Opioid-Induced Hyperalgesia: How Painkillers Can Paradoxically Cause More Pain

What is opioid-induced hyperalgesia?

Opioid-induced hyperalgesia is the occurrence of increased pain sensitivity in response to opioid administration. In other words, taking opioids in excess and/or for a long period of time has been known to lower the individual’s pain threshold so pain seems worse even if the opioid dose is increased. This phenomenon is often associated with opioid tolerance and opioid inefficiency.


What is the difference between opioid tolerance, and opioid-induced hyperalgesia?

“Tolerance” suggests that the drug has progressively stopped causing a pharmacological response, but that the issue can generally be overcome by increasing the dosage. “Opioid-induced hyperalgesia” suggests that the drug has progressively caused increased sensitivity to pain and that the issue is only made worse by increasing the dose.


Does opioid-induced hyperalgesia cause existing pain to get worse? Or does is cause new pain?

Either way. Some individuals with painful injuries or chronic pain find that the pain causing them to seek opioids is getting worse; others find that they experience allodynia: a painful response to a typically non-painful stimulus. There are a few different types of allodynia: mechanical/tactile allodynia, in which pain emerges in response to touch, thermal allodynia, in which pain emerges in response to a certain temperature, and movement allodynia, in which pain emerges in response to joint or muscle movement.


What causes opioid-induced hyperalgesia?

More research is needed, but the cause is likely related to changes in neuroplasticity. The neural pathways that communicate pain signals, “pronociceptive pathways,” may adjust to fire more frequently in response to painful stimuli. NMDA receptors in the central nervous system may become abnormally activated and signal the body to sense pain unnecessarily. Additionally, long-term potentiation may occur between nociceptive C fibers and spinal dorsal horn neurons, which means that some of the connections needed to sense pain are strengthened so the brain can more easily pick up on painful stimuli.


All opioids


Which opioids induce hyperalgesia, and at what dosage?

All opioids have the potential to cause opioid-induced hyperalgesia, including codeine, morphine, oxycodone, hydrocodone, tramadol, etc. Methadone and Suboxone may have a tendency to cause opioid-induced hyperalgesia in patients with chronic pain, but the risk is much lower for non-pain patients. The dosage and length of time necessary to cause hyperalgesia varies from person to person, but technically it could occur after only one high-dose of an opioid.


How is opioid-induced hyperalgesia diagnosed?

Physicians should investigate the possibility of opioid-induced hyperalgesia if the suffering individual has worsening pain with increased opioid dosage and/or without disease progression. It should also be considered in the case of newly localized allodynia, or central pain sensitization that causes typically non-painful stimuli to seem painful.


Can opioid-induced hyperalgesia be treated?

Although it may seem paradoxical, the best treatment for increased pain seems to be tapering off of the painkillers. After reducing opioid dosage or tapering off completely, the body has a chance to “reset” to normal pain sensitivity levels once again. Another technique involves supplementing the opioid regimen with NMDA receptor modulators, which can make the receptors respond more appropriately to pain signals. These NMDA antagonists include methadone, ketamine, dextromethorphan, etc. Pharmacological targeting of pain pathology is difficult since the nervous system is so ubiquitous, but researchers are still working on it.


What is opioid rotation?

Opioid rotation is the act of switching between different types of opioids in order to prevent drug tolerance. It’s not especially helpful for opioid-induced hyperalgesia, since the best treatment for that is to taper off of opioids entirely, but it is useful for achieving algesia with low doses of opioids which could ultimately prevent the onset of hyperalgesia.

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