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Tolerance and Withdrawal from Prolonged Opioid Use in Critically Ill Children

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Tolerance and Withdrawal from Prolonged Opioid Use in Critically Ill Children 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
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