The effect of naloxone-3-glucuronide on colonic transit time in healthy men after acute morphine administration: a placebo-controlled double-blinded crossover preclinical volunteer study.
BACKGROUND
Constipation is a significant side effect of opioid therapy. We have previously demonstrated that naloxone-3-glucuronide (NX3G) antagonizes the motility-lowering-effect of morphine in the rat colon.


OBJECTIVE
To find out whether oral NX3G is able to reduce the morphine-induced delay in colonic transit time (CTT) without being absorbed and influencing the analgesic effect.


METHODS
Fifteen male volunteers were included. Pharmacokinetics: after oral administration of 0.16 mg/kg NX3G, blood samples were collected over a 6-h period. Pharmacodynamics: NX3G or placebo was then given at the start time and every 4 h thereafter. Morphine (0.05 mg/kg) or placebo was injected s.c. 2 h after starting and thereafter every 6 h for 24 h. CTT was measured over a 48-h period by scintigraphy. Pressure pain threshold tests were performed.


RESULTS
Neither NX3G nor naloxone was detected in the venous blood. The slowest transit time was observed during the morphine phase, which was significantly different from morphine with NX3G and placebo. The pain perception was not significantly influenced by NX3G.


CONCLUSIONS
Orally administered NX3G is able to reverse the morphine-induced delay of CTT in humans without being detected in peripheral blood samples. Therefore, NX3G may improve symptoms of constipation in-patients using opioid medication without affecting opioid-analgesic effects.
Netzer
P
P
Department of Gastroenterology, Inselspital, University Hospital Bern, Bern, Switzerland. netzer@gzl.ch
Sendensky
A
A
Wissmeyer
M P
MP
Baumeler
S
S
Batista
C
C
Scheurer
U
U
Krause
T
T
Reber
P
P
Brenneisen
R
R
D000328:Adult; D000701:Analgesics, Opioid / Q000009:adverse effects; D003106:Colon / Q000000981:diagnostic imaging / Q000187:drug effects* / Q000502:physiology*; D018592:Cross-Over Studies; D004311:Double-Blind Method; D005772:Gastrointestinal Transit / Q000187:drug effects; D006801:Humans; D007205:Indium Radioisotopes; D008297:Male; D009020:Morphine / Q000009:adverse effects; D009270:Naloxone / Q000031:analogs & derivatives* / Q000097:blood / Q000493:pharmacokinetics / Q000494:pharmacology; D009292:Narcotic Antagonists / Q000097:blood / Q000493:pharmacokinetics / Q000494:pharmacology*; D011877:Radionuclide Imaging; D012684:Sensory Thresholds / Q000187:drug effects; D055815:Young Adult
D000701:Analgesics, Opioid; D007205:Indium Radioisotopes; D009292:Narcotic Antagonists; D009270:Naloxone; D009020:Morphine; C518509:naloxone-3-glucuronide