Peri-operative opioid analgesia - when is enough too much? A review of opioid-induced tolerance and hyperalgesia

Lesley Colvin (Lead / Corresponding author), Fiona Bull, Tim Hales

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11 Citations (Scopus)
140 Downloads (Pure)

Abstract

Opioids are a mainstay of acute pain management but can have many adverse effects, contributing to problematic long-term use. Opioid tolerance (increased dose needed for analgesia) and opioid-induced hyperalgesia (paradoxical increase in pain with opioid administration) can contribute to both poorly controlled pain and dose escalation. Hyperalgesia is particularly problematic as further opioid prescribing is largely futile. The mechanisms of opioid tolerance and hyperalgesia are complex, involving μ opioid receptor signalling pathways that offer opportunities for novel analgesic alternatives. The intracellular scaffold protein β-arrestin-2 is implicated in tolerance, hyperalgesia, and other opioid side-effects. Development of agonists biased against recruitment of β-arrestin-2 could provide analgesic efficacy with fewer side-effects. Alternative approaches include inhibition of peripheral μ opioid receptors and blockade of downstream signalling mechanisms, such as the non-receptor tyrosine kinase Src or N-methyl-D-aspartate receptors. Furthermore, it is prudent to use multimodal analgesic regimens to reduce reliance on opioids during the perioperative period. In the third paper in this Series we focus on clinical and mechanism-based understanding of tolerance and opioid-induced hyperalgesia, and discuss current and future strategies for pain management.
Original languageEnglish
Pages (from-to)1558-1568
Number of pages11
JournalLancet
Volume393
Issue number10180
Early online date11 Apr 2019
DOIs
Publication statusPublished - Apr 2019

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Hyperalgesia
Analgesia
Opioid Analgesics
Analgesics
Opioid Receptors
Pain Management
Pain
Perioperative Period
src-Family Kinases
Acute Pain
N-Methyl-D-Aspartate Receptors

Cite this

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title = "Peri-operative opioid analgesia - when is enough too much? A review of opioid-induced tolerance and hyperalgesia",
abstract = "Opioids are a mainstay of acute pain management but can have many adverse effects, contributing to problematic long-term use. Opioid tolerance (increased dose needed for analgesia) and opioid-induced hyperalgesia (paradoxical increase in pain with opioid administration) can contribute to both poorly controlled pain and dose escalation. Hyperalgesia is particularly problematic as further opioid prescribing is largely futile. The mechanisms of opioid tolerance and hyperalgesia are complex, involving μ opioid receptor signalling pathways that offer opportunities for novel analgesic alternatives. The intracellular scaffold protein β-arrestin-2 is implicated in tolerance, hyperalgesia, and other opioid side-effects. Development of agonists biased against recruitment of β-arrestin-2 could provide analgesic efficacy with fewer side-effects. Alternative approaches include inhibition of peripheral μ opioid receptors and blockade of downstream signalling mechanisms, such as the non-receptor tyrosine kinase Src or N-methyl-D-aspartate receptors. Furthermore, it is prudent to use multimodal analgesic regimens to reduce reliance on opioids during the perioperative period. In the third paper in this Series we focus on clinical and mechanism-based understanding of tolerance and opioid-induced hyperalgesia, and discuss current and future strategies for pain management.",
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AU - Bull, Fiona

AU - Hales, Tim

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N2 - Opioids are a mainstay of acute pain management but can have many adverse effects, contributing to problematic long-term use. Opioid tolerance (increased dose needed for analgesia) and opioid-induced hyperalgesia (paradoxical increase in pain with opioid administration) can contribute to both poorly controlled pain and dose escalation. Hyperalgesia is particularly problematic as further opioid prescribing is largely futile. The mechanisms of opioid tolerance and hyperalgesia are complex, involving μ opioid receptor signalling pathways that offer opportunities for novel analgesic alternatives. The intracellular scaffold protein β-arrestin-2 is implicated in tolerance, hyperalgesia, and other opioid side-effects. Development of agonists biased against recruitment of β-arrestin-2 could provide analgesic efficacy with fewer side-effects. Alternative approaches include inhibition of peripheral μ opioid receptors and blockade of downstream signalling mechanisms, such as the non-receptor tyrosine kinase Src or N-methyl-D-aspartate receptors. Furthermore, it is prudent to use multimodal analgesic regimens to reduce reliance on opioids during the perioperative period. In the third paper in this Series we focus on clinical and mechanism-based understanding of tolerance and opioid-induced hyperalgesia, and discuss current and future strategies for pain management.

AB - Opioids are a mainstay of acute pain management but can have many adverse effects, contributing to problematic long-term use. Opioid tolerance (increased dose needed for analgesia) and opioid-induced hyperalgesia (paradoxical increase in pain with opioid administration) can contribute to both poorly controlled pain and dose escalation. Hyperalgesia is particularly problematic as further opioid prescribing is largely futile. The mechanisms of opioid tolerance and hyperalgesia are complex, involving μ opioid receptor signalling pathways that offer opportunities for novel analgesic alternatives. The intracellular scaffold protein β-arrestin-2 is implicated in tolerance, hyperalgesia, and other opioid side-effects. Development of agonists biased against recruitment of β-arrestin-2 could provide analgesic efficacy with fewer side-effects. Alternative approaches include inhibition of peripheral μ opioid receptors and blockade of downstream signalling mechanisms, such as the non-receptor tyrosine kinase Src or N-methyl-D-aspartate receptors. Furthermore, it is prudent to use multimodal analgesic regimens to reduce reliance on opioids during the perioperative period. In the third paper in this Series we focus on clinical and mechanism-based understanding of tolerance and opioid-induced hyperalgesia, and discuss current and future strategies for pain management.

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