FRCA Notes

Opioid-Induced Hyperalgesia

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  • Opioid-induced hyperalgesia (OIH) describes a paradoxical increased sensitivity to painful stimulus, a phenomenon usually (but not always) observed following chronic and/or high-dose opioid use
  • It is different from opioid tolerance, where a larger dose of opioid is needed over time to produce the same level of analgesia (i.e. dose-response curve shifted to the right)

  • Evidence for OIH includes:
    • Increased sensitivity to pain in those expose to long-term methadone maintenance therapy
    • Significant reduction in pain threshold/pain tolerance in patients taking oral morphine for 1 month for back pain
    • Healthy volunteers acutely exposed to opioids demonstrate features of OIH
    • Perioperative fentanyl or remifentanil infusions can increase post-operative opioid requirements, suggesting development of OIH or opioid tolerance
    • High intraoperative doses of opioids are associated with significantly higher postoperative pain intensity and opioid consumption
    • Opioid infusions administered at different times of the day produce varying degrees of opioid-induced hyperalgesia (BJA, 2023)

  • The mechanisms underlying OIH are not fully elucidated, although several theories exist

Excitatory opioid actions

  • Although the opioid receptors are classically inhibitory in nature, in vitro studies demonstrate morphine can cause excitatory actions at subtherapeutic (1000x smaller) doses
  • The excitatory effect is postulated to be via alternative second messenger signalling pathways
  • At clinically used doses, this excitatory effect is masked by the inhibitory functions of receptor activation

Central mechanisms

  • Activation of glial cells via TLR-4
  • COMT gene polymorphisms
  • Glutamatergic systems
    • Opioid use (acute and chronic) increases NMDA receptor activity
    • Furthermore, prolonged morphine administration down-regulates spinal glutamate transporters in the spinal cord
    • This increases glutamate levels available for NMDA receptors
    • Glutamate-associated NMDA receptor activation can cause spinal neurone sensitisation, which may contribute to OIH development
    • These effects can be prevented through NMDA receptor antagonism

  • Spinal dynorphins
    • MOP receptor agonists can increase dynorphin levels
    • Higher levels lead to excitatory neuropeptide release e.g. CGRP, CCK
    • These neuropeptides are pro-nociceptive agents which enhance nociceptive inputs at the spinal level

  • Descending facilitation
    • Subsets of cells within the rostral ventrolateral medulla can mediate nociceptive transmission:
      • On cells (ON) facilitate pain signalling
      • Off cells (OFF) inhibit pain signals
    • ON cells are opioid-sensitive and opioid exposure may promote spinal nociceptive processing

Opioid receptor responsiveness

  • Chronic opioid exposure may alter G-protein activity
  • This may modify second messenger systems, converting them from inhibitory to excitatory functions
  • The increase in excitatory activity is a possible contribute to OIH (and analgesic tolerance)
  • These effects can be blocked by ultra-low doses of opioid antagonist in vitro

Peripheral mechanisms

  • Serotonergic receptor (5-HT2 and 5-HT3) activation can shift the balance from descending inhibitory control towards a pro-nociceptive state
  • Other peripheral mechanisms implicated include activation of Substance P, altered cytokine production, calcium channel changes and changes in NOS

  • Onset may be abrupt or gradual
  • Paradoxical increase in pain associated with either or both of hyperalgesia and allodynia
  • Pain location may occur at a different location to the initial insult and/or be widespread
  • Nature of the pain is of different quality to the original presenting pain, although often poorly defined
  • Pain not improved by further opioid treatment

  • Quantitative sensory testing (QST) is a pain assessment tool which used mechanical and thermal stimuli to measure an individual's pain threshold
  • It assesses the function both central and peripheral (Aβ, Aδ, and C-fibres) pain processing pathways
  • It is currently used in the diagnosis of peripheral neuropathies and radiculopathies, and is being investigated for diagnosis of opioid-induced harm
  • QST has been used to demonstrate:
    • Changes in pain perception in those on long-term opioid therapy
    • Opioid-induced hyperalgesia in those receiving remifentanil

Minimise risk of developing hyperalgesia

  • Reducing the total opioid dose by using a multi-modal opioid-sparing analgesic approach
  • Use interventional therapies to block nociceptive input e.g. regional anaesthesia, spinal cord stimulators
  • Cognitive behavioural therapies and other psychological interventions to improve pain/disability and reduce opioid use

Managing symptoms once OIH occurs

  • Establish diagnosis; initially increase opioid dose and if symptoms worsen this suggests OIH - if they improve this implies tolerance
  • Reduce or discontinue opioid therapy
  • Consider opioid rotation to opioids such as fentanyl, buprenorphine or methadone
  • Consider adding NMDA receptor antagonists or other non-opioid analgesics such as antidepressants, anticonvulsants or NSAIDs
  • Consider non-pharmacological therapies e.g. physical therapies, psychological therapies, interventional therapies

NMDA receptor antagonists

  • An IV or SC infusion of 0.125 - 0.3mg/kg/hr is suggested in the management of chronic pain
  • Oral dosing is initially 0.5mg/kg ketamine (or half the dose of esketamine) with monitoring for response
    • Dosing can be increased in 0.5mg/kg increments until there is optimum response with minimal adverse effects
    • The mean effective dose is 200mg/24hrs
    • Limited by undesirable psychotropic side-effects, abuse potential and lack of commercially available oral preparations