Clinical potential of naloxegol in the management of opioid-induced bowel dysfunction

Abstract

Opioid-induced bowel dysfunction (OIBD) is a burdensome condition which limits the therapeutic benefit of analgesia. It affects the entire gastrointestinal tract, predominantly by activating opioid receptors in the enteric nervous system, resulting in a wide range of symptoms, such as reflux, bloating, abdominal cramping, hard, dry stools, and incomplete evacuation. The majority of studies evaluating OIBD focus on constipation experienced in approximately 60% of patients. Nevertheless, other presentations of OIBD seem to be equally frequent. Furthermore, laxative treatment is often insufficient, which in many patients results in decreased quality of life and discontinuation of opioid treatment. Novel mechanism-based pharmacological approaches targeting the gastrointestinal opioid receptors have been marketed recently and even more are in the pipeline. One strategy is prolonged release formulation of the opioid antagonist naloxone (which has limited systemic absorption) and oxycodone in a combined tablet. Another approach is peripherally acting, μ-opioid receptor antagonists (PAMORAs) that selectively target μ-opioid receptors in the gastrointestinal tract. However, in Europe the only PAMORA approved for OIBD is the subcutaneously administered methylnaltrexone. Alvimopan is an oral PAMORA, but only approved in the US for postoperative ileus in hospitalized patients. Finally, naloxegol is a novel, oral PAMORA expected to be approved soon. In this review, the prevalence and pathophysiology of OIBD is presented. As PAMORAs seem to be a promising approach, their potential effect is reviewed with special focus on naloxegol's pharmacological properties, data on safety, efficacy, and patient-focused perspectives. In conclusion, as naloxegol is administered orally once daily, has proven efficacious compared to placebo, has an acceptable safety profile, and can be used as add-on to existing pain treatment, it is a welcoming addition to the targeted treatment possibilities for OIBD.

Keywords: constipation; dysfunction; gut; naloxegol; opioid antagonists; opioids.

Figure 1

Principle of the motility tracking system for evaluation of gut motility. Notes: An elastic belt with detector is fixed to the patient’s abdomen. The magnetic capsule(s) is swallowed, and information about the position, direction, velocity, and amplitude of bowel movements can be recorded. When the capsule is expelled, data is extracted from the detector and segmental transit times can be calculated.

Figure 2

Schematic representation of the Ussing chamber measuring gut secretion. Notes: Viable biopsies are mounted between two chambers filled with Krebs-Ringer solution. The two chambers respectively simulate blood stream and gut lumen. The mounted intestinal mucosa actively pumps ions from one chamber to the other and the resultant electrical gradient between chambers is measured with electrodes inserted on both sides.

Figure 3

The FLIP probe. Notes: The balloon is placed in the anal sphincter and filled with saline water. Through 16 electrodes the cross-sectional area and pressure can be monitored real-time and recorded, which can be used to derive the geometric profile of the sphincter function both during relaxation and challenge-testing. Abbreviation: FLIP, functional lumen imaging probe technique.

Figure 4

Pharmacological principle of naloxegol under normal conditions (left column), during opioid treatment (middle) and opioid and naloxegol treatment (right). Notes: First row: opioids in the systemic circulation cross the blood–brain barrier and induce analgesia. Peripheral restriction prevents naloxegol from crossing the blood–brain barrier, thus centrally mediated analgesia is maintained. Second row: opioids bind to enteric nervous system μ-opioid receptors and cause non-propulsive motility. Due to higher affinity, naloxegol displaces opioids from the receptors in the gut and thus prevents dysmotility. Third row: naloxegol antagonizes the decreased secretion of electrolytes and water to the intestinal lumen, which results in a less dry, softer stool. Fourth row: in the gastrointestinal sphincters (here illustrated by the anal sphincter), naloxegol (at least theoretically) prevents sphincter dyscoordination and increased resting tone, with a net result of less straining and easier evacuation. Abbreviations: ENS, enteric nervous system; BBB, blood–brain barrier.