An observational post-authorization safety study (PASS) of naloxegol drug utilization in four European countries.

PURPOSE: Naloxegol has been shown to be an efficient alternative to treat opioid-induced constipation (OIC). This study aimed at describing the characteristics of naloxegol users and assessing patterns of naloxegol use and associated factors. METHODS: This drug utilization cohort study used observational registry data on patients newly prescribed naloxegol in four European countries. Patient characteristics and patterns of naloxegol use and associated factors were described. RESULTS: A total of 17 254 naloxegol users were identified across the countries. Their median age was 56-71 years, and each country had a majority of women (ranging 57.5%-62.9%). Multiple comorbidities, including cancer, were common. Natural opium alkaloids and osmotically acting laxatives (excluding saline) were the most frequently used opioids and laxatives. Overall prior use of opioids ranged from 91.9% to 99.6% and overall prior use of laxatives ranged from 69.9% to 92.4%. Up to 77.7% had prior use of medications with interaction potential, and up to 44.5% used them concurrently with naloxegol. Naloxegol was discontinued by 55.1%-90.9% of users, typically during the first 30 days. Approximately 10%-30% switched to or augmented the treatment with another constipation medication or restarted naloxegol after discontinuation. Augmentation with another constipation medication was relatively common, suggesting that naloxegol was used for multifactorial constipation. CONCLUSION: The present study reflects real-world clinical use of naloxegol, including in vulnerable patient groups. Some naloxegol users lacked laxative or regular opioid use within six months before index date or used naloxegol concomitantly with medications presenting an interaction potential.

A Review of the Cardiovascular Safety of Prucalopride in Patients With Chronic Idiopathic Constipation.

Prokinetic agents, specifically 5-hydroxytryptamine type 4 (5-HT 4 ) receptor agonists, have been shown to provide relief in chronic idiopathic constipation (CIC). The first-generation 5-HT 4 agonists were initially withdrawn from use owing to associations with serious cardiovascular (CV) events. This review summarizes CV safety data for prucalopride, a high-affinity 5-HT 4 agonist approved in the United States in 2018 for adults with CIC. No significant effects of prucalopride on CV safety were observed in animal models or early-phase clinical studies, including a thorough QT study at therapeutic (2 mg) or supratherapeutic (10 mg) doses. Among 1,750 patients with CIC who received prucalopride (2-4 mg) in 5 phase 3 studies, no trends in CV adverse events, electrocardiogram parameters, or blood pressure were documented; ≤1.0%-2.0% of patients had prolonged QT interval corrected for heart rate (HR) using Fridericia formula after placebo or prucalopride treatment, and low HR occurred in ≤6.1% and ≤3.3% of these patients, respectively. In two 24-month observational studies among 2,468 patients, changes in electrocardiogram parameters over time were minor, except at occasional time points when significant changes from baseline were reported for HR or QT interval. In a real-world European CV safety study among 35,087 patients (prucalopride, 5,715; polyethylene glycol 3350 [PEG3350], 29,372), results were consistent for no evidence of increased risk of major adverse CV events among patients treated with prucalopride vs PEG3350 (incidence rate ratio = 0.64; 95% confidence interval 0.36-1.14). Studies to date have not raised concerns regarding the impact of prucalopride treatment on CV parameters.

Efficacy and safety analysis of prucalopride in refractory chronic constipation cases in a tertiary care hospital in Eastern India: A randomized, single-blind, placebo-controlled study.

OBJECTIVES: Chronic constipation (CC), a common functional gastrointestinal disorder, has laxatives as its mainstay of treatment. Refractoriness to laxatives calls for better treatment options. Prucalopride is a novel, well-tolerated enterokinetic with high 5-hydroxytryptamine 4 receptor selectivity. This study was undertaken with the intention to establish the efficacy and safety of prucalopride with placebo in adults with refractory CC. MATERIALS AND METHODS: Patients were screened and 180 patients fulfilling the inclusion criteria were simply randomized into 2 groups either to receive prucalopride 2 mg (n = 90) or placebo (n = 90) once daily for a duration of 12 weeks. The efficacy endpoints (primary) were intended to measure the proportion of patients with three or more spontaneous complete bowel movements (SCBMs) per week over 12 weeks. Secondary endpoints were assessed via the validated questionnaires. Adverse events, electrocardiogram, and other laboratory parameters were monitored at different time intervals. RESULTS: Efficacy and safety were analyzed in 180 patients simply randomized (1:1) into group A (prucalopride arm, n = 90) and group B (placebo arm, n = 90). Patients having three or more SCBMs per week in the prucalopride arm (2 mg) were 41% as against to 12% in the placebo arm (P < 0.001). A significant increase (P < 0.001) in the number of spontaneous bowel movements per week plus an increase of average bowel movement by 1 point per week was seen in the prucalopride arm. Secondary efficacy endpoints which included patients' treatment satisfaction, improvement in the perception of constipation symptoms using the patient assessment of constipation -symptoms and stool consistency score changes were more pronounced in the prucalopride arm than the placebo. The most common adverse events reported from both the groups were headache, nausea, bloating, and diarrhea. No significant cardiovascular changes or laboratory abnormality was detected throughout the study period. CONCLUSION: Prucalopride is effective in laxative refractory CC cases with a good safety profile.

Relation between laxative use and risk of major bleeding in patients with atrial fibrillation and heart failure.

Constipation has been reported to increase the risk of cardiovascular mortality. Patients with atrial fibrillation (AF) and heart failure (HF) have more comorbidities and an increased bleeding risk. However, it remains unclear whether constipation is associated with an increased risk of incident bleeding complications in AF with HF. Here, we investigated the association between constipation requiring laxatives and major bleeding in AF and HF. We retrospectively analyzed the medical records of 370 consecutive patients hospitalized for AF and congestive HF. Constipation was defined as regularly taking laxatives or having at least two prescriptions for a ≥ 30-day supply of laxatives. Sixty patients experienced major bleeding events during a median follow-up of 318 days. The most common sites of bleeding were lower gastrointestinal (28%, 17/60), upper gastrointestinal (27%, 16/60), and intracranial (20%, 12/60). There were 33 (55%) patients with constipation in the bleeding group and 107 (35%) in the non-bleeding group (P = 0.004). Multivariate Cox regression analysis adjusted for HAS-BLED score, hemoglobin, and direct oral anticoagulant use showed that constipation (hazard ratio [HR] 1.85, 95% confidence interval [CI] 1.11-3.08; p = 0.019) was a significant risk factor for major bleeding. We found a significant association between constipation requiring laxatives and major bleeding in patients with AF and HF. These findings indicate the need for constipation prevention in these patients to avoid reliance on invasive defecation management, including laxatives.

Association Between Regular Laxative Use and Incident Dementia in UK Biobank Participants.

BACKGROUND AND OBJECTIVES: The use of over-the-counter laxatives is common in the general population. The microbiome-gut-brain axis hypothesis suggests that the use of laxatives could be associated with dementia. We aimed to examine the association between the regular use of laxatives and the incidence of dementia in UK Biobank participants. METHODS: This prospective cohort study was based on UK Biobank participants aged 40-69 years without a history of dementia. Regular use of laxatives was defined as self-reported use in most days of the week for the last 4 weeks at baseline (2006-2010). The outcomes were all-cause dementia, Alzheimer disease (AD), and vascular dementia (VD), identified from linked hospital admissions or death registers (up to 2019). Sociodemographic characteristics, lifestyle factors, medical conditions, family history, and regular medication use were adjusted for in the multivariable Cox regression analyses. RESULTS: Among the 502,229 participants with a mean age of 56.5 (SD 8.1) years at baseline, 273,251 (54.4%) were female, and 18,235 (3.6%) reported regular use of laxatives. Over a mean follow-up of 9.8 years, 218 (1.3%) participants with regular use of laxatives and 1,969 (0.4%) with no regular use developed all-cause dementia. Multivariable analyses showed that regular use of laxatives was associated with increased risk of all-cause dementia (hazard ratio [HR] 1.51; 95% CI 1.30-1.75) and VD (HR 1.65; 95% CI 1.21-2.27), with no significant association observed for AD (HR 1.05; 95% CI 0.79-1.40). The risk of both all-cause dementia and VD increased with the number of regularly used laxative types (p trend 0.001 and 0.04, respectively). Among the participants who clearly reported that they were using just 1 type of laxative (n = 5,800), only those using osmotic laxatives showed a statistically significantly higher risk of all-cause dementia (HR 1.64; 95% CI 1.20-2.24) and VD (HR 1.97; 95% CI 1.04-3.75). These results remained robust in various subgroup and sensitivity analyses. DISCUSSION: Regular use of laxatives was associated with a higher risk of all-cause dementia, particularly in those who used multiple laxative types or osmotic laxative.

Fatal complication caused by laxative suppository agent on pediatric patient with hydrocephalus on ventriculo-peritoneal shunt: a case report.

INTRODUCTION: Laxative suppository agent is oftenly used for patient with constipation due to its effectiveness and rapid onset. However, beside the benefit of the drugs, it could cause several side effects which could lead to life-threatening complication. In this report, we present a rare case of laxative's side effect that leads to fatal complication in pediatric patient with history of hydrocephalus and ventriculo-peritoneal (VP) shunt placement. CASE REPORT: An 11 years old boy admitted with general weakness, low nutrition intake, and constipation for 4 days. Patient had a history of VP shunt surgery at half months old due to congenital hydrocephalus. Abdominal X-ray found colon dilatation and fecal material collection. Laxative suppository agent was given to the patient. An hour after the treatment, patient had an abdominal pain followed by defecation, and 30 min after defecation, patient was unresponsive with irregular breathing followed by cardiac arrest. Code blue was activated and resuscitation was done for about 40 min, and patient did not respond to resuscitation and pronounced dead 2.5 h after drug's administration. DISCUSSION: The pathophysiology of this complication is related with elevated intraabdominal pressure that caused abdominal compartment syndrome (ACS), and this condition could lead to several organ dysfunction such as cardiopulmonary and abdominal organ dysfunction inducing central nervous system impairment through raised intracranial pressure (ICP). Pediatric patient with history of hydrocephalus on VP shunt could have a low brain compliance and very susceptible to fatal complication due to acute raised of ICP. CONCLUSION: Laxative suppository agent on pediatric patient with hydrocephalus on VP shunt could lead to fatal complication through ACS and acute elevated ICP pressure. Oral laxative agent should be chosen in constipated patient with neurologic preexisting condition, and patient should be closely monitored if suppository agent is given.

Association between prevalence of laxative use and history of bone fractures and cardiovascular diseases in patients with chronic kidney disease: the Fukuoka Kidney disease Registry (FKR) study.

BACKGROUND: Constipation is a common complication in patients with chronic kidney disease (CKD) and is involved in the pathogenesis of dysbiosis and progression of CKD. However, little is known about its association with disorders of the bone-cardiovascular axis in patients with CKD. METHODS: We performed a cross-sectional analysis of 3878 patients with CKD using the baseline dataset of the Fukuoka Kidney disease Registry study, as a multicenter, prospective cohort study of pre-dialysis CKD patients. The main exposure of interest was constipation defined as use of at least one type of laxative. The main outcomes were the histories of bone fractures and cardiovascular diseases (CVDs) as manifestations of disorders of the bone-cardiovascular axis. RESULTS: The prevalences of laxative use and histories of bone fractures and CVDs increased as kidney function declined. Among the 3878 patients, 532 (13.7%) patients used laxatives, 235 (6.1%) patients had prior bone fractures, and 1001 (25.8%) patients had prior CVDs. Histories of bone fractures and CVDs were significantly more prevalent among laxative users (P < 0.05). Multivariable-adjusted logistic regression analysis revealed that patients with laxatives had a significantly higher odds ratios for histories of bone fractures and CVDs than those without laxatives [adjusted odds ratios (95% confidence intervals) 1.67 (1.20-2.31) and 1.70 (1.30-2.22), respectively, P < 0.05]. CONCLUSIONS: These results suggest that constipation indicated by laxative use is associated with increased prevalences of historical bone fractures and CVDs in pre-dialysis patients with CKD.

Effect of acid suppressant medications on the laxative action of magnesium preparations in patients with opioid-induced constipation: A pharmacovigilance analysis of the FDA Adverse Event Reporting System.

Objective: Magnesium oxide is widely used for treating opioid-induced constipation, a serious analgesic-associated problem. Opioid analgesic users are often prescribed non-steroidal anti-inflammatory drugs, which are sometimes combined with acid suppressants to prevent gastrointestinal adverse events. Magnesium preparations combined with acid suppressants may diminish magnesium preparations' laxative effect. This study was aimed at evaluating the effect of magnesium preparations combined with acid suppressants on the incidence of opioid-induced constipation by using the Food and Drug Administration Adverse Event Reporting System. Methods: Adverse events were defined per the Medical Dictionary for Regulatory Activities; the term 'constipation (preferred term code: 10010774)' was used for analysis. After adjusting for patient background factors using propensity score matching, acid suppressants' effect on constipation incidence was evaluated in opioid users prescribed magnesium preparations alone as laxatives by using a test for independence. Key Findings: The Food and Drug Administration Adverse Event Reporting System contains 14,475,614 reports for January 2004 to December 2021. Significantly increased constipation incidence was related to magnesium preparations combined with acid suppressants, especially proton pump inhibitors (P < 0.0001, McNemar's test). Conclusion: Magnesium preparations combined with acid suppressants may diminish magnesium preparations' laxative effect; healthcare professionals should pay attention to this issue.

Relationship between mental disorders, psychotropic drugs, and constipation in psychiatric outpatients.

Constipation has been reported to be more common in patients with mental disorders than in the general population. However, its relationships with psychiatric diagnosis, medication, age, and sex have not been fully identified. A total of 875 patients from the outpatient department were included in the study. As a retrospective observational study, the psychiatric diagnoses and psychotropic medications were examined based on the medical charts. Fecal conditions, including problems with defecation, abdominal pain, sense of incomplete evacuation, use of laxatives, frequency of defecation, and stool characteristics according to the Bristol Scale, were investigated. The study included 368 males and 507 females, with median ages of 48 and 52 years, respectively. The most common psychiatric diagnoses were depressive disorders (33%), followed by anxiety disorders (19%). Females had significantly higher rates of problems with defecation and laxative use than males (P < .001, P < .0001, respectively). The frequency of laxative use increased significantly with age (P < .0001). The multivariate analyses revealed the close relationship between hypnotics and problems of defecation and that between hypnotics, antipsychotics, and laxative use. In psychiatric outpatients, females had significantly higher rates of problems with defecation and laxative use than males. The use of laxatives significantly increased with age. Problems with defecation were significantly more common in patients taking hypnotics and laxative use was significantly more common in patients taking hypnotics and antipsychotics.

Adverse events related to herbal dietary supplements and over-the-counter medications containing laxatives: a 10-year update from the Italian Phytovigilance and Pharmacovigilance systems.

INTRODUCTION: Products containing anthraquinones (AQ) are associated with an increased risk of serious adverse events (AEs). We performed an update of the available evidence retrieved by the spontaneous reports of AE associated with herbal dietary supplement (DS) and over-the-counter medications (OTC-M) used as laxatives. METHODS: Analysis and evaluation of AE reports retrieved from the Italian Phytovigilance and Pharmacovigilance systems was performed from February 2011 to December 2020. RESULTS: Totally 110 AE reports, 24 related to herbal DS and 86 to OTC-M, were analyzed. Most subjects were females. Herbal products analyzed mostly contained AQ derivatives. Most AEs were gastrointestinal (41.6%), central nervous system (18.2%), and dermatological disorders (12.6%). CONCLUSIONS: The number of AE reports recorded in the last 10 years is still relatively low. However, given the seriousness of some AEs, that does not represent a guarantee of safety. This study may contribute to enhance public awareness on the risks associated with misuse or abuse of laxatives.

The orange-III study: the use of preoperative laxatives prior to liver surgery in an enhanced recovery programme, a randomized controlled trial.

BACKGROUND: This study evaluates the effect of preoperative macrogol on gastrointestinal recovery and functional recovery after liver surgery combined with an enhanced recovery programme in a randomized controlled setting. METHODS: Patients were randomized to either 1 sachet of macrogol a day, one week prior to surgery versus no preoperative laxatives. Postoperative management for all patients was within an enhanced recovery programme. The primary outcome was recovery of gastrointestinal function, defined as Time to First Defecation. Secondary outcomes included Time to Functional Recovery. RESULTS: Between August 2012 and September 2016, 82 patients planned for liver resection were included in the study, 39 in the intervention group and 43 in the control group. Median Time to First Defecation was 4.0 days in the intervention group (IQR 2.8-5.0) and 4.0 days in the control group (IQR 2.9-5.0), P = 0.487. Median Time to Functional Recovery was day 6 (IQR 4.0-8.0) in the intervention group and day 5 (IQR 4.0-7.5) in the control group, P = 0.752. No significant differences were seen in complication rate, reinterventions or mortality. CONCLUSION: This randomized controlled trial showed no advantages of 1 sachet of macrogol preoperatively combined with an enhanced recovery programme, for patients undergoing liver surgery.

[Lipid pneumonitis, a serious iatrogenic event with lubricating laxatives]. / La pneumopathie lipidique, un accident iatrogène grave aux laxatifs lubrifiants.

The prescription of lubricating laxatives (paraffin oil) is widespread in geriatrics because of the frequency of constipation. These molecules can cause serious adverse effects such as lipoid pneumonia, especially in subjects with swallowing disorders.

Risk factors for opioid-induced constipation in cancer patients: a single-institution, retrospective analysis.

PURPOSE: To identify risk factors for opioid-induced constipation (OIC). METHODS: This study retrospectively analyzed 175 advanced cancer patients who were receiving pain treatment with opioids and were newly prescribed laxatives for OIC at Seirei Hamamatsu General Hospital between November 2016 and June 2021. For the regression analysis of factors associated with OIC, variables were extracted manually from clinical records. The effect of newly prescribed laxatives for OIC was evaluated as "effective" in cases where the number of spontaneous bowel movements increased at least once in the first 3 days. The OIC was defined based on Rome IV diagnostic criteria. Multivariate logistic regression analysis was performed to identify risk factors for OIC. Optimal cutoff thresholds were determined using receiver operating characteristic analysis. Values of P < 0.05 (two-tailed) were considered significant. RESULTS: Significant factors identified included body mass index (BMI) (odds ratio [OR] = 0.141, 95% confidence interval [CI] = 0.027-0.733; P = 0.020), chemotherapy with taxane within 1 month of evaluation of laxative effect (OR = 0.255, 95% CI = 0.068-0.958; P = 0.043), use of naldemedine (OR = 2.791, 95% CI = 1.220-6.385; P = 0.015), and addition or switching due to insufficient prior laxatives (OR = 0.339, 95% CI = 0.143-0.800; P = 0.014). CONCLUSION: High BMI, chemotherapy including a taxane within 1 month of evaluation of laxative effect, no use of naldemedine, and addition or switching due to insufficient prior laxatives were identified as risk factors for OIC in advanced cancer patients with cancer pain.

Biofeedback, biofeedback plus fiber laxative, and biofeedback plus osmotic laxative regimens to treat constipation in patients with pelvic floor dyssynergia: A randomized controlled trial.

BACKGROUND: Pelvic floor dyssynergia (PFD) is one of the causes of chronic constipation. Laxative-based therapies are not very effective in treating this type of constipation. The therapeutic effectiveness of three therapeutic strategies, including biofeedback (BOF) alone, BOF+ fiber laxative (psyllium), and BOF +osmotic laxative (polyethylene glycol; [PEG]), was assessed in patients with constipation secondary to PFD. METHODS: Eighty-eight patients with constipation were included during a period from 2017 to 2018. Thirty-two patients were treated with BOF alone, 25 patients received BOF+ fiber laxative (psyllium), and 31 patients received BOF+ osmotic laxative (PEG) for 2 to 3 months. A checklist was used to compare outcomes before and after the interventions. RESULTS: Satisfaction rates from the treatments were 60.83%, 46.88%, and 41.32% in the BOF, BOF + psyllium, and BOF + PEG groups, respectively. Women had a higher satisfaction rate compared to men. Defecation quality improved, and the frequency of enema usage decreased (p <0.05) in all the groups after intervention. Difficulty in evacuation, need for digitation, and return to the toilet after defecation significantly improved in the BOF alone group. Using laxatives reduced straining during evacuation and increased the duration of defecation. All the three regimens reduced rectal bleeding (p <0.05). CONCLUSIONS: Combinations of laxatives with BOF did not offer significant therapeutic benefit. As laxatives may cause dissatisfaction and incomplete/prolonged defecations in patients with PFD, adding laxatives to the BOF regimen is not recommended for these patients.

Opioid-Related Constipation.

Opioid-related constipation encompasses constipation directly caused by opioid use (opioid-induced constipation [OIC]) as well as pre-existing constipation worsened by opioid use (opioid-exacerbated constipation [OEC]). Over-the-counter laxatives should be used as first-line agents for both OIC and OEC, given their efficacy, low cost, and high safety profiles. Symptoms of OIC and responses to therapy can be assessed with the Bowel Function Index. Individuals with OIC refractory to laxatives may be responsive to peripherally acting µ-opioid receptor antagonists. Although data supporting the superiority of one prescription agent over another is lacking, all have proven effective for the treatment of OIC.