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Serotonin syndrome (toxicity) describes adverse drug effects from toxic amounts of intra-synaptic central nervous system serotonin. A wide range of drugs have been implicated to cause serotonin toxicity, not all justifiably. The plausible agents all have a final common pathway resulting in a substantial increase in central nervous system serotonergic neurotransmission. Serotonin toxicity is characterized by neuromuscular excitation, mental status changes, and autonomic dysregulation. Signs and symptoms represent a spectrum of toxicity (mild to life-threatening) related to increasing serotonin concentrations. As there is no consensus on the threshold for "toxicity" or diagnostic criteria, the true incidence of serotonin toxicity is unknown. The incidence in overdose is easier to quantify and is reasonably common in serotonergic antidepressant overdoses. In a large case series of overdoses, moderate serotonin toxicity occurred in 14% of poisonings with a selective serotonin reuptake inhibitor. While half those ingesting a monoamine oxidase inhibitor in combination with a serotonergic agent in overdose exhibit at least moderately severe serotonin toxicity. In contrast, the incidence of serotonin toxicity in those on therapeutic serotonergic agents appears to be very low. To provide a narrative review of the current diagnostic criteria, utilizing case reports of fatalities to evaluate how many meet the various diagnostic criteria and propose practical solutions to resolve controversies in diagnosis. A review of serotonin toxicity diagnostic criteria in the English literature was completed by searching Embase and PubMed from January 1990 to July 2021 for the keywords "serotonin syndrome/toxicity" paired with "diagnostic criteria" or "diagnosis." Also, fatal cases of serotonin toxicity identified from a recent systematic review were independently examined to determine what diagnostic criteria were met and whether serotonin toxicity or another cause was most likely. Serotonin toxicity is a clinical diagnosis, four diagnostic criteria (Sternbach, Serotonin Syndrome Scale, Radomski, and Hunter) have been proposed. However, the Serotonin Syndrome Scale has not been validated in patients with serotonin toxicity and only utilized in those on a serotonergic agent. The remaining three criteria are utilized more widely but have undergone little refinement or validation. Shortfalls with diagnostic criteria can be illustrated by examining case fatalities. Of 55 fatal cases reviewed, 12 (22%) were unlikely to be serotonin toxicity. Sternbach and Radomski criteria were met by 25 (45%), 20 (36%) had insufficient data reported and 10 (18%) met an exclusion criterion. Few had sufficient information reported to determine whether Hunter Criteria were met, with only 13 (24%) documented as meeting the criteria, the remaining 42 (76%) had insufficient data. As serotonin toxicity is a clinical diagnosis, issues arise when basing the diagnosis on symptom criteria alone, without considering whether the drug/s ingested increase central nervous system serotonin or whether there is an alternative diagnosis. This has resulted in case reports and government warnings for drugs that cannot plausibly cause significant serotonin toxicity (e.g., ondansetron and antipsychotics). We propose when assessing for a serotonin toxidrome, both the causative agent(s) and clinical scenario is considered to determine the likelihood of serotonin toxicity. Then the clinical features assessed, those with a moderate to high prior probability (e.g., serotonergic drug–drug interaction, overdose, recent initiation or increase in dose of serotonergic agent/s) could be diagnosed based on the Hunter criteria. However, those with a low probability (e.g., stable therapeutic doses of a serotonergic agent) require more specific and stringent criteria. Finally, we propose a minimum dataset for case reports/series of serotonin toxicity. More complete and accurate reporting of serotonin toxicity cases is required in the future, to avoid further misleading associations that are physiologically implausible. [ABSTRACT FROM AUTHOR]

The clinical characteristics following self-poisoning with organophosphorus (OP) insecticides differs according to the insecticide ingested. Phenthoate is a dimethoxy WHO Hazard Class II OP pesticide with limited literature on its clinical characteristics and outcome. We aimed to better understand its clinical characteristics by studying patients with phenthoate self-poisoning in Sri Lanka. We conducted a prospective cohort study of patients presenting with phenthoate self-poisoning to eight hospitals in Sri Lanka between 2002 and 2018. Clinical outcomes were recorded for each patient. Blood samples for measuring plasma phenthoate concentration, cholinesterase activity, and response to oximes were available for a very small number of patients recruited to a clinical trial. Two hundred and ninety-two patients who ingested agricultural phenthoate formulations were included in the study. Median time to admission was 3.9 (IQR 2.4 - 6.8) h. Forty-two (14.4%) patients were intubated, mostly (30/37, 81%) within 24 h of ingestion (median time to intubation 7.2 [IQR 2.6–20.9] h). Median duration of intubation was 74.8 (IQR 26.8–232.5) h; the longest duration in a survivor was 592 h. Nineteen died (case fatality 6.5%, 95% CI 4.0–10.0); median time to death was 37 (IQR 16 - 101.7) h. Median plasma phenthoate concentration in patients with samples (n = 81) was 135 (IQR 62.7–356.5) ng/mL (0.42 µmol/mL [0.2 to 1.1 µmol/mL]). Five of six patients receiving pralidoxime chloride 2 g showed an initial increase in AChE and BuChE activity that was not sustained despite an infusion of pralidoxime. Phenthoate self-poisoning has a 6.5% case fatality rate. Most patients who experience respiratory failure undergo early intubation; most deaths occurred among those patients who were intubated less than 24 h after ingestion. There was a non-sustained increase in cholinesterase activity with pralidoxime, but further studies are required to analyse the extent to which oximes are clinically effective in phenthoate self-poisoning. [ABSTRACT FROM AUTHOR]

There is growing evidence in the literature that patients' age is associated with increased risk of death in acute pesticide poisoning. However, few studies have investigated whether the age effect differs between males and females. We aimed to examine the association between age-sex and risk of death in acute pesticide self-poisoning. A prospective cohort of deliberate pesticide-poisoned patients admitted to ten rural Sri Lankan hospitals between March 2002 and December 2019. The pesticide ingested was identified based on identification of container or history. A mixed effects logistic regression was fitted to investigate the effect of age-sex on death in acute pesticide self-poisoning adjusting for clinical symptoms on admission, measured by Glasgow Coma Scale and Poison Severity Score, and controlling for clustering among hospital sites. In total, 201 different pesticides were ingested by patients. 6,643 patients ingested an unknown pesticide. A single pesticide was co-ingested with alcohol by 4,603 patients. Of the 28,303 patients enrolled, 2,028 patients died, resulting in case fatality of 7.2% (95% CI 6.9–7.5). The effect of age on case fatality was stronger for males after 21 years of age. The odds of dying for each 5 years increase in age was 1.26 (95% CI 1.23–1.28) times higher for males versus 1.14 (95% CI 1.10–1.19) times higher for females. Missing data were handled by multiple imputation. Patient's age-sex are important risk factors for death in acute pesticide self-poisoning even after controlling for clinical effects. The age effect on the odds of dying was significantly different for males and females, with this effect being stronger for males. Given that patient's age and sex are very easy to collect on admission, our study highlights the need for incorporating these risk factors in policy and clinical decisions. [ABSTRACT FROM AUTHOR]

Introduction: Fentanyl‐related overdose is an ongoing concern among countries with high prescription opioid utilisation. This study examines trends in transdermal fentanyl utilisation and fatal fentanyl overdose across Australia between 2003 and 2015, overall, and by age/sex. Methods: This was a retrospective nationwide study of prescription dispensings and coronial records. Transdermal fentanyl utilisation was examined using Pharmaceutical Benefits Scheme dispensing records. Details of fatal fentanyl overdoses were extracted from the National Coronial Information System. Results: Transdermal fentanyl utilisation increased 5.1‐fold between 2003 and 2015, from 0.28 to 1.39 mg/1000 population/day and was consistently higher among females and adults aged ≥85 years. The utilisation of higher strength patches (75 and 100 mcg/h) was more common among males aged 25–44 years. A total of 291 fatal fentanyl overdoses were recorded, increasing from no recorded deaths in 2003 to 2.23 deaths/1 000 000 population in 2015. Rates were higher among males (increasing from 0 to 3.72 deaths/1 000 000 population) and for adults aged 25–44 years (increasing from 0 to 5.34 deaths/1 000 000 population). The number of deaths/kg fentanyl dispensed was highest among males aged <25 years (45.45, 95% confidence interval 21.80–83.59). Most deaths (70.1%) involved the intravenous administration of fentanyl from transdermal patches. Discussion and Conclusions: Rates of transdermal fentanyl utilisation and fatal fentanyl overdose across Australia increased between 2003 and 2015. Although transdermal fentanyl utilisation was consistently greater among females and older adults, rates of fatal fentanyl overdose were highest among younger males. Interventions to reduce extramedical use among this high‐risk population group are necessary to minimise fentanyl‐related harms. [ABSTRACT FROM AUTHOR]

Background: This study aims to compare the price difference between the official price for pharmaceutical drugs and the price when sourced from the black market in Australia. Methods: Drug prices recorded on the StreetRx database between 2014 and June 2018 were retrieved and the base pharmacy dispensed price was also retrieved from the Australian Pharmaceutical Benefits Scheme (PBS) website. The difference in Australian dollars between the street and base pharmacy dispensed prices for each mg of drug was calculated and the price mark-up per mg for each drug was compared. Results: 2704 reports were made for Australia between 2014 and 2018 on StreetRx. Buprenorphine accounted for 26% of all reports. After the number of reports for each drug was adjusted to their respective defined daily dose (DDD)/1000 persons/day bromazepam was the most commonly reported drug with 413.2 reports per DDD/1000/day, clonazepam (399.9), lisdexamphetamine (177.1) and oxycodone (138.4), respectively. The mark-up on opioids was the highest. Of the opioids, fentanyl's median price mark-up per mg was the highest (90 AUD). Conclusion: This study has shown that users of prescription medication pay a significant mark-up for those drugs on the street. This is a measure of the perceived value by those misusing drugs. [ABSTRACT FROM AUTHOR]

Abstract Background The WHO recognises pesticide poisoning to be the single most important means of suicide globally. Pesticide self-poisoning is a major public health and clinical problem in rural Asia, where it has led to case fatality ratios 20-30 times higher than self-poisoning in the developed world. One approach to reducing access to pesticides is for households to store pesticides in lockable "safe-storage" containers. However, before this approach can be promoted, evidence is required on its effectiveness and safety. Methods/Design A community-based cluster randomised controlled trial has been set up in 44,000 households in the North Central Province, Sri Lanka. A census is being performed, collecting baseline demographic data, socio-economic status, pesticide usage, self-harm and alcohol. Participating villages are then randomised and eligible households in the intervention arm given a lockable safe storage container for agrochemicals. The primary outcome will be incidence of pesticide self-poisoning over three years amongst individuals aged 14 years and over. 217,944 person years of follow-up are required in each arm to detect a 33% reduction in pesticide self-poisoning with 80% power at the 5% significance level. Secondary outcomes will include the incidence of all pesticide poisoning and total self-harm. Discussion This paper describes a large effectiveness study of a community intervention to reduce the burden of intentional poisoning in rural Sri Lanka. The study builds on a strong partnership between provincial health services, local and international researchers, and local communities. We discuss issues in relation to randomisation and contamination, engaging control villages, the intervention, and strategies to improve adherence. Trial Registritation The trial is registered on ClinicalTrials.gov ref: NCT1146496 (http://clinicaltrialsfeeds.org/clinical-trials/show/NCT01146496).