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Genetic and Non-genetic Factors Associated With Constipation in Cancer Patients Receiving Opioids.

ABSTRACT: To examine whether the inter-individual variation in constipation among patients receiving opioids for cancer pain is associated with genetic or non-genetic factors.Cancer patients receiving opioids were included from 17 centers in 11 European countries. Intensity of constipation was reported by 1,568 patients on a four-point categorical scale. Non-genetic factors were included as covariates in stratified regression analyses on the association between constipation and 75 single-nucleotide polymorphisms (SNPs) within 15 candidate genes related to opioid- or constipation-signaling pathways (HTR3E, HTR4, HTR2A, TPH1, ADRA2A, CHRM3, TACR1, CCKAR, KIT, ARRB2, GHRL, ABCB1, COMT, OPRM1, and OPRD1).The non-genetic factors significantly associated with constipation were type of laxative, mobility and place of care among patients receiving laxatives (N=806), in addition to Karnofsky performance status and presence of metastases among patients not receiving laxatives (N=762) (P<0.01). Age, gender, body mass index, cancer diagnosis, time on opioids, opioid dose, and type of opioid did not contribute to the inter-individual differences in constipation. Five SNPs, rs1800532 in TPH1, rs1799971 in OPRM1, rs4437575 in ABCB1, rs10802789 in CHRM3, and rs2020917 in COMT were associated with constipation (P<0.01). Only rs2020917 in COMT passed the Benjamini-Hochberg criterion for a 10% false discovery rate.Type of laxative, mobility, hospitalization, Karnofsky performance status, presence of metastases, and five SNPs within TPH1, OPRM1, ABCB1, CHRM3, and COMT may contribute to the variability in constipation among cancer patients treated with opioids. Knowledge of these factors may help to develop new therapies and to identify patients needing a more individualized approach to treatment.

SUBMITTER: Laugsand EA

PROVIDER: S-EPMC4816247 | biostudies-literature | 2015

REPOSITORIES: biostudies-literature

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Genetic and Non-genetic Factors Associated With Constipation in Cancer Patients Receiving Opioids.

Laugsand Eivor A EA Skorpen Frank F Kaasa Stein S Sabatowski Rainer R Strasser Florian F Fayers Peter P Klepstad Pål P

Clinical and translational gastroenterology 20150618

<h4>Objectives</h4>To examine whether the inter-individual variation in constipation among patients receiving opioids for cancer pain is associated with genetic or non-genetic factors.<h4>Methods</h4>Cancer patients receiving opioids were included from 17 centers in 11 European countries. Intensity of constipation was reported by 1,568 patients on a four-point categorical scale. Non-genetic factors were included as covariates in stratified regression analyses on the association between constipat ...[more]

PMID: 26087058

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Project description:ImportanceOne of the main aims of research on nonmedical opioid use (NMOU) is to reduce the frequency of NMOU behaviors through interventions such as universal screening, reduced opioid exposure, and more intense follow-up of patients with elevated risk. The absence of data on the frequency of NMOU behavior is the major barrier to conducting research on NMOU.ObjectiveTo determine the overall frequency of and the independent predictors for NMOU behavior.Design, setting, and participantsIn this prognostic study, 3615 patients with cancer were referred to the supportive care center at MD Anderson Cancer Center from March 18, 2016, to June 6, 2018. Patients were eligible for inclusion if they had cancer and were taking opioids for cancer pain for at least 1 week. Patients were excluded if they had no follow-up within 3 months of initial consultation, did not complete the appropriate questionnaire, or did not have scheduled opioid treatments. After exclusion, a total of 1554 consecutive patients were assessed for NMOU behavior using established diagnostic criteria. All patients were assessed using the Edmonton Symptom Assessment Scale, the Screener and Opioid Assessment for Patients with Pain (SOAPP), and the Cut Down, Annoyed, Guilty, Eye Opener-Adapted to Include Drugs (CAGE-AID) survey. Data were analyzed from January 6 to September 25, 2020.ResultsA total of 1554 patients (median [interquartile range (IQR)] age, 61 [IQR, 52-69] years; 816 women [52.5%]; 1124 White patients [72.3%]) were evaluable for the study, and 299 patients (19.2%) had 1 or more NMOU behaviors. The median (IQR) number of NMOU behaviors per patient was 1 (IQR, 1-3). A total of 576 of 745 NMOU behaviors (77%) occurred by the first 2 follow-up visits. The most frequent NMOU behavior was unscheduled clinic visits for inappropriate refills (218 of 745 [29%]). Eighty-eight of 299 patients (29.4%) scored 7 or higher on SOAPP, and 48 (16.6%) scored at least 2 out of 4 points on the CAGE-AID survey. Results from the multivariate model suggest that marital status (single, hazard ratio [HR], 1.58; 95% CI, 1.15-2.18; P = .005; divorced, HR, 1.43; 95% CI, 1.01-2.03; P = .04), SOAPP score (positive vs negative, HR, 1.35; 95% CI, 1.04-1.74; P = .02), morphine equivalent daily dose (MEDD) (HR, 1.003; 95% CI, 1.002-1.004; P < .001), and Edmonton Symptom Assessment Scale pain level (HR, 1.11; 95% CI, 1.06-1.16; P < .001) were independently associated with the presence of NMOU behavior. In recursive partition analysis, single marital status, MEDD greater than 50 mg, and SOAPP scores greater than 7 were associated with a higher risk (56%) for the presence of NMOU behavior.Conclusions and relevanceThis prognostic study of patients with cancer taking opioids for cancer pain found that 19% of patients developed NMOU behavior within a median duration of 8 weeks after initial supportive care clinic consultation. Marital status (single or divorced), SOAPP score greater than 7, higher levels of pain severity, and MEDD level were independently associated with NMOU behavior. This information will assist clinicians and investigators designing clinical and research programs in this important field.

Project description:BackgroundConstipation is frequent in critically ill adults receiving opioids. Naloxegol (N), a peripherally acting mu-receptor antagonist (PAMORA), may reduce constipation. The objective of this trial was to evaluate the efficacy and safety of N to prevent constipation in ICU adults receiving opioids. Methods and Patients. In this single-center, double-blind, randomized trial, adults admitted to a medical ICU receiving IV opioids (≥100 mcg fentanyl/day), and not having any of 17 exclusion criteria, were randomized to N (25 mg) or placebo (P) daily randomized to receive N (25mg) or placebo (P) and docusate 100 mg twice daily until ICU discharge, 10 days, or diarrhea (≥3 spontaneous bowel movement (SBM)/24 hours) or a serious adverse event related to study medication. A 4-step laxative protocol was initiated when there was no SBM ≥3 days.ResultsOnly 318 (20.6%) of the 1542 screened adults during the 1/17-10/19 enrolment period met all inclusion criteria. Of these, only 19/381 (4.9%) met all eligibility criteria. After 7 consent refusals, 12 patients were randomized. The study was stopped early due to enrolment futility. The N (n = 6) and P (n = 6) groups were similar. The time to first SBM (N 41.4 ± 31.7 vs. P 32.5 ± 25.4 hours, P = 0.56) was similar. The maximal daily abdominal pressure was significantly lower in the N group (N 10 ± 4 vs. P 13 ± 5, P = 0.002). The median (IQR) daily SOFA scores were higher in N (N 7 (4, 8) vs. P 4 (3, 5), P < 0.001). Laxative protocol use was similar (N 83.3% vs. P 66.6%; P = 0.51). Diarrhea prevalence was high but similar (N 66.6% vs. P 66.6%; P = 1.0). No patient experienced opioid withdrawal.ConclusionsImportant recruitment challenges exist for ICU trials evaluating the use of PAMORAs for constipation prevention. Despite being underpowered, our results suggest time to first SBM with naloxegol, if different than P, may be small. The effect of naloxegol on abdominal pressure, SOFA, and the interaction between the two requires further research.

Project description:Objectives: To determine the prevalence and factors associated with the use of opioids among patients with chronic non-cancer pain (CNCP). Methods: A systematic review and meta-analysis. Comprehensive literature searches in Medline-PubMed, Embase and SCOPUS databases. Original studies published between 2009 and 2019 with a cross-sectional design were included. The quality of the studies was assessed with Critical Appraisal Checklist for Studies Reporting Prevalence Data from the Joanna Briggs Institute. Protocol registered in the International Prospective Register of Systematic Reviews with reference number: CRD42019137990. Results: Out of the 1,310 potential studies found, 25 studies fulfilled the inclusion criteria. Most of the studies were of high quality. High levels of heterogeneity were found in the studies included. In the general population, the prevalence of long-term opioid use was 2.3% (95% CI: 1.5-3.6%), the prevalence of short-term opioid use was 8.1% (95% CI: 5.6-11.6%), and among people with chronic low back pain it was 5.8% (95% CI: 0.5-45.5%). The prevalence of opioid use among patients from the health records or medical surveys was 41% (95% CI: 23.3-61.3%). Finally, in patients with musculoskeletal pain, the prevalence was 20.5% (95% CI: 12.9-30.9%) and in patients with fibromyalgia, 24.5% (95% CI: 22.9-26.2%). A higher prevalence of opioid use was observed among men, younger people, patients receiving prescriptions of different types of drugs, smokers and patients without insurance or with noncommercial insurance. In addition, non-white and Asian patients were less likely to receive opioids than non-Hispanic white patients. Conclusions: The prevalence of opioid use among patients with CNCP was higher in subjects with short or occasional use compared to those with long-term use. Men, younger people, more chronic pain conditions, and patients without insurance or with noncommercial insurance were most related to opioid use. However, non-white and Asian patients, and those treated by a physician trained in complementary medicine were less likely to use opioids.

Project description:BackgroundNaldemedine, a novel peripherally-acting mu-opioid receptor antagonist, has improved opioid-induced constipation in randomized controlled trials. The most frequent adverse event of naldemedine is diarrhea, which can cause abdominal pain and often leads to treatment discontinuation. We aimed to identify risk factors and appropriate management strategies for key adverse events including diarrhea associated with naldemedine, since those have not been extensively studied.MethodsWe conducted a multi-center retrospective cohort study. Eligible patients had cancer, had undergone palliative care at participating centers, had been prescribed regular opioids, and had taken at least one dose of naldemedine between June 2017 and March 2018. The primary endpoint was the incidence of diarrhea according to baseline characteristics. Secondary endpoints included the duration of naldemedine administration, daily defecation counts before and after starting naldemedine, duration and severity of diarrhea as an adverse event of naldemedine, other adverse events, and the incidence of constipation within 7 days after recovery from diarrhea. We defined patients who started naldemedine within three days of starting a regularly prescribed opioid as the early group, and the remainder as the late group.ResultsAmong 103 patients who received naldemedine, 98 fulfilled the eligibility criteria. The median age was 68 years and 48% of the patients were female. Median performance status was 3, and the median oral intake was 50%. The median duration of naldemedine administration and overall survival were 25 and 64 days, respectively. The incidence of diarrhea in the early group (n = 26) was significantly lower than in the late group (n = 72) (3.9% vs. 22.2%, p = 0.02). Daily defecation counts increased after late (median 0.43 to 0.88, p < 0.001), but remained stable after early naldemedine administration (median 1.00 to 1.00, p = 0.34). Constipation after the diarrhea was resolved was common (53%), especially among patients who stopped naldemedine (78%). The diarrhea was improved within three days in 92% of patients who stopped other laxatives.ConclusionsThe early administration of naldemedine is beneficial because it reduces adverse events including diarrhea. Diarrhea caused by naldemedine can be effectively managed by stopping other laxatives while continuing naldemedine.

Project description:ImportanceOpioid-prescribing policies and guidelines aimed at reducing inappropriate opioid prescribing may lead physicians to stop prescribing opioids. Patients may thus encounter difficulties finding primary care practitioners willing to care for them if they take opioids.ObjectivesTo assess practitioner willingness to accept and continue prescribing opioids to new patients with pain and whether this willingness differs across payer types.Design, setting, and participantsThis survey study used a simulated patient call audit method. A brief telephone survey was administered to all clinics followed by a call using a patient script simulating an adult patient with chronic pain who was taking long-term opioids. The patient had Medicaid or private insurance. Calls were made between June 22 and October 30, 2018, to 667 primary care clinics that served a general adult population in Michigan. Clinics that accepted both Medicaid and private insurance, took new patient appointments, and were successfully recontacted for the simulated call were eligible for the study.Main outcomes and measuresPrevalence of clinics' acceptance of new patients receiving prescription opioids overall and by clinic characteristics and insurance type.ResultsOf the 194 eligible clinics, 94 (48.4%) were randomized according to insurance type to receive calls from research assistants posing as children of patients with Medicaid and 100 (51.5%) to receive calls from those with private insurance. Overall, 79 (40.7%) stated that their practitioners would not prescribe opioids to the simulated patient. Thirty-three clinics (17.0%) requested more information before making a decision. Compared with single-practitioner clinics, clinics with more than 3 practitioners were more likely (odds ratio [OR], 2.99; 95% CI, 1.48-6.04) to accept new patients currently taking opioids. No difference was found in access based on insurance status (OR, 0.92; 95% CI, 0.52-1.64) or whether the clinic offered medications for opioid use disorders (OR, 1.10; 95% CI, 0.45-2.69).Conclusions and relevanceThe findings suggest that access to primary care may be reduced for patients taking prescription opioids, which could lead to unintended consequences, such as conversion to illicit substances or reduced management of other medical comorbidities.

Dataset Information

Genetic and Non-genetic Factors Associated With Constipation in Cancer Patients Receiving Opioids.

Publications

Genetic and Non-genetic Factors Associated With Constipation in Cancer Patients Receiving Opioids.

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