Pruritus is an early and often debilitating symptom of primary biliary cholangitis (PBC), significantly impairing quality of life through fatigue, sleep disturbance, anxiety and social withdrawal. Traditional management relies on a stepwise approach, with bile acid sequestrants as first-line therapy and rifampin, naltrexone, or sertraline for refractory cases, but these agents often provide incomplete relief and are limited by tolerability and drug-drug interaction concerns. Advances in understanding the mechanisms of cholestatic itch have expanded treatment options to include peroxisome proliferator-activated receptor (PPAR) agonists, such as seladelpar, elafibranor and bezafibrate that uniquely offer both antipruritic effects and improvement in biochemical markers of disease activity. Therapies targeting specific pruritogenic pathways now include ileal bile acid transporter (IBAT) inhibitors, one of which is now approved specifically for PBC-related pruritus, as well as κ-opioid receptor agonists, MrgprX4 antagonists, and autotaxin inhibitors. Optimal management integrates pharmacological therapy with supportive strategies, including skin care, lifestyle modifications and psychosocial support tailored to the individual patient's disease activity, symptom severity, and comorbidities. By addressing both the biological and experiential dimensions of pruritus, this comprehensive framework enables clinicians to improve symptom control and enhance overall quality of life for patients living with PBC. Emerging therapies and a mechanism-informed treatment approach offer promise for more effective, individualized care in this challenging clinical context.

Expanded use of buprenorphine-naloxone use, particularly for marginalized communities, such as the unhoused, is an established priority. Unfortunately, due to fear of the precipitation of opioid withdrawal, this goal remains unmet. In response, microdosing methods during the initial week of treatment do not require opioid abstinence and do not precipitate withdrawal. This review establishes the scientific basis for microdosing that is centered on the pharmacodynamic principle of pseudo-irreversibility for a partial agonist, such as buprenorphine.

A series of N-(1,2,3,4-tetrahydro-3-isoquinolinylmethyl)benzamides, which are potent μ-opioid receptor (MOR) agonists, has been discovered. The most promising compound, compound 56 (BPR1M492), is an MOR agonist without a clear signaling bias between cAMP and β-arrestin-2 pathways, a cAMP-biased nociceptin-orphanin FQ opioid peptide agonist, and a weak cAMP-biased δ/κ-opioid receptor agonist. Compound 56 demonstrated potent in vivo antinociception at 0.027 mg/kg, offering rapid pain relief within 5 min of subcutaneous injection. It produced markedly milder withdrawal symptoms than TRV130 in mice, whereas differences in respiratory, gastrointestinal, reward-related, and tolerance-related measures were less pronounced and should be interpreted cautiously in light of the substantially lower dose required for antinociception. Compound 56 is a highly stable, slightly hygroscopic, low-moisture-containing crystalline solid that is safe at its in vivo effective dose.

This case report highlights the severe clinical course of a 30-year-old woman with a history of intravenous drug abuse, who presented to the emergency department with debilitating lower back pain. Initial evaluations revealed a critical condition, with septic emboli disseminated throughout her lungs, brain, and kidneys, likely secondary to her intravenous drug use. Further investigation suggested the involvement of krokodil (desomorphine), a potent and highly corrosive opioid, which has recently resurfaced in rural American communities due to its low cost and availability compared to fentanyl and xylazine. Krokodil, produced from codeine and toxic chemicals, causes extreme tissue damage, including ulcerations and gangrene. Radiological studies confirmed septic thrombosis, multiple septic emboli, and bilateral acute pyelonephritis, prompting immediate broad-spectrum antibiotic treatment. Despite initial stabilization, the patient's condition escalated, necessitating a laminectomy for epidural abscess evacuation. Her treatment was complicated by withdrawal symptoms, and further bacterial cultures identified Staphylococcus aureus as the causative agent. The patient's management included extended antibiotic therapy and a long-term anticoagulation regimen due to septic thrombosis. While krokodil use has been documented in other regions, including Russia and Ukraine, its prevalence in the United States remains low. Enhanced diagnostic tools and better surveillance systems are crucial to understanding and mitigating the impact of this dangerous substance.

Opioid addiction and misuse are a serious national crisis that affects public health, as well as social and economic welfare. Mortality due to opioid misuse is further exasperated by the combination of opioids with non-opioid respiratory depressants such as xylazine that are resistant to mu opioid receptor antagonists such as naloxone. This study tested the hypothesis that oxytocin can mitigate the severe opioid induced respiratory depression (OIRD) and mortality induced by high doses of fentanyl or the combination of fentanyl with xylazine. Our results show OXT can improve survival and respiratory function in both male and female rats with opioid induced respiratory depression caused by fentanyl, as well as a combination of fentanyl and xylazine. The improvement in respiratory function by OXT post fentanyl-xylazine was significantly greater than the recovery using only naloxone. Chemogenetic activation of OXT receptor positive neurons in the ventral respiratory group (VRG) provided similar benefits to that of OXT administration in reversing OIRD. These results indicate OXT is a promising therapeutic target for reversing OIRD and the respiratory depression that occurs with the combination of opioids and xylazine, a situation where naloxone is only partially effective. Additional translational benefits of OXT include it can be repurposed as it is already a FDA approved drug for other uses, has a high safety profile, and is unlikely to induce the withdrawal or reversal of analgesia that occurs with naloxone.

Background/Objectives: A sub-anesthetic dose of ketamine has shown promise in reducing craving, withdrawal symptoms, and use of drugs such as alcohol, cocaine, and opioids among individuals with substance use disorders. Ketamine's therapeutic potential for tobacco use is unknown. Here, we investigated a single sub-anesthetic dose among adults with tobacco use disorder who were not interested in changing their smoking behavior. Methods: Utilizing a randomized, within-subject crossover, double-blinded, counter-balanced, midazolam-controlled design, participants (n = 18) received a 0.71 mg/kg infusion of ketamine and a 0.025 mg/kg infusion of midazolam (i.e., active placebo) at least two weeks apart. Participants were asked to abstain from smoking after the infusions until the post-infusion sessions, 1 day following infusion, where participants completed measures of smoking behavior, craving, and withdrawal symptoms. Participants continued to record their smoking behavior over the 7 days following infusion. Participants also completed a semi-structured qualitative interview regarding their experiences. Results: Compared to midazolam, ketamine infusion led to a non-significant reduction (p = 0.10, ηp[2] = 0.153) in the number of cigarettes smoked during the requested abstinence period. Following this period, there were no significant differences in ad lib smoking. Ketamine showed no effect on craving or withdrawal symptoms. Participants reported more intense psychological experiences following ketamine infusion (p < 0.001, ηp[2] = 0.830) and about half reported it felt easier to abstain from smoking after the ketamine infusion. Conclusions: While well tolerated, these findings suggest ketamine has little to no direct effect on quantitative measures of cigarette smoking, craving, or withdrawal. However, the qualitative measures suggest ketamine improves mood and reduces craving in some individuals for several days. Future studies should investigate whether ketamine can indirectly support smoking cessation among individuals with comorbid psychiatric indications for ketamine treatment.

Cannabis use, both medical and recreational, is increasing and poses a growing challenge for anesthesiologists, given the scarcity of specific clinical data. The main phytocannabinoids, Δ9-tetrahydrocannabinol (THC) and cannabidiol (CBD), interact with CB1 and CB2 receptors, affecting cardiovascular, respiratory, neurological, and immune systems, as well as the metabolism of several anesthetic drugs. Chronic or high-dose use can alter anesthetic requirements, increase risk of perioperative complications, and modify postoperative pain responses, often leading to greater opioid consumption. ASRA and PAIN guidelines recommend universal preoperative screening, assessment for cannabis use disorder, dose tapering or discontinuation in high-use patients, and postponement of elective procedures in the presence of acute intoxication. Differentiating medical use - characterized by standardized formulations and titrated dosing - from recreational use, which is more variable and often associated with polysubstance use, is essential. Cardiovascular (tachycardia, hypotension, arrhythmias), respiratory (bronchitis, airway hyperreactivity), and neurological (cognitive impairment, delirium risk) effects require targeted intra- and postoperative monitoring. Multimodal analgesic strategies, opioid-sparing approaches, and postoperative nausea/vomiting prevention are recommended. The pain specialist plays a key role in managing chronic therapy patients, avoiding abrupt discontinuation and preventing withdrawal syndrome, including through oral cannabinoid substitution. A multidisciplinary approach involving anesthesiologists, pain specialists, and pharmacologists, integrating thorough history-taking, risk assessment, and personalized perioperative planning, is essential to optimize safety and outcomes in surgical patients who consume cannabis.

Substance withdrawal syndromes pose significant challenges in addiction treatment, often leading to poor treatment adherence and high relapse rates. This review evaluates metformin's potential as a therapeutic option for substance withdrawal syndromes, focusing on its mechanisms (AMPK activation, neurotransmitter modulation, gut microbiome effects) and clinical implications. Proposed mechanisms of action, including the involvement of signaling pathways, neurotransmitter regulation, and gut microbiome modulation, are also discussed. The study also highlights key areas requiring further investigation, such as the need for well-designed clinical trials, exploration of metformin dosage and treatment duration, and a deeper understanding of the specific molecular pathways underlying metformin's impact on withdrawal syndromes. Preclinical and clinical evidence suggest that metformin alleviates withdrawal symptoms and reduces relapse risk, but further research is needed to optimize dosing and validate efficacy. Overall, this review supports metformin's potential as a promising therapeutic option for managing substance withdrawal syndromes, offering improved treatment outcomes and reduced relapse rates and vulnerabilities.

Data integration approaches are increasingly used to enhance the efficiency and generalizability of studies. However, a key limitation of these methods is the assumption that outcome measures are identical across datasets - an assumption that often does not hold in practice. Consider the following opioid use disorder (OUD) studies: the XBOT trial and the POAT study, both evaluating the effect of medications for OUD on withdrawal symptom severity (not the primary outcome of either trial). While XBOT measures withdrawal severity using the subjective opiate withdrawal scale, POAT uses the clinical opiate withdrawal scale. We analyze this realistic yet challenging setting where outcome measures differ across studies and where neither study records both types of outcomes. Our paper studies whether and when integrating studies with disparate outcome measures leads to efficiency gains. We introduce three sets of assumptions - with varying degrees of strength - linking both outcome measures. Our theoretical and empirical results highlight a cautionary tale: integration can improve asymptotic efficiency only under the strongest assumption linking the outcomes. However, misspecification of this assumption leads to bias. In contrast, a milder assumption may yield finite-sample efficiency gains, yet these benefits diminish as sample size increases. We illustrate these trade-offs via a case study integrating the XBOT and POAT datasets to estimate the comparative effect of two medications for opioid use disorder on withdrawal symptoms. By systematically varying the assumptions linking the SOW and COW scales, we show potential efficiency gains and the risks of bias. Our findings emphasize the need for careful assumption selection when fusing datasets with differing outcome measures, offering guidance for researchers navigating this common challenge in modern data integration.