Can buprenorphine cause opioid-induced hyperalgesia?

From the Guidelines

Buprenorphine can cause opiate-induced hyperalgesia, as evidenced by studies showing that maintenance therapy with buprenorphine has significant effects on pain tolerance, although to a lesser degree than methadone 1.

Key Points

• Buprenorphine is a partial mu-opioid agonist and kappa-opioid antagonist used to treat both pain and opioid use disorder.
• Opiate-induced hyperalgesia (OIH) is a paradoxical condition where opioid use leads to increased sensitivity to pain rather than pain relief.
• Patients experiencing buprenorphine-induced hyperalgesia may report worsening pain despite stable or increasing doses, pain that becomes more diffuse than the original complaint, or unusual sensitivity to mild stimuli.
• The mechanism likely involves neuroplastic changes in the central nervous system, including NMDA receptor activation and altered glutamate signaling.
• Management options include dose reduction, opioid rotation, addition of NMDA antagonists like ketamine or methadone, or in some cases, complete opioid tapering, as suggested by guidelines for managing chronic pain in patients living with HIV 1.

Clinical Considerations

• Clinicians should distinguish OIH from tolerance, withdrawal, or disease progression when evaluating patients on buprenorphine who report worsening pain.
• The presence of hyperalgesia with ongoing opioid use has resulted in reexamination of the previously described phenomenon of opioid analgesic tolerance, suggesting that what seems to be opioid analgesic tolerance may in fact be an expression of an opioid-induced increased sensitivity to pain 1.
• Accumulating evidence supports increased sensitivity to experimental pain in patients receiving opioid agonist therapy, such that patients receiving maintenance methadone therapy tolerate cold-pressor pain only half as long as do matched controls, with buprenorphine having similar but less severe effects 1.

From the Research

Opiate-Induced Hyperalgesia and Buprenorphine

• Buprenorphine, a partial mu-opioid agonist, has been studied for its potential to cause opiate-induced hyperalgesia, a condition where opioid use leads to increased sensitivity to pain 2, 3, 4.
• Research suggests that buprenorphine can indeed cause hyperalgesia, particularly at ultra-low doses, and that this effect is mediated by NMDA receptor mechanisms 2.
• A study in rats found that repeated administration of buprenorphine led to tolerance and hyperalgesia, which was blocked by the NMDA receptor antagonist ketamine 2.
• In humans, buprenorphine-maintained subjects were found to be hyperalgesic and did not experience antinociception despite high plasma morphine concentrations 3.
• However, buprenorphine has also been shown to be effective in reducing hypersensitivity in neuropathic pain, suggesting that it may have a unique role in mediating analgesic signaling at spinal opioid receptors 5, 6.

Clinical Implications

• Opioid-induced hyperalgesia is a recognized complication of opioid therapy, and buprenorphine is no exception 3, 4.
• The diagnosis and treatment of opioid-induced hyperalgesia require careful consideration, as it can be difficult to distinguish from tolerance or worsening pain 4.
• Treatment options for opioid-induced hyperalgesia include office-based detoxification, reduction of opioid dose, opioid rotation, and the use of specific NMDA receptor antagonists, such as ketamine 4.
• Buprenorphine may be a useful option for the treatment of opioid-induced hyperalgesia, particularly in cases where other opioids have failed or are not tolerated 4, 6.