Withdrawal Scores Research Articles

Methadone-Buprenorphine Transfers Using Low Dosing of Buprenorphine: An Open-Label, Nonrandomized Clinical Trial.

To compare a low-dosing protocol to standard practice for methadone-buprenorphine transfers. We undertook a nonrandomized open-label clinical trial across 8 sites from NSW, Australia. Participants prescribed methadone wishing to transfer to buprenorphine could either choose or be randomized to a low-dose transfer or standard care transfer as per NSW health guidelines. The low-dose protocol started at 0.2 mg BD and increased to 16 mg on day 6, with flexible dosing thereafter. The primary outcome was continuation of buprenorphine 1 week post-transfer. Binary logistic regression was used to access the primary outcome with demographic differences between the groups included as covariates. There were 117 participants who commenced the study, 101 in the low-dose arm and 16 in standard care. Mean methadone dose was 82 mg in the low-dose arm and 46 mg in standard care. The primary outcome was met by 81 participants in the low-dose arm (80%) and 13 participants in standard care (81%). There was no significant between-arm difference in the odds of the primary outcome (OR = 2.22; 95% CI: 0.45-10.91; P = 0.327). Four participants (4%) in the low-dose arm experienced precipitated withdrawal against 1 (6%) in standard care. Higher methadone dose decreased the odds of successful transfer by 20% (OR = 0.8 per 10 mg methadone; 95% CI: 0.7-0.99; P = 0.04). Withdrawal scores between the 2 arms were similar. We were unable to detect a difference between low dosing and standard care for methadone to buprenorphine transfers. Increasing methadone dose was a predictor of success; setting (ambulatory or inpatient) was not.

Examining the Severity and Progression of Illicitly Manufactured Fentanyl Withdrawal: A Quasi-Experimental Comparison.

Illicitly manufactured fentanyl has largely replaced heroin throughout the United States. Characteristics of fentanyl-specific withdrawal are not well understood compared to traditional opioid withdrawal. This study examines opioid withdrawal severity among 2 cohorts of study participants who underwent identical morphine stabilization procedures before and after fentanyl was introduced to the local drug market. The Non-Fentanyl study (n = 103) included participants testing positive for non-fentanyl opioids, and the Fentanyl study (n = 30) included participants testing positive for fentanyl. Both studies completed a 7-day morphine stabilization protocol (30 mg subcutaneous, 4 times daily) and multiple daily self-report and observer-rated assessments of opioid withdrawal and vital signs. Two-way repeated-measures analyses of variance (ANOVAs) examined the effects of study, time, and study × time on daily peak ratings for each outcome. There were significant elevations in self-report and observer-rated withdrawal scores among the Fentanyl versus Non-Fentanyl study (study × time, P < 0.05) during stabilization days 2-5 and days 2-6, respectively. There was a higher rate of tachycardia among the Fentanyl group compared to the Non-Fentanyl study, and peak diastolic blood pressure was greater among the Fentanyl study compared to the Non-Fentanyl study. Individuals with fentanyl exposure were less stabilized by morphine and experienced more severe opioid withdrawal via several metrics compared to persons with non-fentanyl opioid exposure. Withdrawal also remained elevated for several days despite morphine initiation. Adjustments to existing treatment induction protocols may be needed given the permeation of fentanyl into the heroin supply.

A quality improvement project on implementing a standardized pain assessment and opioid stewardship guidance at a level IV NICU

Background Balancing between adequate analgesia and preventing the harmful side effects of opioids in the NICU is an important clinical conundrum. Lack of awareness among caregivers and guidance on pain management are the key limiting factors. By initiating this quality improvement (QI) project, we aimed to reduce the usage of opioids in a quaternary NICU care by 5% within 1 year. Methods A multidisciplinary team developed standardized guidance focusing on regular pain assessment, appropriate initiation, and weaning of opioids for infants undergoing surgical procedures and those requiring mechanical ventilation. The Plan, Do, Study, Act (PDSA) methodology was used for improvement, beginning with a survey and Pareto analysis to identify key drivers. Data were collected for the baseline period and after implementing the QI interventions. Results We demonstrated a significant decrease in the cumulative opioid use measured as morphine equivalent (mg/kg) from a mean of 2.7 to below 0.85 mg/kg, demonstrating a reduction of &gt;50%. There was no worsening in pain or opioid withdrawal scores within three and 5 days after weaning of opioids, a surrogate measure for appropriate weaning. Conclusion Implementation of standardized guidelines for initiating and weaning of opioids can reduce the overall opioid use and thus minimize opioid withdrawal in critically ill neonates.

Association of bone turnover markers and craving reduction in patients with alcohol use disorder during withdrawal: Exploring the role of bone-brain axis.

Alcohol use disorder (AUD) is associated with imbalanced bone turnover and psychological symptoms, but the relationship between bone and brain remains unclear. The study analyzed serum levels of a bone formation marker, procollagen type 1 N-terminal propeptide (P1NP), and bone resorption marker, C-terminal telopeptide of type I collagen (CTX-1), in AUD patients before and after 2 weeks of alcohol withdrawal and investigated their correlation with psychological symptoms. Ninety patients with AUD and 117 healthy controls were recruited. P1NP and CTX-1 levels were measured using Enzyme-Linked Immunosorbent Assay. The Penn Alcohol Craving Scale (PACS), Beck Depression Inventory (BDI), and Beck Anxiety Inventory (BAI) were assessed in the AUD group at baseline, week 1, and week 2 of withdrawal. Baseline CTX-1 levels, along with the CTX-1/P1NP and P1NP/CTX-1 ratio, were higher in the AUD group than controls. Over the 2-week withdrawal, PACS, BDI, and BAI scores demonstrated significant reductions. P1NP (p < 0.001) and P1NP/CTX-1 ratio increased (p < 0.001), while CTX-1/P1NP ratio decreased (p < 0.001), indicating a propensity toward bone formation. Univariate analysis revealed that reductions in PACS, BDI, and BAI scores during withdrawal correlated with increased P1NP levels and decreased CTX-1/P1NP ratios. However, multivariate analysis indicated that only PACS score reductions correlated with these changes. Bone metabolism shifted toward increased bone formation and decreased bone resorption during 2-week alcohol withdrawal. The correlation between improvements in bone turnover markers and reduction in craving scores during withdrawal supports the concept of the bone-brain axis.

Gabapentin for Delirium in Infants in the Neonatal Intensive Care Unit

OBJECTIVE A protocol was developed for neonatal intensive care unit (NICU) delirium: Step 1, gabapentin for pain or melatonin for sleep; Step 2, add on other Step 1 agent; Step 3, antipsychotics. The purpose of this study was to describe the utility and dosing of gabapentin for NICU delirium. METHODS Retrospective evaluation of NICU patients from January 1, 2021–December 31, 2022 who received &amp;gt;1 dose of gabapentin based on the delirium protocol. Data collection included demographics, gabapentin regimen, and concomitant sedatives and analgesics. The primary objective was to identify the number of patients receiving gabapentin for Step 1 or Step 2. Secondary objectives included identifying the number of patients requiring antipsychotics (Step 3), the gabapentin regimen, comparison of Échelle de Douleur et d'Inconfort du Nouveau-né (EDIN), Cornell Assessment of Pediatric Delirium (CAPD), and Withdrawal Assessment Tool-1 (WAT-1) scores 72 hours pre- and post-gabapentin initiation, and comparison of opioids, clonidine, and melatonin 24 hours pre- and 72 hours post-gabapentin initiation. Wilcoxon signed rank tests were employed with significance defined at p &amp;lt; 0.05. RESULTS Twenty-nine patients were studied. The majority (n = 22; 75.9%) received gabapentin for Step 1; no patients required Step 3. The median initial dose was 14.4 mg/kg/day divided every 8 hours. Twelve (41.4%) required increase to a median of 16.9 mg/kg/day. A significant decrease in EDIN and WAT-1 scores was noted, but there was no change in CAPD scores or opioid, clonidine, or melatonin doses pre- versus post-gabapentin. CONCLUSION The majority received gabapentin at a median dose of 14 mg/kg/day as Step 1 for delirium. Gabapentin was associated with a significant decrease in pain and withdrawal scores.

Comparative Efficacy of Lorazepam and Risperidone in Hospitalized Cannabis-induced Psychotic Disorder

Abstract Background: There is a lack of a standardized treatment protocol for cannabis-induced psychotic disorder (CIPD). Current practice involves using antipsychotics and benzodiazepines concurrently for treating CIPD. Aim: The index study aimed to assess and compare the efficacy of lorazepam against risperidone in patients with CIPD. Methods: Hospitalized patients with a diagnosis of CIPD according to the Diagnostic and Statistical Manual of Mental Disorders Fifth Edition were randomized to receive either lorazepam or risperidone orally. Positive and Negative Syndrome Scale (PANSS), Young Mania Rating Scale (YMRS), Cannabis Withdrawal Scale, and the Marijuana Craving Questionnaire were administered at baseline and daily to assess the improvement in psychopathology, withdrawal, and craving over a period of 10 days. Monitoring was also done for any adverse effects associated with treatment. Results: A total of 40 patients with a diagnosis of CIPD were included; 20 each in lorazepam and risperidone group. Both groups were comparable with respect to baseline PANSS (P = 0.13) and YMRS (P = 0.92) scores. The baseline withdrawal score was higher in the risperidone group (P = 0.03). There was a significant reduction in PANSS and YMRS scores in both groups by day 5 and day 10 (values of &lt;0.001). However, there was no significant difference between the two groups. The degree of improvement during the initial 5 days was significantly more (P ≤ 0.001) than that observed from day 5 to day 10 in both groups. Conclusion: There was no statistically significant difference between lorazepam and risperidone groups in terms of improvement in PANSS and YMRS scores. The use of antipsychotic did not have any additional benefit in CIPD and was rather associated with more adverse effects.

Comparing withdrawal- and anxiety-like behaviors following oral and subcutaneous oxycodone administration in C57BL/6 mice.

Excessive prescribing and misuse of prescription opioids, such as oxycodone, significantly contributed to the current opioid crisis. Although oxycodone is typically consumed orally by humans, parenteral routes of administration have primarily been used in preclinical models of oxycodone dependence. To address this issue, more recent studies have used oral self-administration procedures to study oxycodone seeking and withdrawal in rodents. Behavioral differences, however, following oral oxycodone intake versus parenteral oxycodone administration remain unclear. Thus, the goal of the current studies was to compare anxiety- and withdrawal-like behaviors using established opioid dependence models of either home cage oral intake of oxycodone (0.5 mg/ml) or repeated subcutaneous (s.c.) injections of oxycodone (10 mg/kg) in male and female mice. Here, mice received 10 days of oral or s.c. oxycodone administration, and following 72 h of forced abstinence, anxiety- and withdrawal-like behaviors were measured using elevated zero maze, open field, and naloxone-induced precipitated withdrawal procedures. Global withdrawal scores were increased to a similar degree following oral and s.c. oxycodone use, while both routes of oxycodone administration had minimal effects on anxiety-like behaviors. When examining individual withdrawal-like behaviors, mice receiving s.c. oxycodone exhibited more paw tremors and jumps during naloxone-induced precipitated withdrawal compared with oral oxycodone mice. These results indicate that both models of oxycodone administration are sufficient to elevate global withdrawal scores, but, when compared with oral consumption, s.c. oxycodone injections yielded more pronounced effects on some withdrawal-like behaviors.

Standard Versus Rapid Inpatient Methadone Titration for Pregnant Patients With Opioid Use Disorder: A Retrospective Cohort Study.

Our study evaluated if rapid inpatient titration of methadone for pregnant patients with opioid use disorder (OUD) improved outcomes without increasing the risk for overdose. This is a retrospective cohort study of pregnant patients admitted for inpatient methadone titration from January 2020 to June 2022. Outcomes were compared between standard versus rapid titration protocols. Standard titration involved an initial methadone dose with additional doses every 6 hours if clinical opiate withdrawal score (COWS) is >9. Rapid titration involved an initial methadone dose with additional doses every 4 hours if COWS is >9. The primary outcome was time required to achieve stable dose. Secondary outcomes included elopement prior to achieving stable dose, methadone-related readmission, opioid overdose, and final dose. There were 97 patients in the standard titration (STP) and 97 patients in the rapid titration (RTP) groups. Demographic characteristics and substance use history did not differ between the 2 groups. Time to stable dose did not differ between the 2 groups (RTP, 5.0 days ±4.0; STP, 4.0 days ±3.0; P = 0.08). Patients in the rapid titration group were less likely to elope from the hospital prior to stabilization (RTP 23.0% vs STP 37.9%, P = 0.03) and had fewer methadone-related readmissions ( P < 0.001). One patient (1.0%) in the RTP group required naloxone treatment while inpatient for concern for overdose, while none did in the STP group ( P = 0.32). There was no difference in median final stable dose between the 2 groups ( P = 0.07). Rapid titration of methadone for pregnant patients with OUD was associated with decreased medical elopement and methadone-related readmission, without increasing the risk for overdose.

Machine Learning-Driven Analysis of Individualized Treatment Effects Comparing Buprenorphine and Naltrexone in Opioid Use Disorder Relapse Prevention.

A trial comparing extended-release naltrexone and sublingual buprenorphine-naloxone demonstrated higher relapse rates in individuals randomized to extended-release naltrexone. The effectiveness of treatment might vary based on patient characteristics. We hypothesized that causal machine learning would identify individualized treatment effects for each medication. This is a secondary analysis of a multicenter randomized trial that compared the effectiveness of extended-release naltrexone versus buprenorphine-naloxone for preventing relapse of opioid misuse. Three machine learning models were derived using all trial participants with 50% randomly selected for training (n = 285) and the remaining 50% for validation. Individualized treatment effect was measured by the Qini value and c-for-benefit, with the absence of relapse denoting treatment success. Patients were grouped into quartiles by predicted individualized treatment effect to examine differences in characteristics and the observed treatment effects. The best-performing model had a Qini value of 4.45 (95% confidence interval, 1.02-7.83) and a c-for-benefit of 0.63 (95% confidence interval, 0.53-0.68). The quartile most likely to benefit from buprenorphine-naloxone had a 35% absolute benefit from this treatment, and at study entry, they had a high median opioid withdrawal score ( P < 0.001), used cocaine on more days over the prior 30 days than other quartiles ( P < 0.001), and had highest proportions with alcohol and cocaine use disorder ( P ≤ 0.02). Quartile 4 individuals were predicted to be most likely to benefit from extended-release naltrexone, with the greatest proportion having heroin drug preference ( P = 0.02) and all experiencing homelessness ( P < 0.001). Causal machine learning identified differing individualized treatment effects between medications based on characteristics associated with preventing relapse.

Rapid Initiation of Injection Naltrexone for Opioid Use Disorder

Injectable extended-release (XR)-naltrexone is an effective treatment option for opioid use disorder (OUD), but the need to withdraw patients from opioid treatment prior to initiation is a barrier to implementation. To compare the effectiveness of the standard procedure (SP) with the rapid procedure (RP) for XR-naltrexone initiation. The Surmounting Withdrawal to Initiate Fast Treatment with Naltrexone study was an optimized stepped-wedge cluster randomized trial conducted at 6 community-based inpatient addiction treatment units. Units using the SP were randomly assigned at 14-week intervals to implement the RP. Participants admitted with OUD received the procedure the unit was delivering at the time of their admission. Participant recruitment took place between March 16, 2021, and July 18, 2022. The last visit was September 21, 2022. Standard procedure, based on the XR-naltrexone package insert (approximately 5-day buprenorphine taper followed by a 7- to 10-day opioid-free period and RP, defined as 1 day of buprenorphine at minimum necessary dose, 1 opioid-free day, and ascending low doses of oral naltrexone and adjunctive medications (eg, clonidine, clonazepam, antiemetics) for opioid withdrawal. Receipt of XR-naltrexone injection prior to inpatient discharge (primary outcome). Secondary outcomes included opioid withdrawal scores and targeted safety events and serious adverse events. All analyses were intention-to-treat. A total of 415 participants with OUD were enrolled (mean [SD] age, 33.6 [8.48] years; 205 [49.4%] identified sex as male); 54 [13.0%] individuals identified as Black, 91 [21.9%] as Hispanic, 290 [69.9%] as White, and 22 [5.3%] as multiracial. Rates of successful initiation of XR-naltrexone among the RP group (141 of 225 [62.7%]) were noninferior to those of the SP group (68 of 190 [35.8%]) (odds ratio [OR], 3.60; 95% CI, 2.12-6.10). Withdrawal did not differ significantly between conditions (proportion of days with a moderate or greater maximum Clinical Opiate Withdrawal Scale score (>12) for RP vs SP: OR, 1.25; 95% CI, 0.62-2.50). Targeted safety events (RP: 12 [5.3%]; SP: 4 [2.1%]) and serious adverse events (RP: 15 [6.7%]; SP: 3 [1.6%]) were infrequent but occurred more often with RP than SP. In this trial, the RP of XR-naltrexone initiation was noninferior to the standard approach and saved time, although it required more intensive medical management and safety monitoring. The results of this trial suggest that rapid initiation could make XR-naltrexone a more viable treatment for patients with OUD. ClinicalTrials.gov Identifier: NCT04762537.

Development and Psychometric Evaluation of a Novel Measure of Nicotine E-cigarette Withdrawal for Use With Adolescents and Young Adults.

Nicotine withdrawal is a well-established construct that prompts continued nicotine product use and contributes to failed cessation efforts. Despite ongoing public health concerns about nicotine e-cigarette use in adolescents and young adults (AYAs), no psychometrically sound measure of nicotine e-cigarette withdrawal exists for this population. A mixed methods approach comprising a literature review to identify existing nicotine withdrawal items; subject matter expert feedback on existing items and novel item generation; cognitive interviews assessing the measure's instructions, items, and response options; and a large quantitative validation survey (N = 997) was employed to develop the novel retrospective measure of nicotine e-cigarette withdrawal. A 25-item solution comprising four subscales-negative affect, negative physical symptoms, craving, and appetite/food-and an overall withdrawal score was supported. Internal reliability was excellent (mean alpha = 0.91), and scalar measurement invariance was reached for all subgroups tested (eg, sex, age, exclusive e-cigarette use vs. dual tobacco product use, and daily vs. non-daily nicotine vaping). Overall withdrawal and its subscales evidenced concurrent validity with time to first vape in the morning, e-cigarette dependence, and previous vaping cessation attempts, although not each subscale was associated with each outcome. Importantly, cross-sectional incremental validity analyses indicated that retrospective withdrawal accounted for variance in each outcome above and beyond e-cigarette dependence. The novel retrospective AYA Nicotine E-cigarette Withdrawal Scale (AYA NEWS) evidenced strong psychometric properties for use in this population. Future research can determine whether the AYA NEWS can be used to assess acute e-cigarette nicotine withdrawal. While e-cigarette use remains the most prevalent form of nicotine product use among AYAs, there are limited options for psychometrically sound measures of e-cigarette-related constructs in this population. Withdrawal from nicotine is associated with failed cessation attempts and continued use of nicotine-containing products, making it a critical construct within tobacco-related research. This study outlines the development and preliminary psychometric evaluation of a novel, retrospective measure of nicotine e-cigarette withdrawal. Study findings support using the Adolescent and Young Adult Nicotine E-cigarette Withdrawal Scale (NEWS) to assess retrospective withdrawal from nicotine e-cigarettes in young people.

Identifying Challenges in Social Functioning Among Women with Schizophrenia

IntroductionSchizophrenia spectrum disorders profoundly impacts social functioning, affecting interpersonal relationships, work interactions, and self-care. This disorder often leads to cognitive, perceptual, motor, and emotional challenges that result in social withdrawal.ObjectivesThe aim of the study is to identify the specific challenges in social functioning faced by women diagnosed with schizophrenia spectrum disorders.MethodsWe conducted a descriptive cross-sectional study among stabilized female patients with schizophrenia or schizoaffective disorder, in the ‘B’ psychiatry department at Hedi Chaker University Hospital in Sfax, Tunisia, from May to June 2023. We collected both sociodemographic and clinical data from the participants. The Social Functioning Scale (SFS) and Global Functioning Scale (EGF) were used to assess social and global functioning, respectively.ResultsForty-one patients were included: 65.9% had schizophrenia, and 34.2% had schizoaffective disorder. The mean age was 49.19 years, ranging from 17 to 79 years. More than a third (39%) of our patients had significant impairment in global functioning (EGF&lt;50). The average total score on the social functioning scale was 13.65, with a range from 6.29 to 20.29. Additionally, 39% of our patients exhibited low social functioning, and 51.21% had a high withdrawal score. The most impacted domains were leisure (63.41%) and employment (60.97%), followed by interpersonal behavior (58.53%), prosocial activities (48.78%), independence competence (41.46%), and lastly, independence performance (36.85%).ConclusionsSocial skills training is crucial for enabling women with schizophrenia to function well in their environment.Disclosure of InterestNone Declared

The polymorphisms of candidate pharmacokinetic and pharmacodynamic genes and their pharmacogenetic impacts on the effectiveness of risperidone maintenance therapy among Saudi children with autism.

Antipsychotics, including risperidone (RIS), are frequently indicated for various autism spectrum disorder (ASD) manifestations; however, "actionable" PGx testing in psychiatry regarding antipsychotic dosing and selection has limited applications in routine clinical practice because of the lack of standard guidelines, mostly due to the inconsistency and scarcity of genetic variant data. The current study is aimed at examining the association of RIS effectiveness, according to ABC-CV and CGI indexes, with relevant pharmacokinetics (PK) and pharmacodynamics (PD) genes. Eighty-nine ASD children who received a consistent RIS-based regimen for at least 8weeks were included. The Axiom PharmacoFocus Array technique was employed to generate accurate star allele-predicted phenotypes of 3 PK genes (CYP3A4, CYP3A5, and CYP2D6). Genotype calls for 5 candidate PD receptor genes (DRD1, DRD2, DRD3, HTR2C, and HTR2A) were obtained and reported as wild type, heterozygous, or homozygous for 11 variants. Based on the ABC total score, 42 (47.2%) children were classified as responders, while 47 (52.8%) were classified as nonresponders. Multivariate logistic regression analyses, adjusted for nongenetic factors, suggested nonsignificant impacts of the star allele-predicted phenotypes of all 3 PK genes on improvement in ASD symptoms or CGI scores. However, significant positive or negative associations of certain PD variants involved in dopaminergic and serotonergic pathways were observed with specific ASD core and noncore symptom subdomains. Our significant polymorphism findings, mainly those in DRD2 (rs1800497, rs1799978, and rs2734841), HTR2C (rs3813929), and HTR2A (rs6311), were largely consistent with earlier findings (predictors of RIS effectiveness in adult schizophrenia patients), confirming their validity for identifying ASD children with a greater likelihood of core symptom improvement compared to noncarriers/wild types. Other novel findings of this study, such as significant improvements in DRD3 rs167771 carriers, particularly in ABC total and lethargy/social withdrawal scores, and DRD1 rs1875964 homozygotes and DRD2 rs1079598 wild types in stereotypic behavior, warrant further verification in biochemical and clinical studies to confirm their feasibility for inclusion in a PGx panel. In conclusion, we provide evidence of potential genetic markers involved in clinical response variability to RIS therapy in ASD children. However, replication in prospective samples with greater ethnic diversity and sample sizes is necessary.

Right frontal cingulate cortex mediates the effect of prenatal complications on youth internalizing behaviors

Prenatal and perinatal complications represent well-known risk factors for the future development of psychiatric disorders. Such influence might become manifested during childhood and adolescence, as key periods for brain and behavioral changes. Internalizing and externalizing behaviors in adolescence have been associated with the risk of psychiatric onset later in life. Both brain morphology and behavior seem to be affected by obstetric complications, but a clear link among these three aspects is missing. Here, we aimed at analyzing the association between prenatal and perinatal complications, behavioral issues, and brain volumes in a group of children and adolescents. Eighty-two children and adolescents with emotional-behavioral problems underwent clinical and 3 T brain magnetic resonance imaging (MRI) assessments. The former included information on behavior, through the Child Behavior Checklist/6-18 (CBCL/6-18), and on the occurrence of obstetric complications. The relationships between clinical and gray matter volume (GMV) measures were investigated through multiple generalized linear models and mediation models. We found a mutual link between prenatal complications, GMV alterations in the frontal gyrus, and withdrawn problems. Specifically, complications during pregnancy were associated with higher CBCL/6-18 withdrawn scores and GMV reductions in the right superior frontal gyrus and anterior cingulate cortex. Finally, a mediation effect of these GMV measures on the association between prenatal complications and the withdrawn dimension was identified. Our findings suggest a key role of obstetric complications in affecting brain structure and behavior. For the first time, a mediator role of frontal GMV in the relationship between prenatal complications and internalizing symptoms was suggested. Once replicated on independent cohorts, this evidence will have relevant implications for planning preventive interventions.

The Role of Twice-Daily N-acetylcysteine (NAC) 2400 mg in Smoking Cessation: A Randomized, Placebo-Controlled Trial in Indonesia.

Tobacco smoking remains a health concern, especially in developing countries. Nicotine is significantly linked to many cancers and even second-hand exposure. Hence, smoking can increase the risk of lung and heart disease.This makes quitting smoking important and challenging. Success tends to rise by achieving abstinence with assisted pharmacology. These treatments aim to reduce symptoms of nicotine withdrawal. This is a preclinical trial on glutamate modulator in N-acetylcysteine (NAC) as a new potential treatment for smoking cessation.It is based on the administration of NAC related to elevated levels of dopamine in the central nervous system to accomplish successful smoking cessation. This study evaluated the efficacy and tolerability of NAC for smoking cessation. The primary outcome was abstinence rate and the secondary outcomes of the study were to assess carbon monoxide exhalation value (COexh), the withdrawal symptoms, craving score, safety, and tolerability associated with the administration of NAC. This is a randomized clinical trial. Eligible smokers were treated with NAC 2400 mg twice daily (BID) or placebo to obtain a potential effective abstinence rate.Subjects recruited from the smoking cessation clinic were screened for eligibility and wererandomized to either the NAC or placebo group. The trial consisted of a four-week treatment phase and participants were evaluated each week with a brief counseling. Intention to treat data analysis was performed from 2018 to 2019. Smoking cessation status was verified by measuring the amount of carbon monoxide exhaled and by documenting their smoking habits.Adverse events (AEs) have also been observed on each visit. A total of 90male smokers with a mean (SD) age of 38.7 (11) years were randomized into two groups to receive NAC (n=45) and placebo (n=45). The primary outcome revealed that the abstinence rate was significantly higher for the NACgroup than the placebo group (37.7% vs 6.6%; p=0.02). These findings were supported by data comparison between the NAC group and placebo group of COexh (ppm)(9.59±7.4 vs 13,4±6.1; p=0.04) and cigarette consumption/week (10 vs 46; p <0.001), which were statistically significant. Comparison of withdrawal with the Minnesota Nicotine Withdrawal Score between theNACgroup and the placebo group showed lower values (8 (1-31) vs 11 (0-43); p=0.178), respectively, even though not statistically significant. Compared to the placebo group, the craving score (6 (2-29) vs 12 (6-31); p=0.04) in the NAC group was significantly lower. The most common adverse event was mild gastrointestinal effects (28.9%) and arthralgia (2.2%). No serious adverse events were detected. Despite a small sample size, the data demonstrate the potential benefits of NAC that may help elevate abstinence rates and promote successful smoking cessation pharmacotherapy. Comprehensive treatment combining pharmacologic therapy and counseling increases smoking cessation success rates. It is essential to conduct a randomized multicenter study with a large population to support a sustained abstinence rate using NAC.

Neonatal Abstinence Signs during Treatment: Trajectory, Resurgence and Heterogeneity.

Neonatal abstinence syndrome (NAS) presents with a varying severity of withdrawal signs and length of treatment (LOT). We examined the course and relevance of each of the NAS withdrawal signs during treatment in a sample of 182 infants with any prenatal opioid exposure, gestational age ≥ 35 weeks, without other medical conditions, and meeting the criteria for pharmacological treatment. Infants were monitored using the Finnegan Neonatal Abstinence Scoring Tool. Daily mean Finnegan scores were estimated using linear mixed models with random subject effects to account for repeated withdrawal scores from the same subject. Daily item prevalence was estimated using generalized estimating equations with a within-subject exchangeable correlation structure. The median LOT was 12.86 days. The prevalence of withdrawal signs decreased from day one to day three of treatment. However, certain central nervous system (CNS) and gastrointestinal (GI) signs showed sporadic increases in prevalence notable around two weeks of treatment, accounting for increases in Finnegan scores that guided pharmacotherapy. We question whether the resurgence of signs with a prolonged LOT is mainly a consequence of opioid tolerance or withdrawal. Monitoring CNS and GI signs throughout treatment is crucial. Future studies directed to better understand this clinical phenomenon may lead to the refining of NAS pharmacotherapy and perhaps the discovery of treatment alternatives.

Somatic and anxiety-like behaviors in male and female rats during withdrawal from the non-selective cannabinoid agonist WIN 55,212–2

Synthetic cannabinoids are associated with higher risk of dependence and more intense withdrawal symptoms than plant-derived Δ9-tetrahydrocannabinol (THC). Avoidance of withdrawal symptoms, including anxiogenic effects, can contribute to continued cannabinoid use. Adult male and female Long-Evans rats were given escalating doses of WIN 55,212–2 (WIN) via twice daily intrajugular infusions. Precipitated withdrawal was elicited with SR 141716 (rimonabant) 4 h after the final infusion. Global withdrawal scores (GWS) were compiled by summing z-scores of observed somatic behaviors over a 30-min period with locomotor activity simultaneously collected via beam breaks. Rimonabant precipitated withdrawal in female and male rats at 3 or 10 mg/kg, respectively, but the individual behaviors contributing to GWS were not identical. 3 mg/kg rimonabant did not impact locomotor behavior in females, but 10 mg/kg decreased locomotion in male controls. Spontaneous withdrawal observed between 6 and 96 h after the final infusion was quantifiable up to 24 h following WIN administration. Individual behaviors contributing to GWS varied by sex and time point. Males undergoing spontaneous withdrawal engaged in more locomotion than females undergoing withdrawal. Separate groups of rats were subjected to a battery of anxiety-like behavioral tests (elevated plus maze, open field test, and marble burying test) one or two weeks after WIN or vehicle infusions. At one week abstinence, sex-related effects were noted in marble burying and the open field test but were unrelated to drug treatment. At two weeks abstinence, females undergoing withdrawal spent more time grooming during marble burying and performed more marble manipulations than their male counterparts. WIN infusions did not impact estrous cycling, and GWS scores were not correlated with estrous at withdrawal. Collectively, these results show qualitative sex differences in behaviors contributing to the behavioral experience of cannabinoid withdrawal supporting clinical findings from THC.

Low dose lofexidine for medically directed outpatient opioid tapering in adults with chronic pain: a prospective case series

BackgroundIn adults with chronic pain, mild-to-moderate withdrawal symptoms during medically directed opioid tapering in the outpatient setting may not be accompanied by hypertension or tachycardia. This clinical scenario could limit the use of lofexidine at dosages reported in clinical trials of opioid withdrawal precipitated by abrupt opioid discontinuation. Thus, the primary aim of this prospective case series is to describe the use of low dose lofexidine for opioid withdrawal in patients with chronic pain undergoing medically directed opioid tapering in an outpatient setting.MethodsSix patients (white 5, Latino 1) admitted to an outpatient interdisciplinary pain rehabilitation program met inclusion and exclusion criteria. Patients self-selected to undergo medically directed opioid tapering, and the medication the patients were prescribed upon admission was used in the taper schedule. Upon initiation of the opioid taper, patients received 0.18 mg of lofexidine every 6 hours. ResultsFive of the six patients were women, and the median morphine milligram equivalents at baseline were 36.9. The median taper duration was 15 days, and the median duration of lofexidine administration was 14 days. Withdrawal scores were mild throughout the taper in four patients, and two patients with fibromyalgia experienced single episodes of moderately severe withdrawal symptoms at the median morphine milligram equivalent midpoint of the taper. No hypotension or sustained bradycardia were observed, and no adverse effects related to lofexidine were reported.ConclusionThe observations from this prospective case series suggest that low-dose lofexidine may be a feasible adjunct medication to attenuate withdrawal symptoms in adults with chronic pain undergoing outpatient opioid tapering.

Efficacy of tDCS on craving in patients of alcohol dependence syndrome: A single-blind, sham-controlled trial.

Craving is attributed as one of the main reasons for relapse in alcohol dependence syndrome. Neurostimulation techniques targeting craving in substance use disorders are being researched. Neuroimaging has shown dorsolateral prefrontal cortex (DLPFC) as one of the potential targets responsible for craving, with frontal dysfunction being quintessential in alcohol use disorder. Evidence suggests that stimulation of DLPFC with low-dose current can help in reducing craving. To study the effectiveness of transcranial direct current stimulation (tDCS) on craving in patients with alcohol dependence syndrome. We performed a single-blind, sham-controlled study involving 76 patients with alcohol dependence syndrome (according to ICD-10 DCR). Participants with Clinical Institute of Withdrawal Assessment in Alcohol Withdrawal (CIWA-Ar) scores less than 10, not on any anti-craving medications were included in the study. Patients were allocated to active and sham tDCS groups in a ratio of 1:1. Such that 38 patients received active, and 38 patients sham tDCS stimulations; with anode as right DLPFC and cathode as left DLPFC receiving 2 mA current (twice daily session, total of 10 sessions). The Alcohol Craving Questionnaire (ACQ-NOW) was administered to measure the severity of alcohol craving at baseline and after the last tDCS session. Our study showed a significant reduction in craving in the Post-tDCS, ACQ-NOW scores as compared to sham tDCS. There was a significant reduction in the compulsivity and emotionality domain of craving after tDCS. The effect size for treatment with time interaction was (0.58). tDCS was superior to sham in reducing caving in patients with alcohol dependence syndrome.

Serum Malondialdehyde Levels Decreased Along with the Alleviating Effects of Marrubium Parviflorum on Morphine Withdrawal Syndrome in Rats

As a major concern for the clinicians, better treatment of the patients hospitalized to quit opioid abuse has always been a target for the researchers working in this field. On the other hand, therapeutic potentials of medicinal plants are greatly becoming of interest to both researchers and consumers in recent years. Among the plants, we can mention those belonging to the genus Marrubium, which has been reported to exert many therapeutic outcomes. The aim of this research was to investigate the effect of Marrubium parviflorum on morphine withdrawal syndrome and the possible relationship with malondialdehyde (MDA), the indicator for lipid peroxidation which is elevated during the syndrome. To perform this study, 48 rats were divided into 6 groups as follows: 1) Saline-Saline 2) Saline-Morphine; 3, 4, 5) Different doses of the extract-Morphine (10, 20 and 40 mg.kg-1); 6) The most effective dose of the extract-Saline. In order to evaluate withdrawal syndrome, the increasing doses of morphine were injected subcutaneously for 9 days followed by a single dose of naloxone (4 mg.kg-1, i.p.). Then the withdrawal symptoms was evaluated and total withdrawal score (TWS) was calculated. On the other hand, in order to confirm the effectiveness biochemically and to investigate the possible relationship between the observed effects and lipid peroxidation, blood samples were collected for malondialdehyde (MDA) measurement. According to the data, administration of the extract (in two higher doses) alleviated the syndrome-related behavioral signs as well as MDA levels significantly. Altogether, based on the results, aerial parts of Marrubium parviflorum seem to be beneficial for coping better with morphine withdrawal syndrome through complex pathways such as suppressing lipid peroxidation, further preclinical and clinical studies are required in this regard though.