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Review
. 2010 May;125(5):e1208-25.
doi: 10.1542/peds.2009-0489. Epub 2010 Apr 19.

Tolerance and withdrawal from prolonged opioid use in critically ill children

Kanwaljeet J S Anand  1 , 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; Eunice Kennedy Shriver National Institute of Child Health and Human Development Collaborative Pediatric Critical Care Research Network
Affiliations
Review

Tolerance and withdrawal from prolonged opioid use in critically ill children

Kanwaljeet J S Anand et al. Pediatrics. 2010 May.

Abstract

Objective: After prolonged opioid exposure, children develop opioid-induced hyperalgesia, tolerance, and withdrawal. Strategies for prevention and management should be based on the mechanisms of opioid tolerance and withdrawal.

Patients and methods: Relevant manuscripts published in the English language were searched in Medline by using search terms "opioid," "opiate," "sedation," "analgesia," "child," "infant-newborn," "tolerance," "dependency," "withdrawal," "analgesic," "receptor," and "individual opioid drugs." Clinical and preclinical studies were reviewed for data synthesis.

Results: Mechanisms of opioid-induced hyperalgesia and tolerance suggest important drug- and patient-related risk factors that lead to tolerance and withdrawal. Opioid tolerance occurs earlier in the younger age groups, develops commonly during critical illness, and results more frequently from prolonged intravenous infusions of short-acting opioids. Treatment options include slowly tapering opioid doses, switching to longer-acting opioids, or specifically treating the symptoms of opioid withdrawal. Novel therapies may also include blocking the mechanisms of opioid tolerance, which would enhance the safety and effectiveness of opioid analgesia.

Conclusions: Opioid tolerance and withdrawal occur frequently in critically ill children. Novel insights into opioid receptor physiology and cellular biochemical changes will inform scientific approaches for the use of opioid analgesia and the prevention of opioid tolerance and withdrawal.

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Figures

FIGURE 1
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. μ-OR indicates μ-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.
FIGURE 2
FIGURE 2
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 escalation may overcome pharmacologic tolerance, it enhances opioid-induced hyperalgesia. Opioidinduced hyperalgesia has a generalized distribution as opposed to the localized distribution of preexisting pain, which may progress to a worsening pain state but usually responds to opioid dose escalation.
FIGURE 3
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. μ-OR indicates μ-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; δ-OR, δ opioid receptor; NO, nitric oxide; nNOS, neuronal nitric oxide synthetase; HPETE, hydroperoxyeicosatetraenoic acid.
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References

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