Opioid induced constipation

Opioids delay G.I. transit, stimulate non-propulsive motor activity, increase intestinal segmentation, and decrease electrolyte and water secretion into the gut.

Opioid induced constipation is a result of the binding of opioid agonists mu opioid receptors located in the enteric nervous system.

The development of OIC affects 41 to 94% of opioid users.

The binding of opioid agonists to mu-opioid receptors leads to increased nonpropulsive contractions and inhibition of water and electrolyte secretion.

Mu opioid enteric receptors activation decrease bowel tone and contractibility and increase colonic fluid absorption and anal sphincter tone while reducing rectal sensation: leading to harder stools, which can be difficult to pass.

The binding of opioid agonists to mu-opioid receptors leads to inhibition of gastric emptying, increases pyloric tone, and delays transit through the small and large intestines, increases in resting anal sphincter pressure, and decreases secretion of electrolytes and water into the intestinal lumen as well as increases in the net absorption of luminal fluid.

Dietary modifications, lifestyle changes and laxatives are used to treat opioid induced constipation but have limited efficacy.

The first line treatment of Opioid-induced constipation is non-pharmacological, and includes lifestyle modifications like increasing dietary fiber, fluid intake, and physical activity.

Traditional laxatives such as stool softeners, osmotics,  stimulants, lubricant agents are recommended is the initial treatment of opioid induced constipation.

If non-pharmacological measures are not successfully, laxatives, including stool softeners, bulk-forming laxatives, stimulant laxatives and/or enemas, may be used.

In the laxative refractory patient’s peripheral acting mu opioid receptor antagonist are considered as next line therapies.

Peripherally acting u-opioid receptor antagonists are effective and durable for patients with OIC.

Peripherally acting u-opioid receptor antagonists should be considered only when the traditional laxatives fail.

Opioid formulations or regimens that include a peripherally-selective opioid antagonist, such as methylnaltrexone bromide, naloxegol, alvimopan, or naloxone may be tried for opioid induced constipation.

Peripheral acting mu-opioid receptor antagonists limit the effects of opioids on the gastrointestinal tract while preserving centrally mediated analgesia.

Agents available are methylnaltrexone, alvimopan, naldemine, and naloxegol.

Methylnaltrexone is restricted to subcutaneous administration with an indication of treatment of opioid-induced constipation in patients with advanced medical illness.

Alvimopan is approved for shortening the course of postoperative ileus.

Naloxegol is a pegylated derivative of the mu-opioid receptor antagonist naloxone and is a neutral antagonist of the mu-opioid receptor in vitro.

Pegylation allows the P-glycoprotein transporter-substrate properties and limits the ability of naloxegol to cross the blood brain barrier.

Naloxegol at a daily dose of 25-50 mg increases spontaneous so movements of patients with opioid-induced constipation.

Naloxegol is a pegylated derivative of the opioid antagonist naloxone for oral treatment of opioid induced constipation in adults with chronic noncancer pain.

Presently Naloxegol is the only oral opioid antagonist approved for this indication..

Methylnaltrexone , a subcutaneous injected opioid antagonist, and lubiprostone and oral chloride channel activator are effective in increasing the frequency of bowel movements in opioid induced constipation.

Methylnaltrexone normalizes bowel movements in opioid induced constipation and reduces the need for laxatives, but is also frequently associated with non-serious adverse effects, including abdominal pain, flatulence, and dizziness.

Naloxegol In a dose of 25 mg/day increases the number of spontaneous bowel movements and improve quality-of-life at the expense of a higher risk of abdominal pain in adults with opioid induced constipation.

The above peripheral mu – opioid antagonists do not enter the CNS but inhibit only mu opioid receptors in the G.I. tract.