Activation of P-glycoprotein efflux transport ameliorates opioid CNS effects without diminishing analgesia

Opioids frequently produce adverse neurocognitive effects that limit their use in ambulatory settings, providing a rationale for improving opioid analgesia by minimizing adverse effects (AEs). LIM-5662 is thought to activate the P-glycoprotein (P-gp) efflux transporter at the blood–brain barrier. In this pilot study, we tested the hypothesis that LIM-5662 improves the tolerability of oxycodone without impairing analgesia. Healthy men and women age 18–35 years (N = 65) underwent third molar extraction as part of a single site, randomized, double-blind, parallel groups comparison of 500 mg oral LIM-5662 or matching placebo administered one hour before surgery as an adjunct to analgesia. All subjects received 10 mg of oral oxycodone immediately before surgery. The primary endpoint was the CNS effect of nausea and vomiting (N&V) and the summary score for total nausea and vomiting (TNVS). Other CNS endpoints, pain and AEs were also measured. Differences in measures of N&V were not statistically significant between the drug groups. Women experienced a greater incidence of N&V than men (16, 51.6% versus 5, 17.9%; P = 0.007) and a higher TNVS (P = 0.004). The numbers of women experiencing N&V were equally distributed between the drug and placebo groups, but men in the placebo group had more N&V than men receiving LIM-5662 (P = 0.017). Opioid analgesia was not diminished by the addition of LIM-5662, and there were no differences attributed to gender by drug group in pain experience as measured by the sum of pain intensities over time (P = 0.23), or in time to request rescue analgesic (P = 0.52). In this small study LIM-5662 attenuated N&V in males but did not appear to affect the N&V rates in females. Importantly, LIM-5662 was well tolerated and did not reduce the analgesic efficacy of oxycodone. A study with a broader range of doses and a larger sample size is needed to further delineate the potential benefits of this drug.

Section Editor:Ray Dionne – NINR, NIH (National Institutes of Health), Bethesda, MD, USA