Comparison of pain models to detect opioid-induced hyperalgesia

Abstract

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-dependent subjects; opioid-induced hyperalgesia; pain models.

Figures

Figure 1

Comparison of pain threshold and pain tolerance between control subjects (n = 16), methadone dependent subjects (n = 8), and buprenorphine dependent subjects (n = 8) among the four different pain modalities. (A–D) depict cold pain threshold, cold pain tolerance, ischemic pain threshold, and ischemic pain tolerance, respectively, using Kaplan–Meier survival curves. (E and F) represent the electrical stimulation threshold and tolerance and the mechanical pain threshold and tolerance, presented as the mean ± standard deviation. Abbreviations: Meth, methadone-dependent subjects; Bup, buprenorphine-dependent subjects; C-TR, controls’ threshold; M-TR, methadone-dependent subjects’ threshold; B-TR, buprenorphine-dependent subjects’ threshold; C-TL, controls tolerance; M-TL, methadone-dependent subjects’ tolerance; B-TL, buprenorphine-dependent subjects’ tolerance.