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

Abstract

Preclinical studies suggest that the NK1 receptor may modulate the response to opioids, with NK1 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 inpatient study employed 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 & 200 mg, p.o. given as a 2-hr pretreatment) in combination with one oxycodone dose (placebo, oral [20 & 40 mg/70 kg] and intranasal [15 & 30 mg/70 kg]), were examined. Sessions were conducted at least 48-hr 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, miosis). Pretreatment 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 pretreatment 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.

Differential effects of aprepitant, a clinically used neurokinin-1 receptor antagonist on the expression of conditioned psychostimulant versus opioid reward

“…However, aprepitant significantly enhanced the CPP expression induced by 5 mg/kg morphine. Enhanced morphine CPP expression following aprepitant is not surprising because in human studies, aprepitant indeed enhanced craving for opioid use (Jones et al 2013; Walsh et al 2013). There was no significant interaction between AMPH or cocaine conditioning and aprepitant treatment, suggesting a direct effect of aprepitant on psychostimulant mediated behaviors.…”

“…Interestingly, NK1R knockout mice exhibit lack of AMPH or morphine induced CPP (Gadd et al 2003; Murtra et al 2000; Yan et al 2009). While observations are conflicting with regard to NK1R antagonism on morphine reward (Commons 2010; Jones et al 2013; Murtra et al 2000; Ripley et al 2002; Robinson et al 2012; Walsh et al 2013), NK1R antagonism is shown to attenuate AMPH-induced locomotor activation (Gonzalez-Nicolini and McGinty 2002). Studies from genetic and pharmacological blockade of NK1R show modulation of psychostimulant induced release of NE and DA, indicating a role for NK1R in psychostimulant mediated behaviors as well as a close relationship between neurokinin and catecholaminergic systems (Fisher et al 2007; Yan et al 2009).…”

Mechanisms of Pain in Sickle Cell Disease

“…"prepitant, an FD"-approved NK-1 receptor antagonist for chemotherapy-induced nausea and vomiting, has been assessed for the efects on electrical hyperalgesia models of human volunteers, but did not show any eicacy [112]. However, in a separate study acute doses of aprepitant were shown to signiicantly increase the magnitude of mu agonist signs and symptoms in response to oxycodone [113]. Considering the role of SP in sickle pain and neurogenic inlammation, NK-1 receptor antagonists require further examination in preclinical models of SCD as co-drugs.…”

The Neurokinin-1 Receptor in Addictive Processes

“…One exception is a recent clinical trial in prescription opiate abusers. Unexpectedly, however, NK1R antagonism seemed to heighten the effects of these drugs (Walsh et al, 2013). How this relates to voluntary use of prescription opioid medications or illicit opiate drugs is unknown and will need to be addressed in future studies.…”