Long-term outcome of alcohol withdrawal seizures.

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

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

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

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

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

Somatosensory profiling of patients undergoing alcohol withdrawal: Do neuropathic pain and sensory loss represent a problem?

INTRODUCTION: Chronic heavy alcohol use is known to cause neurological complications such as peripheral neuropathy. Concerning the pathophysiology, few sural nerve and skin biopsy studies showed that small fibers might be selectively vulnerable to degeneration in alcohol-related peripheral neuropathy. Pain has rarely been properly evaluated in this pathology. The present study aims at assessing pain intensity, potential neuropathic characteristics as well as the functionality of both small and large nerve sensitive fibers. METHODS: In this observational study, 27 consecutive adult patients, hospitalized for alcohol withdrawal and 13 healthy controls were recruited. All the participants underwent a quantitative sensory testing (QST) according to the standardized protocol of the German Research Network Neuropathic Pain, a neurological examination and filled standardized questionnaires assessing alcohol consumption and dependence as well as pain characteristics and psychological comorbidities. RESULTS: Nearly half of the patients (13/27) reported pain. Yet, pain intensity was weak, leading to a low interference with daily life, and its characteristics did not support a neuropathic component. A functional impairment of small nerve fibers was frequently described, with thermal hypoesthesia observed in 52% of patients. Patients with a higher alcohol consumption over the last 2 years showed a greater impairment of small fiber function. DISCUSSION: Patients report pain but it is however unlikely to be caused by peripheral neuropathy given the non-length-dependent distribution and the absence of neuropathic pain features. Chronic pain in AUD deserves to be better evaluated and managed as it represents an opportunity to improve long-term clinical outcomes, potentially participating to relapse prevention.

Magnesium in the treatment of alcohol withdrawal syndrome: a multicenter randomized controlled trial.

OBJECTIVE: Alcohol withdrawal syndrome (AWS) is a frequent and potentially life-threatening condition experienced in alcohol use disorder. Since hypomagnesemia is involved in AWS's severity, we conducted a multicenter double-blind randomized placebo-controlled trial to examine the efficacy of oral magnesium supplementation as an adjuvant therapy of AWS. MATERIAL AND METHODS: Inpatients were recruited in six different centers if they had a baseline score higher than eight on the Revised Clinical Institute Withdrawal Assessment for Alcohol (CIWA-Ar). The experimental treatment was magnesium lactate dehydrate, administrated three times per day providing a total of 426.6 mg per day and up to 15 days. The primary endpoint was the significant between-group difference of the CIWA-Ar total score change from baseline to 3 days later. The treatment group and baseline score were introduced as covariables in an analysis of covariance. RESULTS: A total of 98 inpatients were included {71.4% of men; mean age of 49.1 years [standard deviation (SD): 10.3]}. In the intention-to-treat population, the mean reduction of the CIWA-Ar score in the experimental group between baseline and 3 days later was 10.1 (SD: 5.2), whereas it was 9.2 (SD: 3.9) in the control group. The absolute difference of the adjusted mean in the experimental group compared with the control group was -0.69 (SD: 0.72), which did not correspond to a significant between-group difference (P = 0.34). Per-protocol analysis and sensitivity analyses also supported this result. Supplementary analyses found no significant difference regarding benzodiazepine consumption, magnesium blood concentration, and satisfaction to care. CONCLUSIONS: The present study does not support the rationale of systematic oral magnesium supplementation in patients with AWS.

Neonatal opioid toxicity: opioid withdrawal (abstinence) syndrome with emphasis on pharmacogenomics and respiratory depression.

The increasing use of opioids in pregnant women has led to an alarming rise in the number of cases of neonates with drug-induced withdrawal symptoms known as neonatal opioid withdrawal syndrome (NOWS). NOWS is a toxic heterogeneous condition with many neurologic, autonomic, and gastrointestinal symptoms including poor feeding, irritability, tachycardia, hypertension, respiratory defects, tremors, hyperthermia, and weight loss. Paradoxically, for the management of NOWS, low doses of morphine, methadone, or buprenorphine are administered. NOWS is a polygenic disorder supported by studies of genomic variation in opioid-related genes. Single-nucleotide polymorphisms (SNPs) in CYP2B6 are associated with variations in NOWS infant responses to methadone and SNPs in the OPRM1, ABCB1, and COMT genes are associated with need for treatment and length of hospital stay. Epigenetic gene changes showing higher methylation levels in infants and mothers have been associated with more pharmacologic treatment in the case of newborns, and for mothers, longer infant hospital stays. Respiratory disturbances associated with NOWS are not well characterized. Little is known about the effects of opioids on developing neonatal respiratory control and respiratory distress (RD), a potential problem for survival of the neonate. In a rat model to test the effect of maternal opioids on the developing respiratory network and neonatal breathing, maternal-derived methadone increased apneas and lessened RD in neonates at postnatal (P) days P0 and P1. From P3, breathing normalized with age suggesting reorganization of respiratory rhythm-generating circuits at a time when the preBötC becomes the dominant inspiratory rhythm generator. In medullary slices containing the preBötC, maternal opioid treatment plus exposure to exogenous opioids showed respiratory activity was maintained in younger but not older neonates. Thus, maternal opioids blunt centrally controlled respiratory frequency responses to exogenous opioids in an age-dependent manner. In the absence of maternal opioid treatment, exogenous opioids abolished burst frequencies at all ages. Prenatal opioid exposure in children stunts growth rate and development while studies of behavior and cognitive ability reveal poor performances. In adults, high rates of attention deficit disorder, hyperactivity, substance abuse, and poor performances in intelligence and memory tests have been reported.

Does tobacco dependence worsen cannabis withdrawal in people with and without schizophrenia-spectrum disorders?

BACKGROUND AND OBJECTIVES: Rates of cannabis use disorder (CUD) are higher in people with schizophrenia than in the general population. Irrespective of psychiatric diagnosis, tobacco co-use is prevalent in those with CUD and leads to poor cannabis cessation outcomes. The cannabis withdrawal syndrome is well-established and increases cannabis relapse risk. We investigated whether cannabis withdrawal severity differed as a function of high versus no/low tobacco dependence and psychiatric diagnosis in individuals with CUD. METHOD: Men with CUD (N = 55) were parsed into four groups according to schizophrenia diagnosis and tobacco dependence severity using the Fagerstrom Test for Nicotine Dependence (FTND): men with schizophrenia with high tobacco dependence (SCT+, n = 13; FTND ≥ 5) and no/low tobacco dependence (SCT-, n = 22; FTND ≤ 4), and nonpsychiatric controls with high (CCT+, n = 7; FTND ≥ 5) and no/low (CCT-, n = 13; FTND ≤ 4) tobacco dependence. Participants completed the Marijuana Withdrawal Checklist following 12-h of cannabis abstinence. RESULTS: There was a significant main effect of tobacco dependence on cannabis withdrawal severity (p < .001). Individuals with high tobacco dependence had significantly greater cannabis withdrawal severity (M = 13.85 [6.8]) compared to individuals with no/low tobacco dependence (M = 6.49, [4.9]). Psychiatric diagnosis and the interaction effects were not significant. Lastly, cannabis withdrawal severity positively correlated with FTND (r = .41, p = .002). CONCLUSION AND SCIENTIFIC SIGNIFICANCE: Among individuals with CUD and high tobacco dependence, cannabis withdrawal severity was elevated twofold, irrespective of diagnosis, relative to individuals with CUD and no/low tobacco dependence. Findings from this study emphasize the importance of addressing tobacco co-use when treating CUD.

Adult hemiconvulsive hemiatrophy syndrome: a novel clinicoradiologic disorder in adults.

The association of focal motor seizures with cerebral hemiatrophy is a recognised rare paediatric syndrome known as 'hemiconvulsion, hemiatrophy and epilepsy' (HHE). To date, HHE has not been reported in adults. We present four adult patients with striking similarities to HHE, following alcohol withdrawal in chronic alcoholics. We document the imaging findings in the acute and subacute phases, discuss the underlying mechanisms and present a hypothesis regarding the pathophysiology.

Opioid withdrawal symptoms after neurolytic splanchnic nerve block in cancer patients.

PURPOSE: Few reports on opioid withdrawal (OW) due to opioid tapering in cancer patients have been published. The incidence of and risk factors for OW after neurolytic splanchnic nerve block (NSNB) are unknown. This study aimed to elucidate the incidence of and risk factors for OW among cancer patients who could have reduced opioid doses after NSNB. METHODS: This was a multicenter, retrospective, observational study. We reviewed the medical charts of patients who underwent NSNB for intractable cancer pain at four tertiary hospitals in Yokohama City from April 2005 to October 2020. We included patients whose opioid dose was reduced by > 5 mg/day (equivalent oral morphine dose) within 14 days after NSNB. We classified the patients into two groups according to the presence or absence of OW symptoms and compared them. RESULTS: Of the 50 patients who underwent NSNB, 24 were included in the study. OW was observed in five (20.8%) patients. Pain and opioid use duration were significantly longer in OW patients than in non-OW patients (median pain duration 689 vs. 195 days; P < 0.043 and median opioid use duration 486 vs. 136 days; P < 0.030). The opioid tapering dose was significantly larger in patients with OW than in those without OW (median opioid tapering dose 75 vs. 40 mg; P < 0.046). CONCLUSIONS: OW was observed in 20.8% of the patients in the study. A longer pain and opioid use duration and a larger opioid tapering dose may predispose patients to OW.

Delirium Tremens and Central Pontine Myelinolysis in a Patient with Alcohol Use Disorder and Pneumonia: a Case Report and a Narrative Review.

INTRODUCTION: Delirium tremens (DT) is a serious condition occurring in alcohol withdrawal syndrome. Alcohol consumption may also cause additional health problems, such as respiratory infections or neuropsychiatric conditions such as central pontine myelinolysis. In this clinical scenario, managing DT can be expected to be more compelling and complex. Alcohol decreases coughing and mucociliary clearance and disrupts the immunity of the respiratory system. CASE: Here we report on a middle-aged man with alcohol use disorder who had developed DT due to alcohol withdrawal and comorbid pneumonia. DISCUSSION AND CONCLUSION: In this paper, DT, the relation between respiratory infections and alcohol intake, and the correlation of alcohol consumption and central pontine myelinolysis (CPM) are discussed. Also, the literature on alcohol consumption and the additional respiratory and neurologic problems resulting from it are presented.

Functional connectivity abnormalities underlying mood disturbances in male abstinent methamphetamine abusers.

Anxiety and depression are the most common withdrawal symptoms of methamphetamine (METH) abuse, which further exacerbate relapse of METH abuse. To date, no effective pharmacotherapy exists for METH abuse and its withdrawal symptoms. Therefore, understanding the neuromechanism underlying METH abuse and its withdrawal symptoms is essential for developing clinical strategies and improving patient care. The aims of this study were to investigate brain network abnormalities in METH abusers (MAs) and their associations with affective symptoms. Forty-eight male abstinent MAs and 48 age-gender matched healthy controls were recruited and underwent resting state functional magnetic resonance imaging (fMRI). The severity of patient anxiety and depressive symptoms were measured by Hamilton anxiety and depression rating scales, which decreased across the duration of abstinence. Independent component analysis was used to investigate the brain network functional connectivity (FC) properties. Compared with healthy controls, MAs demonstrated hypo-intra-network FC in the cerebellar network and hyper-intra-network FC in the posterior salience network. A whole-brain regression analysis revealed that FC strength of clusters located in the right rostral anterior cingulate cortex (rACC) within the ventromedial network (VMN) was associated with affective symptoms in the patients. Importantly, the intra-network FC strength of the rACC in VMN mediated the association between abstinence duration and the severity level of affective symptoms. Our results demonstrate alterations in brain functional networks underlying METH abuse, and that the FC of rACC within VMN serve as a neural substrate in the association between abstinence length and affective symptom severity in the MAs.

Severe diaphoresis and fever during alcohol withdrawal cause hypovolemic shock: case report.

BACKGROUND: Several fatal medical complications have been associated with alcohol withdrawal, such as seizure, cardiac arrhythmia, and takotsubo cardiomyopathy. However, there have been no reports on hypovolemic shock during alcohol withdrawal, although two physical signs of alcohol withdrawal, i.e., diaphoresis and fever, can lead to hypovolemia and its medical consequences. CASE PRESENTATION: We describe a patient with alcohol use disorder who exhibited hypovolemic shock and its associated acute renal failure during alcohol withdrawal with severe diaphoresis and fever even though he had consumed almost the full amount of food he was offered. Given his excessive diaphoresis and fever that were related to alcohol withdrawal, his water intake was insufficient. Infusion with extracellular fluid resolved all these medical issues. CONCLUSIONS: The increased adrenergic activity associated with alcohol withdrawal might substantially increase a patient's water-intake requirement through diaphoresis and fever and may cause severe hypovolemia and its associated medical complications.

Alcohol Withdrawal Syndrome: Outpatient Management.

Approximately one-half of patients with alcohol use disorder who abruptly stop or reduce their alcohol use will develop signs or symptoms of alcohol withdrawal syndrome. The syndrome is due to overactivity of the central and autonomic nervous systems, leading to tremors, insomnia, nausea and vomiting, hallucinations, anxiety, and agitation. If untreated or inadequately treated, withdrawal can progress to generalized tonic-clonic seizures, delirium tremens, and death. The three-question Alcohol Use Disorders Identification Test-Consumption and the Single Alcohol Screening Question instrument have the best accuracy for assessing unhealthy alcohol use in adults 18 years and older. Two commonly used tools to assess withdrawal symptoms are the Clinical Institute Withdrawal Assessment for Alcohol Scale, Revised, and the Short Alcohol Withdrawal Scale. Patients with mild to moderate withdrawal symptoms without additional risk factors for developing severe or complicated withdrawal should be treated as outpatients when possible. Ambulatory withdrawal treatment should include supportive care and pharmacotherapy as appropriate. Mild symptoms can be treated with carbamazepine or gabapentin. Benzodiazepines are first-line therapy for moderate to severe symptoms, with carbamazepine and gabapentin as potential adjunctive or alternative therapies. Physicians should monitor outpatients with alcohol withdrawal syndrome daily for up to five days after their last drink to verify symptom improvement and to evaluate the need for additional treatment. Primary care physicians should offer to initiate long-term treatment for alcohol use disorder, including pharmacotherapy, in addition to withdrawal management.

Enriched Environment Ameliorates Cognitive Deficits and Locomotor Sensitization in Morphine-Withdrawn Rats Receiving Methadone Maintenance Treatment.

OBJECTIVE: This study was designed to examine whether enriched environments (EE) would attenuate object recognition and spatial learning and memory deficits and locomotor sensitization induced by methadone maintenance treatment (MMT) in morphine-withdrawn rats. METHODS: Male Wistar rats (170 ± 10 g) were injected with bi-daily doses (10 mg/kg, 12-h intervals) of morphine for 14 days. Rats receiving MMT were reared in the standard environment (SE) or EE during 30 days of morphine withdrawal. Then, the rats were tested for object recognition (the object recognition memory test, ORMT) and spatial learning and memory (the water maze) and then challenged with morphine (1 mg/kg, i.p.) and evaluated for locomotor activity (open-field box). RESULTS: The results revealed that the dependent/saline/EE (D/Sal/EE) and D/methadone/EE (D/Meth/EE) rats exhibited significant preference for the new object (p = 0.006 and p = 0.049), spent more time in the target zone (p = 0.045 and p = 0.005) on the water maze, and displayed a lower level of distance traveled (p = 0.002 and p = 0.0001) compared to their control groups reared in SE. CONCLUSIONS: We conclude that exposure to EE could ameliorate the object recognition and spatial memory deficits and also decrease locomotor sensitivity in morphine-withdrawn rats receiving MMT. Thus, EE may be beneficial in the treatment of addiction during MMT.

Iatrogenic Opioid Withdrawal Syndrome in Critically Ill Patients: a Retrospective Cohort Study.

BACKGROUND: Opioid withdrawal syndrome (OWS) may occur following the reduction or discontinuation of opioid analgesics. In critically ill pediatric patients, OWS is a common and clinically significant condition. However, OWS in adult patients has not been assessed in detail. Therefore, we aimed to investigate the incidence, risk factors, and clinical features of OWS in mechanically ventilated patients treated in an adult intensive care unit (ICU). METHODS: This study was a retrospective evaluation of data from patients treated in the medical ICU for > 3 days and who received only one type of opioid analgesic. OWS was assessed over a 24 hours period from discontinuation or reduction (by > 50%) of continuous opioid infusion. OWS was defined as the presence of ≥ 3 central nervous system or autonomic nervous system symptoms. RESULTS: In 126 patients treated with remifentanil (n = 58), fentanyl (n = 47), or morphine (n = 21), OWS was seen in 31.0%, 36.2%, and 9.5% of patients, respectively (P = 0.078). The most common symptom was a change in respiratory rate (remifentanil, 94.4%; fentanyl, 76.5%; morphine, 100%). Multivariate Cox-proportional hazards model showed that OWS was negatively associated with morphine treatment (hazard ratio [HR], 0.17; 95% confidence interval [CI], 0.037-0.743) and duration of opioid infusion (HR, 0.566; 95% CI, 0.451-0.712). CONCLUSION: OWS is not uncommon in mechanically ventilated adult patients who received continuous infusion of opioids for > 3 days. The use of morphine may be associated with a decreased risk of OWS.

Amygdala Arginine Vasopressin Modulates Chronic Ethanol Withdrawal Anxiety-Like Behavior in the Social Interaction Task.

BACKGROUND: Chronic ethanol (EtOH) exposure induces neurobehavioral maladaptations in the brain though the precise changes have not been fully explored. The central nucleus of the amygdala (CEA) regulates anxiety-like behavior induced by withdrawal from chronic intermittent EtOH (CIE) exposure, and the arginine vasopressin (AVP) system within the CEA regulates many anxiety-like behaviors. Thus, adaptations occur in the CEA AVP system due to chronic EtOH exposure, which lead to anxiety-like behaviors in rats. METHODS: Chronic exposure to a low-dose EtOH (4.5% wt/vol) induces anxiety-like behavior in rats. Wistar or Sprague Dawley rats were exposed to a modified CIE or CIE, while intra-CEA microinjections of AVP or a V1b receptor antagonist were used to elicit or block withdrawal-induced anxiety. Additionally, AVP microinjections into the CEA were given 24 hours following 15 days of continuous high-dose EtOH (7% wt/vol), a time period when rats no longer express anxiety. Chemogenetics was also used to activate the basolateral amygdala (BLA) or deactivate the dorsal periaqueductal gray=(dm/dlPAG) therefore PAG=periaqueductal gray to elicit or block withdrawal-induced anxiety. RESULTS: AVP microinjected into the CEA in lieu of exposure to the first 2 cycles of CIE was sufficient to induce anxiety-like behavior in these commonly used rat strains. The V1b receptor antagonist, but not an oxytocin receptor agonist, into the CEA during the first 2 withdrawal cycles suppressed anxiety. However, activation of the BLA in lieu of exposure to the first 2 cycles of CIE was insufficient to induce anxiety-like behavior. AVP microinjection into the CEA 24 hours into withdrawal reelicited anxiety-like behavior, and deactivation of the dm/dlPAG reduced this effect of CEA AVP. CONCLUSIONS: Taken together, this study demonstrates a role of CEA AVP and a CEA-dm/dlPAG circuit in the development of anxiety induced by CIE. Such information is valuable for identifying novel therapeutic targets for alcohol- and anxiety-associated disorders.

Withdrawal Confounding in Randomized Controlled Trials of Antipsychotic, Antidepressant, and Stimulant Drugs, 2000-2017.

BACKGROUND: Results of relapse prevention randomized controlled trials (RCTs) which discontinue psychotropic drug treatment from some participants may be confounded by drug withdrawal symptoms. We test for the confound by calculating whether ≥50% of the difference in relapse risk between drug-discontinued and drug-maintained groups is present at discontinuation time points (DCTs) with "short" and "long" assumptions regarding onset and duration of withdrawal symptoms. METHODS: In eligible RCTs of antidepressants, antipsychotics, and stimulants from 2000 to 2017 (n = 30) selected from a systematic review, differences in relapse risk were examined by arithmetic and graphical comparison of mean behavioral scores or survival plots. RESULTS: Only 14 studies (46.6%) with 15 analyses of relapse risk provided sufficient data. Under short and long DCTs, 9 of 13 (69.2%) and 7 of 9 (77.8%) interpretable analyses, respectively, suggested a withdrawal confound. The proportion of endpoint placebo-maintenance group difference present by the DCT averaged 69.1% (range, 58.7-148.0%, n = 13) for short DCT assumptions, and 79.0% (range, 51.5-183.3%, n = 9) under long DCTs. One study (3.33%) controlled for withdraw al effects, and 1 yielded inconclusive results. CONCLUSIONS: These results support suggestions that withdrawal symptoms confound the results of relapse prevention RCTs. Accounting for such symptoms in RCTs is an ethical, scientific, and clinical imperative. Justifications for relapse prevention RCTs employing a discontinuation procedure require more scrutiny.

Discontinuing Psychotropic Drugs from Participants in Randomized Controlled Trials: A Systematic Review.

BACKGROUND AND OBJECTIVE: Methods and justifications for discontinuing psychotropic drugs in randomized controlled trials (RCTs), and RCTs' acknowledgement of possible withdrawal symptoms following discontinuation, have not been examined systematically, which this review aims to do. Study Eligibility, Data Extraction, and Synthesis: Publications in MEDLINE, EMBASE, and PsycINFO (2000-2017) randomly assigning participants diagnosed with mental disorders to discontinue antipsychotic, antidepressant, anticonvulsant, antimanic, mood-stabilizing, benzodiazepine, or stimulant drugs. Authors independently extracted data, devised a typology of trials, and assessed trials' recognition of with-drawal symptoms. RESULTS: Eighty RCTs (70% with industry participation) discontinued drugs from 5,757 participants to investigate relapse prevention (44%), successful dis-continuation (26%), architecture of withdrawal (14%), and practicality of discontinuation (10%). RCTs of stimulants, antidepressants, and antipsychotics mostly aimed to reach conclusions about relapse prevention by testing abrupt or rapid discontinuations; RCTs of benzodiazepines mostly aimed to reduce drug use by testing longer-lasting, supportive discontinuations. In 67% of RCTs, no justification was given for the specific discontinuation strategy, which lasted under 2 weeks in 60% of RCTs. Possible withdrawal confounding of trial outcomes was addressed in 14% of eligible RCTs. LIMITATIONS: Only the published literature was searched. CONCLUSIONS AND IMPLICATIONS: RCTs use drug discontinuation to study several key issues in psychopharmacology but infrequently justify how they implement it or acknowledge that possible withdrawal symptoms may threaten internal validity. Reappraising the use of drug discontinuation and the recognition of withdrawal symptoms in RCTs is required.

The Effects of Oxytocin on Withdrawal, Craving and Stress Response in Heroin-Dependent Patients: A Randomized, Double-Blind Clinical Trial.

Opioid dependence is an increasing clinical and public health problem. Current pharmacotherapies have limited efficacy and cause serious side effects. Increasing bodies of evidences suggest the neuropeptide, oxytocin (OT), as a potential treatment for drug abuse disorders. The current study was designed to evaluate the effect of OT on withdrawal, craving and anxiety scores, cortisol and dehydroepiandrosterone sulphate (DHEAS) blood level in heroin-dependent male patients. This randomized, double-blind placebo-controlled clinical trial was conducted on 58 males with opioid dependence by Abstinence Center of Addictive People in Iran. The participants were randomly allocated to receive intranasal OT (single dose; 40 IU, n = 29) or placebo (n = 29). Heroine withdrawal, craving and anxiety scores were measured using the Opioid Withdrawal Scale, Visual Analogue Scale and (Desire for Drug Questionnaire), and Hamilton checklist respectively. The cortisol and DHEAS levels at baseline and different post-intervention time were measured using a competitive immunoanalysis method. Acute OT administration reduced craving and withdrawal scores but did not change anxiety significantly. Single dose of OT decreased the level of cortisol and improved the cortisol/DHEAS ratio in the heroin users during abstinence (p < 0.01). These results suggest that OT may be useful in the attenuation of craving, withdrawal symptom in heroin-dependent patients and might be considered a new potential treatment for heroin dependence where positive effects of OT on stress-related hormones may be involved in this effect of OT.

Methanol extract of semen Ziziphi Spinosae attenuates ethanol withdrawal anxiety by improving neuropeptide signaling in the central amygdala.

BACKGROUND: Ethanol withdrawal (EtOHW) anxiety is a crucial risk factor for alcoholic relapse. The neuropeptide nociceptin/orphanin FQ (N/OFQ) acts upon its receptor (NOP) to antagonize corticotropin-releasing factor (CRF) and elicit anxiolytic actions. Semen Ziziphi Spinosae (SZS), a prototypical hypnotic-sedative herb in Oriental medicine, exhibits anxiolytic effects during nicotine withdrawal by improving amygdaloid CRF/CRF1 receptor (CRFR1) signaling. Therefore, we evaluated the effects of SZS on EtOHW anxiety and the involvement of amygdaloid CRF/CRFR1 and N/OFQ/NOP pathways. METHODS: Male Sprague Dawley rats received intraperitoneal injections of 2 g/kg EtOH (20% v/v) once daily for 28 d followed by a 3-d withdrawal. During EtOHW, the rats were given once-daily intragastric treatments of a methanol extract of SZS (MESZS, 60 or 180 mg/kg/d). Anxiety-like behaviors were measured with the open field (OF) and elevated plus maze (EPM) tests, and plasma corticosterone (CORT) levels were examined by an enzyme-linked immunosorbent assay. mRNA and protein expression levels of the neuropeptides and their receptors were determined by quantitative polymerase chain reaction and Western blot assays. RESULTS: MESZS increased the distance traveled in the center zone of the OF and dose-dependently elongated the duration of staying in the center zone in EtOHW rats. MESZS increased both the number of entries into and the time spent in the open arms of the EPM by EtOHW rats. And, MESZS inhibited the over secretion of plasma CORT during EtOHW. EtOHW enhanced CRF and CRFR1 gene and protein expression in the central nucleus of the amygdala (CeA), which were inhibited by 180 mg/kg/d MESZS. EtOHW increased amygdaloid NOP mRNA and protein expression but spared N/OFQ mRNA expression, and 180 mg/kg/d MESZS further promoted these increases. Additionally, a post-MESZS intra-CeA infusion of either CRF or the selective NOP antagonist UFP-101 abolished the expected anxiolytic effect of 180 mg/kg/d MESZS. CONCLUSIONS: These results suggest that MESZS ameliorates EtOHW anxiety by improving both CRF/CRFR1 and N/OFQ/NOP transmissions in the CeA.