Sex Differences in the Development of an Opioid Addiction-Like Phenotype: A Focus on the Telescoping Effect.

Background: Women develop addiction and drug-related health consequences after fewer years of drug use than men; this accelerated time course, or telescoping effect, has been observed clinically for multiple drugs, including opioids. Preclinical studies indicate that this is a biologically based phenomenon; however, these studies have focused exclusively on cocaine, and none have considered health effects. Methods: In this study, we used a rat (Sprague Dawley) model to determine sex differences in the time course for the development of an opioid addiction-like phenotype, as defined by the development of physical dependence (withdrawal-induced weight loss) and an increase in motivation for fentanyl (under a progressive-ratio schedule). Effects were determined following either 10 days (optimized, experiment 1) or 3 days (threshold, experiment 2) of extended-access fentanyl self-administration (24 hours/day, fixed ratio 1, 2- to 5-minute trials/hour) or following short-access fentanyl self-administration (subthreshold, experiment 3; fixed ratio 1, up to 40 infusions/day). Opioid-related adverse health effects were also determined (experiment 4). Results: Motivation for fentanyl was similarly increased in males and females following 10 days of extended-access self-administration (experiment 1), was transiently increased in females, but not males, following 3 days of extended-access self-administration (experiment 2) and was not increased in either sex following short-access self-administration (experiment 3). Females developed fentanyl-associated adverse health effects more readily than males (experiment 4), with particularly robust differences during extended-access self-administration and withdrawal. Conclusions: As with findings in humans, female rats developed opioid addiction-like features and adverse health consequences more readily than male rats. These data provide support for a biologically based telescoping effect in females for opioids, particularly for opioid-related adverse health consequences.

In this issue, we explore how female rats develop signs of opioid addiction and related health issues faster than male rats, a phenomenon known as the telescoping effect. This study expands on previous research by using a rat model to assess addiction-like behaviors and health consequences following different withdrawal period and durations of fentanyl self-administration. The findings underline the biological underpinnings of sex differences in addiction trajectories, previously demonstrated in humans but not yet studied in opioids until now.

Quantitative Measurement of the Direct Public Health Impact of Medicines Withdrawals in Europe: Development of a Modelling Method and Proof-of-Concept Study to Estimate the Morbidity and Mortality Prevented by Regulatory Action.

PURPOSE: Removing medicines from market may benefit public health by preventing adverse drug reactions (ADRs), which should be quantified. This study's aim was to identify a model to quantify the impact of medicines' marketing authorisation (MA) withdrawal and revocation in terms of preventing morbidity and mortality. METHODS: MA withdrawals and revocations for safety reasons in France, Germany and/or the United Kingdom between July 2012 and December 2016 were identified for prescription medicines. Annual exposure was estimated for each medicine, using IQVIA Medical Research Data (IMRD)-France, IMRD-Germany and IMRD-UK primary care electronic health record databases. European Medicines Agency records provided reasons for regulatory action for each medicine. Absolute risks of ADRs which led to MA withdrawal were estimated for patients exposed to each medicine by systematic review of quantitative research. Public health impact, expressed as annual number of ADRs avoided, was estimated by modelling exposure and ADR risk. RESULTS: Four MA withdrawals and two revocations met study inclusion criteria. Each product's usage decreased following MA withdrawal or revocation. Absolute risk for ADRs was 0.1%-41.25%. To estimate impact of each withdrawal or revocation, its average annual exposure within each IMRD population was multiplied by the absolute risk to give the crude number of ADRs prevented annually due to regulatory action. CONCLUSIONS: This model quantifies the public health impact of MA withdrawal and revocation in terms of serious morbidity, resulting from eliminated or reduced usage of medicines. This method can be applied to products in other settings to quantify the impact of other pharmacovigilance actions.

A Rare Phenomenon, Recurrent Acute Dystonia after Withdrawal of 'Methylphenidate-immediate Release Form': A Pediatric Case with ADHD.

Drug-induced acute dystonia is usually associated with combination therapies of neuroleptics, but rarely with the withdrawal or rebound effect of various psychotrops. Very sparse reports have described acute dystonia as a methylphenidate withdrawal (rebound effect), particularly in combination modalities. However, there is no case report or research regarding acute dystonia related to the withdrawal of the short-acting methylphenidate-immediate release form (MPH-IR) in the case of monotherapy of MPH-IR or a combination with guanfacine. Herein, a pediatric case of recurrent acute dystonia with two separate phenomena, locating orolingual and oromandibular/lower extremities, is presented as a withdrawal adverse reaction occurring after abrupt discontinuation of MPH-IR when under a combination therapy with guanfacine. Various options such as anticholinergic agents, re-administrating MPH, or turning to monotherapy from combination modalities, can be suggested in treatment, as well as only hydration may also have the benefit of resolving the symptoms, as in the current case. Practitioners should be aware of all possible adverse effects of MPH, even the rebound effect of short-acting forms.

Withdrawal interference scale: a novel measure of withdrawal-related life disruption in opioid use disorder and alcohol use disorder.

Background: Hyperkatifeia describes amplified emotional and motivational withdrawal due to addiction-related sensitization of brain-stress-systems. Hyperkatifeia has been proposed as a target for addiction treatment development. However, translation of basic research in this area will require new tools designed to measure hyperkatifeia and related phenomena outside of laboratory settings.Objectives: We define a novel concept, withdrawal interference, and introduce a new tool - the Withdrawal Interference Scale (WIS) - which measures the impact of withdrawal on daily life among individuals with OUD or AUD.Methods: Described are the combined results of three separate cross-sectional studies. The structural validity, convergent validity, construct validity, trans-diagnostic (AUD/OUD) configural, metric, and scalar invariance, internal consistency, and composite reliability of WIS was tested among three independent samples of 1) treatment-seeking adults with OUD (n = 132), 2) treatment-seeking adults with AUD (n = 123), and 3) non-treatment-seeking adults with OUD (n = 140). Males numbered 218 and females were 163.Results: WIS exhibited structural validity (1 factor), convergent validity (average variance extracted .670-.676), construct validity, trans-diagnostic configural (χ2/df = 2.10), metric (Δχ2 = 5.70, p = .681), and scalar invariance (Δχ2 = 12.34, p = .338), internal consistency (α .882-928), and composite reliability (.924-.925).Conclusion: These results suggest WIS is a valid and reliable instrument for measuring withdrawal-related life disruption in AUD and OUD. Further, given our findings of transdiagnostic measurement invariance, WIS scores of individuals with AUD and OUD can be meaningfully compared in future statistical analyses.

Withdrawal of Inhaled Corticosteroids from Patients with COPD; Effect on Exacerbation Frequency and Lung Function: A Systematic Review.

Background: Inhaled corticosteroid (ICS) therapy has been demonstrated to reduce the risk of COPD exacerbations. It should only be prescribed to COPD patients who are not adequately controlled by dual long-acting bronchodilator therapy and who have ≥2 exacerbations per year and a blood eosinophil count ≥300cells/µL. ICS therapy is widely prescribed outside guidelines to COPD patients, making ICS withdrawal an important consideration. This systematic review aims to provide an up-to-date analysis of the effect of ICS withdrawal on exacerbation frequency, change in lung function (FEV1) and to determine the proportion of COPD patients who resume ICS therapy following withdrawal. Methods: Randomised controlled trials (RCTs) and observational studies which compared ICS withdrawal with ICS continuation treatment were included. Cochrane Central, Web of Science, CINHAL, Embase and OVID Medline were searched. Risk of bias was assessed using the Cochrane RoB2 tool and the Newcastle-Ottawa Scale. Quality assessment of RCTs was conducted using GRADE. Meta-analysis of post-hoc analyses of RCTs of ICS withdrawal, stratified by blood eosinophil count (BEC), was undertaken. Results: Ten RCTs (6642 patients randomised) and 6 observational studies (160,029 patients) were included in the results. When ICS was withdrawn and long-acting bronchodilator therapy was maintained, there was no consistent difference in exacerbation frequency or lung function change between the ICS withdrawal and continuation trial arms. The evidence for these effects was of moderate quality. There was insufficient evidence to draw a firm conclusion on the proportion of patients who resumed ICS therapy following withdrawal (estimated range 12-93% of the participants). Discussion: Withdrawal of ICS therapy from patients with COPD is safe and feasible but should be accompanied by maintenance of bronchodilation therapy for optimal outcomes.

Residue, distribution and depletion of fluralaner in egg following a single intravenous and transdermal administration in healthy shaver hens: fluralaner residue in egg.

The demand for the use of fluralaner in an extra label manner is increasing due to lack of efficacious treatment to combat mites and bed bugs in the poultry industry in the United States. Fluralaner residue data in eggs is lacking and residues might cause risks to human health. The present study aimed to determine the depletion profiles of fluralaner in eggs and estimate the drug withdrawal interval in whole eggs by adopting the US Food and Drug administration tolerance limit method with single intravenous (0.5 mg/kg) or transdermal administration (average 58.7 mg/kg) in healthy shaver hens. Hens were treated intravenously or trans-dermally with fluralaner. The eggs were collected daily for 28 d for intravenous treated and for 40 d from the transdermal route group. Fluralaner concentrations in yolk and albumen were determined by mass spectrometry. The greater percentage of fluralaner was observed in yolk when compared to the albumen for both administration routes. Noncompartmental analysis was used to calculate the pharmacokinetic parameters in yolk, albumen and whole egg. The longest apparent half-life confirmed in yolk was 3.7 d for intravenous and 14.3 d for the transdermal route. The withdrawal intervals in whole egg for fluralaner following the intravenous and transdermal administration were 7 d and 81 d, respectively, with maximum residue limits (1.3 µg/g) at 13 d and 171 d, respectively, based on the limit of quantification (0.4 µg/g) from the analytical assay reported by EMA and APVMA.

Deprescribing: An umbrella review.

This umbrella review examined systematic reviews of deprescribing studies by characteristics of intervention, population, medicine, and setting. Clinical and humanistic outcomes, barriers and facilitators, and tools for deprescribing are presented. The Medline database was used. The search was limited to systematic reviews and meta-analyses published in English up to April 2022. Reviews reporting deprescribing were included, while those where depre-scribing was not planned and supervised by a healthcare professional were excluded. A total of 94 systematic reviews (23 meta--analyses) were included. Most explored clinical or humanistic outcomes (70/94, 74 %); less explored attitudes, facilitators, or barriers to deprescribing (17/94, 18 %); few focused on tools (8/94, 8.5 %). Reviews assessing clinical or humanistic outcomes were divided into two groups: reviews with deprescribing intervention trials (39/70, 56 %; 16 reviewing specific deprescribing interventions and 23 broad medication optimisation interventions), and reviews with medication cessation trials (31/70, 44 %). Deprescribing was feasible and resulted in a reduction of inappropriate medications in reviews with deprescribing intervention trials. Complex broad medication optimisation interventions were shown to reduce hospitalisation, falls, and mortality rates. In reviews of medication cessation trials, a higher frequency of adverse drug withdrawal events underscores the importance of prioritizing patient safety and exercising caution when stopping medicines, particularly in patients with clear and appropriate indications.

Quantitative Measurement of Serum HBcrAg Can Be Used to Assess the Feasibility of Safe Discontinuation of Antiviral Therapy for Chronic Hepatitis B.

Hepatitis B virus (HBV) infection is a serious global health problem, and chronic HBV infection significantly increases the risk of liver fibrosis, cirrhosis, and even hepatocellular carcinoma in patients. Current first-line therapeutics such as nucleos(t)ide analogues and interferons are unable to completely clear cccDNA, so the vast majority of patients need to take long-term or even lifelong medication. However, long-term virological and biochemical responses can be achieved in some patients after drug withdrawal. Successfully screening these patients with drug withdrawal advantages is difficult. Hepatitis-B-core-related antigen (HBcrAg) is a new HBV serological marker that which can reflect the level and transcription activity of cccDNA in hepatocytes. Therefore, HBcrAg has potential value in guiding patients in drug withdrawal. This review summarizes previous reports on HBcrAg and evaluates the application value of HBcrAg in safe drug discontinuation.

Punitive legal responses to prenatal drug use in the United States: A survey of state policies and systematic review of their public health impacts.

BACKGROUND: Punitive legal responses to prenatal drug use may be associated with unintended adverse health consequences. However, in a rapidly shifting policy climate, current information has not been summarized. We conducted a survey of U.S. state policies that utilize criminal or civil legal system penalties to address prenatal drug use. We then systematically identified empirical studies evaluating these policies and summarized their potential public health impacts. METHODS: Using existing databases and original statutory research, we surveyed current U.S. state-level prenatal drug use policies authorizing explicit criminalization, involuntary commitment, civil child abuse substantiation, and parental rights termination. Next, we systematically identified quantitative associations between these policies and health outcomes, restricting to U.S.-based peer-reviewed research, published January 2000-December 2022. Results described study characteristics and synthesized the evidence on health-related harms and benefits associated with punitive policies. Validity threats were described narratively. RESULTS: By 2022, two states had adopted policies explicitly authorizing criminal prosecution, and five states allowed pregnancy-specific and drug use-related involuntary civil commitment. Prenatal drug use was grounds for substantiating civil child abuse and terminating parental rights in 22 and five states, respectively. Of the 16 review-identified articles, most evaluated associations between punitive policies generally (k = 12), or civil child abuse policies specifically (k = 2), and multiple outcomes, including drug treatment utilization (k = 6), maltreatment reporting and foster care entry (k = 5), neonatal drug withdrawal syndrome (NDWS, k = 4) and other pregnancy and birth-related outcomes (k = 3). Most included studies reported null associations or suggested increases in adverse outcome following punitive policy adoption. CONCLUSIONS: Nearly half of U.S. states have adopted policies that respond to prenatal drug use with legal system penalties. While additional research is needed to clarify whether such approaches engender overt health harms, current evidence indicates that punitive policies are not associated with public health benefits, and therefore constitute ineffective policy.

Tocilizumab discontinuation after remission achievement in patients with adult-onset Still's disease.

OBJECTIVES: Tocilizumab, an IL-6 inhibitor, has been proven effective in patients with adult-onset Still's disease (AOSD). This study aimed to clarify whether tocilizumab can be discontinued after achieving remission and to identify factors relevant to its successful discontinuation. METHODS: Consecutive patients with AOSD diagnosed according to Yamaguchi's criteria from April 2012 to July 2022, who were treated with tocilizumab, were retrospectively reviewed. RESULTS: Forty-eight patients with AOSD treated with intravenous tocilizumab, with sufficient information, were included. Thirty-eight patients (79.2%) achieved remission after 6 months of tocilizumab treatment, 12 of whom discontinued tocilizumab during remission. Within 1 year after tocilizumab discontinuation, six patients (50.0%) recurred at a mean of 5.5 months, while the other six (50.0%) remained in remission. Between the non-recurrence and recurrence groups, no difference was found in disease activity at tocilizumab discontinuation (systemic feature score, p = 0.24; ferritin, p = 0.46). While the duration of tocilizumab use was not different (p = 0.32), the interval of tocilizumab administration at tocilizumab discontinuation in the recurrence group was 21 (14-35) days, which tended to be shorter than 35 (28-53) days in the non-recurrence group (p = 0.08). Patients with prednisolone dose < 7 mg/day at last tocilizumab treatment had fewer recurrences than those without (p = 0.001). After recurrence, tocilizumab was resumed in half of the patients, resulting in successful disease control. CONCLUSIONS: The recurrence rate after tocilizumab discontinuation was 50% in 1 year. Patients who remained in remission with a longer interval of tocilizumab administration and lower prednisolone dose were likely to succeed in the withdrawal of tocilizumab.

Withdrawal catastrophizing scale: initial psychometric properties and implications for the study of opioid use disorder and hyperkatifeia.

Background: Discovery of modifiable factors influencing subjective withdrawal experience might advance opioid use disorder (OUD) research and precision treatment. This study explores one factor - withdrawal catastrophizing - a negative cognitive and emotional orientation toward withdrawal characterized by excessive fear, worry or inability to divert attention from withdrawal symptoms.Objectives: We define a novel concept - withdrawal catastrophizing - and present an initial evaluation of the Withdrawal Catastrophizing Scale (WCS).Methods: Prospective observational study (n = 122, 48.7% women). Factor structure (exploratory factor analysis) and internal consistency (Cronbach's α) were assessed. Predictive validity was tested via correlation between WCS and next-day subjective opiate withdrawal scale (SOWS) severity. The clinical salience of WCS was evaluated by correlation between WCS and withdrawal-motivated behaviors including risk taking, OUD maintenance, OUD treatment delay, history of leaving the hospital against medical advice and buprenorphine-precipitated withdrawal.Results: WCS was found to have a two-factor structure (distortion and despair), strong internal consistency (α = .901), and predictive validity - Greater withdrawal catastrophizing was associated with next-day SOWS (rs (99) = 0.237, p = .017). Withdrawal catastrophizing was also correlated with risk-taking behavior to relieve withdrawal (rs (119) = 0.357, p < .001); withdrawal-motivated OUD treatment avoidance (rs (119) = 0.421, p < .001), history of leaving the hospital against medical advice (rs (119) = 0.373, p < .001) and buprenorphine-precipitated withdrawal (rs (119) = 0.369, p < .001).Conclusion: This study provides first evidence of withdrawal catastrophizing as a clinically important phenomenon with implications for the future study and treatment of OUD.

Withdrawal syndrome after antipsychotics discontinuation: an analysis of the WHO database of spontaneous reports (Vigibase) between 2000 and 2022.

RATIONALE: Withdrawal syndrome (WDS) has been described after discontinuation of antipsychotics. WDS could be the consequence of an over-activation of the dopaminergic pathway. Antipsychotics with a higher affinity for dopamine D2 receptors could be associated with a higher risk of WDS. This study aims to address this statement and evaluate the risk difference for withdrawal syndrome between antipsychotics based on pharmacovigilance data. METHODS: We collected individual reports registered in Vigibase® between 01/01/2000 and 31/12/2022 of patients treated with antipsychotics and who had presented WDS. A disproportionality analysis was performed to evaluate the risk of reporting WDS with each antipsychotic compared to all other antipsychotics. We performed a correlation analysis to assess the correlation between the risk of reporting WDS for each antipsychotic in relation with their pKi for D2 and 5HT2A receptors. RESULTS: The most frequent psychiatric withdrawal symptoms after antipsychotic discontinuation were insomnia, anxiety and depression. Tremor, headache and dizziness were among the most frequently reported neurologic withdrawal symptoms. Tiotixene had the highest risk of reporting WDS (ROR 7.08; 95%CI 3.49 - 14.35) followed by pimozide (ROR 4.35; 95%CI 1.93 - 9.77), quetiapine (ROR 4.24; 95%CI 3.87 - 4.64), thioridazine (ROR 4.17; 95%CI 2.50-6.98) and ziprasidone (ROR 2.98; 95%CI 2.41-3.67). We found a poor correlation between D2/5HT2A binding affinity and the risk of reporting withdrawal syndrome (R2 = 0,094). CONCLUSION: Our results suggest that there might be a risk difference for WDS between antipsychotics. Tiotixene, pimozide and quetiapine were associated with a higher risk of reporting a WDS whereas this risk was lower with chlorpromazine, clozapine and fluphenazine. We could not address the issue of withdrawal psychosis, withdrawal dyskinesia, rebound psychosis or supersensitivity psychosis due to the lack of specific WHO medDRA coded terms to identify potential cases.

Postoperative interictal epileptiform discharges predict seizure recurrence after antiepileptic drug withdrawal regardless of concordance with surgical site.

Objective: The study aimed to explore the association between the site of interictal epileptic discharges (IEDs) on postoperative electroencephalogram (EEG) and seizure recurrence after antiepileptic drug (AED) withdrawal. The study hypothesizes that the concordance of IED sites with surgical sites indicates incomplete resection of epileptic focus, while non-concordance of IED sites with surgical sites indicates postoperative changes or cortical stimulation. The former has a higher risk of seizure recurrence. Methods: We retrospectively analyzed the postoperative EEG pattern of 182 consecutive children who underwent resection surgery. To identify the risk factors for seizure recurrence, we compared the attributes of seizure recurred and seizure-free groups by univariate and multivariate analyses. AED tapering was standardized, involving a 25% reduction in the dose of a single type of AED every 2 weeks, independent of the presurgical AED load. Results: We attempted AED withdrawal in 116 (63.7%) children. Twenty-eight (24.1%) children experienced seizure recurrence during or after AED withdrawal. A greater number of AEDs used at the time of surgery (p=0.005), incomplete resection (p=0.001), and presence of IED on postoperative EEG (p=0.011) are predictors of seizure recurrence. The completeness of resection and seizure recurrence after AED withdrawal were related to the presence of IED on the EEG, but not to the concordance of IED with surgical sites. Conclusion: For children with abnormal EEG, the decision to discontinue AED should be made more cautiously, regardless of the relative location of the discharge site and the surgical site.

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.

Microglia-mediated calcium-permeable AMPAR accumulation in the nucleus accumbens drives hyperlocomotion during cocaine withdrawal.

During withdrawal from cocaine, calcium permeable-AMPA receptors (CP-AMPAR) progressively accumulate in nucleus accumbens (NAc) synapses, a phenomenon linked to behavioral sensitization and drug-seeking. Recently, it has been suggested that neuroimmune alterations might promote aberrant changes in synaptic plasticity, thus contributing to substance abuse-related behaviors. Here, we investigated the role of microglia in NAc neuroadaptations after withdrawal from cocaine-induced conditioned place preference (CPP). We depleted microglia using PLX5622-supplemented diet during cocaine withdrawal, and after the place preference test, we measured dendritic spine density and the presence of CP-AMPAR in the NAc shell. Microglia depletion prevented cocaine-induced changes in dendritic spines and CP-AMPAR accumulation. Furthermore, microglia depletion prevented conditioned hyperlocomotion without affecting drug-context associative memory. Microglia displayed fewer number of branches, resulting in a reduced arborization area and microglia control domain at late withdrawal. Our results suggest that microglia are necessary for the synaptic adaptations in NAc synapses during cocaine withdrawal and therefore represent a promising therapeutic target for relapse prevention.

Your Heart Function Has Normalized-What Next After TRED-HF?

PURPOSE OF REVIEW: With the widespread implementation of contemporary disease-modifying heart failure therapy, the rates of normalization of ejection fraction are continuously increasing. The TRED-HF trial confirmed that heart failure remission rather than complete recovery is typical in patients with dilated cardiomyopathy who respond to therapy. The present review outlines key points related to the management and knowledge gaps of this growing patient group, focusing on patients with non-ischaemic dilated cardiomyopathy. RECENT FINDINGS: There is substantial heterogeneity among patients with normalized ejection fraction. The specific etiology is likely to affect the outcome, although a multiple-hit phenotype is frequent and may not be identified without comprehensive characterization. A monogenic or polygenic genetic susceptibility is common. Ongoing pathophysiological processes may be unraveled with advanced cardiac imaging, biomarkers, multi-omics, and machine learning technologies. There are limited studies that have investigated the withdrawal of specific heart failure therapies in these patients. Diuretics may be safely withdrawn if there is no evidence of congestion, while continued therapy with at least some disease-modifying therapy is likely to be required to reduce myocardial workload and sustain remission for the vast majority. Understanding the underlying disease mechanisms of patients with normalized ejection fraction is crucial in identifying markers of myocardial relapse and guiding individualized therapy in the future. Ongoing clinical trials should inform personalized approaches to therapy.

Treatment of Opioid Withdrawal Syndrome Triggered by Oxycodone/Naloxone with Dexmedetomidine.

The combination of oxycodone and naloxone is useful for cancer pain management. Naloxone, as a pure opioid antagonist, cannot be used simultaneously with opioids. However, owing to its low bioavailability, it can be used in an oral composite formulation. We present the case of a 55-year-old man with gastric cancer who experienced severe opioid withdrawal syndrome (OWS) triggered by oxycodone/naloxone that was successfully managed with dexmedetomidine. He had been in a stable condition on intravenous morphine to alleviate cancer pain. Intravenous morphine was switched to oral oxycodone/naloxone for discharge from the hospital. The patient suddenly developed restlessness, heartburn, and violent behavior 30 minutes after taking oxycodone/naloxone. We attempted sedation with midazolam and propofol, but paradoxical agitation and desaturation occurred. Next, we tried dexmedetomidine and the patient showed a decreased heart rate and reduced agitation. The patient was eventually stabilized by increasing the dose of dexmedetomidine. This report informs clinicians of the possibility of OWS when switching from opioids to oxycodone/naloxone, which can be overcome with the appropriate use of sedatives and dexmedetomidine depending on the patient's condition.

Targeting Opioid Receptors in Addiction and Drug Withdrawal: Where Are We Going?

This review article offers an outlook on the use of opioids as therapeutics for treating several diseases, including cancer and non-cancer pain, and focuses the analysis on the opportunity to target opioid receptors for treating opioid use disorder (OUD), drug withdrawal, and addiction. Unfortunately, as has been well established, the use of opioids presents a plethora of side effects, such as tolerance and physical and physiological dependence. Accordingly, considering the great pharmacological potential in targeting opioid receptors, the identification of opioid receptor ligands devoid of most of the adverse effects exhibited by current therapeutic agents is highly necessary. To this end, herein, we analyze some interesting molecules that could potentially be useful for treating OUD, with an in-depth analysis regarding in vivo studies and clinical trials.

Age-dependent memory impairment induced by co-exposure to nicotine and a synthetic cannabinoid in mice.

Co-use of marijuana and tobacco products is the second most common drug combination among adolescents. Nicotine (NIC) and cannabinoid use during adolescence induce similar detrimental changes, raising the hypothesis that simultaneous exposure could result in even more severe outcomes. Thus, we investigated whether the co-exposure to NIC and the synthetic cannabinoid WIN 55,212-2 (WIN) in adolescent mice causes behavioral outcomes different from those observed after exposure to a single drug. Male Swiss mice were exposed twice daily to NIC, WIN, or NIC + WIN during adolescence (PND28-47) or adulthood (PND70-89). Drug combination led to a greater reduction in weight gain in adolescent mice, while NIC-induced weight loss was observed in adults. During administration, NIC provoked hypothermia, and WIN produced hyperlocomotion in adolescent and adult mice. Animals exposed to NIC + WIN presented a profile of changes similar to those exposed to NIC. After drug exposure, changes in locomotion, thigmotaxis, social preference, prepulse inhibition, and working and recognition memory were evaluated. Adolescent but not adult mice exposed to NIC showed withdrawal-related hyperlocomotion unaffected by WIN co-administration. An age-specific impairment in object recognition memory was induced only by drug co-exposure during adolescence, which resolved spontaneously before reaching early adulthood. A transient decrease in hippocampal α7 nAChR subunit and CB1 receptor mRNA levels was induced by NIC exposure, which may be involved but is not enough to explain the memory impairment. Our work confirms the potential of NIC and cannabinoids association to aggravate some of the individual drug effects during critical neurodevelopmental periods.

Pattern of Inpatient Consultation-liaison Psychiatry Utility in a Tertiary Care Hospital.

Background: Consultation-liaison psychiatry (C-LP) is an interface between physical and psychological health where the psychiatrists become a part of the medical team for a holistic approach in the treatment of the patient. Aims: Our study aimed to see the pattern and utility of C-LP services among inpatient referrals to the department of psychiatry. Settings and Design: This observational descriptive study recorded inpatient referrals to the department of psychiatry of a tertiary care hospital for 2 months. Subjects and Methods: The Mini-International Neuropsychiatric Interview (M. I. N. I.) was administered for identifying the comorbid psychiatric diagnoses. Results: Most of the received inpatient referrals were for male patients (73.7%) in the age group of 30-60 years (58%). Overall, the referral rate was significantly higher from the emergency department and intensive care units (ICU) (50%), followed by specialty (medicine and surgery) wards (20%) and super specialty (cardiology, gastroenterology, and oncology) wards (16%). Altered sensorium and restlessness were the most common reasons for referral (42%), followed by alcohol/drug withdrawal (21.6%), somatic complaints (7.3%), sadness of mood, disturbed sleep, and deliberate self-harm (6% each). Substance use disorders, including alcohol and opioid (32%), delirium (25%), and depression (19%), were among the most common psychiatric diagnoses seen in the referred patients. Conclusions: The pattern observed indicates that most inpatient referrals for psychological evaluation are received for altered sensorium from emergency and ICU than wards. The utility of C-LP helps to understand the reciprocal interdependence between the medical illness and the psychiatric comorbidity.