Fragile-like regulatory T cells modulate opioid withdrawal in humans and mice.

Opioid use alters peripheral immune functions via unknown mechanisms. In a recent issue of Cell, Zhu et al. report increased fragile-like regulatory T cells in patients with opioid use disorder and in morphine-treated mice. In mice, Treg cell-derived interferon-γ within the brain promotes withdrawal-associated alterations in synapses.

Eat, Sleep, Console Approach or Usual Care for Neonatal Opioid Withdrawal.

BACKGROUND: Although clinicians have traditionally used the Finnegan Neonatal Abstinence Scoring Tool to assess the severity of neonatal opioid withdrawal, a newer function-based approach - the Eat, Sleep, Console care approach - is increasing in use. Whether the new approach can safely reduce the time until infants are medically ready for discharge when it is applied broadly across diverse sites is unknown. METHODS: In this cluster-randomized, controlled trial at 26 U.S. hospitals, we enrolled infants with neonatal opioid withdrawal syndrome who had been born at 36 weeks' gestation or more. At a randomly assigned time, hospitals transitioned from usual care that used the Finnegan tool to the Eat, Sleep, Console approach. During a 3-month transition period, staff members at each hospital were trained to use the new approach. The primary outcome was the time from birth until medical readiness for discharge as defined by the trial. Composite safety outcomes that were assessed during the first 3 months of postnatal age included in-hospital safety, unscheduled health care visits, and nonaccidental trauma or death. RESULTS: A total of 1305 infants were enrolled. In an intention-to-treat analysis that included 837 infants who met the trial definition for medical readiness for discharge, the number of days from birth until readiness for hospital discharge was 8.2 in the Eat, Sleep, Console group and 14.9 in the usual-care group (adjusted mean difference, 6.7 days; 95% confidence interval [CI], 4.7 to 8.8), for a rate ratio of 0.55 (95% CI, 0.46 to 0.65; P<0.001). The incidence of adverse outcomes was similar in the two groups. CONCLUSIONS: As compared with usual care, use of the Eat, Sleep, Console care approach significantly decreased the number of days until infants with neonatal opioid withdrawal syndrome were medically ready for discharge, without increasing specified adverse outcomes. (Funded by the Helping End Addiction Long-term (HEAL) Initiative of the National Institutes of Health; ESC-NOW ClinicalTrials.gov number, NCT04057820.).

Withdrawal from 3-Fluoroethamphetamine induces hyperactivity and depression-like behaviors in male mice.

3-Fluoroethamphetamine (3-FEA) belongs to the amphetamine class of stimulant drugs and functions as a releasing agent for the monoamine neurotransmitters norepinephrine, dopamine, and serotonin. 3-FEA acts on the central nervous system and elicits physical and mental side effects, such as euphoria, increased heart rate, and excitement. However, little is known about the withdrawal symptoms and behavioral changes induced by 3-FEA administration. This study aimed to evaluate the short-term consequences of 3-FEA administration (twice a day, 7 days, i.p.; 1 and 10 mg/kg) in C57BL/6J mice (male, 7 weeks old) at three behavioral levels following 1-4 days of withdrawal. The evaluation included (1) withdrawal score, (2) hyperactivity (open field [OF], elevated plus maze [EPM], and cliff avoidance [CA] test), and (3) depression-like behavior (forced-swim test). In the withdrawal score test, withdrawal behavior increased in all 3-FEA groups at 16 and 40 h after withdrawal. In the OF, EPM, and CA tests, the 3-FEA administration group showed significant changes in terms of hyperactivity. In addition, in the forced-swim test, both the 1 mg/kg and 10 mg/kg 3-FEA groups showed increased immobility time. These findings indicate that 3-FEA administration may lead to physical dependence, demonstrated by the withdrawal score increase and significant changes in hyperactivity and depression-like behavior following repeated administration and drug cessation. In conclusion, this study reveals the adverse consequences of 3-FEA administration and highlights the need for awareness raising and regulatory action to control the use of this new psychoactive substance.

Examining Adult Patients' Success with Discontinuing Long-term Benzodiazepine Use: a Qualitative Study.

BACKGROUND: Little is known about patients' experiences with benzodiazepine (BZD) discontinuation, which is thought to be challenging given the physiological and psychological dependence and accompanying potential for significant withdrawal symptoms. The marked decline in BZD prescribing over the past decade in the US Department of Veterans Affairs healthcare system presents an important opportunity to examine the experience of BZD discontinuation among long-term users. OBJECTIVE: Examine the experience of BZD discontinuation among individuals prescribed long-term BZD treatment to identify factors that contributed to successful discontinuation. DESIGN: Descriptive qualitative analysis of semi-structured interviews conducted between April and December of 2020. PARTICIPANTS: A total of 21 Veterans who had been prescribed long-term BZD pharmacotherapy (i.e., > 120 days of exposure in a 12-month period) and had their BZD discontinued. APPROACH: We conducted semi-structured interviews with Veteran participants to learn about their BZD use and the process of discontinuation, with interviews recorded and transcribed verbatim. Data were deductively and inductively coded and coded text entered into a matrix to identify factors that contributed to successful BZD discontinuation. KEY RESULTS: The mean age of interview participants was 63.0 years (standard deviation 3.9); 94.2% were male and 76.2% were white. Of 21 participants, only 1 had resumed BZD treatment (prescribed by a non-VA clinician). Three main factors influenced success with discontinuation: (1) participants' attitudes toward BZDs (e.g., risks of long-term use, perceived lack of efficacy, potential for dependence); (2) limited withdrawal symptoms; and (3) effective alternatives, either from their clinician (e.g., medication, psychotherapy) or identified by participants. CONCLUSIONS: BZD discontinuation after long-term use is relatively well tolerated, and participants appreciated reducing their medication exposure, particularly to one associated with physical dependence. These findings may help reduce both patient and clinician anxiety related to BZD discontinuation.

Liraglutide Reduces Alcohol Consumption, Anxiety, Memory Impairment, and Synapse Loss in Alcohol Dependent Mice.

Glucagon-like peptide 1 (GLP-1) analogues have been commercialized for the management of type 2 diabetes. Recent studies have underscored GLP-1's role as a modulator of alcohol-related behavior. However, the role of the GLP-1 analogue liraglutide on alcohol-withdrawal responses have not been fully elucidated. Liraglutide binds to the G-protein-coupled receptor and activates an adenylyl cyclase and the associated classic growth factor signaling pathway, which acts growth factor-like and neuroprotective properties. The underlying neurobiological mechanisms of liraglutide on alcohol withdrawal remains unknown. This study endeavored to explore the effects of liraglutide on the emotion and memory ability of alcohol-withdrawal mice, and synaptic morphology in the medial prefrontal cortex (mPFC) and the hippocampus (HP), and thus affects the relapse-like drinking of alcohol-withdrawal mice. The alcohol-withdrawal group was reintroduced to a 20% v/v alcohol and water through the two-bottle choice for four consecutive days, a period referred to as alcohol re-drinking. Male C57BL/6J mice were exposed to a regimen of 20% alcohol and water for a duration of 6 weeks. This regimen established the two-bottle choice model of alcohol exposure. Learning capabilities, memory proficiency, and anxiety-like behavior were evaluated using the Morris water maze, open field, and elevated plus maze paradigms. Furthermore, synaptic morphology and the levels of synaptic transport-related proteins were assessed via Golgi staining and Western Blot analysis after a two-week alcohol deprivation period. Alcohol re-drinking of alcohol-withdrawal mice was also evaluated using a two-bottle choice paradigm. Our findings indicate that liraglutide can substantially decrease alcohol consumption and preference (p < 0.05) in the alcohol group and enhance learning and memory performance (p < 0.01), as well as alleviate anxiety-like behavior (p < 0.01) of alcohol-withdrawal mice. Alcohol consumption led to a reduction in dendritic spine density in the mPFC and HP, which was restored to normal levels by liraglutide (p < 0.001). Furthermore, liraglutide was found to augment the levels of synaptic transport-related proteins in mice subjected to alcohol withdrawal (p < 0.01). The study findings corroborate that liraglutide has the potential to mitigate alcohol consumption and ameliorate the memory impairments and anxiety induced by alcohol withdrawal. The therapeutic efficacy of liraglutide might be attributed to its role in counteracting synapse loss in the mPFC and HP regions and thus prevented relapse-like drinking in alcohol-withdrawal mice.

Behavioral characterization of early nicotine withdrawal in the mouse: a potential model of acute dependence.

BACKGROUND: Clinical and preclinical research have demonstrated that short-term exposure to nicotine during the initial experimentation stage can lead to early manifestation of withdrawal-like signs, indicating the state of "acute dependence". As drug withdrawal is a major factor driving the progression toward regular drug intake, characterizing and understanding the features of early nicotine withdrawal may be important for the prevention and treatment of drug addiction. In this study, we corroborate the previous studies by showing that withdrawal-like signs can be precipitated after short-term nicotine exposure in mice, providing a potential animal model of acute dependence on nicotine. RESULTS: To model nicotine exposure from light tobacco use during the initial experimentation stage, mice were treated with 0.5 mg/kg (-)-nicotine ditartrate once daily for 3 days. On the following day, the behavioral tests were conducted after implementing spontaneous or mecamylamine-precipitated withdrawal. In the open field test, precipitated nicotine withdrawal reduced locomotor activity and time spent in the center zone. In the elevated plus maze test, the mecamylamine challenge increased the time spent in the closed arm and reduced the number of entries irrespective of nicotine experience. In the examination of the somatic aspect, precipitated nicotine withdrawal enhanced the number of somatic signs. Finally, nicotine withdrawal did not affect cognitive functioning or social behavior in the passive avoidance, spatial object recognition, or social interaction test. CONCLUSIONS: Collectively, our data demonstrate that early nicotine withdrawal-like signs could be precipitated by the nicotinic antagonist mecamylamine in mice, and that early withdrawal from nicotine primarily causes physical symptoms.

Long-term outcome of alcohol withdrawal seizures.

BACKGROUND AND PURPOSE: Alcohol withdrawal seizures (AWS) are a well-known complication of chronic alcohol abuse, but there is currently little knowledge of their long-term relapse rate and prognosis. The aims of this study were to identify risk factors for AWS recurrence and to study the overall outcome of patients after AWS. METHODS: In this retrospective single-center study, we included patients who were admitted to the Emergency Department after an AWS between January 1, 2013 and August 10, 2021 and for whom an electroencephalogram (EEG) was requested. AWS relapses up until April 29, 2022 were researched. We compared history, treatment with benzodiazepines or antiseizure medications (ASMs), laboratory, EEG and computed tomography findings between patients with AWS relapse (r-AWS) and patients with no AWS relapse (nr-AWS). RESULTS: A total of 199 patients were enrolled (mean age 53 ± 12 years; 78.9% men). AWS relapses occurred in 11% of patients, after a median time of 470.5 days. Brain computed tomography (n = 182) showed pathological findings in 35.7%. Risk factors for relapses were history of previous AWS (p = 0.013), skull fractures (p = 0.004) at the index AWS, and possibly epileptiform EEG abnormalities (p = 0.07). Benzodiazepines or other ASMs, taken before or after the index event, did not differ between the r-AWS and the nr-AWS group. The mortality rate was 2.9%/year of follow-up, which was 13 times higher compared to the general population. Risk factors for death were history of AWS (p < 0.001) and encephalopathic EEG (p = 0.043). CONCLUSIONS: Delayed AWS relapses occur in 11% of patients and are associated with risk factors (previous AWS >24 h apart, skull fractures, and pathological EEG findings) that also increase the epilepsy risk, that is, predisposition for seizures, if not treated. Future prospective studies are mandatory to determine appropriate long-term diagnostic and therapeutic strategies, in order to reduce the risk of relapse and mortality associated with AWS.

Anticholinergic deprescribing: A case report demonstrating improved cognition and function with minimal adverse withdrawal effects.

Anticholinergic-induced cognitive impairment may be partially reversible upon cessation. A barrier to deprescribing of anticholinergics is the unknown risk of anticholinergic adverse drug withdrawal events (ADWE), with only limited information available on the incidence, timing and severity of anticholinergic ADWE. We report the case of a 76-year-old woman who experienced significant cognitive improvement following deprescribing long-term use of a strong anticholinergic drug, doxepin, and dose reduction of another possible anticholinergic agent. The patient decided to abruptly stop taking doxepin, despite a planned careful taper with twice weekly monitoring, but did not experience any severe anticholinergic ADWE and subsequently had significantly improved cognitive function. Future research should focus on better understanding the risk of anticholinergic ADWE so that anticholinergic deprescribing decisions, including how often and by how much to taper, can be made confidently and safely.

A Comparison of Injectable Diazepam and Lorazepam in the Goal-Directed Management of Severe Alcohol Withdrawal.

BACKGROUND: Benzodiazepines are the gold standard for treatment of alcohol withdrawal, yet the selection of a preferred benzodiazepine is limited due to a lack of comparative studies. OBJECTIVES: The primary objective of this study was to compare the efficacy and safety of injectable lorazepam (LZP) and diazepam (DZP) in the treatment of severe alcohol withdrawal syndrome (AWS). METHODS: Retrospective cohort study of adult patients admitted to an intensive care unit with a primary diagnosis of AWS. Subjects who received at least 12 LZP equivalent units (LEU) of injectable DZP or LZP within 24 hours of initiation of the severe AWS protocol were included. The primary outcome was time with Clinical Institute Withdrawal Assessment for Alcohol-Revised (CIWA-Ar) scores at goal over the first 24 hours of treatment. RESULTS: A total of 191 patients were included (DZP n = 89, LZP n = 102). Time with CIWA-Ar scores at goal during the first 24 hours was similar between groups (DZP 12 hours [interquartile range, IQR, = 9-15] vs LZP 14 hours [IQR = 10-17]), P = 0.06). At 24 hours, LEU requirement was similar (DZP 40 [IQR = 22-78] vs LZP 32 [IQR = 18-56], P = 0.05). Drug cost at 24 hours was higher in the DZP group ($204.6 [IQR = 112.53-398.97] vs $8 [IQR = 4.5-14], P < 0.01). CONCLUSION AND RELEVANCE: DZP or LZP are equally efficacious for the treatment of severe AWS. LZP may be preferred due to cost but both medications can be used interchangeably based on availability.

Patient Perspectives on Pharmacotherapy of Alcohol Dependence.

INTRODUCTION: Pharmacotherapy with drugs like naltrexone or acamprosate is a well-evaluated element in the treatment of alcohol dependence (AD). However, in many countries, these medications are rarely administered. The objective of the present study was to identify from patients' perspective factors that prevent the initiation and compliance with pharmacological treatment of AD. METHODS: Patients from inpatient alcohol withdrawal treatment underwent a standardized interview. Questions included socio-demographic data, history of AD, treatment history, knowledge and personal experience regarding pharmacotherapy of AD, and personal views about the causes of AD. RESULTS: Three hundred patients (mean age 47.3 years, 27.7% female, mean duration of AD 8.9 years, 67% with a history of previous inpatient withdrawal treatment) were included. The majority of patients (58.7%) already knew drugs for the pharmacotherapy of AD. Thirty percent had ever used such medications, most often acamprosate. Except for disulfiram, pharmacotherapy of AD had lasted only a few weeks, on average. Medication usually had been applied without additional psychotherapy. No severe side effects were reported. Patients had often stopped pharmacotherapy on their own, when assuming they had reached stable abstinence. Openness to start pharmacotherapy for AD was currently stated by 67% of the total sample. In multiple logistic regression, openness was predicted by having a concept of AD as a medical disease and by a shorter duration of AD. DISCUSSION: To improve the administration of pharmacotherapy for AD implementation strategies should be systematically developed and evaluated with a focus on the concept of AD as a medical disease.

Attenuation of cannabis withdrawal symptoms by Prosopis farcta extract, its luteolin and melatonin in mice: Involvement of brain-derived neurotrophic factor and dopamine.

The aim of this study was the identification of luteolin in Prosopis farcta extract (PFE) and melatonin to evaluate its effect on THC withdrawal syndrome in mice. Luteolin was identified by high-performance liquid chromatography (HPCL). Signs of toxicity of mice in PFE and luteolin were monitored for LD50 calculation. The behavioral symptoms of THC withdrawal (stereotypies, ambulation, and inactivity time) induced by the rimonabant challenge were illustrated in THC-dependent mice receiving PFE, luteolin, and melatonin. The expression of mature BDNF (mBDNF) was evaluated by Western blot analysis. The dopamine concentrations were measured using HPLC. PFE and luteolin LD50 were 650 and 220 mg/kg, respectively. PFE (300 mg/kg), all doses of luteolin, and melatonin increased significantly the mBDNF expression and decreased the dopamine concentration. The findings suggest that PFE, luteolin, and melatonin are mighty in reducing the signs of THC withdrawal. It seems these effects were due to a decrease in dopamine concentration level and an increase in mBDNF protein expression in mice brains.

Ameliorating effects of Acanthopanax koreanum extract and components on nicotine dependence and withdrawal symptoms.

Tobacco smoking is a serious health problem in society. While smoking rates are declining, smoking remains a serious risk to national health. Currently, there are several medications available to aid in smoking cessation. However, these medications have the disadvantages of low success rates in smoking cessation and various side effects. Therefore, natural-based smoking cessation aids are being suggested as a good alternative due to their accessibility and minimal side effects. The roots and stems of Acanthopanax koreanum (AK) Nakai, a plant that is native to Jeju Island, South Korea, have traditionally been used as tonic and sedatives. Moreover, eleutheroside B and chlorogenic acid are the main components of AK stem extract. In the present study, we investigated the effect of 70% ethanol AK extract and its components on ameliorating nicotine dependence and withdrawal symptoms by using behavioural tests in mice. In addition, alterations in the dopaminergic and DRD1-EPAC-ERK-CREB pathways were observed using dopamine ELISA and western blotting using mouse brains. Our findings demonstrate that the AK extract and its components effectively mitigated the effects of nicotine treatment in behavioural tests. Furthermore, it normalized the dopamine concentration and the expression level of nicotine acetylcholine receptor α7. Additionally, it was observed that AK extract and its components led to the normalization of DRD1, ERK and CREB expression levels. These results indicate that AK extract exhibits effects in ameliorating nicotine dependence behaviour and alleviating withdrawal symptoms. Moreover, EB and CGA are considered potential marker components of AK extract.

Precipitated opioid withdrawal in a patient started on olanzapine/samidorphan.

BACKGROUND: Olanzapine/Samidorphan (Lybalvi®) is a novel oral agent for the treatment of schizophrenia and bipolar I disorder. It was designed to reduce weight gain associated with olanzapine. Samidorphan is an analog of naltrexone, initially intended to treat substance use disorders by antagonizing mu, delta, and kappa opioid receptors. CASE REPORT: We present the case of a 36-year-old who took their first dose of olanzapine/samidorphan shortly before calling for emergency services. The patient took diphenhydramine and an epinephrine autoinjector for what they thought was an allergic reaction but continued to have symptoms. EMS reported involuntary muscle movements thought to be due to dystonia from olanzapine. In the ED, they experienced generalized muscle spasms lasting for several seconds and diaphoresis. Initially, the staff treated for a presumed dystonic reaction to olanzapine and administered diphenhydramine 25 mg IV, diazepam 2 mg IV, midazolam 5 mg IV, and benztropine 1 mg IV without improvement. It was later determined that the patient took 16 mg of buprenorphine SL daily. With this information, precipitated opioid withdrawal was felt to be the likely cause of symptoms. The patient received 16 mg of buprenorphine for an initial Clinical Opiate Withdrawal Scale (COWS) score of 11 with repeat COWS of 6. Why should an emergency physician be aware of this? Initiating olanzapine/samidorphan in the setting of chronic opioid therapy may result in precipitated opioid withdrawal. Additional SL buprenorphine may be a reasonable treatment modality.

Measuring Objective and Subjective Sleep during Lisdexamfetamine Treatment of Acute Methamphetamine Withdrawal: A Feasibility Study.

INTRODUCTION: Sleep disturbance is common during methamphetamine (MA) use and withdrawal; however, the feasibility of combined subjective-objective measurement of sleep-wake has not been shown in this population. Actigraphy is a well-established, non-invasive measure of sleep-wake cycles with good concordance with polysomnography. This study aimed to investigate the feasibility and utility of using actigraphy and sleep diaries to investigate sleep during MA withdrawal. METHODS: We conducted a feasibility and utility study of actigraphy and sleep diaries during a clinical trial of lisdexamfetamine for MA withdrawal. Participants were inpatients for 7 days, wore an actigraph (Philips Actiwatch 2) and completed a modified Consensus Sleep Diary each morning. Participants were interviewed between days 3-5. RESULTS: Ten participants (mean age 37 years, 90% male) were enrolled. No participant removed the device prematurely. Participants interviewed (n = 8) reported that the actigraph was not difficult or distracting to wear or completion of daily sleep diary onerous. Actigraphic average daily sleep duration over 7 days was 568 min, sleep onset latency 22.4 min, wake after sleep onset (WASO) 75.2 min, and sleep efficiency 83.6%. Sleep diaries underreported daily sleep compared with actigraphy (sleep duration was 56 min (p = 0.008) and WASO 47 min (p < 0.001) less). Overall sleep quality was 4.4 on a nine-point Likert scale within the diary. CONCLUSIONS: Continuous actigraphy is feasible to measure sleep-wake in people withdrawing from MA, with low participant burden. We found important differences in self-reported and actigraphic sleep, which need to be explored in more detail.

Managing Selected Chronic Conditions in Hospitalized Patients.

The management of chronic illnesses should continue during hospitalization. Some chronic conditions require immediate intervention, whereas intensification of therapy for other conditions may be delayed until after discharge. Factors such as pain, anxiety, poor sleep hygiene, and concurrent illness can result in a transient elevation of blood pressure. Acute lowering of blood pressure in hospitalized patients who do not have target-organ damage is not recommended and may lead to harm. If treatment is needed, intravenous antihypertensive agents should be avoided. Patients with diabetes mellitus require continued management of their blood glucose while hospitalized. Noninsulin agents are typically discontinued. Blood glucose levels should be managed using basal, prandial, and/or correction insulin. During hospitalization, conservative blood glucose targets (140 to 180 mg per dL) are preferred vs. lower targets to reduce length of stay, mortality, and the risk of hypoglycemic events in critically ill patients. Alcohol use disorder is common and hospitalization for other conditions necessitates identification and management of alcohol withdrawal syndrome. The mainstay of therapy for alcohol withdrawal syndrome is benzodiazepines; however, phenobarbital is an alternative treatment option. The risk of venous thromboembolic disease is significantly increased for hospitalized patients. Venous thromboprophylaxis is recommended for all but low-risk patients. Pharmacologic prophylaxis with subcutaneous low-molecular-weight heparin is preferred; mechanical prophylaxis is an alternative for patients who are at high risk of bleeding or have contraindications to anticoagulation.

Fixed-Dose Phenobarbital Versus As-Needed Benzodiazepines for the Management of Alcohol Withdrawal in Acute Care General Internal Medicine.

OBJECTIVES: The management of patients at risk of severe alcohol withdrawal is challenging because conventional treatment with as-needed benzodiazepines may be ineffective. We created a fixed-dose phenobarbital protocol and compared patient outcomes using this protocol with an as-needed benzodiazepine protocol. METHODS: Patients admitted from the emergency department (ED) to General Medicine from January 1 to June 30, 2022 and treated for alcohol withdrawal with a novel phenobarbital protocol were compared with all of the patients admitted from the ED to General Medicine from January 1 to June 30, 2018, and treated with as-needed benzodiazepines. The primary outcome was a composite of intensive care unit (ICU) transfer or mortality. Secondary outcomes included mortality, ICU transfer, seizure, length of stay, excess sedation, delirium, against medical advice discharge, 30-day re-admission, 30-day ED reevaluation, and antipsychotic use. RESULTS: There were 54 patients in the phenobarbital group and 197 in the benzodiazepine group. The phenobarbital group was less medically complex but had more risk factors for severe withdrawal. There was no difference in the primary outcome, although there was a trend toward benefit in the phenobarbital group (3.7 vs 8.1%, P = 0.26), and there was a lower incidence of delirium in the phenobarbital cohort (0 vs 8.6%, P = 0.03). Secondary outcome trends favored phenobarbital, with lower mortality, ICU transfer, seizure, oversedation, against medical advice discharge, and 30-day re-admissions. A subgroup analysis accounting for differences in patient populations in the primary analysis found similar results. CONCLUSIONS: Phenobarbital is as safe and effective as benzodiazepine-based protocols for the treatment of high-risk alcohol withdrawal, with lower rates of delirium.

Withdrawal during outpatient low dose buprenorphine initiation in people who use fentanyl: a retrospective cohort study.

BACKGROUND: Buprenorphine is an effective treatment for opioid use disorder (OUD); however, buprenorphine initiation can be complicated by withdrawal symptoms including precipitated withdrawal. There has been increasing interest in using low dose initiation (LDI) strategies to reduce this withdrawal risk. As there are limited data on withdrawal symptoms during LDI, we characterize withdrawal symptoms in people with daily fentanyl use who underwent initiation using these strategies as outpatients. METHODS: We conducted a retrospective chart review of patients with OUD using daily fentanyl who were prescribed 7-day or 4-day LDI at 2 substance use disorder treatment clinics in San Francisco. Two addiction medicine experts assessed extracted chart documentation for withdrawal severity and precipitated withdrawal, defined as acute worsening of withdrawal symptoms immediately after taking buprenorphine. A third expert adjudicated disagreements. Data were analyzed using descriptive statistics. RESULTS: There were 175 initiations in 126 patients. The mean age was 37 (SD 10 years). 71% were men, 26% women, and 2% non-binary. 21% identified as Black, 16% Latine, and 52% white. 60% were unstably housed and 75% had Medicaid insurance. Substance co-use included 74% who used amphetamines, 29% cocaine, 22% benzodiazepines, and 19% alcohol. Follow up was available for 118 (67%) initiations. There was deviation from protocol instructions in 22% of these initiations with follow up. 31% had any withdrawal, including 21% with mild symptoms, 8% moderate and 2% severe. Precipitated withdrawal occurred in 10 cases, or 8% of initiations with follow up. Of these, 7 had deviation from protocol instructions; thus, there were 3 cases with follow up (3%) in which precipitated withdrawal occurred without protocol deviation. CONCLUSIONS: Withdrawal was relatively common in our cohort but was mostly mild, and precipitated withdrawal was rare. Deviation from instructions, structural barriers, and varying fentanyl use characteristics may contribute to withdrawal. Clinicians should counsel patients who use fentanyl that mild withdrawal symptoms are likely during LDI, and there is still a low risk for precipitated withdrawal. Future studies should compare withdrawal across initiation types, seek ways to support patients in initiating buprenorphine, and qualitatively elicit patients' withdrawal experiences.

The Perceived Role of Withdrawal in Maintaining Opioid Addiction among Adults with Untreated Opioid Use Disorder: A Survey of Syringe Exchange Program Participants.

Background: Withdrawal is believed to play a central role in the brain disease model of addiction. However, little research describes withdrawal-motives among untreated individuals in community settings. Methods: This cross-sectional study surveyed syringe exchange program participants (n = 139) with untreated opioid use disorder (OUD) in Columbus, Ohio from January 10th to March 25th, 2023, to assess their perceptions of the role of withdrawal in OUD maintenance, treatment delay, and OUD's refractoriness to buprenorphine. Participants responded to a survey including DSM-5 OUD criteria, demographics, and questions about substance use and opioid withdrawal. Participant ages ranged from 21 to 65 years with a mean age of 37.5 years and standard deviation of 8.1. The racial distribution of the sample was as follows: 81% White/Caucasian, 12% Black/African American, 3% Native American or Alaskan Native. Results: Sixty-six percent of participants agreed, or strongly agreed that opioid withdrawal was "the most important reason" they had been unable to stop using opioids. Almost seventy-one percent agreed, or strongly agreed that worry about opioid withdrawal had caused them to "put off or delay" OUD treatment. Although all participants had active, untreated OUD at the time of recruitment, most (85%) had previously tried buprenorphine, and the majority (78%) reported having experienced buprenorphine-precipitated withdrawal. Conclusions: Among this community sample of individuals with untreated OUD, withdrawal was perceived to have an important role in maintaining OUD, including by motivating OUD treatment delay. Prior buprenorphine-precipitated withdrawal was common, suggesting aversion to withdrawal might possibly be associated with OUD's refractoriness to buprenorphine.

A Retrospective Evaluation of Adjunctive Phenobarbital vs. Benzodiazepine Alone for the Treatment of Moderate Alcohol Withdrawal in the Emergency Department.

BACKGROUND: Phenobarbital has been used in the emergency department (ED) as both a primary and adjunctive medication for alcohol withdrawal, but previous studies evaluating its impact on patient outcomes are limited by heterogenous symptom severity. OBJECTIVES: We compared the clinical outcomes of ED patients with moderate alcohol withdrawal who received phenobarbital, with or without benzodiazepines, with patients who received benzodiazepine treatment alone. METHODS: This is a retrospective cohort study conducted at a single academic medical center utilizing chart review of ED patients with moderate alcohol withdrawal between 2015 and 2020. Patient encounters were classified into two treatment categories based on medication treatment: phenobarbital alone or in combination with benzodiazepines vs. benzodiazepines alone. Chi-square test or Fisher's exact was used to analyze categorical variables and the Student's t-test for continuous data. RESULTS: Among the 287 encounters that met inclusion criteria, 100 received phenobarbital, compared with 187 that received benzodiazepines alone. Patients who received phenobarbital were provided significantly more lorazepam equivalents. There was a significant difference in the percentage of patient encounters that required admission to the hospital in the phenobarbital cohort compared with the benzodiazepine cohort (75% vs. 43.3%, p < 0.001). However, there was no difference in admission level of care to the floor (51.2% vs. 52.0%), stepdown (33.8% vs. 28%), or intensive care unit (15% vs. 20%), respectively. CONCLUSIONS: Patients who received phenobarbital for moderate alcohol withdrawal were more likely to be admitted to the hospital, but there was no difference in admission level of care when compared with patients who received benzodiazepines alone. Patients who received phenobarbital were provided greater lorazepam equivalents in the ED.

Prevalence, Characteristics, and Reasons for Kratom Use among Psychiatrically Ill Inpatients Who Use Substances.

OBJECTIVE: Despite kratom impacting neurobiological systems involved in psychiatric disorders, little is known about the prevalence of use among patients with severe psychopathologies. Here, we investigated the prevalence of kratom use, motives for use, and the clinical associations among inpatients with severe psychiatric disorders. METHODS: A total of 578 patients, aged 18 to 65, were evaluated by New Hampshire Hospital's Addiction Services from January 1, 2020, to February 28, 2022. The study collected demographic information and used chi-square tests, multivariable logistic regression, and subgroup analyses with 95% confidence intervals to examine trends among kratom users. A receiver operating characteristic curve analysis was also conducted. All statistical tests were performed using IBM SPSS Version 28.0.1. RESULTS: Of the patients assessed, 2.2% (n = 13) reported using kratom. The reasons for kratom use were managing withdrawal symptoms (15.4%), maintaining sobriety and reducing cravings for opioids (53.8%), improving focus and concentration (30.8%), alleviating low moods (38.5%), and managing pain (15.4%). Compared to non-kratom users, the only factor with a fair to good association with kratom use is postsecondary education (Area Under Curve, AUC = 0.77). CONCLUSIONS: Prevalence of kratom use among patients with serious mental illness at our site aligns with that reported in the general population. Users often cite self-management of cravings and sobriety from opioids, as well as treatment of low mood states, as motivations for consumption. While observations suggest a possible association between kratom use and individuals with post-secondary education, multiple substance use, and experience of substance-induced psychosis or mood disorders, it is essential to interpret these links cautiously until further rigorous studies are carried out to substantiate these findings.