Opioid-Induced Hyperalgesia: What is the Evidence?

“Multiple published reports have shown that opioid rotation to methodone significantly improved or resolved suspected OIH,” said Dr. Gudin. 

Other studies have shown that preoperative administration of low-dose ketamine might modulate the expression of OIH postoperatively after acute intraoperative opioid exposure. “The clinical significance of these benefits still needs to be demonstrated in larger prospective studies and in patients with chronic pain,” cautioned Dr. Gudin.

Other options include gabapentin and buprenorphine.  A study evaluating cold-pressor pain threshold among patients on methadone maintenance after a 5-week trial of gabapentin (titrated to 2400 mg/day) indicated significant improvements in pain thresholds and tolerance at both peak and trough methadone levels (P<.05).5

In a study involving volunteers with experimentally induced hyperalgesia, buprenorphine was superior to fentanyl. Because buprenorphine is a kappa receptor antagonist it may work to combat spinal dynorphin contributing to OIH.6

Future research should focus on determining time courses and magnitude of tolerance and hyperalgesia among patients treated with opioids, whether different opioids or dosage regimens effect the probability of OIH, and the degree to which OIH limits the utility of opioids for chronic pain management, according to Dr. Gudin.


  1. Gudin J. “Opioid Induced Hyperalgesia.” Presented at: AAPM 2015; Sept. 17-20; National Harbor, Maryland. 
  2. Voice F. “The way forward on opioid abuse: A call to action for science-based, comprehensive strategies.” FDA Voice. Available at: http://blogs.fda.gov/fdavoice/index.php/2014/04/the-way-forward-on-opioid-abuse-a-call-to-action-for-science-based-comprehensive-strategies-2/. Accessed September 18, 2015.
  3. Chu LF, Angst MS Clark D. “Opoid-induced hyperalgesia in humans: molecular mechanisms and clinical considerations.” Clin J Pain. 2008;24:479-496.
  4. Axelrod DJ, Reville J. Using methadone to treat opioid-induced hyperalgesia and refractory pain. J Opioid Manag. 2007;3:113-114.  
  5. Compton P et al. “Gabapeptin improves cold-pressor pain responses in methadone-maintained patients.” Drug Alcohol Depend. 2010; 109(1-3):213-219.
  6. Koppert W, Ihmsen H. “Different profiles of buprenorphine induced analgesia and antihyperalgesia in a human pain model.” Pain. 2005;118:15-22.