n-methylnaloxone and Constipation

Opioids are the drugs of choice for treating moderate-to-severe pain, especially for patients in the end stage of cancer or other advanced illnesses, and also in critical care or for the treatment of chronic pain. Side effects such as nausea, pruritus, dizziness and constipation have to be controlled in order to use these drugs to their full potential. Opioid-induced bowel syndrome and constipation caused by activation of μ-receptors in the gut can have such distressing effects that some patients prefer to forego adequate pain control. Methylnaltrexone is a μ-opioid receptor antagonist that, unlike naltrexone or naloxone, does not pass the blood-brain barrier, and therefore does not impair the centrally mediated analgesic effect of opioids. It is licensed for the treatment of opioid-induced constipation in palliative care in more than 50 countries. This article presents practically relevant pharmacological data, basic research results and evidence from clinical research about methylnaltrexone, and outlines potential future therapeutic options for this promising drug.

Topics: Analgesics, Opioid; Constipation; Humans; Naloxone; Narcotic Antagonists; Pain; Palliative Care; Quaternary Ammonium Compounds; Receptors, Opioid, mu; Treatment Outcome

Endomorphins are endogenous opioid peptides in mammals and display a strong antinociceptive effect after central administration. However, the clinical usage of these peptides is limited because of their diminished analgesic effect following systemic injection and their inability to cross the blood-brain barrier. In this study, we characterized the in vivo effects of four novel endomorphin-1 analogues (termed MELs), which previously showed potential as highly potent analgesics with a good pharmacological profile in vitro. The analogues were administered intravenously to several rodent pain models to examine their antinociception and blood-brain barrier permeability. The tested peptides, especially MEL1214, showed good analgesic activity and blood-brain barrier permeability. Behavioral studies showed dose-dependent analgesic effect after systematic administration of MEL1214 in the tested pain models. Pre-treatment of subcutaneous administration of naloxone methiodide did not affect the antinociception of these peptides. As compared to morphine, MEL1214 was less prone to induce tolerance after consecutive intravenous administration for 5 days. Gastrointestinal transit was evaluated by the isolated colon response and bead expulsion to determine the potential constipation effect. In contrast to morphine, MEL1214 produced no significant constipation effect at an equivalent dose. MEL1214 shows promise as a suitable compound to treat pain with reduced side effects, and exhibits good potential to be further developed as a novel opioid analgesic in pain treatment.

Topics: Analgesics, Opioid; Animals; Blood-Brain Barrier; Capillary Permeability; Colon; Constipation; Disease Models, Animal; Drug Tolerance; Male; Mice; Morphine; Naloxone; Narcotic Antagonists; Nociceptive Pain; Oligopeptides; Quaternary Ammonium Compounds