Significant Withdrawal Symptoms Research Articles

Postoperative Delirium Screening Characteristics in Pediatric Intestinal, Liver, and Renal Transplant Recipients: Single-Center Retrospective Cohort Study.

To describe and compare the results of delirium screening in the immediate post-transplant PICU admission for pediatric intestinal, liver, and renal transplant recipients. We also examined associations with known and suspected risk factors for pediatric delirium (PD). Retrospective analysis of a single-center cohort, 2016-2022. Twenty-four-bed PICU in a high-volume transplant center. All intestinal, liver, and renal transplant recipients under 23 years old admitted between July 2016 and August 2022. We identified 211 pediatric transplant recipients: intestinal (n = 36), liver (n = 78), and renal (n = 97). Results of the Cornell Assessment for PD during the immediate post-transplant PICU admission were reviewed and patients were categorized into screen positive, screen negative, and unscreened. Corresponding data on known and suspected risk factors for PD were also collected. Data on delirium subtypes were not collected. Screens were available for 156 of 211 patients (74%) who were included in the final analysis. The prevalence of a positive screen by transplant category was: intestine 80% (24/30), liver 75% (47/63), and renal 14% (9/63). A positive screen was associated with younger age, greater duration of mechanical ventilation, and greater PICU length of stay (LOS) in bivariate analysis. In multivariable analysis, age and PICU LOS remained strongly correlated with a positive screen (p < 0.05). Deep sedation and agitation as categorized by the State Behavioral Scale was associated with a positive screen, as was significant iatrogenic withdrawal symptoms (p < 0.05). Most patients screened positive by post-transplant days 2 and 3 (58/80 [72%] and 64/80 [80%], respectively). In our 2016 to 2022 experience, we found a high prevalence of positive PD screens in pediatric intestinal and liver transplant recipients in the immediate post-transplant PICU admission. A positive screen was associated with younger age and greater PICU LOS.

Low-dose ketamine infusion to facilitate opioid tapering in chronic non-cancer pain with opioid-use disorder: a historical cohort study

BackgroundLong-term opioid use is associated with pharmacological tolerance, a risk of misuse and hyperalgesia in patients with chronic pain (CP). Tapering is challenging in this context, particularly with comorbid opioid-use...

Smartphone Addiction and Subjective Withdrawal Effects: A Three-Day Experimental Study

Smartphones have arguably become a common necessity in modern society. While they can be used for many practical purposes, their many features increase the risk of overuse, a key element in behavioral addiction. The present study examined withdrawal-related scores on the Smartphone Withdrawal Scale, the Fear of Missing Out Scale, and the Positive and Negative Affect Schedule during a smartphone restriction period, lasting 72 h. In total, 127 participants were randomly assigned either to a condition without smartphone access or to a control condition. The scales were administered three times a day during the restriction period and smartphone addiction scores were assessed on Day 1. The results showed that participants with the highest scores on smartphone addiction in the restricted condition were significantly more negatively affected by the restriction (compared to those with lower scores). This appears to indicate that being restricted from using smartphones can generate significant withdrawal symptoms, especially for those at risk of smartphone addiction.

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

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

Trends in Neonatal Opioid Withdrawal Syndrome and Opioid Exposure Diagnoses Among Infants With Private Health Insurance, 2016-2021: Introduction of the P04.14 ICD-10-CM Code.

The opioid epidemic has led to a surge in diagnoses of neonatal opioid withdrawal syndrome (NOWS). Many states track the incidence of NOWS by using the P96.1 International Classification of Diseases, Tenth Revision, Clinical Modification (ICD-10-CM) code for "neonatal withdrawal symptoms from maternal use of drugs of addiction." In October 2018, an ICD-10-CM code for neonatal opioid exposure (P04.14) was introduced. This code can be used when an infant is exposed to opioids in utero but does not have clinically significant withdrawal symptoms. We analyzed the effect of the P04.14 code on the incidence rate of NOWS (P96.1) and "other" neonatal drug exposure diagnoses (P04.49). We used private health insurance data collected for infants in the United States from the first quarter of 2016 through the third quarter of 2021 to describe incidence rates for each code over time and examine absolute and percentage changes before and after the introduction of code P04.14. The exclusive use of code P96.1 declined from an incidence rate per 1000 births of 1.08 in 2016-2018 to 0.70 in 2019-2021, a -35.7% (95% CI, -47.6% to -23.8%) reduction. Use of code P04.49 only declined from an incidence rate of 2.34 in 2016-2018 to 1.64 in 2019-2021, a -30.0% (95% CI, -36.4% to -23.7%) reduction. Use of multiple codes during the course of treatment increased from an average incidence per 1000 births of 0.56 in 2016-2018 to 0.79 in 2019-2021, a 45.5% (95% CI, 24.8%-66.1%) increase. The introduction of ICD-10-CM code P04.14 altered the use of other neonatal opioid exposure codes. The use of multiple codes increased, indicating that some ambiguity may exist about which ICD-10-CM code is most appropriate for a given set of symptoms.

Transitioning From High-dose Methadone to Buprenorphine Using a Microdosing Approach: Unique Considerations at ASAM Level 3 Facilities.

Transitions from high-dose methadone to buprenorphine for treatment of opioid use disorder (OUD) present risk of precipitated withdrawal related to the introduction of a high-affinity partial agonist at the mu-opioid receptor after occupancy by a lower-affinity full agonist. Various strategies have been explored to maintain patient stability during this process, including microdosing buprenorphine. Current literature lacks consensus on an optimal setting and strategy for initiating a buprenorphine microdosing protocol and gives little detail on patients' conditions after the acute transition period. We report a 6-day microdosing transition from methadone 100 mg directly to sublingual buprenorphine, followed by a 20-day period of monitoring and additional treatment. This patient tolerated a sublingual buprenorphine microdosing protocol while using supportive medications with a peak Clinical Opiate Withdrawal Scale score of 6. The patient's most significant withdrawal symptoms occurred several days after completion of the microdosing process. This case demonstrates the feasibility of using a transmucosal buprenorphine formulation in microdosing transitions from high-dose methadone directly to buprenorphine, and highlights the utility of a medically monitored intensive inpatient setting (American Society of Addiction Medicine level 3.7) in providing appropriate monitoring and treatment during and after a microdosing transition.

Ketamine Infusion After Abrupt Cessation of High-Dose Intrathecal Hydromorphone: A Case Report

We report the successful use of intravenous ketamine infusion for preventing opioid withdrawal in a patient who was receiving long-term, high-dose intrathecal (IT) hydromorphone therapy. The four-day ketamine infusion helped facilitate weaning from approximately 25,000 mg oral daily morphine equivalent (MME) to 48 MME in a matter of six days. Our case report endorses the hypothesis that N-methyl D-aspartate (NMDA) antagonists may inhibit the expression of opioid withdrawal. The patient did not experience significant withdrawal symptoms.

Successful outcomes using Long Acting Buprenorphine (LAB - Buvidal) to treat Codeine, Tramadol and other Opioid Analgesia Dependencies (OAD) in Wales during the Pandemic

IntroductionLong Acting Buprenorphine (LAB) – Buvidal (CAM2038) – is a prolonged release treatment for opioid dependence in adults. Its extensive use was funded by Welsh Government during the pandemic in Wales and it has been found to be a significantly better than oral medications in improving quality of life, possibly through providing allostatic craving and anxiety reductionObjectivesThis is a case series of 10 patients who were referred to Community Addiction Services in North and South West Wales with OAD.MethodsPatients were mainly using Codeine or Tramadol and were referred due to either ongoing illicit use or via primary care services requesting support. As part of the pandemic initiative, they were initiated on Buvidal and followed up.ResultsAll ten patients successfully started on Buvidal without significant issues. As a group, if transferred straight to Buvidal, they tended to have fewer significant withdrawal symptoms prior to starting on the Buvidal compared to those on Methadone or Heroin. They were treated on the usual range of Buvidal doses (1 on 64mg, the others on 96-128mg monthly). They have all stabilised and successfully moved on with their lives on Buvidal. One has used the time on Buvidal to have psychological input around past traumas and successfully detoxified in the community using Buvidal.ConclusionsRecommendations for services considering OAD - it is a surprisingly effective treatment which is easy to start. It has the scope for being both an effective OAD recovery medication and a potentially simple detoxification strategy for this patient group.DisclosureProfessor Melichar has provided consultancy work, presentations, training and chaired panel discussions for all the companies in this area in the UK and some outside the UK. Recent work includes Althea (UK), Britannia (UK), Camurus (UK and Global), Martin

Management of Psychiatric Disorders during the Perinatal Period.

Management of Psychiatric Disorders during the Perinatal Period.

Behavioral Effects of 4-CMC and 4-MeO-PVP in DBA/2J Mice After Acute and Intermittent Administration and Following Withdrawal from Intermittent 14-Day Treatment

Synthetic cathinones appeared on the market in the 2000s as new psychoactive substances and gained significant prevalence among drug abusers. Cathinones produce psychostimulant and empathogenic effects by enhancing dopaminergic, noradrenergic, and serotoninergic neurotransmission in the brain, and those which potently and selectively enhance dopaminergic transmission are considered to have higher abuse potential. The present study examines the behavioral effects related to psychostimulant properties, abuse potential, and addiction in DBA/2J mice of two cathinones with different profile of action on monoamine system, 4-chloromethcathinone (4-CMC), and 4-methoxy-pyrrolidinopentiophenone (4-MeO-PVP). 4-CMC and 4-MeO-PVP increase spontaneous locomotor activity after acute treatment and produce behavioral sensitization after 7-day intermittent treatment, which is a common feature of drugs of abuse. 4-MeO-PVP, but not 4-CMC, produces conditioned place preference after 4 days, indicating its rewarding properties. Finally, the ability of 4-CMC and 4-MeO-PVP to induce withdrawal symptoms after discontinuation from 14-day treatment was assessed using a battery of tests for behavioral markers of depression in mice: a tail suspension test, a forced swim test, measuring despair, and a sucrose preference test, measuring anhedonia. None of the three tests revealed increased depressive symptoms. Moreover, neither spontaneous locomotor activity nor motor performance on a rotarod was impaired after 14-day treatment with the tested compounds. These results indicate that 14-day treatment of mice with 4-CMC or 4-MeO-PVP does not induce significant withdrawal symptoms after cessation, nor significant impairment of dopaminergic circuitry resulting in motor impairment. The current study shows that 4-CMC and 4-MeO-PVP produce abuse-related behavioral changes in mice, which are more pronounced after more dopamine-selective 4-MeO-PVP.

Time-varying effects of 'optimized smoking treatment' on craving, negative affect and anhedonia.

To identify when smoking cessation treatments affect craving, negative affect and anhedonia, and how these symptoms relate to abstinence, to help evaluate the effects of particular intervention components in multi-component treatments and accelerate treatment refinement. Secondary analysis of data from a two-arm randomized controlled trial. Seven primary care clinics in Wisconsin, United States. Adult primary care patients who smoked daily (n=574). Intervention was abstinence-optimized treatment (A-OT, n=276) comprising 3weeks of nicotine mini-lozenges pre-target quit day (TQD), 26weeks of combination nicotine patch and mini-lozenges post-TQD and extensive psychosocial support. The comparator was recommended usual care (RUC, n=298), comprising brief counseling and 8weeks of nicotine patch post-TQD. Time-varying effect models examined dynamic effects of A-OT (versus RUC) on the primary outcomes of nightly cigarette craving, negative affect and anhedonia from 1week pre- to 2weeks post-TQD. Exploratory models examined within-person relations between nicotine medication use and same-day symptom ratings. Secondary logistic regression analyses examined associations between post-TQD craving, negative affect and anhedonia and 1-month post-TQD abstinence. A-OT significantly suppressed pre- and post-TQD craving (β=-0.27 to -0.46 across days) and post-TQD anhedonia (β=-0.24 to -0.38 across days), relative to RUC. Within individuals, using patches was associated with lower negative affect in RUC (β=-0.42 to -0.52), but not in A-OT. Using more mini-lozenges was associated with greater craving (β=0.04-0.07) and negative affect (β=0.03-0.05) early, and with lower anhedonia (β=-0.06 to -0.12) later. Greater post-TQD craving (OR=0.68) and anhedonia (OR=0.85) predicted lower odds of abstinence 1month post-TQD. Time-varying effect models showed that a multi-component treatment intervention for smoking cessation suppressed significant withdrawal symptoms more effectively than recommended usual care among daily adult smokers motivated to quit. The intervention reduced craving pre- and post-target quit day (TQD) and anhedonia post-TQD.

Iatrogenic withdrawal syndrome in specialty pediatric critical care

AimTo describe the occurrence of opioid and benzodiazepine withdrawal symptoms in a cohort of pediatric intensive care unit (PICU) patients, the characteristics of this group, and patterns of withdrawal scoring observed during medication weaning. BackgroundPatients in the PICU are a complex and vulnerable population. Opioids and benzodiazepines are routinely administered in this setting. Providers must be equipped to recognize and assess symptoms of narcotic and benzodiazepine withdrawal. MethodsA retrospective chart review was conducted to describe all patients admitted to the medical intensive care unit who received continuous infusions of morphine and midazolam during a one-year period. Patient demographics, diagnosis, and presence of co-morbidities were abstracted. The number of days on continuous infusions was measured, along with Withdrawal Assessment Tool-1 (WAT-1) scores and documented symptoms that could be associated with withdrawal. WAT-1 scoring ranges from 0 to 12, a WAT-1 score of 3 or higher is considered to indicate clinically significant withdrawal symptoms. Descriptive statistics were utilized to summarize demographic and clinical variables. ResultsAmong 60 cases, patient ages ranged 5 weeks to 29 years (median 3.5 years). Eighty percent of patients had a primary respiratory diagnosis and 88.3% had one or more co-morbidities. Forty-four patients (73.3%) had symptoms consistent with withdrawal. Thirty-one percent of patients had a maximum WAT-1 score between 3 and 8. The majority of patients (55%) had a history of opioid and/or benzodiazepine exposure. ConclusionsThe information learned highlights the need for ongoing conversation and continued study of how best to assess and manage withdrawal syndrome in pediatric critical care environments.

Evaluating the temporal relationships between withdrawal symptoms and smoking relapse.

Smokers attempting to quit often attribute smoking relapse to negative affect, craving, and other nicotine withdrawal symptoms. In addition, there is evidence that smoking relapse can increase these symptoms, particularly negative affect. To address this issue, we analyzed data from an 11-week smoking cessation clinical trial in which smokers (n = 1,246) were randomized to receive either nicotine replacement therapy (NRT), varenicline, or placebo, combined with behavioral counseling. Using cross-lagged analyses, we examined the temporal bidirectional relationships between self-reported measures of affect, craving, and composite withdrawal symptoms and biochemically verified smoking abstinence. The relative strength of these temporal relationships was examined by comparing the explained variances of the models. The results showed that higher negative affect, craving, and composite withdrawal symptoms increased the likelihood of subsequent smoking relapse, and that smoking relapse led to subsequent increases in these same symptoms. A comparison of the explained variances found symptom predicting subsequent relapse models to be stronger than those where relapse predicted subsequent symptoms. Although the explained variance findings generally support a negative reinforcement conceptualization of nicotine dependence, the bidirectional relationship between symptoms and smoking relapse suggests that struggling with quitting smoking leads to significant negative affect, craving, and other withdrawal symptoms that do not quickly resolve. These findings highlight the importance of addressing specific symptoms within the context of smoking cessation. (PsycINFO Database Record (c) 2019 APA, all rights reserved).

Deprescribing benzodiazepines.

Deprescribing benzodiazepines.

Short- and long-term complications of in utero exposure to lamotrigine.

The present study evaluates the effect of antenatal lamotrigine exposure, on short- and long-term paediatric outcome. The study included the children of 83 epileptic women treated with lamotrigine during pregnancy, at a tertiary medical centre between 2004-2014. All newborns were monitored for vital signs, congenital malformations and Finnegan score. In addition, the parents completed a questionnaire regarding their child's development and health up to the age of 12years. No major malformations were found in the newborns. None of the newborns had significant withdrawal symptoms by Finnegan score. The children were followed-up to the age of 12years (56.6% were 6-12years at the time of evaluation). There were no significant findings in the incidence of neurodevelopmental disorders. According to our experience, lamotrigine is generally safe for pregnancy use, associated with minimal short-term complications with no long-term effects on the outcome.

Design, syntheses, and pharmacological characterization of 17-cyclopropylmethyl-3,14β-dihydroxy-4,5α-epoxy-6α-(isoquinoline-3′-carboxamido)morphinan analogues as opioid receptor ligands

A series of 17-cyclopropylmethyl-3,14β-dihydroxy-4,5α-epoxy-6α-(isoquinoline-3′-carboxamido)morphinan (NAQ) analogues were synthesized and pharmacologically characterized to study their structure–activity relationship at the mu opioid receptor (MOR). The competition binding assay showed two-atom spacer and aromatic side chain were optimal for MOR selectivity. Meanwhile, substitutions at the 1′- and/or 4′-position of the isoquinoline ring retained or improved MOR selectivity over the kappa opioid receptor while still possessing above 20-fold MOR selectivity over the delta opioid receptor. In contrast, substitutions at the 6′- and/or 7′-position of the isoquinoline ring reduced MOR selectivity as well as MOR efficacy. Among this series of ligands, compound 11 acted as an antagonist when challenged with morphine in warm-water tail immersion assay and produced less significant withdrawal symptoms compared to naltrexone in morphine-pelleted mice. Compound 11 also antagonized the intracellular Ca2+ increase induced by DAMGO. Molecular dynamics simulation studies of 11 in three opioid receptors indicated orientation of the 6′-nitro group varied significantly in the different ‘address’ domains of the receptors and played a crucial role in the observed binding affinities and selectivity. Collectively, the current findings provide valuable insights for future development of NAQ-based MOR selective ligands.

Benzodiazepine dependence and its treatment with low dose flumazenil

Globally benzodiazepines remain one of the most prescribed medication groups, especially in the primary care setting. With such high levels of prescribing it is not surprising that benzodiazepine dependence is common, cutting across all socioeconomic levels. Despite recognition of the potential for the development of iatrogenic dependence and the lack of any effective treatment, benzodiazepines continue to be widely prescribed in general practice. Conventional dependence management, benzodiazepine tapering, is commonly a protracted process over several weeks or months. It is often associated with significant withdrawal symptoms and craving leading to patient drop out and return to use. Accordingly, there is a worldwide need to find effective pharmacotherapeutic interventions for benzodiazepine dependence. One drug of increasing interest is the GABAA benzodiazepine receptor antagonist/partial agonist, flumazenil. Multiple bolus intravenous infusions of low dose flumazenil used either with or without benzodiazepine tapering can reduce withdrawal sequelae, and/or longer term symptoms in the months following withdrawal. Preliminary data suggest that continuous intravenous or subcutaneous flumazenil infusion for 4 days significantly reduces acute benzodiazepine withdrawal sequelae. The subcutaneous infusion was shown to be tissue compatible so the development of a longer acting (i.e. several weeks) depot flumazenil formulation has been explored. This could be capable of managing both acute and longer term benzodiazepine withdrawal sequelae. Preliminary in vitro water bath and in vivo biocompatibility data in sheep show that such an implant is feasible and so is likely to be used in clinical trials in the near future.

Inpatient Alcohol Withdrawal: Time to Prevent the Preventable?

Inpatient Alcohol Withdrawal: Time to Prevent the Preventable?

Withdrawal from Buprenorphine/Naloxone and Maintenance with a Natural Dopaminergic Agonist: A Cautionary Note

While numerous studies support the efficacy of methadone and buprenorphine for the stabilization and maintenance of opioid dependence, clinically significant opioid withdrawal symptoms occur upon tapering and cessation of dosage. We present a case study of a 35 year old Caucasian female (Krissie) who was prescribed increasing dosages of prescription opioids after carpel tunnel surgery secondary to chronic pain from reflex sympathetic dystrophy and fibromyalgia. Over the next 5 years, daily dosage requirements increased to over 80 mg of Methadone and 300 ug/hr Fentanyl transdermal patches, along with combinations of 12-14 1600 mcg Actig lollipop and oral 100 mg Morphine and 30 mg oxycodone 1-2 tabs q4-6hr PRN for breakthrough pain. Total monthly prescription costs including supplemental benzodiazepines, hypnotics and stimulants exceeded $50,000. The patient was subsequently transferred to Suboxone® in 2008, and the dosage was gradually tapered until her admission for inpatient detoxification with KB220Z a natural dopaminergic agonist. We carefully documented her withdrawal symptoms when she precipitously stopped taking buprenorphine/naloxone and during follow-up while taking KB220Z daily. We also genotyped the patient using a reward gene panel including (9 genes 18 alleles): DRD 2,3,4; MOA-A; COMT; DAT1; 5HTTLLR; OPRM1; and GABRA3. At 432 days post Suboxone® withdrawal the patient is being maintained on KB220Z, has been urine tested and is opioid free. Genotyping data revealed a moderate genetic risk for addiction showing a hypodopaminergic trait. This preliminary case data suggest that the daily use of KB220Z could provide a cost effective alternative substitution adjunctive modality for Suboxone®. We encourage double-blind randomized -placebo controlled studies to test the proposition that KB220Z may act as a putative natural opioid substitution maintenance adjunct.

Cannabidiol for the treatment of cannabis withdrawal syndrome: a case report

Cannabis withdrawal in heavy users is commonly followed by increased anxiety, insomnia, loss of appetite, migraine, irritability, restlessness and other physical and psychological signs. Tolerance to cannabis and cannabis withdrawal symptoms are believed to be the result of the desensitization of CB1 receptors by THC. This report describes the case of a 19-year-old woman with cannabis withdrawal syndrome treated with cannabidiol (CBD) for 10 days. Daily symptom assessments demonstrated the absence of significant withdrawal, anxiety and dissociative symptoms during the treatment. CBD can be effective for the treatment of cannabis withdrawal syndrome.