Opioid-induced Constipation Research Articles

Real-World Evidence for the Safety and Effectiveness of Naldemedine in the Management of Opioid-Induced Constipation in Patients With Cancer Pain: Post-hoc Subgroup Analysis of Post-marketing Surveillance in Japan.

Opioid-induced constipation is common and greatly affects the quality of life but is often under-recognised and undertreated. This study aimed to investigate the safety and effectiveness of naldemedine for opioid-induced constipation with cancer pain according to specific subgroups of clinical interest. In this exploratory post-hoc subgroup analysis of post-marketing surveillance from Japan (UMIN: 000042851), data were investigated by the subgroups: age (≥75, <75 years), Eastern Cooperative Oncology Group performance status (PS 0-2, 3-4), constipation severity (mild, moderate, severe), brain metastasis (yes, no), anticancer drug treatment (yes, no), opioid at naldemedine initiation (fentanyl only, only strong opioids other than fentanyl, weak opioids only, other), and prior or concomitant use of laxative (only osmotic/saline laxatives, only stimulant laxatives, other, none). Enrolled patients (n = 1184) received naldemedine (0.2 mg once daily) orally for up to 12 weeks. Regarding safety endpoints, the incidence of adverse drug reactions, including diarrhoea, was determined within each subgroup. Regarding effectiveness endpoints, improvement rates in the frequency and condition of bowel movements were investigated by subgroups. The incidence of adverse drug reactions, including diarrhoea, among subgroups ranged from 7.74% to 16.08% (diarrhoea: 5.95% to 13.19%), compared to 11.30% (diarrhoea: 9.09%) in the total population. Through week two to week 12, improvement rates in the frequency and condition of bowel movement among subgroups ranged from 63.6% to 89.7% and 67.6% to 94.9%, compared to 75.0% to 83.2% and 80.0% to 88.0% in the total population, respectively. Naldemedine was well tolerated and effective in patients with opioid-induced constipation and cancer pain regardless of the subgroups investigated.

Management of Constipation in Hospitalized Patients.

Constipation is frequently encountered in hospital settings and can have potentially serious consequences yet is often underrecognized and undertreated. Opioid-induced constipation is a common cause of constipation in hospitalized patients. Opioids induce constipation through agonistic effects on enteric µ-opioid receptors. This review aims to provide insight on the identification and management of constipation in inpatient settings, with a particular focus on opioid-induced constipation. Constipation assessment should be routinely initiated at hospital admission and can be facilitated by thorough symptom assessments; relevant patient history, including recent medication use; physical examination; and patient assessment tools developed to evaluate the impact of constipation. Management of opioid-induced constipation should begin with ensuring adequate hydration and electrolyte balance and encouraging patient mobilization. Other treatments may include laxatives, enemas, intestinal secretagogues, peripherally acting µ-opioid receptor antagonists, and manual disimpaction. Surgical intervention may be required for some patients as a salvage therapy in severe, refractory cases.

Iatrogenic Side Effects of Pain Therapies.

Pain regimens, particularly for chronic cancer and noncancer pain, must balance the important analgesic benefits against potential risks. Many effective and frequently used pain control regimens are associated with iatrogenic adverse events. Interventional procedures can be associated with nerve injuries, vascular injuries, trauma to the spinal cord, and epidural abscesses. Although rare, these adverse events are potentially catastrophic. Pharmacologic remedies for pain must also consider potential side effects that can occur even at therapeutic doses of over-the-counter remedies such as paracetamol (acetaminophen) or nonsteroidal anti-inflammatory drugs. Opioids are effective pain relievers but are associated with many side effects, some of which can be treatment limiting. A prevalent and distressing side effect of opioid therapy is constipation. Opioid-induced constipation is caused by binding to opioid receptors in the gastrointestinal system, making conventional laxatives ineffective. Peripherally acting mu-opioid receptor antagonists are a new drug class that offers the benefits of preserving opioid analgesia without side effects in the gastrointestinal system. An important safety concern, particularly among geriatric patients is the increasingly prevalent condition of polypharmacy. Many senior patients take five or more medications, including some that may be contraindicated in geriatric patients, duplicative of other drugs, have potential pharmacokinetic drug-drug interactions, or may not be the optimal choice for the patient's age and condition. Careful assessment of medications in the elderly, including possibly deprescribing with tapering of certain drugs, may be warranted but should be done systematically and under clinical supervision.

New insight on the enteric cholinergic innervation of the pig colon by central and peripheral nervous systems: reduction by repeated loperamide administration.

The central and peripheral nervous systems provide cholinergic innervation in the colon. The ability to assess their neuroanatomical distinctions is still a challenge. The pig is regarded as a relevant translational model due to the close similarity of its enteric nervous system (ENS) with that of human. Opioid-induced constipation is one of the most common side effects of opioid therapy. We developed an approach to differentiate the central and peripheral cholinergic innervation of the pig colon using double immunolabeling with a novel mouse anti-human peripheral type of choline acetyltransferase (hpChAT) antibody combined with a rabbit anti-common type of ChAT (cChAT) antibody, a reliable marker of cholinergic neurons in the central nervous system. We examined their spatial configurations in 3D images of the ENS generated from CLARITY-cleared colonic segments. The density was quantitated computationally using Imaris 9.7. We assessed changes in the distal colon induced by daily oral treatment for 4 weeks with the μ opioid receptor agonist, loperamide (0.4 or 3 mg/kg). The double labeling showed strong cChAT immunoreactive (ir) fibers in the cervical vagus nerve and neuronal somata and fibers in the ventral horn of the sacral (S2) cord while hpChAT immunoreactivity was visualized only in the ENS but not in the vagus or sacral neural structures indicating the selectivity of these two antibodies. In the colonic myenteric plexus, dense hpChAT-ir neurons and fibers and varicose cChAT-ir fibers surrounding hpChAT-ir neurons were simultaneously visualized in 3D. The density of cChAT-ir varicose fibers in the outer submucosal plexus of both males and females were higher in the transverse and distal colon than in the proximal colon and in the myenteric plexus compared to the outer submucosal plexus and there was no cChAT innervation in the inner submucosal plexus. The density of hpChAT in the ENS showed no segmental or plexus differences in both sexes. Loperamide at the highest dose significantly decreased the density hpChAT-ir fibers + somata in the myenteric plexus of the distal colon. These data showed the distinct density of central cholinergic innervation between myenteric and submucosal plexuses among colonic segments and the localization of cChAT-ir fibers around peripheral hpChAT neurons in 3D. The reduction of cholinergic myenteric innervation by chronic opiate treatment points to target altered prokinetic cholinergic pathway to counteract opiate constipation.

Efficacy and Safety of Naloxegol in Patients with Chronic Non-Cancer Pain Who Experience Opioid-Induced Constipation: A Pooled Analysis of Two Global, Randomized Controlled Studies.

This study evaluates the onset, magnitude, and consistency of improvement of opioid-induced constipation (OIC) symptoms with naloxegol treatment. This was a pooled analysis of two Phase 3, double-blind, randomized, placebo-controlled studies (KODIAC-04/05, NCT01309841/NCT01323790) in patients with chronic non-cancer pain and OIC treated with naloxegol 25mg or 12.5mg daily. This analysis assessed improvements in response rates, frequency of spontaneous bowel movement (SBM) and complete SBMs (CSBM), OIC constipation symptoms (straining, stool consistency), time to first post-dose SBM and CSBM, and onset of adverse events over the 12-week period. The population of 1337 subjects had a mean age of 52 years and mean duration of opioid use of 3.6 years at baseline. Mean SBM frequency was 1.4/week. Naloxegol 25mg and 12.5mg demonstrated significantly higher response rates vs placebo (PBO) [41.9% (P < 0.001), 37.8% (P = 0.008), 29.4% respectively]. Rapid (within 1 week) and sustained (over 12 weeks) symptom improvement was significantly greater for naloxegol vs PBO (P < 0.05). Both doses showed statistically significant and clinically meaningful improvements in straining, stool consistency, number of SBMs and CSBMs/wk. Significantly shorter times to first post-dose SBM and CSBM were observed with naloxegol vs PBO (SBM HR: 25mg = 1.90, 12.5mg= 1.60; CSBM HR: 25mg = 1.42, 12.5mg = 1.36; P < 0.001 for each regimen). Adverse events occurred more frequently in the naloxegol 25mg group and were most frequently reported during the first week. In patients with chronic non-cancer pain, naloxegol 25mg and 12.5mg demonstrated significantly higher response rates and rapid and sustained improvements in OIC symptoms compared with PBO.

Overcoming barriers to opioid-induced constipation management in cancer patients

Opioid-induced constipation (OIC) is a common adverse effect of opioid therapy. We aim to identify the main barriers hindering clinical recommendations implementation and propose consensus solutions to improve OIC control in cancer patients. Following collaborative and prioritization techniques, a scientific committee generated statements addressing possible barriers to optimal OIC management (related to patients, health providers and health care system), and potential interventions to overcome these barriers. An expert panel of 36 oncologists assessed the statements to reach a consensus. The survey consisted of 70 statements. Consensus was reached on 12/45 items related to barriers (26.6%) and on 19/25 items about corrective interventions (76%). The panel considered that patients are unaware of the existence of a specific OIC treatment, and their information sources are highly variable and unreliable. Regarding health providers, the panel considered that the oncologists prioritize symptoms such as diarrhea, pain, anxiety, or other treatment toxicities, over constipation. Work overload and bureaucratic requirements were the main barriers related to health care system. Regarding potential interventions, best-rated proposals included specific training programs development for primary care physicians and nurses, and multiplatform informative resources development for patients and caregivers, including precisely written instructions about OIC recognition and management. Oncologists assessed positively measures aiming to improve coordination between primary care physicians and oncologists, and nursing consultations implementation. The panel considered useful the OIC treatment algorithms simplification. The expert panel identified the main barriers to optimal OIC management and suggested some feasible approaches to overcome these barriers.

PEG-4000 Ameliorates morphine-induced constipation in mice through inhibition of AQP-3 mRNA Expression

Morphine is μ-opioid receptor (MOR) agonist that is used clinically for patients suffering from moderate to severe pain. Morphine can cause constipation due to activation of μ-opioid receptors in the central nervous system and the nervous system in the gastrointestinal tract. It is caused by increasing the expression of AQP-3 in the instestine through increased of serotonin by enterochromaffin cells. PEG 4000 is one of the osmotic laxatives used to treat Opioid Induced Constipation (OIC). PEG 4000 affects the upregulation of serotonin re-uptake which can lead to expression enhancement of AQP-3. The purpose of this study was to analyze the effect of PEG 4000 on expression changes of aquaporin-3 in mice colon induced acute constipation with morphine.Constipation conditions and the effectiveness of laxative therapy are indicated by constipation parameters in the form of fecal water content and stool weight. This study used 36 male mice of the Balb/c line genus which were divided into 3 groups, normal saline, morphine, and morphine + PEG 4000. Each group was further divided into 2 subgroups based on the time of observation, namely the first hour and fifth hour after morphine induced. The expression of AQP-3 was observed using Polymerase Chain Reaction (PCR) method. The result of this study showed that the administration of PEG 4000 to mice induced constipation with morfine could decrease the expression of AQP-3 from (146,413±1,736) to (118,411±3,476) with p value &lt;0,05, increase the percentage of fecal water content from (0,000±0,000%) to (28,903±12,930%) with p value &lt;0,05 and increase the stool weight from (0,000±0,000g) to (0,928±0,178g) with p value &lt;0,01 From these results, it can be concluded that the administration of PEG 4000 in morphine induced constipation to mice was effective in reducing AQP-3 expression as well as increasing the percentage of fecal water content and stool weight.

Attrition of methylnaltrexone treatment-emergent adverse events in patients with chronic noncancer pain and opioid-induced constipation: a post hoc pooled analysis of two clinical trials.

Background: Opioids prescribed for the management of chronic noncancer pain are associated with nausea, vomiting, and constipation. Methylnaltrexone, a peripherally acting µ-opioid receptor antagonist, has demonstrated robust efficacy and was well-tolerated in treating opioid-induced constipation without affecting central analgesia. Our objective was to assess changes in the frequency of treatment-emergent adverse events (TEAEs) after the first or second dose of methylnaltrexone or placebo. Methods: This post hoc analysis pooled data from two randomized, placebo-controlled clinical trials assessing methylnaltrexone for opioid-induced constipation in the outpatient setting. Patients received subcutaneous methylnaltrexone (12 mg once daily or 12 mg once every other day), oral methylnaltrexone (150, 300, or 450 mg daily), or placebo. TEAEs, opioid withdrawal symptoms, pain intensity, and rescue-free bowel movements (RFBMs) within 4 hours of the first dose (i.e., RFBM responders) were assessed. Associations between TEAE frequencies and RFBM response were also evaluated. Results: The analysis included 1263 adult patients with chronic noncancer pain. TEAE rates declined from treatment day 1 to 2 (methylnaltrexone: 16.2%-5.3%; placebo: 6.6%-5.4%). Among methylnaltrexone-treated patients, significantly greater proportions of RFBM responders versus nonresponders reported gastrointestinal TEAEs on day 1. No associations between RFBM response and the frequency of TEAEs were observed in the placebo group. No meaningful changes in opioid withdrawal symptoms or pain intensity were observed. Conclusions: Early-onset TEAEs following methylnaltrexone treatment, particularly gastrointestinal TEAEs, are at least partially due to laxation. Methylnaltrexone treatment effectively relieves opioid-induced constipation without affecting the central analgesic effects of opioids.

Evaluating the Safety and Efficacy of Naloxegol in Critically Ill Opioid-Induced Constipation Patients.

Background Opioid-induced constipation (OIC) has become more common in the intensive care unit (ICU) due to increased opioid utilization. Traditional laxatives often prove ineffective against OIC, leading to the increased utilization of naloxegol. However, further research is needed to confirm naloxegol's effectiveness and safety in critical care. This study aimed to explore the safety and efficacy of this intervention in critically ill OIC patients. Methods A single-center retrospective study was conducted on 353 patients who received one or more doses of naloxegol from January 1, 2019, to June 30, 2020, for OIC at a tertiary care center. The primary endpoint of this study was to evaluate serious adverse events such as reduced analgesic effect, gastrointestinal perforation, seizure, acute myocardial infarction (AMI), or ventricular arrhythmias using Naranjo Scale in critically ill patients. The secondary goal was to assess the efficacy of naloxegol, measured by the time of the first bowel movement. Results The average duration of naloxegol use was three days, with the first bowel movement occurring at an average of 11.3 hours. Furthermore, 59.8% of individuals had their first bowel movement within 20 hours of receiving naloxegol. There was a low level of causality between naloxegol use and adverse events such as gastrointestinal perforation, seizures, AMI, cardiovascular mortality, stroke, and ventricular arrhythmia. Additionally, reduction in analgesia showed no strong relationship with naloxegol use indicated by the Naranjo Scale assessment. Conclusion Naloxegol showed promising safety and efficacy profiles in treating OIC amongst critically ill patients, though our findings require further validation through prospective studies. This research paves the way for further investigation into naloxegol's role in OIC management, emphasizing the necessity of personalized treatment strategies in critical care settings.

Efficacy and safety of naldemedine treatment for opioid-induced constipation in gastrointestinal cancer: a retrospective analysis.

Gastrointestinal cancers are one of the most common cancer cases worldwide. Cancer treatment is multidisciplinary, which includes opioid pain management. Opioid analgesics cause opioid-induced constipation (OIC) with the onset of effect. Naldemedine, a peripheral opioid receptor antagonist, is an OIC-modifying agent, but no focused efficacy and safety analysis has been conducted for its use in gastrointestinal cancers. We retrospectively evaluated patients with gastrointestinal cancer treated with naldemedine at ten institutions in Japan from June 2017 to August 2019. Patients with gastrointestinal cancer who initiated treatment with opioids during hospitalization and were treated with naldemedine for the first time were included in the study. The gastrointestinal cancer types included were esophageal, gastric, small bowel, and colorectal cancers. We assessed the defecation frequency before and after the initiation of naldemedine use. Responders were defined as patients who defecated three or more times/week, with an increase from the baseline of one or more bowel movements/week over seven days after starting naldemedine. Thirty-three patients were observed for one week before and after starting naldemedine. Twentyone patients had an increase in defecation frequency of at least three times per week or at least once per week above the baseline. The response rate was 63.6% (95% CI: 46.6-77.9%). The median number of bowel movements for a week before and after the initiation of naldemedine treatment was 3 (range, 0-13) and 7 (range, 1-39), respectively, in the overall population (n=33), with a significant increase in defecation frequency following naldemedine administration (Wilcoxon signed rank test, P<0.005). Diarrhea was the predominant gastrointestinal symptom, with 13 (39.4%) patients experiencing grade 1 and none experiencing grade 3 or grade 4 adverse events. The frequency of other grade 1 adverse events was low abdominal pain in two patients, nausea in two patients, and anorexia in one patient, without any grade 2-4 adverse events. The results of the study suggest that naldemedine is effective and safe in clinical practice for gastrointestinal cancer treatment.

Naldemedine-induced opioid withdrawal with restlessness as the predominant symptom in a palliative care setting.

Opioid analgesics play a central role in cancer pain treatment; however, it has been reported that opioid-induced constipation (OIC) develops in 80% of patients using opioid analgesics and leads to a decrease in quality of life. Naldemedine improves constipation without affecting the analgesic action of opioid analgesics via peripheral μ-opioid receptors. We report a terminally ill cancer patient who was diagnosed with opioid withdrawal syndrome (OWS) based on symptoms centered around restlessness and sweating that developed 43days after administration of naldemedine for OIC. The patient was a 78-year-old woman who was diagnosed with stage IVB uterine sarcoma in October, 1 year prior to her visit to our clinic, and underwent chemotherapy after surgery, but the disease became progressive. Thereafter, metastasis to the fourth thoracic vertebrae (Th4) was identified, and loxoprofen and acetaminophen were started for pain at the metastatic site. Oxycodone hydrochloride hydrate 10mg/day was additionally administered on postoperative day 11, followed by naldemedine 0.2mg/day for OIC. On the 43rd day after administration, the patient began to wander the hospital ward in a wheelchair and became noticeably restless. OWS due to naldemedine administration was suspected, and naldemedine was discontinued. The symptoms improved 7days later, and no similar symptoms were observed thereafter. Patients receiving palliative care often exhibit psychiatric symptoms such as anxiety and depression, but OWS due to naldemedine should also be considered as a potential cause.

PREVALENCE AND BURDEN OF ILLNESS OF ROME IV CHRONIC IDIOPATHIC CONSTIPATION, OPIOID-INDUCED CONSTIPATION, AND OPIOID-EXACERBATED CONSTIPATION IN THE UNITED STATES.

Chronic idiopathic constipation (CIC) and opioid-induced constipation (OIC) are disorders that negatively impact quality of life. We sought to assess the prevalence, symptom severity, and medication use among people with Rome IV CIC, OIC, and opioid-exacerbated constipation (OEC) using a nationally representative dataset with nearly 89,000 people in the US. From May 3 to June 24, 2020, we recruited a representative sample of people in the US ≥18yo to complete an online national health survey. The survey guided participants through the Rome IV CIC and OIC questionnaires, Patient-Reported Outcome Measurement Information System (PROMIS®) gastrointestinal scales (percentile 0-100; higher=more severe), and medication questions. Individuals with OEC were identified by asking those with OIC whether they experienced constipation before starting an opioid and if their symptoms worsened afterwards. Among the 88,607 participants, 5,334 (6.0%) had Rome IV CIC, and 1,548 (1.7%) and 335 (0.4%) had Rome IV OIC and OEC, respectively. When compared to people with CIC (PROMIS® score, 53.9±26.5; reference), those with OIC (62.7±28.0; adjusted p<0.001) and OEC (61.1±25.8, adjusted p=0.048) had more severe constipation symptoms. People with OIC (odds ratio [OR] 2.72, 95% confidence interval [CI] 2.04-3.62) and OEC (OR 3.52, 95% CI 2.22-5.59) were also more likely to be taking a prescription medication for their constipation versus those with CIC. In this nationwide US survey, we found that Rome IV CIC is common (6.0%) while Rome IV OIC (1.7%) and OEC (0.4%) are less prevalent. Individuals with OIC and OEC have a higher burden of illness with respect to symptom severity and prescription constipation medication use.

Regulation of enteric nervous system via sacral nerve stimulation in opioid-induced constipated rats.

Sacral nerve stimulation (SNS) has been employed for treating constipation. However, its mechanisms involving enteric nervous system (ENS) and motility are largely unknown. In this study, we investigated the possible ENS involvement of SNS in treating Loperamide-induced constipation in rats. Experiment-1 was designed to study the effects of acute SNS on whole colon transit time (CTT). In experiment-2, we induced constipation by Loperamide and then applied daily SNS or sham-SNS for 1 week. Choline acetyltransferase (ChAT), nitric oxide synthase (nNOS), and PGP9.5 in colon tissue were examined at the end of the study. Moreover, survival factors such as phosphorylated AKT (p-AKT) and Glial cell-derived neurotrophic factor (GDNF) were measures by immunohistochemistry (IHC) and western blot (WB). (1) SNS with one set of parameters shortened CTT starting at 90 min after phenol red administration (p < 0.05). (2) While Loperamide induced slow transit constipation with a significant reduction in fecal pellet number and feces wet weight, daily SNS for a week resolved constipation. (3) Moreover, SNS was able to shorten whole gut transit time comparing to sham-SNS (p = 0.01). (4) Loperamide reduced the number of PGP9.5 and ChAT positive cells, and downregulated ChAT protein expression and upregulated nNOS protein expression, whereas these detrimental effects were significantly reversed by SNS. (5) Furthermore, SNS increased expressions of both GDNF and p-AKT in colon tissue. (6) Vagal activity was reduced following Loperamide (p < 0.01); yet SNS normalized vagal activity. SNS with appropriate parameters improves opioid-induced constipation and reversed the detrimental effects of Loperamide on enteric neurons possibly via the GDNF-PI3K/Akt pathway.GRAPHICAL ABSTRACT.

A Nationwide Hospital Claims Database Analysis of Real-World Patterns of Laxative Use for Opioid-Induced Constipation in Japanese Patients with Cancer.

Opioid-induced constipation (OIC) is one of the most common side effects in patients with cancer treated with opioid analgesics. The actual use of laxatives for OIC in Japan remains unelucidated. This study aimed to investigate the real-world patterns of laxative use for patients with cancer who newly initiated opioid analgesic therapy. We used a Japanese nationwide hospital claims database (January 2018-December 2019). Patients with cancer newly receiving opioid analgesic therapy were included and classified on the basis of opioid classes (weak or strong) and route of administration (oral or transdermal) at initiation. The patients were divided into two groups on the basis of whether they received early medication (starting laxatives within 3days after initiating opioid analgesic therapy), and patterns of laxative use were analyzed. There were 26,939 eligible patients, with 50.7% of them initiated with strong opioids. The proportion of patients who received early medication was 25.0% for weak opioids and 57.3% for strong opioids. Osmotic laxatives were most frequently used as first-line therapy in the early medication group (oral weak opioids: 12.3%, oral strong opioids: 29.4%, transdermal strong opioids: 12.8%). Stimulant laxatives were frequently used as first-line therapy, to the same extent or more than osmotic laxatives in the non-early medication group (oral weak opioids: 13.7%, oral strong opioids: 7.7%, transdermal strong opioids: 15.1%). Peripherally acting μ-opioid receptor antagonists were the second most frequently used in the early medication group for those on oral strong opioids (9.4%). This study demonstrated for the first time that the patterns of laxative use for OIC in Japanese patients with cancer were different, depending on the opioid types at initiation and the timing of laxative medication.

A porcine model of opioid-induced constipation: colon motility characterization and evidence for intestinal opioid receptor modulation

Background: About 41-81% of non-cancer patients receiving opioid analgesics for chronic pain develop opioid induced constipation (OIC). Response of OIC to currently available first line therapies is inadequate and prescription drugs come with side effects. Knowledge on the specific effects of chronic opioids on gut motility mechanisms involved isincomplete. Goal: Develop OIC model and characterize gut motility and colonic opioid receptor (OR) modulation in a high translational value porcine model. Methods: The influence of loperamide, a preferential m-OR agonist, on colon motility, intestinal transit, fecal water content (FWC) and colonic OR expression was studied in Yucatan pigs (adult, male and female) naïve or fitted with a chronic cecal cannula. Loperamide was given orally at 0.2, 0.4, and 3 mg/kg/day for 15-30 days in regular diet mixed with palatants (bananas, marshmallows or yogurt mixed with honey). Manometry recordings of the proximal (pc) and distal (dc) colon motility were done using Millar pressure probes placed in each region (4-5 probes, sensors 3cms apart) in awake pigs with chronic cecal cannulas (n=3). In the same pigs, we tested the effect of the luminal stimulator VibrabotTM (30 min or 18 h) on colon motility and FWC under control and loperamide-induced constipation (1, 2 or 3 days). VibrabotTM was inserted into the proximal colon through the cecal cannula. Colonic tissues were collected and mOR expression was assessed using RNAscope. Results: Colon contraction frequency analysis shows region-specific differential effects of loperamide with an increased activity in the proximal and reduced activity in the distal colon. At the highest dose, it causes selective suppression of 5 cpm peak frequency while inducing 3 cpm peak. Loperamide (0.4mg/kg/day) reduces FWC (69.5±0.9 vs 75.9±0.9, p&lt;0.001), and VibrabotTM stimulation (18-hours) reverses the loperamide-induced decreased FWC (74.7±3.3 vs 69.5±0.0.9). ORs are expressed differentially in the proximal vs distal colon (3.5±0.5 vs 4.6±0.8 dot/cell). Loperamide (0.4 or 3mg/kg/day, 30 days) induces an upregulation of colonic mOR expression (3.1±0.8 vs 4.4±1.2 &amp; 4.3±0.6 dot/cell,). Conclusions: Loperamide in pigs causes constipation as shown by decreased FWC, differential effects on proximal vs distal colon contraction frequency power, with an overall inhibition of motility, while increasing m OR expression in both proximal and distal colon. Whether the differential expression of m OR in the different regions and layers of the colon contribute to the regional differences in motility needs further studies. Prolonged luminal stimulation of the colon with VibrabotTM reverses loperamide-induced decreased FWC. We established a model of OIC in pigs that has high face and construct validity as it is characterized by decreased FWC and alterations of colonic motility patterns akin to that reported in some chronic constipation patients. Supported by NIH SPARC OT2-OD024899. This is the full abstract presented at the American Physiology Summit 2023 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.

Regional differences of extrinsic and intrinsic cholinergic innervation and alterations by chronic opioid-induced constipation in the porcine colonic enteric nerve system

The colon is richly innervated by extrinsic (ext) and intrinsic (int) cholinergic nerves from central and enteric nervous system (CNS and ENS) modulating colonic motility, secretion and inflammation. However, a challenge lies in our inability to anatomically distinguish such innervation in the colon. The porcine colon is regarded as a useful translational research model due to many similarities with human. The present study developed an approach to differentiate ext- and int-cholinergic innervation of the porcine colon using double immunolabeling with a novel mouse antibody against human peripheral choline acetyltransferase (hpChAT) combined with a rabbit antibody anti-common ChAT (cChAT) respectively. The spatial configuration of ext- and int- cholinergic innervation in the ENS was assessed on 3D images generated from CLARITY-cleared porcine colonic samples. Their densities were computationally quantitated using Imaris 9 within the inner and outer submucosal and myenteric plexuses (ISP, OSP, MP) along the proximal, transverse and distal colonic regions (pC, tC, dC) collected from 18 adult Yucatan minipigs including 6 naïve (3 of each sex), 4 vehicle controls (2 of each sex), 8 treated with loperamide, a μ opioid receptor agonist (LOP, 0.4 or 3 mg/kg/day, po, 4 weeks, 4/group, 2 of each sex). The specificities of cChAT and hpChAT antibodies were confirmed with porcine cervical vagal trunk (CVT), sacral spinal cord (SSC, S2-S4) and colonic ENS. The double labeling showed the strong cChAT immunoreactive (+) fibers in the CVT and neuronal somata and fibers in the SSC, but no hpChAT+ labeling was visualized in these structures. In the colonic MP, the dense hpChAT+ neurons and fibers and varicose cChAT+ fibers were simultaneously visualized. 3D images demonstrated that int- cholinergic neurons (hpChAT+) were closely surrounded by ext- cholinergic varicose fibers and dot like structures (cChAT+), presumably nerve terminals. The density of cChAT+ but not hpChAT+ fibers+somata showed significant differences among three segments (dC&gt;tC&gt;pC) within three enteric plexuses (MP&gt;OSP&gt;ISP) in naïve pigs. Compared to control groups, the high dose LOP induced a 1.3-fold decrease of cChAT+ fiber density in males (p&lt;0.05) and 1.5-fold in females (p&lt;0.05), and 2.2-fold decrease of hpChAT+ fibers+somata density in males (p&lt;0.05) and 3.6-fold in female (p&lt;0.01) with a 1.5-fold greater decrease in females than males (p&lt;0.05) in the MP of the dC. This study demonstrates for the first time the ext- and int- cholinergic innervation, the spatial configuration in 3D structure, regional variations in the porcine colonic ENS and the reduction by chronic opiate use with greater in females than males. These findings provide neuroanatomical evidence of CNS-gut cross-talk via cholinergic innervation of the colon and point to the neuromodulation of this pathway to alleviate functional colonic disorders like chronic opioid-induced constipation. Supported by NIH/SPARC OT2OD024899. This is the full abstract presented at the American Physiology Summit 2023 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.

The national prevalence of disorders of gut brain interaction in the United Kingdom in comparison to their worldwide prevalence: Results from the Rome foundation global epidemiology study.

There are minimal epidemiological data comparing the burden of disorders of gut brain interaction (DGBI) in the UK with other countries. We compared the prevalence of DGBI in the UK with other countries that participated in the Rome Foundation Global Epidemiology Study (RFGES) online. Participants from 26 countries completed the RFGES survey online including the Rome IV diagnostic questionnaire and an in-depth supplemental questionnaire with questions about dietary habits. UK sociodemographic and prevalence data were compared with the other 25 countries pooled together. The proportion of participants with at least one DGBI was lower in UK participants compared with in the other 25 countries (37.6% 95% CI 35.5%-39.7% vs. 41.2%; 95% CI 40.8%-41.6%, p = 0.001). The UK prevalence of 14 of 22 Rome IV DGBI, including irritable bowel syndrome (4.3%) and functional dyspepsia (6.8%), was similar to the other countries. Fecal incontinence, opioid-induced constipation, chronic nausea and vomiting, and cannabinoid hyperemesis (p < 0.05) were more prevalent in the UK. Cyclic vomiting, functional constipation, unspecified functional bowel disorder, and proctalgia fugax (p < 0.05) were more prevalent in the other 25 countries. Diet in the UK population consisted of higher consumption of meat and milk (p < 0.001), and lower consumption of rice, fruit, eggs, tofu, pasta, vegetables/legumes, and fish (p < 0.001). The prevalence and burden of DGBI is consistently high in the UK and in the rest of the world. Opioid prescribing, cultural, dietary, and lifestyle factors may contribute to differences in the prevalence of some DGBI between the UK and other countries.

Naloxegol (Movantik®) Provides Rapid Response and Sustained Improvement of Opioid-Induced Constipation Symptoms in Older Adults

Naloxegol (Movantik®), an oral peripherally acting mu-opioid receptor antagonist (PAMORA) has demonstrated rapid and predictable relief of OIC in patients treated with opioids for chronic non-cancer pain in two phase 3 trials (KODIAC 4/5; NCT01309841/NCT01323790). In subjects ≥65 yrs, naloxegol (25mg, 12.5mg) demonstrated significantly better response rates, clinically relevant early symptom relief, and predictable efficacy compared with PBO. Improvements in SBMs, CSBMs, straining, and stool consistency were rapid and sustained across 12 weeks. Naloxegol is effective and safe in individuals ≥65 yrs with non-cancer pain experiencing OIC.Aim: Naloxegol, an oral peripherally acting mu-opioid receptor antagonist (PAMORA) has demonstrated rapid and predictable relief of opioid-induced constipation (OIC) in patients treated with opioids for chronic non-cancer pain in two phase 3 trials (KODIAC 4/5; NCT01309841/NCT01323790). This analysis evaluates the speed and predictability of response, and the rapid and sustained impact of naloxegol on OIC symptoms in subjects aged ≥65 yrs. Methods: Data were pooled from the KODIAC 4/5 intent-to-treat populations (N=1337). Subjects ≥65 yrs treated once daily with naloxegol 25mg, 12.5mg, or placebo (PBO) were evaluated. Response definition: ≥3 SBM/wk and increase of ≥1 SBM/wk over baseline for ≥9 of 12 weeks, and ≥3 of the final 4 weeks. For each SBM, patients documented complete evacuation (CSBM) (Yes/No), degree of straining (scale 1=not at all, 5=extreme), and stool consistency via the Bristol Stool Scale (1=hard, 7=watery). Results: This analysis evaluated 148 subjects ≥65 yrs (11.1% of the overall population). In these older adults, a significantly higher response rate was achieved with naloxegol (25mg, 50.9%, p=0.037; 12.5mg, 53.3%; p=0.036) vs PBO (32.0%). Corresponding HRs (2.52, p< 0.001; 1.90, p=0.005) indicated significant, ∼two-fold reduction in time to first SBM with naloxegol vs PBO. Time to first CSBM was ∼50% shorter for naloxegol vs PBO for both regimens (Hazard Ratios: 1.66, p=0.019; 1.45, p=0.103). Rapid, statistically significant, and clinically relevant symptom improvement (straining and stool consistency) was generally sustained from weeks 1-12 for naloxegol vs PBO. The most common AEs were GI-related and similar across regimens. Conclusion: In subjects ≥65 yrs, naloxegol (25mg, 12.5mg) demonstrated significantly better response rates, clinically relevant early symptom relief, and predictable efficacy compared with PBO. Improvements in SBMs, CSBMs, straining, and stool consistency were rapid and sustained across 12 weeks. Naloxegol is effective and safe in individuals ≥65 yrs with non-cancer pain experiencing OIC.

Naloxegol (Movantik®) Provides Rapid and Sustained Improvement of Opioid-Induced Constipation Symptoms Irrespective of Opioid Dose

AimNaloxegol (Movantik), an oral peripherally acting mu-opioid receptor antagonist has demonstrated rapid relief of opioid-induced constipation (OIC) in patients with chronic non-cancer pain in two phase 3 trials (KODIAC 4/5; NCT01309841/NCT01323790). This analysis aims to characterize the OIC symptom burden and evaluate the efficacy of naloxegol in treating symptoms of OIC based on daily opioid dosages. This is the first naloxegol analysis based on a lower opioid dose cutoff of 100 MEU/day. MethodsData were pooled from the KODIAC 4/5 intent-to-treat populations (N=1337). Subjects treated with placebo (PBO) and naloxegol (12.5mg, 25mg) QD were evaluated based on opioid dose ranges (lower dose, ≤100mg; higher dose, >100mg MEU/day). OIC symptoms assessed include number of spontaneous bowel movements (SBM/wk), complete evacuation (CSBM), straining (scale 1=not at all, 5=extreme) and stool consistency (Bristol Stool Scale: 1=hard, 7=watery). ResultsBaseline OIC symptom burden (SBM/wk, CSBM/wk, straining, stool consistency) was similar between lower (n=764) and higher (n=567) opioid dose subgroups. Naloxegol (12.5mg, 25mg) provided significant improvement vs PBO in SBMs/wk in the lower and higher opioid dose subgroups; ≤100 MEU (mean SBM/wk: 2.41, 2.91 vs 1.99, respectively; p<0.05) and ˃100 MEU (mean SBM/wk: 2.81, 3.53 vs 2.05, respectively; p< 0.05). A significant improvement in CSBMs/wk vs PBO was demonstrated in the lower dose subgroup for naloxegol 25mg (mean CSBM/wk: 1.48, 1.97 vs 1.38; p=0.54 and p<0.05, respectively) and in the higher dose subgroup for both naloxegol regimens (mean CSBM/wk: 1.90, 2.36 vs 1.20, respectively; p<0.05). In both dose subgroups, rapid symptom improvement in SBM, CSBM and stool consistency were seen within the first week with naloxegol (p<0.05). ConclusionsRegardless of opioid dose, naloxegol (12.5mg, 25mg) provided rapid and sustained improvement of clinically relevant OIC symptoms. These data suggest that all patients should routinely be assessed for OIC, as lower opioid doses often induce constipation.

Efficacy and Safety of Naldemedine Administration for Opioid-Induced Constipation in Cancer Patients with Poor Performance Status.

Background: Constipation is a concern among patients with Eastern Cooperative Oncology Group (ECOG) performance status (PS) of 3 and 4. Objectives: To assess naldemedine's efficacy and safety in cancer patients on opioids with poor PS. Design: Multicenter, retrospective study. Setting/Subjects: Japanese cancer patients with ECOG performance status 3 or 4 who received naldemedine. Measurements: Frequency of defecations before/after naldemedine use. Responders were patients whose defecation frequency increased to ≥3 times/week, from baseline ≥1 defecations/week over seven days after naldemedine administration. Results: Seventy-one patients were analyzed; 66.1% were responders (95% confidence interval: 54.5%-76.1%). Defecation frequency increased significantly after naldemedine in the overall population (6 vs. 2, p < 0.0001) and among those who defecated <3 times/week before naldemedine (4.5 vs. 1, p < 0.0001). Diarrhea (38.0%) of all grades was the most common adverse event; 23 (85.2%) events were classified as Grade 1 or 2. Conclusion: Naldemedine is effective and safe among cancer patients with poor PS.