Central nervous system-active drug abused and overdose in children: a worldwide exploratory study using the WHO pharmacovigilance database.

Recent epidemiological studies have reported an increase in central nervous system (CNS)-active drug abuse rates in paediatric settings, raising several public health concerns. No study to date has explored this issue worldwide. We performed an extensive analysis of drugs abuse/overdose reported for children in the last decade by using the largest pharmacovigilance database, i.e. the VigiBase, collecting adverse drug reaction reports that involved at least one suspect drug belonging to the Anatomical Therapeutic Chemical code "Nervous System" through the Standardised Medical Dictionary for Drug Regulatory Affairs Queries for Drug abuse. 8.682 reports matched our criteria. An increase in reporting activity was observed, starting from 2014; an intentional overdose was reported more frequently than an accidental one, with a difference between age groups. We retrieved 997 reports with death outcome. These referred more to adolescents (n = 538) than subjects of any other paediatric age group. Paracetamol and opioid analgesics were the most common suspect drugs in deaths across all age groups due to hypoxic-ischaemic encephalopathy, brain death, and cardio-respiratory arrest.Conclusion: The number of reports associated with drug abuse and overdose is increasing (for opioid and paracetamol-containing products) and a considerable number of adverse drug reactions are serious. Data on the patterns of use of such medicines from each country may help in implementing strategies of risk-minimisation and renewing healthcare recommendations worldwide. An increased clinical awareness of drug abuse and overdose is warranted, while continuing to provide effective treatments. What is Known: • The large increase in paediatric prescriptions for CNS-active drugs in the last 20 years has recently raised public health concerns about drug abuse and overdose. • No study to date has examined this issue in paediatric patients worldwide. What is New: • The number of paediatric reports associated with CNS drug abuse and intentional overdose is increasing, including those with fatal outcome; over 4 years; more than 35% of the reports was entered from European countries. • Opioid and paracetamol were most frequently suspected for ADRs with fatal outcome across all age groups, due to hypoxic-ischaemic encephalopathy and cardio-respiratory arrest, suggesting the need to implement strategies of risk-minimisation.

Neurocognitive Recovery After Hospital-Treated Deliberate Self-Poisoning With Central Nervous System Depressant Drugs: A Longitudinal Cohort Study.

Hospital-treated deliberate self-poisoning (DSP) by central nervous system depressant drugs (CNS-D) has been associated with impairments in cognitive and psychomotor functions at the time of discharge. We aimed to replicate this finding and to compare recovery in the first month after discharge for CNS-D and CNS nondepressant drug ingestions. We also examined a series of multivariate explanatory models of recovery of neurocognitive outcomes over time. The CNS-D group was impaired at discharge compared with the CNS-nondepressant group in cognitive flexibility, cognitive efficiency, and working memory. There were no significant differences at discharge in visual attention, processing speed, visuomotor speed, or inhibition speed. Both groups improved in the latter measures over 1 month of follow-up. However, the CNS-D group's recovery was significantly slower for key neurocognitive domains underlying driving in complex traffic situations, namely, cognitive flexibility, cognitive efficiency, and working memory. Patients discharged after DSP with CNS-D drugs have impairments of some critical cognitive functions that may require up to 1 month to recover. Although more pre- than post-DSP variables were retained as explanatory models of neurocognitive performance overall, recovery over time could not be explained by any one of the measured covariates. Tests of cognitive flexibility could be used in clinical settings as a proxy measure for recovery of driving ability. Regulatory authorities should also consider the implications of these results for the period of nondriving advised after ingestion of CNS-D in overdose. Future research, with adequate sample size, should examine contributions of other variables to the pattern of recovery over time.

Trends in CNS affecting drugs in the calls to the Toxicological Information Center from 1997 to 2012.

OBJECTIVES: To analyze the number and trends in calls to the Toxicological Information Center (TIC) concerning pharmaceutical poisoning retrospectively during the past 15 years and to compare selected characteristics of the poisonings. DESIGN: Inquiries arising from drug poisonings in the years 1997-2012 were extracted and evaluated from the Czech database recording the consultations of TIC specialists. In addition, their cause, severity and dose evaluation (data electronically collected after 2005) were compared in the years 2005-2012 using standard statistical methods. RESULTS: During 15 years total 152,649 calls due to all types of potentially toxic agents were recorded in the TIC database. Central nervous system (CNS) affecting drugs represented 39.8% of calls due to all pharmaceutical poisonings. The proportion of adults was 72.2% and women comprised 64.4% of all patients. Whereas the number of calls caused by poisoning with tricyclic antidepressants (TCAs) and barbiturates decreased (by 366.7% and 340%, respectively), the calls due to selective serotonin reuptake inhibitors (SSRIs) and benzodiazepines overdose increased (by 1347.4% and 359.8%). The dose of CNS affecting drugs in 2005-2012 was considered lethal in 14.6% of the inquiries due to barbiturates and 8.6% due to TCAs, but only in 1.6% calls due to SSRIs and 0.5% of benzodiazepines. The highest percentage of medications errors was found during the treatment with barbiturates (16.4%). CONCLUSIONS: The current drugs prescription with improved safety profiles brings the beneficial effect of lowering the severity of poisonings and better prognosis of intoxications as observed in the TIC statistics.

Analysis of suspected suicides using poison center data.

Although there has been extensive research into the epidemiology and prevention of suicide, there continues to be a paucity of research on non-fatal suicides, in particular persons not treated in hospitals following a suicide attempt. In this study, we analyzed call data from the Illinois Poison Center from 2002 to 2007, which primarily comprises of non-fatal hospitalized and non-hospitalized attempts. We analyzed 43,057 calls by persons suspected of attempting suicide. The three most common groups of substances used were analgesics, antidepressants, and sedative/hypnotics/antipsychotics. The Poisson regression model showed significant declines in calls for suspected suicides during periods of holidays and vacations, and was more pronounced among youths. This study provides a current and detailed description of substances used primarily in non-fatal suicide attempts.

[Subject and basic definitions of the addictive medicine: the notion of addictive disorders].

The definition and classification of psychoactive substances are presented. The basic clinical notions related to non-medical use of drugs are defined and characterized. The criteria of drug dependences are listed. The description of phasic states of addictive diseases is presented. The relationship between addictive disorders and abnormal activity of cerebral reward system is emphasized. The problem of treatment resistance of addictive disorders and low treatment efficacy in addictive medicine is designated.

Age and gender differences in the use of various poisoning methods for deliberate parasuicide cases admitted to loghman hospital in Tehran (2000-2004).

Different methods of poisoning used by individuals with the diagnosis of parasuicide admitted to the Loghman Hospital, Tehran, from 2000 to 2004 were investigated, with particular focus on gender and age differences. Drugs, pesticides, and other agricultural chemicals (women: 12.7%, men: 9%) were the most commonly used methods. In males, the percentage of use of drugs increased with age, but the frequency of pesticides use decreased with age. In females, drugs were most often used in the youngest age group, whereas the use of pesticides was lowest in the youngest age category. Females outnumbered males, especially in the youngest age group of 10 to 19 years olds. Drugs and pesticides were the substances used most often for parasuicide in each age group regardless of gender.

Drugs and violent death: comparative toxicology of homicide and non-substance toxicity suicide victims.

AIMS: To determine the comparative toxicology of death by homicide and suicide by means other than substance toxicity. DESIGN: Cross-sectional (autopsy reports). SETTING: Sydney, Australia. CASES: A total of 1723 cases of violent death were identified, comprising 478 homicide (HOM) cases and 1245 non-substance toxicity suicide (SUI) cases. FINDINGS: Substances were detected in 65.5% of cases, and multiple substances in 25.8%, with no group differences. Illicit drugs were detected in 23.9% of cases, and multiple illicit in 5.3%. HOM cases were significantly more likely to have an illicit drug [odds ratio (OR) 2.09] and multiple illicits (OR 2.94), detected, HOM cases being more likely to have cannabis (OR 2.39), opioids (OR 1.53) and psychostimulants (OR 1.59) present. HOM cases were, however, significantly less likely to have benzodiazepines (OR 0.53), antidepressants (OR 0.22) and antipsychotics (OR 0.23) present. Alcohol was present in 39.6% of cases (median blood alcohol concentration = 0.12), with no group difference in prevalence. CONCLUSIONS: The role drugs play in premature death extends far beyond overdose and disease, with illicit drugs associated strongly with homicide.

Three deaths associated with use of Xyrem.

Fatalities resulting from popular use of gamma hydroxybutyrate (GHB) have previously been reported. We report three deaths associated with use of Xyrem (sodium oxybate), a pharmaceutical preparation of GHB initially approved for treatment of narcolepsy with cataplexy. One death appears associated with Xyrem abuse, with extremely high postmortem blood GHB levels documented. Although postmortem blood GHB levels in two other deaths are consistent with therapeutic levels, cause and effect cannot be established. We discuss these cases and factors which may have exerted contributory respiratory depressant effects, singly or in combination, including concurrent use of sedative hypnotics, obstructive sleep apnea, and obesity.

Variability in the quality of overdose advice in Summary of Product Characteristics (SPC) documents: gut decontamination recommendations for CNS drugs.

AIMS: Deliberate self-poisoning is a major cause of morbidity and mortality. The Summary of Product Characteristics (SPC) document is a legal requirement for all drugs, and Section 4.9 addresses the features of toxicity and clinical advice on management of overdose. The quality and appropriateness of this advice have received comparatively little attention. METHODS: Section 4.9 of the SPC was examined for all drugs in the central nervous system (CNS) category of the British National Formulary. Advice concerning gut decontamination was examined with respect to specific interventions: induced vomiting, oral activated charcoal, gastric lavage, and other interventions. Data were compared with standard reference sources for clinical management advice in poisoning. These were graded 'A' if no important differences existed, 'B' if differences were noted but not thought clinically important, and 'C' if differences were thought to be clinically significant. RESULTS: SPC documents were examined for 258 medications from 67 manufacturers. The overall agreement was 'A' in 23 (8.9%), 'B' in 28 (10.9%) and 'C' in 207 (80.2%). Discrepancies were due to inappropriate recommendation of induced emesis in 21.7% (95% confidence interval 17.1, 27.1), gastric lavage in 38.4% (32.7, 44.4), other gut decontamination in 5.8% (3.6, 9.4) and failure to recommend oral activated charcoal in 57.4% (51.1, 63.4). CONCLUSIONS: Gut decontamination advice in SPC documents with respect to CNS drugs was inadequate. Possible reasons for the observed discrepancies and ways of improving the consistency of advice are proposed.

Intravenous fat emulsion: a potential novel antidote.

Intravenous fat emulsions (IFE) are traditionally used as a component of parenteral nutrition therapy. Recently, IFE was used to resuscitate severe local anesthetic drug toxicity. This review focuses on the potential role of IFE in treatment of toxicity due to local anesthetics and other lipid-soluble drugs. The general properties of IFE, metabolic fate, and associated adverse events are described. Cases of local anesthetic toxicity treated with IFE are presented along with a discussion of the possible antidotal mechanisms. Initial investigations into the antidotal use of IFE for lipophilic central nervous and cardiovascular drug toxicity are also reviewed.

[The diagnosis and treatment of pulmonary hyperhydration in critically ill patients with acute poisoning by neurotropic agents].

Examination of 784 patients with acute intoxication with neurotropic agents yielded criteria for a risk of acute lung injury in this pathology and methods for diagnosing and treating this complication.

Two cases of acute endosulfan toxicity.

BACKGROUND: Endosulfan is widely used in insect control and is absorbed by both humans and animals through the intestinal tract, the lungs, and the skin. Organochlorine insecticides are highly toxic compounds that are responsible for a number of severe intoxications worldwide, with several deaths. A 9-year analysis by one of Turkey's poison control centers reported that pesticide intoxications accounted for 8.8% of 25,572 poisoning calls, with 80.3% of them relating to insecticides and 19.7% concerning rodenticides. CASE REPORTS: We present two cases of unintentional exposure to endosulfan, one of which presented with neurological manifestations, liver toxicity, and required mechanical ventilation and emergent hemodialysis; the other had only neurological manifestations and liver toxicity. CONCLUSION: In cases of endosulfan poisoning, physicians must be aware of neurological manifestations, seizures, and severe metabolic acidosis. If severe metabolic acidosis is present, we suggest that hemodialysis may be an important intervention and should be performed early.

Management of lithium toxicity.

Lithium salts have been used in the prophylaxis and treatment of depression and bipolar disorder for >50 years. Lithium has a narrow therapeutic range, and several well characterised adverse effects limit the potential usefulness of higher doses. Acute ingestion in lithium-naive patients is generally associated with only short-lived exposure to high concentrations, due to extensive distribution of lithium throughout the total body water compartment. Conversely, chronic toxicity and acute-on-therapeutic ingestion are associated with prolonged exposure to higher tissue concentrations and, therefore, greater toxicity. Lithium toxicity may be life threatening, or result in persistent cognitive and neurological impairment. Therefore, enhanced lithium clearance has been explored as a means of minimising exposure to high tissue concentrations. Although haemodialysis is highly effective in removing circulating lithium, serum concentrations often rebound so repeated or prolonged treatment may be required. Continuous arteriovenous haemodiafiltration and continuous venovenous haemodiafiltration increase lithium clearance, albeit to a lesser extent than haemodialysis, and are more widely accessible. Haemodiafiltration sustained for >16 hours allows effective removal of total body lithium, thereby avoiding rebound effects. Enhanced elimination should be considered in patients at greatest risk of severe poisoning: namely those with chronic or acute-on-therapeutic toxicity, those with clinically significant features, and those with chronic toxicity whose serum lithium concentration is >2.5 mmol/L. The choice between haemodialysis and continuous haemodiafiltration techniques will depend on local accessibility and urgency of enhancing lithium elimination. Further research is required to establish the potential benefits of assisted elimination on clinical outcome in patients with lithium poisoning.

Drug abuse in Slovak Republic.

The drug abusing structure has dramatically changed since 1989. While in 1989 the sniffing of the fluid drugs represented 98% of the global drug abuse, the most abused drugs were: heroin, marijuana, cocaine, amphetamine and its derivatives. During last 10 years situation with drug abuse has changed. Currently the most abused drugs: cannabinoides, amphetamines. The plant drugs (Datura stramonium, hallucinogenic mushrooms Psilocybe semilanceata, nutmeg--the seed of Myristica fragrans) combined with the alcohol are popular among the young abusers. According to an analysis of the phone consultations in our Toxicological Information Centre (TIC) we found out, that the number of intoxications with the plant drugs has increased five times during the last year (comparing with the year 2000), because of their easy availability, low price and quick spreading of information.

Comparative assessment of blood and urine analyses in patients with acute poisonings by medical, narcotic substances and alcohol in clinical toxicology.

Acute poisonings by medical, narcotic substances and alcohol are actual in Russia in the recent years. Comparison of analytic facilities of modern analytical techniques: chromatographic (HPLC, GC, GC-MS) and immuno-chemical (FPIA) in clinical toxicology for urgent diagnostics, assessment of the severity of acute poisoning and the efficacy of the treatment in patients with acute poisonings by psychotropic drugs, narcotics and alcohol have been done. The object of the study were serum, blood, urine of 611 patients with acute poisonings by amitriptyline, clozapine, carbamazepine, opiates and also alcohol. Threshold concentrations (threshold, critical and lethal) of the toxicants and their active metabolites which corresponded to different degrees of poisoning severity have been determined. The most comfortable and informative screening method for express diagnostics and assessment of severity of acute poisonings by psychotropic drugs and narcotics showed the HPLC with using automatic analyzers. FPIA using the automatic analyzer could be applied for screening studies, if group identification is enough. GC-FID method is advisable in case of poisoning by medical substances and narcotics in view of repeated investigation for assessment of the efficacy of the therapy. GC-MS could be advisable for confirming the results of other methods. GC-TCD possess high sensitivity and specificity and is optimal for express differential diagnostics and quantitative assessment of acute poisoning by ethanol and other alcohols.

Prolonged gastric emptying half-time and gastric hypomotility after drug overdose.

A prospective study was undertaken to determine if gastric motility and emptying are altered by the ingestion of overdoses of tricyclic antidepressants, acetaminophen, opioid-acetaminophen mixtures, carbamazepine or phenytoin. Gastric scintigraphy was used to measure gastric emptying half-time and assess gastric motility in 104 patients at initial presentation and again at follow-up (n = 85). Patients were imaged for 5 hours after being given 20 MBq of 99mTc tin colloid to drink. Drug serum levels were measured on all patients at initial presentation and at follow-up. We observed markedly prolonged gastric emptying half-times and severe hypomotility at initial presentation compared with follow-up in the vast majority of patients, except for a small group of patients with phenytoin poisoning. Twelve patients had gastric emptying half-times of over 300 minutes, a further 14 had half-times of over 200 minutes and 21 others had half-times of over 120 minutes. Poisoning is associated with hypomotility and a marked delay in gastric emptying that could influence the clinical course and patient management. These abnormalities may not be due to a direct effect of the ingested drug and factors such as stress may play a role.