Effects of the NK1 antagonist, aprepitant, on response to oral and intranasal oxycodone in prescription opioid abusers

Abstract

Pre-clinical studies suggest that the neurokinin-1 (NK1) receptor may modulate the response to opioids, with NK(1) inactivation leading to decreased opioid reinforcement, tolerance and withdrawal. Aprepitant is a selective NK1 antagonist currently marketed for clinical use as an anti-emetic. This 6-week in-patient study used a randomized, double-blind, double-dummy, within-subject, crossover design. Subjects (n = 8; 6 male/2 female) were healthy, adult volunteers who provided subjective and objective evidence of current prescription opioid abuse (without physical dependence) and underwent careful medical and psychiatric screening. Fifteen experimental conditions, consisting of one aprepitant dose (0, 40 and 200 mg, p.o. given as a 2-hour pre-treatment) in combination with one oxycodone dose [placebo, oral (20 and 40 mg/70 kg) and intranasal (15 and 30 mg/70 kg)], were examined. Sessions were conducted at least 48-hour apart and multi-dimensional measures were collected repeatedly throughout the 6-hour session duration. Oxycodone, by both routes of administration, produced significant dose-related effects on the predicted measures (e.g. subjective measures of abuse liability, respiratory depression and miosis). Pre-treatment with aprepitant (200 mg) significantly enhanced ratings of oxycodone subjective effects related to euphoria and liking and doubled the street value estimates for the highest test doses of oxycodone by both routes. Some objective measures (respiratory function, observer-rated opioid agonist effects) were similarly enhanced by pre-treatment with the highest dose of aprepitant. All dose combinations were safely tolerated. These findings are discussed in the context of the potential utility of NK1 antagonists in the treatment of opioid use disorders.

Trial registration: ClinicalTrials.gov NCT00999544.

Figure 1

Mean values (n=8) for the visual analog scale “How much do you LIKE the drug?” as rated by the participants are shown for oral (top row) and intranasal (bottom row) oxycodone as a function of 2-hr pretreatment dose of aprepitant at 0 mg (left column), 40 mg (middle column) and 200 mg (bottom column). Statistical analyses revealed significant main effects of oral (F[2,14]=31.8; p<.001) and intranasal oxycodone (F[2, 14]= 36.9; p<.001) as well as significant time dependent effects (df 16,112; p<.001) for both routes (F=16.6 p.o., & F= 21.5 i.n.).

Figure 2

Mean AUC values (n=8, ±1 S.E.M.) for the visual analog scales “How high do you feel?” (top row) and “Does the drug have any good effects?” (middle row) are depicted after oral (left column) and intranasal oxycodone (right column). For ratings of “high,” there were significant main effects of oxycodone dose by both routes (F[2,14]= 40.4; p<.001 oral; F=42; p<.001 intranasal). A significant aprepitant by oxycodone dose effect (F[4,28]=2.9; p=.039, p.o.) and a main effect of aprepitant (F[2,14]=7.1; p=.007 i.n.) were also observed for ratings of “high.” For the measure of “good effects,” oxycodone produced significant dose-related increases after both oral (F[2,14]=42.8; p <.001) and intranasal dosing (F[2,14]=40.6; p<.0001) along with significant aprepitant × oxycodone interactions (F[4,28]=2.9; p=.041, p.o) or main effects of aprepitant (F[2,14]=6.8; p=.009, i.n.). For Street Value estimates, both oral (F[2,14]=29.5; p<.001) and intranasal (F[2,14]=38; p<.001) oxycodone produced significant dose-related increases in dollar value (and placebo was valued at zero). Significant interaction or main effects of aprepitant were observed with both oral (F[4,28]=3.4; p=.023) and intranasal oxycodone (F[2,14]=8.7; p=.004), whereby street values were higher after 200 mg aprepitant pretreatment compared to placebo.

Figure 3

Data are shown for the composite Opioid Agonist Adjective Scale rated by the subjects (upper panel; maximum possible score 68) and the observers (lower panel; maximum possible score 48) after challenge with oral (left column) and intranasal (right column) oxycodone. Data (n=8) are presented as AUC values (±1 S.E.M). The subject-rated scale revealed significant main effects of oral (F[2,14]=25.7; p<.0001) and intranasal (F[2,14]=29.8; p<.0001) oxycodone and significant main effects of aprepitant (F[2,14]=7; p=.008, oral; F[2,14]=7; p=.008, intranasal). The observer-rated scale revealed significant main effects of oral (F[2,14]=18.6; p<.001) and intranasal (F[2,14]=12; p =.001) oxycodone but no main or interaction effects with aprepitant.

Figure 4

Data are shown for end-tidal CO₂ concentrations (upper panel) and pupil diameter (lower panel) after challenge with oral (left column) and intranasal (right column) oxycodone. Data (n=8) are presented as AUC values generated from change-from-baseline time course data (±1 S.E.M). Both oral (F[2,14]=49.3; p<.001) and intranasal (F[2,14]=29.7; p<.001) oxycodone produced significant increases in end-tidal CO₂ as shown, but aprepitant produced only a trend (p=.095) to further increase CO₂ after oral oxycodone. Both oral (F[2,14]=174.1; p<.001) and intranasal oxycodone (F[2,14]=121.5;p<.001) produced significant dose-related decreases in pupil diameter (lower panels), but no main or interaction effects for aprepitant were observed.