Intestinal Obstruction Clinical Trial
Official title:
Effects of Extended Release Methylnaltrexone Bromide (150 mg b.i.d.) in Comparison to Extended Release Naloxone Hydrochloride (20 mg b.i.d.) on Loperamide-induced Delay of the Oro-cecal, Whole-gut and Colon Transit Time in Healthy Subjects.
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.
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.
;
Allocation: Randomized, Endpoint Classification: Pharmacokinetics/Dynamics Study, Intervention Model: Crossover Assignment, Masking: Double Blind (Subject, Caregiver, Investigator), Primary Purpose: Basic Science
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