A prospective study of withdrawal-associated hyperalgesia in opioid dependent volunteers

Spontaneous opioid withdrawal can affect opioid efficacy during both addiction and chronic pain treatment. Buprenorphine is approved for the office-based treatment of opioid dependence and chronic pain. Although there is some evidence that buprenorphine spontaneous withdrawal is mild, controlled comparisons to full mu opioid receptor agonists (i.e., morphine) are lacking. Six out-of-treatment opioid dependent male volunteers were admitted for a 59-day within-subject residential study of spontaneous opioid withdrawal from morphine versus buprenorphine. Volunteers were stabilized either on double-blind intramuscular (IM) buprenorphine (32 mg/day) or morphine (120 mg/day) administered in 4 divided doses for 9 days. They then underwent an 18-day period of spontaneous withdrawal during which double-blind IM placebo injections were administered. The same time course of stabilization and spontaneous withdrawal were repeated for the 2nd opioid. To objectively measure withdrawal-associated hyperalgesia (WAH), volunteers underwent quantitative sensory testing (QST) 10 times: day 9 of active study drug administration and during early, middle and late withdrawal from each opioid (days 2, 4, 8, and 15 of placebo administration). QST measurements were Z-transformed and combined to create detection, pain threshold, suprathreshold, and overall hyperalgesia indices for each session. Repeated measures 2-factor ANOVA using drug condition, day, and condition-by-day interaction revealed significant time course differences for WAH between opioids (F= 4.56, p=0.01 for condition-by-day interaction). Further analyses revealed a similar significant time course difference for suprathreshold index (F=3.93, p=0.01), but not sensory detection (F= 2.31, p=0.09) or pain threshold (F=1.16, p=0.36) indices. As predicted, Tukey’s post-hoc comparisons demonstrated significantly (p<0.05) greater hyperalgesia during early withdrawal (day 2 of placebo administration) from morphine as compared to buprenorphine; buprenorphine WAH did not peak until day 8 of placebo administration. Buprenorphine WAH appears to be milder and peaks approximately 1 week after morphine, suggesting buprenorphine may be optimal for patients with low tolerance for spontaneous withdrawal.