Pharmacological prevention and treatment of opioid-induced constipation in cancer patients: A systematic review and meta-analysis.

BACKGROUND: Cancer-related pain often requires opioid treatment with opioid-induced constipation (OIC) as its most frequent gastrointestinal side-effect. Both for prevention and treatment of OIC osmotic (e.g. polyethylene glycol) and stimulant (e.g. bisacodyl) laxatives are widely used. Newer drugs such as the peripherally acting µ-opioid receptor antagonists (PAMORAs) and naloxone in a fixed combination with oxycodone have become available for the management of OIC. This systematic review and meta-analysis aims to give an overview of the scientific evidence on pharmacological strategies for the prevention and treatment of OIC in cancer patients. METHODS: A systematic search in PubMed, Embase, Web of Science and the Cochrane Library was completed from inception up to 22 October 2022. Randomized and non-randomized studies were systematically selected. Bowel function and adverse drug events were assessed. RESULTS: Twenty trials (prevention: five RCTs and three cohort studies; treatment: ten RCTs and two comparative cohort studies) were included in the review. Regarding the prevention of OIC, three RCTs compared laxatives with other laxatives, finding no clear differences in effectivity of the laxatives used. One cohort study showed a significant benefit of magnesium oxide compared with no laxative. One RCT found a significant benefit for the PAMORA naldemedine compared with magnesium oxide. Preventive use of oxycodone/naloxone did not show a significant difference in two out of three other studies compared to oxycodone or fentanyl. A meta-analysis was not possible. Regarding the treatment of OIC, two RCTs compared laxatives, of which one RCT found that polyethylene glycol was significantly more effective than sennosides. Seven studies compared an opioid antagonist (naloxone, methylnaltrexone or naldemedine) with placebo and three studies compared different dosages of opioid antagonists. These studies with opioid antagonists were used for the meta-analysis. Oxycodone/naloxone showed a significant improvement in Bowel Function Index compared to oxycodone with laxatives (MD -13.68; 95 % CI -18.38 to -8.98; I2 = 58 %). Adverse drug event rates were similar amongst both groups, except for nausea in favour of oxycodone/naloxone (RR 0.51; 95 % CI 0.31-0.83; I2 = 0 %). Naldemedine (NAL) and methylnaltrexone (MNTX) demonstrated significantly higher response rates compared to placebo (NAL: RR 2.07, 95 % CI 1.64-2.61, I2 = 0 %; MNTX: RR 3.83, 95 % CI 2.81-5.22, I2 = 0 %). With regard to adverse events, abdominal pain was more present in treatment with methylnaltrexone and diarrhea was significantly more present in treatment with naldemedine. Different dosages of methylnaltrexone were not significantly different with regard to both efficacy and adverse drug event rates. CONCLUSIONS: Magnesium oxide and naldemedine are most likely effective for prevention of OIC in cancer patients. Naloxone in a fixed combination with oxycodone, naldemedine and methylnaltrexone effectively treat OIC in cancer patients with acceptable adverse events. However, their effect has not been compared to standard (osmotic and stimulant) laxatives. More studies comparing standard laxatives with each other and with opioid antagonists are necessary before recommendations for clinical practice can be made.

[The use of analgesics in Dutch oral care from 2016 through 2020]. / Het gebruik van pijnstillers in de mondzorg in de periode 2016 tot en met 2020.

Oral care providers frequently prescribe analgesics for the management of dental pain. To get an overview of the analgesics prescribed in the Netherlands from 2016 through 2020, we collected data from the Stichting Farmaceutische Kengetallen (foundation [for] pharmaceutical indicators). Annually, more than 300,000 analgesics are prescribed by dentists in general practice and dental specialists. The largest group concerns NSAIDs (88%), followed by weak opioids (9%), acetaminophen (2%) and strong opioids (1%). Of the NSAIDs, ibuprofen is the most prescribed by all groups of oral care providers (84-91%). Of the weak opioids, dentists and oral and maxillofacial surgeons mainly prescribe codeine and codeine/ acetaminophen (64% and 78%, respectively), while orthodontists mainly prescribe tramadol (53%). Of the strong opioids, oxycodone is the most frequently prescribed by all groups of oral care providers (77-87%). Analgesics are a large part of the prescription medications in Dutch oral care and mainly concern NSAIDs (ibuprofen) and weak opioids (codeine/ acetaminophen). There are no major differences in prescription behaviour among different oral care providers.

[Use of analgesics in oral care]. / Toepassing van pijnstillers in de mondzorg.

To alleviate acute dental pain, dentists and dental specialists frequently prescribe analgesics to patients, either on prescription or not. In order to effectively manage dental pain, it is advisable to follow a step-by-step plan based on the WHO analgesic ladder: step 1, start with acetaminophen step 2, add an NSAID (e.g. ibuprofen, diclofenac, naproxen); step 3, add a weak opioid (e.g. tramadol) in combination with acetaminophen or an NSAID; step 4, replace a weak opioid with a strong opioid (e.g. morphine or oxycodone). A dentist in general practice or a dental specialist needs to know, the mechanism of action and the most important interactions, contraindications and adverse effects of each of these groups of medications. Attention is needed when prescribing analgesics to risk groups such as frail elderly, pregnant and lactating women, and children.

[Can furosemide mask the use of performance-enhancing drugs?] / Maskeert furosemide dopinggebruik?

Furosemide is included in the World Anti-Doping Agency's (WADA) list of prohibited substances because it can be used by athletes to mask the presence of performance-enhancing drugs in urine and/or excrete water for rapid weight loss. But how effective is furosemide in masking prohibited substances in urine? Based on the pharmacology and the available literature, we conclude that the masking effect of furosemide is limited. Furosemide is a doping agent that is mainly relevant for sports with weight categories.

[Can dental students and dental care providers in the Netherlands effectively and safely prescribe drugs?] / Serie: Onderwijs en de tandarts anno 2025. Kunnen tandheelkunde­studenten en mondzorgverleners in Nederland effectief en veilig geneesmiddelen voorschrijven?

Dentists and dental specialists are qualified to prescribe drugs. In this study, we assessed and compared the pharmacotherapeutic knowledge and skills of final year dental students, dentists and dental specialists in the Netherlands. In 2017, a random sample of these three groups was invited to complete an assessment. The knowledge assessment comprised 40 multiple choice questions covering often prescribed drugs. The skills assessment comprised three patient cases for which participants had to write a treatment plan. For the knowledge assessment, the response rates were 26 (20%) dental students, 28 (8%) dentists and 19 (19%) dental specialists, and for the skills assessment the response rates were 14 (11%) dental students, eight (2%) dentists, and eight (8%) dental specialists. On average, all three groups had inadequate knowledge scores (smaller 80%) and only a small proportion (smaller 30%) of their treatment plans was assessed as correct. These results suggest that dental students, dentists and dental specialists lack prescribing competence, which could be caused by poor pharmacotherapy education during under- and postgraduate dental training.

[Medicaments and oral healthcare. Mechanisms of interaction between medicaments]. / Serie: Medicamenten en mondzorg. Mechanismen van interacties van medicamenten.

Interactions between medicaments or between a medicament and another product used by the patient may result in a medicamentbecoming inactive or in an increase in the side effects. By proper historytaking, a dentist will often know which medicaments a patient uses and can take this into account in prescribing a medicament. Self-care medications and specific foods are often not spontaneously reported by a patient but can still interact with a medicament prescribed. A dentist should be aware of the interactions a prescribed medicament can have with other medicaments and products used by the patient. Therefore dentists have to ask directly about such medicaments and products, and record them in the patients' file.

Pharmacology and Therapeutics Education in the European Union Needs Harmonization and Modernization: A Cross-sectional Survey Among 185 Medical Schools in 27 Countries.

Effective teaching in pharmacology and clinical pharmacology and therapeutics (CPT) is necessary to make medical students competent prescribers. However, the current structure, delivery, and assessment of CPT education in the European Union (EU) is unknown. We sent an online questionnaire to teachers with overall responsibility for CPT education in EU medical schools. Questions focused on undergraduate teaching and assessment of CPT, and students' preparedness for prescribing. In all, 185 medical schools (64%) from 27 EU countries responded. Traditional learning methods were mainly used. The majority of respondents did not provide students with the opportunity to practice real-life prescribing and believed that their students were not well prepared for prescribing. There is a marked difference in the quality and quantity of CPT education within and between EU countries, suggesting that there is considerable scope for improvement. A collaborative approach should be adopted to harmonize and modernize the undergraduate CPT education across the EU.

[Thiamine in patients with alcohol use disorder and Wernicke's encephalopathy]. / Thiamine bij een alcoholstoornis en Wernicke-encefalopathie.

- Patients with alcohol use disorder frequently have a thiamine deficiency.- A potential life-threatening complication of thiamine deficiency is Wernicke's encephalopathy.- Since it is clinically difficult to recognize Wernicke's encephalopathy, this condition is often treated inadequately. - Early supplementation of thiamine is important to avoid irreversible neurological damage. - There are differences between the Dutch guidelines regarding the supplementation of thiamine for the treatment of alcoholic use disorder, and those for Wernicke's encephalopathy. - There are no solid evidence-based recommendations about the best dosage, route of administration and duration of thiamine supplementation for the treatment of alcohol use disorder and Wernicke's encephalopathy. - Based on the pharmacokinetic properties of thiamine, it is more appropriate to give patients with alcohol use disorder 25 mg four times a day rather than 50 mg twice a day. - Patients at high risk of Wernicke's encephalopathy should immediately receive an intravenous or intramuscular dose of thiamine; patients with suspected Wernicke's encephalopathy should preferably receive an intravenous dose.- Reports of anaphylactic reaction to parenteral administration of thiamine are rare and are not a reason to refrain from parenteral treatment.

Essential competencies in prescribing: A first european cross-sectional study among 895 final-year medical students.

European medical students should have acquired adequate prescribing competencies before graduation, but it is not known whether this is the case. In this international multicenter study, we evaluated the essential knowledge, skills, and attitudes in clinical pharmacology and therapeutics (CPT) of final-year medical students across Europe. In a cross-sectional design, 26 medical schools from 17 European countries were asked to administer a standardized assessment and questionnaire to 50 final-year students. Although there were differences between schools, our results show an overall lack of essential prescribing competencies among final-year students in Europe. Students had a poor knowledge of drug interactions and contraindications, and chose inappropriate therapies for common diseases or made prescribing errors. Our results suggest that undergraduate teaching in CPT is inadequate in many European schools, leading to incompetent prescribers and potentially unsafe patient care. A European core curriculum with clear learning outcomes and assessments should be urgently developed.

The prescribing performance and confidence of final-year medical students.

It is widely believed that medical students are not as well prepared or as sufficiently skilled in prescribing as they should be at the outset of their careers. However, a preclinical context-learning pharmacotherapy program has been found to improve students' therapeutic skills during an ensuing clinical clerkship in internal medicine.(1) In this Commentary, we argue that a similar approach during a clinical clerkship may further enhance therapeutic skills at the end of the clerkship.