Case of the Month #28: Opioid-induced hyperalgesia by Dr Nofil Mulla

Published: 30/05/2023

Definitions and mechanisms of OIH

OIH is broadly defined as a state of nociceptive sensitisation caused by exposure to opioids, characterised by a paradoxical response whereby a patient receiving opioids for the treatment of pain becomes more sensitive to certain painful stimuli. The type of pain experienced may or may not be different from the original underlying painful condition.  Although the precise molecular mechanism is not yet understood, it is generally thought to result from neuroplastic changes in the peripheral and central nervous systems that lead to sensitisation of the pronociceptive pathways. OIH should be suspected when opioid treatment effect seems to wane in the absence of disease progression, particularly in the context of unexplained pain reports or diffuse allodynia unassociated with the pain as previously observed. 

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. Alternative theories 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. Prolonged morphine administration induces neurotoxicity via NMDA receptor mediated apoptotic cell death in the dorsal horn. Other theories postulate that a calcium regulated intracellular protein kinase C is likely a link between cellular mechanisms of tolerance and OIH. Genetic influence by the activity of the catecholamine breakdown enzyme, Catechol-O-methyltransferase (COMT) is also known to be a possible mechanism.