Effects of Methylnaltrexone in Comparison to Naloxone on Loperamide-induced Delay of the Oro-cecal, Whole-gut and Colon Transit Time.
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 repeated-dose methylnaltrexone in
      preventing loperamide-induced delay of whole-gut, oro-cecal and colon transit time and to
      measure pharmacokinetics of methylnaltrexone and naloxone-3-glucuronide after oral
      administration of methylnaltrexone and naloxone.
    

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. It has a high first-pass metabolism, which is an advantage as the laxative effect can be
      achieved due to the local action in the gut without significant antagonism of the narcotic
      analgesic effect of opioid. In some patients, however, withdrawal symptoms or reduction of
      analgesia was seen.

      Another way to prevent central actions is the use of opioid antagonists which cannot
      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 quatenary 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. The data were obtained in rather small groups with inadequate study
      design (no randomization, no cross-over, lack of sensitive analytical assays etc.)
      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 extended release methylnaltrexone antagonizes the
      loperamide induced delay of oro-cecal and whole-gut transit time in comparison to extended
      release naloxone.

      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 placebo; Loperamide; Colon Transit; Sulfasalazine; Placebo of MNTX and NLX; Naloxone; Methylnaltrexone
Intervention type(s): Drug; Drug; Device; Drug; Drug; Drug; Drug
Intervention description(s): 200 ml apple juice; 20 ml Loperamid-ratiopharm® Lösung (ratiopharm) in 180 ml apple juice containing 4 mg of loperamide hydrochloride (prepared before administration); 5 capsules containing radio-opaque markers of different shapes, respectively; Azulfidine® Tabletten 500 mg (Pharmacia/Pfizer) containing 500 mg immediate release sulfasalazine; Placebo capsule (hard gelatine capsule containing multiple sugar spheres); Naloxone hydrochloride 20 mg Extended Release Capsule equivalent to 18 mg naloxone (hard gelatine capsule containing a single NLX-ER tablet and multiple sugar spheres); Methylnaltrexone bromide 150 mg extended release capsule equivalent to 122 mg methylnaltrexone (hard gelatine capsule containing multiple MNTX-ER micro tablets)
Other intervention name(s): LOP Placebo; LOP; SSP; Placebo; NLX-ER; MNTX-ER
Intervention MeSH terms: Sulfasalazine; Naloxone; Methylnaltrexone; Loperamide; Antidiarrheals
Allocation: Randomized
Intervention model: Crossover Assignment
Masking: Triple (Participant, Care Provider, Investigator)
Primary purpose: Basic Science
Keywords: whole-gut transit time; oro-cecal transit time; colon transit time; loperamide-induced obstipation; pharmacokinetics; Methylnaltrexone; Naloxone