Opioid-Induced Constipation Part 2: Newer Therapies #295

Naloxone

Until recently, naloxone was the only available opioid antagonist for OIC treatment. Typically, patients orally ingest the contents of IV ampules. Naloxone has a high first-pass metabolism, so it is possible for patients who take it orally to have peripheral μ-opioid receptor antagonism without significant impact on central receptors which could lead to opioid withdrawal and loss of analgesia. ² In a small, noncontrolled study, 80% of chronic opioid users had bowel evacuation in one to four hours after naloxone administration. Unfortunately, over two-thirds reported a 10% to 15% loss of analgesia and nearly one-third had withdrawal symptoms. ³ Therefore, if used, it is recommended to start at a low dosage of 0.8 mg twice daily. Effective dosages typically need to be at least 10% of equivalent daily morphine dosage, so naloxone usually requires slow uptitration with max dosing of 12 mg daily. ²

Methylnaltrexone bromide

Methylnaltrexone is a peripherally acting μ-opioid receptor antagonist. It is a methylated form of naltrexone and formulated as a subcutaneous injection. It is less able to cross the blood-brain barrier, reducing the risk of altering analgesia or inducing central opioid withdrawal. An industry-funded randomized controlled trial of chronic opioid users showed that weight-based methylnaltrexone dosing led to laxation in nearly half of subjects within four hours as opposed to 15% of placebo. ⁴ A subsequent meta-analysis of six separate trials with methylnaltrexone demonstrated the number needed to treat (NNT) is three for OIC patients that have failed to respond to standard laxative therapy. ⁵ Its use is limited by cost which averages $55 per dose, and it is also contraindicated when bowel obstruction is suspected or for patients with compromised bowel integrity. The most common side effects are nausea, diarrhea, and cramping—which can be severely painful.

Naloxegol

Two oral peripheral-acting μ-opioid receptor antagonists are available in the United States: alvimopam, which is only approved for postoperative ileus, and naloxegol (pegylated naloxone), which has recently been approved for OIC in noncancer patients. Two separate phase three clinical trials showed an increase from 1 to >3 bowel movements per week in noncancer patients on chronic opioids with daily dosed naloxegol compared to placebo. There was also significant improvement in a subset of patients who had failed traditional laxative therapy. Both 12.5 mg and 25 mg have been studied; the 25 mg dose has a higher success rate but is associated with more abdominal pain, nausea, vomiting, and diarrhea. ⁷ Its current price is approximately $300 for 30 pills.

Other agents

Lubiprostone is a selective chloride channel-2 activator that acts locally on the small intestine to increase fluid secretion and GI motility. It is FDA approved for OIC. Two randomized controlled trials in noncancer chronic opioid users demonstrated an increase in frequency of spontaneous bowel movements by week eight. Moreover, approximately 40% of subjects had a bowel movement at 24 hours, 60% within 48 hours, and 27% of subjects had >3 bowel movements per week.^8,9 The most studied dosage is 24 mcg orally twice per day. Common side effects included nausea, diarrhea, and abdominal distension. Curiously, lubiprostone does not appear to be effective for methadone-induced constipation. ¹⁰

Linactolide has a different mechanism than lubiprostone but is also a small intestinal secretogogue. It currently is approved for irritable bowel syndrome. Though there is interest in its efficacy in OIC, it has yet to be specifically studied in this population.

Prucalopride is a serotonin receptor type-4 agonist that is available in Canada and parts of Europe and Asia to treat chronic constipation. It is a prokinetic agent which has shown promise for treating OIC in a phase 2 study. ⁵ It is unclear if or when it will be released in the United States.