Nicholas A. Buckley

Objectives: To evaluate trends in pregabalin use and overdose in Australia and examine temporal relationships with media coverage (December 2018), prescribing and dispensing restrictions (April 2020), and boxed warnings (February 2021). Design: Retrospective observational study of dispensing and overdose data, with changepoint, interrupted time series, and latent class analysis. Setting and participants: Pharmaceutical Benefits Scheme data (PBS; 10% random sample of people with drug subsidies) and overdose calls (self-harm, recreational use, and misuse) reported to Australia’s largest Poisons Centre (50% national sample), 2016-24. Main outcome measures: Population adjusted rates of dispensing and overdose, timing of breakpoints and rate ratios, proportion of people who use pregabalin at high risk of misuse. Results: 227 864 people were dispensed 3 441 851 pregabalin prescriptions in the PBS 10% sample and 4871 pregabalin overdose calls were made to the Poisons Centre. Pregabalin use peaked in 2018 before plateauing and declining. Three breakpoints were found in dispensing data, with major decreases in level and slope: December 2018, May 2020, December 2021. The combined rate ratio for dispensing was 0.748 (95% confidence interval 0.700 to 0.800). Compared with the projected historical trend in the absence of interventions (counterfactual), approximately 118 390 (93 960 to 140 940) fewer pregabalin prescriptions were recorded nationally in December 2021, and an ongoing reduction of 0.7% (0.5% to 0.9%) was found each month. All breakpoints were associated with declines in overdose rates, with a combined rate ratio of 0.532 (95% CI 0.406 to 0.695). This reduction corresponded to approximately 41.3 (26.9 to 52.4) fewer pregabalin overdose calls in December 2021 and an ongoing reduction of 1.6% (1.0% to 2.3%) each month. Latent class analysis of 57 744 people dispensed pregabalin in the 12 months after the final breakpoint revealed four groups. The high risk group (7790, 13.5%) were more likely male, younger, dispensed more pregabalin, with shorter refill interval and high rates of opioids and benzodiazepine co-use (5120 (65.7%) and 2455 (31.5%), respectively). Conclusions: Pregabalin use and overdose in Australia have declined in recent years. Major decreases in trend corresponded with media coverage (December 2018) and prescribing and dispensing restrictions (May 2020). The third breakpoint may be a delayed impact of boxed warnings (implemented February 2021). These findings suggest that regulatory and risk communication measures may contribute to reducing pregabalin related harm.

Background and aims: People with substance use disorders have reduced life‐expectancy; however, risks of premature death from injuries and natural causes following an accidental overdose are not well characterised. This study aimed to estimate risk of premature death (by cause and over time), and disease burden following hospitalised accidental overdose. Design: An observational study using the Poisoning And enVenomation Linkage to evaluate Outcomes and clinical Variation in Australia (PAVLOVA) cohort. Setting: A population‐based data‐linkage including admissions from all public and private hospitals in New South Wales, Australia (population ~8 million), 2011–2020. Participants: 14 036 individuals [median age 43.5 years, interquartile range (IQR) = 29.4–61.8 years, 46.7% female, n = 6557] with an index non‐fatal accidental poisoning, as defined by hospital coding, followed for a median of 3.9 years (IQR = 1.7–6.3). We restricted our analysis to people with accidental poisonings with prescription and illicit drugs that are associated with non‐medical use and dependence, including opioids and benzodiazepines. Measurements: Standardised mortality ratio (SMR) by cause (natural causes stratified by body system, and external causes stratified by intent and mechanism), SMR over time (post‐index poisoning), years of life lost (YLL) by cause, age and sex. SMR and YLL were calculated based on expected values generated using official statistics. Results: Of the 14 036 people included, there were 2588 deaths. Death was more likely in individuals with accidental poisoning compared with the general population [SMR = 3.5, 95% confidence interval (CI) = 3.4–3.7]. SMRs were highest for external causes (SMR = 12.8, 95% CI = 11.5–14.1), including accidental poisoning (SMR = 59.5, 95% CI = 51.7–67.3) and suicide (SMR = 10.5, 95% CI = 8.2–12.9). Death was also more likely across all natural causes, particularly infectious (SMR = 7.0, 95% CI = 5.1–8.9) and respiratory diseases (SMR = 6.2, 95% CI = 5.4–6.9). Median YLL per death was 21.2 (IQR = 10.0–35.6) and 15.2 (IQR = 7.2–30.2) for males and females, respectively. The main contributors to YLL were natural causes (64.0%): neoplasms (19.5%), circulatory (12.2%) and respiratory disease (11.1%). The remainder of YLL was from external causes (36.0%): mainly accidental poisoning (22.4%). Summary: People in New South Wales, Australia, who experience an accidental overdose appear to have an increased risk of death over subsequent years, but particularly in the first month, compared with the general population; however, accidental poisoning accounts for only 22% of years of life lost, with death from natural causes being much more common.

Acetaminophen overdose can cause liver injury. Hepatotoxicity results from N ‐acetyl‐ p ‐benzoquinone imine (NAPQI), generated via cytochrome P450‐2E1 (CYP2E1). Acetylcysteine is the mainstay of treatment, but efficacy may be reduced with delayed administration or large ingestions. Fomepizole, a CYP2E1 inhibitor, reduces NAPQI when co‐administered with acetaminophen, but its clinical relevance remains uncertain. The objective was to evaluate the effect of fomepizole administered 2 hours after acetaminophen ingestion in immediate‐ and modified‐release overdose. In a randomized crossover study simulating overdose, healthy volunteers received ~≈80 mg/kg of either immediate‐ or modified‐release acetaminophen followed by intravenous fomepizole or placebo 2 hours later. Volunteers crossed over after 2 weeks. Urine and serum were collected over 24 hours to measure acetaminophen, non‐toxic metabolites (APAP‐Glu, APAP‐Sul), and NAPQI metabolites (APAP‐Mer, APAP‐Cys). The primary outcome was the proportion of NAPQI metabolites in urine relative to total excreted compounds. Secondary outcomes included 24‐hour AUCs for metabolites. Five crossover pairs were completed per formulation. Median 24‐hour urinary recovery was 92% (IQR: 89–95%). Fomepizole significantly reduced the mean percentage of urinary NAPQI metabolites for both immediate‐release (4.92% [SD: 0.97] vs. 1.72% [SD: 0.3], mean difference [fomepizole–control]: ‐3.20%, 95% CI: −4.45 to −1.95%, P = 0.0021) and modified release acetaminophen (5.62% [SD: 1.1] vs. 1.43% [SD: 0.3], mean difference [fomepizole–control]: −4.19%, 95% CI: −5.23 to −3.15%, P = 0.0004). Mean serum NAPQI metabolite AUCs were lower with fomepizole: 89.3 [SD: 11.1] vs. 32.5 [SD: 3.3] μmol/L*h (mean difference [fomepizole–control]: −56.8, 95% CI: −72.6 to −41.0, P =0.0006) for immediate‐release, and 96.7 [SD: 15.2] vs. 27.2 [SD:7.2] μmol/L*h (mean difference [fomepizole–control]: −69.5, 95% CI:–84.6 to −54.4, P = 0.0002) for modified‐release acetaminophen. Fomepizole, administered 2 hours after an acetaminophen overdose, reduced NAPQI formation by 60–70%, supporting further evaluation as an adjunct in overdoses where acetylcysteine may be insufficient.

NSW Poisons Information Centre data identified 1030 deliberate prazosin self‐poisonings over 11 years, rising from 13 to 170 per year (2014–2024). Young women predominated, likely due to expanded off‐label (but accepted) psychiatric use of prazosin. Better evidence on benefits of off‐label use is needed to justify increasing risks.

The Clinical Toxicology Recommendations Collaborative was established by three international clinical toxicology societies and tasked to produce recommendations on the management of poisonings. The Activated Charcoal in Clinical Toxicology Workgroup (the Workgroup) was formed to provide recommendations on the administration of activated charcoal for gastrointestinal decontamination and enhanced elimination in poisoning. Based on a systematic review of the literature, 43 poisons or poison categories were selected for appraisal. Voting statements were drafted using a predetermined format. Strength of consensus was measured using the Disagreement Index as defined by the RAND/University of California at Los Angeles Appropriateness Method. A two-round modified Delphi method was used to reach expert consensus. The Workgroup concluded that there is no role for activated charcoal in poisoning from arsenic, caesium, copper, ethanol, methanol, ethylene glycol, iron, lead, lithium, and metformin. Activated charcoal is appropriate after ingestion of antidysrhythmics (types I and III not discussed specifically), beta-adrenergic antagonists, bupropion, calcium-channel blockers, carbamazepine, cardiac glycosides, chloroquine, cocaine, colchicine, cyanide, dapsone, diphenhydramine, disopyramide, factor Xa inhibitors, ibuprofen, isoniazid, lamotrigine, methotrexate, moclobemide, opioids, organophosphorus insecticides, paracetamol (acetaminophen), paraquat, phenobarbital, phenytoin, quinidine and quinine, salicylates, selective serotonin reuptake inhibitors, sulfonylureas, thallium, theophylline, tricyclic antidepressants, valproic acid, venlafaxine, and warfarin. An additional dose of activated charcoal to complete gastrointestinal decontamination is appropriate after ingestion of carbamazepine, paracetamol, paraquat, phenobarbital, salicylates, thallium, theophylline, valproic acid and verapamil. The maximum time post-ingestion for which activated charcoal administration is recommended differs for each poison and different formulations. According to an individualized risk assessment, activated charcoal is appropriate up to 6 h post-ingestion for many poisons. If ongoing absorption is suspected, which may occur, for example, with pharmacobezoar formation, certain modified-release preparations, or when drug burden exceeds the limits of solubility, then activated charcoal can be administered beyond 6 h post-ingestion for gastrointestinal decontamination. Multiple-dose activated charcoal for enhanced elimination is appropriate in poisoning with carbamazepine, cardiac glycosides, colchicine, dapsone, phenobarbital, phenytoin, thallium and theophylline. Before deciding to perform endotracheal intubation to assist with the administration of activated charcoal, every clinician needs to weigh the potential complications and adverse effects of this procedure against the toxicity expected to be prevented by the administration of activated charcoal. This is a challenging decision, and a local poison centre and/or a bedside toxicology consultation can assist with this decision. Endotracheal intubation is not a benign procedure and is associated with a high rate of various adverse events, such as new haemodynamic instability, severe hypoxaemia, and cardiac arrest, which seem more common in children. In three studies that evaluated the risks of endotracheal intubation in over 2,200 poisoned patients, the rates of hypotension were between 1.5% and 11.8%, desaturation between 3.4% and 7.1%, and cardiac arrest in 0.4%. The risk of aspiration following administration of activated charcoal after endotracheal intubation is reported to be low (1-4%). Therefore, the decision to endotracheally intubate a patient to administer activated charcoal needs to carefully assess the patient's other comorbidities and the expected toxicity of the ingestion, which needs to be clinically significant to outweigh the risk of endotracheal intubation. Endotracheal intubation may also be considered if another treatment, such as haemodialysis or extracorporeal circulation, might be required or for transportation to another institution for ongoing clinical care. In these situations, for which endotracheal intubation has been performed for another indication, the risk-benefit will change in favour of activated charcoal administration. The following good practice statements were adopted to address the use of endotracheal intubation to facilitate the administration of activated charcoal.Endotracheal intubation should not be performed solely for the purpose of administration of activated charcoal in patients not anticipated to develop clinically significant complications of poisoning.In patients in whom endotracheal intubation is clinically indicated (e.g., compromised or unprotected airway, respiratory failure, significantly diminished level of consciousness, refractory seizures, hemodynamic instability), insertion of a nasogastric or orogastric tube is reasonable to facilitate gastrointestinal decontamination with activated charcoal.In patients with a clinically significant risk of developing life-threatening toxicity, endotracheal intubation is reasonable to safely facilitate gastrointestinal decontamination, especially if other treatment options are nonexistent or unavailable.Use of nasogastric or orogastric tube insertion without endotracheal intubation to facilitate the administration of activated charcoal: The following good practice statement was adopted: Nasogastric or orogastric tube insertion without endotracheal intubation should not be performed solely for the purpose of administration of AC. The decision to use activated charcoal is complex and depends primarily on the nature of the poison(s), the time since ingestion, the severity of the symptoms present at the time of decision or expected based on the dose ingested or patient comorbidities, and the availability of antidotes or other treatments. Although the existing level of evidence is primarily of low or very low quality, clinical decisions are still necessary. The Workgroup recommends the administration of a single-dose of activated charcoal beyond the traditional 1 h post-ingestion time point in selected poisons and introduces the concept of an additional dose of activated charcoal to prevent further absorption of poisons that may remain in the gastrointestinal tract for prolonged periods of time. Multiple-dose activated charcoal is also recommended to enhance elimination in selected clinical scenarios.

Paracetamol poisoning is the leading cause of paediatric acute liver failure in Australia. This study aimed to describe patterns and characteristics of uni

Background: The relative risk of subsequent suicidal behaviors (and suicide mortality) is high following an episode of hospital-treatment for suicidal behavior. This study evaluated the effectiveness of telehealth aftercare interventions in reducing suicidal behaviors. Methods: A systematic review was conducted using 13 online databases (from inception until July 2024). Analyses included narrative synthesis and random effects meta-analyses based on study design. Risk of bias was assessed by Cochrane tools. Results: We identified n = 14 studies involving n = 14,420 participants. Pooled effect estimates compared to usual treatment showed nonsignificantly reduced suicidal behavior in nonrandomized controlled trials (RR, 0.676 [CI 95% 0.453–1.008]), (7 studies), but no difference in randomized controlled trials (RR, 0.929 [CI 95% 0.734–1.175]) (6 studies, one study precluded analysis). The overall risk of bias was high across studies. Limitations : Many studies were underpowered, telehealth was often delivered in combination with other interventions, and the mode of telehealth was limited to telephone. Conclusions: Telehealth does not appear to confer benefit above usual treatment for suicidal behavior during follow-up, although the small number of studies and high risk of bias limits confidence in the precision of estimates of effect size. Further research might use well-designed studies to examine different clinical end points for suicidal behavior (number of or time to events) or other outcomes (retention in aftercare or other healthcare treatment).

Aims: Off-label use of antipsychotics, often at low doses, is increasing. Exploring the link between individual antipsychotic treatment patterns, including low-dose continuous use, and cardiometabolic health is crucial to prevent long-term morbidity and mortality. The current retrospective study examined the prevalence of cardiometabolic medicine use among antipsychotic-users, and its association with their past antipsychotic treatment patterns. Methods: Using a 10% sample of the Australian national medicine dispensing claims data from 2022, we identified individuals aged 15–64 years with ≥2 antipsychotic dispensings (antipsychotic-users) and non-users. We extracted their past 5-year antipsychotic treatment patterns (dose, duration and use of multiple agents). Using Poisson regression and accounting for age and sex, we calculated adjusted prevalence ratios (aPR) and 95% confidence intervals (CI) for cardiometabolic medicine use (anti-diabetics, antihypertensives, lipid modifiers, anti-thrombotics) among antipsychotic-users versus non-users. We applied unsupervised hierarchical clustering analysis to identify common antipsychotic-cardiometabolic co-dispensing. Results: Use of any cardiometabolic medicine was more prevalent among antipsychotic-users (35.8%, n = 28,345) than non-users (26%, n = 1,106,610) yielding an aPR of 1.30 (CI 1.28–1.33). aPRs for the use of anti-diabetics, lipid modifiers and antihypertensives were the highest among the younger age groups between 20 and 49 years and among women. Clustering analysis revealed increased co-dispensing of antipsychotics and anti-diabetics including sulfonylureas, statins, platelet aggregation inhibitors and beta blockers. The prevalence of cardiometabolic medicine use was associated with higher antipsychotic doses (23–54%), treatment duration (12–37%) and use of multiple agents (51%) compared with non-users. However, the prevalence of cardiometabolic medicine use for continuous (≥1 year) low-dose use of aripiprazole, asenapine, brexpiprazole, chlorpromazine, lurasidone, olanzapine, periciazine and quetiapine was also elevated (13–43%). Conclusions: Use of cardiometabolic medicines is increased among people on long-term antipsychotic treatment. These results highlight the need for active monitoring for cardiometabolic adverse effects, with antipsychotic cessation where possible, or timely interventions to limit morbidity.