Dose-extending placebo effect in a rat model of buprenorphine maintenance treatment

Clinical studies have shown that exposure to placebos or combining placebos with a lower medication dose can mimic the effect of a higher effective medication dose. This "dose-extending placebo effect" has been demonstrated in treatment for pain and other medical conditions but not in addiction. Here, we tested if a "dose-extending placebo effect" occurs in a rat model of opioid (buprenorphine) maintenance.

We trained 27 rats to self-administer remifentanil (5 µg/kg/infusion, 1-h per day). Next, we implanted some rats with buprenorphine minipumps (3 mg/kg/day, Exp. 1) or pretreated others with daily intravenous buprenorphine (0.3 mg/kg, Exp. 2), and introduced a discriminative cue (houselight + tone) during the self-administration sessions (the buprenorphine-maintenance cue). After discontinuing buprenorphine treatment, we retrained the rats for remifentanil self-administration without the cue. Next, we tested the effect of low and high buprenorphine doses (0.15 and 0.3 mg/kg), the buprenorphine-maintenance cue, and the combination of the low-dose with the cue on remifentanil self-administration.

Rats learned to self-administer remifentanil, and buprenorphine maintenance suppressed drug self-administration. The low buprenorphine dose modestly decreased self-administration, while the high dose caused a strong inhibition. Tests for the "dose-extending placebo effect" showed that discriminative buprenorphine cue alone had no effect, while the low dose plus the buprenorphine cue mimicked the inhibitory effect of the high dose.

This proof-of-concept study suggests that a "dose-extending placebo effect" can be modeled in rats undergoing opioid maintenance. This approach could support dose-reduction strategies in humans undergoing opioid maintenance therapy.