title: Methylnaltrexone: its pharmacological effects alone and effects on morphine in healthy volunteers.
abstract: BACKGROUND
  Methylnaltrexone bromide (MTNX) is a peripherally acting mu-opioid receptor antagonist, prescribed for the treatment of opioid-induced constipation in patients with advanced illness who are receiving palliative care. Studies have used this drug to determine if other opioid-induced effects besides constipation are altered by MTNX in humans and have suggested, based on their results, that these other effects are altered by peripheral opioid actions.
  
  
  OBJECTIVE
  The primary objective of this report is to present results that provide indirect evidence that MTNX has centrally mediated effects, albeit slight, and secondarily to describe the effects of MTNX on psychopharmacological effects of morphine.
  
  
  METHODS
  In a crossover, randomized, placebo-controlled, double-blind study, 29 healthy volunteers received 0.45 mg/kg MTNX or saline subcutaneously, followed by saline intravenously. In three other conditions, 0.143 mg/kg of morphine sulfate administered intravenously was preceded by subcutaneous administration of 0, 0.225, or 0.45 mg/kg MTNX. Before and after drug administration, subjective and physiological measures, including pupil diameter, were assessed.
  
  
  RESULTS
  Two separate analyses confirmed that 0.45 mg/kg MTNX alone induced a slight degree of miosis, a centrally mediated opioid agonist effect. This dose had minimal subjective effects. MTNX at either or both the 0.225 and 0.45 mg/kg dose reduced some subjective effects of morphine without altering miosis.
  
  
  CONCLUSIONS
  We present indirect evidence that MTNX crosses the blood-brain barrier in humans. Therefore, whether the reductions in subjective effects of morphine by MTNX that were observed in past studies and in this study can be attributed to peripheral mechanisms is open to question.
authors.affiliation: Department of Anesthesia and Critical Care, The University of Chicago, Chicago, IL, 60637, USA, zacn@uchicago.edu.
authors.forename: James P
authors.initials: JP
authors.lastname: Zacny
authors.forename: Kristen
authors.initials: K
authors.lastname: Wroblewski
authors.forename: Dennis W
authors.initials: DW
authors.lastname: Coalson
mesh_terms: D000328:Adult; D000701:Analgesics, Opioid / Q000008:administration & dosage* / Q000037:antagonists & inhibitors*; D018592:Cross-Over Studies; D004311:Double-Blind Method; D005260:Female; D064368:Healthy Volunteers / Q000523:psychology*; D006339:Heart Rate / Q000187:drug effects / Q000502:physiology; D006801:Humans; D007262:Infusions, Intravenous; D008297:Male; D009020:Morphine / Q000008:administration & dosage* / Q000037:antagonists & inhibitors*; D009271:Naltrexone / Q000031:analogs & derivatives* / Q000494:pharmacology; D009292:Narcotic Antagonists / Q000494:pharmacology; D011680:Pupil / Q000187:drug effects / Q000502:physiology; D000644:Quaternary Ammonium Compounds / Q000494:pharmacology; D017450:Receptors, Opioid, mu / Q000819:agonists; D016896:Treatment Outcome; D055815:Young Adult
chemical_list: D000701:Analgesics, Opioid; D009292:Narcotic Antagonists; D000644:Quaternary Ammonium Compounds; D017450:Receptors, Opioid, mu; C032257:methylnaltrexone; D009271:Naltrexone; D009020:Morphine