By Luke Chan

Key reference:

Velayudhan, Bellingham & Morley-Forster. (2014). Opioid-induced hyperalgesia. Continuing Education in Anaesthesia, Critical Care and Pain, Volume 14, Issue 3, 125 – 129,


  • What is Opioid induced Hyperalgesia (OIH)?

    • Patients treated with opioids who paradoxically demonstrate increased sensitivity to painful stimulus

  • Effectiveness of high-dose opioids can be diminished by OIH and opioid tolerance – difficult to distinguish

  • Evidence primarily from observational studies of patients exposed to long-term methadone maintenance therapy for treatment of substance dependence


Clinical features

  • Hyperalgesia (increased response to painful stimuli)

  • Allodynia (painful response to normally innocuous stimulus)

  • Different region and different quality to original pain


Differential Diagnoses

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Opioid receptor physiology

  • 4 types of receptors: MOP (µ-opioid peptide receptor), DOP (δ-opioid peptide receptor), KOP (κ-opioid peptide receptor), and NOP (nociception/orphanin FQ peptide receptor)

  • Distributed widely in brain, spinal cord, peripheral afferent nerve terminals, and other organs

  • Opioid-sensitive neurons in rostral ventral medulla may facilitate OIH



Although the exact mechanism is not clearly understood, current hypotheses include central and peripheral mechanisms

Central mechanisms

Central glutaminergic system

Acute and chronic opioid use increases NMDA receptor activity

Prolonged morphine administration -> down-regulation of spinal glutamate transporters in spinal cord -> increased glutamate levels available -> spinal neurone sensitisation

Spinal dynorphins

Dynorphins (opioid peptides) increases with continuous infusions of µ-receptor agonists

Increased dynorphins -> release of excitatory neuropeptides

Excitatory neuropeptides act as pronociceptive agents -> enhanced nociceptive inputs at spinal level

Descending facilitation

ON cells and OFF cells in rostral ventral medulla facilitate and inhibit pain signals respectively

Opioid-sensitive ON cells mediate descending facilitation -> promote spinal nociceptive processing

Change in opioid receptor responsiveness

Chronic exposure to opioids -> alteration of G-protein activity (conversion from inhibitory to excitatory-coupled mode) -> increase in excitatory activity

Peripheral mechanisms

Paradoxical serotonergic receptor activity

Activation of serotonergic receptors -> shifts balance from descending inhibitory control towards pro-nociception

Substance P

Neurotransmitter released by C-fibre neurons that augments postsynaptic neuron effects of glutamate

Alteration to neuron cellular environment

Alteration of cytokine production, calcium channels and nitric oxide synthetase


How do we diagnose OIH?

  • No specific test or exam to confirm OIH

  • Establish diagnosis by increasing dose of opioids and evaluating for increased efficacy. Also rule out progression of disease or new pathology

  • Quantitative sensory testing

    • Being investigated as diagnostic tool

    • Involves applying different mechanical and thermal stimuli to measure pain threshold


How can we prevent OIH?

  • Reducing total dose of opioid

  • Pharmacotherapy: combination of anticonvulsants, antidepressants, and NSAIDs

  • Interventional therapy: regional blocks, peripheral nerve blocks, and spinal cord stimulation can assist in diagnosis pain generators and provide therapeutic benefit

  • Psychological therapy: studies have shown effectiveness of cognitive behavioural therapy in chronic pain


How do we manage OIH?

  • Establish diagnosis by increasing dose of opioids and evaluating for increased efficacy

  • Opioid dose reduction

    • Reduction of 40-50% and substitution with low-dose opioid agonist such as methadone

  • Opioid rotation/switching

    • When converting from one opioid to another, decrease dose of new opioid by 25-50% to account for incomplete cross-tolerance

    • Fentanyl, methadone and buprenorphine are commonly used in switching

    • Utilise opioid sparing adjuvants (e.g. NSAID, acetaminophen, anticonvulsant, antidepressant)


    • Advantages: can act as an NMDA antagonist in addition to opioid agonism and norepinephrine and serotonin reuptake inhibition, incomplete cross-tolerance, relatively long half-life (24-36h)

    • Disadvantages: drug interactions are more frequent that with other long-acting opioids, complex conversions


    • Superior safety profile

    • Lower risk of abuse

    • May return to eliciting hyperalgesia over time


    • Physicochemical properties make it ideal to be delivered via transdermal route

    • Low molecular weight, high lipophilicity, high potency, and optimal skin flux

  • Opioid-sparing agent: NMDA antagonists

Ketamine: non-competitive NMDA antagonist

    • Available as racemic mixture or S-ketamine isomer

    • Subcut or IV: 0.125-0.3mg/kg/h

    • Oral: start does not require intensive monitoring but must be produced by a pharmacist. Start with 0.5mg/kg racemic mixture or S-ketamine -> increase by 0.25-0.5mgkg in stepwise manner

    • 3-4 times per day due to short half-life of 2.5h

    • Not comprehensively studied

Dextromethorphan: non-competitive NMDA antagonist

    • Significant clinical effectiveness yet to be demonstrated

      Figure from