Background: The opioid overdose epidemic continues as a serious world problem, with postoperative opioid prescribing recognized as a critical contributor to opioid use disorder (OUD) development. Identifying risk factors associated with OUD in the perioperative setting is essential for developing targeted prevention strategies. This study aimed to evaluate the association of social determinants of health (SDoHs) and mental health conditions in predicting OUD within 1 year following surgery. Methods: This retrospective cohort study used de-identified electronic health records from the TriNetX Research Network, evaluating over 295 000 matched patients across individual risk factor cohorts. The index event was defined as the first opioid exposure within 3 days after their first surgery. Patients with and without risk factors were propensity score matched and then odds ratios (ORs) and absolute risks were calculated for postoperative OUD within 1 year. Results: Significance at P < .001 was present for all SDoHs assessed with individual ORs ranging from 0.77 (benzodiazepine use, n = 3 026 362) to 8.3 (homelessness, n = 16 997). A cohort with known mixed risk factors showed an additive association with OUD risk. A validation cohort confirmed the methodology, showing no association between levothyroxine use and OUD development (OR 1.0, P = .416, n = 222 471). The definition of OUD in this study was based on ICD-10 coding, which does not perfectly align with DSM-5 diagnostic criteria and may capture patients with persistent opioid use but without formal OUD diagnosis. Conclusions: Key SDoHs and mental health conditions significantly increase the risk of postoperative OUD. These findings underscore the need for preoperative risk stratification and targeted interventions, including multimodal analgesia and integrated mental health care to mitigate OUD risk in surgical populations. Addressing these factors is critical for advancing perioperative care and combating the opioid overdose crisis.

The opioid epidemic remains a persistent public health challenge in the United States, leaving many people affected by or vulnerable to opioid use disorder (OUD). Although US Food and Drug Administration-approved medications for OUD improve the odds of recovery and reduce mortality, relapse rates remain high and access, adherence, and individual response variabilities limit their overall impact. The ongoing burden of OUD therefore underscores the need to develop additional therapeutics that target complementary biological mechanisms and support long-term recovery. One strategy of interest is to delineate the biological overlap between OUD and other motivated behaviors, particularly the neurobiology underlying appetitive and reward-driven processes. The orexigenic peptide hormone ghrelin, often referred to as the “hunger hormone,” regulates energy homeostasis, hedonic feeding, and reward sensitivity by binding to the growth hormone secretagogue receptor 1α (GHS1αR), a receptor expressed in mesolimbic circuits implicated in addiction. In the present study, we used the inverse agonist/antagonist PF5190457 to assess the impact of full GHS1αR blockade on fentanyl-mediated behaviors in preclinical models. We found that PF5190457 significantly reduced fentanyl self-administration and attenuated drug-seeking during cue tests while maintaining a favorable pharmacological and safety profile in risk assessment assays, including measures of withdrawal and respiratory depression. Collectively, these findings demonstrate a functional role for ghrelin-GHS1αR signaling in the reinforcing effects of fentanyl and positions GHS1αR inverse agonism as a promising, mechanistically novel therapeutic strategy for OUD treatment. Significance Statement The present work demonstrates that the growth hormone secretagogue receptor 1α (GHS1αR) inverse agonist/antagonist PF5190457 reduces fentanyl self-administration and drug-seeking while maintaining a favorable safety profile in male rats, supporting ghrelin-GHS1αR modulation as a promising therapeutic strategy for opioid use disorder.

Texas has experienced a dramatic increase in unintentional opioid deaths over the past decade, underscoring the urgent need for effective prevention strategies. Access to naloxone nasal spray (NNS) and buprenorphine–naloxone (BUP/NX) is essential for reducing opioid-related fatalities. NNS, a µ-opioid receptor antagonist, rapidly reverses overdoses, while BUP/NX, a partial opioid agonist/antagonist, reduces cravings and withdrawal, decreasing opioid-related and all-cause mortality and improving treatment retention. Despite regulatory advances, barriers such as limited pharmacy stocking, restrictive policies, stigma, and prohibitive costs persist. The availability of NNS and BUP/NX in contiguous metropolitan Texas counties with high opioid-related overdose mortality rates remains underexamined. This study assesses the availability and accessibility of these medications in retail pharmacies across high-risk southeast Texas counties with some of the highest opioid overdose death rates in the state. Between April 30, 2024 and June 6, 2024, a cross-sectional telephone survey was conducted among community pharmacies in Brazoria, Galveston, Chambers, Jefferson, and Orange counties in Texas. Data were collected on medication stock, ordering timelines, and pricing. BUP/NX and NNS availability and accessibility across pharmacies were compared using Fisher’s exact test (p < 0.05). Of 309 pharmacies surveyed (90

Overdose fatalities involving cocaine continue to rise with over 5.3 million cocaine users reported in the United States in 2022. The abuse liability of cocaine is reliant upon inhibition of dopamine (DA) reuptake and consequent increase in DA efflux in meso-corticolimbic circuitry that controls reward and motivation. Cocaine also increases serotonin (5-HT) efflux which is integral in cocaine abuse. The 5-HT2A receptor (5-HT2AR) is a key regulator of meso-corticolimbic DA release and controls cellular mechanisms underlying cocaine effects. 5-HT2AR actions contribute importantly to psychedelic mechanisms of action, and the efficacy of these compounds in limiting cocaine intake is unknown. The present studies evaluated the efficacy of acute administration of a psychedelic to reduce cocaine intake using standard and advanced preclinical models of drug self-administration. Both a standard fixed ratio (FR) schedule and behavioral economics threshold procedure of cocaine intravenous self-administration were employed to evaluate the efficacy of the psychedelic 5-HT2AR agonist (−)-2,5-dimethoxy-4-iodoamphetamine [(−)-DOI] to decrease cocaine intake and motivation for cocaine in male rats. The 5-HT2AR-selective antagonist M100907 was utilized to explore the role of 5-HT2AR in the effects of (−)-DOI on cocaine intake. We found that (−)-DOI dose-dependently reduced intake on the FR5 schedule of cocaine IVSA and left shifted the demand curve to evoke greater sensitivity to price increases in the behavioral economics paradigm. Pretreatment with M100907 abated the efficacy of (−)-DOI on cocaine intake in both paradigms. (−)-DOI ‘devalued’ cocaine reward and motivation to take cocaine in a 5-HT2AR-dependent manner. As serotonergic psychedelics emerge as therapeutic candidates, investigations of 5-HT2AR-acting psychedelics in preclinical analyses of cocaine intake and relapse vulnerability during abstinence will be valuable as prelude to future clinical trials.

Objectives/Goals: One in 14 individuals have a substance use disorder (SUD). We suggest that a trait of poor impulse control, or high impulsivity, may predict relapse risk. We explore how changes in brain structure linked to decision-making and reward might drive high impulsivity, helping create a “biosignature” to identify those most at risk and guide treatment choices. Methods/Study Population: Male rats were phenotyped as high impulsive (HI) or low impulsive (LI) based on premature responses on the one-choice serial reaction time (1-CSRT) task. Rats then received an intracranial infusion of a retrograde virus (AAVr2) in the nucleus accumbens (NAc) to trace corticoaccumbens neurons back to the medial prefrontal cortex (mPFC). After impulsivity phenotyping (ITI8), another cohort of animals performed cocaine self-administration followed by 30 days of abstinence. Cue reactivity, a measure of relapse-like behaviors, was performed on abstinence day 30. Analyses of microtubule-associated protein 2 (MAP2), a cytoskeletal marker of dendrites, spines, and somas was performed with western blotting and fluorescent images of brain slices after phenotyping and cocaine abstinence. Results/Anticipated Results: HI rats made greater premature responses, a marker of impulsive action vs. LI rats at baseline (p Discussion/Significance of Impact: Poor inherent impulse control and drug cues heighten relapse risk. We found high impulsivity linked to brain structure differences and lower protein markers of synaptic (units supporting signaling) strengthening. Future investigations into brain-behavior links with impulsivity may further identify a SUD relapse vulnerability biosignature.

Alcohol misuse remains a leading cause of preventable death worldwide, prompting research into novel pharmacotherapies for alcohol use disorder (AUD). This study investigated the therapeutic potential of full agonism or positive allosteric modulation of the serotonin 2C receptor (5-HT2CR) in addressing alcohol binge drinking and seeking behaviours in mice. Using a drinking-in-the-dark paradigm and a context-induced reinstatement model following punishment-imposed abstinence, we assessed the acute effects of 5-HT2CR ligands lorcaserin, CYD-1-79, VA012 and CTW0415 on alcohol intake and seeking behaviours in mice. Results showed that while lorcaserin effectively reduced both alcohol consumption and seeking behaviours, the 5-HT2CR positive allosteric modulators (PAMs) did not significantly alter these behaviours over the range of doses examined. These findings suggest that 5-HT2CR PAMs, at the tested doses, may lack intrinsic efficacy in modulating alcohol use. However, our lorcaserin data demonstrate that targeting 5-HT2CR remains a valid approach to reduce behaviours associated with AUD.

Understanding the neural mechanisms of drug cue reactivity may improve understanding of therapeutic targets for substance use disorders (SUDs). Preclinical studies indicate that the serotonin (5-HT) 5-HT2A receptor (5-HT2AR) and 5-HT2CR systems considerably but oppositely impact relapse vulnerability. Specifically, 5-HT2AR antagonists and 5-HT2CR agonists reduce drug-seeking behavior and reactivity to drug cues. Our previous neuroimaging study showed that mirtazapine (a non-selective 5-HT2AR antagonist) can reduce the effective connectivity (EC) of the pathway from the anterior cingulate cortex (ACC) to the hippocampus. The EC of this pathway has been consistently found to be associated with attentional bias towards drug cues in individuals with SUDs. To extend this finding, we investigated the effect of lorcaserin (a 5-HT2CR agonist) on the EC linked to attentional bias elicited by drug-related cues by employing dynamic causal modeling on functional magnetic resonance imaging data acquired during a drug-word Stroop task performed by 45 individuals diagnosed with SUDs. We observed a marginally positive correlation between the ACC → hippocampus EC and drug cue-related attentional bias at the pretreatment baseline. Furthermore, compared to the placebo condition, 7-day administration of lorcaserin reduced the ACC → hippocampus EC. Notably, these EC outcomes remained unaffected by factors such as handedness, presence of drug metabolites in urine, pretreatment urine drug screen, and the type of substance used. This study contributes further evidence of serotonergic regulation of the ACC → hippocampus EC, and the potential for this EC to be an early signal of target engagement for medication to treat SUDs.

Introduction: As fentanyl has become more readily available, opioid-related morbidity and mortality in the United States has increased dramatically. Preliminary studies suggest that high-affinity, partial mu-opioid receptor agonists such as the combination product buprenorphine-naloxone may reduce mortality from overdose and promote remission. With the escalating prevalence of opioid use disorder (OUD), it is essential to evaluate the effectiveness of opioid agonists like buprenorphine-naloxone. This study examines mortality and remission rates for OUD patients prescribed buprenorphine-naloxone to determine the efficacy of this treatment toward these outcomes. Methods: We carried out a retrospective analysis using the US Collaborative Network database in TriNetX, examining de-identified medical records from nearly 92 million patients across 56 healthcare organizations. The study spanned the years from January 1, 2017–May 13, 2022. Cohort 1 included OUD patients who began buprenorphine-naloxone treatment within one-year post-diagnosis, while Cohort 2, the control group, consisted of OUD patients who were not administered buprenorphine. The study measured mortality and remission rates within a year of the index event, incorporating propensity score matching for age, gender, and race/ethnicity. Results: Prior to propensity matching, we identified a total of 221,967 patients with OUD. Following exclusions, 61,656 patients treated with buprenorphine-naloxone showed 34% fewer deaths within one year of diagnosis compared to 159,061 patients who did not receive buprenorphine (2.6% vs 4.0%; relative risk [RR] 0.661; 95% confidence interval [CI] 0.627–0.698; P < 0.001). The remission rate was approximately 1.9 times higher in the buprenorphine-naloxone group compared to the control group (18.8% vs 10.1%; RR 1.862; 95% CI 1.812–1.914; P < 0.001). After propensity matching, the effect on mortality decreased but remained statistically significant (2.6% vs 3.0%; RR 0.868; 95% CI 0.813–0.927; P < 0.001) and the remission rate remained consistent (18.8% vs 10.4%; RR 1.812; 95% CI 1.750–1.876; P < 0.001). Number needed to treat for benefit was 249 for death and 12 for remission. Conclusion: Buprenorphine-naloxone was associated with significantly reduced mortality and increased remission rates for patients with opioid use disorder and should be used as a primary treatment. The recognition and implementation of treatment options like buprenorphine-naloxone is vital in alleviating the impact of OUD.

Pain management physicians are increasingly focused on limiting unnecessary opioid prescribing and reducing harmful use, yet existing tools for monitoring opioid adherence have limited accuracy. Medication event monitoring systems (MEMS), such as “smart bottles”, are an emerging technology for tracking medication usage in real-time, but have not been tested in chronic pain patients on long-term opioid regimens. We conducted a preliminary clinical trial to investigate the utility of MEMS for monitoring opioid adherence and compared to traditional adherence monitoring methods. Opioid-maintained patients (OMPs; n=28) were randomly assigned to either receive MEMS bottles containing their opioid medication for a 90-day period or track their own medication usage via self-report diaries. Additional data regarding physician-rated adherence and urine drug screen (UDS) results were collected. OMPs who received MEMS demonstrated highly heterogenous dosing patterns, with a substantial number of patients rapidly using excessive amounts of medication and/or “stockpiling” unused medication. MEMS data did not correlate with physician-rated adherence (p = 0.24) and UDS results (p = 0.77). Our hypothesis that MEMS data would reveal greater non-adherence than self-report data was supported, as scores from MEMS were significantly lower than scores from diaries from participants in the MEMS condition (p < 0.001) as well as from participants in the control condition (p < 0.001). These results highlight the stark contrast between traditional indices of opioid adherence and actual medication usage as well as underscore how real-time monitoring could be used to improve patient outcomes, minimize harm, and aid in clinical decision-making. The findings also demonstrate the limits in our understanding of naturalistic patterns of opioid medication use when administered as needed and the importance of future research on innovative technology-based strategies to limit opioid misuse and diversion. This study was preregistered on ClinicalTrials.gov (NCT03752411).