Review of clinical pharmacokinetics and pharmacodynamics of clonidine as an adjunct to opioids in palliative care.

Clonidine is an α-adrenoceptor agonist acting on receptors in the brain and peripheral tissues, leading to a reduction in sympathetic outflow and release of certain neurotransmitters. Clonidine has multiple uses across various medical conditions. One of its uses is as adjuvant to anaesthetic and analgesic agents specially opioids, mostly administered through intravenous and epidural routes. The opioids, effective in cancer pain management, are associated with various side effects such as sedation, pruritus, constipation, nausea, respiratory depression, tolerance and dependence. Combination of clonidine with opioids seems to help to achieve better pain management and less need of opioids. Use of clonidine in palliative care has been less common, but it is gradually gaining recognition for its potential benefits in managing symptoms like cancer pain and agitation. This combination approach has been explored in palliative care settings, including cancer pain and agitation, where patients experience complex and refractory symptoms. It seems to be well tolerated and gives better symptom relief. The available literature on clonidine's use in cancer pain and agitation management, especially in subcutaneous form, is limited and outdated. Therefore, the optimal dosing, safety profile and overall effectiveness of subcutaneous clonidine requires further exploration through prospective research studies.

Pharmacokinetics and pharmacodynamics of cannabis-based medicine in a patient population included in a randomized, placebo-controlled, clinical trial.

Information on the pharmacokinetics (PK) and pharmacodynamics (PD) of orally administered cannabis-based medicine (CBM) in capsule formulation in patient populations is sparse. In this exploratory study, we aimed to evaluate the PK and PD in a probable steady state of CBM in neuropathic pain and spasticity in a population of patients with multiple sclerosis (MS). Of 134 patients participating in a randomized, double-blinded, placebo-controlled, trial, 23 patients with MS (17 female) mean age 52 years (range 21-67) were enrolled in this substudy. They received oral capsules containing Δ9 -tetrahydrocannabinol (THC, n = 4), cannabidiol (CBD, n = 6), a combination (THC&CBD, n = 4), or placebo (n = 9). Maximum doses were 22.5 mg (THC) and 45 mg (CBD) a day divided into three administrations. PD parameters were evaluated for pain and spasticity. Blood samples were analyzed using an ultra-high-performance liquid chromatography-tandem mass spectrometer after protein precipitation and phospholipid removal. PK parameters were estimated using computerized modeling. The variation in daily dose and PK between individuals was considerable in a steady state, yet comparable with previous reports from healthy controls. Based on a simulation of the best model, the estimated PK parameters (mean) for THC (5 mg) were Cmax 1.21 ng/mL, Tmax 2.68 h, and half-life 2.75 h, and for CBD (10 mg) were Cmax 2.67 ng/mL, Tmax 0.10 h, and half-life 4.95 h, respectively. No effect was found on the PD parameters, but the placebo response was considerable. More immediate adverse events were registered in the active treatment groups compared with the placebo group.

Cannabis-Based Medicine for Neuropathic Pain and Spasticity-A Multicenter, Randomized, Double-Blinded, Placebo-Controlled Trial.

Patients with multiple sclerosis (MS) and spinal cord injury (SCI) commonly sustain central neuropathic pain (NP) and spasticity. Despite a lack of consistent evidence, cannabis-based medicine (CBM) has been suggested as a supplement treatment. We aimed to investigate the effect of CBM on NP and spasticity in patients with MS or SCI. We performed a randomized, double-blinded, placebo-controlled trial in Denmark. Patients aged ≥18 years with NP (intensity >3, ≤9 on a numerical rating scale (NRS0-10) and/or spasticity (>3 on NRS0-10) were randomized to treatment consisting of either delta-9-tetrahydrocannabinol (THC), cannabidiol (CBD), a combination of THC&CBD in maximum doses of 22.5 mg, 45 mg and 22.5/45 mg per day, respectively, or placebo. A baseline registration was performed before randomization. Treatment duration was six weeks followed by a one-week phaseout. Primary endpoints were the intensity of patient-reported NP and/or spasticity. Between February 2019 and December 2021, 134 patients were randomized (MS n = 119, SCI n = 15), where 32 were assigned to THC, 31 to CBD, 31 to THC&CBD, and 40 to placebo. No significant difference was found for: mean pain intensity (THC 0.42 (-0.54-1.38), CBD 0.45 (-0.47-1.38) and THC&CBD 0.16 (-0.75-1.08)), mean spasticity intensity (THC 0.24 (-0.67-1.45), CBD 0.46 (-0.74-1.65), and THC&CBD 0.10 (-1.18-1.39), secondary outcomes (patient global impression of change and quality of life), or any tertiary outcomes. We aimed to include 448 patients in the trial; however, due to COVID-19 and recruitment challenges, fewer were included. Nevertheless, in this four-arm parallel trial, no effect was found between placebo and active treatment with THC or CBD alone or in combination on NP or spasticity in patients with either MS or SCI. The trial was registered with the EU Clinical Trials Register EudraCT (2018-002315-98).

Municipal offers and principles for substitution treatment for abuse and addiction to opioids.

Opioid use disorders can be treated with psychosocial interventions which aim to increase quality of life and minimize problems maintaining drug use. In addition, pharmacological treatment with opioid maintenance therapy (OMT) can help minimize morbidity and mortality. The principle for OMT is substituting to another opioid with a more favourable pharmacological profile, primarily buprenorphine or methadone. The first choice is buprenorphine in combination with naloxone. The aim of this review is to summarize current principles for handling patients in OMT.

Toxic use of baclofen causing cramps during tapering.

The spasmolytic agent baclofen is regarded as having a low dependence potential. This is a case report of a 46-year-old woman with an escalating use of baclofen to four times the highest recommended dose. She was initially admitted to hospital due to decreased consciousness. Later, during tapering, she was readmitted unresponsive with myoclonus. Baclofen was discontinued abruptly during sedation with propofol and remifentanil infusion as well as midazolam in refract doses. Eight days later she was discharged without sequelae.

Is a High Medication Risk Score Associated With Increased Risk of 30-Day Readmission? A Population-Based Cohort Study From CROSS-TRACKS.

OBJECTIVES: The primary aim of this study was to evaluate whether a high Medication Risk Score (MERIS) upon admission to an emergency department is associated with increased risk of 30-day readmission in patients discharged directly home. Mortality, visit to general practitioner, and drug changes within 30 days were included as secondary outcomes. METHODS: This is a historical cohort study with data from the Danish population-based open-cohort CROSS-TRACKS. Cox regression analyses were used to determine whether a high MERIS score was associated with increased risk of 30-day readmission and mortality. Visit to general practitioner and drug changes were tested with χ2 test and Wilcoxon rank sum test. RESULTS: A total of 2106 patients were eligible: 2017 had a MERIS score lower than 14 (low-risk group), and 89 had a score of 14 or higher (high-risk group). The proportion of patients in the high-risk group who were readmitted was 21.3% compared with 16.3% in the low-risk group, resulting in a hazard ratio for readmission of 1.43 (95% confidence interval, 0.9-1.3). The hazard ratio for mortality was 8.3 (95% confidence interval, 3.0-22.8). No statistical significant difference was found in general practitioner visits; however, significantly more drug changes were observed in the high-risk group. CONCLUSIONS: A high MERIS score was associated with increased risk of readmissions and can potentially assist healthcare professionals in the prioritizing of patients who may benefit from further exam, for example, additional medication review in acute care setting. Further investigation of MERIS and exploration of causal inferences between medication-related harm and medication-related readmissions are warranted.

The Effect of Cannabis-Based Medicine on Neuropathic Pain and Spasticity in Patients with Multiple Sclerosis and Spinal Cord Injury: Study Protocol of a National Multicenter Double-Blinded, Placebo-Controlled Trial.

Disease or acquired damage to the central nervous system frequently causes disabling spasticity and central neuropathic pain (NP), both of which are frequent in multiple sclerosis (MS) and spinal cord injury (SCI). Patients with MS and SCI often request treatment with cannabis-based medicine (CBM). However, knowledge about effects, side effects, choice of active cannabinoids (Δ9-tetrahydrocannabinol (THC), cannabidiol (CBD) alone or in combination), and doses of CBM remains limited. Using a double-blind, parallel design in a national multicenter cohort, this study examines the effect of CBM on spasticity and NP. Patients are randomized to treatment with capsules containing either THC, CBD, THC and CBD, or placebo. Primary endpoints are patient-reported pain and spasticity on a numerical rating scale. Other endpoints include quality of life and sleep, depression and anxiety, and relief of pain and spasticity. Side-effects of CBM are described. In a sub-study, the pharmacodynamics (PD) and pharmacokinetics (PK) of oral capsule CBM are examined. We expect that the study will contribute to the literature by providing information on the effects and side-effects of CBD, THC, and the combination of the two for central neuropathic pain and spasticity. Furthermore, we will describe the PD/PK of THC and CBD in a patient population.

External validation of the Medication Risk Score in polypharmacy patients in general practice: A tool for prioritizing patients at greatest risk of potential drug-related problems.

Drug-related problems are important causes of patient harm and increased healthcare costs. To assist general practitioners in prioritizing patients in need of a critical medication review, we aimed to assess the ability of the Medication Risk Score (MERIS) to stratify patients with polypharmacy in general practice according to their risk of drug-related problems. We conducted a cross-sectional multi-centre external validation study. Patients receiving more than five concomitant medications (polypharmacy) were eligible. The outcome was potentially serious drug-related problems as evaluated by expert consensus. Performance was assessed in terms of calibration and discrimination indices. Of 497 patients, 489 were included in the main analysis. The median age (interquartile range) was 70.5 years (60-79). In total, 372 potentially serious drug-related problems were observed in 253 patients (52%). The MERIS was well calibrated above a score level of 10. The area under the receiver operating characteristic curve was 0.70 (95% confidence interval: 0.65-0.74). The performance of the MERIS was fair in patients with polypharmacy in general practice. Given the scale of drug-related problems and the lack of efficient prioritization tools in this setting, the MERIS could be a useful risk indicator to complement usual practice.

[Local anaesthesia and steroid blockades for carpal tunnel syndrome in pregnancy].

The possible impact on the foetus must always be taken into account, whenever non-conservative strategies are considered in pregnancy. As to carpal tunnel syndrome, surgery is usually reserved for severe cases, or when steroid blockades have been insufficient. If only pharmacological considerations are taken into account, surgery with local anaesthetics may however be preferred over blockades. While especially lidocaine is considered quite safe in pregnancy, a foetal risk cannot be ruled out for the synthetic glucocorticoids. Moreover, the duration of exposure is considerably shorter. These issues are summarized and discussed in this review.

Efficacy of the TMPRSS2 inhibitor camostat mesilate in patients hospitalized with Covid-19-a double-blind randomized controlled trial.

BACKGROUND: The trans-membrane protease serine 2 (TMPRSS2) is essential for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) cell entry and infection. Efficacy and safety of TMPRSS2 inhibitors in patients with coronavirus disease 2019 (Covid-19) have not been evaluated in randomized trials. METHODS: We conducted an investigator-initiated, double-blind, randomized, placebo-controlled multicenter trial in patients hospitalized with confirmed SARS-CoV-2 infection from April 4, to December 31, 2020. Within 48 h of admission, participants were randomly assigned in a 2:1 ratio to receive the TMPRSS2 inhibitor camostat mesilate 200 mg three times daily for 5 days or placebo. The primary outcome was time to discharge or clinical improvement measured as ≥2 points improvement on a 7-point ordinal scale. Other outcomes included 30-day mortality, safety and change in oropharyngeal viral load. FINDINGS: 137 patients were assigned to receive camostat mesilate and 68 to placebo. Median time to clinical improvement was 5 days (interquartile range [IQR], 3 to 7) in the camostat group and 5 days (IQR, 2 to 10) in the placebo group (P = 0·31). The hazard ratio for 30-day mortality in the camostat compared with the placebo group was 0·82 (95% confidence interval [CI], 0·24 to 2·79; P = 0·75). The frequency of adverse events was similar in the two groups. Median change in viral load from baseline to day 5 in the camostat group was -0·22 log10 copies/mL (p <0·05) and -0·82 log10 in the placebo group (P <0·05). INTERPRETATION: Under this protocol, camostat mesilate treatment was not associated with increased adverse events during hospitalization for Covid-19 and did not affect time to clinical improvement, progression to ICU admission or mortality. ClinicalTrials.gov Identifier: NCT04321096. EudraCT Number: 2020-001200-42.

Camostat mesylate against SARS-CoV-2 and COVID-19-Rationale, dosing and safety.

The coronavirus responsible for COVID-19, SARS-CoV-2, utilizes a viral membrane spike protein for host cell entry. For the virus to engage in host membrane fusion, SARS-CoV-2 utilizes the human transmembrane surface protease, TMPRSS2, to cleave and activate the spike protein. Camostat mesylate, an orally available well-known serine protease inhibitor, is a potent inhibitor of TMPRSS2 and has been hypothesized as a potential antiviral drug against COVID-19. In vitro human cell and animal studies have shown that camostat mesylate inhibits virus-cell membrane fusion and hence viral replication. In mice, camostat mesylate treatment during acute infection with influenza, also dependent on TMPRSS2, leads to a reduced viral load. The decreased viral load may be associated with an improved patient outcome. Because camostat mesylate is administered as an oral drug, it may be used in outpatients as well as inpatients at all disease stages of SARS-CoV-2 infection if it is shown to be an effective antiviral agent. Clinical trials are currently ongoing to test whether this well-known drug could be repurposed and utilized to combat the current pandemic. In the following, we will review current knowledge on camostat mesylate mode of action, potential benefits as an antiviral agent and ongoing clinical trials.

Effects of stratified medication review in high-risk patients at admission to hospital: a randomised controlled trial.

BACKGROUND: Patients at high risk of medication errors will potentially benefit most from medication reviews. An algorithm, MERIS, can identify the patients who are at highest risk of medication errors. The aim of this study was to examine the effects of performing stratified medication reviews on patients who according to MERIS were at highest risk of medication errors. METHODS: A randomised controlled trial was performed at the Acute Admissions Unit, Aarhus University Hospital, Denmark. Patients were included at admission to the hospital and were randomised to control or intervention. The intervention consisted of stratified medication review at admission on patients with a high MERIS score. Clinical pharmacists and clinical pharmacologists performed the medication reviews; the clinical pharmacologists performed the reviews on patients with the highest MERIS score. The primary outcome measure was the number of prescribing errors during the hospitalisation. Secondary outcomes included self-experienced quality of life, health-care utilisation and mortality measured at follow-up 90 days after discharge. RESULTS: A total of 375 patients were included, of which medication reviews were performed in 64 patients. The medication reviews addressed 63 prescribing errors in 37 patients and 60 other drug-related problems. No difference in the number of prescribing errors during hospitalisation between the intervention group (n = 165) and control group (n = 153) was found, corresponding to 0.11 prescribing errors per drug (95% confidence interval (CI): 0.08-0.14) versus 0.13 per drug (95% CI: 0.09-0.16), respectively. No differences in secondary outcomes were observed. CONCLUSION: A stratified medication review approach based on the individual patient's risk of medication errors did not show impact on the chosen outcomes. PLAIN LANGUAGE SUMMARY: How does a medication review at admission affect patients who are in high risk of medication errors? Patients are at risk of medication errors at admission to hospital. Medication reviews aim to detect and solve these. Yet, due to limited resources in healthcare, it would be beneficial to detect the patients who are most at risk of medication errors and perform medication reviews on those patients.In this study we investigated whether an algorithm, MERIS, could detect patients who are at highest risk of medication errors; we also studied whether performing medication reviews on patients at highest risk of medication errors would have an effect on, for example, the number of medication errors during hospitalisation, qualify of life and number of readmissions. We included 375 patients in a Danish acute admission unit and they were divided into control group and intervention group. Patients in the intervention group received a medication review at admission if they were considered at high risk of medication errors, assessed with the aid of MERIS. In summary, 64 patients in the intervention group were most at risk of medication errors and therefore received a medication review.We conclude in the study that MERIS was useful in identifying relevant patients for medication reviews. Yet, the medication reviews performed at admission did not impact on the chosen outcomes.

Empirical Investigation of Ethical Challenges Related to the Use of Biological Therapies.

The aim of this study was to investigate the ethical dilemma of prioritising financial resources to expensive biological therapies. For this purpose, the four principles of biomedical ethics formulated by ethicists Tom Beauchamp and James Childress were used as a theoretical framework. Based on arguments of justice, Beauchamp and Childress advocate for a health care system organised in line with the Danish system. Notably, our study was carried out in a Danish setting.

The Danish model for the quick and safe implementation of infliximab and etanercept biosimilars.

PURPOSE: A rapidly increasing use of biological drugs has led to substantial costs. Shift to biosimilars enables considerable reduction of these costs without jeopardizing the treatment of patients, but most countries have extensive possibilities of untapped cost-savings. The aim of this study was to describe the Danish quick and near-complete implementation of the two first TNF inhibitor biosimilars (infliximab and etanercept). METHODS: We shed light on the considerations and experiences made during the implementation, and present key figures from the implementation. RESULTS: The infliximab biosimilar constituted 90.6% of the total amount of infliximab four months following patent expiration of the biooriginator. Similar results were seen for etanercept biosimilar. Substantial cost reductions were experienced in the way that e.g. the infliximab-shift reduced cost by two thirds. CONCLUSION: We believe that a thorough preparation and an organizational setting supporting the implementation is crucial for the successful implementation. This same implementation model will be used for future biosimilars.

Heart insufficiency after combination of verapamil and metoprolol: A fatal case report and literature review.

The combination of verapamil or diltiazem with beta-blockers should be avoided because of potentially profound adverse effects on AV (atrioventricular) nodal conduction, heart rate, or cardiac contractility. This effect is unpredictable but may be enhanced due to CYP2D6 poor metabolizer status which could be a special vulnerability factor.

[Potential pharmacological consequences of the development of the opioid consumption in Denmark].

The total consumption of weak opioids (mainly of tramadol) in Denmark was doubled during the period 2001-2013. On the contrary, the total consumption of strong opioids remained almost constant in the same period. The increase in tramadol consumption is not rational, as it has no special benefits with regards to efficacy, side effects and abuse potential. The terms strong- and weak opioids are inappropriate, because it often erroneously is interpreted as if the weak opioids are safer, but it is really just a matter of potency: strong opioids are simply more potent.

Risk of prescribing errors in acutely admitted patients: a pilot study.

Background Prescribing errors in emergency settings occur frequently. Knowing which patients have the highest risk of errors could improve patient outcomes. Objective The aim of this study was to test an algorithm designed to assess prescribing error risk in individual patients, and to test the feasibility of medication reviews in high-risk patients. Setting The study was performed at the Acute Admissions Unit at Aarhus University Hospital, Denmark. Methods The study was an interventional pilot study. Patients included were assessed according to risk of prescribing errors with the aid of an algorithm called 'Medication Risk Score' (MERIS). Based on the score, high-risk patients were offered a medication review. The clinical relevance of the medication reviews was assessed retrospectively. Main outcome measure The number and nature of prescribing errors during the patients' hospitalisation. Results The study included 103 patients, all of whom could be risk assessed with the algorithm MERIS. MERIS stratified 38 patients as high-risk patients and 65 as low-risk patients. The 103 patients were prescribed a total of 848 drugs in which 88 prescribing errors were found (10.4 %). Sixty-two of these were found in patients in the high-risk group. In general, the medication reviews were found to be clinically relevant and approximately 50 % of recommendations were implemented. Conclusion MERIS was found to be applicable in a clinical setting and stratified most patients with prescribing errors into the high-risk group. The medication reviews were feasible and found to be clinically relevant by most raters.

Detection of Patients at High Risk of Medication Errors: Development and Validation of an Algorithm.

Medication errors (MEs) are preventable and can result in patient harm and increased expenses in the healthcare system in terms of hospitalization, prolonged hospitalizations and even death. We aimed to develop a screening tool to detect acutely admitted patients at low or high risk of MEs comprised by items found by literature search and the use of theoretical weighting. Predictive variables used for the development of the risk score were found by the literature search. Three retrospective patient populations and one prospective pilot population were used for modelling. The final risk score was evaluated for precision by the use of sensitivity, specificity and area under the ROC (receiver operating characteristic) curves. The variables used in the final risk score were reduced renal function, the total number of drugs and the risk of individual drugs to cause harm and drug-drug interactions. We found a risk score in the prospective population with an area under the ROC curve of 0.76. The final risk score was found to be quite robust as it showed an area under the ROC curve of 0.87 in a recent patient population, 0.74 in a population of internal medicine and 0.66 in an orthopaedic population. We developed a simple and robust score, MERIS, with the ability to detect patients and divide them according to low and high risk of MEs in a general population admitted at acute admissions unit. The accuracy of the risk score was at least as good as other models reported using multiple regression analysis.

Classification of drugs with different risk profiles.

INTRODUCTION: A risk stratification approach is needed to identify patients at high risk of medication errors and a resulting high need of medication review. The aim of this study was to perform risk stratification (distinguishing between low-risk, medium-risk and high-risk drugs) for drugs found to cause serious adverse reactions due to medication errors. The study employed a modified Delphi technique. METHODS: Drugs from a systematic literature search were included into two rounds of a Delphi process. A panel of experts was asked to evaluate each identified drug's potential for harm and for clinically relevant drug-drug interactions on a scale from 1 (low risk) to 9 (high risk). RESULTS: A total of 36 experts were appointed to serve on the panel. Consensus was reached for 29/57 (51%) drugs or drug classes that cause harm, and for 32/57 (56%) of the drugs or drug classes that cause interactions. For the remaining drugs, a decision was made based on the median score. Two lists, one stating the drugs' potential for causing harm and the other stating clinically relevant drug-drug interactions, were stratified into low-risk, medium-risk and high-risk drugs. CONCLUSION: Based on a modified Delphi technique, we created two lists of drugs stratified into a low-risk, a medium-risk and a high-risk group of clinically relevant interactions or risk of harm to patients. The lists could be incorporated into a risk-scoring tool that stratifies the performance of medication reviews according to patients' risk of experiencing adverse reactions. FUNDING: none. TRIAL REGISTRATION: not relevant.