Medication changes implemented during medication reviews and factors related to deprescribing: Posthoc analyses of a randomized clinical trial in geriatric outpatients with polypharmacy.

AIMS: To provide posthoc analyses of a clinical trial that reported beneficial effects of medication reviews on health-related quality of life. Specifically, to describe the medication changes with a focus on deprescribing and to explore patient- and medication-related factors that may identify patients most likely to benefit from medication reviews. METHODS: Posthoc analyses of data from a pragmatic, nonblinded, randomized clinical trial investigating a medication review intervention (NCT03911934) in 408 geriatric outpatients treated with ≥9 medicines. RESULTS: In the medication review group (n = 196), 26% of the medicines prescribed at baseline were discontinued with 82% still being discontinued after 13 months. The most common reason for discontinuation was lack of indication (72% of discontinuations). The medicines most often discontinued in the medication review group compared with usual care included: metoclopramide (11/15 = 73% discontinued vs. 1/12 = 8% in usual care), acetylsalicylic acid (20/48 = 42% vs. 2/47 = 4%), simvastatin (18/48 = 38% vs. 2/58 = 3%), zopiclone (23/59 = 39% vs. 4/54 = 7%), quinine (9/14 = 64% vs. 6/16 = 38%), citalopram (4/18 = 22% vs. 0/20 = 0%) and tramadol (18/37 = 49% vs. 8/30 = 27%). Factors associated with number of deprescribed medicines included: number of prescribed medicines, Drug Burden Index, patient motivation for medicine changes, and prescriptions of metoclopramide, iron preparations, antidepressants other than selective serotonin reuptake inhibitors, nonsteroidal anti-inflammatory drugs, or drugs for urinary incontinence. CONCLUSION: Physician-led medication reviews resulted in persistent deprescribing of medicines in older polypharmacy patients treated with ≥9 medicines. Motivation for having their medicine changed, treatment with more medicines, and a higher burden of sedative and anticholinergic medicines characterized the patients most likely to benefit from physician-led medication reviews.

Physician-led medication reviews in polypharmacy patients treated with at least 12 medications in a type 2 diabetes outpatient clinic: A randomised trial.

AIMS: Medication reviews can be used to promote appropriate pharmacotherapy and negate the harmful consequences of polypharmacy. This study aimed to evaluate the effect of physician-led medication reviews and increased cross-sectoral communication as a supplement to standard care in a type 2 diabetes outpatient clinic. METHODS: This pragmatic randomised clinical trial enrolled patients with type 2 diabetes treated with at least 12 medications. The subjects were randomised to either standard care (standard care consultation at the outpatient clinic) or standard care plus a medication review consultation and increased cross-sectoral communication. The primary outcome was the number of medications used after six months. Health-related quality of life was quantified using the EuroQoL 5-dimension 5-level (EQ5D-5 L) questionnaire. RESULTS: We recruited 50 participants with a median age of 72 (IQR 67-75) years. The mean number of medications per patient changed from 17.9 to 14.3 in the intervention group and 17.6 to 17.2 in the control group (rate ratio 0.81). The reasons for discontinuations were medication no longer indicated (60%), safety issues (20%), efficacy issues (15%) or patient preferences (5%). There was a significant difference in the change in health-related quality of life (EQ5D-5 L index score) in favour of the intervention (0.111, 95% CI 0.001 to 0.221). CONCLUSIONS: Physician-led medication reviews and increased cross-sectoral communication in patients with type 2 diabetes treated with at least 12 medications reduced the number of medications used and improved health-related quality of life. Implementing and further investigating similar interventions as standard care seems reasonable.

Scoping Review of Randomized Trials With Discontinuation of Medicines in Older Adults.

OBJECTIVES: To map the randomized trial evidence describing the feasibility of discontinuing active medications with potential adverse effects in older patients. DESIGN: Scoping review with systematic search of PubMed, Embase, and Cochrane Library. SETTING AND PARTICIPANTS: Randomized trials investigating discontinuation of a single medicine or medicine class in patients with mean age ≥65 years. METHODS: We extracted trial characteristics including study design and assessed bias. As proxies for the "feasibility of discontinuation," we extracted the "dropout rate" and "disease recurrence rate." RESULTS: We identified 40 trials investigating discontinuation of symptomatic (n = 26), preventive (n = 6), or both preventive and symptomatic medicines (n = 8) against psychiatric (n = 10), neurologic (n = 9), musculoskeletal (n = 8), cardiovascular (n = 5), respiratory (n = 4), and urologic diseases (n = 4). Five discontinuation designs were used, 75% (30/40) of trials were placebo-controlled, and 48% (19/40) of trials had bias disfavoring discontinuation. The dropout rate was similar between the discontinuation group and the continuation group in 79% of the trials (30/38), whereas disease recurrence was similar in 72% (23/32) of the trials. In 42% (13/31) of trials reporting both dropout rate and disease recurrence rate, the differences between groups were statistically insignificant and less than 10%; these trials investigated discontinuation of cholinesterase inhibitors for Alzheimer's disease in various settings (n = 3), alendronate for osteoporosis (n = 3), glucosamine for osteoarthritis, lithium as adjunct for unipolar depression, statins for cardiovascular disease in patients with limited life expectancy, droxidopa for neurogenic orthostatic hypotension, tamsulosin for lower urinary tract symptoms, sertraline for major depressive episode, and fentanyl patch for low back or osteoarthritis pain. CONCLUSIONS AND IMPLICATIONS: We identified 40 randomized trials using a variety of designs investigating discontinuation of both symptomatic and preventive medicines in older patients. Discontinuation of medicines seems feasible for most of the investigated medicines. This scoping review can guide clinical practice and future trials on deprescribing.

Effect of single doses of citalopram and reboxetine on urethral pressure: A randomized, double-blind, placebo- and active-controlled three-period crossover study in healthy women.

AIMS: Urethral closure function is essential for urinary continence in women and decreased urethral pressure is associated with stress urinary incontinence (SUI). For decades, the effects of serotonergic drugs on central neural control of urethral closure have been investigated and discussed. Epidemiological studies suggest that the use of selective serotonin reuptake inhibitors (SSRIs), such as citalopram, is associated with SUI. However, the literature findings are conflicting. This study aimed to evaluate citalopram's effect on opening urethral pressure (OUP) in healthy women. METHODS: We conducted a randomized, double-blind, placebo- and active-controlled crossover study in 24 healthy women. On three study days, which were separated by 8 days of washout, the subjects received single doses of either 40 mg citalopram (and placeboreboxetine ), 8 mg reboxetine (and placebocitalopram ), or two placebos. Study drugs were administered at a 1-h interval due to a difference in estimated time to peak plasma concentration (tmax ). We measured OUP with urethral pressure reflectometry under both resting and squeezing conditions of the pelvic floor at estimated tmax for both study drugs (one timepoint). RESULTS: Compared to placebo, citalopram increased OUP by 6.6 cmH2 0 (95% confidence interval [CI] 0.04-13.1, p = 0.048) in resting condition. In squeezing condition, OUP increased by 7.1 cmH2 0 (95% CI: 1.3-12.9, p = 0.01). Reboxetine increased OUP by 30.0 cmH2 0 in resting condition compared to placebo (95% CI: 23.5-36.5, p < 0.001), and 27.0 cmH2 0 (95% CI: 21.2-32.8, p < 0.001) in squeezing condition. CONCLUSION: Citalopram increased OUP slightly compared to placebo suggesting that SSRI treatment does not induce or aggravate SUI.

Effects of a comprehensive medication review intervention on health-related quality of life and other clinical outcomes in geriatric outpatients with polypharmacy: A pragmatic randomized clinical trial.

AIM: To investigate the effects of a comprehensive medication review intervention on health-related quality of life (HRQoL) and clinical outcomes in geriatric outpatients exposed to polypharmacy. METHODS: Pragmatic, nonblinded, randomized clinical trial with follow-up after 4 and 13 months. Participants were geriatric outpatients taking ≥9 medicines. The intervention was an additional consultation with a physician focusing on reviewing medication, informing patients about their medicines and increasing cross-sectoral communication as supplement to and compared with usual care. The primary outcome was change in HRQoL after 4 months measured with the EuroQoL 5-dimension 5-level (EQ-5D-5L) questionnaire. Secondary outcomes were HRQoL after 13 months, mortality, admissions, falls and number of medicines after 4 and 13 months. RESULTS: Of 785 eligible patients, 408 were included (age: mean 80.6 [standard deviation 7.22] years; number of medicines: median 12 [interquartile range 10-14]; females 71%). After 4 months, the adjusted between-group difference in EQ-5D-5L index score was 0.066 in favour of the medication consultation (95% confidence interval 0.01 to 0.12, P = .02). After 4 months, two (1%) participants had died in the medication-consultation group and nine (4%) in the usual-care group (log-rank test, P = .045). The medication consultation reduced the number of medicines by 2.0 (15.8%) after 4 months and 1.3 (10.7%) after 13 months. There were no statistically significant differences in mortality or HRQoL after 13 months, and no differences in falls or admissions. CONCLUSIONS: An additional consultation with medication review and increased communication as supplement to usual geriatric outpatient care improved HRQoL and reduced mortality after 4 months.

Background sensitivity to chemotherapy-induced nausea and vomiting and response to antiemetics in paediatric patients: a genetic association study.

Chemotherapy-induced nausea and vomiting (CINV) remains a common adverse effect for children with cancer. In children, chemotherapy emetogenicity and patient factors such as susceptibility to motion sickness and age group determine a patient's risk of CINV. Besides known risk factors, genetic factors may play a role in interindividual variation in the occurrence of CINV. We investigated the influence of candidate gene polymorphisms on the efficacy of antiemetics and on the background sensitivity to CINV in children. This prospective study included 100 children with cancer (median age 6.4 years, range 0.8-17.9) who received moderately to highly emetogenic chemotherapy. Participants registered nausea and vomiting episodes in a mobile app. Genotypes were determined by whole-genome sequencing (n = 79) or Sanger sequencing (n = 21) for 71 genetic polymorphisms involved in motion sickness and antiemetic pathways. Odds ratios (ORs) and 95% confidence intervals (CIs) were calculated to estimate associations between acute CINV and genotypes adjusting for susceptibility to motion sickness and age group. Rs3782025 in the 5-hydroxytryptamine type 3 (5-HT3) receptor gene (HTR3B) [minor allele frequency (MAF): 0.48] affected response to 5-HT3 receptor antagonists; acute CINV occurred in 76% of patients with GA/AA genotypes and in 41% of patients with GG genotype (OR 5.59; 95% CI 1.74-17.9, dominant genetic model). Rs2975226 in the dopamine transporter gene (SLC6A3) (MAF: 0.54) was associated with acute CINV (OR 5.79; 95% CI 1.09-30.67, recessive genetic model). Polymorphisms in HTR3B and SLC6A3 may contribute to the variability in response to antiemetic prophylaxis for CINV in children.

Causes of discrepancies between medications listed in the national electronic prescribing system and patients' actual use of medications.

Discrepancies between registered prescriptions and patients' actual use of medications are described as frequent and often resulting in adverse medication events. We aimed to assess the extent of and causes behind discrepancies between medications listed in the Danish national prescription system (Shared Medication Record) and patients' actual use of medications. We prospectively reconciled medication for 260 consecutively admitted polypharmacy patients (>50 years and ≥5 prescriptions) at two hospitals in the Capital Region of Denmark. The type of discrepancies were determined and the cause of the discrepancies were evaluated as primarily caused by (1) the patient (i.e., intentional or unintentional non-adherence) or (2) the health care system (i.e., lack of appropriate update of the SMR by physicians in primary or secondary care). There was a median of 12 [IQR 9-15] medications listed and 3 [IQR 1-5] medication discrepancies per patient (total n = 925). The majority (53%) of discrepancies were caused by the health care system, 32% were caused by the patients, of which 70% were intentional non-adherence, and 15% had an indeterminable cause. In conclusion, discrepancies between medications listed in the Shared Medication Record and actual use of medications were frequent and were most often caused by clinicians not updating the prescription information.

Prevalence of polypharmacy in Denmark.

INTRODUCTION: Polypharmacy is associated with an increased risk of adverse health outcomes. This study aims to describe the prevalence of polypharmacy and medication use among older Danish citizens. METHODS: From national registers, we extracted medicine use in relation to age group and residential region for the entire Danish population for the first half of 2016. The most frequently redeemed medicines among older citizens (≥ 75 years) in 2016 were grouped into clinically meaningful medication classes. RESULTS: The prevalence of polypharmacy (> 5 different medicines) was 51% among citizens ≥ 75 years compared with 12% for the entire Danish population. The prevalence of polypharmacy increased with age and was 7% among citizens aged 40-49 years compared with 66% among citizens aged ≥ 90 years. There were only minor regional differences in the prevalence of polypharmacy. The most commonly redeemed medicine classes and individual medicines for older citizens were: 1) pain medication: paracetamol (50%) and tramadol (14%); 2) cardiovascular medicines: acetylsalicylic acid (26%), simvastatin (25%), metoprolol (22%), amlodipine (21%), furosemide (20%), bendroflumethiazide (17%), and losartan (14%); and 3) gastrointestinal medicines: pantoprazole (15%). CONCLUSIONS: Polypharmacy is prevalent in Denmark with no relevant regional differences. The prevalence of polypharmacy increased with age, and more than half of the population aged ≥ 75 years redeemed prescriptions for > 5 different medicines. The most redeemed medicines among older citizens were against pain and cardiovascular disease. FUNDING: none. TRIAL REGISTRATION: not relevant.

Effect of imipramine on urethral opening pressure: A randomized, double-blind, placebo-controlled crossover study in healthy women.

AIMS: In two open-label trials, imipramine alleviated symptoms in patients with stress urinary incontinence and is therefore used off-label for this indication. However, it has never been confirmed that imipramine increases urethral pressure in a placebo-controlled setting. The purpose of this study was to investigate whether imipramine increases the opening urethral pressure compared to placebo in healthy women using urethral pressure reflectometry. METHODS: A randomized, double-blind, placebo-controlled, crossover study in 16 healthy women. Opening urethral pressure was measured predose and 1 hour after a single dose of 50 mg imipramine or placebo. The washout period was minimum of 1 week. The study was approved by the local ethics committee, conducted according to the Good Clinical Practice guidelines, and registered on ClinicalTrials.gov and EudraCT before recruitment of subjects. Funding was provided by the clinical department. RESULTS: There were no dropouts and no serious adverse events. There were 13 adverse drug reactions related to imipramine in seven subjects, one adverse event related to placebo, and two adverse events related to the measurements with urethral pressure reflectometry. Imipramine compared to placebo increased opening urethral pressure in the resting condition with 6.5 cmH2 O (95% confidence interval [CI]: -0.5, 13.5), P = 0.07, and in the squeeze condition with 7.9 cmH 2 O (95% CI: -0.3, 16.1), P = 0.06. CONCLUSIONS: In conclusion, the increase in opening urethral pressure after imipramine treatment compared to placebo was neither statistically significant nor clinically relevant, and we do therefore not recommend the off-label use of imipramine for the treatment of stress urinary incontinence.

Polypharmacy and medication deprescribing: A survey among multimorbid older adults in Denmark.

Polypharmacy is common among multimorbid adults and associated with increased morbidity and mortality. Excessive polypharmacy (ie, ≥10 medicine) is strongly associated with inappropriate medication use, but little is known about attitudes toward deprescribing in patients with excessive polypharmacy. We surveyed 100 Danish individuals aged 65 years and above with ≥10 prescribed medications, using the validated Patients' Attitudes Towards Deprescribing (PATD) instrument. Most participants (81, 81%) thought they took a large number of medications, and 79 (79%) believed that their medications were necessary. Even so, 85 (85%) reported that they would be willing to stop taking one or more of their regular medications if their doctor told them they could, and 11 (11%) felt that they took at least one regular medication that they no longer needed. When presented with visual presentation of various amounts of tablets and capsules, 62 (62%) of participants reported that they would be comfortable taking fewer medications than they did. Forty-two (42%) participants had experience with stopping a regular medication. Almost all participants (92%) wanted to receive follow-up by various means if a medication was discontinued. Forty-one (41%) participants were interested in a consultation at an outpatient clinic specializing in polypharmacy. Overall, the answers to the PATD questionnaire suggest that our cohort of Danish, multimorbid outpatients with extensive polypharmacy have a high confidence in their healthcare providers for medication-related decisions, even though some feel that they are taking more medications than they would like to and feel that some medications may be unnecessary. Our results underline the need for healthcare providers to offer medication reviews in patients with multimorbidity.

General Practitioners' Barriers Toward Medication Reviews in Polymedicated Multimorbid Patients: How can a Focus on the Pharmacotherapy in an Outpatient Clinic Support GPs?

PURPOSE: The aim of this study was to explore whether general practitioners (GPs) experienced barriers toward medication reviews in polymedicated, multimorbid patients, and how a clinical pharmacologist with a focus on pharmacotherapy can support the GPs in an outpatient clinic. DESIGN: The study was descriptive and exploratory and had a qualitative design with a phenomenological/hermeneutic orientation for the interviews. PARTICIPANTS: The study comprised 14 interviews with 14 different GPs from the Capital Region of Denmark. RESULTS: Three themes emerged from the interviews: (1) The care of patients With polypharmacy is challenged by the lack of professional dialogue and collaboration between GPs and hospital-based clinical pharmacologists, (2) the relationship between the patients with polypharmacy and the GP is characterized by care and individual considerations, and (3) the culture encourages adding medication and inhibits dialogue about medication withdrawal even for patients with polypharmacy. CONCLUSION AND IMPLICATIONS FOR PRACTICE: This study found that the primary barriers toward multimorbid patients with polypharmacy were the need for communication and teamwork with specialists (cardiologists, neurologists, endocrinologists, etc). Often, GPs felt that the specialists at the hospitals were more concerned about following standards and guidelines regarding specific diseases instead of a more holistic patient approach. To improve management of polypharmacy patients, the GPs suggest that a joint force is necessary, a partner-like relationship with greater transparency regarding information transfer, feedback, and shared decision-making, but also more education in the pharmacological field is essential.

[Secondary adrenal insufficiency during opiate treatment].

A 25-year-old previously healthy man developed secondary adrenal insufficiency during opiate treatment with tramadol and morphine for upper back pain. He experienced a 10 kg weight loss in six weeks. MRI of the hypothalamus and the pituitary gland ruled out cerebral pathology. After discontinuation of the opiate treatment the condition normalised. Opiate therapy can cause endocrine dysfunction, and clinicians should always consider adverse drug reactions as a differential diagnosis for unexplained symptoms.