The Dutch list of essential drugs for undergraduate medical education: A modified Delphi study.

AIMS: Prescribing errors among junior doctors are common in clinical practice because many lack prescribing competence after graduation. This is in part due to inadequate education in clinical pharmacology and therapeutics (CP&T) in the undergraduate medical curriculum. To support CP&T education, it is important to determine which drugs medical undergraduates should be able to prescribe safely and effectively without direct supervision by the time they graduate. Currently, there is no such list with broad-based consensus. Therefore, the aim was to reach consensus on a list of essential drugs for undergraduate medical education in the Netherlands. METHODS: A two-round modified Delphi study was conducted among pharmacists, medical specialists, junior doctors and pharmacotherapy teachers from all eight Dutch academic hospitals. Participants were asked to indicate whether it was essential that medical graduates could prescribe specific drugs included on a preliminary list. Drugs for which ≥80% of all respondents agreed or strongly agreed were included in the final list. RESULTS: In all, 42 (65%) participants completed the two Delphi rounds. A total of 132 drugs (39%) from the preliminary list and two (3%) newly proposed drugs were included. CONCLUSIONS: This is the first Delphi consensus study to identify the drugs that Dutch junior doctors should be able to prescribe safely and effectively without direct supervision. This list can be used to harmonize and support the teaching and assessment of CP&T. Moreover, this study shows that a Delphi method is suitable to reach consensus on such a list, and could be used for a European list.

The impact of a summative national prescribing assessment and curriculum type on the development of the prescribing competence of junior doctors.

PURPOSE: The primary aim of this study was to investigate the effect of including the Dutch National Pharmacotherapy Assessment (DNPA) in the medical curriculum on the level and development of prescribing knowledge and skills of junior doctors. The secondary aim was to evaluate the relationship between the curriculum type and the prescribing competence of junior doctors. METHODS: We re-analysed the data of a longitudinal study conducted in 2016 involving recently graduated junior doctors from 11 medical schools across the Netherlands and Belgium. Participants completed three assessments during the first year after graduation (around graduation (+ / - 4 weeks), and 6 months, and 1 year after graduation), each of which contained 35 multiple choice questions (MCQs) assessing knowledge and three clinical case scenarios assessing skills. Only one medical school used the DNPA in its medical curriculum; the other medical schools used conventional means to assess prescribing knowledge and skills. Five medical schools were classified as providing solely theoretical clinical pharmacology and therapeutics (CPT) education; the others provided both theoretical and practical CPT education (mixed curriculum). RESULTS: Of the 1584 invited junior doctors, 556 (35.1%) participated, 326 (58.6%) completed the MCQs and 325 (58.5%) the clinical case scenarios in all three assessments. Junior doctors whose medical curriculum included the DNPA had higher knowledge scores than other junior doctors (76.7% [SD 12.5] vs. 67.8% [SD 12.6], 81.8% [SD 11.1] vs. 76.1% [SD 11.1], 77.0% [12.1] vs. 70.6% [SD 14.0], p < 0.05 for all three assessments, respectively). There was no difference in skills scores at the moment of graduation (p = 0.110), but after 6 and 12 months junior doctors whose medical curriculum included the DNPA had higher skills scores (both p < 0.001). Junior doctors educated with a mixed curriculum had significantly higher scores for both knowledge and skills than did junior doctors educated with a theoretical curriculum (p < 0.05 in all assessments). CONCLUSION: Our findings suggest that the inclusion of the knowledge focused DNPA in the medical curriculum improves the prescribing knowledge, but not the skills, of junior doctors at the moment of graduation. However, after 6 and 12 months, both the knowledge and skills were higher in the junior doctors whose medical curriculum included the DNPA. A curriculum that provides both theoretical and practical education seems to improve both prescribing knowledge and skills relative to a solely theoretical curriculum.

Inhaled Δ9-tetrahydrocannabinol does not enhance oxycodone-induced respiratory depression: randomised controlled trial in healthy volunteers.

BACKGROUND: In humans, the effect of cannabis on ventilatory control is poorly studied, and consequently, the effect of Δ9-tetrahydrocannabinol (THC) remains unknown, particularly when THC is combined with an opioid. We studied the effect of THC on breathing without and with oxycodone pretreatment. We hypothesised that THC causes respiratory depression, which is amplified when THC and oxycodone are combined. METHODS: In this randomised controlled crossover trial, healthy volunteers were administered inhaled Bedrocan® 100 mg (Bedrocan International B.V., Veendam, The Netherlands), a pharmaceutical-grade high-THC cannabis variant (21.8% THC; 0.1% cannabidiol), after placebo or oral oxycodone 20 mg pretreatment; THC was inhaled 1.5 and 4.5 h after placebo or oxycodone intake. The primary endpoint was isohypercapnic ventilation at an end-tidal Pco2 of 55 mm Hg or 7.3 kPa (VE55), measured at 1-h intervals for 7 h after placebo/oxycodone intake. RESULTS: In 18 volunteers (age 22 yr [3]; 9 [50%] female), oxycodone produced a 30% decrease in VE55, whereas placebo was without effect on VE55. The first cannabis inhalation resulted in VE55 changing from 20.3 (3.1) to 23.8 (2.4) L min-1 (P=0.06) after placebo, and from 11.8 (2.8) to 13.0 (3.9) L min-1 (P=0.83) after oxycodone. The second cannabis inhalation also had no effect on VE55, but slightly increased sedation. CONCLUSIONS: In humans, THC has no effect on ventilatory control after placebo or oxycodone pretreatment. CLINICAL TRIAL REGISTRATION: 2021-000083-29 (EU Clinical Trials Register.).

Are psychedelics the answer to chronic pain: A review of current literature.

AIMS: We aim to provide an evidence-based overview of the use of psychedelics in chronic pain, specifically LSD and psilocybin. CONTENT: Chronic pain is a common and complex problem, with an unknown etiology. Psychedelics like lysergic acid diethylamide (LSD) and psilocybin, may play a role in the management of chronic pain. Through activation of the serotonin-2A (5-HT2A) receptor, several neurophysiological responses result in the disruption of functional connections in brain regions associated with chronic pain. Healthy reconnections can be made through neuroplastic effects, resulting in sustained pain relief. However, this process is not fully understood, and evidence of efficacy is limited and of low quality. In cancer and palliative related pain, the analgesic potential of psychedelics was established decades ago, and the current literature shows promising results on efficacy and safety in patients with cancer-related psychological distress. In other areas, patients suffering from severe headache disorders like migraine and cluster headache who have self-medicated with psychedelics report both acute and prophylactic efficacy of LSD and psilocybin. Randomized control trials are now being conducted to study the effects in cluster headache Furthermore, psychedelics have a generally favorable safety profile especially when compared to other analgesics like opioids. In addition, psychedelics do not have the addictive potential of opioids. IMPLICATIONS: Given the current epidemic use of opioids, and that patients are in desperate need of an alternative treatment, it is important that further research is conducted on the efficacy of psychedelics in chronic pain conditions.

Do we become better prescribers after graduation: A 1-year international follow-up study among junior doctors.

AIM: The aim of this study was to investigate how the prescribing knowledge and skills of junior doctors in the Netherlands and Belgium develop in the year after graduation. We also analysed differences in knowledge and skills between surgical and nonsurgical junior doctors. METHODS: This international, multicentre (n = 11), longitudinal study analysed the learning curves of junior doctors working in various specialties via three validated assessments at about the time of graduation, and 6 months and 1 year after graduation. Each assessment contained 35 multiple choice questions (MCQs) on medication safety (passing grade ≥85%) and three clinical scenarios. RESULTS: In total, 556 junior doctors participated, 326 (58.6%) of whom completed the MCQs and 325 (58.5%) the clinical case scenarios of all three assessments. Mean prescribing knowledge was stable in the year after graduation, with 69% (SD 13) correctly answering questions at assessment 1 and 71% (SD 14) at assessment 3, whereas prescribing skills decreased: 63% of treatment plans were considered adequate at assessment 1 but only 40% at assessment 3 (P < .001). While nonsurgical doctors had similar learning curves for knowledge and skills as surgical doctors (P = .53 and P = .56 respectively), their overall level was higher at all three assessments (all P < .05). CONCLUSION: These results show that junior doctors' prescribing knowledge and skills did not improve while they were working in clinical practice. Moreover, their level was under the predefined passing grade. As this might adversely affect patient safety, educational interventions should be introduced to improve the prescribing competence of junior doctors.

Monitoring Opioids in Europe: The Need for Shared Definitions and Measuring Drivers of Opioid Use and Related Harms.

The past 20 years, the USA is facing a serious opioid crisis initiated by an increase in prescription opioid use. Europe has also seen an increase in prescription opioid use, but the extent of related harm is still largely unknown. Given the impact of the US opioid epidemic, it is important to closely monitor signs of emerging opioid-related problems to guarantee early warnings and timely actions. Shared and meaningful definitions for opioid use and related harms, and relevant information about specific drivers for opioid use and related problems are needed for an adequate policy response. In this commentary, we discuss these definitions, the need to know more about the specific drivers for increased opioid use, its related harm, and proposals for strategies to move forward. Policy recommendations include making a distinction between licit and illicit opioids when monitoring and reporting on opioid-related harm, and using oral morphine equivalents to quantify prescription opioid use in a clinically relevant and comparable manner. A major topic of further research is exploring unique and universal drivers of prescription opioid (mis)use across Europe, in particular the role of opioid diversion.

Prior use of therapeutic anticoagulation does not protect against COVID-19 related clinical outcomes in hospitalized patients: A propensity score-matched cohort study.

The hypercoagulable state observed in COVID-19 could be responsible for morbidity and mortality. In this retrospective study we investigated whether therapeutic anticoagulation prior to infection has a beneficial effect in hospitalized COVID-19 patients. This study included 1154 COVID-19 patients admitted to 6 hospitals in the Netherlands between March and May 2020. We applied 1:3 propensity score matching to evaluate the association between prior therapeutic anticoagulation use and clinical outcome, with in hospital mortality as primary endpoint. In total, 190 (16%) patients used therapeutic anticoagulation prior to admission. In the propensity score matched analyses, we observed no associations between prior use of therapeutic anticoagulation and overall mortality (risk ratio 1.02 [95% confidence interval; 0.80-1.30]) or length of hospital stay (7.0 [4-12] vs. 7.0 [4-12] days, P = .69), although we observed a lower risk of pulmonary embolism (0.19 [0.05-0.80]). This study shows that prior use of therapeutic anticoagulation is not associated with improved clinical outcome in hospitalized COVID-19 patients.

Communication about Drug-Related Problems (DRPs) during Patients' Visits to Dutch Physicians and Pharmacies.

The objective of this study is to assess the frequency and type of drug-related problems (DRPs) (1) raised and discussed (2) raised but not discussed or (3) not raised during patients' visits to healthcare practitioners (HCPs). In this cross-sectional study in Dutch outpatient clinics, GP practices and pharmacies, verbal cues from patients and HCPs indicating DRPs were inventoried by an observer during visits. It was also observed whether raised DRPs were discussed between patient and HCP. Post-encounter interviews (HCPs) were conducted and post-encounter questionnaires (patient) were distributed to identify DRPs not raised. In total, 431 patients were observed during a single visit. In 42.2% of these visits, 311 DRPs were raised (weighted mean (SD) 0.7 (±1.1) DRP/patient). Of these 311 DRPs, 82.0% were discussed between HCP and patient. HCPs did not raise existing DRPs in 3.9% of the 431 visits; in 6.3% of the 176 questionnaires the patient reported an existing DRP that had not been raised. In conclusion, almost one in six of the DRPs raised during visits are not discussed between HCP and patient. Furthermore, existing DRPs are not even raised in 4-6% of the visits. HCPs and patients should be aware that, although patients often have DRPs, these are not always discussed or not even raised during patients' visits.

Intravenous flucloxacillin treatment is associated with a high incidence of hypokalaemia.

Intravenous flucloxacillin is one of the most frequently used high-dose penicillin therapies in hospitalized patients, forming the cornerstone treatment of invasive Staphylococcus aureus infection. Being a nonreabsorbable anion, flucloxacillin has been suggested to cause hypokalaemia, although the frequency and magnitude of this unwanted effect is unknown. In a retrospective cohort, we investigated the incidence and extent of hypokalaemia after initiation of intravenous flucloxacillin or ceftriaxone therapy. In total, 77 patients receiving flucloxacillin (62% male, mean age 70.5 years) and 84 patients receiving ceftriaxone (46% male, mean age 70.8 years) were included. Hypokalaemia occurred significantly more often in patients receiving flucloxacillin than ceftriaxone (42% vs 14%, p < 10-4 ). Moreover, follow-up potassium levels were significantly lower during flucloxacillin therapy. In general, women were more prone to develop hypokalaemia than men. In conclusion, intravenous flucloxacillin use is associated with a striking incidence of hypokalaemia. Therefore, standardized potassium measurements are necessary.

Macrolide prescription in Dutch children: compliance with guidelines.

For reasons of antibiotic resistance and side effects, macrolides should be prescribed with care in the pediatric population. We evaluated the adherence to Dutch guidelines of macrolide prescription in children and estimated the risk of Mycoplasma pneumoniae-associated pneumonia based on Fischer's decision tree. In this retrospective study, we included children aged 0-18 years who were treated with azithromycin or clarithromycin for pulmonary disease in four settings from general practice to hospital ward for (1) the prescriptions not in accordance with the guideline of the Dutch Association of Pediatrics and (2) the risk of M. pneumoniae in patients with community-acquired pneumonia (CAP) according to Fischer's decision tree. The latter suggests that children older than three years with a fever lasting more than two days are at high risk for M. pneumoniae and that it is therefore justified to treat them with macrolides. In total, 189 macrolide prescriptions from 2015 until 2017 were analyzed: 139 children used macrolides for a pulmonary indication (75%); 18% (n = 25) of the prescriptions were not in accordance with Dutch guidelines. Only 9.1% of patients with CAP were classified as having a high risk of M. pneumoniae according to Fischer's decision tree. A significant proportion of macrolide prescriptions for Dutch children with a pulmonary disease appears not to be in accordance with the guidelines. Most patients with CAP treated with a macrolide actually had a low risk of having M. pneumoniae according to Fischer's decision tree. Both observations suggest overuse of macrolides in children.

Towards a "prescribing license" for medical students: development and quality evaluation of an assessment for safe prescribing.

PURPOSE: This report describes the development and validation process of an assessment with national consensus in appropriate and safe pharmacotherapy. METHODS: A question-database on safe prescription based on literature of pharmacotherapy-related harm was developed by an expert group from Dutch medical faculties. Final-year medical students concluded a 2-year education program on appropriate and safe prescription by one of nine assessment variants of 40 multiple-choice questions each. An expert panel of professionals (n = 10) answered all database questions and rated questions on relevance. Questions were selected for revision based on lack of relevance or poor test and item characteristics. RESULTS: A total of 576 final-year medical students of the Radboud University was assessed. There was no significant difference in performance between students and content expert group (p = 0.7), probably due to learning behavior. Out of 165 questions, 59 were selected for revision. CONCLUSION: Joint national effort from a team of experts in prescription and pharmacotherapy is an appropriate way to achieve a valid and reliable last-year student drug prescription assessment.

Discontinuation of antidepressant medication in primary care supported by monitoring plus mindfulness-based cognitive therapy versus monitoring alone: design and protocol of a cluster randomized controlled trial.

BACKGROUND: Antidepressant use continues to rise, mainly explained by an increase in the proportion of patients receiving long term treatment. Although treatment guidelines recommend discontinuation after sustained remission, discontinuing antidepressants appears to be challenging for both patients and general practitioners (GPs). Mindfulness-Based Cognitive Therapy (MBCT) is an effective intervention that reduces the risk of relapse in recurrent depression and might facilitate discontinuation by teaching patients to cope with withdrawal symptoms and fear of relapse. The current study aims to investigate the effectiveness of the combination of Supported Protocolized Discontinuation (SPD) and MBCT in comparison with SPD alone in successful discontinuation of long-term use of antidepressants in primary care. METHODS: This study involves a cluster-randomized controlled trial conducted in primary care patients with long-term use antidepressants with baseline and 6, 9 and 12 months follow-up assessments. Patients choosing to discontinue their medication will be offered a combination of SPD and MBCT or SPD alone. Our primary outcome will be full discontinuation of antidepressant medication (= 0 mg) within 6 months after baseline assessment. Secondary outcome measures will be the severity of withdrawal symptoms, symptoms of depression and anxiety, psychological well-being, quality of life and medical and societal costs. DISCUSSION: In theory, stopping antidepressant medication seems straightforward. In practice however, patients and their GPs appear reluctant to initiate and accomplish this process. Both patients and professionals are in need of appropriate tools and information to better support the process of discontinuing antidepressant medication. TRIAL REGISTRATION: ClinicalTrials.gov PRS ID: NCT03361514 retrospectively registered October 2017.

Genetic determinants of impaired awareness of hypoglycemia in type 1 diabetes.

OBJECTIVE: It is likely that impaired awareness of hypoglycemia (IAH) and severe hypoglycemia are in part determined by genetic factors. The aim of this study was to investigate candidate genes for associations with IAH and severe hypoglycemia in a cohort of patients with type 1 diabetes. PARTICIPANTS AND METHODS: Consecutive patients with type 1 diabetes were genotyped for single-nucleotide polymorphisms in or near the genes for the ß1 and ß2 adrenergic receptor (ADRB1, ADRB2), SORCS1, and BNC2, and for the insertion/deletion polymorphism in the ACE gene. IAH and severe hypoglycemia were assessed using a validated questionnaire. RESULTS: Of 486 patients, 32.5% were classified as having IAH. The Arg16Gly polymorphism of ADRB2 was associated with IAH (odds ratio: 1.49, 95% confidence interval: 1.01-2.20, P=0.046) Gly16 (GG) versus carriers of the A allele. In a haplotype analysis, the association was the highest in patients with GG at position 16 and heterozygous at position 27 (odds ratio: 2.19, 95% confidence interval: 1.33-3.61, P=0.03). There were no associations between IAH and other genes, and none of the studied genes was associated with severe hypoglycemia. CONCLUSION: Genotypes at two variants of ADRB2 are associated with IAH. This association is comparable with the risk of classical risk factors for IAH.

Initial anticoagulation in patients with pulmonary embolism: thrombolysis, unfractionated heparin, LMWH, fondaparinux, or DOACs?

The initial treatment of haemodynamically stable patients with pulmonary embolism (PE) has dramatically changed since the introduction of low molecular weight heparins (LMWHs). With the recent discovery of the direct oral anticoagulant drugs (DOACs), initial treatment of PE will be simplified even further. In several large clinical trials it has been demonstrated that DOACs are not inferior to standard therapy for the initial treatment of PE, and because of their practicability they are becoming the agents of first choice. However, many relative contraindications to DOACs were exclusion criteria in the clinical trials. Therefore, LMWHs will continue to play an important role in initial PE treatment and in some cases there still is a role for unfractionated heparin (UFH). In this review we will give an overview of the biophysical, pharmacokinetic and pharmacodynamic properties of anticoagulants currently available for the initial management of PE. In addition, we will provide a comprehensive overview of the indications for the use of UFH, LMWHs and DOACs in the initial management of PE from a pharmacokinetic/-dynamic point of view.

The effect of prescriber education on medication-related patient harm in the hospital: a systematic review.

AIMS: Educating prescribers is a strategy to reduce prescription errors in hospitals. The present systematic review gives an overview of original research papers on the education of prescribers and reporting outcomes on (potential) patient harm. METHODS: A search of the databases Embase and Medline, using the Ovid interface, was performed. Research on the effect of physician education in order to prevent medication-related problems in inpatients, and on reporting original data and outcomes on prescribing errors and/or (potential) patient harm, was included. The assessment of methodological quality and risk of bias was performed using the Methodological Index for Non-Randomized studies (MINORS) checklist and the suggested risk of bias criteria for Effective Practice and Organization of Care (EPOC) reviews. RESULTS: Eight studies investigated an intervention on education alone, and in seven studies education was the main part of a multifaceted intervention. All studies were small and had short follow-up periods. The educational programmes varied and were given to physicians of different specialties and levels of experience. Most studies reported intermediate process parameters as the outcome. The risk of performance and reporting bias were high. CONCLUSION: All included studies suffered from poor methodology. The majority, especially studies in which education was part of a multifaceted intervention, reported effectiveness on intermediate outcome markers as prescription errors and potential adverse drug events. However, we found no firm evidence that educating prescribers in the hospital leads to a decrease in patient harm. Further work is needed to develop educational programmes, accompanied by more high-quality research with outcomes on the improvement of patient care.

Risk of major bleeding and stroke associated with the use of vitamin K antagonists, nonvitamin K antagonist oral anticoagulants and aspirin in patients with atrial fibrillation: a cohort study.

AIMS: Nonvitamin K antagonist oral anticoagulants (NOACs) are now available for the prevention of stroke in patients with atrial fibrillation (AF) as an alternative to vitamin K antagonists (VKA) and aspirin. The comparative effectiveness and safety in daily practice of these different drug classes is still unclear. The objective of this study was to evaluate the risk of major bleeding and stroke in AF patients using NOACs, VKAs or aspirin. METHODS: A retrospective cohort study was conducted among AF patients using the UK Clinical Practice Research Datalink (March 2008-October 2014). New users of VKAs, NOACs and low dose aspirin were followed from the date of first prescription of an antithrombotic drug until the occurrence of stroke or major bleeding. Analyses were adjusted for a history of comorbidities and drug use with Cox regression analysis. RESULTS: A total of 31 497 patients were eligible for the study. The hazard ratio (HR) of major bleeding was 2.07 [95% confidence interval (CI) 1.27-3.38] for NOACs compared with VKAs, which was mainly attributed by the increased risk of gastrointestinal bleeding (HR 2.63, 95% CI 1.50-4.62). This increased bleeding risk was restricted to women (HR 3.14, 95% CI 1.76-5.60). Aspirin showed a similar bleeding risk as VKAs. NOACs showed equal effectiveness as VKA in preventing ischaemic stroke (HR 1.22, 95% CI 0.67-2.19). VKAs were more effective than aspirin (HR 2.18, 95% CI 1.83-2.59). CONCLUSIONS: NOACs were associated with a higher risk on gastrointestinal bleeding, particularly in women. The use of NOACs in patients who are vulnerable for this type of bleeding should be carefully considered. NOACs and VKAs are equally effective in preventing stroke. Aspirin was not effective in the prevention of stroke in AF.

A multifaceted intervention to reduce drug-related complications in surgical patients.

AIM: The P-REVIEW study was a prospective, multicenter, open intervention study, designed to determine whether a multifaceted intervention of educating the prescriber combined with medication review and pharmaceutical visits to the ward by the hospital pharmacist could lead to a reduction in drug-related complications among surgical patients. METHODS: A total of 6780 admissions of 5940 patients to surgical, urological and orthopaedic wards during the usual care period and 6484 admissions of 5711 patients during the intervention period were included. An educational programme covering pain management, antithrombotics, fluid and electrolyte management, prescription in case of renal insufficiency and antibiotics was developed. National and local hospital guidelines were included. Hospital pharmacists performed medication safety consultations, combining medication review of high-risk patients and a visit to the physician on the ward. RESULTS: A significantly lower proportion of admissions with one or more clinically relevant, potentially preventable, drug-related problems (including death, temporary or sustained disability, increased length of hospital stay or readmission within 30 days) occurred in the intervention period (1.1% (73/6484) compared to the usual care period [1.6% (106/6780)] (P = 0.029). The relative risk (RR) was 0.72 (95% CI 0.53-0.97). Several types of drug-related problems occurred less frequently. Costs incurred as result of time spent on study-related activities were not different before and after the intervention. CONCLUSIONS: The P-REVIEW study shows that education and support of the prescribing physician with respect to high-risk patients in surgical departments leads to a significant, clinically relevant benefit for patients without generating additional costs.