Rationale <p>Mu opioid receptor (MOR) analgesics like morphine have high intrinsic MOR efficacy but produce side effects. Lower efficacy MOR agonists like buprenorphine can produce analgesia with improved safety. We recently described a series of novel phenylmorphan-based MOR agonists with graded MOR efficacies, including several with sub-buprenorphine efficacies, and we described their acute effectiveness in mice to produce (a) antinociception in an assay of pain-related locomotor depression, and (b) improved safety on a range of side effects. Effects of repeated treatment with these compounds have not been examined.</p> Objective <p>The present objective was to compare effects of repeated treatment with four opioids that ranged from high to low MOR efficacy (morphine&gt; buprenorphine &gt; JL-2-39 &gt; DC-1-76.1).</p> Methods <p>Female and male ICR mice were treated once daily for 7 days with a selected dose of each drug ± intraperitoneal lactic acid (IP acid) as a noxious stimulus and evaluated for vertical and horizontal locomotor activity on Days 1 and 7.</p> Results <p>IP acid alone produced sustained, concentration-dependent, and pain-related locomotor depression. When administered as a daily pretreatment to IP acid, all four opioids produced sustained antinociception expressed as significant alleviation of IP acid-induced behavioral depression on Days 1 and 7. However, when these opioids were administered alone, effects were efficacy dependent. Morphine produced locomotor stimulation and sensitization; buprenorphine and JL-2-39 produced locomotor stimulation without sensitization; DC-1-76.1 produced neither stimulation or sensitization.</p> Conclusions <p>These findings support continued consideration of low-efficacy MOR agonists as candidate analgesics that can produce sustained antinociception with reduced side effects during repeated treatment. </p>