Aim. This study aimed to assess medication adherence among older people with coronary heart disease and its relationship with hospitalizations. Methods. This is a prospective cohort study conducted at the outpatient clinics of a major hospital in Vietnam from November 2022 to June 2023. Consecutive older patients with coronary heart disease were recruited and followed for 6 months. Medication adherence was defined using the five‐item Medication Adherence Report Scale (MARS-5). Multivariable logistic regression models were applied to examine the impact of medication adherence on hospitalization due to cardiovascular disease (CVD) and all-cause hospitalization. Results. There were 643 participants. They had a mean age of 73 (SD 8), and 74.3% were male. Overall, 76.4% (491/643) were classified as “adherence”. Over 6 months follow-up, 23.3% of the participants admitted to hospital and of these, 9.2% were due to CVD. The CVD hospitalization rate was significantly lower in the adherence group compared to the non-adherence group (7.7% versus 13.8%, p = 0.023, respectively). In logistic regression models, medication adherence was associated with a significant reduced likelihood of CVD hospitalization (adjusted OR 0.48, 95%CI 0.27 – 0.86). Medication adherence was also associated with a trend of reduced all-cause hospitalization (adjusted OR 0.75, 95%CI 0.49 – 1.15). Conclusions. This study showed a positive relationship between medication adherence and reduced risk of CVD hospitalization in older people with coronary heart disease. Healthcare providers should consider incorporating adherence assessment into the long-term care for older patients with coronary heart disease.

Aims: The aim of this phase 1 trial was to assess the pharmacokinetics, safety, and tolerability of balcinrenone (previously AZD9977) in participants with severe renal impairment versus those with normal renal function. Methods: Participants with severe renal impairment (estimated glomerular filtration rate [eGFR] <30 mL/min/1.73 m2) not on dialysis were compared with group-matched control participants with eGFR ≥90 mL/min/1.73 m2. Eligible participants received a single oral dose of 150 mg balcinrenone, and blood and urine samples were collected for analysis. Results: The total apparent balcinrenone clearance was 50% lower in the severe renal impairment group, resulting in a ~two-fold higher area under the curve (AUC) and a 1.4-fold higher maximum observed plasma concentration in the severe renal impairment group versus the control group. The terminal half-life and plasma protein binding were similar in both groups. Balcinrenone was safe and well tolerated in all participants. All adverse events reported were of mild-to-moderate severity and not considered related to balcinrenone. Conclusions: Balcinrenone exposure was approximately two-fold higher in participants with severe renal impairment compared with the group-matched control participants. Based on obtained results, the AUC exposure is predicted to be <50% higher in patients with an eGFR of 20 mL/min/1.73 m2 compared with those with an eGFR of 60 mL/min/1.73 m2. In light of these findings, no dose adjustment based on eGFR is needed in two ongoing studies that target these patients (MIRO-CKD [NCT06350123] and BalanceD-HF [NCT06307652]).

Thiopurines are a class of immunosuppressant and anti-neoplastic agents. They are widely used in the treatment of inflammatory bowel disease, hematological malignancies, and autoimmune diseases, but can cause significant toxicity. Inherited gene mutations are now recognized as independent risk factors for severe adverse drug reactions to thiopurines even at tenfold dose reductions. We present a case of thiopurine toxicity resulting in severe myelosuppression, hepatotoxicity, and alopecia in an individual with homozygous *3/*3 loss-of-function alleles in the NUDT15 gene. Our case highlights important differences in gene mutation frequencies between races that can help guide pharmacogenomic testing.

Low-Dose Amitriptyline: A Potential Therapeutic Option for Chronic Pain in Older PeopleTakayuki Suga, DDS, PhD1; Trang Thi Huyen Tu, DDS, PhD1,2; Motoko Watanabe, DDS, PhD1; Takahiko Nagamine MD, PhD1,3; and Akira Toyofuku, DDS, PhD11 Department of Psychosomatic Dentistry, Graduate School of Medical and Dental Sciences, Institute of Science Tokyo2 Department of Basic Dental Sciences, Faculty of Odonto- stomatology, University of Medicine and Pharmacy at Ho Chi Minh City, Ho Chi Minh City, Vietnam3 Department of Psychiatric Internal Medicine, Sunlight Brain Research Center, Yamaguchi, Japan.Word count:798Acknowledgements: noneConflict of interest statement: There are no conflicts of interest to declare.Keywords: psychopharmacology, safety Pharmacology, chronic pain, antidepressive agents, older adultCorrespondence to:Takayuki Suga, DDS, PhD1-5-45 Yushima, Bunkyo-ku, Tokyo 113-8510, Japan.Phone number: +81358035898; Fax: +81358035898; Email: [email protected] use of antidepressants in older adults with chronic pain is controversial. We found Dr. Narayan et al.’s article, titled “Efficacy and Safety of Antidepressants for Pain in Older Adults: A Systematic Review and Meta-Analysis,” on the use of antidepressants in older people with chronic pain to be highly engaging. (Narayan et al., 2024) They conducted a systematic review and meta-analysis on the efficacy and safety of antidepressants for chronic pain in older people. Due to various limitations, they concluded that the benefits and harms of antidepressant medicines for most types of chronic pain, especially knee OA, are unclear.Conducting clinical research with older adults poses challenges, often excluding them due to pre-existing conditions. Randomized controlled trials (RCTs) in this population are particularly difficult for several reasons:1. Comorbidities and Polypharmacy: older people often have multiple chronic conditions and take various medications, complicating group allocation, the isolation of the intervention’s effects and increasing the risk of drug interactions.2. Heterogeneity and Follow-up Challenges: Due to mobility impairments and other factors, it is difficult for older people to make regular visits to hospitals conducting RCTs, leading to high dropout rates.3. Ethical Considerations: The older people are often regarded as a vulnerable population, requiring ethical considerations when involving them in risk-related interventions.Despite these challenges, studies using real-world data suggest that, when used carefully, antidepressants might help manage chronic pain in older adults, particularly for conditions like burning mouth syndrome (BMS).BMS, a common type of chronic orofacial pain affecting mainly postmenopausal women, has uncertain pathophysiology.We previously reported that low doses of amitriptyline are effective in managing pain in older people with BMS. (Suga et al., 2019) Furthermore, even in patients over 80 years old, amitriptyline demonstrates efficacy when used in low doses with careful administration. (Watanabe et al., 2022) Regarding common side effects, managing these side effects in elderly patients will be effective through regular visits and examination. (Suga et al., 2019; Watanabe et al., 2022) Hence, it is crucial to monitor for anticholinergic side effects such as drowsiness, dry mouth, and constipation, as well as potential falls due to dizziness and any changes in cognitive function in clinical assessment.A therapeutic window exists for the dosages of amitriptyline that are effective in managing chronic pain, indicating that its efficacy is not dose-dependent. (Nagamine, 2024) In contrast to the doses used in psychiatry for depression (typically 100 mg/day or more), amitriptyline is effective at doses of 5-20 mg/day in the treatment of BMS. The use of amitriptyline at this dosage is considerably lower than the doses employed in the RCTs included in the authors’ study, suggesting a reduced risk of side effects and withdrawal symptoms.The challenges of administering antidepressants to older people with chronic pain are not limited to concerns about side effects but also encompass issues related to their overall efficacy in this population. Serotonin’s role in pain modulation is complex, as it can either exacerbate or alleviate pain depending on the receptor subtype activated. This bidirectional effect is attributed to the distinct pathways involved in serotonin-mediated pain processing, with some receptors promoting analgesia and others enhancing nociception. (Bannister & Dickenson, 2016) Additionally, the elevation of serotonin levels might disrupt the delicate equilibrium with dopamine, thus hindering pain inhibition via the reward pathway. Therefore, increasing serotonin levels alone may exacerbate pain rather than produce therapeutic benefits.Moreover, chronic pain modulation involves not only serotonin but also other monoamines, such as dopamine and noradrenaline. Consequently, antidepressants that modulate serotonergic, noradrenergic, or dopaminergic pathways may exhibit therapeutic potential in managing chronic pain. (Bannister & Dickenson, 2016) This is also reflected in the study by Narayan et al., which demonstrated the efficacy of duloxetine, a dual serotonin and noradrenaline reuptake inhibitor, albeit with a modest effect size. Amitriptyline, which similarly targets both serotonin and noradrenaline, and to some dopamine transporters, may offer superior efficacy compared to other antidepressants. However, as previously mentioned, its therapeutic effect does not appear to be dose-dependent, suggesting that there may be an optimal therapeutic window at lower doses. Although not specifically in older people, other reports have also demonstrated the effectiveness of low-dose amitriptyline (5-25 mg/day) in managing conditions such as lower back pain, chronic neck pain, and chest pain. (Maarrawi et al., 2018; Park et al., 2013; Urquhart et al., 2018) Given the above, it is conceivable that low doses of certain antidepressants, such as amitriptyline, may be effective and safe for patients with other types of chronic pain. Research on the use of antidepressants for chronic pain in older people is still limited; therefore, as the authors have pointed out, there is a need for more prospective studies and numerous real-world investigations. In conclusion, careful clinical management and the accumulation of treatment data are essential for the effective treatment of chronic pain in older people using antidepressants.ReferencesBannister, K., & Dickenson, A. H. (2016). What do monoamines do in pain modulation? Curr Opin Support Palliat Care , 10 (2), 143-148. https://doi.org/10.1097/SPC.0000000000000207Maarrawi, J., Abdel Hay, J., Kobaiter-Maarrawi, S., Tabet, P., Peyron, R., & Garcia-Larrea, L. (2018). Randomized double-blind controlled study of bedtime low-dose amitriptyline in chronic neck pain. Eur J Pain , 22 (6), 1180-1187. https://doi.org/10.1002/ejp.1206Nagamine, T. (2024). Amitriptyline at low dose for burning mouth syndrome. Oral Diseases , 30 (7), 4650-4652. https://doi.org/10.1111/odi.14966Narayan, S. W., Naganathan, V., Vizza, L., Underwood, M., Ivers, R., McLachlan, A. J., Zhou, L., Singh, R., Tao, S., Xi, X., & Abdel Shaheed, C. (2024). Efficacy and safety of antidepressants for pain in older adults: A systematic review and meta-analysis. Br J Clin Pharmacol . https://doi.org/10.1111/bcp.16234Park, S. W., Lee, H., Lee, H. J., Park, J. C., Shin, S. K., Lee, S. K., Lee, Y. C., & Kim, J. E. (2013). Low-dose amitriptyline combined with proton pump inhibitor for functional chest pain. World J Gastroenterol , 19 (30), 4958-4965. https://doi.org/10.3748/wjg.v19.i30.4958Suga, T., Takenoshita, M., Watanabe, T., Tu, T. T. H., Mikuzuki, L., Hong, C., Miura, K., Yoshikawa, T., Nagamine, T., & Toyofuku, A. (2019). Therapeutic Dose of Amitriptyline for Older Patients with Burning Mouth Syndrome. Neuropsychiatric Disease and Treatment ,Volume 15 , 3599-3607. https://doi.org/10.2147/ndt.S235669Urquhart, D. M., Wluka, A. E., van Tulder, M., Heritier, S., Forbes, A., Fong, C., Wang, Y., Sim, M. R., Gibson, S. J., Arnold, C., & Cicuttini, F. M. (2018). Efficacy of Low-Dose Amitriptyline for Chronic Low Back Pain: A Randomized Clinical Trial. JAMA Intern Med ,178 (11), 1474-1481. https://doi.org/10.1001/jamainternmed.2018.4222Watanabe, M., Takao, C., Liu, Z., Nayanar, G., Suga, T., Hong, C., Tu, T. T. H., Yoshikawa, T., Takenoshita, M., Motomura, H., Nagamine, T., & Toyofuku, A. (2022). The Effectiveness and Adverse Events of Amitriptyline and Aripiprazole in Very Elderly Patients With BMS.Frontiers in Pain Research , 3 . https://doi.org/10.3389/fpain.2022.809207

Residual neuromuscular blockade (RNB) commonly occurs when using neuromuscular blockers and increases the risk for pulmonary complications, such as airway obstruction and severe hypoxemia, in extubated patients. Rocuronium exhibits a high variability in recovery time, contributing to an increased risk for RNB. This study aimed to identify and characterize the sources of variability in rocuronium exposure and response via a population pharmacokinetic/pharmacodynamic (PK/PD) analysis and to apply the developed PK/PD model to investigate clinical implications. A nonlinear mixed-effect model was developed for rocuronium in patients undergoing general anaesthesia, using doses of 0.3–1.2 mg/kg. Plasma concentrations and the neuromuscular block [train of four ratio] were assessed up to 6 h after dosing. The influence of age, body mass index, renal function, and sex on PK and PD was explored. Simulations were performed to predict the recovery time. A two-compartment model with linear elimination and an indirect sigmoid I-max model was used to describe PK and PD. The transfer rate into the periphery increases with age. The predicted recovery time was significantly longer in older subjects compared to young adults following single bolus administrations of doses ≥ 0.7 mg/kg. Our findings suggest that geriatric patients take slightly longer to recover than younger adults due to an age-dependent increase in tissue uptake. However, a priori dose adjustments for rocuronium in elderly patients are not feasible, since age contribution is overshadowed by the overall variability in the recovery time.

A document by Francis Williams. Click on the document to view its contents.

This is just an editorial and does not include an abstract

Aim: To assess the risk of major congenital malformations following first-trimester PSE exposure. Methods: A population-based retrospective cohort study was conducted on pregnancies of women aged 15-49 years, insured by Clalit Health Services in southern Israel, who gave birth or had elective pregnancy terminations due to suspected fetal malformation at Soroka Medical Center (1999-2017). The study focused on the drug Clarinase (120 mg PSE, 5 mg loratadine). Multivariate negative binomial regression models were used to evaluate the risk for major congenital malformations, adjusting for potential confounders. Results: Of 251,543 pregnancies, 313 (0.12%) were exposed to Clarinase in the first trimester. PSE exposure was not associated with major congenital malformations overall (adjusted Relative Risk [aRR] = 0.90, 95% CI 0.558-1.45; p=0.66) or by organ system (cardiovascular: aRR = 0.938, p=0.841; central nervous: aRR = 0.618, p=0.633; musculoskeletal: aRR = 1.800, p=0.155; gastrointestinal: aRR = 1.013, p=0.990; genitourinary: aRR = 0.704, p=0.547). Conclusion: First-trimester PSE exposure was not associated with major congenital malformations, either overall or by organ system.

Introduction: Suboptimal adherence to antipsychotics leads to poorer outcomes and relapse. The adherence behaviour of people may be influenced by several factors including the number of antipsychotics used and their formulation. This study aimed to identify longitudinal adherence patterns to oral and long-acting injectable (LAI) antipsychotics in monotherapy or polypharmacy through group-based trajectory modelling (GBTM). Methods: This was a retrospective cohort study that linked prescription and dispensing data of adult patients with a new antipsychotic prescribed between 2015-2019 in Catalonia (Spain). GBTM was used to classify patients following a similar longitudinal pattern of adherence. The response variable was adherence, estimated through the continuous medication availability measure (CMA), in each 30-day period during 12 months of follow-up. Baseline and treatment characteristics were used to characterize the trajectories identified. Results: Among the 7,730 patients included in the study, we identified seven clinically distinct trajectory groups of adherence to antipsychotics: “non-adherent” (19%), “low adherent” (9%), “early-decline” (6%), “mid-decline” (5%), “late-decline” (5%), “high adherent” (21%), and “fully adherent” (35%). Trajectories with better adherence were more likely to receive the prescription from a psychiatrist, receive LAIs and have previous exposure to other antipsychotics. Intermittent medication use patterns and high levels of polypharmacy were characteristics of the “low” and “high adherent” groups. Conclusions: The trajectories reflect three adherence behaviours: stable over time; patients who discontinue treatment and; patients with an intermittent refill pattern. Patients on polypharmacy should have more regular adherence monitoring and LAIs should be considered, as they appear to be associated with better adherence.

Fung and colleagues observed improvements in Prescribing Safety Assessment (PSA) pass rates following targeted teaching interventions in their medical school cohorts. They showed that the PSA captured the effect of the intervention providing further evidence of its validity as a test of prescribing competence, and its sensitivity as an instrument to measure this. It also demonstrates that a dedicated prescribing assessment can influence the design of student learning pathways and encourage the development of authentic prescribing tasks in undergraduate medical training. In contrast, the Applied Knowledge Test (AKT), which necessarily tests multiple domains and areas of practice and knowledge, exclusively with single-best-answer (SBA) questions, did not detect the educational impact of this intervention. The PSA focuses on various aspects of prescribing skills including drug selection, dosing, timing and frequency of administration; as well as providing information to patients, recognising adverse drug reactions, dose calculations, monitoring, prescription review and planning management. It uses a testing approach that more closely aligned with prescribing practice including simulation of electronic prescribing in ‘white space’ fields, avoiding the potential cuing effects of SBA questions, and using a semi-open book design, in which the candidates use the key resource that they will use in practice – the British National Formulary. Fung and colleagues’ findings underscore the importance of passing the PSA as a measure of competence to enter practice and the complementarity of the PSA and the AKT in determining this.

Editorial for the Themed Issue: Addressing the Dual Challenges of Opioid Use Disorder and Chronic Pain in the Context of the Opioid CrisisMehmet Sofuoglu, M.D., Ph.D. 1,2R. Ross MacLean, Ph.D. 1,2Joao P. De Aquino, M.D.1,2,3Yale University School of Medicine, Department of Psychiatry, 300 George Street, New Haven, CT 06511, USAVA Connecticut Healthcare System, 950 Campbell Avenue, West Haven, CT 06516, USAClinical Neuroscience Research Unit, Connecticut Mental Health Center, 34 Park Street, 3rd Floor, New Haven, CT, 06519CORRESPONDING AUTHOR: Mehmet Sofuoglu, VA Connecticut Healthcare System, 950 Campbell Avenue, West Haven, CT 06516, USA

not-yet-known not-yet-known not-yet-known unknown In 2015, the United States Food and Drug Administration (FDA) approved uridine triacetate to treat overdose and severe toxicity of the fluoropyrimidine chemotherapy agents 5-fluorouracil (5-FU) and its oral prodrug capecitabine. Uridine triacetate is as an oral prodrug of uridine which competes with cytotoxic fluoropyrimidine metabolites for incorporation into nucleotides. Two million people worldwide start fluoropyrimidine chemotherapy each year with 20-30% developing severe or life-threatening adverse effects, often attributable to a genetic predisposition such as dihydropyrimidine dehydrogenase deficiency. Whilst genetic pre-screening is recommended prior to starting fluoropyrimidine agents, this only prevents 20-30% of early-onset life-threatening toxicity and so does not obviate the need for an antidote. Initial in-human studies established that uridine triacetate more than doubles the maximum tolerated weekly 5-FU bolus dose . A lack of clinical equipoise meant a placebo-controlled phase-III trial was not ethical and so the phase-III trials used historical controls. These found that uridine triacetate improved survival in those with fluoropyrimidine overdose and severe toxicity from 16% to 94%, with 34% able to resume chemotherapy within 30days. Five case reports of delayed fluoropyrimidine toxicity demonstrate improvement following uridine triacetate treatment 120-504 hours after last fluoropyrimidine administration suggesting efficacy beyond the FDA licensing indications. Mechanistically uridine triacetate would be expected to be effective for overdose and severe toxicity of Tegafur (a 5-FU prodrug), but there are no published case reports describing this. Uridine triacetate is available internationally through an expanded access scheme and has been available in the UK since 2019 on a named patient basis.

Structured Medication Reviews (SMRs) were introduced into the National Health Service (NHS) Primary Care to support the delivery of the NHS Long-Term Plan for medicines optimisation. SMRs improve the quality of care, reduce harm, and offer value for money. However, evidence to support SMRs for patients with chronic kidney disease (CKD) stage G4-5D with elevated risk of cardiovascular disease and premature mortality is unknown. This scoping review aimed to assess the extent and nature of SMR research in the population of patients with CKD stage G4-5D. Electronic databases were searched on 20 October 2023. Studies were eligible if they described an SMR in adults with CKD stage G4-5D, regardless of the study design. Data detailing the global patterns, population and intervention descriptions, professionals performing SMR, and reported areas for future research were extracted. The extracted outcome data were categorised as clinically important, patient-important, medication-related, and experience-related. A narrative synthesis was completed. Seventeen studies (81%) were conducted in nephrology outpatient setting, three (14%) during acute hospital admissions, and one (5%) within the community pharmacy. Eighteen studies (86%) were quantitative, to include five randomised controlled trials. Ten (48%) studies were undertaken in the United States of America and Canada, and two in Europe (France and Norway). No such studies have been conducted in the United Kingdom. Our review revealed that there is a lack of evidence for SMR as a strategy to reduce polypharmacy and harms from medication for adults with CKD stage G4-5D. Therefore, further research is required in this area.

Aim: Currently, therapeutic drug monitoring for astronauts faces limitations in conventional blood sampling and sample management onboard the international space station. Here, we explore the feasibility of dried blood spot (DBS) collection method during parabolic flights (PF) to overcome these constraints. Methods: We assessed the feasibility of blood deposition on blotting paper for preanalytical aspects in a PF using synthetic blood. Subsequently, DBS sampling validation was carried out in another PF campaign. Twenty volunteers participated in a pharmacokinetic study on caffeine and its metabolite, paraxanthine (as proof of concept), conducted during parabolic flights. After >18h caffeine washout, coffee (115 mg) or tea (30 mg), or 3 dark chocolate squares (11 mg) were administered. DBS samples were collected at baseline, during weightlessness, and post-flight. Caffeine and paraxanthine were analyzed using liquid chromatography-tandem mass spectrometry. Genotyping for Cytochrome P450-1A2 (CYP1A2) was performed and a metabolic ratio by areas under the curves for caffeine and paraxanthine (AUCPAX/AUCCAF) for CYP1A2 was determined. User experience survey was also conducted. Results: Full in-flight pharmacokinetic was feasible in 17 volunteers with 3 failures due to motion-sickness. We observed expected differences in kinetic profiles, consistent with consumption habits, the ingested dose and the genotypic/phenotypic information. The metabolic ratio did not significantly differ between parabolic flights conditions and ground conditions. Overall participants were satisfied with the usability of the method. Conclusion: DBS collection was safe, stable, feasible and well accepted in weightlessness. This method would offer valuable insights into human metabolism adaptation during long-term spaceflight, addressing space pharmacology challenges.

Medication errors cause preventable patient harm with annual costs of USD$42 billion globally. In England, 237 million errors occur annually, accounting for 1700 deaths, with trainee doctors being responsible for the highest proportion of errors. The UK introduced the national Prescribing Safety Assessment (PSA) in 2013 to ensure prescribing competency. Imperial College School of Medicine (ICSM) sought to increase learning opportunities and reduce errors through a monthly Prescribing Practice Questions (PPQs) programme. PSA scores from 2020 (prior to PPQ introduction) to 2024 (first cohort to receive entire PPQ programme), the prescription writing skills (PWS) subsection and applied knowledge test (AKT) scores in 2020 and 2024 were analysed. 1505 students sat the PSA between 2020 and 2024. PSA fails significantly reduced from 2.51% in 2020 to 0% in 2024 (p=0.0054). Median PSA scores significantly improved from 78.5% in 2020 to 84.0% in 2024 (p<0.0001). Median AKT scores decreased between 2020 and 2024 (78.0% vs 74.5%, p<0.0001). Absolute increase in PSA scores from lowest to highest quintiles was 10 percentage points (pp), 7pp, 5pp, 4pp and 1pp, respectively, between 2020 and 2024. Median PWS scores significantly improved from 76.3 % (61/80) in 2020 to 87.5% (70/80) in 2024 (p<0.0001). Since introducing PPQs, PSA and PWS scores have statistically significantly improved, with progressively greater impact on students at the bottom of the performance distribution. Early, targeted and repeated opportunities for authentic prescribing activities, such as the PPQs, in undergraduate training may lead to significant improvement in prescribing competency as determined by the PSA.

Aim Recording the indication for a medicine in the prescription supports communication. In May 2023 our district hospitals made the free-text indication field in prescriptions compulsory for all medicines in the inpatient prescribing system. This study aimed to evaluate the effect of introducing a compulsory indication field in an inpatient prescribing system. Methods Text in the indication field was manually classified as an indication, ‘other text’, ‘rubbish text’, ‘to be determined’, and ‘blank’. Prescribing data were extracted from the district data warehouse. The change in proportion of prescriptions with an indication was compared for eight-weeks after introduction of a compulsory indication field to an equivalent eight-weeks in 2022. Secondary outcomes included patient outcomes, medication cessation, and indication recording before discharge. Results We analysed 81,634 prescriptions before and 82,726 after indications were made compulsory. The proportion of prescriptions with an indication increased from 29.2% to 75.6%. ‘Rubbish text’ increased from 0% to 2.3%, ‘other text’ from 2.5% to 14.7%, and ‘to be determined’ from 0.0% to 6.6%. Of 5,557 prescriptions with ‘to be determined’ initially, 18.1% were ceased and 2.7% had an indication before discharge. There was minimal change in patient outcomes. Conclusion Introducing a compulsory indication field increased the proportion of medicines with an indication from 29% to 76%, with only a small increase in ‘rubbish text’. The carefully selected compulsory field improved information quality but did not alter medicine use or patient outcomes. Compulsory fields should be combined with improvements in other components of care to improve medicine use.

The use of tramadol and other opioids for pain management has been accompanied by a multitude of challenges and concerns worldwide. The use of tramadol saw a decline in Denmark during 2017-2019 accompanied by a slight increase in the use of morphine and oxycodone. Using the Danish National Prescription Registry and utilizing data until and including 2023, we aimed to provide updated data on the utilization patterns of tramadol and other opioids in Denmark. We found a 35% decline in the use of tramadol from 2017-2023 most likely due to media attention, regulatory actions, health campaigns, and targeted education of physicians and patients by the Danish health authorities. This decline was accompanied by an increase in the number of new (+90%) and current users of morphine (+57%) which surpassed those of tramadol, oxycodone, and other opioids in 2023.

Spotlight Commentary: Examining Safety Profiles of Topical Ocular MedicationLorena Karla Šklebar1,2, Robert Likić2,3, Sonja Jandroković1,21 Department of ophthalmology, University Hospital Centre Zagreb, Zagreb, Croatia2 University of Zagreb, School of medicine, Zagreb, Croatia3 Division for clinical pharmacology and therapeutics, Department of internal medicine, University Hospital Centre Zagreb, Zagreb, CroatiaKeywords: eye drops; systemic side effect; ocular side effect; safety profile; topical ocular medicationWord count: 1085Table count: 1Figure count: 0Topical medications are frequently used in treating a wide range of ocular diseases due to their efficiency in delivery directly to the afflicted area. However, localized administration cannot prevent side effects, both local and systemic, which can sometimes be overlooked or underestimated. The aim of this spotlight commentary is to provide a review of safety profiles of topical ocular medications, analysing their effect on the ocular structures as well as their systemic and environmental impacts. 1Although topical ocular medications are designed for localized treatment and are administered directly on the surface of the eye, there is a significant systemic absorption of these drugs through several pathways. The first of two major pathways is from the lacrimal sac through the nasolacrimal duct into the nasopharynx where drugs can be systemically absorbed through the nasal mucosa. This pathway can easily be circumvented by manually providing pressure to the medial canthus or by closing the eyes for 5 minutes after the instillation of each drop, which will cause compression on the nasolacrimal duct. The other major pathway for systemic absorption is through the conjunctiva and conjunctival blood vessels. Minor pathways of systemic drug delivery are through the pharynx, gastrointestinal tract, skin of the cheeks and the eyelids, aqueous humour, and inner ocular tissues. Special care must be taken when treating the paediatric patients who have a much higher risk of developing systemic side effects, due to inadequate dosage and increased systemic permeability of the drugs. 2Localised adverse effects of topical ocular medications commonly arise due to preservatives, which are used in eye drops and ointments in order to prolong their shelf life and guard against microbiological contamination. Benzalkonium chloride (BAC) is the most used preservative in ophthalmic medications. Clinical studies have extensively examined the toxic effects of BAC, revealing that its prolonged use causes time- and dose-dependent cytotoxicity on the ocular surface, leading to tear film instability and the development of ocular surface disease, dry eye, and Meibomian gland dysfunction 3,4. Therefore, the European Medicine Agency recommends avoiding preservatives in patients who have pre-existing ocular surface disease or who develop dry eye or ocular irritation over time. 3Among eye drops, the most commonly discussed side effects, both local (as stated in Table 1) and systemic, in certain groups of topical ocular medications, pertain to antiglaucoma eyedrops, such as β receptor blockers, α receptor agonists and pilocarpine. Due to their chronic usage, physicians must take special care in choosing the right therapy for their patients as well as monitor for potential adverse events. β receptor blockers have a major limitation in their usage due to their frequent systemic side effects, although they are a potent antiglaucoma medications. Targeting β1-receptor causes reduced cardiac contractility and heart rate, bradycardia, and a blood pressure decrease and β2-receptor targeting leads to exacerbated asthma and chronic obstructive pulmonary disease symptoms. Additionally, central nervous system symptoms such as headaches, depression, and confusion may occur. Betaxolol is a selective β1-receptor antagonist which therefore causes fewer side effects to the respiratory system. 5 When α2 adrenergic agonists are applied, systemic side effects such as dry mouth, dizziness, fatigue, and drowsiness may occur, particularly in patients predisposed to bradycardia.6Excessive use of pilocarpine can also have numerous adverse effects due to its parasympathomimetic action which includes excessive sweating, drooling, bronchospasm, vomiting, diarrhea, stomach-ache, bradycardia, a drop in blood pressure, hallucinations and depression.Special caution also must be taken when prescribing topical ocular or systemic steroid medication. Because of their potential to change the microstructure of the trabecular meshwork, they can induce a rise in intraocular pressure by decreasing aqueous humour outflow and potentially causing the development of steroid induced glaucoma. Prolonged use of topical corticosteroids can also induce cataract formation and increase susceptibility to infection. If used in eyes with epithelial defects, they can inhibit growth factors and delay wound healing.Another group of eye drops which can have substantial systemic effects are mydriatics, such as phenylephrine and atropine. Phenylephrine, a selective α1-receptor, is applied in the form of eye drops for dilating the pupils during ophthalmological examinations. Due to its sympathomimetic effect it can cause major cardiovascular side effects, especially when administered in patients with pre-existing hypertension conditions.7 Atropine is a muscarinic receptor antagonist often used in ophthalmology in the form of eye drops for its mydriatic and cycloplegic effect. When systemically absorbed, it can potentially cause side effects like mouth and eye dryness, flushed skin and face, fever, tachycardia, delirium or restlessness, urinary retention, and constipation. If used in higher doses or over a longer period, in severe cases, central anticholinergic syndrome may occur, which is characterized by confusion, agitation, and hallucinations.8 Mydriatics also affect inner ocular structures. Phenylephrine is linked with a decrease in choroidal thickness, while atropine eye drops are associated with an increase in choroidal thickness. This necessitates careful monitoring of patients on long-term topical therapies for any alterations in choroidal structure because of their potential effect on visual function.9Other eyedrops, such as antiallergics, can also be sometimes used in treating eye conditions. Topical H1-receptor blockers and mast cell stabilizers in the form of antiallergic eye drops infrequently cause systemic side effects following ocular use. When they do occur, these side effects are usually mild, presenting as dry mouth, nausea, headache, or drowsiness.7The environmental effect is another part of pharmaceutical safety profiles which cannot be disregarded. Inappropriate disposal of drugs, including eye medications, poses a significant risk to public health and environmental sustainability by contaminating water supplies and disrupting ecosystems.10 Other than the drug itself, its packaging can also cause substantial waste, as is the case with monodose eye drops. These eyedrops are stored in small single-use containers, in order to prevent microbial growth which can occur in standard eye drop bottles after opening. However, their disposal creates a lot of waste. 11 Pharmaceutical companies should provide education and raise awareness among healthcare providers and patients about how to properly manage pharmaceutical waste.In conclusion, although topical ocular medication is the foundation of ophthalmic treatment, before prescribing physicians must be aware of their safety profiles. Although they are generally considered safe, their potential adverse effects on ocular and systemic health highlights challenges in the management of ocular diseases. Healthcare practitioners should choose preservative-free formulations where possible, monitor for both local and systemic side effects, and act responsibly while taking into consideration the environmental implications of pharmaceutical use. These safety concerns should be further investigated in future studies with the goal of improving therapeutic outcomes for patients while minimizing risks.