Evaluation of the abuse potential of pitolisant, a selective [H.sub.3]-receptor antagonist/inverse agonist, for the treatment of adult patients with narcolepsy with or without cataplexy

Objectives: To evaluate the human abuse potential of pitolisant, a selective histamine 3 ([H.sub.3])-receptor antagonist/inverse agonist recently approved by the US Food and Drug Administration for the treatment of excessive daytime sleepiness in adult patients with narcolepsy. Methods: Nondependent, recreational stimulant users able to distinguish phentermine HCl 60 mg from placebo in a drug discrimination test were randomized in a four-period, double-blind, crossover design to receive single doses of pitolisant 35.6 mg (therapeutic dose), pitolisant 213.6 mg (supratherapeutic dose), phentermine HCl 60 mg, and placebo. The primary endpoint was maximum effect ([E.sub.max]) on the 100-point Drug Liking ("at this moment") visual analog scale. Results: In 38 study completers (73.7% male; 65.8% white; mean age, 33.3 years), mean Drug Liking [E.sub.max] was significantly greater for phentermine versus pitolisant 35.6 mg (mean difference, 21.4; p < 0.0001) and pitolisant 213.6 mg (mean difference, 19.7; p < 0.0001). Drug Liking [E.sub.max] was similar for pitolisant (both doses) and placebo. Similarly, for key secondary measures of Overall Drug Liking and willingness to Take Drug Again, mean [E.sub.max] scores were significantly greater for phentermine versus pitolisant (both doses) and similar for pitolisant (both doses) versus placebo. The incidence of adverse events was 82.1% after phentermine HCl 60 mg, 72.5% after pitolisant 213.6 mg, 47.5% after pitolisant 35.6 mg, and 48.8% after placebo administration. Conclusions: In this study, pitolisant demonstrated significantly lower potential for abuse compared with phentermine and an overall profile similar to placebo; this suggests a low risk of abuse for pitolisant. Clinical Trial Registration: ClinicalTrials.gov NCT03152123. Determination of the abuse potential of pitolisant in healthy, nondependent recreational stimulant users. Key words: drug abuse; narcolepsy; pitolisant