Emerging therapies for patients with symptoms of opioid-induced bowel dysfunction

Abstract

Opioid-induced bowel dysfunction (OIBD) comprises gastrointestinal (GI) symptoms, including dry mouth, nausea, vomiting, gastric stasis, bloating, abdominal pain, and opioid-induced constipation, which significantly impair patients’ quality of life and may lead to undertreatment of pain. Traditional laxatives are often prescribed for OIBD symptoms, although they display limited efficacy and exert adverse effects. Other strategies include prokinetics and change of opioids or their administration route. However, these approaches do not address underlying causes of OIBD associated with opioid effects on mostly peripheral opioid receptors located in the GI tract. Targeted management of OIBD comprises purely peripherally acting opioid receptor antagonists and a combination of opioid receptor agonist and antagonist. Methylnaltrexone induces laxation in 50%–60% of patients with advanced diseases and OIBD who do not respond to traditional oral laxatives without inducing opioid withdrawal symptoms with similar response (45%–50%) after an oral administration of naloxegol. A combination of prolonged-release oxycodone with prolonged-release naloxone (OXN) in one tablet (a ratio of 2:1) provides analgesia with limited negative effect on the bowel function, as oxycodone displays high oral bioavailability and naloxone demonstrates local antagonist effect on opioid receptors in the GI tract and is totally inactivated in the liver. OXN in daily doses of up to 80 mg/40 mg provides equally effective analgesia with improved bowel function compared to oxycodone administered alone in patients with chronic non-malignant and cancer-related pain. OIBD is a common complication of long-term opioid therapy and may lead to quality of life deterioration and undertreatment of pain. Thus, a complex assessment and management that addresses underlying causes and patomechanisms of OIBD is recommended. Newer strategies comprise methylnaltrexone or OXN administration in the management of OIBD, and OXN may be also considered as a preventive measure of OIBD development in patients who require opioid administration.

Pharmacokinetic Bioequivalence Studies of an Extended-Release Oxycodone Hydrochloride Tablet in Healthy Japanese Subjects Under Fasting and Fed Conditions Without an Opioid Antagonist

“…Opioid-induced bowel dysfunction, which includes constipation, hard dry stools, incomplete evacuation, bloating, abdominal cramping, and increased gastric reflux, is the most distressing symptom, and the frequency of symptoms ranges from 26 to 49% in patients receiving oxycodone [16]. An ER tablet comprising oxycodone and naloxone was developed, and analgesic efficacy was reported as comparable with a significant and clinically relevant improvement in opioid-induced constipation in various types of pain even after long-term treatment [17, 18]. Both test and reference products in the present study were well tolerated, with no severe AEs experienced.…”

The role of naloxegol in the management of opioid-induced bowel dysfunction

“…Opioid switch or change of route of opioid administration may also be considered although the evidence is limited. The final steps are rectal measures and manual stool evacuation (under analgesia and sedation) when all measures fail [Leppert, 2015].…”

Management of opioid-induced constipation in pregnancy: a concise review with emphasis on the PAMORAs

“…The results of studies of methylnaltrexone and naloxegol suggest the induction of bowel movement in 50–60% of patients within 4 h from administration and show minimal occurrence of adverse effects (abdominal pain, nausea and diarrhoea at <5%) . On the other hand, the results for lubiprostone are equivocal to date.…”

“…Compared to conventional treatments such as laxatives, PAMORA has the advantage of improving bowel movements without undermining the analgesic effects of the opioid. They have been reported to show significantly superior efficacy for the management of OIC . If well‐controlled studies demonstrate safety and efficacy of PAMORA for pregnant women, they could provide a breakthrough for the treatment of OIC in pregnancy.…”