title: Clinical evaluation of the efficacy of methylnaltrexone in resolving constipation induced by different opioid subtypes combined with laboratory analysis of immunomodulatory and antiangiogenic effects of methylnaltrexone.
abstract: BACKGROUND
  Opioid-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.
  
  
  METHODS
  In 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.
  
  
  CONCLUSIONS
  In 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.
  
  
  BACKGROUND
  This trial is registered at clinicaltrials.gov: NCT01955213 and in the Dutch trial register: NTR4272.
authors.affiliation: Department of Medical Oncology, VU University Medical Center, Cancer Center Amsterdam, Amsterdam, The Netherlands.
authors.forename: Elisabeth Cw
authors.initials: EC
authors.lastname: Neefjes
authors.affiliation: Department of Medical Oncology, VU University Medical Center, Cancer Center Amsterdam, Amsterdam, The Netherlands.
authors.forename: Maurice Jdl
authors.initials: MJ
authors.lastname: van der Vorst
authors.affiliation: Bardo Hospice, Hoofddorp, The Netherlands.
authors.forename: Manon Sa
authors.initials: MS
authors.lastname: Boddaert
authors.affiliation: Department of Anesthesiology, VU University Medical Center, Amsterdam, The Netherlands.
authors.forename: Wouter Wa
authors.initials: WW
authors.lastname: Zuurmond
authors.affiliation: Department of Medical Oncology, VU University Medical Center, Cancer Center Amsterdam, Amsterdam, The Netherlands.
authors.forename: Hans J
authors.initials: HJ
authors.lastname: van der Vliet
authors.affiliation: Department of Internal Medicine, Spaarneziekenhuis, Hoofddorp, The Netherlands.
authors.forename: Aart
authors.initials: A
authors.lastname: Beeker
authors.affiliation: Department of Internal Medicine, Tergooi, Hilversum, The Netherlands.
authors.forename: Hendrik P
authors.initials: HP
authors.lastname: van den Berg
authors.affiliation: Department of Internal Medicine, Amstelland Ziekenhuis, Amstelveen, The Netherlands.
authors.forename: Cornelis J
authors.initials: CJ
authors.lastname: van Groeningen
authors.affiliation: Department of Internal Medicine, Medisch Centrum Alkmaar, Alkmaar, The Netherlands.
authors.forename: Suzan
authors.initials: S
authors.lastname: Vrijaldenhoven
authors.affiliation: Department of Medical Oncology, VU University Medical Center, Cancer Center Amsterdam, Amsterdam, The Netherlands.
authors.forename: Henk Mw
authors.initials: HM
authors.lastname: Verheul
keywords: Angiogenesis; Constipation; Immunomodulation; Methylnaltrexone; Opioids; Palliative care