6β-Naltrexol, a Peripherally Selective Opioid Antagonist that Inhibits Morphine-Induced Slowing of Gastrointestinal Transit: An Exploratory Study

Abstract

6β-Naltrexol acts as a potent, peripherally selective opioid antagonist. The compound was well-tolerated in this study and may have clinical potential in the therapy of peripheral opioid effects such as opioid-induced constipation.

Preferential Delivery of an Opioid Antagonist to the Fetal Brain in Pregnant Mice

“…From the current study, we can estimate that the half-life of 6b-naltrexol in mice is in the range of 1-2 hours at most. In contrast, the half-life of 6b-naltrexol in humans is much longer than that in mice (.11 hours;Yancey-Wrona et al, 2011). Similarly, the half-life of methadone in rodents is only 1-3 hours, approximating the clearance and analgesic time profile of morphine (Pacifici et al, 1994;Kalvass et al, 2007b), highlighting species differences in opioid PK.…”

“…We previously described the relative exclusion of 6b-naltrexol from the brain compared with naltrexone in adult mice (Wang et al, 2004), and the peripheral selectivity of 6b-naltrexol in humans (Yancey-Wrona et al, 2011). We note that 6b-naltrexol is a main metabolite of naltrexone in humans, whereas metabolic conversion is much reduced in mice.…”

P2Y 12 Receptor Antagonists and Morphine

“…On the contrary, there is no definitive evidence that morphine use is associated with higher rate of hard clinical end points in the setting of current management of STEMI and non-STEMI patients treated with PCI, and the lack of randomized studies with clinical end points precludes drawing incontrovertible informed conclusions. In addition to this central unresolved issue regarding the true clinical significance of the observed interaction in terms of hard outcomes, future research should probably address other aspects of the situation as well, including the generalizability of findings regarding morphine to other opioids, the exact mechanisms underlying the observed interactions, the efficacy of potential measures that could counteract inadequate platelet inhibition resulting from these interactions (eg, novel opioid antagonists are being tested, which inhibit peripheral/gastrointestinal morphine effects, with no or minimal antagonism in the central nervous system 36,37 ), and the relative significance of these effects in different patient subgroups and clinical settings. Another question to be answered is whether there are significant differences between available P2Y 12 receptor antagonists, in terms of their susceptibility to be affected, pharmacodynamically or pharmacokinetically, by morphine.…”

<p>The Use of Peripheral μ-Opioid Receptor Antagonists (PAMORA) in the Management of Opioid-Induced Constipation: An Update on Their Efficacy and Safety</p>

“…A product related to naltrexone, 6β-naltrexol was explored as a PAMORA for OIC but never commercially developed. 49 Alvimopan, a PAMORA that was approved for accelerating upper and lower gastrointestinal tract recovery following partial bowel resection with primary anastomosis, never sought regulatory approval for treatment of OIC. 50 Alvimopan is an oral agent indicated for the short-term treatment of postoperative ileus in hospitalized patients.…”