Mu-opioid antagonists for opioid-induced bowel dysfunction in people with cancer and people receiving palliative care.
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ABSTRACT:
SUBMITTER: Candy B
PROVIDER: S-EPMC6513061 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:Opioid-induced constipation (OIC) is one of the most troublesome and the most common effects of opioid use leading to deterioration in quality of life of the patients and also has potentially deleterious repercussions on adherence and compliance to opioid therapy. With the current guidelines advocating liberal use of opioids by physicians even for non-cancer chronic pain, the situation is further complicated as these individuals are not undergoing palliative care and hence there cannot be any justification to subject these patients to the severe constipation brought on by opioid therapy which is no less debilitating than the chronic pain. The aim in these patients is to prevent the opioid-induced constipation but at the same time allow the analgesic activity of opioids. Many drugs have been used with limited success but the most specific among them were the peripherally acting mu opioid receptor antagonists (PAMORA). Methylnaltrexone and alvimopan were the early drugs in this group but were not approved for oral use in OIC. However naloxegol, the latest PAMORA has been very recently approved as the first oral drug for OIC. This article gives an overview of OIC, its current management and more specifically the development and approval of naloxegol, including pharmacokinetics, details of various clinical trials, adverse effects and its current status for the management of OIC.
| S-EPMC4544149 | biostudies-literature
Project description:BackgroundThis article describes the second update of a Cochrane review on the effectiveness of laxatives for the management of constipation in people receiving palliative care. Previous versions were published in 2006 and 2010 where we also evaluated trials of methylnaltrexone; these trials have been removed as they are included in another review in press. In these earlier versions, we drew no conclusions on individual effectiveness of different laxatives because of the limited number of evaluations. This is despite constipation being common in palliative care, generating considerable suffering due to the unpleasant physical symptoms and the availability of a wide range of laxatives with known differences in effect in other populations.ObjectivesTo determine the effectiveness and differential efficacy of laxatives used to manage constipation in people receiving palliative care.Search methodsWe searched the Cochrane Central Register of Controlled Trials (CENTRAL; The Cochrane Library), MEDLINE, EMBASE, CINAHL and Web of Science (SCI & CPCI-S) for trials to September 2014.Selection criteriaRandomised controlled trials (RCTs) evaluating laxatives for constipation in people receiving palliative care.Data collection and analysisTwo authors assessed trial quality and extracted data. The appropriateness of combining data from the studies depended upon clinical and outcome measure homogeneity.Main resultsWe identified five studies involving the laxatives lactulose, senna, co-danthramer, misrakasneham, docusate and magnesium hydroxide with liquid paraffin. Overall, the study findings were at an unclear risk of bias. As all five studies compared different laxatives or combinations of laxatives, it was not possible to perform a meta-analysis. There was no evidence on whether individual laxatives were more effective than others or caused fewer adverse effects.Authors' conclusionsThis second update found that laxatives were of similar effectiveness but the evidence remains limited due to insufficient data from a few small RCTs. None of the studies evaluated polyethylene glycol or any intervention given rectally. There is a need for more trials to evaluate the effectiveness of laxatives in palliative care populations. Extrapolating findings on the effectiveness of laxatives evaluated in other populations should proceed with caution. This is because of the differences inherent in people receiving palliative care that may impact, in a likely negative way, on the effect of a laxative.
| S-EPMC6956627 | biostudies-literature
Project description:Opioid ligands have found use in a number of therapeutic areas, including for the treatment of pain and opiate addiction (using agonists) and alcohol addiction (using antagonists such as naltrexone and nalmefene). The reaction of imines, derived from the opioid ligands oxymorphone and naltrexone, with Michael acceptors leads to pyridomorphinans with structures similar to known pyrrolo- and indolomorphinans. One of the synthesized compounds, 5e, derived from oxymorphone had substantial agonist activity at delta opioid receptors but not at mu and/or kappa opioid receptors and in that sense profiled as a selective delta opioid receptor agonist. The pyridomorphinans derived from naltrexone and naloxone were all found to be non-selective potent antagonists and as such could have utility as treatments for alcohol abuse.
| S-EPMC4112151 | biostudies-literature
Project description:Opioid-induced bowel dysfunction (OIBD) comprises gastrointestinal (GI) symptoms, including dry mouth, nausea, vomiting, gastric stasis, bloating, abdominal pain, and opioid-induced constipation, which significantly impair patients' quality of life and may lead to undertreatment of pain. Traditional laxatives are often prescribed for OIBD symptoms, although they display limited efficacy and exert adverse effects. Other strategies include prokinetics and change of opioids or their administration route. However, these approaches do not address underlying causes of OIBD associated with opioid effects on mostly peripheral opioid receptors located in the GI tract. Targeted management of OIBD comprises purely peripherally acting opioid receptor antagonists and a combination of opioid receptor agonist and antagonist. Methylnaltrexone induces laxation in 50%-60% of patients with advanced diseases and OIBD who do not respond to traditional oral laxatives without inducing opioid withdrawal symptoms with similar response (45%-50%) after an oral administration of naloxegol. A combination of prolonged-release oxycodone with prolonged-release naloxone (OXN) in one tablet (a ratio of 2:1) provides analgesia with limited negative effect on the bowel function, as oxycodone displays high oral bioavailability and naloxone demonstrates local antagonist effect on opioid receptors in the GI tract and is totally inactivated in the liver. OXN in daily doses of up to 80 mg/40 mg provides equally effective analgesia with improved bowel function compared to oxycodone administered alone in patients with chronic non-malignant and cancer-related pain. OIBD is a common complication of long-term opioid therapy and may lead to quality of life deterioration and undertreatment of pain. Thus, a complex assessment and management that addresses underlying causes and patomechanisms of OIBD is recommended. Newer strategies comprise methylnaltrexone or OXN administration in the management of OIBD, and OXN may be also considered as a preventive measure of OIBD development in patients who require opioid administration.
| S-EPMC4404965 | biostudies-literature
Project description:Increased responding to drug-associated stimuli (cue reactivity) and an inability to tolerate delayed gratification (reward impulsivity) have been implicated in the development and maintenance of drug addiction. Whereas data from animal studies suggest that both the dopamine and opioid system are involved in these two reward-related processes, their role in humans is less clear. Moreover, dopaminergic and opioidergic drugs have not been directly compared with regard to these functions, even though a deeper understanding of the underlying mechanisms might inform the development of specific treatments for elevated cue reactivity and reward impulsivity. In a randomized, double-blind, between-subject design we administered the selective dopamine D2/D3 receptor antagonist amisulpride (400 mg, n=41), the unspecific opioid receptor antagonist naltrexone (50 mg, n=40) or placebo (n=40) to healthy humans and measured cue-induced responding with a Pavlovian-instrumental transfer task and reward impulsivity with a delay discounting task. Mood was assessed using a visual analogue scale. Compared with placebo, amisulpride significantly suppressed cue-induced responding and reward impulsivity. The effects of naltrexone were similar, although less pronounced. Both amisulpride and naltrexone decreased average mood ratings compared with placebo. Our results demonstrate that a selective blockade of dopamine D2/D3 receptors reduces cue-induced responding and reward impulsivity in healthy humans. Antagonizing μ-opioid receptors has similar effects for cue-induced responding and to a lesser extent for reward impulsivity.
| S-EPMC4969763 | biostudies-literature
Project description:The mechanisms underlying gut development, especially peristalsis, are widely studied topics. However, the causes of gut peristalsis-related diseases, especially Opioid-Induced Bowel Dysfunction (OIBD) disorder, have not been well defined. Therefore, our study used zebrafish, a popular model for studying both gut development and peristalsis, and DCFH-DA, a dye that clearly labels the live fish gut lumen, to characterize the formation process of gut lumen as well as the gut movement style in vivo. By applying Loperamide Hydrochloride (LH), the ?-opioid receptor-specific agonist, we established an OIBD-like zebrafish model. Our study found that acetylcholine (ACh) was a key transmitter that derepressed the phenotype induced by LH. Overall, the study showed that the antagonistic role of ACh in the LH-mediated opioid pathway was evolutionarily conserved; moreover, the OIBD-like zebrafish model will be helpful in the future dissection of the molecular pathways involved in gut lumen development and pathology.
| S-EPMC4083263 | biostudies-literature
Project description:BACKGROUND:People with advanced cancer experience multiple symptoms during their illness trajectory, which can fluctuate in intensity. AIM:To describe the course of self-reported quality of life, emotional functioning, physical functioning and symptom intensity over time in cancer patients receiving palliative care. DESIGN:Longitudinal study with monthly assessments, using the EORTC QLQ-C15-PAL. Data were analysed (1) prospectively, from baseline to ?8-month follow-up; and (2) retrospectively, by taking death as index date and comparing results from three cross-sectional subsamples at different stages of illness (time to death ?6, 5-3 and 2-0 months). Linear mixed models were calculated. SETTING/PARTICIPANTS:A total of 1739 patients (mean age 66, 50% male) from 30 palliative care centers in 12 countries were included. RESULTS:In prospective analyses, quality of life, functioning and symptoms-except nausea/vomiting-remained generally stable over time. In retrospective analyses, patients 2-0 months before death reported significantly lower quality of life and physical functioning scores than those 5-3 months before death, who in turn scored lower than those ?6 months before death, suggesting progressive decline. Emotional functioning remained initially unchanged, but decreased in the last months. Pain, fatigue and appetite loss showed a stable increase in intensity towards death. Dyspnea, insomnia and constipation increased from 5-3 to 2-0 months before death. Nausea/vomiting only increased when comparing those ?6 months before death with those 2-0 months before death. CONCLUSION:While the prospective approach showed predominantly stable patterns for quality of life, functioning and symptom severity throughout study duration, retrospective analyses indicated that deterioration was already apparent before the terminal phase and accelerated close to death. Our findings support the importance of early symptom identification and treatment in this population, and highlight the need for further studies to explore what characterizes those with either lower or higher symptom burden at different time points towards death.
| S-EPMC6784977 | biostudies-literature
Project description:ObjectivesDespite growing research interest in spirituality and health, and recommendations on the importance of spiritual care in advanced cancer and palliative care, relationships between spiritual belief and psychological health near death remain unclear. We investigated (i) relationships between strength of spiritual beliefs and anxiety and depression, intake of psychotropic/analgesic medications and survival in patients with advanced disease; and (ii) whether the strength of spiritual belief changes as death approaches.MethodsWe conducted a prospective cohort study of 170 patients receiving palliative care at home, 97% of whom had a diagnosis of advanced cancer. Data on strength of spiritual beliefs (Beliefs and Values Scale [BVS]), anxiety and depression (Hospital Anxiety and Depression Scale [HADS]), psychotropic/analgesic medications, daily functioning, global health and social support were collected at recruitment then 3 and 10 weeks later. Mortality data were collected up to 34 months after the first patient was recruited.ResultsRegression analysis showed a slight increase in strength of spiritual belief over time approaching statistical significance (+0.16 BVS points per week, 95% CI [-0.01, 0.33], p = 0.073). Belief was unrelated to anxiety and depression (-0.15 points decrease in HADS for 10 points increased in BVS (95% CI [-0.57, 0.27], p = 0.49) or consumption of psychotropic medication). There was a non-significant trend for decreasing analgesic prescription with increasing belief. Mortality was higher over 6 months in participants with lower belief at recruitment.ConclusionResults suggest that although religious and spiritual beliefs might increase marginally as death approaches, they do not affect levels of anxiety or depression in patients with advanced cancer.
| S-EPMC4350444 | biostudies-literature
Project description:The prescribing and use of opioid analgesics is increasing in Italy owing to a profusion in the number and types of opioid analgesic products available, and the increasing prevalence of conditions associated with severe pain, the latter being related to population aging. Herein we provide the expert opinion of an Italian multidisciplinary panel on the management of opioid-induced constipation (OIC) and bowel dysfunction. OIC and opioid-induced bowel dysfunction are well-recognised unwanted effects of treatment with opioid analgesics that can profoundly affect quality of life. OIC can be due to additional factors such as reduced mobility, a low-fibre diet, comorbidities, and concomitant medications. Fixed-dose combinations of opioids with mu (μ) opioid receptor antagonists, such as oxycodone/naloxone, have become available, but have limited utility in clinical practice because the individual components cannot be independently titrated, creating a risk of breakthrough pain as the dose is increased. A comprehensive prevention and management strategy for OIC should include interventions that aim to improve fibre and fluid intake, increase mobility or exercise, and restore bowel function without compromising pain control. Recommended first-line pharmacological treatment of OIC is with an osmotic laxative (preferably polyethylene glycol [macrogol]), or a stimulant laxative such as an anthraquinone. A second laxative with a complementary mechanism of action should be added in the event of an inadequate response. Second-line treatment with a peripherally acting μ opioid receptor antagonist (PAMORA), such as methylnaltrexone, naloxegol or naldemedine, should be considered in patients with OIC that has not responded to combination laxative treatment. Prokinetics or intestinal secretagogues, such as lubiprostone, may be appropriate in the third-line setting, but their use in OIC is off-label in Italy, and should therefore be restricted to settings such as specialist centres and clinical trials.
| S-EPMC8279968 | biostudies-literature
Project description:ContextPain management in palliative care remains inadequate; the development of innovative therapeutic options is needed.ObjectivesTo determine the feasibility and preliminary effectiveness for larger randomised controlled trials of 3D head-mounted (HMD) virtual reality (VR) for managing cancer pain (CP) in adults.MethodsThirteen people receiving palliative care participated in a single-session randomised cross-over trial, after which they completed a qualitative semi-structured interview. We also compared the effects of 3D HMD VR and 2D screen applications on CP intensity and levels of perceived presence. Feasibility was assessed with recruitment, completion rates and time required to recruit target sample.ResultsAlthough recruitment was slow, completion rate was high (93%). Participants reported that the intervention was acceptable and caused few side effects. Although participants reported significantly reduced CP intensity after 3D HMD VR (1.9 ± 1.8, P = .003) and 2D screen applications (1.5 ± 1.6, P = .007), no significant differences were found between interventions (-.38 ± 1.2, 95% CI: -1.1-.29, P = .23). Participants reported significantly higher levels of presence with the 3D HMD VR compared to 2D screen (60.7 ± SD 12.4 versus 34.3 ± SD 17.1, mean 95% CI: 16.4-40.7, P = .001). Increased presence was associated with significantly lower pain intensity (mean 95% CI: -.04--0.01, P = 0.02).ConclusionsOur preliminary findings support growing evidence that both 3D and 2D virtual applications provide pain relief for people receiving palliative care. Given the relative lack of cybersickness and increasing access to portable VR, we suggest that larger clinical studies are warranted.
| S-EPMC8782583 | biostudies-literature