γ-Hydroxybutyric Acid: Pharmacokinetics, Pharmacodynamics, and Toxicology.

Gamma-hydroxybutyrate (GHB) is a short-chain fatty acid present endogenously in the brain and used therapeutically for the treatment of narcolepsy, as sodium oxybate, and for alcohol abuse/withdrawal. GHB is better known however as a drug of abuse and is commonly referred to as the "date-rape drug"; current use in popular culture includes recreational "chemsex," due to its properties of euphoria, loss of inhibition, amnesia, and drowsiness. Due to the steep concentration-effect curve for GHB, overdoses occur commonly and symptoms include sedation, respiratory depression, coma, and death. GHB binds to both GHB and GABAB receptors in the brain, with pharmacological/toxicological effects mainly due to GABAB agonist effects. The pharmacokinetics of GHB are complex and include nonlinear absorption, metabolism, tissue uptake, and renal elimination processes. GHB is a substrate for monocarboxylate transporters, including both sodium-dependent transporters (SMCT1, 2; SLC5A8; SLC5A12) and proton-dependent transporters (MCT1-4; SLC16A1, 7, 8, and 3), which represent significant determinants of absorption, renal reabsorption, and brain and tissue uptake. This review will provide current information of the pharmacology, therapeutic effects, and pharmacokinetics/pharmacodynamics of GHB, as well as therapeutic strategies for the treatment of overdoses. Graphical abstract.

Association Between Opioid Dose Variability and Opioid Overdose Among Adults Prescribed Long-term Opioid Therapy.

Importance: Attempts to discontinue opioid therapy to reduce the risk of overdose and adhere to prescribing guidelines may lead patients to be exposed to variability in opioid dosing. Such dose variability may increase the risk of opioid overdose even if therapy discontinuation is associated with a reduction in risk. Objective: To examine the association between opioid dose variability and opioid overdose. Design, Setting, and Participants: A nested case-control study was conducted in a large Colorado integrated health plan and delivery system from January 1, 2006, through June 30, 2018. Cohort members were individuals prescribed long-term opioid therapy. Exposures: Dose variability was defined as the SD of the milligrams of morphine equivalents across each patient's follow-up and categorized based on the quintile distribution of the SD in the cohort (0-5.3, 5.4-9.1, 9.2-14.6, 14.7-27.2, and >27.2 mg of morphine equivalents). Main Outcomes and Measures: Opioid overdose cases were identified using International Classification of Diseases, Ninth Revision and International Statistical Classification of Diseases and Related Health Problems, Tenth Revision codes. Each case patient with overdose was matched to up to 20 control patients using risk set sampling. Conditional logistic regression models were used to generate matched odds ratios and 95% CIs, adjusted for age, sex, race/ethnicity, drug or alcohol use disorder, tobacco use, benzodiazepine dispensings, medical comorbidities, mental health disorder, opioid dose, and opioid formulation. Results: In a cohort of 14 898 patients (mean [SD] age, 56.3 [16.0] years; 8988 [60.3%] female) prescribed long-term opioid therapy, 228 case patients with incident opioid overdose were matched to 3547 control patients. The mean (SD) duration of opioid therapy was 36.7 (33.7) months in case patients and 33.0 (30.9) months in control patients. High-dose variability (SD >27.2 mg of morphine equivalents) was associated with a significantly increased risk of overdose compared with low-dose variability (matched odds ratio, 3.32; 95% CI, 1.63-6.77) independent of opioid dose. Conclusions and Relevance: Variability in opioid dose may be a risk factor for opioid overdose, suggesting that practitioners should seek to minimize dose variability when managing long-term opioid therapy.

Using the 150 rule to prevent hepatotoxicity from acetaminophen.

Acetaminophen-induced hepatotoxicity is the most common cause of acute liver failure in adults and a major cause of acute liver failure in children. Prompt treatment with N-acetylcysteine can mitigate hepatotoxicity and progression to liver failure. This article describes a 16-year-old girl who ingested a large dose of extra-strength acetaminophen, and how the 150 rule was used in her management.

Protection of mouse brain from paracetamol-induced stress by Centella asiatica methanol extract.

ETHNOPHARMACOLOGICAL RELEVANCE: Centella asiatica (CA) is a medicinal herb traditionally used as a brain tonic in Ayurvedic medicine. Various ethnomedical leads revealed the effective use of CA in the treatment of symptoms associated to oxidative stress and inflammation. AIM OF THE STUDY: The aim of this study was to evaluate the therapeutic ability of CA methanol extract (CAM) in protecting mouse brain and astrocytes from oxidative stress and inflammation induced by Paracetamol, and thus to substantiate the allied traditional/ethnomedical claims of CA. MATERIALS AND METHODS: Chemical profiling of CAM and quantification of its major constituents were carried out by HPTLC-densitometry. Mice were administered with CAM and Paracetamol in various combinations, and oxidative stress parameters (lipid peroxidation, radical scavenging) as well as nitric oxide stress were estimated from isolated mouse brain. Cellular toxicity was investigated by apoptosis/necrosis in primary astrocytes isolated from brain tissues of mouse (which was challenged by CAM/Paracetamol) by flow cytometry and fluorescent microscopy. Expression of inflammatory cytokine mediators (monocyte chemo attractant protein 1, interleukin 1, interferon γ, tumor necrosis factor ß, interleukin 10 and mitogen activated protein kinase 14 gene) in CAM/Paracetamol administered mouse brain tissues was analyzed by real time PCR. Mouse brain tissues challenged by CAM/Paracetamol were also assessed for gross and histopathology. In addition, staining with acridine orange was carried out in C6 cell lines treated with CAM, and viewed under fluorescent microscopy. RESULTS: Paracetamol elicited reactive oxygen species generation was revealed through Ferric Reducing Antioxidant Power (FRAP) activity. CAM reversed the Paracetamol induced free radical and reactive nitrogen species production and increased the scavenging activity which was more pronounced at the higher dose (80 mg/kg b.wt). CAM negated the Paracetamol-induced damage by inhibiting expression of pro-inflammatory cytokines (MCP 1, IL 1, TNF ß), and increasing the expression of the anti-inflammatory cytokine (IL 10) profoundly. Interestingly, MAPK 14 gene expression was decreased gradually and became same as normal control with increase in the dose of CAM. Also, it was evident that CAM protected mouse primary astrocytes from Paracetamol by maintaining a normal morphology. Similarly, apoptosis of primary astrocytes (treated with Paracetamol/CAM) decreased with the increase in CAM dose (80 mg/kg b.wt.) which was evident from flow cytometric data. Severe brain damage in the form of lesions was apparent from the histology of Paracetamol alone treated mouse brain. Whereas, CAM treated together with Paracetamol upturned these lesions. Surprisingly, CAM alone proved to be cytotoxic to C6 Glioma cells. CONCLUSIONS: CAM showed antioxidant and anti-inflammatory effects (which were pronounced at higher doses) against Paracetamol-induced oxidative stress and associated inflammation in mouse brain. The underlying mechanisms may be mediated by inhibiting the pro-inflammatory cytokines TNF ß, IL 1 and MCP 1 via regulation of the antioxidant mediated INF γ and MAPK 14 gene signalling pathways. The major bioactive constituents in CAM are the triterpenoid saponins, asiaticoside and madecassoside. The present results provide pharmacological evidence that CAM acts as an antioxidant and anti-inflammatory agent. Furthermore, this study validates the use of CA as an antioxidant and anti-inflammatory agent in ethnomedicine.

Legally Lethal Kratom: A Herbal Supplement with Overdose Potential.

This case report describes an overdose on kratom, and elicits the potential dangers of overdose on the regulated dietary supplement. A young male presented to the emergency department intubated after being found unresponsive. He was found by his family to be unarousable and agonal breathing with minimal response to naloxone administered by Emergency Medical Services (EMS). Urine toxicology and blood alcohol content were negative. Physical exam was significant for tachycardia, hypotension, and pinpoint pupils with sluggish reactivity to light. Laboratory studies were significant for elevated liver enzymes, blood urea nitrogen, creatinine, lipase, amylase, troponins, and lactic acid. Family members revealed that the patient consumed kratom, which he obtained through an e-commerce business, and had consumed over 500 grams the previous day. Urine sample for kratom on day 3 tested positive with levels of more than 500 ng/dL. The patient received supportive care and, by day 10, pupillary reflexes returned to normal and he was extubated by day 14. Most of the medications/drugs labelled under herbal supplements by the U.S. Food and Drug Administration (FDA) are not regulated and can be purchased over the counter. The safety and side-effect profile of kratom is not well-studied, especially in an overdose scenario.

Critical Care Pain Management in Patients Affected by the Opioid Epidemic: A Review.

The rapid rise in the opioid epidemic has had a deleterious impact across the United States. This increase has drawn the attention of the critical care community not only because of the surge in acute opioid overdose-related admissions, but also due to the increase in the number of opioid-dependent and opioid-tolerant patients being treated in the intensive care unit (ICU). Opioid-related issues relevant to the critical care physician include direct care of patients with opioid overdoses, the provision of sufficient analgesia to patients with opioid dependence and tolerance, and the task of preventing long-term opioid dependence in patients who survive ICU care. This review identifies the challenges facing the ICU physician working with patients presenting with opioid-related complications, discusses current solutions, and suggests future areas of research and heightened ICU clinician attention.

Prediction Model for Two-Year Risk of Opioid Overdose Among Patients Prescribed Chronic Opioid Therapy.

BACKGROUND: Naloxone is a life-saving opioid antagonist. Chronic pain guidelines recommend that physicians co-prescribe naloxone to patients at high risk for opioid overdose. However, clinical tools to efficiently identify patients who could benefit from naloxone are lacking. OBJECTIVE: To develop and validate an overdose predictive model which could be used in primary care settings to assess the need for naloxone. DESIGN: Retrospective cohort. SETTING: Derivation site was an integrated health system in Colorado; validation site was a safety-net health system in Colorado. PARTICIPANTS: We developed a predictive model in a cohort of 42,828 patients taking chronic opioid therapy and externally validated the model in 10,708 patients. MAIN MEASURES: Potential predictors and outcomes (nonfatal pharmaceutical and heroin overdoses) were extracted from electronic health records. Fatal overdose outcomes were identified from state vital records. To match the approximate shelf-life of naloxone, we used Cox proportional hazards regression to model the 2-year risk of overdose. Calibration and discrimination were assessed. KEY RESULTS: A five-variable predictive model showed good calibration and discrimination (bootstrap-corrected c-statistic = 0.73, 95% confidence interval [CI] 0.69-0.78) in the derivation site, with sensitivity of 66.1% and specificity of 66.6%. In the validation site, the model showed good discrimination (c-statistic = 0.75, 95% CI 0.70-0.80) and less than ideal calibration, with sensitivity and specificity of 82.2% and 49.5%, respectively. CONCLUSIONS: Among patients on chronic opioid therapy, the predictive model identified 66-82% of all subsequent opioid overdoses. This model is an efficient screening tool to identify patients who could benefit from naloxone to prevent overdose deaths. Population differences across the two sites limited calibration in the validation site.

Gabapentin, opioids, and the risk of opioid-related death: A population-based nested case-control study.

BACKGROUND: Prescription opioid use is highly associated with risk of opioid-related death, with 1 of every 550 chronic opioid users dying within approximately 2.5 years of their first opioid prescription. Although gabapentin is widely perceived as safe, drug-induced respiratory depression has been described when gabapentin is used alone or in combination with other medications. Because gabapentin and opioids are both commonly prescribed for pain, the likelihood of co-prescription is high. However, no published studies have examined whether concomitant gabapentin therapy is associated with an increased risk of accidental opioid-related death in patients receiving opioids. The objective of this study was to investigate whether co-prescription of opioids and gabapentin is associated with an increased risk of accidental opioid-related mortality. METHODS AND FINDINGS: We conducted a population-based nested case-control study among opioid users who were residents of Ontario, Canada, between August 1, 1997, and December 31, 2013, using administrative databases. Cases, defined as opioid users who died of an opioid-related cause, were matched with up to 4 controls who also used opioids on age, sex, year of index date, history of chronic kidney disease, and a disease risk index. After matching, we included 1,256 cases and 4,619 controls. The primary exposure was concomitant gabapentin use in the 120 days preceding the index date. A secondary analysis characterized gabapentin dose as low (<900 mg daily), moderate (900 to 1,799 mg daily), or high (≥1,800 mg daily). A sensitivity analysis examined the effect of concomitant nonsteroidal anti-inflammatory drug (NSAID) use in the preceding 120 days. Overall, 12.3% of cases (155 of 1,256) and 6.8% of controls (313 of 4,619) were prescribed gabapentin in the prior 120 days. After multivariable adjustment, co-prescription of opioids and gabapentin was associated with a significantly increased odds of opioid-related death (odds ratio [OR] 1.99, 95% CI 1.61 to 2.47, p < 0.001; adjusted OR [aOR] 1.49, 95% CI 1.18 to 1.88, p < 0.001) compared to opioid prescription alone. In the dose-response analysis, moderate-dose (OR 2.05, 95% CI 1.46 to 2.87, p < 0.001; aOR 1.56, 95% CI 1.06 to 2.28, p = 0.024) and high-dose (OR 2.20, 95% CI 1.58 to 3.08, p < 0.001; aOR 1.58, 95% CI 1.09 to 2.27, p = 0.015) gabapentin use was associated with a nearly 60% increase in the odds of opioid-related death relative to no concomitant gabapentin use. As expected, we found no significant association between co-prescription of opioids and NSAIDs and opioid-related death (OR 1.11, 95% CI 0.98 to 1.27, p = 0.113; aOR 1.14, 95% CI 0.98 to 1.32, p = 0.083). In an exploratory analysis of patients at risk of combined opioid and gabapentin use, we found that 46.0% (45,173 of 98,288) of gabapentin users in calendar year 2013 received at least 1 concomitant prescription for an opioid. This study was limited to individuals eligible for public drug coverage in Ontario, we were only able to identify prescriptions reimbursed by the government and dispensed from retail pharmacies, and information on indication for gabapentin use was not available. Furthermore, as with all observational studies, confounding due to unmeasured variables is a potential source of bias. CONCLUSIONS: In this study we found that among patients receiving prescription opioids, concomitant treatment with gabapentin was associated with a substantial increase in the risk of opioid-related death. Clinicians should consider carefully whether to continue prescribing this combination of products and, when the combination is deemed necessary, should closely monitor their patients and adjust opioid dose accordingly. Future research should investigate whether a similar interaction exists between pregabalin and opioids.

Understanding opioid overdose characteristics involving prescription and illicit opioids: A mixed methods analysis.

BACKGROUND: Opioid abuse and misuse are significant public health issues. The CDC estimated 72% of pharmaceutical-related overdose deaths in the US in 2012 involved opioids. While studies of opioid overdoses have identified sociodemographic characteristics, agents used, administration routes, and medication sources associated with overdoses, we know less about the context and life circumstances of the people who experience these events. METHODS: We analyzed interviews (n=87) with survivors of opioid overdoses or family members of decedents. Individuals experiencing overdoses were members of a large integrated health system. Using ICD codes for opioid overdoses and poisonings, we identified participants from five purposefully derived pools of health-plan members who had: 1) prescriptions for OxyContin(®) or single-ingredient sustained-release oxycodone, 2) oxycodone single-ingredient immediate release, 3) other long-acting opioids, 4) other short-acting opioids, or 5) no active opioid prescriptions. RESULTS: Individuals who experienced opioid overdoses abused and misused multiple medications/drugs; experienced dose-related miscommunications or medication-taking errors; had mental health and/or substance use conditions; reported chronic pain; or had unstable resources or family/social support. Many had combinations of these risks. Most events involved polysubstance use, often including benzodiazepines. Accidental overdoses were commonly the result of abuse or misuse, some in response to inadequately treated chronic pain or, less commonly, medication-related mistakes. Suicide attempts were frequently triggered by consecutive negative life events. CONCLUSIONS: To identify people at greater risk of opioid overdose, efforts should focus on screening for prescribed and illicit polysubstance use, impaired cognition, and changes in life circumstances, psychosocial risks/supports, and pain control.

A Retrospective Study of Clinical Effects of Powdered Caffeine Exposures Reported to Three US Poison Control Centers.

INTRODUCTION: Anhydrous caffeine, often sold on the Internet as a powdered caffeine product, is sold as "pure caffeine" to be used as an additive to beverages and has also been used as an ingredient in energy supplement products. METHODS: This is a retrospective multiple-poison center chart review of calls regarding powdered caffeine to poison centers covering Oregon, Alaska, Guam, Washington, and Utah between January 1, 2013 and June 30, 2015. RESULTS: There were 40 calls to three poison centers over 30 months for powdered caffeine exposure. The majority of patients were over age 19 (52.5 %; 21/40) and male (70 %; 28/40). Sixty percent (24/40) of the patients were symptomatic but only 10 % (4/40) required admission; 52.5 % (21/40) of the patient calls were for inadvertent overdose of powdered caffeine; one patient overdosed in a self-harm attempt. DISCUSSION: Powdered caffeine calls to three poison centers during a 30-month study period were rare, and severe caffeine toxicity due to exposure was found in few patients. The majority of symptoms were reported after an inadvertent powdered caffeine overdose. CONCLUSIONS: An analysis of calls to three poison centers for powdered caffeine found that exposures were uncommon, but did result in toxicity, and highlighted that the lack of clear dosing instructions on product packaging may place patients at risk of inadvertent overdose.

Vitamin D toxicity resulting from overzealous correction of vitamin D deficiency.

BACKGROUND: Vitamin D toxicity, often considered rare, can be life-threatening and associated with substantial morbidity, if not identified promptly. OBJECTIVE: To describe clinical and biochemical features, risk factors and management of patients with vitamin D toxicity seen between January 2011 and January 2013. METHODOLOGY: Patients presenting with vitamin D toxicity, between January 2011 and January 2013, at single tertiary care centre in Delhi-NCR, India, were included. Evaluation included detailed clinical history and biochemical tests including serum calcium, phosphorus, creatinine, intact parathyroid hormone and 25-hydroxyvitamin D (25(OH)D). RESULTS: Sixteen patients with vitamin D toxicity could be identified. Clinical manifestations included nausea, vomiting, altered sensorium, constipation, pancreatitis, acute kidney injury and weight loss. Median (range) age was 64·5 (42-86) years. Median (range) serum 25(OH)D level and median (range) serum total serum calcium level were 371 (175-1161) ng/ml and 13·0 (11·1-15·7) mg/dl, respectively. Overdose of vitamin D caused by prescription of mega-doses of vitamin D was the cause of vitamin D toxicity in all cases. Median (range) cumulative vitamin D dose was 3,600,000 (2,220,000-6,360,000) IU. CONCLUSION: Our data demonstrate an emergence of vitamin D toxicity as an increasingly common cause of symptomatic hypercalcaemia. Irrational use of vitamin D in mega-doses resulted in vitamin D toxicity in all cases. Awareness among healthcare providers regarding the toxic potential of high doses of vitamin D and cautious use of vitamin D supplements is the key to prevent this condition.

Ritualistic Use of Ayahuasca versus Street Use of Similar Substances Seized by the Police: A Key Factor Involved in the Potential for Intoxications and Overdose?

The ritualistic use of ayahuasca is becoming a global phenomenon. This beverage contains a combination of monoamine oxidase inhibitors (harmine, harmaline, and tetrahydroharmine) and N,N-dimethyltryptamine, the main substance responsible for its visionary effect. The recreational use of similar alkaloids and N,N-dimethyltryptamine has increased in recent years, mainly because of their hallucinogenic effects. In the present study, the concentrations of psychoactive alkaloids in three powder samples seized by the São Paulo State Police and nine ayahuasca aqueous extracts were analyzed by HPLC-DAD in an attempt to distinguish between illicit drugs and the religious beverage. The alkaloids detected (µg/mL) in the ayahuasca aqueous extracts were N,N-dimethyltryptamine (402-2070.3), harmaline (27.5-181.3), harmine (294.5-2893.8), and tetrahydroharmine (849.5-2052.5), whereas, of the three powder samples, one contained only N,N-dimethyltryptamine (82% and 2% w/w, respectively) while the other contained only harmaline (16%, w/w) and harmine (12%, w/w). The ritualistic use of ayahuasca involves oral intake and the probability of overdose is minimized by serotonergic stimulation of vagal pathways, leading to vomiting and diarrhea. In contrast, the recreational use of N,N-dimethyltryptamine involves consumption mainly by smoking or inhalation, both of which markedly increase its bioavailability and the potential for intoxications.

Anesthetic propofol overdose causes vascular hyperpermeability by reducing endothelial glycocalyx and ATP production.

Prolonged treatment with a large dose of propofol may cause diffuse cellular cytotoxicity; however, the detailed underlying mechanism remains unclear, particularly in vascular endothelial cells. Previous studies showed that a propofol overdose induces endothelial injury and vascular barrier dysfunction. Regarding the important role of endothelial glycocalyx on the maintenance of vascular barrier integrity, we therefore hypothesized that a propofol overdose-induced endothelial barrier dysfunction is caused by impaired endothelial glycocalyx. In vivo, we intraperitoneally injected ICR mice with overdosed propofol, and the results showed that a propofol overdose significantly induced systemic vascular hyperpermeability and reduced the expression of endothelial glycocalyx, syndecan-1, syndecan-4, perlecan mRNA and heparan sulfate (HS) in the vessels of multiple organs. In vitro, a propofol overdose reduced the expression of syndecan-1, syndecan-4, perlecan, glypican-1 mRNA and HS and induced significant decreases in the nicotinamide adenine dinucleotide (NAD+)/NADH ratio and ATP concentrations in human microvascular endothelial cells (HMEC-1). Oligomycin treatment also induced significant decreases in the NAD+/NADH ratio, in ATP concentrations and in syndecan-4, perlecan and glypican-1 mRNA expression in HMEC-1 cells. These results demonstrate that a propofol overdose induces a partially ATP-dependent reduction of endothelial glycocalyx expression and consequently leads to vascular hyperpermeability due to the loss of endothelial barrier functions.

[Acute intoxication in adults - what you should know]. / Akute Intoxikationen bei Erwachsenen - was Sie wissen sollten.

Ingestion of household products and plants are the leading cause for calls to the poison control centres as far as children are involved. Severe intoxication in children has become infrequent due to childproofed package and blister packs for drugs. Chemical accidents in adults give rise to hospital admission in only 5 %. Suicidal selfpoisonings are still a challenge for paramedics, emergency and hospital doctors. Natural toxins as amatoxins, cholchicine and snakebites can lead to severe intoxication. Sedatives, antidepressants and analgesics are the drugs which are often used for suicidal intent due to their availability. Quetiapine and paracetamol are the drugs which are ingested for attempted suicide/ suicide mostly. The treatment of poisoning centers on the severity which can be judged by the poison severity score, the Reed classification or the GCS.Most intoxicated patients can be treated symptomatically or by intensive care measurements. Antidotal treatment however is needed for some specific poisonings.Exact sample drawing is essential for diagnostic and forensic purposes. There is no evidence based proof for the effectiveness of primary detoxification from the gastrointestinal tract like forced emesis, gastric lavage or the use of cathartics. Early after the ingestion of a harmful substance the administration of activated charcoal seems advisable. Hemodialysis can remove water soluble substances with a small volume of distribution. Multiple charcoal administration may exhibit some influence on secondary detoxification. Provision of evidence of the efficacy for newer antidotes like hydroxocobalamin in smoke inhalation, fomepizol for toxic alcohols and silibinin for amanita poisoning are emerging. Two recently recommended therapeutic principles have still to demonstrate their ability: Firstly the treatment of patients with calcium receptor antagonistic and beta-receptor antagonistic agents poisoning by high dose of insulin plus glucose, secondly the treatment for severe intoxication with cardiotoxic and psychotropic drugs with a lipid emulsion (Lipid rescue).It is essential for all doctors to contact a poison control center whenever they are confronted with an intoxicated patient. There they can get advice about which dose is toxic and about the newest therapeutic procedure.

The marginalization of chronic pain patients on chronic opioid therapy.

The realities of treating chronic pain do not reflect the attention that marginalization of patients taking opioids has received. Physicians continue the same prejudices and biases that were present decades ago. One theory proposed to explain this poor treatment has been titled, the "barriers to pain management." The barriers are not treated as moral issues, but rather as clinical aberrations and do not explain continued poor treatment. However, the barriers do not explain certain types of cases where there appears to be specific unfounded concerns related to a specific class of medications, e.g, opioids. Four cases are presented, from the authors experience, illustrating the marginalization of chronic pain patients on chronic opioid therapy admitted to a tertiary care hospital. These types of cases have not been presented in the literature previously and illustrate the failure of the barriers to explain marginalization. In each of these cases mental status changes was the presenting problem. However, in each of these cases, these changes were not related to their opioids, but were explained by clear reasons, other than opioids. Regardless, in each case, the attending physician blamed the opioids, without further workup and stopped them reflexively. It is proposed that there may be more complex psychosocial issues involved in the marginalization of chronic pain patients. This case series illustrates a ubiquitous problem demanding further examination and discussion. It is hoped that this case series will create interest in further research in this area.

Prevalence of over-the-counter drug-related overdoses at Accident and Emergency departments in Northern Ireland--a retrospective evaluation.

BACKGROUND AND OBJECTIVES: One major concern associated with misuse/abuse of over-the-counter (OTC) products is the potential for over-dosage. The aim of this research study was to evaluate, over a 3-month period, OTC medicine-related overdoses (those involving OTC drugs only and OTC drugs in combination with other drugs) that led to patients presenting at the Accident and Emergency (A & E) departments in four Belfast hospitals. METHODS: A data collection sheet was designed to capture the information required from the A & E records in each hospital. A retrospective week-by-week data collection, reviewing A & E records, took place over a 3-month period (starting on 1 December 2002). All data related to cases presenting at the A & E departments because of drug overdoses (either accidental or deliberate according to Read Clinical Classification) were included in the study. Data were coded and entered into a custom designed SPSS database for analysis, using Chi square and Fisher exact tests. RESULTS: OTC drug-related overdoses comprised 40.1% of all overdoses, of which 24.0% were OTC-only overdoses. Those who overdosed on OTC drugs (solely or combined with other drugs) were mainly female (62.3%) and in the age category 31-50 years (44.9%; P <0.05). The majority (n=215) of OTC-related overdoses were intentional, whereas only 28 were accidental. Of those who attended the A & E departments and had an overdose history, one-third overdosed on OTC-related products and two-thirds overdosed on OTC drugs only. CONCLUSIONS: OTC drugs accounted for a significant proportion of overdose presentations at the A & E departments in Northern Ireland. Higher awareness of the potential of OTC product use in overdose cases (intentional or accidental) is recommended for both the public and health care professionals.

[Kava, kavapyrones and toxic liver injury]. / Kava, Kava-Pyrone und toxische Leberschäden.

Kava extracts are obtained from the rhizoma of the kava shrub (Piper methysticum) and contain various pyrones which are used as herbal anxiolytic remedies for generalized anxiety syndromes of low and intermediate grades. The commonly recommended daily dose of 60-120 mg kavapyrones and the duration of the therapy of up to 3 months should not be increased without consultation of a physician and were not followed by most patients, since herbal drugs are considered by the population not only as effective but also as safe. Whereas kava extracts are well tolerated by most patients and rare side effects are rapidly reversible upon drug discontinuation, there are suspected hepatotoxic reactions reported during the last years in temporal and not necessarily causal association with a therapy with kava extracts. Almost 80 % of the patients took kavapyrones in overdose (maximally 480 mg/d) and/or for a prolonged time of more than 3 months up to 2 years. Additional risks factors include co-medication with up to 5 other chemically defined or herbal drugs with in part potentially hepatotoxic properties as well as a genetic deficiency of the hepatic microsomal cytochrome P450 2D6. Severe clinical courses with liver transplantation and possible fatal outcome occurred in 7 patients with overdose and/or long duration of the therapy with kavapyrones. Preventive measures should therefore include a dose of 120, maximally 210 mg kavapyrones per day for 1 month, maximally 2 months, as well as a prescription by a physician. Laboratory test (ALT and gamma-GT) should be done before and during the therapy, and co-medication and alcohol consumption should be avoided. With these measures the hepatotoxic risks under the treatment with kavapyrones might be minimized which are also available via internet and from abroad with possible severe consequences when taken without medical supervision.

[Nightshade plants act almost like LSD. Poisoning cases are on the rise]. / Nachtschattengewächse wirken fast wie LSD. Vergiftungsfälle häufen sich.

Intoxicated states can be induced not only by the typical narcotic drugs, but also by other psychotropic substances, such as the thorn-apple and angel's trumpet. In recent times there has been an increase in the reported number of cases of such intoxications. Clinical symptoms, toxicological analysis and possible forms of treatment are discussed.