Peripherally Acting μ-Opioid Receptor Antagonists for the Treatment of Opioid-Related Side Effects: Mechanism of Action and Clinical Implications

Abstract

Opioid receptors are distributed throughout the central and peripheral nervous systems and on many nonneuronal cells. Therefore, opioid administration induces effects beyond analgesia. In the enteric nervous system (ENS), stimulation of µ-opioid receptors triggers several inhibitory responses that can culminate in opioid-induced bowel dysfunction (OBD) and its most common side effect, opioid-induced constipation (OIC). OIC negatively affects patients' quality of life (QOL), ability to work, and pain management. Although laxatives are a common first-line OIC therapy, most have limited efficacy and do not directly antagonize opioid effects on the ENS. Peripherally acting µ-opioid receptor antagonists (PAMORAs) with limited ability to cross the blood-brain barrier have been developed. The PAMORAs approved by the U S Food and Drug Administration for OIC are subcutaneous and oral methylnaltrexone, oral naloxegol, and oral naldemedine. Although questions of cost-effectiveness and relative efficacy versus laxatives remain, PAMORAs can mitigate OIC and improve patient QOL. PAMORAS may also have applications beyond OIC, including reducing the increased cardiac risk or potential tumorigenic effects of opioids. This review discusses the burden of OIC and OBD, reviews the mechanism of action of new OIC therapies, and highlights other potential opioid-related side effects mediated by peripheral opioid receptors in the context of new OIC therapies.

Safety and Efficacy of Naldemedine for the Treatment of Opioid-Induced Constipation in Patients with Chronic Non-Cancer Pain Receiving Opioid Therapy: A Subgroup Analysis of Patients ≥ 65 Years of Age

“…Additionally, studies of nursing home residents show that OIC is associated with worse physical and mental outcomes in older patients [9,10]. Naldemedine is an oral, once-daily, peripherally acting µ-opioid receptor antagonist (PAMORA) approved in Japan, the United States, and the European Union for the treatment of OIC in adults [11][12][13][14].…”

What to Do and What Not to Do in the Management of Opioid-Induced Constipation: A Choosing Wisely Report

“…Panel consensus was congruent with this recommendation: laxatives can be offered at the initiation of opioid treatment for prevention or should otherwise be prescribed for the emergence of constipation symptoms. That said, the efficacy of laxatives for OIC is controversial in some studies indicating low patient satisfaction and the persistence of OIC despite continued laxative treatment [28,29]. This is likely to due to the fact that laxatives do not specifically target the mechanism of action that causes OIC, i.e., opioid receptors expressed in the gastrointestinal tract.…”

Biased Opioid Antagonists as Modulators of Opioid Dependence: Opportunities to Improve Pain Therapy and Opioid Use Management

“…Some reports propose that opioid receptors and specifically MOR exist in different forms in peripheral versus central neurons [ 13 ]. Peripheral and central opioid receptor systems could interact dynamically, for example in the induction of opioid induced hyperalgesia, reported to be mediated both centrally and peripherally [ 14 , 15 ]. Peripheral MOR sites could have relevance to inflammation induced neuropathic pain, invoking beta-arestin-2 silenced MOR sites in afferent nociceptors [ 14 , 16 ], that get activated upon inflammatory stimuli.…”

“…tract and in nociceptor neurons, the latter involved in peripheral analgesia [ 37 ]. PAMORAs including methylnaltrexone, naloxegol, alvimopan, and naldemdine are in clinical use to treat opioid-induced bowel dysfunction and constipation [ 15 , 38 ]. Peripheral selectivity is thought to depend on limited access to the CNS through the blood–brain-barrier (BBB), either because of high polarity or by extrusion via export transporters [ 39 ].…”