[Medication verification in hospital: is it proportional?] / Medicatieverificatie in ziekenhuizen: een proportioneel instrument?

In 2008 in the Netherlands the Guideline 'Transmission of medication in the chain' was published. This guideline described that upon admission and discharge in the hospital verification of medication should take place. This caused significant investments in staff by hospitals to meet with this guideline. However, despite these efforts 15 years later this has not led to adequate transmission of medication. In this article it is described that the organization of medication verification in hospitals has features of the Risk Regulation Reflex. A better possible solution of this problem is proposed: making community pharmacies responsible for updating the medication overview. This pharmacist should perform this task together with the patient. This should be done in parallel with improving compliance. In hospitals medication reviews in high risk patients could take place.

[Consider (es)ketamine for treatment-resistant depression]. / Overweeg (es)ketamine bij therapieresistente depressie.

Major depressive disorder has a high prevalence globally. Although pharmacotherapy and psychotherapy are effective for most patients, about one third is treatment resistant. Ketamine, known as an anesthetic, is a new treatment option that can be effective in patients with treatment-resistant depression. (es)ketamine works relatively fast. However, the long-term effects are still relatively unknown. In the Netherlands, S-Ketamine is currently administered in various forms, of which only the nasal spray is registered for treatment-resistant depression. Currently, many studies have been conducted on the use of (es)ketamine. In this article we describe the latest state of affairs regarding its effectiveness and safety.

[Combination diuretic therapy in heart failure]. / Combinaties van diuretica bij hartfalen.

Loop diuretics are the cornerstone of the treatment of volume overload in decompensated heart failure. However, often complete decongestion cannot be achieved rapidly with loop diuretics alone, partly due to compensatory upregulation of sodium resorption at other parts of the nephron. These compensatory mechanisms can be antagonized by using a combination of diuretics. In earlier research, a number of those combinations have been investigated, but no diuretic combination has been proven to be both efficient and safe yet. A recent multicenter, double-blind, randomized, placebo-controlled study - performed by Mullens et al. in 2022 - investigated adding acetazolamide (Diamox) to loop diuretics in patients with decompensated heart failure. They found that a higher rate of decongestion was achieved with the addition of acetazolamide without seemingly more side effects. The addition of acetazolamide can be considered in the treatment of decompensated heart failure.

Practice variation in opioid prescribing for non-cancer pain in Dutch primary care: A retrospective database study.

BACKGROUND: Prescription opioid use has increased steadily in many Western countries over the past two decades, most notably in the US, Canada, and most European countries, including the Netherlands. Especially the increasing use of prescription opioids for chronic non-cancer pain has raised concerns. Most opioids in the Netherlands are prescribed in general practices. However, little is known about variation in opioid prescribing between general practices. To better understand this, we investigated practice variation in opioid prescribing for non-cancer pain between Dutch general practices. METHODS: Data from 2017-2019 of approximately 10% of all Dutch general practices was used. Each year included approximately 1000000 patients distributed over approximately 380 practices. The primary outcome was the proportion of patients with chronic (>90 days) high-dose (≥90 oral morphine equivalents) opioid prescriptions. The secondary outcome was the proportion of patients with chronic (<90 oral morphine equivalents) opioid prescriptions. Practice variation was expressed as the ratio of the 95th/5th percentiles and the ratio of mean top 10/bottom 10. Funnel plots were used to identify outliers. Potential factors associated with unwarranted variation were investigated by comparing outliers on practice size, patient neighbourhood socioeconomic status, and urbanicity. RESULTS: Results were similar across all years. The magnitude of variation for chronic high-dose opioid prescriptions in 2019 was 7.51-fold (95%/5% ratio), and 15.1-fold (top 10/bottom 10 ratio). The percentage of outliers in the funnel plots varied between 13.8% and 21.7%. Practices with high chronic high-dose opioid prescription proportions were larger, and had more patients from lower income and densely populated areas. CONCLUSIONS: There might be unwarranted practice variation in chronic high-dose opioid prescriptions in primary care, pointing at possible inappropriate use of opioids. This appears to be related to socioeconomic status, urbanicity, and practice size. Further investigation of the factors driving practice variation can provide target points for quality improvement and reduce inappropriate care and unwarranted variation.

[Dealing with opioid dependence and withdrawal in hospitals]. / Omgaan met opioïdafhankelijkheid en -onthouding in het ziekenhuis.

BACKGROUND: In opioid addiction tolerance occurs requiring substitution with unusually high doses. A balance must be struck between the risk of overdose with respiratory depression and QTc interval prolongation on one hand and underdosing with withdrawal syndrome on the other hand. An unreliable anamnesis can complicate adequate dosing. CASE DESCRIPTION: A 30-year-old polydrug user with a severe dependence on methadone and heroin was admitted to the Intensive Care Unit after surgery for thoracic surgery. Upon cautious initiation with methadone, severe withdrawal and pain symptoms occurred. Doubling the dose made the withdrawal symptoms disappear without signs of overdose. CONCLUSION: During hospital admission of patients with high opioid tolerance the anamnestic equivalent high opioid dose can be started immediately, provided there is a possibility of monitoring the respiration and heart rhythm. The risk of withdrawal and insufficient pain relief in a hospital is generally greater than the risk of an overdose.

[Toxidromes]. / Toxidromen.

In this Clinical Lesson, using two illustrating cases, we explain how to do the initial assessment and treatment of an intoxicated patient. An approach aimed at toxidromes can serve as a stepping stone. A toxidrome is a combination of symptoms and clinical features that can occur with the use of certain drugs and substances. The most commonly encountered toxidromes are sympathomimetic, serotonergic, anticholinergic, cholinergic, sedative-hypnotic and opioid. All patients need to be approach according to the ABCDE method. The treatment is based on pharmacokinetics by means of the ADME principle (absorption, distribution, metabolism and excretion) and based on pharmacodynamics, aimed at the toxidrome.

CYP2C19 genotype-guided antithrombotic treatment versus conventional clopidogrel therapy in peripheral arterial disease: study design of a randomized controlled trial (GENPAD).

BACKGROUND: Clopidogrel is recommended in international guidelines to prevent arterial thrombotic events in patients with peripheral arterial disease (PAD). Clopidogrel itself is inactive and metabolism is dependent on the CYP2C19 enzyme. About 30% of Caucasian PAD patients receiving clopidogrel carry 1 or 2 CYP2C19 loss-of-function allele(s) and do not or to a limited extent convert the prodrug into its active metabolite. As a result, platelet inhibition may be inadequate which could lead to an increased risk of adverse clinical events related to arterial thrombosis. A CYP2C19 genotype-guided antithrombotic treatment might be beneficial for PAD patients. METHODS: GENPAD is a multicenter randomized controlled trial involving 2,276 PAD patients with an indication for clopidogrel monotherapy. Patients with a separate indication for dual antiplatelet therapy or stronger antithrombotic therapy are not eligible for study participation. Patients randomized to the control group will receive clopidogrel 75 mg once daily without pharmacogenetic guidance. Patients randomized to the intervention group will be tested for carriage of CYP2C19 *2 and *3 loss-of-function alleles, followed by a genotype-guided antithrombotic treatment with either clopidogrel 75 mg once daily for normal metabolizers, clopidogrel 150 mg once daily for intermediate metabolizers, or acetylsalicylic acid 80 mg once daily plus rivaroxaban 2.5 mg twice daily for poor metabolizers. The primary outcome is a composite of myocardial infarction, ischemic stroke, cardiovascular death, acute or chronic limb ischemia, peripheral vascular interventions, or death. The secondary outcomes are the individual elements of the primary composite outcome and clinically relevant bleeding complications. CONCLUSION: The aim of the GENPAD study is to evaluate the efficacy, safety, and cost-effectiveness of a genotype-guided antithrombotic treatment strategy compared to conventional clopidogrel treatment in PAD patients.

[Side effects of medicinal products: assessment and registration of causality]. / Bijwerkingen van geneesmiddelen.

The Farmacotherapeutisch Kompas (FK) and the KNMP Kennisbank report on side effects of medicinal products, in order of frequency. However, data regarding causality and its assessment are lacking, while this information is crucial when the discontinuation of a drug due to putative side effects is considered. In this article, we describe the role of pharmaceutical companies, the agencies in charge of the evaluation and supervision of medicinal products and Lareb. We also describe how this information is included in the FK and the Kennisbank. Only side effects with a probable causal relation to the drug are registered. However, to err on the side of caution, side effects with a questionable causal relation to the drug are sometimes also registered. It would be helpful for the physician if the FK and the Kennisbank also reported the degree of assessed causality, next to the frequency.

[Metamizol: current status in Dutch practice]. / Pijnbestrijding met metamizol in de Nederlandse praktijk.

Metamizole is a non-selective NSAID with a strong analgesic and spasmolytic effect. In the late 1970s, metamizole has been withdrawn from the market in many industrialized countries because of an allegedly unacceptable high risk of agranulocytosis. The absolute risk of metamizole-related agranulocytosis is estimated to be less than 1 per million daily doses. The incidence of agranulocytosis may be reduced by short-term use and careful consideration when prescribing to specific patient categories. Metamizole has a relatively favorable safety profile with respect to morbidity and mortality compared to other NSAIDs. In the Netherlands the official registration of metamizole has been limited for years to intravenous and postoperative use. In March 2021, the Dutch Medicine Assessment Board certified one oral formulation of metamizol under strict conditions. The debate about the wider application of (oral) metamizole in the Netherlands should be re-opened.

[Why do patients find it difficult to discontinue their medication?] / Waarom vinden patiënten het moeilijk om te stoppen met medicijnen?

Tapering medication is difficult for many patients using chronic medication. Physicians must be aware of why patients experience difficulties in discontinuation. Important are the cognitions of patients about why the medication is necessary, for example because of the deficit of a certain substance that is supplemented by the medication. Or a too favourable expectation of the effect while time-to-benefit has passed. The experience of withdrawal effects during earlier attempts or the experience of dependency hamper new attempts to stop. This is important in medication that induces physical dependency: antipsychotics, antidepressants, benzodiazepines, or proton pump inhibitors. Fear for relapse is also hampering discontinuation; this is at stake in patients with psychosis, depression and epilepsy. Finally, poor communication and not having a trusted professional are impediments for discontinuation. To be successful in helping patients discontinue their medication professionals must communicate well about the patient's personal attitude, experience, emotions, and life circumstances as well as to possess expertise about the technical aspects of the procedure of stopping medication.

[Tapering of opioid use in primary care]. / Opioïden afbouwen in de eerstelijnszorg.

Although opioids are frequently used as treatment for chronic non-cancer related pain, the long term benefits on pain intensity and physical functioning are rather limited. Prolonged use of opioids is accompanied by multiple risks and side effects. It is important to regularly evaluate the effectiveness and the possibility of tapering of an opioid therapy. Tapering opioid use may improve physical function. Structured counselling by a healthcare professional facilitates successful tapering. In most cases, it will be possible to taper opioids in a primary care setting. If the treating physician feels incompetent to manage the tapering process, referral to specialized psychiatric care or a pain specialist can be considered. We propose a tapering rate between 10-35% of the previous dose per week in the primary care setting. Both pharmacological and non-pharmacological interventions can be used to ease the tapering.

[Don't stop medication too abruptly: advice about the discontinuation of medication]. / Stop niet te snel, dan lukt het wél.

Polypharmacy may result in interactions and side effects that lead to morbidity and mortality. Therefore, it is important to evaluate on a regular basis the possibility to stop medication. Sometimes it is necessary to temporarily discontinue certain medication, for example when a patient is unable to swallow or suffers from a delirium. Not all drugs can be stopped abruptly, since this can result in a rebound-effect or withdrawal symptoms Especially drugs that act on the central nervous system (e.g. psychotropic drugs, dopaminergic drugs, opioids) are known to cause (severe) withdrawal symptoms when stopped abruptly In addition, beta-blockers, corticosteroids and proton-pump inhibitors cause symptoms when stopped without tapering. Gradually tapering off these medicines is needed, sometimes under guidance from a specialist. Moreover, it is important to realize that stopping medication can also introduce interactions.

[Stop conducting one-size-fits-all medication reviews in patients with polypharmacy; rather begin with personalized and transmural medication guidance]. / Stop met eenmalige medicatiereviews.

The negative OPERAM study results, which are in line with recent trials and reviews, warn against expecting positive patient related outcomes from single standardized medication reviews in all patients with polypharmacy admitted to hospital. The big underlying problem is the enormous heterogeneity of patients with polypharmacy. However, it remains possible that a personalized medication review in well selected vulnerable patients can have positive effects, especially if the review is integrated in a linked hospital and general practice medication policy. Thus, there also is sufficient evidence to stop conducting a one size fits all drug review randomized trials on polypharmacy, but we need pragmatic trials with smart selection of patient with polypharmacy-related health problems, whose personalized and transmural medication guidance may still contribute to positive outcomes of integrated care innovations, especially when the outcomes can be personalized as well.

[Topical NSAIDs: ineffective or undervalued?] / Topicale NSAID's: ineffectief of ondergewaardeerd?

Topical NSAIDs are currently recommended in several national and international guidelines for knee osteoarthritis, hand osteoarthritis and acute musculoskeletal pain. However, there is still widespread skepticism about the effectiveness of this treatment. This article discusses different reasons for this skepticism, a short summary of the pharmacokinetics and pharmacodynamics of topical NSAIDs and an overview of available evidence regarding efficacy and safety. Based on this evidence topical NSAIDs have a clear place in the treatment of knee and hand osteoarthritis and acute musculoskeletal pain. Due to less systemic side effects they should be recommended before an oral NSAID is considered. Topical NSAIDs might even be an option for patients with contra-indications for oral NSAIDs. There is a large variety of available topical NSAIDs. Of the available topical NSAIDs in the Netherlands, diclofenac gel seems the most sensible choice.

[COVID-19 vaccines: the facts]. / COVID-19-vaccins: hoe zit het?

Not all physicians advocate for large-scale vaccination programmes against COVID-19. In this article, we respond on some of their reflections. Moreover, we explain that there are strong arguments for these large-scale vaccination programmes, aimed to prevent COVID-19 associated morbidity, mortality and overwhelmed health care systems, and to hinder the emergence of new strains of SARS-CoV-2 by reducing the virus transmission.

[Temporary suspension of AstraZeneca's vaccine; a reconstruction]. / Prikpauze AstraZeneca proportioneel?

In the middle of the worldwide COVID-19 crisis, the whole of Europe was alarmed about a possible side effect of the AstraZeneca vaccine against COVID-19. Consequently, the use of this AstraZeneca vaccine was temporarily suspended in many European nations including the Netherlands. In this article, we chronologically describe the decisions that were made about the use of this vaccine in the Netherlands and we discuss the risk-benefit ratios of these actions as well as possible non-medical reasons that may explain why these actions were taken.

[Ingested medication blister packs]. / Ingeslikte blisterverpakkingen.

BACKGROUND: Single dose blister packs (BP) are commonly used in pharmaceutical packaging. Accidental ingestion of medication BPs can cause serious harm as the sharp edges can severely damage the esophageal wall. CASE DESCRIPTIONS: We describe 2 cases of accidental BP ingestion. An 88-year-old man self-administered his medication during hospital admission. Afterwards, he started to complain about dysphagia. Endoscopic examination the next day revealed a BP stuck in the esophageal wall, which was successfully removed. A 66-year-old man presented to the emergency department with acute onset hematemesis and dysphagia for one week. Upper endoscopy showed a deep tear in the esophageal mucosa and an intact BP in the stomach. The BP was removed and the patient recovered. CONCLUSION: Patients are often not aware of the ingested BP. Urgent endoscopic intervention is needed in order to prevent further damage to the esophageal wall. Supervision during specific moments of intake could help to prevent accidental ingestion.

Nephrotoxicity of concomitant piperacillin/tazobactam and teicoplanin compared with monotherapy.

OBJECTIVES: Piperacillin/tazobactam combined with vancomycin has been associated with a decline in renal function when compared with monotherapy. Teicoplanin is a glycopeptide similar to vancomycin. We investigated whether piperacillin/tazobactam combined with teicoplanin is associated with a decline in renal function as well. METHODS: We conducted a single-centre retrospective cohort study with data from our electronic health records from 9 August 2013 to 15 November 2019, including all adult patients that received either piperacillin/tazobactam, teicoplanin or piperacillin/tazobactam + teicoplanin. The incidence of acute kidney injury (AKI) at 48-72 h served as the primary outcome, whereas change in serum creatinine served as a secondary outcome. RESULTS: Of the 4202 included patients, 3188 (75.9%) received piperacillin/tazobactam, 791 (18.8%) received teicoplanin and 223 (5.3%) received piperacillin/tazobactam + teicoplanin. The incidence of AKI at 48-72 h after commencement of antibiotic therapy was 5.4% for piperacillin/tazobactam, 3.4% for teicoplanin and 11.7% for piperacillin/tazobactam + teicoplanin (P < 0.001). However, mean serum creatinine at 48-72 h was slightly higher in the piperacillin/tazobactam + teicoplanin group therapy compared with baseline [+1.61% (95% CI -2.25 to 5.70)], indicating a slight decrease in renal function, and decreased for piperacillin/tazobactam [-1.98% (95% CI -2.73 to -1.22)] and teicoplanin [-8.01% (95% CI -9.54 to -6.45)]. After correcting for significant confounders in a multivariate linear regression analysis, these patterns remained. CONCLUSIONS: Our study suggests that piperacillin/tazobactam + teicoplanin is associated with a higher prevalence of AKI compared with monotherapy. However, as the overall decline in renal function with piperacillin/tazobactam + teicoplanin is very small, its clinical relevance is likely limited. Therefore, piperacillin/tazobactam + teicoplanin can probably be safely combined.

Characteristics associated with polypharmacy in people with type 2 diabetes: the Dutch Diabetes Pearl cohort.

AIM: To describe the prevalence and characteristics of polypharmacy in a Dutch cohort of individuals with type 2 diabetes. METHODS: We included people with type 2 diabetes from the Diabetes Pearl cohort, of whom 3886 were treated in primary care and 2873 in academic care (secondary/tertiary). With multivariable multinomial logistic regression analyses stratified for line of care, we assessed which sociodemographic, lifestyle and cardiometabolic characteristics were associated with moderate (5-9 medications) and severe polypharmacy (≥10 medications) compared with no polypharmacy (0-4 medications). RESULTS: Mean age was 63 ± 10 years, and 40% were women. The median number of daily medications was 5 (IQR 3-7) in primary care and 7 (IQR 5-10) in academic care. The prevalence of moderate and severe polypharmacy was 44% and 10% in primary care, and 53% and 29% in academic care respectively. Glucose-lowering and lipid-modifying medications were most prevalent. People with severe polypharmacy used a relatively large amount of other (i.e. non-cardiovascular and non-glucose-lowering) medication. Moderate and severe polypharmacy across all lines of care were associated with higher age, low educational level, more smoking, longer diabetes duration, higher BMI and more cardiovascular disease. CONCLUSIONS: Severe and moderate polypharmacy are prevalent in over half of people with type 2 diabetes in primary care, and even more in academic care. People with polypharmacy are characterized by poorer cardiometabolic status. These results highlight the significance of polypharmacy in type 2 diabetes.

[Black particles in plasma and carcinogenic pills]. / Zwarte deeltjes in plasma en kankerverwekkende pillen.

Recently in a national newspaper presumed large hazards in care were described. Visible black particles were seen in blood plasma and a cancerogenic substance was found in paracetamol. Every year 300.000 bags of plasma are produced. The black particles were found in 11 bags of plasma. Possibly one of these was administered. During administration 175 micron filters are used. Presumably remaining particles will be degraded by the mononuclear-phagocytic system. In paracetamol 6 ppm of para-chloroaniline was found. Depending of the limit used by either the ICH or the EFSA this means for patients using lifelong 6 grams of paracetamol a risk off respectively 1: 200.000 or 1:20.000. This risk is neglectable compared of the life time risks of cancer in the population (1:3). Journalists should realize that this exaggerated commentary can lead to real serious risks (taking NSAID's instead of paracetamol) and mistrust in regular care.