Treatment of Chronic Insomnia in Adults.

Insomnia affects 30% of the U.S. population, with 5% to 15% meeting criteria for chronic insomnia. It can negatively impact quality of life, decrease productivity, increase fatigue and drowsiness, and put patients at higher risk of developing other health problems. Initial treatment focuses on nonpharmacologic therapies such as cognitive behavior therapy, which improves negative thought patterns and behaviors through sleep restriction, stimulus control, and relaxation techniques. Other nonpharmacologic treatments include exercise, mindfulness, and acupuncture. If these approaches are ineffective, pharmacologic agents may be considered. Medications such as benzodiazepines and Z-drugs are often prescribed for insomnia but should be avoided, if possible, due to short- and long-term risks associated with their use. Melatonin receptor agonists are safer and well tolerated but have limited effectiveness. Dual orexin receptor antagonists are effective in patients who have sleep maintenance insomnia or difficulty with sleep onset. Evidence for the use of antihistamines to treat insomnia is generally lacking, but doxylamine is effective for up to four weeks.

A systematic review of phenibut withdrawal focusing on complications, therapeutic approaches, and single substance versus polysubstance withdrawal.

INTRODUCTION: Phenibut is an unregulated supplement that acts primarily as a gamma-aminobutyric acid type B receptor agonist. Use of phenibut can lead to dependence and subsequent withdrawal when use is stopped. Phenibut withdrawal can cause severe symptoms such as delirium, hallucinations, and seizures. The purpose of this systematic review is to characterize the natural history of phenibut withdrawal and summarize treatment strategies published in the literature. METHODS: A systematic review was conducted using the preferred reporting items for systematic reviews and meta-analyses checklist. English language peer-reviewed articles or conference abstracts in humans describing phenibut withdrawal after cessation of use were included. Databases (Ovid/MEDLINE, Web of Science, and Science Direct) and references of included articles were searched. Case reports were appraised using the Joanna Briggs Institute critical appraisal checklist for case reports. Patient demographics and key outcomes, including withdrawal characteristics and treatment characteristics, were collected into a predefined data collection sheet by six independent reviewers. RESULTS: Search results yielded 515 articles of which 25 were included. All articles were case reports or published conference abstracts. All of the cases (100 percent) involved male patients and the median age was 30 years, (interquartile range 23.5-34 years, range 4 days-68 years). The median daily phenibut dose prior to experiencing withdrawal was 10 g (interquartile range 4.75-21.5 g, range 1-200 g). The shortest duration of phenibut use (2-3 g daily) prior to withdrawal was one week. Withdrawal symptoms occurred as quickly as two hours after the last phenibut dose. Sixteen patients (64 percent) reported progression of withdrawal severity within the first 24 hours of healthcare contact. Seizures were reported in two patients (8 percent), intubation in six patients (24 percent), and intensive care unit admission in 11 patients (44 percent). Withdrawal patterns and outcomes were similar in those using phenibut alone and those with comorbid polysubstance use. Withdrawal treatment strategies varied widely. Only three cases (12 percent) were managed outpatient and all three utilized a phenibut tapering strategy. All patients undergoing medication-assisted abstinence were admitted inpatient for symptom management and received a drug that acts on gamma-aminobutyric acid receptors. The most commonly used medication was a benzodiazepine, reported in 17 cases (68 percent). Nineteen patients (76 percent) required at least two drug therapies to manage symptoms. Baclofen was used in 15 cases (60 percent), primarily in conjunction with gamma-aminobutyric acid type A agonists (12 of 15 cases) or as monotherapy during a phenibut taper (two of 15 cases). Two patients using baclofen monotherapy outpatient, after initial stabilization with multiple drug classes, reported adverse effects. One patient had a seizure and the other experienced recurrent withdrawal symptoms, returned to using phenibut, and was admitted to a hospital for withdrawal symptom management with benzodiazepines. LIMITATIONS: This review is subject to several limitations. Due to the manual nature of article selection, it is possible relevant articles may not have been included. As the entire data set is comprised of case reports it may suffer from publications bias. Outcomes and meaningful conclusions from specific treatment strategies were rarely available because of the heterogeneous nature of case reports. It is possible those reporting only phenibut use were actually using multiple substances. The doses of phenibut a user believed they were taking may be different from what was present in the unregulated product. CONCLUSIONS: Phenibut withdrawal appears to have a range of severity. It is important to recognize that patients undergoing phenibut abstinence may have progressive symptom worsening during early withdrawal. All published cases of abrupt phenibut abstinence were admitted inpatients for symptom management. Benzodiazepines or barbiturates with adjunctive baclofen appear to be the most commonly used drugs for moderate to severe withdrawal. Outpatient management via slow phenibut tapers with or without adjunctive gamma-aminobutyric acid agonist therapy may be successful. However, there is no standard treatment, and consultation with experts (e.g., toxicologists, addiction specialists) experienced in managing withdrawal syndromes is recommended. Significant study is warranted to develop methods of triaging phenibut withdrawal (e.g., severity scoring, inpatient versus outpatient management) and creating optimal treatment regimens.

The European Insomnia Guideline: An update on the diagnosis and treatment of insomnia 2023.

Progress in the field of insomnia since 2017 necessitated this update of the European Insomnia Guideline. Recommendations for the diagnostic procedure for insomnia and its comorbidities are: clinical interview (encompassing sleep and medical history); the use of sleep questionnaires and diaries (and physical examination and additional measures where indicated) (A). Actigraphy is not recommended for the routine evaluation of insomnia (C), but may be useful for differential-diagnostic purposes (A). Polysomnography should be used to evaluate other sleep disorders if suspected (i.e. periodic limb movement disorder, sleep-related breathing disorders, etc.), treatment-resistant insomnia (A) and for other indications (B). Cognitive-behavioural therapy for insomnia is recommended as the first-line treatment for chronic insomnia in adults of any age (including patients with comorbidities), either applied in-person or digitally (A). When cognitive-behavioural therapy for insomnia is not sufficiently effective, a pharmacological intervention can be offered (A). Benzodiazepines (A), benzodiazepine receptor agonists (A), daridorexant (A) and low-dose sedating antidepressants (B) can be used for the short-term treatment of insomnia (≤ 4 weeks). Longer-term treatment with these substances may be initiated in some cases, considering advantages and disadvantages (B). Orexin receptor antagonists can be used for periods of up to 3 months or longer in some cases (A). Prolonged-release melatonin can be used for up to 3 months in patients ≥ 55 years (B). Antihistaminergic drugs, antipsychotics, fast-release melatonin, ramelteon and phytotherapeutics are not recommended for insomnia treatment (A). Light therapy and exercise interventions may be useful as adjunct therapies to cognitive-behavioural therapy for insomnia (B).

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.

Application of gabapentinoids and novel compounds for the treatment of benzodiazepine dependence: the glutamatergic model.

BACKGROUND: Current approaches for managing benzodiazepine (BZD) withdrawal symptoms are daunting for clinicians and patients, warranting novel treatment and management strategies. This review discusses the pharmacodynamic properties of BZDs, gabapentinoids (GBPs), endozepines, and novel GABAergic compounds associated with potential clinical benefits for BZD-dependent patients. The objective of this study was to review the complex neuromolecular changes occurring within the GABAergic and glutamatergic systems during the BZD tolerance and withdrawal periods while also examining the mechanism by which GBPs and alternative pharmacological therapies may attenuate withdrawal symptoms. METHODS AND RESULTS: An elaborative literature review was conducted using multiple platforms, including the National Center for Biotechnology (NCBI), AccessMedicine, ScienceDirect, pharmacology textbooks, clinical trial data, case reports, and PubChem. Our literature analysis revealed that many distinctive neuroadaptive mechanisms are involved in the GABAergic and glutamatergic systems during BZD tolerance and withdrawal. Based on this data, we hypothesize that GBPs may attenuate the overactive glutamatergic system during the withdrawal phase by an indirect presynaptic glutamatergic mechanism dependent on the α2δ1 subunit expression. CONCLUSIONS: GBPs may benefit individuals undergoing BZD withdrawal, given that the α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptor current significantly increases during abrupt BZD withdrawal in animal studies. This may be a conceivable explanation for the effectiveness of GBPs in treating both alcohol withdrawal symptoms and BZD withdrawal symptoms in some recent studies. Finally, natural and synthetic GABAergic compounds with unique pharmacodynamic properties were found to exert potential clinical benefits as BZD substitutes in animal studies, though human studies are lacking.

Early treatment with thiamine and mortality among patients with alcohol use disorder who are hospitalized for pneumonia.

BACKGROUND: The paucity of research linking thiamine treatment with improved outcomes may be driving its underutilization among patients at risk for Wernicke encephalopathy. OBJECTIVE: To assess relationships of thiamine usage to outcomes of patients hospitalized with alcohol use disorder and pneumonia. DESIGN, SETTING AND PARTICIPANTS: This is a retrospective cohort study of adult patients hospitalized with pneumonia who also have alcohol use disorder and were treated with benzodiazepines during the initial two hospital days, between 2010 and 2015 at hospitals participating in the Premier Healthcare Database. EXPOSURE: Any thiamine treatment, and, among those treated, high-dose thiamine treatment, during the initial two hospital days. MAIN OUTCOME AND MEASURES: Death on days 3-14 of hospitalization (primary); discharge home; transfer to intensive care unit; length of stay (LOS). We used propensity-weighted models to estimate treatment effects. RESULTS: Among 36,732 patients from 625 hospitals, 26,520 (72.2%) patients received thiamine, with mortality of 6.5% and 8.1% among recipients and nonrecipients, respectively. With propensity score adjustment, thiamine was associated with reduced mortality (odds ratio [OR]: 0.80, 95% confidence interval [CI]: 0.75-0.85) and more frequent discharges to home (OR: 1.10, 95% CI: 1.06-1.14). Other outcomes were similar. Relative to low-dose thiamine, high-dose thiamine was not associated with mortality (adjusted OR: 0.99, 95% CI: 0.89-1.10), but LOS was longer (ratio of means: 1.06, 95% CI: 1.04-1.08), and discharges to home were less frequent (OR: 0.92, 95% CI: 0.87-0.97). CONCLUSION: Thiamine is not reliably given to patients with pneumonia and alcohol use disorder receiving benzodiazepines. Improving thiamine administration may represent an opportunity to save lives in this high-risk group of inpatients.

Association between chiropractic spinal manipulative therapy and benzodiazepine prescription in patients with radicular low back pain: a retrospective cohort study using real-world data from the USA.

OBJECTIVES: Although chiropractic spinal manipulative therapy (CSMT) and prescription benzodiazepines are common treatments for radicular low back pain (rLBP), no research has examined the relationship between these interventions. We hypothesise that utilisation of CSMT for newly diagnosed rLBP is associated with reduced odds of benzodiazepine prescription through 12 months' follow-up. DESIGN: Retrospective cohort study. SETTING: National, multicentre 73-million-patient electronic health records-based network (TriNetX) in the USA, queried on 30 July 2021, yielding data from 2003 to the date of query. PARTICIPANTS: Adults aged 18-49 with an index diagnosis of rLBP were included. Serious aetiologies of low back pain, structural deformities, alternative neurological lesions and absolute benzodiazepine contraindications were excluded. Patients were assigned to cohorts according to CSMT receipt or absence. Propensity score matching was used to control for covariates that could influence the likelihood of benzodiazepine utilisation. OUTCOME MEASURES: The number, percentage and OR of patients receiving a benzodiazepine prescription over 3, 6 and 12 months' follow-up prematching and postmatching. RESULTS: After matching, there were 9206 patients (mean (SD) age, 37.6 (8.3) years, 54% male) per cohort. Odds of receiving a benzodiazepine prescription were significantly lower in the CSMT cohort over all follow-up windows prematching and postmatching (p<0.0001). After matching, the OR (95% CI) of benzodiazepine prescription at 3 months was 0.56 (0.50 to 0.64), at 6 months 0.61 (0.55 to 0.68) and 12 months 0.67 (0.62 to 0.74). Sensitivity analysis suggested a patient preference to avoid prescription medications did not explain the study findings. CONCLUSIONS: These findings suggest that receiving CSMT for newly diagnosed rLBP is associated with reduced odds of receiving a benzodiazepine prescription during follow-up. These results provide real-world evidence of practice guideline-concordance among patients entering this care pathway. Benzodiazepine prescription for rLBP should be further examined in a randomised trial including patients receiving chiropractic or usual medical care, to reduce residual confounding.

Systematic review of guideline-recommended medications prescribed for treatment of low back pain.

OBJECTIVE: To identify and descriptively compare medication recommendations among low back pain (LBP) clinical practice guidelines (CPG). METHODS: We searched PubMed, Cochrane Database of Systematic Review, Index to Chiropractic Literature, AMED, CINAHL, and PEDro to identify CPGs that described the management of mechanical LBP in the prior five years. Two investigators independently screened titles and abstracts and potentially relevant full text were considered for eligibility. Four investigators independently applied the Appraisal of Guidelines for Research and Evaluation (AGREE) II instrument for critical appraisal. Data were extracted for pharmaceutical intervention, the strength of recommendation, and appropriateness for the duration of LBP. RESULTS: 316 citations were identified, 50 full-text articles were assessed, and nine guidelines with global representation met the eligibility criteria. These CPGs addressed pharmacological treatments with or without non-pharmacological treatments. All CPGS focused on the management of acute, chronic, or unspecified duration of LBP. The mean overall AGREE II score was 89.3% (SD 3.5%). The lowest domain mean score was for applicability, 80.4% (SD 5.2%), and the highest was Scope and Purpose, 94.0% (SD 2.4%). There were ten classifications of medications described in the included CPGs: acetaminophen, antibiotics, anticonvulsants, antidepressants, benzodiazepines, non-steroidal anti-inflammatory drugs (NSAIDs), opioids, oral corticosteroids, skeletal muscle relaxants (SMRs), and atypical opioids. CONCLUSIONS: Nine CPGs, included ten medication classes for the management of LBP. NSAIDs were the most frequently recommended medication for the treatment of both acute and chronic LBP as a first line pharmacological therapy. Acetaminophen and SMRs were inconsistently recommended for acute LBP. Meanwhile, with less consensus among CPGs, acetaminophen and antidepressants were proposed as second-choice therapies for chronic LBP. There was significant heterogeneity of recommendations within many medication classes, although oral corticosteroids, benzodiazepines, anticonvulsants, and antibiotics were not recommended by any CPGs for acute or chronic LBP.

Long-term Cannabis-based oil therapy and pain medications prescribing patterns: an Italian observational study.

OBJECTIVE: Chronic pain is one of the most common medical conditions in developed countries. The 2020 Italian National Report on Medicines shows how, in the last years, there was a light but constant increase in the prescription of pain medications. The purpose of our study was to assess the effects of long-term cannabis-based oil consumption on the distribution of patients with analgesics prescriptions for chronic pain in a Pain Medicine Unit in Northern Italy. PATIENTS AND METHODS: This is a retrospective, observational study in which patients treated with long-term medical cannabis-based oils, followed between June 2016 and July 2019, were enrolled. The effects of cannabis-based oil consumption on the distribution of patients with pain medications, before and after its long-term use, were evaluated with a Related Samples McNemar Test. Subgroups analyses were performed based on sex, age, comorbidity, duration of cannabis treatment, and condition driving cannabis prescription. RESULTS: A significant difference in opioid non-users after a long-term cannabis-based oil therapy was identified (from 32.1% to 55.4%, p = 0.0023), while no significant differences were found in the distribution of anticonvulsant, antidepressant, and benzodiazepine users. A high benzodiazepine use prevalence was revealed, while subgroup analyses showed increased antidepressant use in people over 65 years old (from 93.7% to 56.2%; p = 0.0313). CONCLUSIONS: Pain medication patterns of prescribing show how necessary it is to improve prescription practices among chronic pain patients. Opioid-sparing medications represent a crucial aspect of the pain treatment process, along with deprescribing protocols. Clinicians and clinical pharmacologists must cooperate to meet the need of a guide that can represent the most possible appropriate therapy for these patients.

Outcomes After Implementation of a Benzodiazepine-Sparing Alcohol Withdrawal Order Set in an Integrated Health Care System.

Importance: Alcohol withdrawal syndrome (AWS) is a common inpatient diagnosis managed primarily with benzodiazepines. Concerns about the adverse effects associated with benzodiazepines have spurred interest in using benzodiazepine-sparing treatments. Objective: To evaluate changes in outcomes after implementation of a benzodiazepine-sparing AWS inpatient order set that included adjunctive therapies (eg, gabapentin, valproic acid, clonidine, and dexmedetomidine). Design, Setting, and Participants: This difference-in-differences quality improvement study was conducted among 22 899 AWS adult hospitalizations from October 1, 2014, to September 30, 2019, in the Kaiser Permanente Northern California integrated health care delivery system. Data were analyzed from September 2020 through November 2021. Exposures: Implementation of the benzodiazepine-sparing AWS order set on October 1, 2018. Main Outcomes and Measures: Adjusted rate ratios for medication use, inpatient mortality, length of stay, intensive care unit admission, and nonelective readmission within 30 days were calculated comparing postimplementation and preimplementation periods among hospitals with and without order set use. Results: Among 904 540 hospitalizations in the integrated health care delivery system during the study period, AWS was present in 22 899 hospitalizations (2.5%), occurring among 16 323 unique patients (mean [SD] age, 57.1 [14.8] years; 15 764 [68.8%] men). Of these hospitalizations, 12 889 (56.3%) used an order set for alcohol withdrawal. Among hospitalizations with order set use, any benzodiazepine use decreased after implementation from 6431 hospitalizations (78.1%) to 2823 hospitalizations (60.7%) (P < .001), with concomitant decreases in the mean (SD) total dosage of lorazepam before vs after implementation (19.7 [38.3] mg vs 6.0 [9.1] mg; P < .001). There were also significant changes from before to after implementation in the use of adjunctive medications, including gabapentin (2413 hospitalizations [29.3%] vs 2814 hospitalizations [60.5%]; P < .001), clonidine (1476 hospitalizations [17.9%] vs 2208 hospitalizations [47.5%]; P < .001), thiamine (6298 hospitalizations [76.5%] vs 4047 hospitalizations [87.0%]; P < .001), valproic acid (109 hospitalizations [1.3%] vs 256 hospitalizations [5.5%]; P < .001), and phenobarbital (412 hospitalizations [5.0%] vs 292 hospitalizations [6.3%]; P = .003). Compared with AWS hospitalizations without order set use, use of the benzodiazepine-sparing order set was associated with decreases in intensive care unit use (adjusted rate ratio [ARR], 0.71; 95% CI, 0.56-0.89; P = .003) and hospital length of stay (ARR, 0.71; 95% CI, 0.58-0.86; P < .001). Conclusions and Relevance: This study found that implementation of a benzodiazepine-sparing AWS order set was associated with decreased use of benzodiazepines and favorable trends in outcomes. These findings suggest that further prospective research is needed to identify the most effective treatments regimens for patients hospitalized with alcohol withdrawal.

Association Between Prenatal Cannabis Use and Psychotropic Medication Use in Pregnant Patients With Depression and Anxiety.

OBJECTIVES: This cross-sectional study examined associations between prenatal cannabis use and prescribed psychotropic medication use among pregnant patients with depression or anxiety in a large, integrated healthcare system. METHODS: Study patients had a confirmed pregnancy and a depressive or anxiety disorder defined by International Classification of Diseases codes between 2012 and 2018 at Kaiser Permanente Northern California. Patients were screened for prenatal substance use via a self-reported questionnaire and urine toxicology test as part of standard prenatal care. Generalized estimating equation models tested for associations between prenatal cannabis use and any dispensation of antidepressants, benzodiazepines, and hypnotics during gestation. Models were stratified by diagnosis (depression or anxiety) and depression symptom severity. RESULTS: This study included 35,047 pregnancies (32,278 patients; 17.6% aged <25 years, 48.1% non-Hispanic White). Adjusting for patient age, income, race/ethnicity, and depression symptom severity, the 12.6% of patients who screened positive for prenatal cannabis use demonstrated higher odds of prenatal benzodiazepine (adjusted odds ratios [aOR] = 1.40; 95% confidence interval [CI] = 1.20-1.62) and hypnotic (aOR = 1.28; 95% CI = 1.11-1.48), but not antidepressants (aOR = 1.05, 95% CI = 0.96-1.14) use. This pattern persisted when diagnostic groups were examined separately. The odds of prenatal benzodiazepine and hypnotic use associated with prenatal cannabis use were higher among pregnancies with severe depression symptom severity (31.8% of the sample). CONCLUSIONS: Among pregnant patients with depression or anxiety, prenatal cannabis use was associated with higher odds of prenatal benzodiazepine and hypnotic use. As patients may be using cannabis to address depression and anxiety, prescribers should remain vigilant for under- or untreated psychiatric symptoms among pregnant patients and provide evidence-based treatments.

Opioid agonist treatment and patient outcomes during the COVID-19 pandemic in south east Sydney, Australia.

INTRODUCTION: In early 2020, many services modified their delivery of opioid treatment in response to the COVID-19 pandemic, to limit viral spread and maintain treatment continuity. We describe the changes to treatment and preliminary analysis of the association with patients' substance use and well-being. METHODS: A pre-post comparison of treatment conditions and patient self-reported outcomes using data extracted from electronic medical records in the 5 months before (December 2019-April 2020) and after (May 2020-September 2020) changes were implemented in three public treatment services in South Eastern Sydney Local Health District. RESULTS: Data are available for 429/460 (93%) patients. Few (21, 5%) dropped out of treatment. In the 'post' period there was significantly more use of depot buprenorphine (12-24%), access to any take-away doses (TAD; 24-69%), access to ≥6 TAD per week (7-31%), pharmacy dosing (24-52%) and telehealth services. There were significant reductions in average opioid and benzodiazepine use, increases in cannabis use, with limited group changes in social conditions, or quality of life, psychological and physical health. At an individual level, 22% of patients reported increases in their use of either alcohol, opioids, benzodiazepines or stimulants of ≥4 days in the past 4 weeks. Regression analysis indicates increases in substance use were associated with higher levels of supervised dosing. DISCUSSION AND CONCLUSIONS: These preliminary findings suggest that the modified model of care continued to provide safe and effective treatment, during the pandemic. Notably, there was no association between more TAD and significant increases in substance use. Limitations are discussed and further evaluation is needed.

Anti-CD19 monoclonal antibodies for the treatment of relapsed or refractory B-cell malignancies: a narrative review with focus on diffuse large B-cell lymphoma.

PURPOSE: CD19 is a cell surface protein that is found on both healthy and malignant B cells. Accordingly, it has become an important target for novel treatments for non-Hodgkin lymphomas and B-cell leukaemia. Three anti-CD19 monoclonal antibodies with distinct mechanisms of action have been developed for the treatment of B-cell malignancies. METHODS: We reviewed the preclinical and clinical data on the development of the newly approved anti-CD19 monoclonal antibodies blinatumomab, tafasitamab and loncastuximab tesirine, and consider their place in the treatment of relapsed or refractory B-cell malignancies. RESULTS: Blinatumomab is a bispecific T-cell engager that binds to both CD19 on B cells and CD3 on T cells, facilitating antibody-dependent cytotoxicity. Blinatumomab significantly prolongs overall survival in patients with relapsed or refractory B-cell acute lymphoblastic leukaemia, although cytokine release syndrome and severe neurotoxicity may necessitate discontinuation. Tafasitamab, which has modified anti-CD19 Fab and Fc regions, has significantly enhanced affinity for both CD19 and effector cell receptors compared with unmodified anti-CD19. In L-MIND, tafasitamab plus lenalidomide provided an overall response rate (ORR) of 57.5% in patients with relapsed or refractory diffuse large B-cell lymphoma (DLBCL) in patients non-transplant eligible. Loncastuximab tesirine is an antibody-drug conjugate that has been studied as monotherapy and in combination with ibrutinib in 3L + relapsed or refractory DLBCL. The ORR was 48.3% in a phase II trial of loncastuximab tesirine. The optimal place of anti-CD19 monoclonal antibodies in therapy has yet to be determined, but the prospect of improved outcomes for at least some patients with treatment-resistant B-cell malignancies appears likely, particularly in those with limited therapeutic options and poor prognosis.

Medicine reviews: do they reduce benzodiazepine use in older Australians?

OBJECTIVES: Medicine reviews are an opportunity to identify and address inappropriate prescribing. The aim of this study was to explore changes in benzodiazepine use among older Australians following a medicine review. STUDY TYPE: Retrospective observational cohort study using linked administrative data. METHODS: We used Medicare Benefits Schedule and Pharmaceutical Benefits Scheme claims from a random 10% sample of Medicare beneficiaries. We identified people aged 65 years or older who received a medicine review in 2013-14 and were using benzodiazepines at the time of review. We identified a propensity score matched comparison cohort of those using benzodiazepines who did not receive a review. Two outcome measures were used: any benzodiazepine use and changes to the quantity of benzodiazepines dispensed (diazepam equivalents) from baseline to 90 and 180 days following a medicine review. RESULTS: We identified 4002 people using benzodiazepines on the day of their medicine review, of whom approximately one-third discontinued benzodiazepines within 90 days (29.7%) and 180 days (36.4%;) after the review. We observed a similar discontinuation rate in the comparison group (32.6%, p = 0.006; and 38.0%, p = 0.12, respectively). In people who were dispensed lower quantities of benzodiazepines (less than 250 mg of diazepam equivalents in the 90 days before the medicine review), we found that 50.3% ceased using benzodiazepines or used lower quantities (measured as diazepam equivalents) following the medicine review (28.7% and 19.7% respectively). We also observed a reduction in the quantities used in people where initial exposure was high (3.4% ceased; 59.4% decreased). We observed a similar change in volume within the matched comparison group. CONCLUSIONS: Medicine reviews are not associated with any additional reduction in benzodiazepine use among older adults, up to 180 days after review, beyond what was observed in the general population.

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.

Pharmacological and non-pharmacological treatments for insomnia: A protocol for a systematic review and network meta-analysis.

BACKGROUND: Although nonpharmacological therapies are recommended as first-line treatments for insomnia, they do not widely implement in practice owing to costly or time-consuming. As a result, pharmacotherapy remains to be commonly prescribed for patients with the sleep disorder. Pharmacotherapy for insomnia consists of different types of drugs. Few studies focused on comprehensively evaluating all available drugs for insomnia. Our review aims to compare efficacy and safety of pharmacological and nonpharmacological treatments by synthesizing direct evidence and indirect evidence to help clinicians and patients make informed decisions for insomnia. METHODS: We will search the MEDLINE, EMBASE, and Cochrane Register of Controlled Trials between January 2000 and June 12, 2021. Randomized controlled trials of pharmacological and nonpharmacological interventions for insomnia will be included. Study quality will be assessed on the basis of the methodology and categories described in the Cochrane Collaboration Handbook. Eight network meta-analyses were conducted. A Bayesian network meta-analysis would be performed, and relative ranking of agents would be assessed. A node splitting method will be used to examine the inconsistency between direct and indirect comparisons when a loop connecting 3 arms exists. RESULTS: The results of this paper will be submitted to a peer-reviewed journal for publication. CONCLUSION: The conclusion of our study will provide updated evidence to rank the effectiveness and safety of pharmacological and nonpharmacological interventions for insomnia. ETHICS AND DISSEMINATION: Ethical approval is not applicable, as this study is a network meta-analysis based on published trials. INPLASY REGISTRATION NUMBER: INPLASY202160031.

Substituting Cannabidiol for Opioids and Pain Medications Among Individuals With Fibromyalgia: A Large Online Survey.

People report substituting cannabis for pain medications, but whether cannabidiol (CBD) is used similarly remains unknown. CBD products can be CBD alone (isolate), hemp extract (containing <0.3% Δ-9-tetrahydrocannabinol [THC], other cannabinoids, and terpenes), or CBD-cannabis (containing >0.3% THC). In a secondary analysis from a cross-sectional survey, we examined substitution patterns among n = 878 individuals with fibromyalgia who currently used CBD. We sub-grouped participants by most commonly used CBD product (CBD isolate, hemp, CBD-cannabis, no preference) and whether they substituted CBD for medications. We investigated rationale for substituting, substitution-driven medication changes, CBD use patterns, and changes in pain-related symptoms (eg, sleep, anxiety). The study population was 93.6% female and 91.5% Caucasian, with an average age of 55.5 years. The majority (n = 632, 72.0%) reported substituting CBD products for medications, most commonly NSAIDs (59.0%), opioids (53.3%), gabapentanoids (35.0%), and benzodiazepines (23.1%). Most substituting participants reported decreasing or stopping use of these pain medications. The most common reasons for substitution were fewer side effects and better symptom management. Age, hemp products, past-year use of marijuana, and higher somatic burden were all associated with substituting (P's ≤ .05). Those who substituted reported larger improvements in health and pain than those who did not. Participants using CBD-cannabis reported significantly more substitutions than any other group (P's ≤ .001) and larger improvements in health, pain, memory, and sleep than other subgroups. This widespread naturalistic substitution for pain medications suggests the need for more rigorous study designs to examine this effect. PERSPECTIVE: This article shows that people with fibromyalgia are deliberately substituting CBD products for conventional pain medications despite the dearth of evidence suggesting CBD products may be helpful for fibromyalgia. CBD's medication-sparing and therapeutic potential should be examined in more rigorous study designs.

Biopsychosocial factors and health outcomes associated with cannabis, opioids and benzodiazepines use among older veterans.

Background: Older Veterans may experience injuries that result in chronic pain and mental health conditions. Given the increasing availability of medical cannabis, it is important to examine if it serves as a viable or undesirable form of care relative to existing approaches.Objectives: We compared cannabis, prescription opioids, and benzodiazepines use between older Veteran and non-Veterans, and identified outcomes of cannabis use among Veterans. Because of the physical and mental conditions experienced by older Veterans we expected Veterans to report higher use of opioids and benzodiazepines compared to non-Veterans.Methods: We collected surveys from individuals aged 60 and older enrolled in the Illinois Medical Cannabis Patient Program and conducted logistic regression to identify factors associated with cannabis, opioids and benzodiazepines use between Veterans (N = 514, 90.2% male) and Non-Veterans (N = 2758, 41.1% male) across biopsychosocial factors.Results: Both groups reported similar levels of pain, quality of life, social satisfaction, and sleep quality. Veterans were more likely to use cannabis for mental health conditions (p = <.001) while they reported lower use for pain-related conditions (p = <.001) than non-Veterans. Veterans were less likely to use opioids (p = .013) and benzodiazepines (p < .01) compared to non-Veterans. Veterans also reported desirable health outcomes of cannabis use for pain, sleep quality, health conditions, and quality of life.Conclusions: Our work provides insights for clinicians and policy makers to consider whether cannabis can be a viable option to reduce or replace opioid and benzodiazepine use by older Veterans with chronic physical and mental health conditions.

Chronic pain (primary and secondary) in over 16s: assessment of all chronic pain and management of chronic primary pain

This guideline covers assessing all chronic pain (chronic primary pain, chronic secondary pain, or both) and managing chronic primary pain in people aged 16 years and over. Chronic primary pain is pain with no clear underlying cause, or pain (or its impact) that is out of proportion to any observable injury or disease. This guideline should be used alongside NICE guidelines for other chronic pain conditions, including the NICE guidelines on headaches, low back pain and sciatica, rheumatoid arthritis, osteoarthritis, spondyloarthritis, endometriosis, neuropathic pain and irritable bowel syndrome.

Alcohol withdrawal syndrome: improving outcomes in the emergency department with aggressive management strategies.

Alcohol use disorder is a prevalent medical and psychiatric disease, and consequently, alcohol withdrawal is encountered frequently in the emergency department. Patients commonly manifest hyperadrenergic signs and symptoms, necessitating admission to the intensive care unit, administration of intravenous sedatives, and frequently, adjunctive pharmacotherapy. This issue reviews the pathophysiology of alcohol withdrawal syndrome, describes the manifestations of alcohol withdrawal, and examines the available evidence for optimal treatment of alcohol withdrawal. An aggressive frontloading approach with benzodiazepines is presented, and the management of benzodiazepine-resistant disease is addressed.