Metabolome analysis in patients with heart failure and implantable cardioverter defibrillators.

Heart failure (HF) is a complex, heterogeneous syndrome with several comorbidities, often life-threatening and requires urgent therapy. In HF, metabolic alterations that can be assessed using comprehensive plasma, and tissue profiling will help establish new biomarkers and therapeutic targets. Metabolomic analysis of sudden death in HF cases remains unresolved. We prospectively evaluated 19 patients who underwent implantable cardioverter defibrillator (ICD) placement for the primary prevention of sudden cardiac death (SCD). Metabolomic analysis was performed using plasma samples before ICD implantation. Ventricular arrhythmia (VA)/SCD was defined as VA with an appropriate ICD therapy or SCD. During a median follow-up of 29 months (range, 13-35 months), four patients developed VA and one patient developed SCD. Using metabolomic analysis, arginine, lysine, and valine were significantly reduced in patients with VA/SCD (n = 5) compared with those without VA/SCD (n = 14). The molecules involved in energy metabolism might be associated with VA/SCD, thus requiring further investigation as a predictive value of metabolomic analysis of VA/SCD.

Psychotherapeutic drug-induced life-threatening arrhythmias: A retrospective analysis using the Japanese adverse drug event report database.

Background: Drug-induced life-threatening ventricular arrhythmias including torsade de pointes (TdP), ventricular tachycardia (VT), and ventricular fibrillation (VF) are serious cardiac side effects. Psychotherapeutic drugs are known to be risk factors for arrhythmias. The aim of this study was to evaluate psychotherapeutic drugs associated with life-threatening ventricular arrhythmias using the Japanese Adverse Drug Event Report (JADER) database. Methods: From the JADER database (April 2004 to September 2022), cases of TdP, VT, VF, and QT prolongation in patients taking psychotherapeutic drugs as 'suspected drugs' were extracted. The adjusted reported odds ratio (aROR) was calculated to identify potential drugs involved in combined TdP/VF/VT or combined QT prolongation/TdP. Results: Of the 4,530,772 cases reported, life-threatening arrhythmia-related adverse events were reported in 1760 cases (QT prolongation 1261, TdP 192, VF 108, VT 199) among 909 patients; 58.9% of patients were female, and the highest incidence was among patients aged 80-89 years (18.6%), followed by patients aged 70-79 years (15.4%). The highest aROR for TdP/VF/VT was found for trazodone (17.1), followed by sulpiride (10.8), haloperidol (9.8), donepezil (9.1), and fluvoxamine (7.9). The highest aROR for QT prolongation/TdP was found for guanfacine (87.8), followed by sultopride (60.1), escitalopram (21.0), trazodone (12.8), and donepezil (9.3). Conclusions: This study showed that typical antipsychotics, antidepressants, and antidementia drugs were associated with life-threatening arrhythmia-related adverse events in a Japanese clinical setting. These events were more frequent in women and elderly individuals.

Direct Link Between Cardiac Failure and Global Cerebral Atrophy in a Young Adult: A Case Report on Reduced Cerebral Artery Blood Flow.

BACKGROUND Heart failure is associated with structural brain abnormalities, including atrophy of multiple brain regions. Previous studies have reported brain atrophy in middle-aged patients with systolic heart failure. In this report, we present the case of a 21-year-old woman with idiopathic dilated cardiomyopathy, cardiac failure, and global cerebral atrophy due to reduced cerebral artery blood flow. We also discuss the impact of brain atrophy in this young adult patient with severe heart failure and no risk factors for atherosclerosis. CASE REPORT A 21-year-old woman with dyspnea and leg edema was admitted to our hospital. After several examinations, an endomyocardial biopsy led to a diagnosis of idiopathic dilated cardiomyopathy, and transthoracic ultrasound cardiography revealed that her left ventricular ejection fraction was 36%. One year after the first hospitalization, her heart failure was classified as New York Heart Association Class III. Magnetic resonance imaging showed severe global brain atrophy, and single-photon emission computed tomography combined with brain computed tomography showed reduced blood flow to the entire brain. She had no risk factors for atherosclerosis and no atherosclerotic changes to her brain or carotid arteries, but her neuropsychological and neurological findings indicated more pronounced brain and cognitive dysfunction. CONCLUSIONS This young adult patient with idiopathic dilated cardiomyopathy, cardiac failure, and global cerebral atrophy showed reduced cerebral artery blood flow and cognitive impairment. The findings of this report indicate that low cardiac output may directly cause brain atrophy in patients with systolic heart failure.

Rationale and Design of the Effect of Ivabradine on Exercise Tolerance in Patients With Chronic Heart Failure (EXCILE-HF) Trial　- Protocol for a Multicenter Randomized Controlled Trial.

Background: A high resting heart rate is an independent risk factor for mortality and morbidity in patients with cardiovascular diseases. Ivabradine selectively inhibits the funny current (I f) and decreases heart rate without affecting cardiac conduction, contractility, or blood pressure. The effect of ivabradine on exercise tolerance in patients with heart failure with reduced ejection fraction (HFrEF) on standard drug therapies remains unclear. Methods and Results: This multicenter interventional trial of patients with HFrEF and a resting heart rate ≥75 beats/min in sinus rhythm treated with standard drug therapies will consist of 2 periods: a 12-week open-label, randomized, parallel-group intervention period (standard drug treatment+ivabradine group and standard drug treatment group) to compare changes in exercise tolerance between the 2 groups; and a 12-week open-label ivabradine treatment period for all patients to evaluate the effect of adding ivabradine on exercise tolerance. The primary endpoint will be the change in peak oxygen uptake (V̇O2) during the cardiopulmonary exercise test from Week 0 (baseline) to Week 12. Secondary endpoints will be time-dependent changes in peak V̇O2 from Week 0 to Weeks 12 and 24. Adverse events will also be evaluated. Conclusions: The EXCILE-HF trial will provide meaningful information regarding the effects of ivabradine on exercise tolerance in patients with HFrEF receiving standard drug therapies and suggestions for the initiation of ivabradine treatment.

Comparison of creatinine-based equations for estimating renal function for digoxin dose adjustment in patients with atrial fibrillation and heart failure.

The aim of this study was to determine an appropriate equation for estimating renal function to dose regulate the serum digoxin trough concentration to a target of <0.9 ng/ml in patients with atrial fibrillation (AF) and heart failure (HF). All patients received 0.125 mg oral digoxin daily. The estimated glomerular filtration rate by the Modification of Diet in Renal Disease (eGFRMDRD ) equation deindexed based on body surface area had the highest correlation with digoxin trough concentrations (r = -0.450) compared to the Cockcroft-Gault equation (r = -0.415) or deindexed eGFR based on the Chronic Kidney Disease Epidemiology Collaboration (eGFRCKD-EPI ) equation (r = -0.416). The median digoxin trough concentrations were 0.60, 0.77, 0.97 and 1.30 ng/ml in patients with a deindexed eGFRMDRD ≥ 60, 45-59, 30-44 and < 30 ml/min, respectively. The deindexed eGFRMDRD is an appropriate equation for digoxin dose adjustment in patients with AF and HF.

Depression and cardiovascular diseases.

Depression is a well-known risk factor for adverse cardiovascular outcomes in patients with cardiovascular diseases. The prevalence of depression in patients with cardiovascular diseases has been reported to be approximately 20 %. A two-step depression screening protocol using the 2-item Patient Health Questionnaire (PHQ-2) and the 9-item Patient Health Questionnaire (PHQ-9) is recommended for patients with cardiovascular diseases. Cardiovascular diseases and depression share a common pathology, including increased activity of the sympathetic nervous system, hyperactivity of hypothalamic-pituitary-adrenal axis, and inflammation. Psychosocial and environmental factors are also associated with depression and cardiovascular outcomes. Randomized controlled trials of antidepressant treatment for patients with depression and cardiovascular diseases have shown no advantage regarding cardiovascular outcomes. However, improvement in depressive symptoms, regardless of the method, may lead to a reduction in subsequent cardiovascular events. A collaborative approach between cardiologists and psychiatrists is recommended to manage depression in patients with cardiovascular diseases. Future research should identify more specific targets for treating patients with cardiovascular diseases, involve collaboration with professionals across fields, and establish community support systems.

Implication of modified MELD scores for postdischarge prognosis in hospitalized patients with heart failure.

We evaluated whether modified Model for End-Stage Liver Disease (MELD) scores are useful for predicting the postdischarge prognosis in hospitalized patients with heart failure (HF) who are discharged alive. The MELD-XI and MELD-Na scores were calculated at discharge for a total of 1156 patients in the HIJ-HF II study. We also studied 3 groups on the basis of the left ventricular ejection fraction (LVEF): the HFrEF (LVEF < 40%), HFmrEF (LVEF 40-49%) and HFpEF (LVEF ≥ 50%) groups. The primary outcome was all-cause mortality, and the secondary outcome was rehospitalization due to worsening HF. The median MELD-XI and MELD-Na scores were 12 and 14, respectively. After a median follow-up of 19 months, there were significantly higher rates of all-cause mortality in patients with MELD-XI scores ≥ 12 than in those with MELD-XI scores < 12; there were also higher rates of all-cause mortality in patients with MELD-Na scores ≥ 14 than in those with MELD-Na scores < 14 (both log-rank p < 0.001). The cumulative incidence function based on a competing risks model showed a higher rate of rehospitalization due to worsening HF in patients with MELD-XI scores ≥ 12 than in those with MELD-XI scores < 12 and a higher rate of rehospitalization due to worsening HF in those with MELD-Na scores ≥ 14 than in those with MELD-Na scores < 14 (both Gray's test p < 0.001). The adjusted hazard ratios (HRs) of all-cause mortality for patients with MELD-XI scores ≥ 12 and those with MELD-Na scores ≥ 14 were 2.07 [95% confidence interval (CI) 1.25-3.44] and 2.79 [95% CI 1.63-4.79], respectively, in the HFrEF group; however, the HRs were not significant in the HFmrEF or HFpEF groups. Thus, MELD-XI and MELD-Na scores may be useful for predicting prognosis in hospitalized HF patients who are discharged alive, especially for those in the HFrEF group.

Meta-Analysis Comparing Bivalirudin Versus. Unfractionated Heparin in Adult Patients With Extracorporeal Membrane Oxygenation.

Introduction: Unfractionated heparin (UFH) has traditionally been the agent of choice in patients on extracorporeal membrane oxygenation (ECMO). However, direct thrombin inhibitors (DTI) have recently garnered more attention in ECMO because of their advantages over UFH. Given the heterogeneous results of multiple recent published studies, we performed a meta-analysis to describe pooled outcomes between bivalirudin and UFH anticoagulation in patients on ECMO. Methods: Relevant studies were identified from MEDLINE and Google Scholar database searches through April 23, 2022. The primary efficacy outcome was thromboembolism (TE), and secondary efficacy outcomes included all-cause mortality and circuit thrombosis. The primary safety outcome was major bleeding. Results: A total of 6 studies were included in the meta-analysis. Bivalirudin use was associated with significantly lower risk of TE (OR 0.61; 95% CI 0.38-.99; P = .05; I2 = 0%) and circuit thrombosis (OR 0.51; 95% CI .32-.80; P = .004; I2 = 0%) compared with UFH. There was no significant difference in all-cause mortality risk (OR 0.75; 95% CI .52-1.09; P = .13; I2 = 30%) between the bivalirudin and UFH groups. No significant difference in the risk of major bleeding between 2 groups was found (OR 0.67; 95% CI 0.25-1.81; P = .43; I2 = 80%). Conclusion: These data support that bivalirudin is a reasonable alternative to UFH in patients on ECMO. Randomized controlled trials are needed to confirm bivalirudin's efficacy and safety results compared with UFH.

Effects of a Pharmacist-Led Educational Interventional Program on Electronic Monitoring-assessed Adherence to Direct Oral Anticoagulants: A Randomized, Controlled Trial in Patients with Nonvalvular Atrial Fibrillation.

PURPOSE: Several landmark trials have reported that direct oral anticoagulants (DOACs) are more effective in preventing stroke and systemic embolism than vitamin K antagonists. However, nonadherence to DOACs worsens prognosis in patients with nonvalvular atrial fibrillation (NVAF) despite the effectiveness of the drugs. The purpose of this study was to evaluate the effects of a pharmacist-led educational interventional program involving motivational interviewing on medication adherence, as assessed by electronic monitoring, in patients receiving DOACs for the treatment of NVAF. METHODS: This prospective, randomized, interventional study was conducted at outpatient cardiology clinics at general hospitals and pharmacies in Japan. Patients with NVAF who were treated with a once-daily DOAC (edoxaban) or a twice-daily DOAC (apixaban) were randomized to receive either: (1) an educational interventional program involving motivational interviewing regarding adherence to anticoagulants; or (2) standard medication counseling. The primary end point was the change in the medication adherence rate, calculated as the number of days that patients appropriately took the drug, as assessed by an electronic monitoring device, divided by the total number of days that the drug was prescribed, from a 12-week observation period to a 12-week intervention period. The secondary end points were tolerability outcomes. The effect of the educational interventional program on the primary end point was analyzed in subgroups stratified by gender and type of DOAC received. FINDINGS: A total of 268 patients completed the observation period and were randomly assigned to one of the two study groups. The difference in the primary end point between the educational interventional program group and the standard medication counseling group was not significant (mean [SD], 2.9% [7.5%] vs 3.4% [8.3%]). On multiple linear regression analysis, the difference in DOAC adherence between the two groups was not significant, but that adherence to apixaban was significantly improved among men in the educational interventional program (ß = 0.219; P = 0.012). Two patients died of causes considered unrelated to treatment; no stroke/systemic embolism or major bleeding events were observed. IMPLICATIONS: In this randomized, controlled study of the effects of a pharmacist-led educational interventional program using motivational interviewing on adherence to DOACs among patients with NVAF, adherence to DOACs, as assessed using an electronic monitoring device, was not improved with the educational interventional program compared to standard medication counseling . However, adherence to twice-daily apixaban was improved among men, but not among women, in the educational interventional program group. In this study, the selection of DOACs was not randomized, and the lack of assessment of the association between adherence to DOACs and clinical outcomes was a limitation. Japan Registry of Clinical Trials (jRCT) indentifier: jRCTs031180142.

Prognostic Impact of Landiolol in Patients with Acute Heart Failure and Atrial Fibrillation with Rapid Ventricular Rates: A Pilot Observational Study.

INTRODUCTION: Guidelines recommend ventricular rate control to <130 bpm during atrial fibrillation (AF) in patients with acute decompensated heart failure (ADHF) to avoid aggravating deteriorations in cardiac outputs. We aimed to evaluate the prognostic impact of landiolol in patients with ADHF and AF. METHODS: This observational study included 60 patients who were urgently hospitalized with ADHF and presented with AF and a heart rate (HR) ≥130 bpm at admission. The patients were assigned to the landiolol group (n = 37) or the reference group (n = 23) based on their intravenous landiolol use within 24 h after admission. The primary endpoint was death from any cause. RESULTS: The groups' baseline characteristics were similar. A significant HR reduction occurred in the landiolol group at 2 h after admission. Compared with the reference group, the HR was significantly lower (111.6 vs. 97.9 bpm, p = 0.02) and the absolute HR reduction was greater (-32.2 vs. -50.0 bpm, p = 0.006) in the landiolol group at 48 h after admission. The landiolol group's mortality rate was significantly lower than that in the reference group (log-rank test, p = 0.032). landiolol use within 24 h after admission was independently associated with lower all-cause mortality (adjusted hazard ratio: 0.15, 95% confidence interval: 0.02-0.92). CONCLUSION: Patients with ADHF and AF who received landiolol for rate control during the acute phase had better prognoses than those who did not receive landiolol.

Drug-Induced QT Prolongation and Torsade de Pointes in Spontaneous Adverse Event Reporting: A Retrospective Analysis Using the Japanese Adverse Drug Event Report Database (2004-2021).

BACKGROUND: Drugs with new mechanisms of action are continually being developed, but it is difficult to capture whether a drug induces QT prolongation/torsade de pointes (TdP) in preclinical and preapproval clinical trials. OBJECTIVE: To evaluate drugs associated with drug-induced QT prolongation/TdP using a real-world database in Japan. PATIENTS AND METHODS: A search was performed in the Japanese Adverse Drug Event Report (JADER) database for QT prolongation and TdP. The reporting odds ratio (ROR) was calculated to identify potential drug-induced QT prolongation/TdP association. RESULTS: Among the reported 4,326,484 data entries, 3410 patients exhibited QT prolongation/TdP (2707 with QT prolongation, 703 with TdP) with the suspected drugs. Of these patients, 53.9% were females. The highest occurrence was in the 70- to 79-year-old age group (24.7%). The most common types of drugs involved were cardiovascular drugs, central nervous system (CNS) drugs, anticancer drugs, and anti-infective drugs; the rate of overdose was reportedly very low at 1.6%. The highest adjusted RORs were observed for nifekalant (351.41, 95% confidence interval (CI) 235.85-523.59), followed by vandetanib (182.55, 95% CI 108.11-308.24), evocalcet (181.59, 95% CI 132.96-248.01), bepridil (160.37, 95% CI 138.17-186.13), diarsenic trioxide (79.43, 95% CI 63.98-98.62), and guanfacine (78.29, 95% CI 58.51-104.74). Among the drugs launched in Japan during the last decade, vandetanib had the highest adjusted RORs. CONCLUSIONS: This study using the JADER database showed that antiarrhythmic drugs, calcium-sensing receptor agonists, small-molecule targeted anticancer drugs, and CNS drugs are associated with QT prolongation/TdP. Further pharmacoepidemiological studies, such as cohort studies using large databases, are needed to prove these causal relationships.

Impact of signal-averaged electrocardiography findings on appropriate shocks in prophylactic implantable cardioverter defibrillator patients with nonischemic systolic heart failure.

BACKGROUND: Appropriate shock therapy is associated with subsequent all-cause death in heart failure (HF) patients who receive an implantable cardioverter defibrillator (ICD) for the primary prevention of sudden cardiac death. To evaluate the impact of signal-averaged electrocardiography (SAECG) findings on appropriate shocks in prophylactic ICD patients with nonischemic systolic HF. METHODS: We studied 86 patients with nonischemic HF and a left ventricular ejection fraction ≤ 35% who underwent new ICD implantation for the primary prevention of sudden cardiac death. We excluded patients who had a previously implanted permanent pacemaker and patients who received cardiac resynchronization therapy with an ICD. SAECG was performed before implantation. Abnormal SAECG findings were defined if 2 of the following 3 conditions were identified: filtered QRS duration (fQRS) ≥ 114 ms, root-mean-square voltage during the last 40 ms of the fQRS (RMS 40) < 20 µV, and duration of the low-amplitude potentials < 40 µV (LAS 40) > 38 ms; additionally, patients with a QRS complex ≥ 120 ms who met both the RMS 40 and LAS 40 criteria were also considered to have abnormal SAECG findings. The primary outcome was the first occurrence of appropriate shock after implantation of the ICD. The secondary outcomes were the first occurrence of inappropriate shock and all-cause mortality. RESULTS: Forty-two patients met the criteria for abnormal SAECG findings (49%). During a median follow-up period of 61 months, 17 patients (20%) died, 24 (28%) received appropriate shock therapy, and 19 (22%) received inappropriate shock therapy. There was a significantly higher incidence of appropriate shocks in patients with abnormal SAECG findings than in those with normal SAECG findings (log-rank test, p = 0.025). Multivariate analysis revealed that abnormal SAECG findings were independently associated with the occurrence of appropriate shock (hazard ratio 2.67, 95% confidential interval 1.14-6.26). However, abnormal SAECG findings were not related to inappropriate shock. There was no difference in the incidence of all-cause death between patients with abnormal and normal SAECG findings. CONCLUSIONS: Our results suggest that abnormal SAECG findings are associated with a high probability of appropriate shocks in prophylactic ICD patients with nonischemic systolic HF.

Benefits and safety of landiolol for rapid rate control in patients with atrial tachyarrhythmias and acute decompensated heart failure.

Atrial tachyarrhythmias often occur in patients with worsening heart failure (HF), and the development of atrial tachyarrhythmias in acute decompensated HF (ADHF) causes an uncontrolled heart rate (HR) and leads to further exacerbation of HF and persistence of a decompensated HF state. Landiolol, a short-acting intravenous beta-1 blocker, shows very high cardiac beta-1 selectivity and has a very short elimination half-life of approximately 4 min. As shown in several reports, the benefit of intravenous landiolol is that it lowers the ventricular rate early after the start of use without markedly deteriorating haemodynamics. After the cardiac status is stabilized by rapid control of HR, subsequent basic HF pharmacotherapy and rhythm control therapies will be effective for improving outcomes. Because of the pharmacokinetic properties of landiolol, if the patient suffers an adverse reaction such as hypotension or bradycardia, such effects can be quickly reversed by tapering the dose or discontinuing use altogether. Based on several clinical studies, this review discusses the efficacy, safety and role of intravenous landiolol in acute HR control in patients with atrial tachyarrhythmias and ADHF.

Population pharmacokinetic analysis and dosage recommendations for digoxin in Japanese patients with atrial fibrillation and heart failure using real-world data.

BACKGROUND: Digoxin is an important treatment option for reducing the ventricular rate in patients with atrial fibrillation (AF) and heart failure (HF). Digoxin has a narrow therapeutic window and large interindividual variability. A low target blood concentration, especially ≤0.9 ng/mL, is recommended for patients with HF who are taking digoxin. This study aimed to develop a population pharmacokinetic model and to identify clinical factors that affect digoxin exposure and an optimal digoxin dosing regimen in Japanese patients with AF and HF. METHODS: A population pharmacokinetic analysis was performed by using a nonlinear mixed effects model based on 3465 concentration points from 391 patients (>18 years) who were receiving oral digoxin. Using trough serum digoxin concentrations and clinical data, a population pharmacokinetic model was developed for determining covariates of clearance. A 1-compartment model was used to examine the interindividual variability of the oral clearance (CL/F) of digoxin. An appropriate dosage of digoxin was identified using Monte Carlo simulation. RESULTS: The final model demonstrated that creatinine clearance (CLCR) and the use of amiodarone were factors that contributed to the CL/F of digoxin. Monte Carlo simulation results showed that with a daily maintenance dose of 0.25 mg, the intoxication risk window of a trough serum concentration of ≥0.9 ng/mL could be reached in more than half of patients regardless of renal function category or concurrent use of amiodarone. The appropriate maintenance dosage was 0.125 mg daily for most Japanese patients with AF and HF. However, with a daily dose of 0.125 mg, a trough serum concentration of ≥0.9 ng/mL could be reached in more than half of patients with renal impairments (CLCR 30 mL/min) or concurrent use of amiodarone. A daily maintenance dose of 0.0625 mg was acceptable for these patients. CONCLUSIONS: CLCR and the use of amiodaron were found to contribute to digoxin clearance using a population pharmacokinetic methodology. For Japanese patients with AF and HF, 0.125 mg is an appropriate daily digoxin maintenance dose, but a dose reduction is required for patients with CLCR <30 mL/min or concurrent amiodarone use.

Adverse Drug Reactions in Japanese Patients with End-Stage Heart Failure Receiving Continuous Morphine Infusion: A Single-Center Retrospective Cohort Study.

BACKGROUND: Opioids have been reported to be effective for refractory dyspnea in patients with advanced heart failure (HF) in the palliative care setting. OBJECTIVE: The aim of this study was to evaluate the incidence of adverse drug reactions (ADRs) and their relationship with morphine dose/duration or renal insufficiency in patients with end-stage HF receiving continuous morphine infusion. METHODS: We retrospectively studied 38 patients with end-stage HF receiving continuous intravenous or subcutaneous morphine infusion for the relief of breathlessness between 2014 and 2019 (mean age 78 years). The endpoints were nausea/vomiting, respiratory depression, and drowsiness, which are common morphine-related ADRs. RESULTS: Of 38 patients with end-stage HF receiving continuous intravenous/subcutaneous morphine infusion, 14 (37%) experienced ADRs. The median estimated glomerular filtration rate (eGFR) was lower in patients with than in those without ADRs (16 [range 9-48] vs. 41 [range 8-133], respectively; p = 0.011). The ADRs with the highest incidence were drowsiness (n = 13), nausea/vomiting (n =5), and respiratory depression (n =3). There were no differences in the maintenance dose or duration of morphine administration between patients with and without ADRs. A baseline eGFR of 32 mL/min/1.73 m2 was a good cutoff value for ADR prediction (sensitivity 86%, specificity 96%). A baseline eGFR < 32 mL/min/1.73 m2 was significantly associated with the occurrence of morphine-related ADRs (odds ratio 6.63, 95% confidence interval 1.19-37.01). CONCLUSIONS: Our results showed that 37% of patients with end-stage HF receiving continuous intravenous/subcutaneous morphine infusion experienced ADRs, especially drowsiness. Patients with eGFR < 32 mL/min/1.73 m2 were likely to experience morphine-related ADRs.