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1.
Am J Gastroenterol ; 119(10): 1970-1978, 2024 Oct 01.
Artigo em Inglês | MEDLINE | ID: mdl-38870087

RESUMO

Opioid receptors are found throughout the gastrointestinal tract, including the large intestine. Many patients treated with opioids experience opioid-induced constipation (OIC). Laxatives are not effective in most patients, and in those who do initially respond, the efficacy of laxatives generally diminishes over time. In addition, OIC does not spontaneously resolve for most patients. However, complications of opioids extend far beyond simply slowing gastrointestinal transit. Opioid use can affect intestinal permeability through a variety of mechanisms. Toll-like receptors are a crucial component of innate immunity and are tightly regulated within the gut epithelium. Pathologic µ-opioid receptor (MOR) and toll-like receptor signaling, resulting from chronic opioid exposure, disrupts intestinal permeability leading to potentially harmful bacterial translocation, elevated levels of bacterial toxins, immune activation, and increased cytokine production. Peripherally active MOR antagonists, including methylnaltrexone, are effective at treating OIC. Benefits extend beyond simply blocking the MOR; these agents also act to ameliorate opioid-induced disrupted intestinal permeability. In this review, we briefly describe the physiology of the gastrointestinal epithelial border and discuss the impact of opioids on gastrointestinal function. Finally, we consider the use of peripherally active MOR antagonists to treat disrupted intestinal permeability resulting from opioid use and discuss the potential for improved morbidity and mortality in patients treated with methylnaltrexone for opioid-induced bowel disorders.


Assuntos
Analgésicos Opioides , Mucosa Intestinal , Antagonistas de Entorpecentes , Permeabilidade , Receptores Opioides mu , Humanos , Receptores Opioides mu/antagonistas & inibidores , Receptores Opioides mu/efeitos dos fármacos , Receptores Opioides mu/metabolismo , Analgésicos Opioides/farmacologia , Permeabilidade/efeitos dos fármacos , Antagonistas de Entorpecentes/farmacologia , Mucosa Intestinal/efeitos dos fármacos , Mucosa Intestinal/metabolismo , Constipação Induzida por Opioides/tratamento farmacológico , Naltrexona/farmacologia , Naltrexona/análogos & derivados , Trato Gastrointestinal/efeitos dos fármacos , Trato Gastrointestinal/metabolismo , Compostos de Amônio Quaternário/farmacologia , Compostos de Amônio Quaternário/uso terapêutico , Função da Barreira Intestinal
2.
BMC Gastroenterol ; 24(1): 23, 2024 Jan 08.
Artigo em Inglês | MEDLINE | ID: mdl-38191294

RESUMO

This study was designed to explore the expression changes of P2Y1 receptors in the distal colonic myenteric layer of rats. An opioid induced constipation(OIC) rat model was generated by intraperitoneal (i.p) injection of loperamide. At 7 days post-treatment, the model rats were assessed by calculating the fecal water content and the gastrointestinal transit ratio. The immunofluorescence (IF)-based histochemical study was used to observe the distribution of P2Y1 receptors in the distal colonic myenteric plexus. Western blotting (WB) was performed to evaluate the expression changes of P2Y1 proteins in the myenteric layer, and the electrophysiological approaches were carried out to determine the regulatory roles of P2Y1 receptors on distal colonic motor function. IF showed that P2Y1 receptors are co-expressed MOR in the enteric nerve cells of the distal colonic myenteric plexus. Moreover, the WB revealed that the protein levels of P2Y1 were significantly decreased in the distal colonic myenteric layer of OIC rats. In vitro tension experiments exhibited that the P2Y1 receptor antagonist MRS2500 enhanced the spontaneous contraction amplitude, adding EM2 and ß-FNA did not have any effect on MRS2500. Therefore, P2Y1 receptor expression could be associated with the occurrence of OIC in this rat model and the regulation of colonic motility by MOR may be related to the release of purine neurotransmitters such as ATP in the colonic nervous system.


Assuntos
Plexo Mientérico , Constipação Induzida por Opioides , Animais , Ratos , Analgésicos Opioides/efeitos adversos , Constipação Intestinal/induzido quimicamente , Western Blotting
3.
Support Care Cancer ; 32(8): 504, 2024 Jul 10.
Artigo em Inglês | MEDLINE | ID: mdl-38985364

RESUMO

PURPOSE: In this study, we aimed to evaluate the safety and effectiveness of naldemedine for treating opioid-induced constipation (OIC) in patients with advanced cancer, who are receiving palliative care, and particularly explored its early effects. METHODS: Palliative care teams and inpatient palliative care units across 14 institutions in Japan were included in this multicenter, prospective, observational study. Patients who were newly prescribed a daily oral dose of 0.2 mg naldemedine were enrolled. The spontaneous bowel movement (SBM) within 24 h after the first dose of naldemedine was considered the primary outcome, whereas, the secondary outcomes included weekly changes in SBM frequency and adverse events. RESULTS: A total of 204 patients were enrolled and 184 completed the 7-day study. The average age of the participants (103 males, 101 females) was 63 ± 14 years. The primary cancer was detected in the lungs (23.5%), gastrointestinal tract (13.7%), and urological organs (9.3%). A considerable proportion of patients (34.8%) had ECOG performance status of 3-4. Most patients were undergoing active cancer treatment, however, 40.7% of the patients were receiving the best supportive care. Within 24 h of the first naldemedine dose, 146 patients (71.6%, 95% CI: 65.4-77.8%) experienced SBMs. The weekly SBM counts increased in 62.7% of the participants. The major adverse events included diarrhea and abdominal pain, detected in 17.6% and 5.4% of the patients, respectively. However, no serious adverse events were observed. CONCLUSION: Conclusively, naldemedine is effective and safe for OIC treatments in real-world palliative care settings. TRIAL REGISTRATION NUMBER: UMIN000031381, registered 20/02/2018.


Assuntos
Analgésicos Opioides , Naltrexona , Antagonistas de Entorpecentes , Neoplasias , Constipação Induzida por Opioides , Cuidados Paliativos , Humanos , Masculino , Feminino , Pessoa de Meia-Idade , Estudos Prospectivos , Cuidados Paliativos/métodos , Idoso , Neoplasias/tratamento farmacológico , Neoplasias/complicações , Constipação Induzida por Opioides/tratamento farmacológico , Naltrexona/análogos & derivados , Naltrexona/uso terapêutico , Naltrexona/administração & dosagem , Naltrexona/efeitos adversos , Analgésicos Opioides/efeitos adversos , Analgésicos Opioides/administração & dosagem , Analgésicos Opioides/uso terapêutico , Antagonistas de Entorpecentes/administração & dosagem , Antagonistas de Entorpecentes/uso terapêutico , Antagonistas de Entorpecentes/efeitos adversos , Japão , Adulto , Constipação Intestinal/induzido quimicamente , Constipação Intestinal/tratamento farmacológico , Idoso de 80 Anos ou mais , Dor do Câncer/tratamento farmacológico , Resultado do Tratamento
4.
Support Care Cancer ; 32(10): 701, 2024 Oct 05.
Artigo em Inglês | MEDLINE | ID: mdl-39367106

RESUMO

PURPOSE: The objectives of the study were to determine the prevalence of (uncontrolled) OIC, relevant medications / interventions employed by healthcare professionals, and the additional strategies utilised by patients, amongst European patients with cancer pain. METHODS: This study was a prospective observational study conducted at 24 research sites in ten European countries. Cancer patients receiving opioid analgesics for at least a week were recruited, and asked to complete a questionnaire including background information, single question (Are you constipated?), Rome IV diagnostic criteria for OIC, Bowel Function Index (BFI), and Patient Assessment of Constipation Quality of Life questionnaire (PAC-QOL). Participants were characterised as having / not having OIC on the basis of the Rome IV diagnostic criteria. RESULTS: 1200 participants completed the study. 59.5% met the Rome IV diagnostic criteria for OIC: only 61.5% that met these criteria self-reported constipation. 72% participants were prescribed a regular conventional laxative / peripherally acting mu-opioid receptor antagonist (PAMORA). However, only 66% took their prescribed laxatives every day. Many participants had utilised other strategies / interventions to manage their OIC. Furthermore, 27% had needed to use suppositories, 26.5% had needed to use an enema, and 8% had had a manual evacuation. The use of PAMORAs, and other novel effective medications, was relatively uncommon. CONCLUSION: The results of this study suggest that management in Europe is often inadequate, and this undoubtedly relates to a combination of inadequate assessment, inappropriate treatment, and inadequate reassessment.


Assuntos
Analgésicos Opioides , Dor do Câncer , Laxantes , Constipação Induzida por Opioides , Qualidade de Vida , Humanos , Dor do Câncer/tratamento farmacológico , Estudos Prospectivos , Feminino , Masculino , Pessoa de Meia-Idade , Europa (Continente) , Analgésicos Opioides/efeitos adversos , Analgésicos Opioides/uso terapêutico , Analgésicos Opioides/administração & dosagem , Idoso , Laxantes/uso terapêutico , Laxantes/administração & dosagem , Inquéritos e Questionários , Adulto , Prevalência , Constipação Intestinal/epidemiologia , Constipação Intestinal/induzido quimicamente , Constipação Intestinal/tratamento farmacológico
5.
J Oncol Pharm Pract ; 30(1): 4-8, 2024 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-36946143

RESUMO

INTRODUCTION: Peripherally acting µ-opioid receptor antagonists (PAMORAs) are used in the treatment of opioid induced constipation without impacting the actions of opioid analgesics. Subcutaneous methylnaltrexone was one of the first PAMORAs approved in April 2008 for the treatment of opioid induced constipation in adult patients. The safety and effectiveness of methylnaltrexone has not been established in pediatric patients. In this study, the use of subcutaneous methylnaltrexone in pediatric patients is analyzed and reviewed. The primary outcome is occurrence of a bowel movement within 24 h after methylnaltrexone (MNTX) administration and the number of bowel movements following treatment with methylnaltrexone. Secondary outcomes include safety in this patient cohort. METHODS: This is a retrospective study of 79 pediatric patients with opioid induced constipation. Patients were administered methylnaltrexone during their inpatient stay. Data on bowel activity after methylnaltrexone was obtained from the hospital information system. RESULTS: Out of the 79 patients who received methylnaltrexone, there were seven patients from whom data could not be analyzed. Of the 72 patients whose data was available, 38% (N = 27) were documented as having a bowel movement, 62% (N = 45) did not have a bowel movement. Reported adverse events were minimal with nausea (N = 3), vomiting (N = 1), and flatulence (N = 6). CONCLUSION: Methylnaltrexone appears safe in the pediatric population and produces bowel movements in more than a third of pediatric patients. It is a feasible and safe option for opioid induced constipation in pediatric patients.


Assuntos
Naltrexona/análogos & derivados , Neoplasias , Constipação Induzida por Opioides , Adulto , Humanos , Criança , Analgésicos Opioides/efeitos adversos , Constipação Induzida por Opioides/tratamento farmacológico , Estudos Retrospectivos , Constipação Intestinal/induzido quimicamente , Constipação Intestinal/tratamento farmacológico , Antagonistas de Entorpecentes/efeitos adversos , Neoplasias/tratamento farmacológico , Compostos de Amônio Quaternário
6.
Am J Gastroenterol ; 118(11): 2033-2040, 2023 11 01.
Artigo em Inglês | MEDLINE | ID: mdl-37335135

RESUMO

INTRODUCTION: Chronic idiopathic constipation (CIC) and opioid-induced constipation (OIC) are disorders that negatively affect 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 data set with nearly 89,000 people in the United States. METHODS: From May 3, 2020, to June 24, 2020, we recruited a representative sample of people in the United States ≥ 18 years 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 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 whether their symptoms worsened afterward. RESULTS: 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 with people with CIC (Patient-Reported Outcome Measurement Information System 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 2.72, 95% confidence interval 2.04-3.62) and OEC (odds ratio 3.52, 95% confidence interval 2.22-5.59) were also more likely to be taking a prescription medication for their constipation vs those with CIC. DISCUSSION: 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.


Assuntos
Constipação Intestinal , Constipação Induzida por Opioides , Humanos , Estados Unidos/epidemiologia , Constipação Intestinal/induzido quimicamente , Constipação Intestinal/tratamento farmacológico , Constipação Intestinal/epidemiologia , Analgésicos Opioides/efeitos adversos , Constipação Induzida por Opioides/tratamento farmacológico , Qualidade de Vida , Prevalência , Cidade de Roma , Efeitos Psicossociais da Doença
7.
J Clin Gastroenterol ; 57(1): 39-47, 2023 Jan 01.
Artigo em Inglês | MEDLINE | ID: mdl-36504229

RESUMO

Opioid-induced constipation (OIC) is a common condition in older adults who may not be responsive to traditional laxative therapy. OIC is defined as new or worsening constipation symptoms that occur with initiation of or altering the dose of opioid analgesia. For adult patients with OIC and noncancer pain, we recommend considering nonpharmacologic interventions (eg, dietary measures, increased physical activity, and biofeedback training) and over-the-counter laxatives, followed by prescription opioid receptor antagonists (methylnaltrexone, naloxegol, and naldemedine) if traditional over-the-counter laxatives fail. Other options may include lubiprostone, linaclotide, plecanatide, and prucalopride; however, these are not indicated for OIC specifically or studied in older adults. Because of the complex nature of absorption, distribution, metabolism, and excretion in the aging population, all agents used to treat OIC must be evaluated individually and reevaluated as patients continue to age. This review will serve as a guide to managing OIC in older adults.


Assuntos
Constipação Induzida por Opioides , Humanos , Idoso , Constipação Induzida por Opioides/tratamento farmacológico , Analgésicos Opioides/efeitos adversos , Constipação Intestinal/induzido quimicamente , Constipação Intestinal/tratamento farmacológico , Laxantes/uso terapêutico , Envelhecimento
8.
Ann Pharmacother ; 57(7): 762-768, 2023 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-36314271

RESUMO

BACKGROUND: Opioid-induced constipation (OIC) may occur in up to 81% of critically ill patients and can lead to many complications. Opioid antagonists are a reasonable approach and may be used for managing OIC. OBJECTIVE: The purpose of this study was to assess the efficacy of enteral naloxone (NLX) versus subcutaneous methylnaltrexone (MNTX) for the management of OIC in critically ill patients. METHODS: A retrospective analysis was conducted on adult patients who received NLX or MNTX and a continuous opioid infusion for at least 48 hours. The primary end point was time to resolution of constipation, defined as hours to first bowel movement (BM) after the first dose of an opioid antagonist. Reversal of analgesia was assessed by comparing the total number of morphine milligram equivalents (MME) 24 hours preopioid and postopioid antagonist administration. Univariate and multivariate analyses were conducted to assess treatment response within 48 hours. RESULTS: Baseline characteristics were similar between patients receiving NTX (n = 89) and MNTX (n = 71). However, the time to the first BM with NLX was 18 hours compared with 41 hours with MNTX (P = 0.004). There was no difference in MME requirements 24 hours pre/post NLX or MNTX administration. Naloxone administration was identified as a statistically significant predictor of BM within 48 hours (odds ratio [OR] = 2.68 [1.33-5.38]). CONCLUSION AND RELEVANCE: The time to first BM was shorter with enteral NLX. Both NLX and MNTX appear to be effective for the management of OIC without causing reversal of analgesia. Future controlled, prospective trials comparing these agents are warranted.


Assuntos
Naloxona , Constipação Induzida por Opioides , Adulto , Humanos , Naloxona/uso terapêutico , Analgésicos Opioides/efeitos adversos , Constipação Induzida por Opioides/tratamento farmacológico , Estado Terminal , Estudos Retrospectivos , Estudos Prospectivos , Constipação Intestinal/induzido quimicamente , Constipação Intestinal/tratamento farmacológico , Naltrexona , Antagonistas de Entorpecentes/uso terapêutico , Compostos de Amônio Quaternário/uso terapêutico , Dor/tratamento farmacológico
9.
Biol Pharm Bull ; 46(12): 1826-1831, 2023.
Artigo em Inglês | MEDLINE | ID: mdl-38044102

RESUMO

Naldemedine is indicated for the treatment of opioid-induced constipation (OIC), but reports on its efficacy in preventing OIC are few. Therefore, we retrospectively investigated factors affecting the efficacy of concurrent prescription of naldemedine on OIC. Outpatients with cancer who were started on oxycodone 10 mg/d were included in the study. The eligible patients were classified by their physicians into the following three groups: Group A used regular laxatives before the introduction of oxycodone and initiated naldemedine treatment simultaneously with oxycodone administration, Group B did not take laxatives before the introduction of oxycodone and started naldemedine simultaneously with oxycodone administration, and Group C had been administering regular laxatives before the introduction of oxycodone and were not prescribed naldemedine simultaneously with oxycodone treatment. The Support Team Assessment Schedule Japanese edition score for constipation, frequency of defecation, Bristol Stool Form Scale, sense of incomplete rectal evacuation, and development or worsening of straining to pass bowel movements were compared among the three groups before and after oxycodone administration. In Group B, there was significant worsening of the four parameters except for the sense of incomplete rectal evacuation, whereas Groups A and C did not present any changes. In logistic regression analysis, body weight ≥51.8 kg was a factor significantly decreasing the preventive effect of naldemedine on OIC, and regular use of laxatives was a factor significantly increasing the preventive effect of naldemedine on OIC. Thus, the initiation of naldemedine should be considered depending on the body weight and regular laxative use.


Assuntos
Constipação Induzida por Opioides , Oxicodona , Humanos , Analgésicos Opioides/efeitos adversos , Peso Corporal , Constipação Intestinal/induzido quimicamente , Constipação Intestinal/tratamento farmacológico , Constipação Intestinal/prevenção & controle , Laxantes/uso terapêutico , Constipação Induzida por Opioides/tratamento farmacológico , Oxicodona/efeitos adversos , Estudos Retrospectivos
10.
BMC Palliat Care ; 22(1): 22, 2023 Mar 14.
Artigo em Inglês | MEDLINE | ID: mdl-36915062

RESUMO

BACKGROUND: Opioid-induced constipation (OIC) is a common symptom in cancer patients treated with opioids with a prevalence of up to 59%. International guidelines recommend standard laxatives such as macrogol/electrolytes and magnesium hydroxide to prevent OIC, although evidence from randomized controlled trials is largely lacking. The aim of our study is to compare magnesium hydroxide with macrogol /electrolytes in the prevention of OIC in patients with incurable cancer and to compare side-effects, tolerability and cost-effectiveness. METHODS: Our study is an open-label, randomized, multicenter study to examine if magnesium hydroxide is non-inferior to macrogol/electrolytes in the prevention of OIC. In total, 330 patients with incurable cancer, starting with opioids for pain management, will be randomized to treatment with either macrogol/electrolytes or magnesium hydroxide. The primary outcome measure is the proportion of patients with a score of < 30 on the Bowel Function Index (BFI), measured on day 14. The Rome IV criteria for constipation, side effects of and satisfaction with laxatives, pain scores, quality of life (using the EQ-5D-5L), daily use of laxatives and escape medication, and cost-effectiveness will also be assessed. DISCUSSION: In this study we aim to examine if magnesium hydroxide is non-inferior to macrogol/electrolytes in the prevention of OIC. The outcome of our study will contribute to prevention of OIC and scientific evidence of guidelines on (opioid-induced) constipation. TRIAL REGISTRATION: This trial is registered at clinicaltrials.gov: NCT05216328 and in the Dutch trial register: NTR80508. EudraCT number 2022-000408-36.


Assuntos
Neoplasias , Constipação Induzida por Opioides , Humanos , Hidróxido de Magnésio/efeitos adversos , Analgésicos Opioides/efeitos adversos , Laxantes/uso terapêutico , Constipação Intestinal/induzido quimicamente , Constipação Intestinal/tratamento farmacológico , Constipação Intestinal/prevenção & controle , Constipação Induzida por Opioides/tratamento farmacológico , Qualidade de Vida , Neoplasias/complicações , Neoplasias/tratamento farmacológico , Polietilenoglicóis/efeitos adversos , Ensaios Clínicos Controlados Aleatórios como Assunto , Estudos Multicêntricos como Assunto
11.
Molecules ; 28(23)2023 Nov 24.
Artigo em Inglês | MEDLINE | ID: mdl-38067494

RESUMO

Opioid receptor agonists, particularly those that activate µ-opioid receptors (MORs), are essential analgesic agents for acute or chronic mild to severe pain treatment. However, their use has raised concerns including, among others, intestinal dysbiosis. In addition, growing data on constipation-evoked intestinal dysbiosis have been reported. Opioid-induced constipation (OIC) creates an obstacle to continuing treatment with opioid analgesics. When non-opioid therapies fail to overcome the OIC, opioid antagonists with peripheral, fast first-pass metabolism, and gastrointestinal localized effects remain the drug of choice for OIC, which are discussed here. At first glance, their use seems to only be restricted to constipation, however, recent data on OIC-related dysbiosis and its contribution to the appearance of several opioid side effects has garnered a great of attention from researchers. Peripheral MORs have also been considered as a future target for opioid analgesics with limited central side effects. The properties of MOR antagonists counteracting OIC, and with limited influence on central and possibly peripheral MOR-mediated antinociception, will be highlighted. A new concept is also proposed for developing gut-selective MOR antagonists to treat or restore OIC while keeping peripheral antinociception unaffected. The impact of opioid antagonists on OIC in relation to changes in the gut microbiome is included.


Assuntos
Antagonistas de Entorpecentes , Constipação Induzida por Opioides , Humanos , Antagonistas de Entorpecentes/uso terapêutico , Analgésicos Opioides/efeitos adversos , Constipação Intestinal/induzido quimicamente , Constipação Intestinal/tratamento farmacológico , Constipação Intestinal/metabolismo , Constipação Induzida por Opioides/tratamento farmacológico , Disbiose/induzido quimicamente , Disbiose/tratamento farmacológico , Receptores Opioides/metabolismo
12.
Pharmazie ; 78(11): 245-250, 2023 Dec 04.
Artigo em Inglês | MEDLINE | ID: mdl-38178284

RESUMO

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.


Assuntos
Laxantes , Constipação Induzida por Opioides , Estados Unidos/epidemiologia , Humanos , Laxantes/efeitos adversos , Analgésicos Opioides/efeitos adversos , Constipação Intestinal/induzido quimicamente , Constipação Intestinal/epidemiologia , Magnésio/uso terapêutico , Constipação Induzida por Opioides/tratamento farmacológico , Farmacovigilância
13.
Medicina (Kaunas) ; 59(3)2023 Mar 02.
Artigo em Inglês | MEDLINE | ID: mdl-36984494

RESUMO

Background and Objectives: Opioid analgesics, which are used for cancer-related pain management, cause opioid-induced constipation (OIC). 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 hepatobiliary pancreatic cancers. We performed a multi-institutional study on the efficacy and safety of naldemedine in patients with hepatobiliary pancreatic cancer using opioids in clinical practice. Materials and Methods: We retrospectively evaluated patients with hepatobiliary pancreatic cancer (including liver, biliary tract, and pancreatic cancers) treated with opioids and naldemedine during hospitalization at ten institutions in Japan from June 2017 to August 2019. We assessed the frequency of bowel movements before and after the initiation of naldemedine therapy. Responders were defined as patients who defecated ≥3 times/week, with an increase from a baseline of ≥1 defecations/week over seven days after the initiation of naldemedine administration. Results: Thirty-four patients were observed for one week before and one week after starting naldemedine. The frequency of bowel movements increased by one over the baseline frequency or to at least thrice per week in 21 patients. The response rate was 61.7% (95% confidence interval: 45.4-78.0%). The median number of weekly bowel movements before and after naldemedine treatment was 2 (range: 0-9) and 6 (range: 1-17), respectively, in the overall population (n = 34); the increase in the number of bowel movements following naldemedine administration was statistically significant (Wilcoxon signed-rank test, p < 0.0001). Diarrhea was the predominant gastrointestinal symptom, and 10 (29.4%) patients experienced grade 1, grade 2, or grade 3 adverse events. The only other adverse event included fatigue in one patient; grade 2-4 adverse events were absent. Conclusions: Naldemedine is effective, and its use may be safe in clinical practice for patients with hepatobiliary pancreatic cancer receiving opioid analgesics.


Assuntos
Antagonistas de Entorpecentes , Constipação Induzida por Opioides , Neoplasias Pancreáticas , Humanos , Analgésicos Opioides/efeitos adversos , Antagonistas de Entorpecentes/uso terapêutico , Constipação Induzida por Opioides/tratamento farmacológico , Neoplasias Pancreáticas/complicações , Neoplasias Pancreáticas/tratamento farmacológico , Estudos Retrospectivos , Naltrexona/análogos & derivados , Neoplasias Pancreáticas
14.
Clin Gastroenterol Hepatol ; 20(4): 855-863, 2022 04.
Artigo em Inglês | MEDLINE | ID: mdl-33965574

RESUMO

BACKGROUND & AIMS: Opioids have a role in chronic pain management. However, opioid-induced constipation may cause patients to skip or reduce opioid doses, leading to inadequate pain relief and negatively impacting quality of life. We sought to establish a minimal clinically important difference to understand whether changes in quality of life scores are of value to patients. METHODS: Integrated data from the double-blind, controlled, phase 3 COMPOSE-1 and COMPOSE-2 trials of naldemedine in chronic noncancer pain and opioid-induced constipation were used to determine minimal clinically important differences using Patient Assessment of Constipation Symptoms (PAC-SYM) and Patient Assessment of Constipation Quality of Life (PAC-QOL) questionnaires. Patients completed the questionnaires (5-point Likert scale; predose, Weeks 2, 4, and 12), kept a daily log of Bowel Movement and Constipation Assessment, and rated satisfaction at end of study. Minimal clinically important differences were computed using an anchor-based method with 6 anchors: 5 from the Bowel Movement and Constipation Assessment and 1 from patient satisfaction. Threshold values for each anchor were set to define responders versus nonresponders based on score definitions. Clinically meaningful cutoff values for changes in PAC-SYM and PAC-QOL scores were determined using receiver operating characteristic curves. RESULTS: Data from 1095 patients (549, naldemedine; 546, placebo) were analyzed. The area under the curve for the receiver operating characteristic curves (ranges, 0.719 to 0.798 for PAC-SYM and 0.734 to 0.833 for PAC-QOL) indicated that both instruments can discriminate responders and nonresponders for each anchor. PAC-SYM cutoff values ranged from -1.04 to -0.83; PAC-QOL cutoff values ranged from -0.93 to -0.82. CONCLUSIONS: Based on data derived from the anchor method, reductions in PAC-SYM and PAC-QOL scores of >1.0 in patients with chronic noncancer pain and opioid-induced constipation are clinically meaningful. CLINICALTRIALS: gov Registration: NCT01965158; NCT01993940.


Assuntos
Dor Crônica , Constipação Induzida por Opioides , Analgésicos Opioides/efeitos adversos , Dor Crônica/tratamento farmacológico , Constipação Intestinal/induzido quimicamente , Constipação Intestinal/tratamento farmacológico , Humanos , Diferença Mínima Clinicamente Importante , Qualidade de Vida
15.
Curr Treat Options Oncol ; 23(7): 936-950, 2022 07.
Artigo em Inglês | MEDLINE | ID: mdl-35441979

RESUMO

OPINION STATEMENT: Constipation is one of the most frequent problems in cancer patients, and its etiology is multifactorial. It leads to decreased quality of life and impedes optimal pain treatment. Despite the high prevalence, constipation is frequently underdiagnosed mainly because of lack of validated diagnostic criteria or widely accepted definition of constipation in cancer patients. All cancer patients should be evaluated regularly for constipation, and concomitant causes and risk factors were assessed. Opioids are responsible for a much of the secondary constipation in cancer patients. The management of constipation in cancer patients should be multifaceted, addressing dietary and behavioral issues and optimizing pharmacological interventions. Prevention of opioid-induced constipation (OIC) is pivotal, as treatment is often unsatisfactory or inefficient. Dietary and behavioral interventions should be considered. Non-pharmacological measures include hydration and nutrition, ensuring privacy during defecation, using a commode or footstool, and the availability of a caregiver. Abdominal massage may be of value. Traditional laxatives are recommended in prevention but not in the treatment of OIC. Peripherally acting mu-opioid receptor antagonists (PAMORA) appear the first choice in the treatment and an alternative to laxatives in some recent clinical practice guidelines in preventing OIC. Naldemedine, naloxegol, and methylnaltrexone are supported by quality evidence for OIC management. Naloxone or naltrexone, taken orally in combined formulations with opioids, may be valuable in preventing or reducing OIC symptoms.


Assuntos
Neoplasias , Constipação Induzida por Opioides , Analgésicos Opioides/efeitos adversos , Constipação Intestinal/diagnóstico , Constipação Intestinal/etiologia , Constipação Intestinal/terapia , Humanos , Laxantes/uso terapêutico , Neoplasias/complicações , Neoplasias/epidemiologia , Neoplasias/terapia , Qualidade de Vida
16.
Support Care Cancer ; 30(7): 5831-5836, 2022 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-35355120

RESUMO

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.


Assuntos
Neoplasias , Constipação Induzida por Opioides , Analgésicos Opioides/efeitos adversos , Constipação Intestinal/induzido quimicamente , Constipação Intestinal/tratamento farmacológico , Humanos , Laxantes/efeitos adversos , Neoplasias/complicações , Neoplasias/tratamento farmacológico , Constipação Induzida por Opioides/tratamento farmacológico , Constipação Induzida por Opioides/epidemiologia , Estudos Retrospectivos , Fatores de Risco , Taxoides/efeitos adversos
17.
Support Care Cancer ; 30(6): 5201-5210, 2022 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-35257230

RESUMO

PURPOSE: Opioid-induced constipation is one of the heath problems with a negative impact on the quality of life. This randomized-controlled trial aimed to investigate the effects of acupressure therapy on the management of opioid-induced constipation in patients with cancer. METHODS: The trial was conducted on 140 cancer patients, who were assigned to the acupressure (n = 70) and the control groups (n = 70). In addition to routine care, patients in the acupressure group received 8-min acupressure from the Zhongwan (CV12), Guanyuan (CV4), and Tianshu (ST25) acupoints once a day for 4 weeks. The outcomes included Defecation Diary (DD), Visual Analog Scale Questionnaire (VASQ), and Patient Assessment of Constipation Quality of Life Questionnaire (PAC-QOL). RESULTS: We found a statistically significant difference between the acupressure and control groups in terms of stool consistency (2.22 ± 0.49 vs 1.80 ± 0.55) (p = 0.001), straining (1.98 ± 0.71 vs 2.91 ± 0.37) (p = 0.001), incomplete evacuation (0.37 ± 0.29 vs 0.61 ± 0.43) (p = 0.001), stool amount (0.93 ± 0.14 vs 0.95 ± 0.20) (p = 0.001), and the number of defecations (0.70 ± 0.22 vs 0.46 ± 0.29), (p = 0.001) measured at the fifth week. Besides, with the exception of stool amount, the DD scores obtained by the acupressure group significantly increased in the fifth week. Inter-group comparison of the pre-test and post-test scores showed that acupressure group obtained statistically significantly lower scores from the PAC-QOL (p = 0.0001). CONCLUSIONS: Findings of this trial suggested that a 4-week acupressure was an effective way to improve the quality of life and to reduce both the subjective and the objective constipation symptoms in patients with opioid-induced constipations. CLINICAL TRIAL NUMBER: NCT04876508.


Assuntos
Acupressão , Neoplasias , Constipação Induzida por Opioides , Analgésicos Opioides/efeitos adversos , Constipação Intestinal/induzido quimicamente , Constipação Intestinal/terapia , Humanos , Neoplasias/complicações , Neoplasias/tratamento farmacológico , Qualidade de Vida , Método Simples-Cego , Resultado do Tratamento
18.
Support Care Cancer ; 30(5): 3943-3954, 2022 May.
Artigo em Inglês | MEDLINE | ID: mdl-35044484

RESUMO

PURPOSE: This prospective post-marketing surveillance (PMS) was designed to collect data on the safety and effectiveness of naldemedine in routine clinical practice in patients with opioid-induced constipation (OIC) and cancer pain in Japan and explore the characteristics of patients prone to diarrhea. METHODS: The enrolled patients received naldemedine (0.2 mg, once a day) orally for up to 12 weeks. In the safety analysis, adverse drug reactions (ADRs), including diarrhea as a special interest, were assessed. Effectiveness was evaluated, especially regarding the frequency and condition of bowel movement. RESULTS: In the safety analysis set (n = 1177), 145 ADRs occurred in 133 (11.30%) patients, and diarrhea was the most frequent event (n = 107, 9.09%). Most cases of diarrhea were non-serious (98.1%). Most ADRs were non-serious (93.8%), and they resolved within 2 weeks (75.9%). No patient characteristics influenced the risk of diarrhea development or aggravation. Both the frequency (75.0% and 83.2%) and condition of bowel movement (80.0% and 88.0%) were improved at 2 and 12 weeks, respectively in the effectiveness analysis set (n = 953). Frequency and condition of bowel movement were also improved in patients excluded (e.g., Eastern Cooperative Oncology Group performance status was ≥ 3) or with very small numbers (e.g., received weak opioid) in the clinical trials. CONCLUSIONS: This PMS indicates that naldemedine is well tolerated and effective in patients of various backgrounds in routine clinical practice who have OIC and cancer pain. TRIAL REGISTRATION: UMIN000042851.


Assuntos
Dor do Câncer , Neoplasias , Constipação Induzida por Opioides , Analgésicos Opioides/efeitos adversos , Dor do Câncer/induzido quimicamente , Dor do Câncer/tratamento farmacológico , Constipação Intestinal/induzido quimicamente , Constipação Intestinal/tratamento farmacológico , Constipação Intestinal/epidemiologia , Humanos , Japão , Naltrexona/análogos & derivados , Antagonistas de Entorpecentes/uso terapêutico , Neoplasias/complicações , Neoplasias/tratamento farmacológico , Vigilância de Produtos Comercializados , Estudos Prospectivos
19.
Cochrane Database Syst Rev ; 9: CD006332, 2022 09 15.
Artigo em Inglês | MEDLINE | ID: mdl-36106667

RESUMO

BACKGROUND: Opioid-induced bowel dysfunction (OIBD) is characterised by constipation, incomplete evacuation, bloating, and gastric reflux. It is one of the major adverse events (AEs) of treatment for pain in cancer and palliative care, resulting in increased morbidity and reduced quality of life. This review is a partial update of a 2008 review, and critiques as previous update (2018) trials only for people with cancer and people receiving palliative care. OBJECTIVES: To assess for OIBD in people with cancer and people receiving palliative care the effectiveness and safety of mu-opioid antagonists (MOAs) versus different doses of MOAs, alternative pharmacological/non-pharmacological interventions, placebo, or no treatment. SEARCH METHODS: We searched CENTRAL, MEDLINE, Embase, CINAHL, and Web of Science (December 2021), clinical trial registries and regulatory websites. We sought contact with MOA manufacturers for further data. SELECTION CRITERIA: Randomised controlled trials (RCTs) assessing the effectiveness and safety of MOAs for OIBD in people with cancer and people at a palliative stage irrespective of the type of terminal disease. DATA COLLECTION AND ANALYSIS: Two review authors assessed risk of bias and extracted data. The appropriateness of combining data from the trials depended upon sufficient homogeneity across trials. Our primary outcomes were laxation response, effect on analgesia, and AEs. We assessed the certainty of evidence using GRADE and created summary of findings tables. MAIN RESULTS: We included 10 studies (two new trials) randomising in-total 1343 adults with cancer irrespective of stage, or at palliative care stage of any disease. The MOAs were oral naldemedine and naloxone (alone or in combination with oxycodone), and subcutaneous methylnaltrexone. The trials compared MOAs with placebo, MOAs at different doses, or in combination with other drugs. Two trials of naldemedine and three of naloxone with oxycodone were in people with cancer irrespective of disease stage. The trial on naloxone alone was in people with advanced cancer. Four trials on methylnaltrexone were in palliative care where most participants had advanced cancer. All trials were vulnerable to biases; most commonly, blinding of the outcome assessor was not reported.  Oral naldemedine versus placebo Risk (i.e. chance) of spontaneous laxations in the medium term (over two weeks) for naldemedine was over threefold greater risk ratio (RR) 2.00, 95% confidence interval (CI) 1.59 to 2.52, 2 trials, 418 participants, I² = 0%. Number needed to treat for an additional beneficial outcome (NNTB) 3, 95% CI 3 to 4; moderate-certainty evidence). Earlier risk of spontaneous laxations and patient assessment of bowel change was not reported. Very low-certainty evidence showed naldemedine had little to no effect on opioid withdrawal symptoms. There was little to no difference in the risk of serious (non-fatal) AEs (RR 3.34, 95% CI 0.85 to 13.15: low-certainty evidence). Over double the risk of AEs (non-serious) reported with naldemedine (moderate-certainty evidence). Low-dose oral naldemedine versus higher dose Risk of spontaneous laxations was lower for the lower dose (medium term, 0.1 mg versus 0.4 mg: RR 0.69, 95% CI 0.53 to 0.89, 1 trial, 111 participants (low-certainty evidence)). Earlier risk of spontaneous laxations and patient assessment of bowel change not reported. Low-certainty evidence showed little to no difference on opioid withdrawal symptoms (0.1 mg versus 0.4 mg mean difference (MD) -0.30, 95% CI -0.85 to 0.25), and occurrences of serious AEs (0.1 mg versus 0.4 mg RR 0.25, 95% CI 0.03 to 2.17). Low-certainty evidence showed little to no difference on non-serious AEs. Oral naloxone versus placebo Risk of spontaneous laxations and AEs not reported. Little to no difference in pain intensity (very low-certainty evidence). Full data not given. The trial reported that no serious AEs occurred. Oral naloxone + oxycodone versus oxycodone Risk of spontaneous laxations within 24 hours and in the medium term not reported. Low-certainty evidence showed naloxone with oxycodone reduced the risk of opioid withdrawal symptoms. There was little to no difference in the risk of serious (non-fatal) AEs (RR 0.68, 95% CI 0.44 to 1.06), 3 trials, 362 participants, I² = 55%: very low-certainty evidence). There was little to no difference in risk of AEs (low-certainty evidence).  Subcutaneous methylnaltrexone versus placebo Risk of spontaneous laxations within 24 hours with methylnaltrexone was fourfold greater than placebo (RR 2.97, 95% CI 2.13 to 4.13. 2 trials, 287 participants, I² = 31%. NNTB 3, 95% CI 2 to 3; low-certainty evidence). Risk of spontaneous laxations in the medium term was over tenfold greater with methylnaltrexone (RR 8.15, 95% CI 4.76 to 13.95, 2 trials, 305 participants, I² = 47%. NNTB 2, 95% CI 2 to 2; moderate-certainty evidence). Low-certainty evidence showed methylnaltrexone reduced the risk of opioid withdrawal symptoms, and did not increase risk of a serious AE (RR 0.59, 95% CI 0.38 to 0.93. I² = 0%; 2 trials, 364 participants). The risk of AEs was higher for methylnaltrexone (low-certainty evidence). Lower-dose subcutaneous methylnaltrexone versus higher dose There was little to no difference in risk of spontaneous laxations in the medium-term (1 mg versus 5 mg or greater: RR 2.91, 95% CI 0.82 to 10.39; 1 trial, 26 participants very low-certainty evidence), or in patient assessment of improvement in bowel status (RR 0.98, 95% CI 0.71 to 1.35, 1 trial, 102 participants; low-certainty evidence). Medium-term assessment of spontaneous laxations and serious AEs not reported. There was little to no difference in symptoms of opioid withdrawal (MD -0.25, 95% CI -0.84 to 0.34, 1 trial, 102 participants) or occurrence of AEs (low-certainty evidence). AUTHORS' CONCLUSIONS: This update's findings for naldemedine and naloxone with oxycodone have been strengthened with two new trials, but conclusions have not changed. Moderate-certainty evidence for oral naldemedine on risk of spontaneous laxations and non-serious AEs suggests in people with cancer that naldemedine may improve bowel function over two weeks and increase the risk of AEs. There was low-certainty evidence on serious AEs. Moderate-certainty evidence for methylnaltrexone on spontaneous laxations over two weeks suggests subcutaneous methylnaltrexone may improve bowel function in people receiving palliative care, but certainty of evidence for AEs was low. More trials are needed, more evaluation of AEs, outcomes patients rate as important, and in children.


Assuntos
Neoplasias , Constipação Induzida por Opioides , Síndrome de Abstinência a Substâncias , Adulto , Analgésicos Opioides/efeitos adversos , Criança , Humanos , Naloxona , Naltrexona/análogos & derivados , Antagonistas de Entorpecentes/efeitos adversos , Neoplasias/tratamento farmacológico , Oxicodona , Cuidados Paliativos , Compostos de Amônio Quaternário
20.
J Emerg Med ; 62(2): 231-239, 2022 02.
Artigo em Inglês | MEDLINE | ID: mdl-34893381

RESUMO

BACKGROUND: Opioid-induced constipation (OIC) is a frequent consequence of opioid analgesia that may increase patient risk for emergency department visits and hospitalization. Methylnaltrexone is a peripherally acting µ-opioid receptor antagonist indicated for the treatment of OIC. OBJECTIVE: To assess the safety and efficacy of a single methylnaltrexone dose. METHODS: Results were pooled from three randomized, placebo-controlled methylnaltrexone (MNTX) studies in opioid-treated patients with advanced illness and OIC, despite treatment with conventional laxatives. Baseline assessments included demographics, disease/treatment characteristics, and functional levels. Efficacy endpoints included rescue-free laxation (RFL) rates within 4 and 24 h, time to first RFL, pain score change, and adverse events (AEs) after a single MNTX dose or placebo. RESULTS: The analysis included 281 patients receiving MNTX and 237 receiving placebo. Mean age was 66.2 years for MNTX and 65.8 for placebo; ∼50% were men. The most frequent primary diagnosis was cancer (MNTX = 70.5%; placebo = 66.2%) and most (∼98%) were receiving at least one laxative at baseline. RFL occurred in 61.4% vs. 16.0%, and 72.1% vs. 40.1% MNTX vs. placebo patients, within 4 and 24 h of the initial dose, respectively. Relative to placebo, MNTX use reduced the time to first RFL, with most MNTX-treated patients achieving RFL within 2 h. Baseline and posttreatment pain scores were similar (p = 0.9556 vs. placebo for current and worst pain change from baseline), demonstrating that MNTX did not negatively affect opioid analgesia. Most AEs were gastrointestinal related and dissipated by the second dose. CONCLUSIONS: Methylnaltrexone provides early RFL without compromising analgesia in patients receiving chronic opioid therapy.


Assuntos
Analgésicos Opioides , Constipação Induzida por Opioides , Idoso , Analgésicos Opioides/efeitos adversos , Constipação Intestinal/induzido quimicamente , Constipação Intestinal/tratamento farmacológico , Humanos , Masculino , Naltrexona/efeitos adversos , Naltrexona/análogos & derivados , Compostos de Amônio Quaternário
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