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Opioid-Induced Constipation: New and Emerging Therapies—Update 2016

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Docusate, a surfactant stool softener, is not habit forming but also does not assist with muscle contractility.1 Bulk-forming laxatives, for example psyllium, may lead to increased abdominal pain and bowel obstruction, and are often avoided my most pain practitioners.4 Lactulose and polyethylene glycol are osmotic laxatives that pull water into the GI tract and have evidence for use in OIC, but they do not target the actual OIC cause, and they may provoke electrolyte abnormalities.1,9,10,12 Unfortunately, patients may have inadequate symptom relief from OIC with these laxatives alone or combined. Additionally, clinicians may rotate through different opioids to assess patient response and constipation profile. According to the 2015 consensus statement, “Prescription treatments for OIC should be considered for patients who have a BFI score of ≥ 30 points and an inadequate response to first-line interventions.”11

Pharmaceutical Therapy

It is not often in medicine that a pharmacological antidote exists to a drug treatment or adverse effect. Although newer select agents (ie, ion channel activators) have been approved for OIC, there is only 1 class of drug that targets the specific underlying cause of OIC—binding of opioids to the mu receptors in the enteric nervous system. This new class, known as PAMORAs (Peripheral Acting Mu Opioid Receptor Antagonists), work by selectively inhibiting opioid receptors in the gut, thereby decreasing the constipating effects of opioids without affecting opioid-mediated analgesic effects within the CNS or precipitating withdrawal symptoms (Table 2).2,19


The first available medication in this class was alvimopan (Entereg), which is indicated to accelerate the time to upper and lower GI recovery following surgeries that include partial bowel resection with primary anastomosis.20 It is not specifically approved for OIC. In a study assessing alvimopan for patients on opioids with chronic non-cancer pain (CNCP), alvimopan was associated with an increased risk of myocardial infarction compared to placebo, leading to the issuance of a boxed warning and Risk Evaluation and Mitigation Strategies (REMS) program.20


The next PAMORA introduced to the market was methylnaltrexone bromide (Relistor).21 In 2010, methylnaltrexone subcutaneous injection was Food and Drug Administration (FDA)-approved for the treatment of OIC in patients with advanced illness receiving palliative care. With further study, the agent was approved for the treatment of OIC in adult patients with CNCP.22 In July 2016, the FDA approved an oral formulation of methylnaltrexone bromide (450 mg/day).23 Methylnaltrexone bromide is a quaternary amine with limited penetration through the blood-brain barrier.

The clinical trials leading to approval of methylnaltrexone injection approval found that the agent produced reliable relief of constipation in opioid-treated pain patients—59% of patients receiving methylnaltrexone (12 mg subcutaneous injection daily for 4 weeks) had more than 3 spontaneous bowel movements (SBMs) per week compared to 38% in the placebo treatment group.22 The most common side effects are abdominal pain, nausea, and vomiting. Furthermore, methylnaltrexone did not appear to reverse the opioid’s analgesic effect or cause opioid withdrawal symptoms.21

In addition, significantly more methylnaltrexone-treated patients had a bowel movement within 4 hours than did placebo-treated patients (52% vs 9%; P<0.0001). In approximately 30% of treated patients, laxation was reported within 30 minutes of a dose of methylnaltrexone. Two open-label extension studies suggested the laxation response appeared to be maintained over the course of 3 to 4 months.24

For approval of the oral tablet formulation, the FDA reviewed a randomized placebo-controlled trial of 200 noncancer patients taking methylnaltrexone (450 mg/day) and 201 patients assigned to placebo. The patients had been on opioid therapy for 1 month or longer and had been diagnosed with OIC (< 3 bowel movement per week). The study findings reported significant improvements in rescue-free bowel movement within 4 hours of administration in the treatment arm over 28 days of dosing compared with placebo treatment. In addition, the treatment group also had a higher percentage of responders (those with 3 or more bowel movements per week, with an increase of 1 or more from baseline for at least 3 of the 4 weeks) than the placebo group.21

According to the prescribing information, methylnaltrexone is available in single-use vials, single-use pre-filled syringes, and a tablet oral formulation The dosage for injection is 12 mg, similar to those patients with OIC in advanced illness weighing 62 to 114 kg; patients weighing 38 to 62 kg should receive 8 mg. Outside of this range, dosing is recommended at 0.15 mg/kg. For tablets, the recommended dosage is 450 mg once daily in the morning. Administration for CNCP is daily, with the caveat to discontinue all maintenance laxative therapy prior to methylnaltrexone; laxative(s) can be used as needed if there is a suboptimal response to the agent after 3 days. Dosage reduction is recommended for patients with severe renal impairment.21 The most common adverse reactions with the new oral formulation were abdominal pain, diarrhea, headache, abdominal distention, vomiting, hyperhidrosis, anxiety, muscle spasms, rhinorrhea, and chills. Patient taking methylnaltrexone injection experienced abdominal pain, nausea, diarrhea, hyperhidrosis, hot flush, tremor, and chills.21


Naloxegol (Movantik) was the first orally administered, once-daily PAMORA approved for OIC in patients with CNCP. Naloxegol is a polyethylene glycol (PEG)ylated form of naloxone.25 The efficacy of naloxegol was studied in over 1,300 patients who had been on oral opioids for an average of 3.6 years. OIC was defined as less than 3 SBMs per week with hard/lumpy stools, straining, or sensation of incomplete evacuation or obstruction in 25% or more bowel movements in the preceding 4 weeks.26

Patients were randomly assigned to 3 treatment arms: naloxegol 25 mg daily, naloxegol 12.5 mg daily, or placebo daily for 12 weeks. During the study, no other bowel regimens were permitted, but bisacodyl was allowed as rescue medication if patients did not have a bowel movement in 3 days.26

Last updated on: January 11, 2017
First published on: December 1, 2016
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