manifests after stopping or reversing a Superactivation of AC; opioid receptor coupling to Gs drug after prolonged exposure to that drug protein; activation of excitatory amino acid receptors Tachyphylaxis Rapid loss of drug effects caused by compensatory Exhaustion of synaptic neurotransmitters; activation of neurophysiologic mechanisms antagonist signaling systems; activation of NMDA receptors and iNOS Addiction A chronic, relapsing syndrome of psychological dependence and Activation of dopaminergic reward systems in nucleus craving a drug for its psychedelic, sedative, or euphoric accumbens; mechanisms associated with tolerance and effects; characterized by compulsion, loss of control, and dependence continued use of a substance despite harmful effects

Critically ill children and neonates rou- endanger the stability of endotracheal combinations, it is likely that most tinely receive opioids for analgesia tubes, vascular access devices, or drug-related complications remain and sedation to reduce pain, anxiety, other interventions that are necessary unreported. agitation, and stress responses; retain for intensive care. Unplanned extuba- Opioid tolerance was identified from a monitoring devices; facilitate ventila- tions in children with a critical airway retrospective chart review in neo- 24,25 tion; and avoid secondary complica- can be fatal. nates,31 which showed fivefold in- 1–3 tions. Prolonged opioid therapy Overuse of these agents, however, creases in fentanyl infusions coupled often leads to tolerance, seen as may also have untoward conse- with increases in plasma fentanyl con- diminishing pharmacologic effects, quences. Results of recent studies centrations to maintain the same clin- and is associated with opioid with- have suggested that critically ill pa- ical effect.31,32 Total fentanyl doses of drawal when opioids are weaned or tients are often oversedated, which more than 1.6 mg/kg or infusions that 4–8 discontinued (Table 1). Opioid with- prolongs their ventilator course and lasted longer than 5 days led to opioid drawal can be treated or prevented by ICU stay.26 The need to wean seda- withdrawal.31,32 Katz et al33 reported using a variety of therapeutic ap- tives or treat withdrawal symptoms opioid withdrawal in 13 of 23 infants on proaches,4,9 but it may be more desir- can also delay ICU and hospital dis- fentanyl infusions and in all those who able to block the mechanisms that lead charge.7 received fentanyl for more than 9 days. to opioid tolerance.10–12 We review here Results of subsequent reports4,31,34–38 the epidemiology of opioid tolerance No consensus exists regarding the suggested that opioid withdrawal oc- and withdrawal, the underlying cel- optimal choice, route, or dosing of curs in up to 57% of PICU patients33 and lular mechanisms, and novel ap- analgesic/sedative drugs in children in 60% of PICUs.39–42 Multiple studies proaches to avoiding these complica- (Table 2). The Paediatric Intensive have revealed complications39,40 and tions in critically ill children. Care Society (of the United Kingdom) recently published 20 recommenda- prolonged hospitalization that re- SCOPE OF THE PROBLEM tions regarding analgesia/sedation, sulted from opioid tolerance after crit- 7,41 Treatment of pain is a priority for all but none of these were based on ran- ical illness. Clearer understanding patients,13 especially for children be- domized clinical trials or dealt with of opioid pharmacology may improve cause of their vulnerability and limited tolerance or withdrawal.27 The most the management of opioid tolerance, understanding.14 Appropriate analge- commonly used drugs include mor- dependence, and withdrawal in pediat- sia reduces the stress responses and phine, fentanyl, midazolam, and ric patients. improves the clinical outcomes of pe- lorazepam,28–30 but none of these diatric patients,15–17 whereas inade- drugs have been well studied in chil- CELLULAR CHANGES AFTER OPIOID quately treated pain may alter their dren. Given that opioids are often THERAPY subsequent development.18–20 Up to used for extended periods of time, in Six major categories of opioid recep- 74% of children recalled their painful continuous infusions as opposed to tors and their subtypes have been experiences during PICU admis- their initially intended periodic described: ␮, ␬, ␦,nociceptin,␴,and sion.21–23 Pain-induced agitation can administration, and in unstudied ␧ (Table 3). Opioid agonists elicit

PEDIATRICS Volume 125, Number 5, May 2010 e1209 Downloaded from www.pediatrics.org. Provided by Eccles Health Sciences Lib on May 11, 2010 TABLE 2 Equivalent Analgesic Doses of Opioids Generic Name Total Adult Pediatric Dose, Oral/Parenteral Duration of Maximum Dose, mg mg/kg Potency Ratio Analgesia, h Efficacy Opioid analgesics used frequently in PICU patients Morphine 10 0.05–0.1 Low 4–5 High Fentanyl 0.1 0.001–0.003 Low 1–1.5 High Methadone 10 0.025–0.1 High 8–24 High Hydromorphone 1.5 0.002–0.005 Low 4–5 High Meperidine 60–100 0.5–1.5 Medium 2–4 High Opioid analgesics used less frequently in PICU patients Oxymorphone 0.5–1.5 Insufficient data Low 3–4 High Sufentanil 0.02 0.0001–0.0003 Parenteral only 1–1.5 High Alfentanil 0.3 0.01–0.05 Parenteral only 0.25–0.75 High Remifentanil 0.003a 0.001–0.003a Parenteral only 0.05b High Levorphanol 2–3 Insufficient data High 4–5 High Nalbuphine 10 0.1–0.2 Parenteral only 3–6 High Buprenorphine 0.3 0.002–0.006 Low 4–8 High Butorphanol 2 0.01–0.025 Parenteral only 3–4 High Tramadolc 50–100 0.5–1.5 High 4–6 Moderate Codeine 30–60 0.5–1 High 3–4 Low Hydrocodonec 5–10 0.1–0.15 Medium 4–6 Moderate Oxycodonec 4.5 0.1–0.2 Medium 3–4 Moderate Propoxyphene 60–120d Insufficient data Oral only 4–5 Low Pentazocinec 30–50d 0.5–1 Medium 3–4 Moderate a Administered as a continuous infusion at 0.025–0.2 ␮g/kg per minute. b Duration depends on a context-sensitive half-time of 3 to 4 minutes. c Also available in sustained-release forms. d Analgesic efficacy at this dose is not equivalent to 10 mg of morphine. Adapted from Schumacher MA, Basbaum AI, Way WL. Chapter 31, Opioid analgesics and antagonists. In: Katzung B, Masters S, Trevor A, eds. Basic and Clinical Pharmacology. New York, NY: The McGrow-Hill Companies, Inc; 2009. Classification of opioids into those used frequently and less frequently is based on unpublished data from a survey of current analgesic practices in PICUs that belong to the Eunice Kennedy Shriver National Institute of Child Health and Human Development–funded Collaborative Pediatric Critical Care Research Network (September 2007).

TABLE 3 Major Classes of Opioid Receptors Opioid Receptor Cellular Expression Physiologic Effect Endogenous Ligand

␮, ␮1, ␮2 Cortical layers III and IV, thalamic nuclei, Supraspinal analgesia, euphoria, respiratory ␤-Endorphin, methionine- and striosomes within the striatum, depression, sedation, miosis, reduced leucine-enkephalins; periaqueductal gray, dorsal horn gastrointestinal motility, physical endomorphin-1, endomorphin-2 (lamina I and II) of the spinal cord dependence

␬, ␬1, ␬2, ␬3 Hypothalamic nuclei, periaqueductal Spinal analgesia, sedation, miosis, respiratory ␤-Endorphin, dynorphin A1–17 gray, claustrum, dorsal horn of the depression, dysphoria, inhibition of anti- spinal cord diuretic hormone release

␦, ␦1, ␦2 Deep cortical layers, striatum, Spinal and supraspinal analgesia, dysphoria, Methionine-enkephalin, ␤-Endorphin amygdalar nuclei, pontine nuclei, sedation, mild psychotomimetic effects, olfactory bulbs respiratory/vasomotor control Nociceptin/orphanin FQ Cortex, olfactory nuclei, lateral septum, Spinal and supraspinal analgesia, appetite, Nociceptin (ORL) central gray, hypothalamus, pontine anxiety, memory processing, autonomic and interpeduncular nuclei, regulation, cardiovascular and renal hippocampus, amygdala, substantia functions, locomotor activity, nigra, raphe magnus, locus gastrointestinal motility tolerance to ␮- coeruleus, spinal cord agonists ␴ Cortex, nucleus of tractus solitarius, Dysphoria, psychotomimetic effects, mydriasis Sigmaphin raphe nuclei, pontine nuclei, rostral ventrolateral medulla ⑀ Nucleus accumbens, arcuate and Supraspinal analgesia, sedation, maturation ␤-Endorphin, cholecystokinin,

preoptic hypothalamic nuclei, of sperm, other functions endorphin1–27 ventromedial periaqueductal gray, locus coeruleus, medullary nuclei

physiologic, pharmacologic, or ad- tors on the basis of their specific opioid peptides or other mediators verse effects by activating single or binding properties. These receptors that regulate various physiologic multiple populations of these recep- are also activated by endogenous functions. e1210 ANAND et al Downloaded from www.pediatrics.org. Provided by Eccles Health Sciences Lib on May 11, 2010 REVIEW ARTICLES

NMDA receptor 2+ Ca µ-Opioid agonist Glutamate- + binding site K channel µ-OR AC Gi PLA2 cAMP G o Arachidonic acid +

nNOS 12-lipoxygenase PKC 2+ + Mg NO 12-HPETE

Analgesia cascade: 2+ Ca threshold, APD, cGMP neurotransmitter release

Adjacent neurons FIGURE 1 Diagrammatic representation of the neuronal mechanisms underlying opioid analgesia. Mechanisms that support the analgesia cascade increase resting membrane potential, reduce action potential duration, and decrease neurotransmitter release. ␮-OR indicates ␮-opioid receptor; Gi/Go, inhibitory G proteins; nNOS, neuronal nitric oxide synthetase; NO, nitric oxide; cGMP, cyclic guanosine monophosphate; PLA2, phospholipase A2; APD, action potential duration; HPETE, hydroperoxyeicosatetraenoic acid.

Opioid Analgesia Opioid-Induced Hyperalgesia and those who receive opioid ther- Binding of specific ligands to opioid Some opioid agonists elicit naloxone- apy with morphine, fentanyl, receptors leads to conformational reversible and dose-dependent excita- remifentanil, hydrocodone, oxyc- 46 47 changes in the receptor protein that tory effects at the opioid receptor.10,43 odone, or methadone. Finkel et al initiate signal transduction with the These effects result from opioid recep- postulated its occurrence in children with intractable cancer pain and suc- activation of inhibitory G proteins (Gi2␣ tors coupling with stimulatory G pro- cessfully treated them with low-dose and Go). Activation of Gi protein down- teins (G ), which stimulate AC, increas- s infusions of ketamine. Proposed regulates adenylate cyclase (AC), thus ing cAMP and activating protein kinase A mechanisms include the sensitization reducing intracellular cyclic adeno- and ultimately leading to neuronal acti- of primary afferent neurons, enhanced sine monophosphate (cAMP) levels, vation.44 Neuraminidase increases these production and release of excitatory whereas Go proteins regulate an inter- effects, whereas treatment with a neur- ϩ neurotransmitters, decreased re- nally rectifying K channel to cause hy- aminidase inhibitor (eg, oseltamivir) perpolarization of the neuronal mem- uptake of excitatory neurotransmit- blocks the “paradoxical” hyperalgesia brane.42 Signal transduction from ters, sensitization of second-order caused by opioid therapy.45 activated opioid receptors lowers neu- neurons, and descending facilitation ronal excitability, reduces action- Opioid-induced hyperalgesia occurs from the rostral ventromedial medulla potential duration, and decreases neu- even in the absence of opioid toler- associated with upregulation of the rotransmitter release, which leads to ance (Fig 2), as demonstrated in opi- central dynorphin and glutamatergic opioid analgesia (Fig 1). oid addicts, normal adult volunteers, systems.46,48,49

PEDIATRICS Volume 125, Number 5, May 2010 e1211 Downloaded from www.pediatrics.org. Provided by Eccles Health Sciences Lib on May 11, 2010 ␥-amino butyric acid (GABA) A recep- Diminished opioid 83 84 analgesic effects tors, ␣2-adrenergic receptors, and cholecystokinin-B receptors.79,85 The activation of PKC, increases in in- 57,86 Opioid tolerance Opioid-induced hyperalgesia Worsening pain state tracellular calcium ions, and avail- ability of postsynaptic density protein 95 (PSD-95)87 are critical factors in the receptor interactions that lead to opi- Mechanisms: Mechanisms: Mechanisms: • Receptor desensizaon • Sensizaon of primary • Disease progression oid tolerance (Fig 3). • Superacvaon of cAMP afferent neurons • Neuropathic pain pathway • Acvaon of dynorphin and mechanisms Different opioids produce differential Therapeucapproaches: central glutamatergic systems • Enhanced opioid metabolism • Opioid dose escalaon Therapeuc approaches: Therapeuc approaches: effects on these mechanisms, which • Use longer-acng opioids • Tapering opioid doses • Opioid dose escalaon • Add nonopioid analgesics • Add NMDA antagonists • Add nonopioid analgesics contribute to their variable potential • Add drugs that prevent or • Try longer-acng opioids • Treat for neuropathic pain or for producing opioid tolerance (eg, delay tolerance • Aempt rotaon of opioids other pain mechanisms fentanyl Ͼ morphine Ͼ methadone Ͼ FIGURE 2 dihydroetorphine).42,88 Changes in Algorithm showing that clinical signs of diminished opioid analgesia may result from developing opioid tolerance, a worsening pain state, or opioid-induced hyperalgesia. Although opioid dose esca- these protein-kinase systems and lation may overcome pharmacologic tolerance, it enhances opioid-induced hyperalgesia. Opioid- downstream receptor functions occur induced hyperalgesia has a generalized distribution as opposed to the localized distribution of pre- existing pain, which may progress to a worsening pain state but usually responds to opioid dose in supraspinal areas including the escalation. forebrain, striatum, thalamus, and brainstem,89–91 as well as in the spinal cord dorsal horn,73,74 dorsal root Opioid Tolerance and N-methyl-D-aspartate (NMDA) ganglia, and peripheral nocicep- 55,63,77,82,92,93 Although opioid-induced hyperalgesia receptors. tors. Prolonged opioid expo- and tolerance use similar mecha- Neuronal protein kinases play a major sure also activates the expression of nisms, (Fig 3) tolerance primarily re- role in opioid tolerance,42 including (1) antiopioid peptides including vaso- sults from receptor desensitization second messenger-dependent protein pressin, oxytocin, neuropeptide FF, and upregulation of the cAMP path- kinases (eg, PKC, calcium/calmodulin- cholecystokinin, or nociceptin, and way.50,51 Other mechanisms such as dependent protein kinase II [CaMK-II] mainly occurs in the spinal cord and 94–98 neuroimmune activation,52 production or protein kinase A [PKA]),42,63 (2) G brainstem. of antiopioid peptides, or activation of protein–coupled receptor kinases the spinal dynorphin system53,54 also (GRKs),64–66 (3) mitogen-activated pro- PHARMACOGENETICS OF OPIOID contribute to opioid tolerance. tein kinases (MAPKs),50,67,68 (4) extra- ANALGESIA AND TOLERANCE Opioid receptor desensitization can be cellular signal-regulated kinases Information on the genetic mecha- 69–72 caused by (1) downregulation of opioid (ERK1/2), (5) spinally expressed nisms that regulate these cellular 73 receptors,55 (2) ␤-arrestin–mediated EphB receptor tyrosine kinases, (6) changes is emerging, but their clinical receptor internalization,56,57 (3) uncou- the c-Jun N-terminal kinases (JNK), via importance remains to be defined.99–101 56,74 pling of opioid receptors from inhibi- expression of TRPV1 receptors, and Genetic variants affect different as- tory G proteins,58 (4) increased pro- (7) cyclin-dependent kinase 5 (Cdk5), pects of nociception and responses to duction of nitric oxide via inducible via regulation of mitogen-activated opioid analgesia.102–104 Altered pain nitric oxide synthase (iNOS) activa- protein kinase kinase 1/2 (MEK1/2).75 perception and opioid analgesia oc- 59 tion, and (5) signaling via G(z) pro- Activation of these protein-kinase sys- cur from widely prevalent gene vari- teins.60 Upregulation of the cAMP tems results in opioid receptor phos- ants for (1) ␮-opioid receptor pathway results from (1) supersen- phorylation,76 altered function of the (OPRM1),100,105,106 (2) catechol-O- sitization of AC,51 (2) coupling of opi- ion channels involved in nocicep- methyltransferase (COMT),99,107,108 (3) 43 77,78 oid receptors with Gs proteins, and tion, increased expression of imme- guanosine triphosphate cyclohydro- (3) upregulation of spinal glucocorti- diate early genes (eg, FosB),79 and lase 1 (GCH1), (4) transient receptor coid receptors61 via a cAMP response iNOS.80,81 These protein-kinase sys- potential cation channel, subfamily element-binding (CREB) protein– tems are regulated by interactions V, member 1 (TRPV1), and (5) the dependent pathway,62 which acti- between opioid receptors and the melanocortin-1 receptor (MC1R).109,110 vate protein kinase C␥ (PKC␥) excitatory glutamate receptors,82 Metabolism and transport of opioids are e1212 ANAND et al Downloaded from www.pediatrics.org. Provided by Eccles Health Sciences Lib on May 11, 2010 REVIEW ARTICLES

NMDA receptor 2+ Prolonged exposure Ca to µ-opioid agonist δ-Opioid receptor trafficking

Glutamate- + binding site AC K channel µ-OR AC GS Gi δ-OR cAMP PLA 2 cAMP Go Arachidonic PKC acid PKA nNOS 12-lipoxygenase 2+ CREB pCREB Mg 12-HPETE IEG induction (FosB) NO CaMK-II

Analgesia cascade: threshold APD, Calmodulin threshold, 2+ tolerance [Ca] events APD, iNOS transmitter release cGMP

NO

Adjacent neurons FIGURE 3 Diagrammatic representation of neuronal mechanisms underlying opioid tolerance, which decreases resting membrane potential, increases the action- potential duration (APD), and increases neurotransmitter release. ␮-OR indicates ␮-opioid receptor; IEG, immediate early genes (c-fos, FosB); PKA, protein kinase A; CREB, cAMP response element-binding protein; APD, action-potential duration; pCREB, phosphorylated CREB protein; Gi/Go, inhibitory G proteins; Gs, stimulatory G protein; CaMK-II, calcium/calmodulin-dependent protein kinase II; PLA2, phospholipase A2; ␦-OR, ␦ opioid receptor; NO, nitric oxide; nNOS, neuronal nitric oxide synthetase; HPETE, hydroperoxyeicosatetraenoic acid. also affected by the genetic variants of of our knowledge. The SNPs currently significantly reduces the potency of cytochrome P450 2D6 (CYP2D6),111–117 known to modulate the clinical ef- morphine-6-glucuronide (M6G) in hu- Pglycoprotein(ABCB1),118 and uridine fects of analgesic drugs are listed in mans.130,131 It is unlikely that this SNP diphosphate-glucuronosyltransferase Table 4. plays a role in opioid addiction,132,133 2B7 (UGT2B7).119–121 With the explosion This genetic variability may explain but its role in opioid tolerance has of genetic information from the Hu- some of the interindividual differ- not been investigated. man Genome Project, thousands of single-nucleotide polymorphisms ences in analgesic requirements Opioid doses for analgesia are also re- (SNPs) have been identified in opioid noted among critically ill chil- duced by an SNP of the COMT gene en- 127,128 receptors, transport proteins, intra- dren. In the ␮-opioid receptor coding the substitution of valine by me- 134–137 cellular signaling proteins, and met- gene, a nucleotide substitution at po- thionine at codon 158, which abolic enzymes that may affect opi- sition 118 (A118G) predicts an amino reduces COMT enzyme activity by oid analgesia and tolerance. This acid change at codon 40, from aspar- three- to fourfold and is associated complexity, coupled with the difficul- agine to aspartate, which binds with greater activation of the endoge- ties in studying pediatric develop- ␤-endorphin 3 times more potently nous ␮-opioid system in response to ment,122–126 limits the clinical utility than the wild-type receptor129 and pain (M158M Ͻ V158M Ͻ V158V). Pre-

PEDIATRICS Volume 125, Number 5, May 2010 e1213 Downloaded from www.pediatrics.org. Provided by Eccles Health Sciences Lib on May 11, 2010 TABLE 4 SNPs That Affect Opioid Analgesia/Tolerance Gene Varianta Frequency of Patients Affected Analgesics (Only Drugs With Multiply Standard Reference Affected, %c Positive Evidence Are Listed) Dose by This Factor, if SNP Is Presentb OPRM1 (␮-opioid receptor) 118A3G exon 1 11.5 Alfentanil, morphine, M6G, methadone 2.2 102–104 C3T intron 1 6 Morphine Ͼ1 IVS2–31G3A intron 2 8.9 Morphine, M6G IVS2–691C3G intron 2 44.5 No effect COMT (catechol-O-methyl 472G3A exon 4 46.2 Morphine, M6G, fentanyl 0.67d 105–107 transferase) MC1R (melanocortin-1 receptor) 29insAa 2 Morphine 108, 109 451C3T 4.5 M6G 478C3T 4.3 Pentazocine (only in females) 880G3C3 CYP2D6 (cytochrome P450 2D6) 2549A3del 2 Codeine Drug is ineffective 110–116 1846G3A 20.7 Tramadol 1.3 Gene deletion 2 1707T3del 0.9 2935A3C 0.1 1758G3T Rare Gene amplification 2 Codeine Ͻ1 (dosing unknown) ABCB1 (P glycoprotein) 3435C3T exon 1 47.6 Morphine ϽϽ 1 (less nausea) 117 2677 G3T/A exon 3 2 UGT2B7 (uridine diphosphate- 211G3T exon 1 14.8 Morphine/M6G Dosing unknown 118–120 glucuronosyltransferase 2B7) 802 C3T exon 2 53.7 Morphine/M3G Dosing unknown 1059 C3G exon 4 2.9 1062C3T exon 4 Rare 1192G3A exon 5 Ͻ1 a The notation of the SNP is as follows: The number (eg, 118) denotes the complementary DNA position of the variant. The first letter (A, T, G, or C) denotes the most commonly found nucleotide (ie, the wild type), and the second letter denotes the nucleotide for variant alleles at this position. In case of MC1R 29insA, the variant is an insertion of an additional adenine after the nucleotide at complementary DNA position 29. b A rough and preliminary estimate of dosing in carriers of this particular variant is based on a limited amount of quantitative data. c Frequencies according to the dbSNP database (www.ncbi.nlm.nih.gov/SNP) were available and if not otherwise indicated. d The factor of 0.67 ϭ 1/1.5 comes from the ϳ1.5 times higher doses in wild-type patients as compared to carriers of the variant. liminary data have suggested that this induce tolerance more rapidly than in- (M3G) with antiopioid effects, whereas SNP reduces the need for postopera- termittent therapy,140,141,146 a random- older age groups form M6G with po- tive opioid analgesia in infants138 and ized trial demonstrated no significant tent analgesic effects, and both metab- adults.139 differences between 0- to 3-year-old olites have longer half-lives than that children who were randomly assigned of morphine.152–155 M3G accumulation FACTORS THAT AFFECT to continuous versus intermittent mor- in preterm neonates antagonizes the DEVELOPMENT OF OPIOID phine for postoperative analgesia.147 effects of morphine and contributes to TOLERANCE opioid tolerance. Developmental dif- Clinical and experimental data have Early Development ferences also explain why midazolam suggested that development of opioid Infants at early developmental stages attenuates opioid tolerance in adult tolerance and dependence can be 143 156 show greater vulnerability, because rats but not infant rats or why co- modulated by various factors. Except tolerance to sedative and analgesic ef- for duration of therapy, most of these opioid therapy during critical brain de- velopment may produce long-term opi- fects of fentanyl occurs in infant rats factors have not been investigated in but not in adult rats.156 Age-related dif- children. oid tolerance.148,149 Indirect evidence has suggested that opioid tolerance ferences among children in the devel- Duration of Therapy develops earlier in preterm versus opment of opioid tolerance have not been investigated. Duration of opioid receptor occupancy term newborns,144,150 supported by is clearly important for the develop- emerging animal data.145,148 The clini- Gender Differences ment of tolerance.31,140–143 Opioid toler- cal signs of opioid withdrawal, how- ance rarely occurs after therapy for ever, are more prominent in term neo- Gender differences suggest greater less than 72 hours.144,145 Although con- nates.151 Preterm neonates metabolize development of opioid tolerance in tinuous infusions of opioids seem to morphine to morphine-3-glucuronide males than in females. After 2 weeks of e1214 ANAND et al Downloaded from www.pediatrics.org. Provided by Eccles Health Sciences Lib on May 11, 2010 REVIEW ARTICLES twice-daily morphine, the analgesic ef- other factors are undoubtedly opera- drawal Symptoms Scale was designed fective dose for 50% of subjects in- tive but have not been studied (see for measuring opioid and/or benzodi- creased 6.9-fold in male rats versus previous discussion). Opioid with- azepine withdrawal in ventilated pa- 3.7-fold in female rats; subsequent nal- drawal must be treated aggressively tients aged 0 to 18 years.165,167 These oxone treatment produced greater by using combined pharmacologic, en- methods seem clinically useful, and opioid withdrawal in males than in fe- vironmental, and nursing care ap- psychometric evaluations of their sen- males.157 No gender differences oc- proaches to decrease clinical com- sitivity, specificity, validity, and reliabil- curred in opioid withdrawal after ex- plications and intense suffering. ity are currently underway. posure to morphine or fentanyl in Therapeutic goals include reducing Franck et al172 developed the Opioid 145,158 infant rats, but gender differ- withdrawal symptoms, allowing regu- and Benzodiazepine Withdrawal Scale ences occurred in morphine analgesia lar sleep cycles, and reducing the agi- as a 21-item checklist to evaluate the 159 after fentanyl exposure in infancy. tation caused by medical interventions frequency and severity of withdrawal Human infants respond to aversive or nursing care. symptoms. This tool was later refined stimuli in a gender-specific man- to develop the 12-item Withdrawal As- 160,161 ner, but gender differences in opi- Assessment of Opioid Withdrawal sessment Tool 1 (WAT-1), which was oid analgesia and tolerance have not Authors of a recent systematic review tested in 83 PICU patients. Opioid with- been studied. noted the paucity of empirically devel- drawal occurred in patients with Drug-Related Factors oped and validated methods for as- WAT-1 scores of Ͼ3, with high sensitiv- sessment of opioid withdrawal in chil- ity (0.87) and specificity (0.88) and ex- Greater tolerance occurs with the dren.165 The neonatal abstinence cellent convergent and construct valid- use of synthetic or short-acting opi- syndrome has been well defined, but ity.172 Given its empirical development, oids.156,162 Infants who received fent- many of its clinical findings cannot be ease of use at the patient’s bedside, anyl during extracorporeal mem- applied to children.166 In older chil- and psychometric properties, this brane oxygenation required more dren, common neurologic signs in- method has shown the greatest prom- supplemental analgesia, frequently clude anxiety, agitation, grimacing, in- ise for the assessment of opioid with- developed opioid withdrawal, and re- somnia, increased muscle tone, drawal in children. quired longer durations of opioid abnormal tremors, and choreoathe- weaning compared with morphine- toid movements. Gastrointestinal Strategies for Treatment of Opioid treated infants.7 Drugs that cause symptoms include vomiting, diarrhea, Withdrawal opioid receptor internalization, de- and poor appetite, whereas autonomic creased receptor phosphorylation The mainstay of pharmacologic man- signs include tachypnea, tachycardia, by G protein–coupled receptor ki- agement is gradual opioid weaning. In fever, sweating, and hypertension.167 nases, and less downregulation of the acute situation, most opioids are opioid receptors are associated with Previous studies of opioid withdrawal given as continuous intravenous infu- less tolerance.42 The NMDA-antagonist in children used the Modified Narcotic sions. These infusions can be substi- effects and ␦-opioid receptor desensiti- Abstinence Scale (MNAS),7,33,34,36,41 tuted with long-acting enterally admin- 35 zation caused by methadone explain its which was originally developed for istered agents or subcutaneous 36,173,174 lower tolerance potential compared newborns of heroin-addicted moth- infusions, which have the advan- with morphine.76,89,163,164 Differences in ers.168 The MNAS was criticized for be- tages of ease of use, decreased need opioid tolerance induced by different ing subjective, clinically biased, and for intravenous access, and early PICU opioids have not been investigated sys- time-consuming. It included items that discharge. Therapy must be directed tematically in infants and children. do not apply to children or ventilated by regular assessments for signs of patients, whereas other signs of the opioid withdrawal. Pharmacologic CLINICAL MANAGEMENT OF OPIOID sedation-agitation spectrum (such as agents commonly used to treat or pre- TOLERANCE AND WITHDRAWAL pupillary size169 and responses to han- vent opiate withdrawal include the Bedside clinicians know that the dura- dling170) were not included. Another following. tion of opioid exposure predicts opioid method, the Sedation Withdrawal 1. Methadone is an effective analgesic tolerance. Katz et al33 found that opioid Score developed by Cunliffe et al,171 in- for pediatric patients.175,176 It has a withdrawal occurred in 100% of the cluded 12 symptoms of withdrawal, prolonged half-life,177,178 inhibits patients who received fentanyl infu- each scored subjectively on a 3-point tolerance by multiple mecha- sions for 9 days or more. Genetic and scale. The Sophia Observation With- nisms,89,164,179 and is used increas-

PEDIATRICS Volume 125, Number 5, May 2010 e1215 Downloaded from www.pediatrics.org. Provided by Eccles Health Sciences Lib on May 11, 2010 TABLE 5 Methadone-Weaning Protocols After Opioid Therapy for 7 to 14 or Ͼ14 Days of preclinical and clinical stud- Short-term Therapy Protocol (7–14 d) Long-term Therapy Protocol (Ͼ14 d) ies.216,217 In 11 children who re- Use 1-h dose to convert to methadone (OD) Use 1-h dose to convert to methadone (OD) quired mechanical ventilation, Day 1: give OD PO every 6 h for 24 h Day 1: give OD PO every 6 h for 24 h propofol infusions facilitated the Day 2: reduce OD 20%, give PO every 8 h for 24 h Day 2: give OD, change to PO every 6 h for 24 h Day 3: reduce OD 20%, give PO every 8 h for 24 h Day 3: reduce OD 20%, give PO every 6 h for 48 h rapid weaning of opioid and benzo- Day 4: reduce OD 20%, give PO every 12 h for 24 h Day 5: reduce OD 20%, give PO every 8 h for 48 h diazepine infusions, which led to Day 5: reduce OD 20%, give PO every 24 h for 24 h Day 7: reduce OD 20%, give PO every 12 h for 48 h successful extubation,218 but no Day 6: discontinue methadone Day 9: reduce OD 20%, give PO every 24 h for 48 h Day 11: discontinue methadone other studies have replicated these Those who are converting from other opioids to methadone should take into account the relative potency (see Table 2) and observations. duration of action of the other opioids. OD indicates original dose; PO, by mouth. 7. Previous case reports have sug- Adapted from Robertson RC, Darsey E, Fortenberry JD, Pettignano R, Hartley G. Evaluation of an opiate-weaning protocol using methadone in pediatric intensive care unit patients. Pediatric Critical Care Medicine. Vol 1. 2000;1(2):19–123. gested the utility of propoxyphene for treating morphine-induced opi- oid tolerance; few signs and symp- ingly for opioid withdrawal in chil- sedative, antihypertensive, and an- toms of withdrawal and decreased dren.34,35,180–182 A methadone dose tiarrhythmic effects. Initial reports respiratory depression were seen, equivalent to 2.5 times the total suggested its usefulness for pre- which enabled these PICU patients daily fentanyl dose was effective for venting opioid withdrawal in to be weaned off the ventilator.218,219 preventing opioid withdrawal in adults,204,205 with increasing experi- There is little cross-tolerance be- children.182 A methadone-weaning ence in PICU patients. Finkel et tween morphine and propoxy- protocol, such as that depicted in al206,207 first reported its use in an phene,220 although further evidence Table 5, also prevented opioid with- infant with Hunter syndrome and 2 is required before it can be used drawal and reduced hospital stay.41 children after cardiac transplanta- clinically. 2. Buprenorphine is a long-acting tion. Tobias reported 2 case series Other experimental agents such as ␮-opioid partial agonist with potent (7 patients each) using intraven- memantine (a clinically available analgesic properties183–186 and ous or subcutaneous infusions of NMDA receptor antagonist221–223) or naloxone-reversible187 respiratory dexmedetomidine to treat opioid glycyl-L-glutamine (a naturally occur- depression.184,188 It is now being withdrawal.174,208 Additional studies ring dipeptide, produced by posttrans- used as a substitute for high-dose are necessary to define its role in lational processing of ␤-endorphin224–226) methadone for the treatment of opi- the clinical management of patients have been suggested as therapies for oid addiction.9,189–192 Buprenorphine who are receiving opioids.209 opioid withdrawal but have not been was safely substituted for metha- 5. Gabapentin was developed as an tested in pediatric patients. done in opioid-addicted mothers anticonvulsant but reduces neuro- Strategies for the Prevention of and induced less prolonged opioid pathic pain via effects on ␣2-⌬ cal- withdrawal in newborns,193–196 but it cium channels.210,211 In adults who Opioid Tolerance has not been studied in children. were undergoing rapid opioid de- Strategies to prevent or delay opioid tol-

3. Clonidine is an ␣2-adrenergic re- toxification, gabapentin effectively erance have the advantage of avoiding ceptor agonist with potent analge- attenuated the severe back pain, dependency and withdrawal, thereby re-

sic effects. Because ␣2-adrenergic limb thrashing, and restless-leg ducing the costs and complications of and ␮-opioid receptors activate the syndrome associated with opioid prolonged opioid weaning. The true inci- same Kϩ channel via inhibitory G withdrawal and also changed their dence of opioid tolerance and the exact proteins, clonidine has been used somatosensory evoked potentials strategies for preventing it remain un- to treat opioid withdrawal in neo- and increased their tolerance to derstudied in children. nates,197–199 adolescents,13 and painful stimulation.212 Additional adults200–202 but not in critically ill studies corroborated the efficacy of Practical Approaches children.203 gabapentin for opioid withdrawal in Procedural changes such as the daily adults,213–215 but it has not been 227 4. Dexmedetomidine is an ␣2- interruption of sedatives, nurse- adrenergic agonist with eightfold tested in children. controlled sedation,228 sequential rota- greater affinity than clonidine. It 6. Propofol can be used for preventing tion of analgesics229 (although associ- 230 binds to ␣2-adrenergic and imida- benzodiazepine and opioid with- ated with some concerns ), or the zoline type 1 receptors to mediate drawal, as suggested by the results use of epidural/intrathecal opioids in e1216 ANAND et al Downloaded from www.pediatrics.org. Provided by Eccles Health Sciences Lib on May 11, 2010 REVIEW ARTICLES pediatric patients231–235 may decrease ICU stay.227 This approach must be terminated early on the grounds of the incidence of opioid tolerance and used with caution in infants and chil- futility revealed no differences.248 withdrawal. dren, because awakening may cause more acute changes in their respira- Use of Noncompetitive NMDA Nursing-Controlled Sedation tory and hemodynamic variables and Antagonists Management Protocols 249,250 children are much more likely to pull Opioids such as ketobemidone Adult patients who were randomly 89,163,250 out catheters and tubes than adult and methadone block NMDA re- assigned to a nurse-managed sedation ICU patients. ceptors and also produce less toler- protocol compared with nonprotocol ance than morphine or fentanyl. Com- sedation required shorter durations of Promising but Experimental bined exposure to methadone and mechanical ventilation and ICU and Therapies morphine reverses the opioid toler- hospital stays and less frequent tra- On the basis of the mechanisms of opi- ance caused by morphine via a desen- 228 cheostomy. Similar nurse-managed oid tolerance, novel approaches for re- sitization of ␦-opioid receptors164 and sedation protocols developed by ducing or delaying its occurrence may uncoupling of these receptors from G 236,237 238 Curley et al and Sury et al are be proposed, although the safety and proteins.179 currently under investigation in a efficacy of these approaches have Use of Nitric Oxide Synthase cluster-randomized trial in ventilat- not been investigated for critically ill Inhibitors ed children (Martha A. Q. Curley, per- children. sonal communication, December 2008). Inhibition of iNOS induction was Concomitant Infusion of Opioid noted to decrease the neuroadaptive Use of Epidural or Other Forms of Agonists and NMDA Antagonists changes associated with opioid depen- Neuraxial Analgesia NMDA receptors play multiple roles dence,251,252 which suggests the Effective analgesic doses for chil- in the mechanisms that lead to opioid investigation of an iNOS inhibitor, dren are significantly reduced by epi- tolerance. Clinicians using combined 7-nitroindazole, in clinical trials for dural opioids compared with intrave- intravenous infusions of morphine and opioid addiction.253,254 nous opioids. Given that the total low-dose ketamine (0.25–0.5 mg/kg) opioid dose is a strong predictor for Use of Selective Serotonin-Reuptake have noted significant opioid-sparing the occurrence of opioid withdrawal, Inhibitors effects in patients with postoperative greater use of neuraxial opioids may Preliminary data have suggested or cancer pain,48,240–242 which sup- also reduce opioid tolerance.232,239 that fluoxetine may suppress the de- ports similar findings from animal velopment of tolerance to morphine Sequential Rotation of Analgesic/ models.243,244 analgesia, which is further accentu- Sedative Agents Continuous Infusions of Opioid ated by L-arginine and nitro-L-arginine The sequential use of different Agonists and Low-Dose Naloxone methyl ester treatment.255 These re- classes of drugs (opioids, benzodiaz- Low concentrations of opioid antag- sults suggest a role for the nitric epines, barbiturates, butyrophenones, onists selectively block opioid recep- oxide–cyclic guanosine monophos- halogenated hydrocarbons) is recom- tors coupled with stimulatory G pro- phate–serotonin signaling system in mended for analgesia and sedation in s teins, thus blocking mechanisms for the development of opioid tolerance adult ICU patients to reduce the inci- superactivation of the cAMP pathway.10 and withdrawal. dence of tolerance and withdrawal.4 Al- Three clinical trials in adults revealed Despite the availability of multiple though such an approach is not prac- that low-dose naloxone improves the therapies for opioid withdrawal, or tical for all pediatric patients, it may be efficacy of opioid analgesia and re- practical approaches and promising an option for PICU patients at high risk duces tolerance,12,187,245 although 1 trial experimental therapies for preventing who are receiving opioid therapy for revealed opposite effects.246 All these opioid tolerance, a high incidence of longer than 7 days.28 studies were limited to 24 hours after opioid withdrawal still occurs in the Daily Interruption of Sedative surgery, a period during which the ef- PICU.28,256 Randomized trials compar- Infusions fects of opioid tolerance may not oc- ing these therapeutic options are Ascheduleddailyinterruptionof cur.141,146 Results of a retrospective needed to define their relative value all sedative infusions in adult ICU pa- case-control study in children sug- for particular groups of PICU patients, tients (until the patients were fully gested that low-dose naloxone infu- thus enhancing the ability of clinicians awake) resulted in a shorter dura- sions may reduce opioid require- to treat these complications of pro- tion of mechanical ventilation and ments,247 but a clinical trial that was longed opioid exposure.

PEDIATRICS Volume 125, Number 5, May 2010 e1217 Downloaded from www.pediatrics.org. Provided by Eccles Health Sciences Lib on May 11, 2010 RECOMMENDATIONS 2. Short-acting opioids can be used with low-dose ketamine or nalox- Opioid tolerance occurs in 35% to 57% for procedural or breakthrough one or other classes of drugs. of PICU patients and often results in a pain, whereas longer-acting opi- Critically ill children routinely re- oids can be used for established, prolonged hospital stay or other com- ceive opioids for pain management; prolonged, or chronic pain. Avoid plications.33,34,36,38,41,182,231 The effects this treatment often leads to opioid using opioids if only sedation or mo- of pharmacogenetic/genomic, drug- tolerance and withdrawal, both of tion control are required. Sched- related, or patient-related factors which occur more commonly in in- uled intermittent doses of longer- (age, gender, diagnosis) on the devel- fants and children because of devel- acting opioids may substitute for opment of opioid tolerance and with- opmental changes in metabolism, ex- opioid infusions (see Table 2) to re- drawal are currently unknown. A long- cretion, or dose/response curves, duce tolerance. receptor subtypes, signal transduc- term goal is to develop therapeutic 3. Opioid withdrawal can be assessed tion, receptor induction, and regula- approaches that provide safe and ef- by using various methods (MNAS, tory pathways. Advances in opioid fective opioid analgesia without induc- Sedation Withdrawal Score, Sophia pharmacology cannot be applied to ing tolerance or withdrawal. By pre- Observation Withdrawal Symptoms critically ill children, because the in- venting or delaying opioid tolerance in Scale, Opioid and Benzodiazepine cidence and risk factors for opioid critically ill infants and children, we Withdrawal Scale). Currently, how- tolerance in PICU patients remain un- can improve analgesic efficacy, avoid ever, the WAT-1 scale seems to show known. We need prospective obser- secondary complications, expedite re- the greatest promise for efficient vational studies to define the current covery from critical illness, and reduce assessment of opioid withdrawal in incidence and risk factors for opioid the need for prolonged intensive care PICU patients. tolerance in critically ill children, as support.41,257 Specific recommenda- 4. Management of opioid withdrawal well as randomized trials to compare tions to achieve these goals include includes gradual opioid weaning the various therapies available for the following. (see Table 5), environmental and prevention and treatment of opioid 1. Opioid doses should match the in- nursing supportive measures, withdrawal. tensity and frequency of pain expe- and treatment with methadone, rienced by PICU patients, be titrated clonidine, or both7 or alternative ACKNOWLEDGMENTS initially to achieve adequate analge- therapies such as buprenorphine, This work was supported by Eunice sia, and be adjusted to find the dexmedetomidine, propofol, or Kennedy Shriver National Institute of minimum effective dose for each gabapentin. Child Health and Human Development patient. Increased opioid require- 5. Prevention of opioid tolerance may cooperative agreements U10HD050096, ments may be dictated by opioid include practical approaches such U10HD049981, U10HD500009, U10HD- tolerance or opioid-induced hyper- as nurse-controlled sedation or se- 049945, U10HD049983, U10HD050012, algesia or worsening pain states, quential rotation of analgesics, al- and U01HD049934. We thank Pam Cate each of which are treated differ- though promising experimental and Kris Dudoich for administrative ently (see Fig 2). therapies include opioids combined assistance. REFERENCES

1. Berde CB, Sethna NF. Analgesics for the diatric intensive care unit. Crit Care Med. continuous infusions of morphine or treatment of pain in children. NEngl 2000;28(6):2122–2132 fentanyl during extracorporeal mem- J Med. 2002;347(14):1094–1103 5. Anand KJS; International Evidence-Based brane oxygenation. Am J Crit Care. 1998; 2. Chambliss CR, Anand KJS. Pain manage- Group for Neonatal Pain. Consensus state- 7(5):364–369 ment in the pediatric intensive care ment for the prevention and management 8. Suresh S, Anand KJS. Opioid tolerance in unit. Curr Opin Pediatr. 1997;9(3): of pain in the newborn. Arch Pediatr Ado- neonates: a state-of-the-art review. Paedi- 246–253 lesc Med. 2001;155(2):173–180 atr Anaesth. 2001;11(5):511–521 3. Anand KJS. Relationships between stress 6. Anand KJS, Ingraham J. Tolerance, depen- 9. Krantz MJ, Mehler PS. Treating opioid responses and clinical outcome in new- dence, and strategies for compassionate dependence: growing implications for pri- borns, infants, and children. Crit Care withdrawal of analgesics and anxiolytics mary care. Arch Intern Med. 2004;164(3): Med. 1993;21(9 suppl):S358–S359 in the pediatric ICU. Crit Care Nurse. 1996; 277–288 4. Tobias JD. Tolerance, withdrawal, and 16(6):87–93 10. Crain SM, Shen KF. Antagonists of excita- physical dependency after long-term se- 7. FranckLS,VilardiJ,DurandD,PowersR. tory opioid receptor functions enhance dation and analgesia of children in the pe- Opioid withdrawal in neonates after morphine’s analgesic potency and attenu-

e1218 ANAND et al Downloaded from www.pediatrics.org. Provided by Eccles Health Sciences Lib on May 11, 2010 REVIEW ARTICLES

ate opioid tolerance/dependence liability. quality improvement programme. Anaes- 37. Tobias JD, Berkenbosch JW. Tolerance Pain. 2000;84(2–3):121–131 thesia. 2008;63(11):1209–1216 during sedation in a pediatric ICU patient: 11. Crain SM, Shen KF. Modulatory effects of 25. Sadowski R, Dechert RE, Bandy KP, et al. effects on the BIS monitor. J Clin Anesth. Gs-coupled excitatory opioid receptor Continuous quality improvement: reduc- 2001;13(2):122–124 functions on opioid analgesia, tolerance, ing unplanned extubations in a pediatric 38. Fonsmark L, Rasmussen YH, Carl P. Occur- and dependence. Neurochem Res. 1996; intensive care unit. Pediatrics. 2004; rence of withdrawal in critically ill sedated 21(11):1347–1351 114(3):628–632 children. Crit Care Med. 1999;27(1): 12. Gan TJ, Ginsberg B, Glass PS, Fortney J, 26. Ostermann ME, Keenan SP, Seiferling RA, 196–199 Jhaveri R, Perno R. Opioid-sparing effects Sibbald WJ. Sedation in the intensive care 39. Bergman I, Steeves M, Burckart G, Thomp- of a low-dose infusion of naloxone in pa- unit: a systematic review. JAMA. 2000; son A. Reversible neurologic abnormali- tients administered morphine sulfate. An- 283(11):1451–1459 ties associated with prolonged intrave- esthesiology. 1997;87(5):1075–1081 27. Playfor S, Jenkins I, Boyles C, et al. Consen- nous midazolam and fentanyl 13. Colvin LA, Lambert DG. Pain medicine: ad- sus guidelines on sedation and analgesia administration. JPediatr.1991;119(4): vances in basic sciences and clinical prac- in critically ill children. Intensive Care 644–649 tice. Br J Anaesth. 2008;101(1):1–4 Med. 2006;32(8):1125–1136 40. Lane JC, Tennison MB, Lawless ST, Green- 14. Howard RF. Current status of pain man- 28. Jenkins IA, Playfor SD, Bevan C, Davies G, wood RS, Zaritsky AL. Movement disorder agement in children. JAMA. 2003;290(18): Wolf AR. Current United Kingdom sedation after withdrawal of fentanyl infusion. J Pe- 2464–2469 practice in pediatric intensive care. Paedi- diatr. 1991;119(4):649–651 15. Anand KJS, Hickey PR. Halothane- atr Anaesth. 2007;17(7):675–683 41. Robertson RC, Darsey E, Fortenberry JD, morphine compared with high-dose sufen- 29. Long D, Horn D, Keogh S. A survey of seda- Pettignano R, Hartley G. Evaluation of an tanil for anesthesia and postoperative an- tion assessment and management in Aus- opiate-weaning protocol using methadone algesia in neonatal cardiac surgery. N Engl tralian and New Zealand paediatric inten- in pediatric intensive care unit patients. J Med. 1992;326(1):1–9 sive care patients requiring prolonged Pediatr Crit Care Med. 2000;1(2):119–123 16. Barker DP, Rutter N. Stress, severity of ill- mechanical ventilation. Aust Crit Care. 42. Liu JG, Anand KJS. Protein kinases modu- ness, and outcome in ventilated preterm 2005;18(4):152–157 late the cellular adaptations associated infants. Arch Dis Child Fetal Neonatal Ed. 30. Sarkar S, Schumacher RE, Baumgart S, with opioid tolerance and dependence. 1996;75(3):F187–F190 Donn SM. Are newborns receiving premed- Brain Res Brain Res Rev. 2001;38(1–2): 17. Quinn MW, Otoo F, Rushforth JA, et al. Effect ication before elective intubation? J Peri- 1–19 of morphine and pancuronium on the natol. 2006;26(5):286–289 43. Crain SM, Shen KF. Modulation of opioid stress response in ventilated preterm in- 31. Arnold JH, Truog RD, Orav EJ, Scavone JM, analgesia, tolerance and dependence by fants. Early Hum Dev. 1992;30(3):241–248 Hershenson MB. Tolerance and depen- Gs-coupled, GM1 ganglioside-regulated 18. Grunau RE, Haley DW, Whitfield MF, Wein- dence in neonates sedated with fentanyl opioid receptor functions. Trends Phar- berg J, Yu W, Thiessen P. Altered basal cor- during extracorporeal membrane oxygen- macol Sci. 1998;19(9):358–365 tisol levels at 3, 6, 8 and 18 months in in- ation. Anesthesiology. 1990;73(6): 44. Crain SM, Shen KF. Ultra-low concentra- fants born at extremely low gestational 1136–1140 tions of naloxone selectively antagonize age. J Pediatr. 2007;150(2):151–156 32. Arnold JH, Truog RD, Scavone JM, Fenton T. excitatory effects of morphine on sensory 19. Holsti L, Weinberg J, Whitfield MF, Grunau Changes in the pharmacodynamic re- neurons, thereby increasing its antinoci- RE. Relationships between adrenocortico- sponse to fentanyl in neonates during con- ceptive potency and attenuating tropic hormone and cortisol are altered tinuous infusion. JPediatr.1991;119(4): tolerance/dependence during chronic co- during clustered nursing care in preterm 639–643 treatment. Proc Natl Acad Sci U S A. 1995; infants born at extremely low gestational 33. Katz R, Kelly HW, Hsi A. Prospective study 92(23):10540–10544 age. Early Hum Dev. 2007;83(5):341–348 on the occurrence of withdrawal in criti- 45. Crain SM, Shen KF. Neuraminidase inhibi- 20. Whitfield MF, Grunau RV, Holsti L. Ex- cally ill children who receive fentanyl by tor, oseltamivir blocks GM1 ganglioside- tremely premature (Ͻ or ϭ 800 g) continuous infusion. Crit Care Med. 1994; regulated excitatory opioid receptor- schoolchildren: multiple areas of hidden 22(5):763–767 mediated hyperalgesia, enhances opioid disability. Arch Dis Child Fetal Neonatal Ed. 34. Tobias JD, Schleien CL, Haun SE. Metha- analgesia and attenuates tolerance in 1997;77(2):F85–F90 done as treatment for iatrogenic narcotic mice. Brain Res. 2004;995(2):260–266 21. Karande S, Kelkar A, Kulkarni M. Recollec- dependency in pediatric intensive care 46. Chu LF, Angst MS, Clark D. Opioid-induced tions of Indian children after discharge unit patients. Crit Care Med. 1990;18(11): hyperalgesia in humans: molecular mech- from an intensive care unit. Pediatr Crit 1292–1293 anisms and clinical considerations. Clin J Care Med. 2005;6(3):303–307 35. Tobias JD, Deshpande JK, Gregory DF. Out- Pain. 2008;24(6):479–496 22. Playfor SD, Thomas DA, Choonara II. Recall patient therapy of iatrogenic drug depen- 47. Finkel JC, Pestieau SR, Quezado ZM. Ket- following paediatric intensive care. Paedi- dency following prolonged sedation in the amine as an adjuvant for treatment of can- atr Anaesth. 2000;10(6):703–704 pediatric intensive care unit. Intensive cer pain in children and adolescents. J 23. Playfor S, Thomas D, Choonara I. Recollec- Care Med. 1994;20(7):504–507 Pain. 2007;8(6):515–521 tion of children following intensive care. 36. Tobias JD. Subcutaneous administration 48. Luginbu¨hl M, Gerber A, Schnider TW, Arch Dis Child. 2000;83(5):445–448 of fentanyl and midazolam to prevent with- Petersen-Felix S, Arendt-Nielsen L, Cura- 24. da Silva PS, de Aguiar VE, Neto HM, de Car- drawal after prolonged sedation in chil- tolo M. Modulation of remifentanil- valho WB. Unplanned extubation in a pae- dren. Crit Care Med. 1999;27(10): induced analgesia, hyperalgesia, and tol- diatric intensive care unit: impact of a 2262–2265 erance by small-dose ketamine in

PEDIATRICS Volume 125, Number 5, May 2010 e1219 Downloaded from www.pediatrics.org. Provided by Eccles Health Sciences Lib on May 11, 2010 humans. Anesth Analg. 2003;96(3): PKCgamma after chronic morphine is reg- 72. Narita M, Ioka M, Suzuki M, Suzuki T. Effect 726–732 ulated by spinal glucocorticoid receptor. of repeated administration of morphine 49. Mao J. Opioid-induced hyperalgesia. Pain J Neurosci. 2005;25(48):11145–11154 on the activity of extracellular signal reg- Clin Updates. 2008;XVI(2):1–4 62. Maldonado R, Blendy JA, Tzavara E, et al. ulated kinase in the mouse brain. Neurosci 50. Schulz S, Hollt V. Opioid withdrawal acti- Reduction of morphine abstinence in mice Lett. 2002;324(2):97–100 vates MAP kinase in locus coeruleus neu- with a mutation in the gene encoding 73. Liu WT, Li HC, Song XS, Huang ZJ, Song XJ. rons in morphine-dependent rats in vivo. CREB. Science. 1996;273(5275):657–659 EphB receptor signaling in mouse spinal Eur J Neurosci. 1998;10(3):1196–1201 63. Liang D, Li X, Clark JD. Increased expres- cord contributes to physical dependence 51. Avidor-Reiss T, Nevo I, Saya D, Bayewitch M, sion of Ca2ϩ/calmodulin-dependent pro- on morphine. FASEB J. 2009;23(1):90–98 Vogel Z. Opiate-induced adenylyl cyclase tein kinase II alpha during chronic mor- 74. Chen Y, Geis C, Sommer C. Activation of superactivation is isozyme-specific. J Biol phine exposure. Neuroscience. 2004; TRPV1 contributes to morphine tolerance: Chem. 1997;272(8):5040–5047 123(3):769–775 involvement of the mitogen-activated pro- 52. DeLeo JA, Tanga FY, Tawfik VL. Neuroim- 64. McLaughlin JP, Myers LC, Zarek PE, et al. tein kinase signaling pathway. J Neurosci. mune activation and neuroinflammation Prolonged kappa opioid receptor phos- 2008;28(22):5836–5845 in chronic pain and opioid tolerance/ phorylation mediated by G-protein recep- 75. Pareek TK, Kulkarni AB. Cdk5: a new player hyperalgesia. Neuroscientist. 2004;10(1): tor kinase underlies sustained analgesic in pain signaling. Cell Cycle. 2006;5(6): 40–52 tolerance. JBiolChem.2004;279(3): 585–588 53. Ossipov MH, Lai J, King T, Vanderah TW, 1810–1818 76. Callahan RJ, Au JD, Paul M, Liu C, Yost CS. Porreca F. Underlying mechanisms of 65. Zhang J, Ferguson SS, Barak LS, et al. Role Functional inhibition by methadone of pronociceptive consequences of pro- for G protein-coupled receptor kinase in N-methyl-D-aspartate receptors expressed longed morphine exposure. Biopolymers. agonist-specific regulation of mu-opioid in Xenopus oocytes: stereospecific and 2005;80(2–3):319–324 receptor responsiveness. Proc Natl Acad subunit effects. Anesth Analg. 2004;98(3): 54. Quartilho A, Mata HP, Ibrahim MM, et al. Sci U S A. 1998;95(12):7157–7162 653–659, table of contents Production of paradoxical sensory hyper- 66. Thakker DR, Standifer KM. Induction of G 77. Díaz A, Flo´rez J, Pazos A, Hurle´MA. Opioid sensitivity by alpha 2-adrenoreceptor ago- protein-coupled receptor kinases 2 and 3 tolerance and supersensitivity induce re- nists. Anesthesiology. 2004;100(6): contributes to the cross-talk between mu gional changes in the autoradiographic 1538–1544 and ORL1 receptors following prolonged density of dihydropyridine-sensitive cal- 55. Gomes BA, Shen J, Stafford K, Patel M, agonist exposure. Neuropharmacology. cium channels in the rat central nervous Yoburn BC. Mu-opioid receptor down- 2002;43(6):979–990 system. Pain. 2000;86(3):227–235 regulation and tolerance are not equally 67. Eitan S, Bryant CD, Saliminejad N, et al. 78. McCleskey EW, Gold MS. Ion channels of dependent upon G-protein signaling. Phar- Brain region-specific mechanisms for nociception. Annu Rev Physiol. 1999;61: macol Biochem Behav. 2002;72(1–2): acute morphine-induced mitogen- 835–856 273–278 activated protein kinase modulation and 79. Mitchell JM, Basbaum AI, Fields HL. A locus 56. Fan XL, Zhang JS, Zhang XQ, Ma L. Chronic distinct patterns of activation during anal- and mechanism of action for associative morphine treatment and withdrawal in- gesic tolerance and locomotor sensitiza- morphine tolerance. Nat Neurosci. 2000; duce up-regulation of c-Jun N-terminal ki- tion. J Neurosci. 2003;23(23):8360–8369 3(1):47–53 nase 3 gene expression in rat brain. Neu- 68. Asensio VJ, Miralles A, Garcia-Sevilla JA. 80. Liang DY, Clark JD. Modulation of the NO/ roscience. 2003;122(4):997–1002 Stimulation of mitogen-activated protein CO-cGMP signaling cascade during 57. Bohn LM, Lefkowitz RJ, Caron MG. Differen- kinase kinases (MEK1/2) by mu-, delta- and chronic morphine exposure in mice. Neu- tial mechanisms of morphine antinocicep- kappa-opioid receptor agonists in the rat rosci Lett. 2004;365(1):73–77 tive tolerance revealed in (beta)arrestin-2 brain: regulation by chronic morphine and 81. Polakiewicz RD, Schieferl SM, Gingras AC, knock-out mice. J Neurosci. 2002;22(23): opioid withdrawal. Eur J Pharmacol. 2006; Sonenberg N, Comb MJ. mu-Opioid recep- 10494–10500 539(1–2):49–56 tor activates signaling pathways impli- 58. Cox BM, Crowder AT. Receptor domains 69. Moule´dous L, Diaz MF, Gutstein HB. Extra- cated in cell survival and translational regulating mu opioid receptor uncoupling cellular signal-regulated kinase (ERK) in- control. JBiolChem.1998;273(36): and internalization: relevance to opioid hibition does not prevent the development 23534–23541 tolerance. Mol Pharmacol. 2004;65(3): or expression of tolerance to and depen- 82. Mao J, Price DD, Lu J, Mayer DJ. Antinoci- 492–495 dence on morphine in the mouse. Pharma- ceptive tolerance to the mu-opioid agonist 59. Heinzen EL, Pollack GM. Pharmacodynam- col Biochem Behav. 2007;88(1):39–46 DAMGO is dose-dependently reduced by ics of morphine-induced neuronal nitric 70. Rozenfeld R, Devi LA. Receptor heterodimer- MK-801 in rats. Neurosci Lett. 1998;250(3): oxide production and antinociceptive tol- ization leads to a switch in signaling: beta- 193–196 erance development. Brain Res. 2004; arrestin2-mediated ERK activation by mu- 83. Vaughan CW, Ingram SL, Connor MA, 1023(2):175–184 delta opioid receptor heterodimers. FASEB J. Christie MJ. How opioids inhibit GABA- 60. Leck KJ, Bartlett SE, Smith MT, et al. Dele- 2007;21(10):2455–2465 mediated neurotransmission. Nature. tion of guanine nucleotide binding protein 71. Bilecki W, Zapart G, Ligeza A, Wawrzczak- 1997;390(6660):611–614 alpha z subunit in mice induces a gene Bargiela A, Urbanski MJ, Przewlocki R. 84. Ingram SL, Vaughan CW, Bagley EE, Connor dose dependent tolerance to morphine. Regulation of the extracellular signal- M, Christie MJ. Enhanced opioid efficacy in Neuropharmacology. 2004;46(6):836–846 regulated kinases following acute and opioid dependence is caused by an altered 61. Lim G, Wang S, Zeng Q, Sung B, Yang L, Mao chronic opioid treatment. Cell Mol Life Sci. signal transduction pathway. J Neurosci. J. Expression of spinal NMDA receptor and 2005;62(19–20):2369–2375 1998;18(24):10269–10276

e1220 ANAND et al Downloaded from www.pediatrics.org. Provided by Eccles Health Sciences Lib on May 11, 2010 REVIEW ARTICLES

85. Lu L, Huang M, Liu Z, Ma L. Cholecystokinin-B pression develops morphine tolerance in mice and humans. Proc Natl Acad Sci receptor antagonists attenuate morphine and dependence. J Neurosci. 2000;20(20): USA. 2003;100(8):4867–4872 dependence and withdrawal in rats. Neu- 7640–7647 111. Enggaard TP, Poulsen L, Arendt-Nielsen L, roreport. 2000;11(4):829–832 98. Rothman RB. A review of the role of anti- Brosen K, Ossig J, Sindrup SH. The analge- 86. Mao J. NMDA and opioid receptors: their opioid peptides in morphine tolerance and sic effect of tramadol after intravenous in- interactions in antinociception, tolerance dependence. Synapse. 1992;12(2): jection in healthy volunteers in relation to and neuroplasticity. Brain Res Brain Res 129–138 CYP2D6. Anesth Analg. 2006;102(1): Rev. 1999;30(3):289–304 99. Lo¨tsch J, Flu¨hr K, Neddermayer T, Doehring 146–150 87. Liaw WJ, Zhang B, Tao F, Yaster M, Johns A, Geisslinger G. The consequence of con- 112. Stamer UM, Lehnen K, Hothker F, et al. Im- RA, Tao YX. Knockdown of spinal cord comitantly present functional genetic vari- pact of CYP2D6 genotype on postoperative postsynaptic density protein-95 prevents ants for the identification of functional tramadol analgesia. Pain. 2003;105(1–2): the development of morphine tolerance in genotype-phenotype associations in pain. 231–238 rats. Neuroscience. 2004;123(1):11–15 Clin Pharmacol Ther. 2009;85(1):25–30 113. Stamer UM, Musshoff F, Kobilay M, Madea 88. Liu JG, Prather PL. Chronic agonist treat- 100. Lo¨tsch J, Geisslinger G. Relevance of fre- B, Hoeft A, Stuber F. Concentrations of tra- ment converts antagonists into inverse quent mu-opioid receptor polymorphisms madol and O-desmethyltramadol enanti- agonists at delta-opioid receptors. J Phar- for opioid activity in healthy volunteers. omers in different CYP2D6 genotypes. Clin macol Exp Ther. 2002;302(3):1070–1079 Pharmacogenomics J. 2006;6(3):200–210 Pharmacol Ther. 2007;82(1):41–47 89. Davis AM, Inturrisi CE. D-Methadone blocks 101. Lo¨tsch J, Skarke C, Liefhold J, Geisslinger 114. Stamer UM, Stuber F. Codeine and tram- morphine tolerance and N-methyl-D- G. Genetic predictors of the clinical re- adol analgesic efficacy and respiratory ef- aspartate-induced hyperalgesia. JPhar- sponse to opioid analgesics: clinical utility fects are influenced by CYP2D6 genotype. macol Exp Ther. 1999;289(2):1048–1053 and future perspectives. Clin Pharmacoki- Anaesthesia. 2007;62(12):1294–1295; au- 90. Langerman L, Zakowski MI, Piskoun B, net. 2004;43(14):983–1013 thor reply 1295–1296 Grant GJ. Hot plate versus tail flick: evalu- 102. Oertel B, Lo¨tsch J. Genetic mutations that 115. Kirchheiner J, Keulen JT, Bauer S, Roots I, ation of acute tolerance to continuous prevent pain: implications for future pain Brockmoller J. Effects of the CYP2D6 gene morphine infusion in the rat model. medication. Pharmacogenomics. 2008; duplication on the pharmacokinetics and J Pharmacol Toxicol Methods. 1995;34(1): 9(2):179–194 pharmacodynamics of tramadol. JClin 23–27 103. Stamer UM, Stuber F. Genetic factors in Psychopharmacol. 2008;28(1):78–83 91. Hiltunen P, Raudaskoski T, Ebeling H, Moil- pain and its treatment. Curr Opin Anaes- 116. Gan SH, Ismail R, Wan Adnan WA, Zulmi W. anen I. Does pain relief during delivery de- thesiol. 2007;20(5):478–484 Impact of CYP2D6 genetic polymorphism crease the risk of postnatal depression? 104. Stamer UM, Stuber F. The pharmacogenet- on tramadol pharmacokinetics and phar- Acta Obstet Gynecol Scand. 2004;83(3): ics of analgesia. Expert Opin Pharmaco- macodynamics. Mol Diagn Ther. 2007; 257–261 ther. 2007;8(14):2235–2245 11(3):171–181 92. Crain SM, Shen KF. After chronic opioid ex- 105. Campa D, Gioia A, Tomei A, Poli P, Barale R. 117. Voronov P, Przybylo HJ, Jagannathan N. Ap- posure sensory neurons become super- Association of ABCB1/MDR1 and OPRM1 nea in a child after oral codeine: a genetic sensitive to the excitatory effects of opioid gene polymorphisms with morphine pain variant—an ultra-rapid metabolizer. Pae- agonists and antagonists as occurs after relief. Clin Pharmacol Ther. 2008;83(4): diatr Anaesth. 2007;17(7):684–687 acute elevation of GM1 ganglioside. Brain 559–566 118. Coulbault L, Beaussier M, Verstuyft C, et al. Res. 1992;575(1):13–24 106. Shabalina SA, Zaykin DV, Gris P, et al. Ex- Environmental and genetic factors associ- 93. Grisel JE, Watkins LR, Maier SF. Associative pansion of the human mu-opioid receptor ated with morphine response in the post- and non-associative mechanisms of mor- gene architecture: novel functional vari- operative period. Clin Pharmacol Ther. phine analgesic tolerance are neuro- ants. Hum Mol Genet. 2009;18(6): 2006;79(4):316–324 chemically distinct in the rat spinal cord. 1037–1051 119. Holthe M, Rakvag TN, Klepstad P, et al. Psychopharmacology. 1996;128(3): 107. Diatchenko L, Nackley AG, Slade GD, et al. Sequence variations in the UDP- 248–255 Catechol-O-methyltransferase gene poly- glucuronosyltransferase 2B7 (UGT2B7) 94. Laurent P, Becker JA, Valverde O, et al. The morphisms are associated with multiple gene: identification of 10 novel single nu- prolactin-releasing peptide antagonizes pain-evoking stimuli. Pain. 2006;125(3): cleotide polymorphisms (SNPs) and analy- the opioid system through its receptor 216–224 sis of their relevance to morphine glucu- GPR10. Nat Neurosci. 2005;8(12): 108. Mukherjee N, Kidd KK, Pakstis AJ, et al. The ronidation in cancer patients [published 1735–1741 complex global pattern of genetic varia- correction appears in Pharmacogenomics 95. Ueda H. Anti-opioid systems in morphine tion and linkage disequilibrium at J.2003;3(4):248].Pharmacogenomics J. tolerance and addiction: locus-specific in- catechol-O-methyltransferase. Mol Psychi- 2003;3(1):17–26 volvement of nociceptin and the NMDA re- atry. 2010;15(2):216 120. Innocenti F, Liu W, Fackenthal D, et al. Sin- ceptor. Novartis Found Symp. 2004;261: 109. Mogil JS, Ritchie J, Smith SB, et al. gle nucleotide polymorphism discovery 155–162; discussion 162–156, 191–153 Melanocortin-1 receptor gene variants af- and functional assessment of variation in 96. McCleane G. Cholecystokinin antagonists a fect pain and mu-opioid analgesia in mice the UDP-glucuronosyltransferase 2B7 new way to improve the analgesia from and humans. JMedGenet.2005;42(7): gene. Pharmacogenet Genomics. 2008; old analgesics? Curr Pharm Des. 2004; 583–587 18(8):683–697 10(3):303–314 110. Mogil JS, Wilson SG, Chesler EJ, et al. The 121. Mehlotra RK, Bockarie MJ, Zimmerman PA. 97. Ueda H, Inoue M, Takeshima H, Iwasawa Y. melanocortin-1 receptor gene mediates Prevalence of UGT1A9 and UGT2B7 nonsyn- Enhanced spinal nociceptin receptor ex- female-specific mechanisms of analgesia onymous single nucleotide polymor-

PEDIATRICS Volume 125, Number 5, May 2010 e1221 Downloaded from www.pediatrics.org. Provided by Eccles Health Sciences Lib on May 11, 2010 phisms in West African, Papua New Guin- methyltransferase and multidrug 147. Bouwmeester NJ, Anand KJS, van Dijk M, ean, and North American populations. Eur resistance-1 gene polymorphisms are as- Hop WC, Boomsma F, Tibboel D. Hormonal J Clin Pharmacol. 2007;63(1):1–8 sociated with central side effects. Cancer. and metabolic stress responses after ma- 122. Blake MJ, Abdel-Rahman SM, Pearce RE, 2008;112(6):1390–1403 jor surgery in children aged 0–3 years: a Leeder JS, Kearns GL. Effect of diet on the 135. Wager TD, Scott DJ, Zubieta JK. Placebo ef- double-blind, randomized trial comparing development of drug metabolism by cyto- fects on human mu-opioid activity during the effects of continuous versus intermit- chrome P-450 enzymes in healthy infants. pain. Proc Natl Acad Sci U S A.2007; tent morphine. Br J Anaesth. 2001;87(3): Pediatr Res. 2006;60(6):717–723 104(26):11056–11061 390–399 123. Blake MJ, Gaedigk A, Pearce RE, et al. On- 136. Ribeiro SC, Kennedy SE, Smith YR, Stohler 148. Bardo MT, Hughes RA. Single-dose toler- togeny of dextromethorphan O-and CS, Zubieta JK. Interface of physical and ance to morphine-induced analgesic and N-demethylation in the first year of life. emotional stress regulation through the hypoactive effects in infant rats. Dev Psy- Clin Pharmacol Ther. 2007;81(4):510–516 endogenous opioid system and mu-opioid chobiol. 1981;14(5):415–423 124. Allegaert K, Anderson BJ, van den Anker receptors. Prog Neuropsychopharmacol 149. Eaton DG, Wertheim D, Oozeer R, Royston P, JN, Vanhaesebrouck S, de Zegher F. Renal Biol Psychiatry. 2005;29(8):1264–1280 Dubowitz L, Dubowitz V. The effect of pethi- drug clearance in preterm neonates: rela- 137. Zubieta JK, Heitzeg MM, Smith YR, et al. dine on the neonatal EEG. Dev Med Child tion to prenatal growth. Ther Drug Monit. COMT val158met genotype affects mu- Neurol. 1992;34(2):155–163 2007;29(3):284–291 opioid neurotransmitter responses to a 150. Franck LS, Miaskowski C. The use of intra- 125. Anderson BJ, Allegaert K, Holford NH. Pop- pain stressor. Science. 2003;299(5610): venous opioids to provide analgesia in crit- ulation clinical pharmacology of children: 1240–1243 ically ill, premature neonates: a research general principles. Eur J Pediatr. 2006; 138. Simons SH, Anand KJS. Pain control: opioid critique. J Pain Symptom Manage. 1998; 165(11):741–746 dosing, population kinetics and side- 15(1):41–69 126. Anderson BJ, Allegaert K, Holford NH. Pop- effects. Semin Fetal Neonatal Med. 2006; 151. Doberczak TM, Kandall SR, Wilets I. Neona- ulation clinical pharmacology of children: 11(4):260–267 tal opiate abstinence syndrome in term modelling covariate effects. Eur J Pediatr. 139. Zubieta JK, Ketter TA, Bueller JA, et al. Reg- and preterm infants. JPediatr.1991; 2006;165(12):819–829 ulation of human affective responses by 118(6):933–937 anterior cingulate and limbic mu-opioid 127. Evans WE, McLeod HL. Pharmacogenomics: 152. Bhat R, Abu-Harb M, Chari G, Gulati A. Mor- neurotransmission. Arch Gen Psychiatry. drug disposition, drug targets, and side ef- phine metabolism in acutely ill preterm 2003;60(11):1145–1153 fects. N Engl J Med. 2003;348(6):538–549 newborn infants. JPediatr.1992;120(5): 128. Weinshilboum R. Inheritance and drug re- 140. Dewey WL. Various factors which affect the 795–799 sponse. N Engl J Med. 2003;348(6):529–537 rate of development of tolerance and phys- 153. Hartley R, Quinn M, Green M, Levene MI. ical dependence to abused drugs. NIDA Res 129. Bond C, LaForge KS, Tian M, et al. Single- Morphine glucuronidation in premature Monogr. 1984;54:39–49 nucleotide polymorphism in the human neonates. Br J Clin Pharmacol. 1993;35(3): mu opioid receptor gene alters beta- 141. Hovav E, Weinstock M. Temporal factors in- 314–317 endorphin binding and activity: possible fluencing the development of acute toler- 154. Barrett DA, Barker DP, Rutter N, Pawula M, implications for opiate addiction. Proc ance to opiates. JPharmacolExpTher. Shaw PN. Morphine, morphine-6- Natl Acad Sci U S A. 1998;95(16):9608–9613 1987;242(1):251–256 glucuronide and morphine-3-glucuronide 142. Ceger P, Kuhn CM. Opiate withdrawal in the 130. Ho¨llt V. A polymorphism (A118G) in the mu- pharmacokinetics in newborn infants re- neonatal rat: relationship to duration of opioid receptor gene affects the response ceiving diamorphine infusions. Br J Clin to morphine-6-glucuronide in humans. treatment and naloxone dose. Psychop- Pharmacol. 1996;41(6):531–537 Pharmacogenetics. 2002;12(1):1–2 harmacology. 2000;150(3):253–259 155. Faura CC, Collins SL, Moore RA, McQuay HJ. 131. Lotsch J, Skarke C, Tegeder I, Geisslinger G. 143. Kissin I, Lee SS, Arthur GR, Bradley EL Jr. Systematic review of factors affecting the Drug interactions with patient-controlled Effect of midazolam on development of ratios of morphine and its major metabo- analgesia. Clin Pharmacokinet. 2002;41(1): acute tolerance to alfentanil: the role of lites. Pain. 1998;74(1):43–53 31–57 pharmacokinetic interactions. Anesth 156. Choe CH, Smith FL. Sedative tolerance ac- 132. Compton P, Geschwind DH, Alarcon M. As- Analg. 1997;85(1):182–187 companies tolerance to the analgesic ef- sociation between human mu-opioid re- 144. Anand KJS, McIntosh N, Lagercrantz H, fects of fentanyl in infant rats. Pediatr Res. ceptor gene polymorphism, pain toler- Young TE, Vasa RK, Barton BA. Analgesia 2000;47(6):727–735 ance, and opioid addiction. Am J Med and sedation in ventilated preterm Genet B Neuropsychiatr Genet. 2003; neonates: results from the pilot N.O.P.A.I.N. 157. Craft RM, Stratmann JA, Bartok RE, Wal- 121B(1):76–82 trial. Arch Pediatr Adolesc Med. 1999; pole TI, King SJ. Sex differences in develop- 133. Beyer A, Koch T, Schroder H, Schulz S, Hollt 153(4):331–338 ment of morphine tolerance and depen- V. Effect of the A118G polymorphism on 145. Thornton SR, Smith FL. Characterization of dence in the rat. Psychopharmacology. binding affinity, potency and agonist- neonatal rat fentanyl tolerance and depen- 1999;143(1):1–7 mediated endocytosis, desensitization, dence. J Pharmacol Exp Ther. 1997;281(1): 158. Thornton SR, Wang AF, Smith FL. Character- and resensitization of the human mu- 514–521 ization of neonatal rat morphine tolerance opioid receptor. J Neurochem. 2004;89(3): 146. Marshall H, Porteous C, McMillan I, MacPher- and dependence. Eur J Pharmacol. 1997; 553–560 son SG, Nimmo WS. Relief of pain by infusion 340(2–3):161–167 134. Ross JR, Riley J, Taegetmeyer AB, et al. Ge- of morphine after operation: does tolerance 159. Thornton SR, Smith FL. Long-term alter- netic variation and response to mor- develop? Br Med J (Clin Res Ed). 1985; ations in opiate antinociception resulting phine in cancer patients: catechol-O- 291(6487):19–21 from infant fentanyl tolerance and depen-

e1222 ANAND et al Downloaded from www.pediatrics.org. Provided by Eccles Health Sciences Lib on May 11, 2010 REVIEW ARTICLES

dence. Eur J Pharmacol. 1998;363(2–3): 171. Cunliffe M, McArthur L, Dooley F. Managing nates. Br J Clin Pharmacol. 1993;36(3): 113–119 sedation withdrawal in children who un- 215–219 160. Guinsburg R, de Araujo Peres C, Branco de dergo prolonged PICU admission after dis- 184. Hamunen K, Olkkola KT, Maunuksela EL. Almeida MF, et al. Differences in pain ex- charge to the ward. Paediatr Anaesth. Comparison of the ventilatory effects of pression between male and female new- 2004;14(4):293–298 morphine and buprenorphine in children. born infants. Pain. 2000;85(1–2):127–133 172. Franck LS, Harris SK, Soetenga DJ, Amling Acta Anaesthesiol Scand. 1993;37(5): 161. Bartocci M, Winberg, J, Papendieck G, Mus- JK, Curley MA. The Withdrawal Assessment 449–453 tica T, Serra G, Lagercrantz H. Cerebral he- Tool-1 (WAT-1): an assessment instrument 185. Maunuksela EL, Korpela R, Olkkola KT. Com- modynamic response to unpleasant odors for monitoring opioid and benzodiazepine parison of buprenorphine with morphine in the preterm newborn measured by withdrawal symptoms in pediatric pa- in the treatment of postoperative pain in near-infrared spectroscopy. Pediatr Res. tients. Pediatr Crit Care Med. 2008;9(6): children. Anesth Analg. 1988;67(3): 2001;50(3):324–330 573–580 233–239 162. Bot G, Blake AD, Li S, Reisine T. Fentanyl and 173. Bell RF. Low-dose subcutaneous ketamine 186. Maunuksela EL, Korpela R, Olkkola KT. its analogs desensitize the cloned mu opi- infusion and morphine tolerance. Pain. Double-blind, multiple-dose comparison of oid receptor. J Pharmacol Exp Ther. 1998; 1999;83(1):101–103 buprenorphine and morphine in postoper- 285(3):1207–1218 174. Tobias JD. Subcutaneous dexmedetomi- ative pain of children. Br J Anaesth. 1988; 163. Gorman AL, Elliott KJ, Inturrisi CE. The dine infusions to treat or prevent drug 60(1):48–55 D- and L-isomers of methadone bind to the withdrawal in infants and children. J Opi- 187. Lehmann KA, Reichling U, Wirtz R. Influence non-competitive site on the N-methyl-D- oid Manag. 2008;4(4):187–191 of naloxone on the postoperative analgesic aspartate (NMDA) receptor in rat fore- 175. Chana SK, Anand KJS. Can we use metha- and respiratory effects of buprenorphine. brain and spinal cord. Neurosci Lett. 1997; done for analgesia in neonates? Arch Dis Eur J Clin Pharmacol. 1988;34(4):343–352 223(1):5–8 Child Fetal Neonatal Ed. 2001;85(2): 188. Olkkola KT, Hamunen K, Maunuksela EL. 164. Liu JG, Liao XP, Gong ZH, Qin BY. The differ- F79–F81 Clinical pharmacokinetics and pharmaco- ence between methadone and morphine in 176. Berde CB, Beyer JE, Bournaki MC, Levin CR, dynamics of opioid analgesics in infants regulation of delta-opioid receptors un- Sethna NF. Comparison of morphine and and children. Clin Pharmacokinet. 1995; derlies the antagonistic effect of metha- methadone for prevention of postopera- 28(5):385–404 done on morphine-mediated cellular ac- tive pain in 3- to 7-year-old children. J Pe- 189. Johnson RE, Chutuape MA, Strain EC, Walsh tions. Eur J Pharmacol. 1999;373(2–3): diatr. 1991;119(1 pt 1):136–141 SL, Stitzer ML, Bigelow GE. A comparison of 233–239 177. Berde CB, Sethna NF, Holzman RS, Reidy P, levomethadyl acetate, buprenorphine, and 165. Ista E, van Dijk M, Gamel C, Tibboel D, de Gondek EJ. Pharmacokinetics of metha- methadone for opioid dependence. N Engl Hoog M. Withdrawal symptoms in children done in children and adolescents in the J Med. 2000;343(18):1290–1297 after long-term administration of seda- perioperative period. Anesthesiology. 190. Robinson SE. Buprenorphine: an analgesic tives and/or analgesics: a literature re- 1987;67(3A):A519 with an expanding role in the treatment of view. “Assessment remains troublesome.” 178. Gourlay GK, Wilson PR, Glynn CJ. Pharma- opioid addiction. CNS Drug Rev. 2002;8(4): Intensive Care Med. 2007;33(8):1396–1406 codynamics and pharmacokinetics of 377–390 166. Franck L, Vilardi J. Assessment and man- methadone during the perioperative pe- 191. O’Connor PG. Treating opioid dependence: agement of opioid withdrawal in ill neo- riod. Anesthesiology. 1982;57(6):458–467 new data and new opportunities. N Engl nates. Neonatal Netw. 1995;14(2):39–48 179. Liu JG, Liao XP, Gong ZH, Qin BY. J Med. 2000;343(18):1332–1334 167. Ista E, van Dijk M, Gamel C, Tibboel D, de Methadone-induced desensitization of the 192. Gowing L, Ali R, White J. Buprenorphine for Hoog M. Withdrawal symptoms in critically delta-opioid receptor is mediated by un- the management of opioid withdrawal. Co- ill children after long-term administration coupling of receptor from G protein. Eur chrane Database Syst Rev. 2000;(3): of sedatives and/or analgesics: a first eval- J Pharmacol. 1999;374(2):301–308 CD002025 uation [published correction appears in 180. Lugo RA, MacLaren R, Cash J, Pribble CG, 193. Kayemba-Kay’s S, Laclyde JP. Buprenor- Neonatal Netw.1995;14(4):83].Crit Care Vernon DD. Enteral methadone to expedite phine withdrawal syndrome in newborns: Med. 2008;36(8):2427–2432 fentanyl discontinuation and prevent opi- areportof13cases.Addiction. 2003; 168. Finnegan LP. Effects of maternal opiate oid abstinence syndrome in the PICU. Phar- 98(11):1599–1604 abuse on the newborn. Fed Proc. 1985; macotherapy. 2001;21(12):1566–1573 194. Marquet P, Chevrel J, Lavignasse P, Merle 44(7):2314–2317 181. Williams PI, Sarginson RE, Ratcliffe JM. Use L, Lachatre G. Buprenorphine withdrawal 169. Gru¨nberger J, Linzmayer L, Fodor G, Press- of methadone in the morphine-tolerant syndrome in a newborn. Clin Pharmacol lich O, Praitner M, Loimer N. Static and dy- burned paediatric patient. Br J Anaesth. Ther. 1997;62(5):569–571 namic pupillometry for determination of 1998;80(1):92–95 195. Herve´F, Quenum S. Buprenorphine (Subu- the course of gradual detoxification of 182. Siddappa R, Fletcher JE, Heard AM, Kielma tex) and neonatal withdrawal syndrome opiate-addicted patients. Eur Arch Psychi- D, Cimino M, Heard CM. Methadone dosage [in French]. Arch Pediatr. 1998;5(2): atry Clin Neurosci. 1990;240(2):109–112 for prevention of opioid withdrawal in chil- 206–207 170. Curley MA, Harris SK, Fraser KA, Johnson dren. Paediatr Anaesth. 2003;13(9): 196. Lacroix I, Berrebi A, Chaumerliac C, RA, Arnold JH. State Behavioral Scale: a se- 805–810 Lapeyre-Mestre M, Montastruc JL, dation assessment instrument for infants 183. Barrett DA, Simpson J, Rutter N, Kurihara- Damase-Michel C. Buprenorphine in preg- and young children supported on mechan- Bergstrom T, Shaw PN, Davis SS. The phar- nant opioid-dependent women: first re- ical ventilation. Pediatr Crit Care Med. macokinetics and physiological effects of sults of a prospective study. Addiction. 2006;7(2):107–114 buprenorphine infusion in premature neo- 2004;99(2):209–214

PEDIATRICS Volume 125, Number 5, May 2010 e1223 Downloaded from www.pediatrics.org. Provided by Eccles Health Sciences Lib on May 11, 2010 197. McClain BC, Probst LA, Pinter E, Hart- mendations. Arch Neurol. 2003;60(11): 223. Popik P, Kozela E. Clinically available NMDA mannsgruber M. Intravenous clonidine 1524–1534 antagonist, memantine, attenuates toler- use in a neonate experiencing opioid- 211. Backonja MM. Use of anticonvulsants for ance to analgesic effects of morphine in a induced myoclonus. Anesthesiology. 2001; treatment of neuropathic pain. Neurology. mouse tail flick test. Pol J Pharmacol. 95(2):549–550 2002;59(5 suppl 2):S14–17 1999;51(3):223–231 198. Hoder EL, Leckman JF, Ehrenkranz R, Kle- 212. Freye E, Levy JV, Partecke L. Use of gabap- 224. Unal CB, Owen MD, Millington WR. ber H, Cohen DJ, Poulsen JA. Clonidine in entin for attenuation of symptoms follow- Cyclo(Gly-Gln) inhibits the cardiorespira- neonatal narcotic-abstinence syndrome. ing rapid opiate detoxification (ROD): cor- tory depression produced by beta- N Engl J Med. 1981;305(21):1284 relation with neurophysiological endorphin and morphine. Brain Res. 1997; 199. Hoder EL, Leckman JF, Poulsen J, et al. parameters. Neurophysiol Clin. 2004;34(2): 747(1):52–59 Clonidine treatment of neonatal narcotic 81–89 225. Owen MD, Gurun S, Zaloga GP, Millington abstinence syndrome. Psychiatry Res. 213. Kumar P, Jain MK. Gabapentin in the man- WR. Glycyl-L-glutamine [beta-endorphin- 1984;13(3):243–251 agement of pentazocine dependence: a po- (30–31)] attenuates hemorrhagic hypo- 200. Kosten TR, Rounsaville BJ, Kleber HD. Com- tent analgesic-anticraving agent. J Assoc tension in conscious rats. Am J Physiol. parison of clinician ratings to self reports Physicians India. 2003;51:673–676 1997;273(5 pt 2):R1598–R1606 of withdrawal during clonidine detoxifica- 214. Andrews N, Loomis S, Blake R, Ferrigan L, 226. Unal CB, Owen MD, Millington WR. Beta- tion of opiate addicts. Am J Drug Alcohol Singh L, McKnight AT. Effect of gabapentin- endorphin-induced cardiorespiratory de- Abuse. 1985;11(1–2):1–10 like compounds on development and main- pression is inhibited by glycyl-L-glutamine, 201. Gold MS, Pottash AL, Extein I, Finn LB, Kle- tenance of morphine-induced conditioned a dipeptide derived from beta-endorphin ber HD. Clonidine in opiate withdrawal. place preference. Psychopharmacology processing. J Pharmacol Exp Ther. 1994; Curr Psychiatr Ther. 1981;20:285–291 (Berl). 2001;157(4):381–387 271(2):952–958 202. Gold MS, Pottash AC, Sweeney DR, Kleber 215. Gustorff B, Kozek-Langenecker S, Kress HG. 227. Kress JP, Pohlman AS, O’Connor MF, Hall HD. Opiate withdrawal using clonidine: a Gabapentin: the first preemptive anti- JB. Daily interruption of sedative infusions safe, effective, and rapid nonopiate treat- hyperalgesic for opioid withdrawal hyper- in critically ill patients undergoing me- ment. JAMA. 1980;243(4):343–346 algesia? Anesthesiology. 2003;98(6): chanical ventilation. N Engl J Med. 2000; 203. Honey BL, Benefield RJ, Miller JL, Johnson 1520–1521 342(20):1471–1477 PN. ␣ -receptor agonists for treatment 2 216. Sheridan RL, Keaney T, Stoddard F, Enfanto 228. Brook AD, Ahrens TS, Schaiff R, et al. Effect and prevention of iatrogenic opioid absti- R, Kadillack P, Breault L. Short-term propo- of a nursing-implemented sedation proto- nence syndrome in critically ill patients. fol infusion as an adjunct to extubation in col on the duration of mechanical ventila- Ann Pharmacother. 2009;43(9):1506–1511 burned children. JBurnCareRehabil. tion. Crit Care Med. 1999;27(12): 2003;24(6):356–360 204. Farag E, Chahlavi A, Argalious M, Ebrahim 2609–2615 Z, Hill R, Bourdakos D, et al. Using dexme- 217. Feng JQ, Kendig JJ. Propofol potentiates 229. Mercadante S. Opioid rotation for cancer detomidine to manage patients with co- the depressant effect of alfentanil in iso- pain: rationale and clinical aspects. Can- caine and opioid withdrawal, who are un- lated neonatal rat spinal cord and blocks cer. 1999;86(9):1856–1866 dergoing cerebral angioplasty for naloxone-precipitated hyperresponsive- cerebral vasospasm. Anesth Analg. 2006; ness. Neurosci Lett. 1997;229(1):9–12 230. Moryl N, Santiago-Palma J, Kornick C, et al. Pitfalls of opioid rotation: substituting an- 103(6):1618–1620 218. Hasday JD, Weintraub M. Propoxyphene in other opioid for methadone in patients 205. Multz AS. Prolonged dexmedetomidine in- children with iatrogenic morphine depen- with cancer pain. Pain. 2002;96(3):325–328 fusion as an adjunct in treating sedation- dence. Am J Dis Child. 1983;137(8):745–748 231. Haberkern CM, Lynn AM, Geiduschek JM, et induced withdrawal. Anesth Analg. 2003; 219. Udkow G, Weintraub M. Use of propoxy- 96(4):1054–1055, table of contents phene napsylate for detoxification of a al. Epidural and intravenous bolus mor- 206. Finkel JC, Elrefai A. The use of dexmedeto- child with morphine sulfate tolerance and phine for postoperative analgesia in in- midine to facilitate opioid and benzodiaz- physical dependence. JPediatr.1978; fants. Can J Anaesth. 1996;43(12): epine detoxification in an infant. Anesth 92(5):829–831 1203–1210 Analg. 2004;98(6):1658–1659 220. Neil A, Terenius L. D-Propoxyphene acts dif- 232. Malviya S, Pandit UA, Merkel S, et al. A com- 207. Finkel JC, Johnson YJ, Quezado ZM. The use ferently from morphine on opioid parison of continuous epidural infusion of dexmedetomidine to facilitate acute dis- receptor-effector mechanisms. Eur and intermittent intravenous bolus doses continuation of opioids after cardiac J Pharmacol. 1981;69(1):33–39 of morphine in children undergoing selec- tive dorsal rhizotomy. Reg Anesth Pain transplantation in children. Crit Care Med. 221. Bisaga A, Comer SD, Ward AS, Popik P, Kle- 2005;33(9):2110–2112 ber HD, Fischman MW. The NMDA antago- Med. 1999;24(5):438–443 208. Tobias JD. Dexmedetomidine to treat opi- nist memantine attenuates the expression 233. Henneberg SW, Hole P, Madsen de Haas I, oid withdrawal in infants following pro- of opioid physical dependence in humans. Jensen PJ. Epidural morphine for postop- longed sedation in the pediatric ICU. J Opi- Psychopharmacology (Berl). 2001;157(1): erative pain relief in children. Acta Anaes- oid Manag. 2006;2(4):201–205 1–10 thesiol Scand. 1993;37(7):664–667 209. Phan H, Nahata MC. Clinical uses of dexme- 222. Maldonado C, Cauli O, Rodriguez-Arias M, 234. McCrory C, Diviney D, Moriarty J, Luke D, detomidine in pediatric patients. Paediatr Aguilar MA, Minarro J. Memantine pre- Fitzgerald D. Comparison between repeat Drugs. 2008;10(1):49–69 sents different effects from MK-801 in mo- bolus intrathecal morphine and an epi- 210. Dworkin RH, Backonja M, Rowbotham MC, tivational and physical signs of morphine durally delivered bupivacaine and fentanyl et al. Advances in neuropathic pain: diag- withdrawal. Behav Brain Res. 2003; combination in the management of post- nosis, mechanisms, and treatment recom- 144(1–2):25–35 thoracotomy pain with or without cycloox-

e1224 ANAND et al Downloaded from www.pediatrics.org. Provided by Eccles Health Sciences Lib on May 11, 2010 REVIEW ARTICLES

ygenase inhibition. JCardiothoracVasc Pereira NL. Oral ketamine and transder- done has a NMDA blocking effect. Pain. Anesth. 2002;16(5):607–611 mal nitroglycerin as analgesic adjuvants 1996;67(2–3):369–374 235. Yaster M, Tobin JR, Billett C, Casella JF, Do- to oral morphine therapy for cancer pain 250. Ebert B, Thorkildsen C, Andersen S, Chris- ver G. Epidural analgesia in the manage- management. Anesthesiology. 1999;90(6): trup LL, Hjeds H. Opioid analgesics as non- ment of severe vaso-occlusive sickle cell 1528–1533 competitive N-methyl-D-aspartate (NMDA) crisis. Pediatrics. 1994;93(2):310–315 243. Huang C, Long H, Shi YS, Han JS, Wan Y. antagonists. Biochem Pharmacol. 1998; 236. Curley MAQ, Amling J, Gedeit RG, et al. Se- Ketamine enhances the efficacy to and de- 56(5):553–559 lays the development of tolerance to dation management in pediatric patients 251. Highfield DA, Grant S. Ng-nitro-L-arginine, supported on mechanical ventilation. Pedi- electroacupuncture-induced antinocicep- an NOS inhibitor, reduces tolerance to atr Crit Care Med. 2007;8(3 suppl):A106 tion in rats. Neurosci Lett. 2005;375(2): morphine in the rat locus coeruleus. Syn- 138–142 237. Curley MAQ, Dodson BL, Arnold JH. Design- apse. 1998;29(3):233–239 244. Shimoyama N, Shimoyama M, Inturrisi CE, ing a nurse-implemented sedation algo- 252. Lue WM, Su MT, Lin WB, Tao PL. The role of Elliott KJ. Ketamine attenuates and re- rithm for use in a pediatric intensive care nitric oxide in the development of mor- verses morphine tolerance in rodents. An- unit: a preliminary report. Pediatr Crit phine tolerance in rat hippocampal slices. esthesiology. 1996;85(6):1357–1366 Care Med. 2003;4(3 suppl):A158 Eur J Pharmacol. 1999;383(2):129–135 238. Sury MR, Hatch DJ, Deeley T, Dicks-Mireaux 245. Levine JD, Gordon NC, Taiwo YO, Coderre 253. Vaupel DB, Kimes AS, London ED. Nitric ox- C, Chong WK. Development of a nurse-led TJ. Potentiation of pentazocine analgesia ide synthase inhibitors: preclinical studies sedation service for paediatric magnetic by low-dose naloxone. J Clin Invest. 1988; of potential use for treatment of opioid resonance imaging. Lancet. 1999; 82(5):1574–1577 withdrawal. Neuropsychopharmacology. 353(9165):1667–1671 246. Cepeda MS, Africano JM, Manrique AM, 1995;13(4):315–322 239. Hammer GB, Ramamoorthy C, Cao H, et al. Fragoso W, Carr DB. The combination of 254. Vaupel DB, Kimes AS, London ED. Compari- Postoperative analgesia after spinal low dose of naloxone and morphine in PCA son of 7-nitroindazole with other nitric ox- blockade in infants and children undergo- does not decrease opioid requirements in ing cardiac surgery. Anesth Analg. 2005; the postoperative period. Pain. 2002; ide synthase inhibitors as attenuators of 100(5):1283–1288 96(1–2):73–79 opioid withdrawal. Psychopharmacology (Berl). 1995;118(4):361–368 240. Atangana R, Ngowe Ngowe M, Binam F, 247. Cheung CLS, van Dijk M, Green JG, Tibboel Sosso MA. Morphine versus morphine- D, Anand KJS. Effect of low-dose naloxone 255. Singh VP, Jain NK, Kulkarni SK. Fluoxetine ketamine association in the management infusions on opioid tolerance in pediatric suppresses morphine tolerance and of post operative pain in thoracic surgery. patients: a case-control study. Intensive dependence: modulation of NO-cGMP/DA/ Acta Anaesthesiol Belg. 2007;58(2): Care Med. 2007;33(1):190–194 serotoninergic pathways. Methods Find 125–127 248. Darnell CM, Thompson J, Stromberg D, Roy Exp Clin Pharmacol. 2003;25(4):273–280 241. Bossard AE, Guirimand F, Fletcher D, L, Sheeran P. Effect of low-dose naloxone 256. Tobias JD. Sedation and analgesia in the Gaude-Joindreau V, Chauvin M, Bouhas- infusion on fentanyl requirements in criti- pediatric intensive care unit. Pediatr Ann. sira D. Interaction of a combination of mor- cally ill children. Pediatrics. 2008;121(5). 2005;34(8):636–645 phine and ketamine on the nociceptive Available at: www.pediatrics.org/cgi/ 257. Tobias JD. Sedation and analgesia in pae- flexion reflex in human volunteers. Pain. content/full/121/5/e1363 diatric intensive care units: a guide to drug 2002;98(1–2):47–57 249. Andersen S, Dickenson AH, Kohn M, Reeve selection and use. Paediatr Drugs. 1999; 242. Lauretti GR, Lima IC, Reis MP, Prado WA, A, Rahman W, Ebert B. The opioid ketobemi- 1(2):109–126

PEDIATRICS Volume 125, Number 5, May 2010 e1225 Downloaded from www.pediatrics.org. Provided by Eccles Health Sciences Lib on May 11, 2010 Tolerance and Withdrawal From Prolonged Opioid Use in Critically Ill Children Kanwaljeet J. S. Anand, Douglas F. Willson, John Berger, Rick Harrison, Kathleen L. Meert, Jerry Zimmerman, Joseph Carcillo, Christopher J. L. Newth, Parthak Prodhan, J. Michael Dean, Carol Nicholson and for the Eunice Kennedy Shriver National Institute of Child Health and Human Development Collaborative Pediatric Critical Care Research Network Pediatrics 2010;125;e1208-e1225; originally published online Apr 19, 2010; DOI: 10.1542/peds.2009-0489 Updated Information including high-resolution figures, can be found at: & Services http://www.pediatrics.org/cgi/content/full/125/5/e1208 References This article cites 253 articles, 65 of which you can access for free at: http://www.pediatrics.org/cgi/content/full/125/5/e1208#BIBL Permissions & Licensing Information about reproducing this article in parts (figures, tables) or in its entirety can be found online at: http://www.pediatrics.org/misc/Permissions.shtml Reprints Information about ordering reprints can be found online: http://www.pediatrics.org/misc/reprints.shtml

Downloaded from www.pediatrics.org. Provided by Eccles Health Sciences Lib on May 11, 2010