Abstract
BackgroundOpioid-induced constipation (OIC) is one of the major symptoms in palliative care with a prevalence of 30-50%. Methylnaltrexone for the treatment of OIC is significantly more effective than placebo, but only in about fifty percent of the patients regardless of dose increase. Dose increases cause increased toxicity without additional efficacy, and are therefore not recommended.While methylnaltrexone is a μ-receptor antagonist, only a few opioids are solely μ-receptor agonists. Therefore, the response to methylnaltrexone may be determined by the receptor-profile of a specific opioid. In addition, methylnaltrexone may also affect the immune system and angiogenesis as was found in pre-clinical studies. Primary aim of this study is to determine differences in the efficacy of methylnaltrexone prescribed to resolve opioid induced constipation between three commonly used opioid subtypes: morphine sulphate, oxycodone and fentanyl. Secondary aim is to explore potential immunomodulatory and antiangiogenic effects of methylnaltrexone.MethodsIn this multi-center, prospective, parallel group trial we will evaluate the efficacy of methylnaltrexone in resolving OIC occurring as a side effect of the most common opioid subtypes: morphine, oxycodone and fentanyl. In total 195 patients with OIC despite prophylactic laxatives will receive methylnaltrexone every other day up to fourteen days. Patients will report its effect in a laxation diary. Group allocation is based on the opioid type the patient is using. At the start and end of the study period patients complete the Bowel Function Index questionnaire. A subgroup of the patients will donate blood for analysis of immunomodulatory- and anti-angiogenic effects of methylnaltrexone.DiscussionIn this study we aim to determine the efficacy of methylnaltrexone per opioid subtype to reduce constipation. We expect that the outcome of this study will improve the clinical use of methylnaltraxone.Trial registrationThis trial is registered at clinicaltrials.gov: NCT01955213 and in the Dutch trial register: NTR4272.
Highlights
Opioid-induced constipation (OIC) is one of the major symptoms in palliative care with a prevalence of 30-50%
In palliative care for patients with cancer mechanical obstruction by tumor depositions or ascites might be a cause of constipation, but often constipation is caused by opioid use
Primary aim of the study is to compare the efficacy of a fixed dose of subcutaneous methylnaltrexone to induce laxation in patients who suffer from constipation due to either fentanyl, oxycodone or morphine sulphate despite optimal prophylactic laxative use
Summary
This study is a multi-center, prospective, parallel-group, observational study to compare the efficacy of methylnaltrexone between patient groups using different types of opioids. Abdominal cramps or sudden increase of pain grade 3 according to the Common Terminology Criteria for Adverse Events (CTCAE), that is related to the study drug according to the investigator, could be reason to skip the dose of methylnaltrexone. If these side-effects re-appear after the following dose, the treatment with methylnaltrexone should be halted. The combination of a high probability that the constipation is opioid induced in the oxycodone group, with its activity on both the central and the peripheral mu, kappa, and gamma receptor leads to an expected response rate that equals that of morphine sulphate. The time to laxation, the number of laxations per week, the change in BFI score and the data from the laboratory part will be continuous variables and will be presented by their mean and standard deviation and analyzed by means of the student t-test, Mann–Whitney U test, or ANOVA, whichever is considered most appropriate
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