A Flawed Design Produces Flawed Results

Peltz, Gary

doi:10.1097/adm.0000000000000394

Cited by 2 publications

(1 citation statement)

References 7 publications

(10 reference statements)

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“…This dosing regimen produces fetal brain ondansetron levels that could inhibit opioid responses for only a short period of time; it was not long enough to cause a sufficient reduction in withdrawal symptoms that would eliminate the need for treating the infant with a prolonged course of opioids. Similarly, another study examining individuals with chronic OUD due to chronic back pain (with a flawed experimental design 28 ), administered a single dose of ondansetron just before opioid withdrawal was experimentally induced, and found that ondansetron treatment did not decrease the opioid withdrawal symptoms. 29 To prevent opioid withdrawal from developing after chronic opioid use, ondansetron must be present in the brain when opioids are administered over a more prolonged period; it cannot only be administered for a short period when the opioids are withdrawn.…”

Section: Discussionmentioning

confidence: 99%

Optimizing a therapy for opiate use disorders: Characterizing ondansetron pharmacokinetics in blood and brain

Cheng

et al. 2022

Clinical Translational Sci

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Administration of a widely used 5‐hydroxytryptamine receptor (5HT3AR) antagonist (ondansetron) potently inhibited the development of experimentally induced opioid dependence and withdrawal responses in mice and humans. However, in several studies examining withdrawal symptoms in subjects with chronic opioid use disorders (OUDs), ondansetron exhibited reduced or absent efficacy. Because attenuation of opioid withdrawal symptomatology is mediated within the brain, this study examined single‐dose ondansetron pharmacokinetics in the blood and brain of mice. We demonstrate that ondansetron concentrations in the brain (Cbrain ng/mg) are 1000‐fold lower than the blood concentrations (Cblood ng/ml) and decrease rapidly after ondansetron administration; and that a large percentage of brain ondansetron remains in the ventricular fluid. These results indicate that the ondansetron dose, and the time window between ondansetron and opioid administration, and when withdrawal is assessed are critical considerations for clinical studies involving subjects with chronic OUD. The pharmacokinetic results and the dosing considerations discussed here can be used to improve the design of subsequent clinical trials, which will test whether a more prolonged period of ondansetron administration can provide a desperately needed therapy that can prevent the development of neonatal opioid withdrawal syndrome in babies born to mothers with chronic OUD.

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Section: Discussionmentioning

confidence: 99%