Acute myocardial infarction due to spontaneous coronary artery dissection in a 6-year-old boy with ADHD on the third day of treatment with methylphenidate.

Methylphenidate (MPH) is an indirect-acting sympathomimetic drug and structurally related to amphetamine. It is widely used to treat children aged 6 years and older, as well as adolescents who have attention-deficit/hyperactivity disorder (ADHD). We report on a 6-year-old boy who presented with typical angina symptoms occurring several hours after intake of an increased dose of MPH, which had been initiated for ADHD treatment 2 days earlier. Despite typical angina symptoms, the diagnosis of myocardial infarction due to spontaneous coronary artery dissection of the right coronary artery was delayed. Most epidemiological studies could not detect an increased risk for cardiovascular events in association with ADHD medications. However, the direct temporal relationship in our case indicates the possibility that MPH may trigger spontaneous coronary artery dissection in predisposed patients. Since myocardial infarction in children is rare but comprises various etiologies, awareness of this possible catastrophic event among medical staff may be lower and may delay immediate life-saving diagnostic and therapeutic measures.

[Perioperative analgesia with nonopioid analgesics : Joint interdisciplinary consensus-based recommendations of the German Pain Society, the German Society of Anaesthesiology and Intensive Care Medicine and the German Society of Surgery]. / Perioperative Schmerztherapie mit Nichtopioidanalgetika : Gemeinsame interdisziplinäre Empfehlung der Deutschen Schmerzgesellschaft, der Deutschen Gesellschaft für Anästhesiologie und Intensivmedizin und der Deutschen Gesellschaft für Chirurgie.

BACKGROUND: Nonopioid analgesics are frequently used for perioperative analgesia; however, insufficient research is available on several practical issues. Often hospitals have no strategy for how to proceed, e.g., for informing patients or for the timing of perioperative administration of nonopioid analgesics. METHODS: An expert panel representing the German national societies of pain, anaesthesiology and intensive care medicine and surgery developed recommendations for the perioperative use of nonopioid analgesics within a formal, structured consensus process. RESULTS: The panel agreed that nonopioid analgesics shall be part of a multimodal analgesia concept and that patients have to be informed preoperatively about possible complications and alternative treatment options. Patients' history of pain and analgesic intake shall be evaluated. Patients at risk of severe postoperative pain and possible chronification of postsurgical pain shall be identified. Depending on the duration of surgery, nonopioid analgesics can already be administered preoperatively or intraoperatively so that plasma concentrations are sufficient after emergence from anesthesia. Nonopioid analgesics or combinations of analgesics shall be administered for a limited time only. An interdisciplinary written standard of care, comprising the nonopioid analgesic of choice, possible alternatives, adequate dosing and timing of administration as well as surgery-specific policies, have to be agreed upon by all departments involved. At discharge, the patient's physician shall be informed of analgesics given and those necessary after discharge. Patients shall be informed of possible side effects and symptoms and timely discontinuation of analgesic drugs. CONCLUSION: The use of nonopioid analgesics as part of a perioperative multimodal concept should be approved and established as an interdisciplinary and interprofessional concept for the adequate treatment of postoperative pain.

[Perioperative analgesia with nonopioid analgesics : Joint interdisciplinary consensus-based recommendations of the German Pain Society, the German Society of Anaesthesiology and Intensive Care Medicine and the German Society of Surgery]. / Perioperative Schmerztherapie mit Nichtopioidanalgetika : Gemeinsame interdisziplinäre Empfehlung der Deutschen Schmerzgesellschaft, der Deutschen Gesellschaft für Anästhesiologie und Intensivmedizin und der Deutschen Gesellschaft für Chirurgie.

BACKGROUND: Nonopioid analgesics are frequently used for perioperative analgesia; however, insufficient research is available on several practical issues. Often hospitals have no strategy for how to proceed, e.g., for informing patients or for the timing of perioperative administration of nonopioid analgesics. METHODS: An expert panel representing the German national societies of pain, anaesthesiology and intensive care medicine and surgery developed recommendations for the perioperative use of nonopioid analgesics within a formal, structured consensus process. RESULTS: The panel agreed that nonopioid analgesics shall be part of a multimodal analgesia concept and that patients have to be informed preoperatively about possible complications and alternative treatment options. Patients' history of pain and analgesic intake shall be evaluated. Patients at risk of severe postoperative pain and possible chronification of postsurgical pain shall be identified. Depending on the duration of surgery, nonopioid analgesics can already be administered preoperatively or intraoperatively so that plasma concentrations are sufficient after emergence from anesthesia. Nonopioid analgesics or combinations of analgesics shall be administered for a limited time only. An interdisciplinary written standard of care, comprising the nonopioid analgesic of choice, possible alternatives, adequate dosing and timing of administration as well as surgery-specific policies, have to be agreed upon by all departments involved. At discharge, the patient's physician shall be informed of analgesics given and those necessary after discharge. Patients shall be informed of possible side effects and symptoms and timely discontinuation of analgesic drugs. CONCLUSION: The use of nonopioid analgesics as part of a perioperative multimodal concept should be approved and established as an interdisciplinary and interprofessional concept for the adequate treatment of postoperative pain.

Comparative risks of bleeding, ischemic stroke and mortality with direct oral anticoagulants versus phenprocoumon in patients with atrial fibrillation.

PURPOSE: The pivotal trials for stroke prevention in non-valvular atrial fibrillation (NVAF) compared rivaroxaban, dabigatran, and apixaban with warfarin, as did most claims-based studies. Comparisons with phenprocoumon, the most frequently used vitamin K antagonist (VKA) in Germany, are scarce. METHODS: Risk of bleeding, ischemic stroke, and all-cause mortality in patients with NVAF were analyzed using data for 2010 to 2014 from a large German claims database. New users of oral anticoagulants from January 2012 to December 2013 were included and observed over 1 year. Baseline characteristics were adjusted using propensity score matching and logistic regression. Several sensitivity analyses were carried out. RESULTS: Fifty-nine thousand four hundred forty-nine rivaroxaban, 23,654 dabigatran, 4894 apixaban, and 87,997 matched phenprocoumon users were included. Adjusted hazard ratios (95% confidence intervals) compared with phenprocoumon were as follows: hospitalized bleedings: rivaroxaban 1.04 (0.97; 1.11), dabigatran 0.87 (0.77; 0.98), and apixaban 0.65 (0.50; 0.86); ischemic stroke: rivaroxaban 1.05 (0.94; 1.17), dabigatran 1.14 (0.96; 1.35), and apixaban 1.84 (1.20; 2.84); all-cause mortality: rivaroxaban 1.17 (1.11; 1.22), dabigatran 1.04 (0.95; 1.13), and apixaban 1.14 (0.97; 1.34). CONCLUSIONS: With rivaroxaban, no significant differences were observed compared to phenprocoumon with regard to hospitalized bleedings or ischemic strokes. Dabigatran was associated with fewer bleedings and a similar risk of ischemic strokes compared to phenprocoumon. Apixaban was also associated with fewer bleedings but was unexpectedly associated with more ischemic strokes, possibly reflecting selective prescribing. The association of rivaroxaban with higher all-cause mortality unrelated to bleedings or strokes has been described previously but remains to be explained.

[Recording and assessment of medication errors : Experience of the Drug Commission of the German Medical Association]. / Erfassung und Bewertung von Medikationsfehlern : Erfahrungen der Arzneimittelkommission der deutschen Ärzteschaft.

Adverse drug reactions (ADRs) are a common problem in daily clinical practice and they may in part result from medication errors. According to the extended interpretation in the new European pharmacovigilance guideline, medication error-related reactions are classified as ADRs. Therefore, the pharmacovigilance system needs to be adjusted to record medication errors. As a partner in the German pharmacovigilance system, the Drug Commission of the German Medical Association (DCGMA) has set up a project for developing a subsystem for the recording and assessment of medication errors within the existing spontaneous reporting system for ADRs. The aim of the project was to evaluate the feasibility of recording and assessing medication errors within the existing structures and to investigate whether it is possible to deduce risk-reducing strategies from the information obtained by the case reports. In the present narrative review, the experience of the DCGMA with the recording and assessment of medication errors is described. The conclusions and recommendations from the analysis of the reports of medication errors show how they can be used to improve medication safety. The project has closed a gap in pharmacovigilance.

[Tardive movement disorders with antipsychotics ­ a case of aripirazole-induced tardive dystonia and review of the literature]. / Antipsychotika-induzierte tardive Bewegungsstörungen ­ Fallbeispiel einer tardiven Dystonie unter Aripiprazol und Literaturübersicht.

Extrapyramidal adverse events (EPS) occur less frequently with second-generation antipsychotics (SGAs) than with first-generation antipsychotics (FGAs). Tardive dyskinesia (TD), but not tardive dystonia (TDt), also seems to occur less often in adults. TD was found to occur less frequently in children and adolescents treated with FGAs than in adults. No data are available on TDt, and the data pertaining to SGAs are limited and conflicting. SGAs differ in their profile of adverse events. Aripiprazole is less frequently associated with adverse metabolic or cardiac events, but more often with EPS, at least in children and adolescents. To date, there are several case reports of TD or TDt with aripiprazole in adults. Symptomatology, differential diagnosis, pathophysiology, prevalence, and therapy of TDt are presented here based on a case report of TDt during aripiprazole therapy in a 13-year-old girl. During medication with SGAs, the occurrence of EPS, including tardive movement disorders, should be considered and regularly monitored.

HLA-DRB1*16: 01-DQB1*05: 02 is a novel genetic risk factor for flupirtine-induced liver injury.

OBJECTIVE: Flupirtine is a nonopioid analgesic with regulatory approval in a number of European countries. Because of the risk of serious liver injury, its use is now limited to short-term pain management. We aimed to identify genetic risk factors for flupirtine-related drug-induced liver injury (DILI) as these are unknown. MATERIALS AND METHODS: Six flupirtine-related DILI patients from Germany were included in a genome-wide association study (GWAS) involving a further 614 European cases of DILI because of other drugs and 10,588 population controls. DILI was diagnosed by causality assessment and expert review. Human leucocyte antigen (HLA) and single nucleotide polymorphism genotypes were imputed from the GWAS data, with direct HLA typing performed on selected cases to validate HLA predictions. Four replication cases that were unavailable for the GWAS were genotyped by direct HLA typing, yielding an overall total of 10 flupirtine DILI cases. RESULTS: In the six flupirtine DILI cases included in the GWAS, we found a significant enrichment of the DRB1*16:01-DQB1*05:02 haplotype compared with the controls (minor allele frequency cases 0.25 and minor allele frequency controls 0.013; P=1.4 × 10(-5)). We estimated an odds ratio for haplotype carriers of 18.7 (95% confidence interval 2.5-140.5, P=0.002) using population-specific HLA control data. The result was replicated in four additional cases, also with a haplotype frequency of 0.25. In the combined cohort (six GWAS plus four replication cases), the haplotype was also significant (odds ratio 18.7, 95% confidence interval 4.31-81.42, P=6.7 × 10(-5)). CONCLUSION: We identified a novel HLA class II association for DILI, confirming the important contribution of HLA genotype towards the risk of DILI generally.

Metamizole (dipyrone)-associated agranulocytosis. An analysis of German spontaneous reports 1990-2012.

PURPOSE: In 1986, the risk of agranulocytosis prompted German authorities to restrict the indications for metamizole use. After an initial decline, prescriptions increased from <20 million defined daily doses in 1990 to >140 million in 2012. Concurrently, spontaneous reports of agranulocytosis increased from about 10 in 1990 to >50 in 2012. In this study, reports were analyzed to identify targets for risk minimization measures. METHODS: Reports of suspected metamizole-induced agranulocytosis (neutrophils < 0.5 × 10(9) cells/l) between 1990 and 2012 were identified in the German spontaneous reporting database. Cases for which original reporting documents were available were eligible for analysis. Patient characteristics, indication, clinical course, and outcome were assessed. RESULTS: One hundred sixty-one reports were analyzed. The mean age of the patients was 56.8 years (11-93) and 64.6 % were female. Off-label use was identified in about 25 % of cases. Neutrophils fell below 100/µl in 63 and intercurrent infections developed in 109 cases. Thirty-eight patients (23.6 %) died. In two thirds of the cases, agranulocytosis occurred within 6 weeks of permanent or intermittent metamizole treatment, in 30.5 % within 7 days, including 18 cases of immediate onset after the first or second administration. CONCLUSION: The reported cases show severe clinical courses and are, to some extent, a result of off-label use. Due to the absence of individual risk factors and presence of variable onset patterns, risk minimization measures should focus on restricting use to defined clinical situations and providing concise risk information for patients and healthcare professionals.

Hospitalisations Related to Adverse Drug Reactions in Switzerland in 2012-2019: Characteristics, In-Hospital Mortality, and Spontaneous Reporting Rate.

INTRODUCTION: Adverse drug reactions (ADRs) contribute to morbidity, and serious ADRs may cause hospitalisation and death. This study characterises and quantifies ADR-related hospitalisations and subsequent in-hospital deaths, and estimates the spontaneous reporting rate to regulatory authorities in Switzerland, where healthcare professionals are legally obliged to report ADRs. METHODS: This retrospective cohort study from 2012 to 2019 analysed nationwide data from the Federal Statistical Office. ICD-10 coding rules identified ADR-related hospitalisations. To estimate the reporting rate, individual case safety reports (ICSRs) collected in the Swiss spontaneous reporting system during the same period were considered. RESULTS: Among 11,240,562 inpatients, 256,550 (2.3%) were admitted for ADRs, 132,320 (51.6%) were female, 120,405 (46.9%) were aged ≥ 65 (median of three comorbidities, interquartile range [IQR] 2-4), and 16,754 (6.5%) were children/teenagers (0 comorbidities, IQR 0-1). Frequent comorbidities were hypertension (89,938 [35.1%]), fluid/electrolyte disorders (54,447 [21.2%]), renal failure (45,866 [17.9%]), cardiac arrhythmias (37,906 [14.8%]), and depression (35,759 [13.9%]). Physicians initiated 113,028 (44.1%) of hospital referrals, and patients/relatives 73,494 (28.6%). Frequently ADR-affected were the digestive system (48,219 [18.8%], e.g. noninfective gastroenteritis and colitis), the genitourinary system (39,727 [15.5%], e.g. acute renal failure), and the mental/behavioural state (39,578 [15.4%], e.g. opioid dependence). In-hospital mortality was 2.2% (5669). Since ICSRs indicated 14,109 hospitalisations and 700 in-hospital deaths, estimated reporting rates were 5% and 12%, respectively. CONCLUSIONS: This 8-year observation in Switzerland revealed that 2.3%, or roughly 32,000 admissions per year, were caused by ADRs. The majority of ADR-related admissions were not reported to the regulatory authorities, despite legal obligations.

[Perioperative analgesia with nonopioid analgesics : Joint interdisciplinary consensus-based recommendations of the German Pain Society, the German Society of Anaesthesiology and Intensive Care Medicine and the German Society of Surgery]. / Perioperative Schmerztherapie mit Nichtopioidanalgetika : Gemeinsame interdisziplinäre Empfehlung der Deutschen Schmerzgesellschaft, der Deutschen Gesellschaft für Anästhesiologie und Intensivmedizin und der Deutschen Gesellschaft für Chirurgie.

BACKGROUND: Nonopioid analgesics are frequently used for perioperative analgesia; however, insufficient research is available on several practical issues. Often hospitals have no strategy for how to proceed, e.g., for informing patients or for the timing of perioperative administration of nonopioid analgesics. METHODS: An expert panel representing the German national societies of pain, anaesthesiology and intensive care medicine and surgery developed recommendations for the perioperative use of nonopioid analgesics within a formal, structured consensus process. RESULTS: The panel agreed that nonopioid analgesics shall be part of a multimodal analgesia concept and that patients have to be informed preoperatively about possible complications and alternative treatment options. Patients' history of pain and analgesic intake shall be evaluated. Patients at risk of severe postoperative pain and possible chronification of postsurgical pain shall be identified. Depending on the duration of surgery, nonopioid analgesics can already be administered preoperatively or intraoperatively so that plasma concentrations are sufficient after emergence from anesthesia. Nonopioid analgesics or combinations of analgesics shall be administered for a limited time only. An interdisciplinary written standard of care, comprising the nonopioid analgesic of choice, possible alternatives, adequate dosing and timing of administration as well as surgery-specific policies, have to be agreed upon by all departments involved. At discharge, the patient's physician shall be informed of analgesics given and those necessary after discharge. Patients shall be informed of possible side effects and symptoms and timely discontinuation of analgesic drugs. CONCLUSION: The use of nonopioid analgesics as part of a perioperative multimodal concept should be approved and established as an interdisciplinary and interprofessional concept for the adequate treatment of postoperative pain.