Topiramate Versus Naltrexone for Alcohol Use Disorder: A Genotype-Stratified Double-Blind Randomized Controlled Trial.

OBJECTIVE: There have been no well-controlled and well-powered comparative trials of topiramate with other pharmacotherapies for alcohol use disorder (AUD), such as naltrexone. Moreover, the literature is mixed on the effects of two polymorphisms-rs2832407 (in GRIK1) and rs1799971 (in OPRM1)-on response to topiramate and naltrexone, respectively. The authors sought to examine the comparative effectiveness of topiramate and naltrexone in improving outcomes in AUD and to examine the role of the rs2832407 and rs1799971 polymorphisms, respectively, on response to these medications. METHODS: In a 12-week, double-blind, placebo-controlled, randomized, multisite, genotype-stratified (rs2832407 and rs1799971) clinical trial comparing topiramate and naltrexone in treating AUD, 147 patients with AUD were randomly assigned to treatment with topiramate or naltrexone, stratified by genotype (rs2832407*CC and *AC/AA genotypes and rs1799971*AA and *AG/GG genotypes). The predefined primary outcome was number of heavy drinking days per week. Predefined secondary outcomes included standard drinks per drinking day per week, body mass index (BMI), craving, markers of liver injury, mood, and adverse events. RESULTS: For the number of heavy drinking days per week, there was a near-significant time-by-treatment interaction. For the number of standard drinks per drinking day per week, there was a significant time-by-treatment interaction, which favored topiramate. There were significant time-by-treatment effects, with greater reductions observed with topiramate than naltrexone for BMI, craving, and gamma-glutamyltransferase level. Withdrawal due to side effects occurred in 8% and 5% of the topiramate and naltrexone groups, respectively. Neither polymorphism showed an effect on treatment response. CONCLUSIONS: Topiramate is at least as effective and safe as the first-line medication, naltrexone, in reducing heavy alcohol consumption, and superior in reducing some clinical outcomes. Neither rs2832407 nor rs1799971 had effects on topiramate and naltrexone treatments, respectively.

Trends in reported GHB-related presentations to Sydney emergency departments between 2012 and 2021.

OBJECTIVES: In overdose, gamma-hydroxybutyrate (GHB) and its precursors can cause decreased levels of consciousness, coma and death. Here, we aim to describe reported exposure to GHB at four EDs in Sydney, New South Wales (NSW), Australia. METHODS: We searched the ED databases of four Sydney metropolitan hospitals for presentations relating to GHB exposure between 2012 and 2021. We calculated annual number of presentations stratified by hospital, age, sex, mode of arrival and triage category. RESULTS: A total of 3510 GHB-related presentations to ED were recorded across the four hospitals. Data for all hospitals were only available from 2015 onwards and between 2015 and 2021; there was a 114% increase in annual presentations (from 228 to 487). Males represented 68.7% of all presentations and the median age was 31 years (range 16-74 years). There was an increase in the proportion of female presentations between 2012 and 2021 (from 27.9% to 37.9%) along with the severity of presentation over the same period, with the proportion of presentations with a triage category 1 increasing from 19.7% to 34.5%. CONCLUSIONS: Increases in recorded absolute number and severity of GHB-related presentations to Sydney EDs are a major public health concern. There may also be shifts in the demographics of those with GHB-related presentations. Renewed efforts are required to understand the drivers of these increases to optimally target harm reduction approaches.

Has there been an increase in nitrous oxide use and associated harms in Australia? An analysis of triangulated data sources, 2003-2020.

BACKGROUND: There is growing concern, globally, regarding use of nitrous oxide (N2O) for intoxication purposes. This paper aims to examine trends in: (i) past six month N2O use among a sample of people who use regularly use ecstasy and/or other illicit stimulants (2003-2020); (ii) volume of N2O-related Google searches and social media posts (2009-2020); and (iii) N2O-related calls to Poisons Information Centres (PIC) (2004-2020). METHODS: Data were obtained from annual interviews with sentinel samples of Australians aged ≥16 years who used ecstasy and/or other illicit stimulants ≥monthly and resided in a capital city (∼800 each year); Google search activity; social media posts; and exposure calls to four PIC. RESULTS: Among samples of people who regularly use ecstasy and/or other illicit stimulants, past six-month N2O use increased 10% each year from 2009 to 2020, with the sharpest increase observed between 2015 and 2018 (25.4% p/year; 95% CI: 14.6-37.1). Frequency and quantity of N2O use remained stable and low. Google search probabilities increased by 1.8% each month from January 2009 and December 2019 (95% CI: 1.5-2.2), with the sharpest increase observed between July 2016 to December 2017 (6.0% p/month; 95% CI: 4.4-7.5). Social media posts increased 2.0% per month from January 2009 and December 2019 (95% CI: 1.1-3.0), with the sharpest increase observed between March and October 2017 (19.2% p/month; 95% CI: 1.7-39.7). The number of N2O-related calls to Australian PIC increased sixfold between 2016 (16) and 2020 (111). CONCLUSIONS: Triangulation of various data sources indicate significant shifts in N2O use and harms in Australia. This includes increases in use, Google searches and social media posts, although these have plateaued in recent years, coupled with increased rates of harm. These findings correspond with evidence of a global increase in N2O use and harm, highlighting the need for education of both people who use N2O and health professionals.

N acetylcysteine in the treatment of alcohol use disorder: a randomized, double-blind, placebo-controlled trial.

N-acetyl cysteine (NAC) is a potent antioxidant that modulates glutamatergic signalling which is thought to play a role in alcohol use disorder (AUD). There have been no clinical trials investigating NAC for AUD. We aimed to conduct a 28 day double-blind, placebo-controlled (PL) randomized trial of NAC in the treatment of AUD (NCT03879759). A total of 42 participants with AUD (56% alcohol-related liver disease) were randomized to receive placebo or NAC 2400 mg/day. Feasibility outcomes included treatment retention and adverse events. Primary clinical outcomes included alcohol consumption (heavy drinking days, standard drinks per drinking day). Secondary clinical outcome measures included craving, liver tests, and psychological outcomes. There were no significant differences in overall retention between treatment groups (χ2(1) = 0.14, P = 0.71: 86% vs 76% for placebo and NAC, respectively). The most commonly reported adverse event in NAC-treated individuals included headache (14%). For standard drinks per drinking day, there was a significant overall effect of time (F = 9.18, P < 0.001), no significant effect of treatment (F = 0.75, P = 0.79), and a significant time x treatment (NAC vs PL) effect (F = 2.73, P < 0.05). For number of heavy drinks per day, there was a significant overall effect of time (F = 3.16, P < 0.05) but no significant effect of treatment or time x treatment (P = 0.17). There were no significant NAC vs PL effects on secondary clinical outcome measures. In the first trial of NAC for the management of AUD, NAC appears to be feasible and safe. Although there was a significant effect of NAC vs placebo on some alcohol measures such as drinks per drinking day, there does appear to be a variable pattern of effect across time suggesting that a larger trial incorporating a longer treatment duration is now required to determine efficacy.

Evaluation of adherence monitoring in buprenorphine treatment: A pilot study using timed drug assays to determine accuracy of testing.

AIMS: Buprenorphine is effective at reducing relapse to opioid misuse, morbidity and mortality in opioid-dependent patients. Urine drug screening (UDS) to assess adherence is used routinely in opioid agonist treatment (OAT). The primary aim of this study was to determine factors which may be associated with a negative qualitative urine drug screen for buprenorphine in OAT patients. METHODS: This prospective pilot study was conducted at a tertiary addiction medicine centre. Twenty participants on stable treatment underwent supervised administration of sublingual buprenorphine. Matched urine and blood samples were collected prior to and 2, 4 and 6 hours after buprenorphine administration. Qualitative urine drug screen results were obtained using gas chromatography-mass spectrometry (GC-MS), while quantitative blood and urine results were obtained using ultra-performance liquid chromatography-tandem mass spectrometry (UPLC-MS/MS). RESULTS: Qualitative urine assay yielded a negative result for buprenorphine in 57% of tested samples. The median concentration of urinary buprenorphine was 167 mcg/L (range: 2-1730 mcg/L). Thirty percent of all blood samples did not detect buprenorphine (range 0-18 mcg/L). Positive qualitative urine drug screen results were associated with higher urine (343 mcg/L compared with 75 mcg/L; P < .05) and blood (4 mcg/L compared with 2 mcg/L; P < .05) buprenorphine concentrations. Median urine concentrations of buprenorphine were highest at 2 hours and were higher in participants receiving CYP3A4 inhibitors. CONCLUSION: Interpretation of qualitative urine drug screens to assess adherence in OAT is complex. Poor adherence with treatment cannot be assumed in patients returning a negative qualitative GC-MS urine drug screen.

Hippocampal ischaemia from accidental 5-Hydroxytryptophan (5-HTP) overdose case report.

We report severe reversible hippocampal ischaemia following an accidental 5-Hydroxytryptophan (5-HTP) overdose. Serious consequences from 5-HTP overdose have not been reported. A 44-year-old previously well man ingested ten times the recommended dose of 5-HTP powder. After four hours he developed marked antegrade and retrograde amnesia, disorientation and confusion in the absence of loss of consciousness, seizure activity or features of serotonin toxicity. Magnetic resonance imaging (MRI) of the brain on day two revealed extensive symmetrical restricted diffusion bilaterally in the hippocampi, suggestive of ischaemia or seizure. Electroencephalogram was normal. Short and long-term memory improved sufficiently to return to work after two months. MRI at eleven months was normal. The most likely mechanism is drug-induced hippocampal ischaemia resulting from marked increase in 5-HTP.

Life-threatening barium carbonate poisoning managed with intravenous potassium, continuous veno-venous haemodialysis and endoscopic removal of retained ceramic glazes.

INTRODUCTION: Barium poisoning is rare but potentially severe. We describe a case of acute barium carbonate poisoning with cardiac arrest, managed with intravenous potassium, dialysis and endoscopic removal of retained ceramic glazes. CASE REPORT: A 38-year-old woman presented with vomiting 90 min after ingesting 3 cups of barium and strontium carbonate. Initial bloods noted potassium 2.8 mmol/L and creatinine 53 µmol/L. Electrocardiogram demonstrated prolonged corrected QT interval 585msec. Initial management included intravenous potassium. Four hours post-ingestion she developed proximal muscle weakness in upper limbs with a potassium of 2.2 mmol/L. At 15 h post-ingestion she developed profound muscle weakness, polymorphic ventricular tachycardia and cardiac arrest. Treatment included defibrillation, endotracheal intubation and continuous veno-venous haemodialysis (CVVHD) for metabolic derangement and enhanced elimination of barium. Chest X-ray 17 h post-ingestion demonstrated a large radio-opaque mass in the stomach, thought to be the ceramic glaze. Endoscopy removed the retained material 41 h post-ingestion. She was extubated 58 h post-ingestion and CVVHD was ceased on day 3. Serum creatinine peaked at 348 µmol/L on day 7, but normalised by discharge. Biphasic barium concentrations were noted, notably 94 µmol/L on admission, 195 µmol/L at 16 h, 95 µmol/L at 20 h, and 193 µmol/L at 30 h post-ingestion. CONCLUSION: In barium poisoning with hypokalaemia, prompt potassium supplementation is required but rebound hyperkalaemia can occur. Endoscopic removal of ceramic glazes may be useful more than 12 h post-ingestion. Consider extracorporeal methods to enhance barium elimination in severe cases.

New Australian guidelines for the treatment of alcohol problems: an overview of recommendations.

OF RECOMMENDATIONS AND LEVELS OF EVIDENCE: Chapter 2: Screening and assessment for unhealthy alcohol use Screening Screening for unhealthy alcohol use and appropriate interventions should be implemented in general practice (Level A), hospitals (Level B), emergency departments and community health and welfare settings (Level C). Quantity-frequency measures can detect consumption that exceeds levels in the current Australian guidelines (Level B). The Alcohol Use Disorders Identification Test (AUDIT) is the most effective screening tool and is recommended for use in primary care and hospital settings. For screening in the general community, the AUDIT-C is a suitable alternative (Level A). Indirect biological markers should be used as an adjunct to screening (Level A), and direct measures of alcohol in breath and/or blood can be useful markers of recent use (Level B). Assessment Assessment should include evaluation of alcohol use and its effects, physical examination, clinical investigations and collateral history taking (Level C). Assessment for alcohol-related physical problems, mental health problems and social support should be undertaken routinely (GPP). Where there are concerns regarding the safety of the patient or others, specialist consultation is recommended (Level C). Assessment should lead to a clear, mutually acceptable treatment plan which specifies interventions to meet the patient's needs (Level D). Sustained abstinence is the optimal outcome for most patients with alcohol dependence (Level C). Chapter 3: Caring for and managing patients with alcohol problems: interventions, treatments, relapse prevention, aftercare, and long term follow-up Brief interventions Brief motivational interviewing interventions are more effective than no treatment for people who consume alcohol at risky levels (Level A). Their effectiveness compared with standard care or alternative psychosocial interventions varies by treatment setting. They are most effective in primary care settings (Level A). Psychosocial interventions Cognitive behaviour therapy should be a first-line psychosocial intervention for alcohol dependence. Its clinical benefit is enhanced when it is combined with pharmacotherapy for alcohol dependence or an additional psychosocial intervention (eg, motivational interviewing) (Level A). Motivational interviewing is effective in the short term and in patients with less severe alcohol dependence (Level A). Residential rehabilitation may be of benefit to patients who have moderate-to-severe alcohol dependence and require a structured residential treatment setting (Level D). Alcohol withdrawal management Most cases of withdrawal can be managed in an ambulatory setting with appropriate support (Level B). Tapering diazepam regimens (Level A) with daily staged supply from a pharmacy or clinic are recommended (GPP). Pharmacotherapies for alcohol dependence Acamprosate is recommended to help maintain abstinence from alcohol (Level A). Naltrexone is recommended for prevention of relapse to heavy drinking (Level A). Disulfiram is only recommended in close supervision settings where patients are motivated for abstinence (Level A). Some evidence for off-label therapies baclofen and topiramate exists, but their side effect profiles are complex and neither should be a first-line medication (Level B). Peer support programs Peer-led support programs such as Alcoholics Anonymous and SMART Recovery are effective at maintaining abstinence or reductions in drinking (Level A). Relapse prevention, aftercare and long-term follow-up Return to problematic drinking is common and aftercare should focus on addressing factors that contribute to relapse (GPP). A harm-minimisation approach should be considered for patients who are unable to reduce their drinking (GPP). Chapter 4: Providing appropriate treatment and care to people with alcohol problems: a summary for key specific populations Gender-specific issues Screen women and men for domestic abuse (Level C). Consider child protection assessments for caregivers with alcohol use disorder (GPP). Explore contraceptive options with women of reproductive age who regularly consume alcohol (Level B). Pregnant and breastfeeding women Advise pregnant and breastfeeding women that there is no safe level of alcohol consumption (Level B). Pregnant women who are alcohol dependent should be admitted to hospital for treatment in an appropriate maternity unit that has an addiction specialist (GPP). Young people Perform a comprehensive HEEADSSS assessment for young people with alcohol problems (Level B). Treatment should focus on tangible benefits of reducing drinking through psychotherapy and engagement of family and peer networks (Level B). Aboriginal and Torres Strait Islander peoples Collaborate with Aboriginal or Torres Strait Islander health workers, organisations and communities, and seek guidance on patient engagement approaches (GPP). Use validated screening tools and consider integrated mainstream and Aboriginal or Torres Strait Islander-specific approaches to care (Level B). Culturally and linguistically diverse groups Use an appropriate method, such as the "teach-back" technique, to assess the need for language and health literacy support (Level C). Engage with culture-specific agencies as this can improve treatment access and success (Level C). Sexually diverse and gender diverse populations Be mindful that sexually diverse and gender diverse populations experience lower levels of satisfaction, connection and treatment completion (Level C). Seek to incorporate LGBTQ-specific treatment and agencies (Level C). Older people All new patients aged over 50 years should be screened for harmful alcohol use (Level D). Consider alcohol as a possible cause for older patients presenting with unexplained physical or psychological symptoms (Level D). Consider shorter acting benzodiazepines for withdrawal management (Level D). Cognitive impairment Cognitive impairment may impair engagement with treatment (Level A). Perform cognitive screening for patients who have alcohol problems and refer them for neuropsychological assessment if significant impairment is suspected (Level A). SUMMARY OF KEY RECOMMENDATIONS AND LEVELS OF EVIDENCE: Chapter 5: Understanding and managing comorbidities for people with alcohol problems: polydrug use and dependence, co-occurring mental disorders, and physical comorbidities Polydrug use and dependence Active alcohol use disorder, including dependence, significantly increases the risk of overdose associated with the administration of opioid drugs. Specialist advice is recommended before treatment of people dependent on both alcohol and opioid drugs (GPP). Older patients requiring management of alcohol withdrawal should have their use of pharmaceutical medications reviewed, given the prevalence of polypharmacy in this age group (GPP). Smoking cessation can be undertaken in patients with alcohol dependence and/or polydrug use problems; some evidence suggests varenicline may help support reduction of both tobacco and alcohol consumption (Level C). Co-occurring mental disorders More intensive interventions are needed for people with comorbid conditions, as this population tends to have more severe problems and carries a worse prognosis than those with single pathology (GPP). The Kessler Psychological Distress Scale (K10 or K6) is recommended for screening for comorbid mental disorders in people presenting for alcohol use disorders (Level A). People with alcohol use disorder and comorbid mental disorders should be offered treatment for both disorders; care should be taken to coordinate intervention (Level C). Physical comorbidities Patients should be advised that alcohol use has no beneficial health effects. There is no clear risk-free threshold for alcohol intake. The safe dose for alcohol intake is dependent on many factors such as underlying liver disease, comorbidities, age and sex (Level A). In patients with alcohol use disorder, early recognition of the risk for liver cirrhosis is critical. Patients with cirrhosis should abstain from alcohol and should be offered referral to a hepatologist for liver disease management and to an addiction physician for management of alcohol use disorder (Level A). Alcohol abstinence reduces the risk of cancer and improves outcomes after a diagnosis of cancer (Level A).

Buprenorphine not detected on urine drug screening in supervised treatment.

INTRODUCTION: Urine drug screens (UDS) assist in clinical planning and assessment of adherence in opioid agonist treatment (OAT). Urine drug screens may also be used in criminal justice and child protection settings. Buprenorphine (BPN) UDS testing is complex. Immunoassay often does not detect BPN and gas chromatography-mass spectrometry (GC-MS) is needed. A limited understanding of testing can negatively influence UDS interpretation and clinical decision making. OBJECTIVES: The primary aim was to determine detection rates of BPN in UDS in participants on BPN or buprenorphine/naloxone (BNX) treatment. The secondary aim was to identify if comorbidities, sex, co-prescribed medications, or dosing site and observation were associated with BPN detection. SETTING: Public outpatient clinic in a specialist addiction treatment service. DESIGN/PARTICIPANTS: In this retrospective observational study, records of clients on supervised BPN/BNX treatment between September 2017 and 2018 were reviewed. MEASURES: Data extracted included UDS results, age, sex, indication for BPN, frequency of observed doses, dose of BPN, dosing site, comorbid medical conditions, and medications. RESULTS: One hundred and sixty-one medical records were reviewed. Ninety-seven (60 percent) underwent screening urine immunoassay. Of these 97, 51 (53 percent) had further GC-MS testing for BPN of which 22 (43 percent) did not detect BPN despite directly observed OAT. Co-prescription of medications known to interact with cytochrome P450 3A4 was associated with nondetection of BPN (p < 0.05). No significant association between median dose, dosing site, and observed dosing and BPN detection was identified. CONCLUSION: Urine drug testing for BPN is complex. Failure to detect BPN does not betoken nonadherence to treatment and is associated with co-prescription of drugs interacting with cytochrome P450 3A4.

Reverse Takotsubo Cardiomyopathy Precipitated by Chronic Cocaine and Cannabis Use.

This case report describes a 31-year-old man with 10 years of cocaine and cannabis dependence who developed reverse Takotsubo cardiomyopathy (rTC), a rare variant of Takotsubo cardiomyopathy. He presented to the Emergency Department (ED) with severe left temporal headache and vomiting which began whilst smoking cannabis and several hours after smoking methamphetamine and using cocaine via insufflation. Computed tomography and angiography of the brain was normal, and the headache resolved with analgesia. Urine drug screen was positive for benzodiazepines, cannabinoids, cocaine, opiates (attributed to morphine administered in ED) and amphetamines. Three hours later he had a seizure and within 10 min developed cardiogenic shock with antero-inferior ST segment depression on electrocardiogram and troponin-T rise to 126 ng/L. Coronary angiography demonstrated normal coronary arteries. Transthoracic echocardiogram demonstrated severely impaired left ventricular (LV) systolic function with ejection fraction 15-20% and hypokinesis sparing the apex. Thyrotoxicosis, nutritional, vasculitic, autoimmune and viral screens were negative. Cardiac magnetic resonance imaging demonstrated severe LV functional impairment with dilated and hypocontractile basal segments, and T2 hyperintensity consistent with myocardial oedema and rTC. He received supportive management. Proposed mechanisms of rTC include catecholamine cardiotoxicity and coronary artery vasospasm. In this case, multiple insults including severe headache, cannabis hyperemesis and cocaine and methamphetamine-induced serotonin toxicity culminated in a drug-induced seizure which led to catecholamine cardiotoxicity resulting in rTC. Clinicians should be cognizant of stress cardiomyopathy as a differential diagnosis in patients with substance use disorders.

Recurrent Takotsubo Cardiomyopathy Associated with Opioid Withdrawal During Buprenorphine Induction.

This case report describes a 65-year-old female with iatrogenic opioid use disorder for chronic lower back pain, who developed Takotsubo cardiomyopathy on multiple occasions following buprenorphine induction. This patient had three opioid transfers to buprenorphine, over 4 years, two of which were complicated by Takotsubo cardiomyopathy. In the transfer where she did not develop Takotsubo cardiomyopathy, she was treated with high doses of the centrally acting agonist, clonidine (three times a day, total of 600 mcg/day), up to and including the day of her transfer. This case highlights the potential consequences of a precipitated withdrawal with buprenorphine in an opioid transfer and its possible prevention with clonidine. To our knowledge, this is the first description of the recurrent Takotsubo cardiomyopathy in an opioid transfer setting. Given that buprenorphine is a partial agonist, in the presence of a full opioid agonist, it can precipitate withdrawal within minutes to hours of its administration. Opioid withdrawal can result in a sympathetic overdrive. Although complications of opioid withdrawal are extensively documented, cardiotoxicity is uncommon. As the use of buprenorphine and its new injectable formulations rise, it is important for prescribers to be aware of this life threatening complication. The prophylactic administration of clonidine can be considered to reduce the risk of cardiotoxicity, as well as manage opioid withdrawal symptoms.

Incomplete responses to the recommended dose of idarucizumab: a systematic review and pharmacokinetic analysis.

Introduction: Dabigatran, a direct thrombin inhibitor, is 80% renally eliminated and demonstrates multi-compartmental pharmacokinetics. Idarucizumab is a monoclonal antibody that reverses dabigatran-induced anticoagulation and displays single compartment pharmacokinetics, with a smaller volume of distribution and shorter elimination half-life than dabigatran. These differences in pharmacokinetics mean that redistribution of dabigatran from peripheral compartments can occur after idarucizumab has been eliminated, resulting in rebound in the dabigatran plasma concentration and treatment failure. Clinical experience notes failure of a single idarucizumab 5 g dose to fully reverse coagulopathy in certain patients.Aims: To identify factors predisposing to an incomplete response to the standard idarucizumab 5 g dose.Methods: A systematic literature search in PubMed using terms "dabigatran" and "idarucizumab" covering 2015 to October 2019 identified 387 entries. Titles and abstracts were screened initially, followed by full text review and data extraction from 97 eligible articles. Data extracted included clinical information, dabigatran concentrations, coagulation results, idarucizumab dosage and patient outcomes. Pharmacokinetic simulations were conducted using a two-compartment model to predict the likelihood that acute or chronic kidney disease will contribute to an incomplete reversal of dabigatran-induced anticoagulation.Results: Of 240 published cases receiving idarucizumab, 33 reported dabigatran concentration rebound, within a median time of 22 h. From 231 cases reporting idarucizumab dose, 10 received repeated administration due to a rebound in dabigatran concentrations. Baseline dabigatran concentrations >228 ng/mL were more likely to experience a rebound post-idarucizumab to >30 ng/mL (detectable). For baseline dabigatran >488 ng/mL, the concentration rebounded to >75 ng/mL (therapeutic). The impact of kidney dysfunction on the effect of the recommended dose of idarucizumab: Idarucizumab is expected to neutralise a maximum plasma dabigatran concentration of 980 ng/mL, but most likely a lesser amount. Pharmacokinetic modelling suggests, for patients taking dabigatran 150 mg twice daily, an incomplete response to 5 g idarucizumab is predicted after approximately 72 h dosing when GFR less than 30 mL/min (25% of normal), and after 36 h with severely impaired renal function (GFR 6 mL/min; GFR 5% of normal). Acute dabigatran self-poisoning: Idarucizumab has neutralised dabigatran following deliberate self-poisoning with dabigatran in a limited number of cases, even in the absence of bleeding. There are insufficient data regarding the use of idarucizumab as part of standard supportive care in this context. Clinical use of idarucizumab in complex circumstances: The dilute thrombin time can be used to determine the dabigatran concentration, but other more standard coagulation assays are less precise. A normal aPTT largely excludes dabigatran. We suggest performing coagulation assays and dabigatran concentrations every 6 h for a minimum of 36 h after idarucizumab administration to detect a rebound in dabigatran. This is particularly necessary in patients with glomerular filtration rate <30 mL/min or those with a plasma dabigatran concentration exceeding approximately 500 ng/mL. If a rebound in dabigatran is noted, then repeat administration of idarucizumab 5 g can be considered for reversal of recurrent coagulopathy if clinically indicated.Conclusion: The use of idarucizumab for reversal of dabigatran is complex and requires consideration of clinical circumstances and laboratory investigations. Monitoring post-idarucizumab may be required in acute or chronic kidney disease to detect a rebound in dabigatran concentration and the need for additional doses of idarucizumab.

Methadone-induced encephalopathy: a case series and literature review.

BACKGROUND: Accidental ingestion or consumption of supra-therapeutic doses of methadone can result in neurological sequelae in humans. We aimed to determine the neurological deficits of methadone-poisoned patients admitted to a referral poisoning hospital using brain magnetic resonance (MR) and diffusion weighted (DW) imaging. METHODS: In this retrospective study, brain MRIs of the patients admitted to our referral center due to methadone intoxication were reviewed. Methadone intoxication was confirmed based on history, congruent clinical presentation, and confirmatory urine analysis. Each patient had an MRI with Echo planar T1, T2, FLAIR, and DWI and apparent deficient coefficient (ADC) sequences without contrast media. Abnormalities were recorded and categorized based on their anatomic location and sequence. RESULTS: Ten patients with abnormal MRI findings were identified. Eight had acute- and two had delayed-onset encephalopathy. Imaging findings included bilateral confluent or patchy T2 and FLAIR high signal intensity in cerebral white matter, cerebellar involvement, and bilateral occipito-parietal cortex diffusion restriction in DWI. Internal capsule involvement was identified in two patients while abnormality in globus pallidus and head of caudate nuclei were reported in another. Bilateral cerebral symmetrical confluent white matter signal abnormality with sparing of subcortical U-fibers on T2 and FLAIR sequences were observed in both patients with delayed-onset encephalopathy. CONCLUSIONS: Acute- and delayed-onset encephalopathies are two rare adverse events detected in methadone-intoxicated patients. Brain MRI findings can be helpful in detection of methadone-induced encephalopathy.

A Review of Baclofen Overdoses in Australia: Calls to a Poisons Information Centre and a Case Series.

AIM: to describe trends in baclofen reports to Australia's largest Poisons Information Centre (PIC) and present a case series detailing severity of overdoses. SHORT SUMMARY: PBS data demonstrates baclofen use is increasing in Australia, while calls to NSWPIC illustrate an increase in number of exposures associated with toxicity. Baclofen toxicity may require prolonged intensive care admission. To minimize harms associated, especially with off-label baclofen prescribing for AUD, prescribers should pay careful attention to psychiatric comorbidities, and closely monitor treatment and dispensing. METHODS: this is a retrospective observational study of baclofen overdoses reported to New South Wales PIC (NSWPIC) from January 1 2004 to 31 December 2016. In addition, referrals to a metropolitan toxicology service relating to baclofen toxicity from 2014 to 2017 were analysed. The number of Pharmaceutical Benefit Scheme (PBS) claims for baclofen were also reviewed. RESULTS: during the 13-year study period, 403 cases of baclofen toxicity were reported to NSWPIC. There was a 230% increase in annual exposures over this period, 71% of patients were symptomatic, with 77% requiring hospitalization. Coingestants were reported in 53%, with 57% being psychoactive medications (including alcohol). An increase in number of baclofen dispensing episodes was also noted. From the five cases of deliberate self-harm reported to the metropolitan toxicology service, three obtained baclofen for management of alcohol use disorder (AUD) and required prolonged treatment in the intensive care unit (ICU). CONCLUSIONS: NSWPIC data shows an increase in number of calls regarding intentional baclofen exposures in parallel with increase the number of baclofen PBS claims. These closely parallel the increase in dispensing of baclofen since 2008. Case studies presented reinforce the severity of baclofen toxicity. Together, they demonstrate the potential risk of harm of baclofen prescribing, and the greater need for caution. Baclofen should be considered carefully in patients high risk of overdose or be used only in specialist services with close monitoring.

Baclofen Response in Alcohol Dependent Patients Concurrently Receiving Antidepressants: Secondary Analysis From the BacALD Study.

Background and Aims: There is little information with regards to the efficacy of baclofen among alcohol patients concurrently receiving antidepressants (AD). The present study aimed to conduct a secondary analysis of the moderating role of antidepressants in the BacALD trial which evaluated the efficacy of baclofen to reduce alcohol consumption in alcohol dependent patients. Methods: Alcohol dependent patients (N = 104) were treated for 12 weeks with 30 mg/day of baclofen (21 = AD and 15 = no AD), 75 mg baclofen (19 = AD and 16 = no AD) or placebo (17 = AD and 16 = no AD). Patients were included in the trial if they were concurrently receiving anti-depressants upon enrolment but were excluded if they commenced antidepressants 2 months prior to enrolment. Patients were also excluded in the case of concurrent psychotropic medications, active major mental disorder such as bipolar disorder, psychosis, or history of suicide attempt. Predefined primary outcomes included time to lapse (any drinking), relapse (>5 drinks per day in men and >4 in women). Other outcomes included drinks per drinking day, number of heavy drinking days, and percentage days abstinent and frequency of adverse events. Results: For the number of days to first lapse, there was a trend of significance for the interaction baclofen × AD (Log Rank: χ2 = 2.98, P = 0.08, OR: 0.41, 95%CI: 0.15-1.12). For the number of days to relapse, there was a trend of significance for the interaction of baclofen × AD (Log Rank: χ2 = 3.72, P = 0.05, OR: 3.40, 95%CI: 1.01-11.46). Placing significant baseline variables into the models as covariates (tobacco, ALD) weakened these interactions (P's > 0.15). There were no significant effects of ADs on the frequency of adverse events reported (P's > 0.19). Conclusion: Concurrent receipt of ADs commenced more than 2 months prior to baclofen treatment did not negatively impact on drinking outcomes. Future research examining the interaction between commencing ADs during baclofen treatment on alcohol dependent patients is required. Trial Registration: ClinicalTrials.gov, NCT01711125, https://clinicaltrials.gov/ct2/show/NCT01711125.