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      Managing opioid-induced constipation in advanced illness: focus on methylnaltrexone bromide

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          Abstract

          Constipation is a common symptom in palliative care patients which can generate considerable suffering. There is uncertainty about the choice of treatment options from varying recommendations for management of constipation and a varying clinical practice in palliative care settings. The purpose of the review was to evaluate the current recommendations of therapy guidelines for the management of opioid-induced constipation in palliative care patients with a focus on methylnaltrexone bromide. Recent findings in the literature and related information on the opioid-induced gastrointestinal disorders in patients with advanced illness, as well as information on the opioid-antagonist methylnaltrexone, are discussed. Knowledge of the role of definitions, the causes of constipation and the pathophysiology of opioid-induced constipation must be given high priority in the treatment of patients receiving opioids. Diagnosis and therapy of constipation, therefore, should relate to findings in clinical investigation. Opioid-induced constipation and its adequate treatment is an important issue for patients with advanced illness and also poses therapeutic challenge for clinicians in daily routine. Methylnaltrexone bromide may represent an important therapeutic option for palliative care patients who are suffering from opioid-induced constipation with failure of conventional prophylactic oral laxative treatment.

          Most cited references48

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          Functional bowel disorders.

          Employing a consensus approach, our working team critically considered the available evidence and multinational expert criticism, revised the Rome II diagnostic criteria for the functional bowel disorders, and updated diagnosis and treatment recommendations. Diagnosis of a functional bowel disorder (FBD) requires characteristic symptoms during the last 3 months and onset > or =6 months ago. Alarm symptoms suggest the possibility of structural disease, but do not necessarily negate a diagnosis of an FBD. Irritable bowel syndrome (IBS), functional bloating, functional constipation, and functional diarrhea are best identified by symptom-based approaches. Subtyping of IBS is controversial, and we suggest it be based on stool form, which can be aided by use of the Bristol Stool Form Scale. Diagnostic testing should be guided by the patient's age, primary symptom characteristics, and other clinical and laboratory features. Treatment of FBDs is based on an individualized evaluation, explanation, and reassurance. Alterations in diet, drug treatment aimed at predominant symptoms, and psychotherapy may be beneficial.
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            Opioid complications and side effects.

            Medications which bind to opioid receptors are increasingly being prescribed for the treatment of multiple and diverse chronic painful conditions. Their use for acute pain or terminal pain is well accepted. Their role in the long-term treatment of chronic noncancer pain is, however, controversial for many reasons. One of the primary reasons is the well-known phenomenon of psychological addiction that can occur with the use of these medications. Abuse and diversion of these medications is a growing problem as the availability of these medications increases and this public health issue confounds their clinical utility. Also, the extent of their efficacy in the treatment of pain when utilized on a chronic basis has not been definitively proven. Lastly, the role of opioids in the treatment of chronic pain is also influenced by the fact that these potent analgesics are associated with a significant number of side effects and complications. It is these phenomena that are the focus of this review. Common side effects of opioid administration include sedation, dizziness, nausea, vomiting, constipation, physical dependence, tolerance, and respiratory depression. Physical dependence and addiction are clinical concerns that may prevent proper prescribing and in turn inadequate pain management. Less common side effects may include delayed gastric emptying, hyperalgesia, immunologic and hormonal dysfunction, muscle rigidity, and myoclonus. The most common side effects of opioid usage are constipation (which has a very high incidence) and nausea. These 2 side effects can be difficult to manage and frequently tolerance to them does not develop; this is especially true for constipation. They may be severe enough to require opioid discontinuation, and contribute to under-dosing and inadequate analgesia. Several clinical trials are underway to identify adjunct therapies that may mitigate these side effects. Switching opioids and/or routes of administration may also provide benefits for patients. Proper patient screening, education, and preemptive treatment of potential side effects may aid in maximizing effectiveness while reducing the severity of side effects and adverse events. Opioids can be considered broad spectrum analgesic agents, affecting a wide number of organ systems and influencing a large number of body functions.
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              Methylnaltrexone for opioid-induced constipation in advanced illness.

              Constipation is a distressing side effect of opioid treatment. As a quaternary amine, methylnaltrexone, a mu-opioid-receptor antagonist, has restricted ability to cross the blood-brain barrier. We investigated the safety and efficacy of subcutaneous methylnaltrexone for treating opioid-induced constipation in patients with advanced illness. A total of 133 patients who had received opioids for 2 or more weeks and who had received stable doses of opioids and laxatives for 3 or more days without relief of opioid-induced constipation were randomly assigned to receive subcutaneous methylnaltrexone (at a dose of 0.15 mg per kilogram of body weight) or placebo every other day for 2 weeks. Coprimary outcomes were laxation (defecation) within 4 hours after the first dose of the study drug and laxation within 4 hours after two or more of the first four doses. Patients who completed this phase were eligible to enter a 3-month, open-label extension trial. In the methylnaltrexone group, 48% of patients had laxation within 4 hours after the first study dose, as compared with 15% in the placebo group, and 52% had laxation without the use of a rescue laxative within 4 hours after two or more of the first four doses, as compared with 8% in the placebo group (P<0.001 for both comparisons). The response rate remained consistent throughout the extension trial. The median time to laxation was significantly shorter in the methylnaltrexone group than in the placebo group. Evidence of withdrawal mediated by central nervous system opioid receptors or changes in pain scores was not observed. Abdominal pain and flatulence were the most common adverse events. Subcutaneous methylnaltrexone rapidly induced laxation in patients with advanced illness and opioid-induced constipation. Treatment did not appear to affect central analgesia or precipitate opioid withdrawal. (Clinical Trials.gov number, NCT00402038 [ClinicalTrials.gov].). Copyright 2008 Massachusetts Medical Society.
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                Author and article information

                Journal
                Ther Clin Risk Manag
                Therapeutics and Clinical Risk Management
                Therapeutics and Clinical Risk Management
                Dove Medical Press
                1176-6336
                1178-203X
                2010
                2010
                3 March 2010
                : 6
                : 77-82
                Affiliations
                [1 ]Department of Science and Research, Centre for Palliative Medicine, University of Bonn, Germany;
                [2 ]Department of Palliative Medicine and Pain Therapy, Malteser Hospital Bonn/Rhein-Sieg, Germany
                Author notes
                Correspondence: Katri Elina Clemens, Department of Science and Research, Centre for Palliative Medicine, Malteser Hospital Bonn/Rhein-Sieg, Von-Hompesch-Str. 1, D-53123, Bonn, Germany, Tel +49 (0)228-6481-13169, Fax +49 (0)228-6481-9020, Email katri-elina.clemens@ 123456malteser.org
                Article
                tcrm-6-077
                2835562
                20234787
                a88033de-d23f-4572-968a-c5b951806581
                © 2010 Clemens and Klaschik, publisher and licensee Dove Medical Press Ltd.

                This is an Open Access article which permits unrestricted noncommercial use, provided the original work is properly cited.

                History
                : 9 February 2010
                Categories
                Review

                Medicine
                opioid-induced constipation,palliative care,opioids,methylnaltrexone bromide
                Medicine
                opioid-induced constipation, palliative care, opioids, methylnaltrexone bromide

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