Additionally, the practice quit model demonstrated specificity in which bupropion, an FDA-approved medication for smoking cessation, increased number of days abstinent, whereas modafinil, a medication ineffective for smoking cessation, was no different than placebo. The success of the practice quit attempt model for screening medications for nicotine dependence provides a basis for the development of a similar approach modified for AUD. In addition to the standard procedures of the practice quit attempt, we have included an established human laboratory paradigm to ensure that the novel model will be sensitive to medication effects. The cue-reactivity paradigm measures alcohol craving by having individuals hold and smell their preferred alcoholic beverage and a control beverage. Naltrexone , which is FDA-approved for AUD, is effective at significantly reducing alcohol-cue elicited craving compared to matched placebo. Similar evidence exists for varenicline, a promising pharmacotherapy for AUD. Thus, our current study will include CR in order to detect medication effects on cue-induced craving which will also verify the sensitivity of the novel practice quit attempt model to those medication effects. In order to appropriately test and validate this model for AUD, we will use an established, FDA-approved medication. NTX is an opioid antagonist with high affinity for mu-opioid and kappa-opioid receptors. Preclinical studies have shown that opioid antagonists at the muopioid receptor reduce ethanol consumption. In humans,drying rack for weed alcohol consumption increases the release of endogenous opioids in the mesolimbic dopamine reward system which contributes to the subjective pleasurable effects of alcohol.
Therefore, NTX’s therapeutic benefit as an opioid antagonist is proposed to block these rewarding effects and reduce alcohol consumption. Previous studies of NTX have shown that it reduces drinks per drinking day, alcohol craving, rates of relapse, and the subjective pleasurable effects of alcoho. The effects of NTX appear to be moderated by craving such that higher levels of craving were found to be associated with greater reduction in alcohol consumption. As an established medication for AUD, NTX is an ideal candidate to test the novel practice quit attempt model. To further validate this novel early efficacy model, we will also test a promising medication to treat AUD. Varenicline is a partial agonist at α4β2 and a full agonist at α7 nicotinic acetylcholine receptors, which is FDA-approved for smoking cessation. In preclinical studies, activation of nicotinic acetylcholine receptors reduced ethanol consumption. In human laboratory studies, VAR reduced alcohol self-administration and craving, compared to placebo. In smoking cessation trials, it also reduced alcohol consumption and craving. Additionally, a multi-site randomized controlled trial of VAR in individuals with AUD found that it reduced drinks per drinking day, alcohol craving, and percentage of heavy drinking days . Together, these studies suggest that VAR is a promising pharmacotherapy for the treatment of AUD. Therefore, including varenicline, a widely studied and promising AUD pharmacotherapy, as a third arm in this study will enable us to further validate this novel alcohol quit paradigm. In designing the current study as a 3-arm trial, we benefit not only from establishing the efficacy of NTX and VAR against placebo, but also from a head-to-head comparison of NTX and VAR in a cost-effective manner.
The 3-arm trial design has been selected to overcome weaknesses present in non-inferiority trials where a novel drug is compared to an active control that is the current standard treatment. In active control trials, medication efficacy of the novel drug is determined by demonstrating non-inferiority to the active control, which rests on the critical assumption that the active control has an actual drug effect. However, as there is no placebo control, this assumption cannot be proven; therefore, non-inferiority/equivalence trials lack assay sensitivity, or the ability to distinguish between effective and ineffective treatments. The 3-arm design essentially combines the advantages of placebo and active controlled trials. The placebo arm will allow us to showcase if VAR is an effective or ineffective medication in the context of a good internal standard. Additionally, if neither NTX nor VAR are shown to be superior to placebo, then we can conclude that the practice quit paradigm is not a valid method for screening medications for AUD .The purpose of the current study is to develop and validate this novel model to screen novel compounds and advance medications development. Naltrexone was chosen to evaluate the novel practice quit attempt model as it is one of the few FDA-approved medications AUD. RCT studies with oral NTX have shown that it reduced drinks per drinking day, alcohol craving, rates of relapse, and the subjective pleasurable effects of alcohol. As such, NTX represents a well-known, well-studied medication that is ideal for testing a novel paradigm. Varenicline is a promising pharmacotherapy for the treatment of AUD. VAR has been shown to reduce alcohol self-administration, consumption, and craving.
A recent RCT of VAR in individuals with AUD found that it reduced drinks per drinking day, alcohol craving, and percentage of heavy drinking days. These studies suggest VAR as a potential AUD pharmacotherapy. The addition of VAR as a third arm in the current study will allow us to further validate this novel practice quit attempt model. Additionally, the inclusion of a promising pharmacotherapy allows us to compare the efficacy of two medications head to-head in a cost-effective manner. The 3-arm design of a novel medication , standard treatment , and placebo allows us to not only establish efficacy of each medication against placebo, but also of the novel medication again the standard treatment. This study design essentially combines the advantages of placebo and active control studies .Participants who are eligible after the physical exam will be randomized to one of three treatment conditions . Urn randomization will be stratified by gender, smoking status , and drinking status . The UCLA Research Pharmacy will manage the blind. The three treatment conditions will not be different in appearance or method of administration. All participants will undergo a week long medication titration period prior to the onset of the practice quit attempt as follows: for the naltrexone condition, 12.5 mg will be taken for the first 3 days, followed by 25 mg dosage from days 4–7. The target dosage of 50 mg will be ingested days 8–14. As for the varenicline condition, a dosage of 0.5 mg will be taken for the first 3 days followed by an increase to 1 mg for days 8–14. The intended dosage of 2 mg will be taken days 8–14. Each condition will the instructed to take prescribed medication twice per day as detailed in Table 1. On study day 1,trimming cannabis participants will report to the laboratory to complete the alcohol CR paradigm and receive their first medication dose under direct observation of study staff. They will receive a 7-day supply of study medication in blister packs with AM and PM dosing clearly distinguished. After reaching the target medication dose at the end of 1 week, participants will come to the laboratory on study day 8 to receive their second, 7- day supply of study medication and to begin the 7-day practice quit attempt. Participants will be asked to take the AM dose of study medication on study day 8 in the lab under direct observation of study staff. During the practice quit attempt, participants will complete daily online and phone visits to report on their drinking, mood, and craving for alcohol during the previous day in a daily diary assessment . For each virtual visit, participants will be contacted over the phone by research staff. Participants will first be asked about adverse events and about use of concomitant medications. Research staff will then administer the CIWA-Ar to measure alcohol withdrawal. Next, they will ask participants to report on their past day drinking as well as cigarette and marijuana use.
Finally, while participants are still on the phone, research staff will send a link to the DDA . All participants will meet with a trained study counselor briefly after the second cue exposure session on day 14. This brief intervention draws from motivational interviewing and Screening, Brief Intervention, and Referral to Treatment models. Consistent with the literature on brief intervention, the therapist will seek opportunities to engage in and amplify change talk. Together, the combination of evidence-based practices and principles applied to AUD, coupled with the experience of change in the context of study participation, is expected to result in an opportunity for health behavior change .Adherence to interventions is facilitated by dividing the medication into separate blister packs for two distributions, the daily virtual visits during the practice quit attempt period, and a completion bonus. The separation of the study medication into two blister packs, each a 7-day supply, will motivate participants to come back to the laboratory for the second supply, and reduce the chance of them misplacing the medication at the start of the study. During the practice quit attempt period, the participants will be asked to send pictures of their blister packs to the study staff after completion of the daily phone visits. This will allow the study staff to count the medication for compliance. Additionally, a completion bonus will be given out to participants on the last day of the study if they have completed at 7 out of the 8 in-person and virtual visits. This is to motivate participants to complete all daily phone visits and online assessments .Alcohol use disorder is a chronic relapsing disorder with a major public health impact. Over 14 million adults in the United States have an AUD; however, only 8% of adults with current AUD received treatment. Only four pharmacotherapies are currently approved by the Food and Drug Administration for the treatment of AUD, and these medications are only modestly effective with number needed to treat ranging from 7–144 across studies. Therefore, there is a clear need to develop more efficacious treatments, particularly those with novel molecular targets. To that end, the modulation of neuroimmune signaling is a promising AUD treatment target. A growing body of literature indicates that the neuroimmune system may play a critical role in the development and maintenance of AUD, termed the neuroimmune hypothesis of alcohol addiction. In animal models, chronic alcohol consumption induces a neuroimmune response through the activation of microglia and increased expression of pro-inflammatory cytokines and neuronal cell death. Elevated microglial markers have been identified in the postmortem brains of individuals with an AUD, and pro-inflammatory cytokine levels are higher in individuals with AUD compared to controls. Neuroinflammation has also been implicated in mood disorders . Moreover, mood states are considered to be a central feature of AUD, with a negative mood state emerging with increasing AUD severity. Interactions between inflammatory pathways and the neurocircuitry activated in depression and addiction are thought to contribute to negative mood. Therefore, a neuroimmune modulator may treat AUD and related negative mood symptoms through similar pathways. Ibudilast shows promise as a novel AUD pharmacotherapy. IBUD reduced alcohol intake by 50% in two rat models, and selectively decreased drinking in alcohol-dependent mice relative to non-dependent mice. In a human laboratory trial, treatment with IBUD was well-tolerated and resulted in reductions in tonic craving and improvements in mood reactivity to stress and alcohol cue exposure compared to placebo. IBUD is a selective phosphodiesterase inhibitor, with preferential inhibition of PDE3A, PDE4, PDE10A, and PDE11A, and a macrophage migration inhibitory factor inhibitor. Both PDE4 and MIF are involved in neuroinflammatory processes through the regulation of inflammatory responses in microglia], and PDE4Bexpression is upregulated after chronic alcohol exposure. Therefore, IBUD is thought to reduce neuroinflammation through the inhibition of these pro-inflammatory molecules. IBUD crosses the blood–brain barrier, and is neuroprotective as it suppresses the production of pro-inflammatory cytokines and enhances the production of anti-inflammatory cytokines. While IBUD is a promising AUD pharmacotherapy, its underlying mechanisms of action on the human brain remain largely unknown. PDE4 is highly expressed in neuronal and non-neuronal cells including glia in brain regions associated with reward and reinforcement, including the ventral striatum, and PDE4 can directly regulate dopamine in the striatum in mice. Functional magnetic resonance imaging alcohol cue-reactivity paradigms have commonly been used to evaluate if pharmacological AUD treatments alter brain activation in reward processing circuity.