Peripheral Opioid Receptor Antagonists for Opioid-Induced Constipation: A Primer on Pharmacokinetic Variabilities with a Focus on Drug Interactions

Jeffrey Gudin, 1, 2 Jeffrey Fudin 3–6 1Department of Anesthesiology, Rutgers New Jersey Medical School, Newark, NJ, USA; 2Department of Anesthesiology, Englewood Hospital and Medical Center, Englewood, NJ, USA; 3Albany College of Pharmacy and Health Sciences, Albany, NY, USA; 4Western New England University College of Pharmacy, Springfield, MA, USA; 5Remitigate, LLC, Delmar, NY, USA; 6Stratton Veterans Affairs Medical Center, Albany, NY, USACorrespondence: Jeffrey GudinDepartment of Anesthesiology, Englewood Hospital and Medical Center, 350 Engle Street, Englewood, NJ 07631, USAEmail jeff@paindr.comAbstract: Opioid analgesics remain a treatment option for refractory acute and chronic pain, despite their potential risk for abuse and adverse events (AEs). Opioids are associated with several common AEs, but the most bothersome is opioid-induced constipation (OIC). OIC is often overlooked but has the potential to affect patient quality of life, increase associated symptom burden, and impede long-term opioid compliance. The peripherally acting μ-receptor antagonists (PAMORAs) are a class of drugs that include methylnaltrexone, naloxegol, and naldemedine. Collectively, each is approved for the treatment of OIC. PAMORAs work peripherally in the gastrointestinal tract, without impacting the central analgesic effects of opioids. However, each has unique pharmacokinetic properties that may be impacted by coadministered drugs or food. This review focuses on important metabolic and pharmacokinetic principals that are pertinent to drug interactions involving μ-opioid receptor antagonists prescribed for OIC. It highlights subtle differences among the PAMORAs that may have clinical significance. For example, unlike naloxegol or naldemedine, methylnaltrexone is not a substrate for CYP3A4 or p-glycoprotein; therefore, its plasma concentration is not altered when coadministered with concomitant medications that are CYP3A4 or p-glycoprotein inducers or inhibitors. With a better understanding of pharmacokinetic nuances of each PAMORA, clinicians will be better equipped to identify potential safety and efficacy considerations that may arise when PAMORAs are coadministered with other medications.Keywords: drug-related side effects and adverse reactions, opioid or opiate mu (μ)-receptor antagonists, opioid analgesics, pharmacokinetics; opioid-induced constipation