Novel Oral Therapies for Opioid‐induced Bowel Dysfunction in Patients with Chronic Noncancer Pain

Abstract

Opioid analgesics are frequently prescribed and play an important role in chronic pain management. Opioid-induced bowel dysfunction, which includes constipation, hardened stool, incomplete evacuation, gas, and nausea and vomiting, is the most common adverse event associated with opioid use. Mu-opioid receptors are specifically responsible for opioid-induced bowel dysfunction, resulting in reduced peristaltic and secretory actions. Agents that reverse these actions in the bowel without reversing pain control in the central nervous system may be preferred over traditional laxatives. The efficacy and safety of these agents in chronic noncancer pain were assessed from publications identified through Ovid and PubMed database searches. Trials that evaluated the safety and efficacy of oral agents for opioid-induced constipation or opioid-induced bowel dysfunction, excluding laxatives, were reviewed. Lubiprostone and naloxegol are approved in the United States by the Food and Drug Administration for use in opioid-induced constipation. Axelopran (TD-1211) and sustained-release naloxone have undergone phase 2 and phase 1 studies, respectively, for the same indication. Naloxegol and axelopran are peripherally acting μ-opioid receptor antagonists. Naloxone essentially functions as a peripherally acting μ-opioid receptor antagonist when administered orally in a sustained-release formulation. Lubiprostone is a locally acting chloride channel (CIC-2) activator that increases secretions and peristalsis. All agents increase spontaneous bowel movements and reduce other bowel symptoms compared with placebo in patients with noncancer pain who are chronic opioid users. The most common adverse events were gastrointestinal in nature, and none of the drugs were associated with severe adverse or cardiovascular events. Investigations comparing these agents to regimens using standard laxative and combination therapy and trials in special populations and patients with active cancer are needed to further define their role in therapy.

Update on Rome IV Criteria for Colorectal Disorders: Implications for Clinical Practice

“…Significant advances have been made in the area of opioid-induced bowel dysfunction in recent years, including development of new therapies and better understanding of underlying mechanisms and differences between the various constellations of symptoms related to the intake of opioids [27–29]. Even though traditionally not consistent with the definition of a functional GI disorder (“underlying cause not known / well defined”), it was decided to include OIC among the functional bowel disorders in Rome IV, based on the frequent overlap and shared underlying mechanisms.…”

Antagonistas periféricos de los receptores opioides Mu en el tratamiento del estreñimiento inducido por opioides: revisión.

“…Solo una proporción de pacientes con EIO no respondieron a la administración de PAMORA en los diferentes estudios y precisaron laxantes de rescate; lo anterior sugiere que los mecanismos fisiopatológicos del estreñimiento, aun en presencia de opioides, son más complejos y que otras causas (como los fármacos con acción anticolinérgica (13) o disfunción intestinal relacionada con el uso de quimioterápicos (65)) deben ser tenidas en cuenta. Por lo tanto, aunque los PAMO-RA constituyen un abordaje etiopatogénico del EIO, ello no obvia el uso de laxantes y pone en cuestión si laxantes y PAMORA deben usarse de forma concomitante, o si bien los PAMORA se deben usar como rescate en pacientes que no responden a los laxantes (66). El uso de laxantes se ha propuesto como primera línea en el estreñimiento en pacientes con enfermedades avanzadas (6), limitando el uso de PAMORA en los casos refractarios; por otra parte se ha recomendado el uso de PAMORA en aquellos pacientes con un Bowel Functional Index (BFI) ≥ 30 (67).…”

Clinical Overview and Considerations for the Management of Opioid-induced Constipation in Patients With Chronic Noncancer Pain

“…All serious adverse events were unrelated to treatment and therefore did not raise any serious safety concerns 35. Long-term safety information on the label for lubiprostone has remained the same since its approval in 2008, suggesting consistent safety data since product approval 70…”