Diclofenac Dose Response Study

Overview

The development of efficacious medications for AUD remains a high research priority with current emphases on identifying novel molecular targets and efficiently screening new compounds. Pharmacological modulation of the kynurenine pathway (KP) represents a promising novel target for AUD. The KP is a complex enzymatic cascade with each step producing biologically active metabolites that are critically involved in diverse physiological and pathological processes. Chronic alcohol exposure produces dysregulation of the KP, particularly as evidenced by decreased levels of the neuroprotective metabolite kynurenic acid (KYNA) and increased levels of the neurotoxic metabolite quinolinic acid (QUIN). This metabolic shift is associated with various alcohol-related pathologies in animals and humans. Thus, a medication that targets the KP to restore KYNA and attenuate QUIN levels may be an effective treatment for AUD. The enzyme kynurenine 3- monooxygenase (KMO) is a major gatekeeper of the KP and resultant KYNA levels. KMO inhibition shifts the KP towards KYNA production in brain and away from QUIN production. Critically, KMO inhibition in rodents, through its increase in brain KYNA levels, decreases alcohol self-administration, preference, cue-reactivity, and relapse behaviors. However, KMO-inhibitors have not been tested in humans because of presumed lack of availability. Diclofenac is an FDA-approved Non-Steroidal Anti-Inflammatory Drug that was recently discovered to inhibit KMO activity. Consistent with KMO inhibition, diclofenac increases KYNA levels in the brain and periphery of rodents. However, it remains unknown whether diclofenac increases KYNA levels and affects alcohol-related behaviors in humans at approved, safe dosages. Investigators propose to conduct a human laboratory pilot study to test whether diclofenac can increase KYNA in individuals with AUD, and if so, which of 3 doses (50, 75, or 100 mg) most effectively increases KYNA. Individuals with AUD (n = 24) will complete four sessions where they receive diclofenac (50, 75, or 100 mg) or placebo. Investigators will examine increases in KYA levels and will also assess QUIN levels, alcohol craving, and negative mood.

Alcohol use disorder (AUD) is a chronic condition for which current pharmacological treatments are only modestly effective \[1,2\]. The development of efficacious medications for AUD remains a high research priority with current emphases on identifying novel molecular targets and efficiently screening new compounds for AUD \[3,4\]. To that end, modulation of the kynurenine pathway (KP) represents a promising novel target for AUD. The KP is a complex enzymatic cascade with each step producing biologically active metabolites that are critically involved in diverse physiological and pathological processes. Accumulating evidence suggests that chronic alcohol exposure produces dysregulation of the KP, particularly as evidenced by altered levels of the metabolites kynurenic acid (KYNA) and quinolinic acid (QUIN). KYNA is an NMDA receptor and α7 nicotinic acetylcholine receptor (nAChR) antagonist that has neuroprotective and anticonvulsant properties \[5,6\]. Conversely, QUIN is an NMDA receptor agonist containing neurotoxic and convulsant properties \[7-9\]. Both NMDA and α7nAChR are critically involved in addiction neurobiology. For example, α7nAChRs control glutamate release from cortical afferents to the nucleus accumbens and thereby modulate mesolimbic dopamine release in response to acute alcohol consumption and alcohol-related cues \[10-12\]. Chronic alcohol exposure produces ametabolic shift away from KYNA and toward QUIN production, and this imbalance is associated with various alcohol-related pathologies in animals and humans \[11-14\]. Thus, a medication that targets the KP to restore KYNA and attenuate QUIN levels may hold promise as an effective treatment for AUD. The enzyme kynurenine 3-monooxygenase (KMO) is increasingly understood to be a major gatekeeper of the KP and its production of KYNA. KMO inhibition shifts the KP towards KYNA production in the brain \[15\], whereas KMO upregulation shifts the KP toward QUIN production. Critically, KMO inhibition in rodents decreases alcohol self-administration, alcohol preference, relapse to alcohol consumption, and cue-induced reinstatement of alcohol-seeking \[11,12,16\]. These anti-alcohol effects were predominantly due to brain increases in KYNA, which blocked alcohol-induced dopamine release in the nucleus accumbens shell through antagonism of α7nAChreceptors11,12. KMO inhibition also reduced nicotine- and cannabinoid-induced extracellular dopamine release in the nucleus accumbens shell, self-administration of nicotine and cannabinoids, cue-induced nicotine and cannabinoid relapse behaviors, and cocaine-seeking behavior; like with alcohol, these effects were also in part to KYNA's antagonism of α7nACh receptors \[11,17-19\]. These preclinical findings suggest increasing KYNA levels though KMO inhibition is a promising target for the treatment of AUD as well as other substances of misuse, but medications with this pharmacological property have not been tested in humans. Diclofenac is an FDA-approved Non-Steroidal Anti-Inflammatory Drug (NSAID), and like all NSAIDs produces anti-inflammatory, antipyretic, and analgesic effects at least in part through inhibiting prostaglandin activity. However, it was recently discovered that diclofenac also potently inhibits KMO activity and that it may be the only FDA-approved medication with this pharmacological property \[20,21\]. Consistent with KMO inhibition, diclofenac increases KYNA levels in the brain and peripheral tissue in rodents \[22,23\]. Thus, diclofenac has a unique and promising pharmacological profile for AUD treatment. However, it remains unknown whether diclofenac increases KYNA levels in humans at approved, safe dosages, and if KMO inhibition in humans is a viable pharmacological target for treating AUD. As diclofenac is currently available and used by millions of patients each year for other indications, the repurposing of diclofenac for the treatment of AUD represents a fast and economically feasible approach to drug development. The first step in determining whether diclofenac can be repurposed for AUD is to determine whether the drug inhibits KMO at FDA-approved safe and tolerable doses. Thus, investigators propose to conduct a human laboratory pilot study to test whether diclofenac can increase KYNA in individuals with AUD. An increase in KYNA would support the proposed pharmacological property of KMO inhibition. Individuals with AUD (n = 24) will complete four sessions where they receive one of three doses of diclofenac (50, 75, or 100 mg) or placebo. Investigators will examine increases in KYA levels and will also assess QUIN levels, alcohol craving, and negative mood.