Effects of 500 mg Immediate Release and Extended Release Methylnaltrexone on Loperamide-induced Delay of the Oro-cecal and Whole-gut Transit Time in Healthy Subjects
Condition: Intestinal Obstruction
MeSH terms: Intestinal Obstruction
Study type: Interventional
Phase: Phase 1

Summary: 
      The purpose of this study is to describe the effects of methylnaltrexone in preventing
      loperamide-induced delay of the oro-cecal and whole-gut transit time and measure
      pharmacokinetics of methylnaltrexone after subcutaneous and oral administration of immediate
      release and extended release capsules.
    

Detailed description: 
      The increasing prevalence of opioid use and consequently, opioid-induced bowel dysfunction
      has prompted interest in identifying effective treatment options. Until now, the treatment of
      opioid-induced constipation (OIC) has been viewed as an extension of constipation in general.
      Traditional therapies for constipation such as bulking agents, stool softeners, stimulant
      laxatives, and osmotic agents are commonly utilized, but the effects of such therapies are
      nonspecific and are often generating diarrhea or cramps and some of these drugs cause severe
      side effects. Furthermore, these conventional measures are sometimes insufficient in some
      patients, especially those requiring increasing doses of opioids.

      Opioid-induced constipation is predominantly mediated by gastrointestinal μ-opioid receptors.
      Selective blockade of these peripheral receptors might relieve constipation without
      compromising centrally mediated effects of opioid analgesia or precipitating withdrawal.

      Naloxone is a competitive antagonist of opioid receptors inside and outside the central
      nervous system used as a solution for injection in the treatment of opioid overdose. When
      administered orally, it can reduce opioid-induced constipation due to a local action in the
      gut.

      Another way to prevent central actions is the use of opioid antagonists which can't penetrate
      the blood-brain barrier such as methylnaltrexone and alvimopan. Their antagonism of μ-opioid
      receptors in the gastrointestinal tract seems to reverse opioid-induced gut hypomotility.

      It is assumed that methylnaltrexone after oral administration influences intestinal motility
      by local blockade of opioid receptors along the luminal surface of the gut. Because
      methylnaltrexone seems to have an absorption window in the proximal small intestine as caused
      by lower activity of P-glycoprotein in that region (similar to other quaternary compounds,
      eg. trospium chloride), immediate release (uncoated) methylnaltrexone is better absorbed form
      the small intestine and might therefore be less active than the enteric-coated drug.

      However, the pharmacokinetic and pharmacodynamic data on oral methylnaltrexone are very
      preliminarily so far. Furthermore, intestinal transit time has been measured using lactulose
      as a probe compound that has an own laxative effect.

      Therefore, the following clinical study was initiated to proof the concept in a controlled
      clinical trial in healthy subjects, whether methylnaltrexone antagonizes the loperamide
      induced delay of oro-cecal and whole-gut transit time after oral administration of immediate
      and extended release capsules in comparison to subcutaneous administration.

      Loperamide is an opioid agonist and acts on the µ-receptors in the myenteric plexus. It does
      not affect the central nervous system like other opioids. Loperamide significantly prolongs
      the mouth-to-cecum transit time as evaluated by the lactulose hydrogen breath test. This
      effect may be antagonized by the concomitant administration of naloxone.
    

Intervention name(s): Loperamide; Loperamide placebo; Methylnaltrexone placebo; Methylnaltrexone 12 mg sc.; Methylnaltrexone IR capsule; Methylnaltrexone ER capsule; Colon Transit; Sulfasalazine
Intervention type(s): Drug; Drug; Drug; Drug; Drug; Drug; Device; Drug
Intervention description(s): 20 ml Loperamid-ratiopharm® Lösung (ratiopharm) in 180 ml apple juice prepared before administration; 200 ml apple juice; Methylnaltrexone placebo capsule (identical to MNTX IR and MNTX ER); RELISTOR 12 mg/0.6 ml Injektionslösung (Wyeth); Methylnaltrexone bromide 500 mg IR capsule; Methylnaltrexone bromide 500 mg ER capsule; 3x1 capsules containing radio-opaque marker of 6 different shapes (in two consecutive study periods, capsules with different shapes of the markers are given); 500 mg Azulfidine® (Pharmacia)
Other intervention name(s): LOP 4 mg; LOP placebo; MNTX placebo; MNTX 12 mg sc.; MNTX IR; MNTX ER; SSP
Intervention MeSH terms: Sulfasalazine; Naltrexone; Methylnaltrexone; Loperamide; Antidiarrheals
Allocation: Randomized
Intervention model: Crossover Assignment
Masking: Triple (Participant, Care Provider, Investigator)
Primary purpose: Basic Science
Keywords: Loperamide-induced obstipation; Methylnaltrexone; oro-cecal transit time; whole gut transit time; Pharmacokinetics