Opioid

Opioids induced hyperalgesia vs tolerance

Frequently confused but often co-exist
Both manifest clinically as need for ↑opioid dose to achieve same analgesic effect

tolerance → give ↑ dose
OIH → avoid opioids, & use other analgesics or adjuncts
- ↑ opioid → ↑ pain
  
  Dose-effect relationship: Tolerance shifts to right (but dose not alter pain sensitivity). OIH shifts down ∵ ↑pain sensitivity

OIH

also read: Remifentanil#Remifentanil induced hyperalgesia
Definition: a state of paradoxically ↑ response to noxious stimuli, presumably as a result of nociceptive sensitisation, caused by an exposure to opioids

a "normal adaptive response" counteracting perturbations from exogenous opioids?

a/w nearly all types of opioids, w/ dose-dependent hypersensitivity e.g.

morphine-6 glucuronide
methadone
phenanthrene-based class opioids
synthetic opioids-piperidines
NOT w/ oxymorphone

OIH incidence & degree of hyperalgesia ∝ opioid dose & exposure duration

Possible mechanisms

predominance of pronociceptive mechanisms e.g. activation of NMDA system
on > off-neurons w/i rostro-ventral medulla

descending spinal facilitation
mediated via NMDA system
exposure to prolonged noxious stimuli induced "on" state
µ opioid receptor ligand → "off" state
↑ dynorphin in spinal cord & primary afferents after noxious stimuli activate release of calcitonin gene related peptide

Remifentanil: activates peripheral & spinal neurons differently, which presumably results in hyperalgesia developing at different time point (early vs late) during post-infusion period.

Table 1 - Cellular mechanisms potentially responsible for the development of OIH

μ-Opioid signaling	↑cAMP & protein, kinase A Protein kinase C, C-Jun N-terminal kinase β-Arrestin-2 SRC kinase
Transcriptional mechanisms	cAMP response element-binding protein Mammalian target of rapamycin complex 1
Pronociceptive ion channels	NMDA receptors Transient receptor potential vanilloid channels
Microglia	Toll-like receptor 4 P2X4 and P2X7 purinergic receptors Brain-derived neurotrophic factor Scaffold protein β-arrestin-2

Prevention & treatment

General

↓ opioid dose & gradual dose tapering
NMDA antagonists

ketamine
- 5 µg/kg/min infusion effective for Remifentanil
dextromethorphan
Buprenorphine
κ-receptor agonism
δ-receptor downregulation
25 µg/h for 24h for RIH
COX-2 inhibitor
Parecoxib
- effective w/ early treatment 30min before application of remi
- concomitant administration ineffective?
  α2 agonists - Dexmedetomidine
  methadone
  MgSO4

RIH

Gradual taper of Remifentanil infusion rate (vs abrupt stop)
addition of Propofol to Remifentanil may ↓OIH

? ∵ inhibitory effects on NMDA receptors
effect on supraspinal GABA-A receptors
even sub-hypnotic dose may help

Opioid tolerance

References

Remifentanil-Induced Hyperalgesia The Current State of Affairs