Comparison of pain models to detect opioid-induced hyperalgesia

Sumithra Krishnan¹, Amy Salter², Thomas Sullivan², Melanie Gentgall³, Jason White⁴, Paul Rolan^1
1Discipline of Pharmacology, School of Medical Sciences, The University of Adelaide, ²Discipline of Public Health, The University of Adelaide, ³Pain and Anesthesia Research Clinic, Royal Adelaide Hospital, ⁴Pharmacy School, University of South Australia, Adelaide, South Australia, Australia

Objective: Chronic opioid therapy may be associated with hyperalgesia. Our objective was to determine if opioid-induced hyperalgesia detection sensitivity is dependent on the stimulus used to detect it.
Methods: This open design study compared the detection of hyperalgesia in opioid-dependent subjects (n = 16) and healthy control subjects (n = 16) using the following pain stimuli: cold pain, electrical stimulation, mechanical pressure, and ischemic pain. The opioid-dependent subjects were maintained on either methadone (n = 8) or buprenorphine (n = 8) for at least 3 months. None of the controls was dependent on opioids or other drugs of abuse.
Results: The opioid-dependent subjects were markedly more sensitive than controls to the cold pain test. Compared with the control group, the hazard ratio for ceasing the test due to intolerable pain was 7.7 (95% confidence interval [CI] 2.6–23.3) in the buprenorphine group and 4.5 (95% CI 1.7–15.6) in the methadone group, with similar data for the cold pain threshold. Of the remaining tests, there were differences only for the electrical pain threshold between treatment groups, with the geometric mean threshold in the buprenorphine group being 1.5 (95% CI 1.1–1.9)-fold higher (ie, less sensitive) than that of the controls; the geometric mean for the methadone group was 1.3 (95% CI 1.04–1.7)-fold higher than that of the controls. There were no significant differences between buprenorphine and methadone patients in test responses. Women were more sensitive to the cold pain (hazard ratio for tolerance, 3.1 [95% CI 1.4–7.3]) and ischemic tests (hazard ratio for tolerance, 2.7 [95% CI 1.2–6.1]). There were significant correlations between cold and ischemic tolerances (r = 0.50; P = 0.003) and between electrical and mechanical pain tolerances (r = 0.52; P = 0.002).
Conclusion: These findings indicate that cold pain is the most suitable of the methods tested to detect opioid-induced hyperalgesia. This is consistent with its sensitivity to detect opioid analgesia.

Keywords: opioid-induced hyperalgesia, opioid-dependent subjects, pain models