Peripherally acting μ-opioid receptor antagonists as treatment options for constipation in noncancer pain patients on chronic opioid therapy

Abstract

Opioid-induced constipation (OIC), a prevalent and distressing side effect of opioid therapy, does not reliably respond to treatment with conventional laxatives. OIC can be a treatment-limiting adverse event. Recent advances in medications with peripherally acting μ-opioid receptor antagonists, such as methylnaltrexone, naloxegol, and alvimopan, hold promise for treating OIC and thus extending the benefits of opioid analgesia to more chronic pain patients. Peripherally acting μ-opioid receptor antagonists have been clinically tested to improve bowel symptoms without compromise to pain relief, although there are associated side effects, including abdominal pain. Other treatment options include fixed-dose combination products of oxycodone analgesic together with naloxone.

Incidence of opioid‐induced constipation in Japanese patients with cancer pain: A prospective observational cohort study

“…Laxatives such as magnesium oxide have been widely used as a prophylactic treatment for OIC in Japan, 11 but these agents have limited efficacy because they do not target the underlying pathophysiology of OIC. 5,[12][13][14] Several targeted drugs (eg, methylnatrexone, naloxegol) belonging to a class known as peripherally acting μ-opioid-receptor antagonists (PAMORAs) are approved in the US for the treatment of OIC. 15,16 Naldemedine, another PAMORA, is approved in the US and Japan for the treatment of OIC in patients with chronic non-cancer pain, and in Japan for patients with cancer.…”

Effects of naloxegol on whole gut transit in opioid‐naïve healthy subjects receiving codeine: A randomized, controlled trial

“…Peripherally active μ‐opioid receptor antagonists (PAMORA) have emerged as a treatment option for chronic opioid‐induced constipation (OIC) . Naloxegol is a novel PAMORA which is efficacious in the treatment of chronic OIC when administered orally at a dose of 25 mg daily .…”

“…11 Peripherally active μ-opioid receptor antagonists (PAMORA) have emerged as a treatment option for chronic opioid-induced constipation (OIC). 12 Naloxegol is a novel PAMORA which is efficacious in the treatment of chronic OIC when administered orally at a dose of 25 mg daily. 13 It is a polyethylene glycol derivative of naloxol, with significantly less central nervous system (CNS) penetration compared with naloxol.…”

Treating opioid‐induced constipation in patients taking other medications: Avoiding CYP450 drug interactions

“…3,11 In all cases, OIC results in a decreased quality of life and lost work productivity. 3,[12][13][14][15] There can also be serious medical sequelae, including pain ("painstipation" 3 ), haemorrhoids, anal fissure, organ prolapse, bowel obstruction and perforation, and peritonitis, among others. 16 All of these have a large negative impact and cost to the patient, provider and healthcare system.…”

“…18,19 Unlike constipation that is caused by infections, disease processes, ageing, stress, lack of physical activity, diet, lack of hydration, functional gastrointestinal disorders, endocrine or metabolic disorders, and other intrinsic and extrinsic factors, 16,21 constipation caused by opioids is part of a normal pharmacodynamics response to an opioid and thus has a clear mechanistic aetiology and immediate cause-direct activation of opioid receptors by the administered opioid analgesic. 22 Therefore, non-directed and non-pharmacological efforts at treatment 15,23 that do not accurately address the mechanistic cause are inherently indirect, less likely to be effective, and may even exacerbate the problem. 3 Bulk-forming agents (such as methylcellulose, psyllium, calcium polycarbophil and bran), prokinetics (such as metoclopramide), stool softeners (such as docusate sodium, emollients (such as mineral oil)), osmotic agents (such as polyethylene glycol, lactulose, sorbitol and magnesium hydroxide), stimulants (such as senna glycoside and bisacodyl), chloride channel activators (such as lubriprostone, FDA-approved for treating OIC), serotonin 5-HT 4 receptor agonists (such as tegaserod and prucalopride) and guanylate cyclase receptor agonists (such as linaclotide) attempt to counteract the physiological changes produced by the opioid analgesic.…”