Opioid Induced Hyperalgesia: when less is more in pain management

Majic Sites — Fri, 15 Mar 2024 23:42:15 +0000

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, https://doi.org/10.1093/bjaceaccp/mkt045

Background

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

Figure from https://www.bjaed.org/article/S1743-1816(17)30101 4/fulltext#:~:text=Opioid%2Dinduced%20hyperalgesia%20(OIH),increased%20sensitivity%20to%20painful%20stimuli.

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

Pathophysiology

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)

Methadone

- 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

Buprenorphine

- Superior safety profile
- Lower risk of abuse
- May return to eliciting hyperalgesia over time

Fentanyl

- 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 https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8023328/

Pain Medicine – The Anaesthesia Collective.

Opioid Induced Hyperalgesia: when less is more in pain management