Extended-Release but Not Immediate-Release and Subcutaneous Methylnaltrexone Antagonizes the Loperamide-Induced Delay of the Whole-Gut Transit Time in Healthy Subjects.

Abstract

The article by Kolbow and colleagues titled “Extended-Release but Not Immediate-Release and Subcutaneous Methylnaltrexone Antagonizes the Loperamide-Induced Delay of the Whole-Gut Transit Time in Healthy Subjects,” published online on August 27, 2015 in The Journal of Clinical Pharmacology, is both informative and interesting.1 The authors used loperamide as a probe drug for the study of opioid-induced constipation (OIC), comparing subcutaneously (SC) administered immediate-release methylnaltrexone (MNTX-IR) with extended-release methylnaltrexone (MNTX-ER). The authors found no significant effects of in the MNTX-IR group on whole cut transit time, whereas MNTX-ER significantly antagonized the opioid-induced delay of intestinal transit in 12 of our 15 healthy subjects. Kolbow et al attributed the lack of effect in the MNTX-IR group to the short duration (3–4 hours) at ∼6 ng/mL, which was deemed sufficient for binding with peripheral opioid receptors. However, we believe that central opioid receptors also contribute significantly to OIC. Anecdotally, we have often encountered OIC in patients receiving intrathecal opioid infusion therapy. Indeed, OIC is a known drug-related side effect in patients on long-term intrathecal morphine infusion.2 The decreased gastrointestinal motility caused by intrathecal morphine has been shown to be due to the interaction with opioid receptors in the spinal cord rather than from systemic absorption.3 In a study on gastrointestinal symptoms in patients on chronic opioid therapy, Wirz et al showed that transdermal fentanyl or transdermal buprenorphine (dose adjusted based on morphine equivalent) showed no benefit over sustained-release oral hydromorphone in developing OIC.4 We have also encountered an interesting case of OIC with transdermal buprenorphine opioid in our practice. An 81-year-old gentleman with severe pain in both hips and knees due to severe osteoarthritis started to experience refractory OIC after switching to transdermal buprenorphine at 5 mg/h. The patient had been on oxycodone 5 mg, 4 times a day as needed, without efficacy for pain, or constipation. He reported significant analgesia with a buprenorphine patch but reported persistent constipation despite the use of multiple laxatives.5 Mori et al investigated the mechanisms of OIC (ie, the inhibition of gastrointestinal transit and colonic expulsion) using the peripherally restricted opioid receptor antagonists naloxone methiodide and naloxonazine in mice.6 The authors found naloxonazine attenuated the fentanyl-induced inhibition of gastrointestinal transit more potently than the inhibition by morphine or oxycodone, whereas naloxone methiodide suppressed the oxycodone-induced inhibition of gastrointestinal transit more potently than that by morphine, indicating that μ-opioid receptor agonists induce the inhibition of gastrointestinal transit through different mechanisms. Furthermore, they found that the route of administration (intracerebroventricular, intrathecal, and/or intraperitoneal) of naloxone methiodide differentially influenced the suppressive effect on the inhibition of colorectal transit induced by morphine, oxycodone, and fentanyl.6 Mori et al concluded that morphine, oxycodone, and fentanyl induced constipation though different mechanisms that involved naloxonazine-sensitive vs -insensitive sites with regard to supraspinal/spinal vs peripheral opioid receptors. We believe the utilization of loperamide as the probe drug to study OIC may have been rudimentary. Loperamide does not cross the blood-brain barrier; therefore, it is unable to interact with supraspinal or spinal opioid receptors, as do other opioids, to contribute to centrally mediated OIC. Thus, the external validity of such a pharmacological study may be affected to some degree. External Funding: None Conflict of Interest: None.