Mild Withdrawal Research Articles

ADVANCEMENTS IN UNDERSTANDING AND MANAGING ALCOHOL WITHDRAWAL SYNDROME: A COMPREHENSIVE REVIEW

Alcohol withdrawal syndrome (AWS) is a clinically significant condition that can arise upon abrupt cessation or reduction of alcohol consumption in individuals with alcohol dependence. This review article provides a comprehensive overview of AWS, encompassing its epidemiology, pathophysiology, clinical manifestations, assessment tools, and management strategies. We discuss the neurobiological mechanisms underlying AWS, including the role of neurotransmitter systems such as gamma-aminobutyric acid (GABA) and glutamate, as well as neuroadaptive changes that occur with chronic alcohol use. Furthermore, we explore the spectrum of clinical manifestations associated with AWS, ranging from mild withdrawal symptoms to severe complications such as delirium tremens and seizures. Diagnostic tools and scoring systems commonly used for assessing AWS severity are examined, along with evidence-based approaches for pharmacological and non-pharmacological management of AWS. Additionally, we highlight emerging research areas and future directions in the field of AWS, including novel treatment modalities and potential biomarkers for predicting withdrawal severity and treatment response. This comprehensive review aims to provide clinicians, researchers, and healthcare professionals with a thorough understanding of AWS to facilitate early recognition, appropriate management, and improved outcomes for individuals affected by this condition.

Seven‐day buprenorphine feasible in patients with minimal to mild opioid withdrawal

Patients with opioid use disorder (OUD) who exhibited minimal to mild withdrawal at baseline experienced positive outcomes with use of an injectable 7‐day formulation of buprenorphine, a nonrandomized trial has found. The study sample of 100 adults reported few serious adverse events and a high degree of satisfaction with the extended‐release formulation of buprenorphine.

Ketamine-assisted buprenorphine initiation: a pilot case series

BackgroundMany people with opioid use disorder who stand to benefit from buprenorphine treatment are unwilling to initiate it due to experience with or fear of both spontaneous and buprenorphine-precipitated opioid withdrawal (BPOW). An effective means of minimizing withdrawal symptoms would reduce patient apprehensiveness, lowering the barrier to buprenorphine initiation. Ketamine, approved by the FDA as a dissociative anesthetic, completely resolved BPOW in case reports when infused at a sub-anesthetic dose range in which dissociative symptoms are common. However, most patients attempt buprenorphine initiation in the outpatient setting where altered mental status is undesirable. We explored the potential of short-term use of ketamine, self-administered sublingually at a lower, sub-dissociative dose to assist ambulatory patients undergoing transition to buprenorphine from fentanyl and methadone.MethodsPatients prescribed ketamine were either (1) seeking transition to buprenorphine from illicit fentanyl and highly apprehensive of BPOW or (2) undergoing transition to buprenorphine from illicit fentanyl or methadone and experiencing BPOW. We prescribed 4–8 doses of sublingual ketamine 16 mg (each dose bioequivalent to 3–6% of an anesthetic dose), monitored patients daily or near-daily, and adjusted buprenorphine and ketamine dosing based on patient response and prescriber experience.ResultsOver a period of 14 months, 37 patients were prescribed ketamine. Buprenorphine initiation was completed by 16 patients, representing 43% of the 37 patients prescribed ketamine, and 67% of the 24 who reported trying it. Of the last 12 patients who completed buprenorphine initiation, 11 (92%) achieved 30-day retention in treatment. Most of the patients who tried ketamine reported reduction or elimination of spontaneous opioid withdrawal symptoms. Some patients reported avoidance of severe BPOW when used prophylactically or as treatment of established BPOW. We developed a ketamine protocol that allowed four of the last patients to complete buprenorphine initiation over four days reporting only mild withdrawal symptoms. Two patients described cognitive changes from ketamine at a dose that exceeded the effective dose range for the other patients.ConclusionsKetamine at a sub-dissociative dose allowed completion of buprenorphine initiation in the outpatient setting in the majority of patients who reported trying it. Further research is warranted to confirm these results and develop reliable protocols for a range of treatment settings.

Extended-Release 7-Day Injectable Buprenorphine for Patients With Minimal to Mild Opioid Withdrawal

Buprenorphine is an effective yet underused treatment for opioid use disorder (OUD). To evaluate the feasibility (acceptability, tolerability, and safety) of 7-day injectable extended-release buprenorphine in patients with minimal to mild opioid withdrawal. This nonrandomized trial comprising 4 emergency departments in the Northeast, mid-Atlantic, and Pacific geographic areas of the US included adults aged 18 years or older with moderate to severe OUD and Clinical Opiate Withdrawal Scale (COWS) scores less than 8 (minimal to mild), in which scores range from 0 to 7, with higher scores indicating increasing withdrawal. Exclusion criteria included methadone-positive urine, pregnancy, overdose, or required admission. Outcomes were assessed at baseline, daily for 7 days by telephone surveys, and in person at 7 days. Patient recruitment occurred between July 13, 2020, and May 25, 2023. Injection of a 24-mg dose of a weekly extended-release formulation of buprenorphine (CAM2038) and referral for ongoing OUD care. Primary feasibility outcomes included the number of patients who (1) experienced a 5-point or greater increase in the COWS score or (2) transitioned to moderate or greater withdrawal (COWS score ≥13) within 4 hours of extended-release buprenorphine or (3) experienced precipitated withdrawal within 1 hour of extended-release buprenorphine. Secondary outcomes included injection pain, satisfaction, craving, use of nonprescribed opioids, adverse events, and engagement in OUD treatment. A total of 100 adult patients were enrolled (mean [SD] age, 36.5 [8.7] years; 72% male). Among the patients, 10 (10.0% [95% CI, 4.9%-17.6%]) experienced a 5-point or greater increase in COWS and 7 (7.0% [95% CI, 2.9%-13.9%]) transitioned to moderate or greater withdrawal within 4 hours, and 2 (2.0% [95% CI, 0.2%-7.0%]) experienced precipitated withdrawal within 1 hour of extended-release buprenorphine. A total of 7 patients (7.0% [95% CI, 2.9%-13.9%]) experienced precipitated withdrawal within 4 hours of extended-release buprenorphine, which included 2 of 63 (3.2%) with a COWS score of 4 to 7 and 5 of 37 (13.5%) with a COWS score of 0 to 3. Site pain scores (based on a total pain score of 10, in which 0 indicated no pain and 10 was the worst possible pain) after injection were low immediately (median, 2.0; range, 0-10.0) and after 4 hours (median, 0; range, 0-10.0). On any given day among those who responded, between 29 (33%) and 31 (43%) patients reported no cravings and between 59 (78%) and 75 (85%) reported no use of opioids; 57 patients (60%) reported no days of opioid use. Improving privacy (62%) and not requiring daily medication (67%) were deemed extremely important. Seventy-three patients (73%) were engaged in OUD treatment on day 7. Five serious adverse events occurred that required hospitalization, of which 2 were associated with medication. This nonrandomized trial of the feasibility of a 7-day buprenorphine injectable in patients with minimal to mild opioid withdrawal (COWS scores, 0-7) found the formulation to be acceptable, well tolerated, and safe in those with COWS scores of 4 to 7. This new medication formulation could substantially increase the number of patients with OUD receiving buprenorphine. ClinicalTrials.gov Identifier: NCT04225598.

Ten years of maintenance treatment of severe melancholic depression in an adult woman including discontinuation experiences.

There are only few publications on long-term treatments for major depressive disorder (MDD) lasting 5 years or longer. Most clinical controlled trials lasted no longer than 2 years and some recent studies suggested an advantage of cognitive behavioral therapy (CBT) over antidepressants in relapse prevention of MDD. Exclusively outpatient "real world" treatment of severe melancholia, prospectively documented over 10 years with different serial treatment strategies, discontinuation phenomena and complications. Compared to CBT, agomelatine, mirtazapine, bupropion and high-dose milnacipran, high-dose venlafaxine (extended-release form, XR) was effective, even sustainably. Asymptomatic premature ventricular contractions (PVCs) were found at the beginning of the treatment of the MDD, which initially led to the discontinuation of high-dose venlafaxine (300 mg daily). Even the various treatment strategies mentioned above were unable to compensate for or prevent the subsequent severe deterioration in MDD (2 rebounds, 1 recurrence). Only the renewed use of high-dose venlafaxine was successful. PVC no longer occurred and the treatment was also well tolerated over the years, with venlafaxine serum levels at times exceeding 5 times the recommended upper therapeutic reference level (known bupropion-venlafaxine interaction, otherwise 2.5 to 3-fold increase with high-dose venlafaxine alone). During dose reduction or after gradual discontinuation of high-dose venlafaxine, rather mild withdrawal symptoms occurred, but as described above, also two severe rebounds and one severe recurrence happened. This long-term observation supports critical reflections on the discontinuation of successful long-term treatment with antidepressants in severe MDD, even if it should be under "the protection" of CBT. The PVC seemed to be more related to the duration of the severe major depressive episode than to the venlafaxine treatment itself. A particular prospective observation of this longitudinal case study is that relapses (in the sense of rebounds) during or after previous venlafaxine tapering seemed to herald the recurrence after complete recovery. Remarkably, neither relapses nor recurrence could be prevented by CBT. In this case, high-dose venlafaxine has a particular relapse-preventive (and "recurrence-preventive") effect with good long-term tolerability.

Rotation from methadone to buprenorphine using a micro-dosing regime in patients with opioid use disorder and serious mental illness: A case series.

Inducting buprenorphine from methadone has traditionally involved initial opioid withdrawal, with risk of mental state deterioration in patients with serious mental illness (SMI). Micro-dosing of buprenorphine, with small incremental doses, is a novel off-label approach to transitioning from methadone and does not require a period of methadone abstinence. Given the limited literature about buprenorphine microdosing, we aimed to evaluate the feasibility and safety of inducting buprenorphine in a series of patients on methadone with SMI. For this retrospective case series, we reviewed the records of 16 patients with SMI at a Melbourne addiction treatment centre, from January 2021 to July 2022, who transitioned via micro-dosing, from high-dose methadone (>30 mg) to buprenorphine and depot-buprenorphine. Psychiatric diagnoses, mental state, other substance withdrawal, transfer success, transition time, opioid withdrawal symptoms and overall patient experience were collected via objective and subjective reporting. Methadone to buprenorphine transfer was completed by 88% of patients. Mental health measures remained stable with the exception of mildly increased anxiety. Median transfer time was 6.5 days for inpatients, 9 days for mixed setting and 10 days for outpatients. Most patients (93%) rated their experience 'manageable' reporting mild withdrawal symptoms. One patient met study criteria for precipitated withdrawal. This retrospective case series provides evidence that the use of a micro-dosing buprenorphine induction for methadone to buprenorphine transitions, including to depot-buprenorphine, has negligible risk, is tolerated by patients with SMI and is unlikely to precipitate an exacerbation of their mental illness.

Rapid induction of transdermal buprenorphine to subcutaneous extended-release buprenorphine for the treatment of opioid use disorder

BackgroundBuprenorphine is an effective and safe treatment for opioid use disorder, but the requirement for moderate opioid withdrawal symptoms to emerge prior to initiation is a significant treatment barrier.Case PresentationWe report on two cases of hospitalized patients with severe, active opioid use disorder, in which we initiated treatment with transdermal buprenorphine over 48 h, followed by the administration of a single dose of sublingual buprenorphine/naloxone and then extended-release subcutaneous buprenorphine. The patients did not experience precipitated withdrawal and only had mild withdrawal symptoms.ConclusionsThis provides preliminary evidence for a rapid induction strategy that may improve tolerability, caregiver burden, and treatment retention as compared to previous induction strategies.

Efficacy of the QuitSure App for Smoking Cessation in Adult Smokers: Cross-Sectional Web Survey.

Cigarette smoking remains one of the leading causes of preventable death worldwide. A worldwide study by the World Health Organization concluded that more than 8 million people die every year from smoking, tobacco consumption, and secondhand smoke. The most effective tobacco cessation programs require personalized human intervention combined with costly pharmaceutical supplementation, making them unaffordable or inaccessible to most tobacco users. Thus, digital interventions offer a promising alternative to these traditional methods. However, the leading smartphone apps available in the market today have either not been studied in a clinical setting or are unable to match the smoking cessation success rates of their expensive offline counterparts. We would like to understand whether QuitSure, a novel smoking cessation app built by Rapidkart Online Private Limited, is able to bridge this efficacy gap and deliver affordable and effective smoking cessation at scale. Our objective was to do an initial exploration into the engagement, efficacy, and safety of QuitSure based on the self-reported experiences of its users. Outcomes measured were program completion, the effect of program completion on smoking behavior, including self-reported cessation outcomes, and negative health events from using the app. All QuitSure registered users who created their accounts on the QuitSure app between April 1, 2021, and February 28, 2022, were sent an anonymized web-based survey. The survey results were added to their engagement data on the app to evaluate the feasibility and efficacy of the app as a smoking cessation intervention. The data were analyzed using descriptive statistics (frequencies and percentages) and the χ2 test of independence. In total, 1299 users who had completed the QuitSure program submitted the survey and satisfied the inclusion criteria of the study. Of these, 1286 participants had completed the program more than 30 days before filling out the survey, and 1040 (80.1%, 95% CI 79.1%-82.6%) of them had maintained prolonged abstinence for at least 30 days after program completion. A majority of participants (770/891, 86.4%) who were still maintaining abstinence at the time of submitting the survey did not experience any severe nicotine withdrawal symptoms, while 41.9% (373/891) experienced no mild withdrawal symptoms either. Smoking quantity prior to completing the program significantly affected quit rates (P<.001), with heavy smokers (>20 cigarettes per day) having a lower 30-day prolonged abstinence rate (relative risk=0.91; 95% CI 90.0%-96.2%) compared to lighter smokers. No additional adverse events outside of known nicotine withdrawal symptoms were reported. The nature of web-based surveys and cohort selection allows for extensive unknown biases. However, the efficacy rates of survey respondents who completed the program were high and provide a case for further investigation in the form of randomized controlled trials on the QuitSure tobacco cessation program.

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

BackgroundBuprenorphine 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.MethodsWe 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.ResultsThere 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.ConclusionsWithdrawal 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.

Effectiveness of the QuitSure Smartphone App for Smoking Cessation: Findings of a Prospective Single Arm Trial.

Digital therapies, especially smartphone apps for active and continuous smoking cessation support, are strongly emerging as an alternative smoking cessation therapy. In the Indian context, there is a growing interest in the use of app-based smoking cessation programs; however, there is limited evidence regarding their effectiveness in achieving long-term continuous abstinence. This study aimed to evaluate the long-term abstinence effect (up to 30-d abstinence postprogram completion) of a smartphone app, QuitSure, for smoking cessation in active smokers from India. In this prospective single-arm study, participants who signed up for the QuitSure app were enrolled in this study. The primary end point was the prolonged abstinence (PA) rate from weeks 1 to 4 (day 7 to day 30). Furthermore, data for withdrawal symptoms, relapse reasons, and reasons for not continuing the program were also assessed. The quit rate was calculated considering only the participants who followed up and completed the survey sent to them (per protocol) at day 7 and at day 30, respectively. The PA rate at day 7 was found to be 64.5% (111/172; 95% CI 56% to 72%), and the PA rate at day 30 was found to be 55.8% (72/129; 95% CI 45% to 65%). Within the 7-day abstinence period, 60.4% (67/111) of the participants did not have any withdrawal symptoms. The most common mild withdrawal symptoms were mild sleep disturbance (21/111, 18.9%), mild digestive changes (19/111, 17.1%), and coughing (17/111, 15.3%). Severe withdrawal symptoms were rare, with only 5.4% (6/111) experiencing them. For those achieving 30-day postprogram abstinence, 85% (61/72) had no mild withdrawal symptoms, and 99% (71/72) had no severe withdrawal symptoms. Among successful quitters at day 7, a total of 72.1% (80/111) reported minimal to no cravings, which increased to 88% (63/72) at day 30. Furthermore, 78% (56/72) of those with PA at day 30 reported no change in weight or reduced weight. Among participants experiencing relapse, 48% (28/58) cited intense cravings, 28% (16/58) mentioned facing a tragedy, and 26% (15/58) reported relapsing due to alcohol consumption. The PA rates as a result of the QuitSure program were found to be better than those reported in the results of other smoking-cessation app programs' studies. The QuitSure app yields high PA rates and ameliorates symptoms associated with smoking cessation. In order to obtain conclusive evidence regarding the effectiveness and efficacy of the QuitSure program, future research should include appropriate control measures. Nevertheless, the QuitSure program can serve as a valuable adjunct to a conventional smoking cessation treatment program to aid sustained abstinence.

Knowing the Dose to Control the Dose: Optimizing Patient-Controlled Analgesia in Adults with Sickle Cell Disease (SCD)

Introduction: Acute painful episodes are the most common cause of hospitalization in SCD. Intravenous (IV) opioids are the analgesic of choice to treat pain requiring hospitalization in adults. On-demand IV opioid dosing can be either via a patient-controlled analgesia (PCA) pump or via intermittent nurse bolus. Advantages of PCA include better analgesia accessibility and relative independence from staff. However, significant variability exists in PCA management. A multicenter, randomized-controlled trial of PCA strategies in SCD was terminated early due to slow accrual, stemming from barriers such as suboptimal communication between inpatient teams. Additional limitations with PCA include technological limitations and incomplete charting through a manual process. We initiated a quality improvement project to understand patterns of PCA use in patients hospitalized for SCD pain crises at our institution. Methods: We performed a retrospective manual chart review on all adult patients diagnosed with SCD pain crises admitted to the University of Cincinnati Medical Center (UCMC) from October 1 through December 31, 2022. Inpatient data collected included reason for admission, length of stay, and documentation of inpatient opioid usage in daily clinical notes. Hospitalizations requiring intensive care admission for severe complications were excluded. Outpatient data collected included demographics and outpatient opioid prescriptions via the state prescription drug monitoring database. The study was approved by the UCMC IRB. Results: Fifteen patients were admitted to UCMC a total of 24 times for SCD pain crises during the 3-month period. The patients ranged in age from 21 years to 73 years (median age 33 years, interquartile range (IQR) 19.5 years) and the majority (11/15) were women. Disease-modifying therapies prescribed included hydroxyurea (8/15, 53%), chronic transfusions (2/15, 13%), chronic transfusions plus hydroxyurea (1/15), voxelotor (1/15), no disease-modifying therapy (2/15). Nine patients were prescribed daily outpatient opioids that included an oral long-acting opioid plus an oral short-acting opioid. Out of the 24 hospitalizations, 11 were for an uncomplicated pain crisis, 10 were complicated by mild acute chest syndrome (mild hypoxia and/or abnormal chest imaging), and 3 patients experienced other treatable complications (2 with Staphylococcus epidermidis bacteremia, 1 with deep venous thrombosis). Five patients were admitted two or more times. Two patients, admitted a total of 5 times, were maintained on nurse-administered IV bolus opioids during their admissions, in addition to oral opioids. The remainder of the patients were treated with a hydromorphone PCA pump with on-demand bolus dosing only, in addition to home long-acting oral opioids when applicable. Two patients were ultimately transitioned from PCA onto nurse-administered bolus IV opioids, due to failure to achieve adequate analgesia with PCA. In 9 out of the 19 admissions using a PCA, daily MME or the equivalent was charted in at least one progress note (47%). The median LOS in the subgroup in which PCA use was charted at least once was 7 (IQR 3.5) days. In the 10 admissions on a PCA in which daily MME was never charted (53%), the median LOS was 11 (IQR 6.25) days. Among patients not receiving outpatient opioids, daily MMEs from the PCA in the first few days of hospitalization (when recorded) ranged from 24 to 520 (median 178, IQR 241) MME. In patients who had daily chronic pain on outpatient opioid therapy, daily inpatient MME from PCA ranged from 360 to 1020 (median 545, IQR 418) MME. In patients with multiple admissions during the study period, the recorded daily opioid use was about two times that in the single admission group (median 673, IQR 500 MME in the multiple admissions group; vs median 329, IQR 351 MME in the single admission group). Conclusions: Our data suggest that length of stay is shortened by ~4 days when clinicians quantify daily opioid use for patients on PCA. In addition, patients with frequent admissions tend to have higher inpatient daily opioid use. This hints that readmission may be partly driven by mild withdrawal when on outpatient opioids at lower MME. A major barrier to data collection was inconsistent documentation of daily opioid use. The next step in our quality improvement project is an educational curriculum on inpatient opioid management for residents and hospitalists.

Alcohol use disorder treatment delivered outside hepatology clinic.

Alcohol use disorder treatment delivered outside hepatology clinic.

Adverse skin reactions to antiepileptic drugs - a review

Introduction and objective: Treatment with antiepileptic drugs (AEDs) is frequently used all around the world. Just like in the course of all the drugs administration, side effects may appear, including characteristic side effects presenting on the skin. The aim of the study was to analyse adverse skin reactions to antiepileptic drugs, focusing on their epidemiology, symptoms and treatment.&#x0D; Methods: Databases including PubMed and Google Scholar were browsed using keywords.&#x0D; Description of the state of knowledge: The majority of adverse skin reactions (ASRs) constitute mild rashes and urticaria, however in about 10% cases severe reactions may occur, which can be life-threatening. They include Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS), Stevens-Johnson syndrome (SJS), Toxic Epidermal Necrolysis (TEN), Serum Sickness and Serum Sickness - like Reactions and Drug Induced Vasculitis. In the course of TEN mortality rates are highest, however all reactions can be dangerous and treatment should be applied immediately. In mild and moderate cases drug withdrawal is usually sufficient, however more severe cases need to be treated with immunosuppressive agents.&#x0D; Summary: The awareness about possible adverse effects and their treatment is crucial as some can be life-threatening and immediate therapy increases the chance of recovery.

Low-dose Initiation of Buprenorphine in Hospitalized Patients Using Buccal Buprenorphine: A Case Series.

To describe a low-dose buprenorphine initiation strategy with buccal buprenorphine. This is a case series of hospitalized patients with opioid use disorder (OUD) and/or chronic pain who underwent low-dose buprenorphine initiation with buccal buprenorphine to sublingual buprenorphine. Results are descriptively reported. Forty-five patients underwent low-dose buprenorphine initiation from January 2020 to July 2021. Twenty-two (49%) patients had OUD only, 5 (11%) patients had chronic pain only, and 18 (40%) patients had both OUD and chronic pain. Thirty-six (80%) patients had documented history of heroin or non-prescribed fentanyl use before admission. Acute pain in 34 (76%) patients was the most commonly documented rationale for low-dose buprenorphine initiation. Methadone was the most common outpatient opioid utilized before admission (53%). The addiction medicine service consulted on 44 (98%) cases and median length of stay was approximately 2 weeks. Thirty-six (80%) patients completed the transition to sublingual buprenorphine with a median completion dose of 16 mg daily. Of the 24 patients (53%) with consistently documented Clinical Opiate Withdrawal Scale scores, no patients experienced severe opioid withdrawal. Fifteen (62.5%) experienced mild or moderate withdrawal and 9 (37.5%) experienced no withdrawal (Clinical Opiate Withdrawal Scale score <5) during the entire process. Continuity of postdischarge prescription refills ranged from 0 to 37 weeks and the median number of buprenorphine refills was 7 weeks. Low-dose buprenorphine initiation with buccal buprenorphine to sublingual buprenorphine was well tolerated and can be safely and effectively utilized for patients whose clinical scenario precludes traditional buprenorphine initiation strategies.

Disrupted diurnal oscillations of the gut microbiota in patients with alcohol dependence.

Patients with alcohol dependence (AD) can exhibit gut dysbacteria. Dysbacteria may co-occur with disruptions of circadian rhythmicity of the gut flora, which can aggravate AD. Herein, this study aimed to investigate diurnal oscillations of the gut microbiota in AD patients. Thirty-two patients with AD, based on the Diagnostic and Statistical Manual of Mental Disorders, 4th edition, and 20 healthy subjects were enrolled in this study. Demographic and clinical data were collected by self-report questionnaires. Fecal samples at 7:00 AM, 11:00 AM, 3:00 PM, and 7:00 PM were collected from each subject. 16S rDNA sequencing was conducted. Wilcoxon and Kruskal-Wallis tests were performed to characterize alterations and oscillations of the gut microbiota. We found that β-diversity of the gut microbiota in AD patients oscillated diurnally compared with healthy subjects (p = 0.01). Additionally, 0.66% of operational taxonomic units oscillated diurnally in AD patients versus 1.68% in healthy subjects. At different taxonomic levels, bacterial abundance oscillated diurnally in both groups, such as Pseudomonas and Prevotella pallens (all p < 0.05). β-diversity of the gut microbiota in AD patients with high daily alcohol consumption, high-level cravings, short AD durations, and mild withdrawal symptoms oscillated diurnally compared with other AD patients (all p < 0.05). The gut microbiota in AD patients exhibits disruptions of diurnal oscillation, which may provide novel insights into mechanisms of AD and the development of therapeutic strategies.

2019 Research Grant. Does opioid tapering prior to spinal fusion improve surgical outcomes: a randomized controlled trial

<h3>BACKGROUND CONTEXT</h3> Preoperative opioid use in spine patients is associated with adverse patient-reported outcomes, higher rates of perioperative complications, increased postoperative opioid dependence, and greater surgical costs. <h3>PURPOSE</h3> The purpose of this study is to determine whether a structured preoperative opioid tapering regimen can successfully reduce postoperative opioid use and improve outcomes in spinal fusion surgery. <h3>STUDY DESIGN/SETTING</h3> Single center RCT. <h3>PATIENT SAMPLE</h3> To date, 12 patients enrolled (5 control, 7 taper). <h3>OUTCOME MEASURES</h3> Milligram morphine equivalent (MME) opioid use; back and leg numeric pain rating scale (NPRS); PROMIS (depression, anxiety, fatigue, sleep, satisfaction, physical function, pain interference, pain behavior); other medication use; intra- and perioperative outcomes; complications; subjective opiate withdrawal scale (SOWS). <h3>METHODS</h3> Patients undergoing thoracolumbar, lumbar, or lumbosacral spinal fusion surgery and taking opioids daily for 4 weeks prior to the preoperative planning visit were eligible for inclusion (buprenorphine and long-acting formulations excluded). Consenting patients were randomized to undergo a 4-week tapering program (reduction of 10% per week for a total of 40% prior to surgery) or to the control group. Patients were guided through the tapering process via weekly phone calls. Control patients also received weekly phone calls with the same outcomes administered, with the exception of the SOWS. All patients were followed postoperatively with weekly phone calls for 6 weeks, and via their 3- and 6-month postoperative visits. A preliminary analysis of the data to date was performed through data visualization and univariate statistics (a=0.5, SAS v9.4). <h3>RESULTS</h3> Initially, this study was powered conservatively for 78 patients. The COVID pandemic resulted in significant study disruptions and enrollment challenges. Patients, many of whom are seeking surgery for poorly controlled pain, were wary of tapering their opiate use, with the top reasons for study refusal including: (1) pain not well controlled, unwilling to risk randomization, (2) pain well controlled, unwilling to risk randomization, (3) Insufficient time, (4) no response after initial contact, and (5) unresponsive to any contact. For the 12 patients enrolled to date [50% female, median age 68 (range 49–74)]. The breakdown of opioids taken was: hydrocodone/acetaminophen 5 (41%), oxycodone/acetaminophen 3 (25%), tramadol 3 (25%), and oxycodone 1 (8%). All but 2 (16%) of patients used additional pain medications, most commonly acetaminophen (50%) and gabapentin (42%). The median number of levels fused in both groups was 5 (range control: 2-5, range experimental: 2-11). There were no obvious differences in baseline demographics, surgical approach, or analgesia. Total in-hospital MME was a median of 365 (IQR 143-395) for the control group and 295 (IQR: 189-322) for the taper group (p = 0.625). Three (60%) of the control group and 1 (15%) of the taper group required a pain consult (p = 0.222). None of the control group and 4 (57%) of the taper group had perioperative complications (p = 0.081). Control and taper patients had similar baseline NPRS pain; however, the taper group had lower back pain during the taper period (median back pain 1.5 to 6 points lower; p <0.05 for taper weeks 1 & 3; p <0.10 for taper weeks 2 and 4). Postoperative pain did not differ between groups. Visually, trends in leg pain were similar, but the variability was larger. No differences were evident in the PROMIS CATs between groups. During the taper period, none of the tapering patients experienced more than mild withdrawal symptoms. <h3>CONCLUSIONS</h3> Patients are hesitant to participate in preoperative opiate tapering, and the COVID epidemic further exacerbated these anxieties. In those patients who did taper, there is some evidence towards reduced preoperative pain and potentially lower in-hospital MMEs. To date, no differences are evident in postoperative PROMs. Enrollment of additional patients is ongoing, as is the analysis of pre- and postoperative MMEs. <h3>FDA DEVICE/DRUG STATUS</h3> This abstract does not discuss or include any applicable devices or drugs.

Differential Experience of Interdose Withdrawal During Long-Term Opioid Therapy and its Association With Patient and Treatment Characteristics: A Latent Class Analysis in Chronic Pain Population

Opioid withdrawal is characterized by a set of physical and psychological symptoms that depend on both opioid and patient specific characteristics. The present study aims to identify different latent classes of chronic pain patients according to the type of opioid withdrawal symptoms experienced, and to analyze the relationships between the classes and demographic, opioid therapy, psychological and substance use variables. This cross-sectional descriptive study included 391 chronic pain patients on long-term opioid therapy. A Latent Class Analysis (LCA) identified 3 classes (BIC = 7051.89, entropy = .87, LRTs P < .01). The mild withdrawal class showed low probabilities of presenting physical and psychological symptoms, the moderate withdrawal class was characterized by experiencing psychological symptoms, and the severe withdrawal class stood out for high probabilities of presenting both types of symptoms. The classes differed from each other, with higher rates of moderate-severe POUD, opioid misuse, anxiety, depression, and greater pain intensity and interference in more severe withdrawal classes (P < .05). The multinomial logistic regression showed that moderate-severe POUD and anxiety were the strongest variables related to moderate (ORPOUD = 3.34, ORAnxiety = 2.58) and severe withdrawal classes (ORPOUD = 4.26, ORAnxiety = 5.15). Considering that POUD and anxiety were strongly related to a more severe withdrawal syndrome, the inclusion of psychological interventions in pain management seems critical in this population. PerspectiveAlthough interdose opioid withdrawal is common in chronic pain patients, this study shows 3 different patterns in its experience (mild, moderate, and severe withdrawal). A more severe withdrawal may result in reduced effectiveness of opioids in relieving pain and increased negative consequences, such as higher risk of POUD. Findings that could help improve chronic pain management.

Risk of developing drug abuse in administration of a new hexaazaisowurtzitane derivative-based analgesic (experimental study)

The aim of the study was to assess the probability of developing withdrawal syndrome caused by discontinuation of 5-day administration of thiowurtzine with naloxone challenge test in the experiment.Materials and methods. The test sample of the analgesic “Thiowurtzine, capsule 120 mg” served as the study object. The active pharmaceutical ingredient is an organic, low molecular weight compound 4-(3,4-dibromothiophene carbonyl)-2,6,8,12-tetraacetyl-2,4,6,8,10,12-hexaazatetracyclo [5,5,0,03,11,05,9]dodecane that was first synthesized according to computer modeling results at the IPCET SB RAS (Biysk).The likelihood of developing physical dependence was explored by per os administration of thiowurtzine and the reference drug tramadol twice a day for 5 days as follows: 1) at 9 a.m. – thiowurtzine 50 mg / kg and tramadol 10 mg / kg, at 3 p.m. – thiowurtzine 50 mg / kg and tramadol 10 mg / kg; 2) at 9 a.m. – thiowurtzine 50 mg / kg and tramadol 10 mg / kg, at 3 p.m. – thiowurtzine 75 mg / kg and tramadol 15 mg / kg; 3) at 9 a.m. – thiowurtzine 75 mg / kg and tramadol 15 mg / kg, at 3 p.m. – thiowurtzine 75 mg / kg and tramadol 15 mg / kg; 4) at 9 a.m. – thiowurtzine 100 mg / kg and tramadol 20 mg / kg, at 3 p.m. – thiowurtzine 100 mg / kg and tramadol 20 mg / kg; 5) at 9 a.m. – thiowurtzine 100 mg / kg and tramadol 20 mg / kg, at 3 p.m. – naloxone 10 mg / kg subcutaneously.In all the groups, the intensity of the withdrawal syndrome was studied by specific features in outbred male CD1 mice. During one hour following the naloxone injection, health of mice was assessed according to dominant abstinence components and recessive traits of mild withdrawal syndrome. Two hours after the naloxone injection, the number of mice with negative body weight gain was determined. 24 hours after discontinuation of test compound administration, the open-field test was used to determine the impact on animal behavioral patterns (horizontal and vertical motor and exploratory activity, emotionality and its vegetative manifestations). The hot plate test was carried out to measure the analgesic activity (55˚). The criterion of the withdrawal syndrome severity was a decrease in the number of jumping reactions, changes in the general condition of the animals, stimulation of motor activity, manifestations of hyperalgesia, and a decrease in body weight.Results. No dominant abstinence components and recessive signs of withdrawal syndrome were detected in animals from the thiowurtzine groups. The data obtained in the study (orientation and exploratory behavior, motor activity, emotionality and its vegetative manifestations, grooming, etc.) allow to conclude that thiowurtzine causes no physical dependence in animals after discontinuation of its 5-day administration with naloxone challenge test, as opposed to the reference drug naloxone. A positive disinhibition effect of this analgesic was revealed due to the activated orientation and exploratory behavior (stress caused by the new environment) in the conditions of the open-field test. The animals showed no manifestations of hyperalgesia in the hot plate test. The animals treated with thiowurtzine did not demonstrate any changes in the body weight.Conclusion. The obtained results prove that thiowurtzine is a non-narcotic analgesic. It evokes no side effects typical of opioid analgesics (tramadol), including development of physical dependence and withdrawal syndrome following naloxone challenge test. Previous in vivo and in silico studies (docking, molecular modeling, molecular dynamics simulation) on the multi-target mechanism of thiowurtzine explain the absence of its morphine-like effect by the fact that the major targets of the analgesic are TRPA1 receptors and voltage-gated Ca 2+ channels. With a high degree of probability, the conclusions made herein predict no drug abuse development when thiowurtzine is used in the clinical setting. Absence of ulcerotoxicity found earlier will enable to administer thiowurtzine in long-term cycles for chronic pain syndrome.

Weaning Dexmedetomidine in Non-ICU Areas: An Implementation Effort.

To develop and implement clinical practice guidelines for safely weaning dexmedetomidine infusions in non-ICU areas. Development, implementation, and analysis of effectiveness of clinical practice guidelines. Quaternary care academic free-standing pediatric hospital. Children, otherwise medically ready for transfer to non-ICU areas, who were undergoing a planned wean of a dexmedetomidine infusion. Subject matter experts developed evidence-based guidelines for weaning dexmedetomidine in patients whose critical phase of illness had resolved. Searches identified no prospective studies of dexmedetomidine weaning. We identified two retrospective reviews of withdrawal symptoms and one on the use of clonidine. There were case studies on withdrawal symptoms. Guidelines were piloted on a cohort of 24 patients while in the ICU. The guidelines were then implemented in non-ICU areas for patients undergoing dexmedetomidine weaning after ICU transfer. Over a 2-year period (October 1, 2018, to September 30, 2020), 63 patients (1 mo to 18 yr old) successfully weaned dexmedetomidine in non-ICU areas. The median time to discontinuation of dexmedetomidine after transfer to non-ICU areas was 5.8 days (interquartile range, 4.75-15 d). Fifty-eight percent (n = 41) of all patients were considered high risk for dexmedetomidine withdrawal based on the dose, duration of exposure, and the risk of experiencing physiologic detriment with more than mild withdrawal. Twenty-nine patients (46%) exhibited no signs or symptoms of withdrawal while weaning per guidelines. For those with signs and symptoms of withdrawal, the most common were tachycardia (n = 26, 40%), agitation (n = 9, 14%), and hypertension (n = 9, 11%). Weaning dexmedetomidine in non-ICU areas is feasible and can be accomplished safely even among pediatric patients at high risk for withdrawal using standardized weaning guidelines. At our institution, implementation was associated with reduced ICU length of stay for patients recovering from critical illness.

Assessment of Psychological Behaviour among Internet Users students in Secondary Schools at Mosul City

Backgrounds and Aims: The term "Internet user" refers to anybody who has a computer and can access the Internet from anywhere in the world. This research sought to examine the amount of internet usage among students by gender, sleep problems among students by gender, and aggressive behaviour among students by gender. To examine the extent to which pupils exhibit withdrawal symptoms based on their gender, and to evaluate the degree to which students exhibit violent behaviour based on their gender. Patients and Methods: A descriptive design was carried out from 15th, January 2021 through 29th, March 2021 to achieve the present study's objectives. The research participants were 100 pupils from Nineveh Education Directorate secondary schools, ranging in age from 13 to 17 years. The data collection period was from the 20th of January to the 1st of February 2021 in order to fulfil the present study's objectives. This scale is prepared to be applied by an interview with pupils Aggressive Behavior Scale, Internet Addiction Test, Social Withdrawal Scale to achieve the goals of the study, The validity of the scale, was done through a review of 10 experts of different specialties related to the field of the present study were chosen. Results: The findings revealed that most pupils had equal male and females pupils had mild use of the Internet, the majority of the similar male and females pupils had soft sleep disorders, excessive aggressive behavior is the highest percentage and frequency in females, outrageous aggressive behavior is the highest percentage and frequency in male, the male and females pupils had similar mild withdrawal symptom, the male more than female had excessive eating disorders. Conclusions: the equal male and females students had mild use of the Internet. The majority of similar male and females students had soft sleep disorders. Excessive aggressive behavior is the highest percentage and frequency in females. The male and females students had similar mild withdrawal symptoms—the male more than female had extreme eating disorders. Conclusion: assist students in expressing their problems, and understand their motivations for behaviors, and make them continue interaction with their communities. Integration care of students with excessive internet usage in all spectrums (psychiatry, healthy, socially, and educationally). Having instructors and parents utilise excessive amounts of the Internet to connect with children. Training teachers on the correct diagnosis of students with excessive usage of the Internet. Keywords: Psychological behaviour, Internet Users.