Retardiert freigesetztes Naloxon oral: Aufhebung der Obstipation durch orales Morphin ohne Beseitigung der Analgesie

Abstract

Prolonged administration of morphine for the treatment of chronic pain causes constipation requiring the use of laxatives, which may result in electrolyte deficits. Morphine-induced constipation is due to the binding of the drug to opioid receptors in the gastrointestinal tract and the brain, where it mimics the actions of enkephalins. The effect on the gastrointestinal tract seems to be more intense than the central effect. The particular pharmacokinetic of naloxone makes it possible to reduce or abolish the constipation that follows oral administration of morphine without markedly interfering with the central effect of morphine, i.e. analgesia. The results obtained with oral administration to rats of morphine and naloxone in aqueous solution have already been published [17]. Oral morphine in doses of 1, 2.5 and 5 mg/kg reduce the intestinal transit time in a dose-dependent manner (Fig. 2, filled circles). Doses of 10 and 20 mg/kg are as effective as 5 mg/kg. Naloxone 10 mg/kg administered together with morphine either prevented or attenuated the constipating effect of morphine (Fig. 2, open circles). Tail-flick latency was used as an indicator of analgesia in the animal experiment; it was significantly increased 1, 2 and 3 h after oral administration of morphine 2.5 mg/kg (Fig. 3, hatched columns). When naloxone 10 mg/kg was given with the morphine, there was no significant reduction in tail-flick latency (Fig. 3, cross-hatched columns). Thus, oral administration of naloxone in aqueous solution antagonized the constipating effect of morphine without interfering with the antinociceptive effect of morphine. Experiments carried out with oral administration to rats of slow-release naloxone instead of naloxone in aqueous solution have not so far been published. Slow-release naloxone 5 mg/kg abolished the slowing of intestinal transit caused by oral morphine 2.5 mg/kg (Fig. 4, left-hand columns). The increase in transit time following morphine 5 mg/kg was deminished by simultaneous oral administration of slow-release naloxone 3 and 5 mg/kg in a dose-dependent manner (Fig. 4, right-hand columns). The increase in tail-flick latency caused by morphine 2.5 mg/kg was reduced but not abolished by simultaneous administration of naloxone 5 mg/kg (Fig. 5). Slow-release naloxone 3 or 5 mg/kg reduced the duration without interfering with the maximum of the antinociceptive effect of morphine 5 mg/kg (Fig. 6). These results show that slow-release naloxone is more effective than naloxone in aqueous solution in antagonizing the effects of morphine: after oral administration of the slow-release preparation, even the central action of morphine is reduced. Provided that the anatomical organization of the haemorrhoidal veins in the rat is similar to that in man, slow-release naloxone will be carried by the matrix, to which it is absorbed further down in the gastrointestinal tract. It may thus even reach the rectum, from where, after having been absorbed, it bypasses the liver, enters the central nervous system and reduces the antinocic...

Constipation?modern laxative therapy

“…Causes and pathophysiology of opioid-induced constipation Peripheral as well as intrathecal and intraventricular application of opioids will lead to a prolonged colon passage of the bowel content due to the fact that opioid-induced constipation is caused by linkage of the opioid to opioid receptors in the bowel and the central nervous system [6,7].…”

Opioide in der Tumorschmerztherapie

“…Ur sa che ei ner Obsti pa ti on durch Opioide ist die Bindung des Opio ids an Opioidre zep to ren im Darm und im ZNS [19,20]. Nicht nur die pe ri phe re, son dern auch die in trathe ka le und in tra ven tri ku lä re Ap pli ka tion von Opioiden führt zu ei ner Ver zö gerung der Darm pas sa ge.…”

Orales Papaverin reduziert die morphinbedingte Obstipation ohne Abschw�chung der Analgesie nach oralem Morphin

“…Die Mechanismen der Entstehung einer Obstipation unter dem Einflug von Morphin wurden in einer vorausgehenden Untersuchung ausfiihrlich beschrieben [23] (siehe auch [33]). Dabei ging es um die Aufhebung der morphinbedingten Obstipation im Tierversuch durch oral verabfolgtes Naloxon, ohne dab die antinozizeptiv-analgetische Wirkung von Morphin beseitigt wurde (siehe auch [27]).…”

“…Orale Anwendung von Morphin in Dosen von 2,5 mg/ kg und 5 mg/kg verl~ingerte die Darmpassagezeit von 7 auf 10h, was mit frtiheren Beobachtungen tibereinstimmt [23,27]. Die durch Morphin ausgel/~ste Obstipation wurde durch oral verabfolgtes Papaverin (0,5, 1 und 2 mg/kg) signifikant vermindert, jedoch nicht vOllig aufgehoben.…”

“…Die durch Morphin ausgel/~ste Obstipation wurde durch oral verabfolgtes Papaverin (0,5, 1 und 2 mg/kg) signifikant vermindert, jedoch nicht vOllig aufgehoben. Dies entspricht frtiher mit Naloxon erhobenen Befunden [23,27] [42], jedoch waren dabei die minimal wirksamen Dosen achtfach h6her als die, die in den an Thalamusneuronen durchgeftihrten Versuchen angewendet wurden und allein gegeben unwirksam waren. Deshalb ist es wahrscheinlicher, dab die Steigerung der Morphinwirkung auf einer Verbesserung der gastrointestinalen Funktion beruhte.…”