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By William T. Elliott, MD, FACP, and James Chan, PharmD, PhD
Dr. Elliott is Chair, Formulary Committee, Northern California Kaiser Permanente; and Assistant Professor of Medicine, University of California, San Francisco. Dr. Chan is Pharmacy Quality and Outcomes Manager, Kaiser Permanente, Oakland, CA
Drs. Elliott and Chan report no financial relationships relevant to this field of study.
The FDA has approved a mu-opioid receptor antagonist for the treatment of opioid-induced constipation (OIC). Naloxegol is a pegylated derivative of naloxone which acts on peripheral (e.g., gut) mu-receptors. It is marketed by AstraZeneca Pharmaceuticals as Movantik.
Naloxegol is indicated for the treatment of OIC in adults with chronic non-cancer pain.1
The recommended dose is 25 mg once daily and if not tolerated, the dose should be reduced to 12.5 mg once daily.1 It should be taken on an empty stomach (at least 1 hour before the first meal or 2 hours after the meal). Grapefruit or grapefruit juice should be avoided. Maintenance laxatives should be discontinued before starting naloxegol, but may be resumed if constipation persists 3 days after starting naloxegol. Naloxegol is available as 12.5 mg and 25 mg tablets.
The pegylated form of naltrexone makes it a substrate for p-glycoprotein transporter, thus limiting its access into the central nervous system and preserving centrally mediated analgesia.1
Symptoms of opioid withdrawal have occurred in patients treated with naloxegol.1 The drug is contraindicated in patients with known or suspected gastrointestinal (GI) obstruction and patients at increased risk of recurrent obstruction due to the potential for GI perforation. Concomitant use with moderate-to-strong CYP3A4 inhibitors and inducers should be avoided.
The efficacy and safety of naloxegol was evaluated in two identical Phase 3, double-blind, 12-week studies in patients (n = 1337) with non-cancer pain and OIC.1,2 Patients received morphine equivalents between 30 mg and 1000 mg daily for at least 4 weeks. OIC was defined as < 3 spontaneous bowel movements ([SBM] without use of rescue laxative) per week. Also, at least 25% of the bowel movements were associated with straining, hard or lumpy stools, and having a sensation of incomplete evacuation. Eligible subjects were randomized at a 1:1:1 ratio to naloxegol 12.5 mg, 25 mg, or placebo once daily for 12 weeks. The primary endpoint was response rate during the 12-week treatment period. This was defined as ¡Ã 3 SBMs per week and an increase of ¡Ã one SBM over baseline for at least 9 of 12 treatment weeks and at least 3 of the final 4 treatment weeks. The response rate for the 25 mg dose was significantly different from placebo (44% vs 29% and 40% vs 29%). The 12.5 mg dose was significantly different from placebo in one study only (41% vs 29%, and 35% vs 29%). Secondary endpoints included response rate in those with inadequate response to laxative. Results for the 25 mg were 49% vs 29% and 47% vs 31%. Naloxegol also decreased the time to first post-dose SBM, increased the number of SBM and stool consistency, reduced the severity of straining, and improved the percent of days per week with complete SBM. Most common adverse events (25 mg vs placebo) were abdominal pain (21% vs 7%), diarrhea (9% vs 5%), and nausea (8% vs 5%).1 The drug appears to be generally safe and well tolerated up to 52 weeks.3
OIC is a common adverse event of opioid treatment. This is due to inhibition of water and electrolyte secretion as a result of stimulation of the mu-opioid receptor in the enteric nervous system. Current treatments include the mu-opioid receptor antagonist methylnaltrexone and the chloride channel activator lubiprostone. Systematic review and meta-analysis of mu-opioid receptor antagonists showed that these agents are safe and effective4 acting on the apical portion of the intestine increasing fluid secretion and intestinal mobility, bypassing the antisecretory actions of opioids. All of these agents seem to be effective and well tolerated.5 There are currently no published comparative trials among these treatments. The cost for naloxegol was not available at the time of this review.
1. Movantik Prescribing Information. Wilmington, DE: AstraZeneca Pharmaceuticals; September 2014.
2. Chey WD, et al. Naloxegol for opioid-induced constipation in patients with noncancer pain. N Engl J Med 2014;370:2387-2396.
3. Webster L, et al. Randomised clinical trial: The long-term safety and tolerability of naloxegol in patients with pain and opioid-induced constipation. Aliment Pharmacol Ther 2014;40:771-779.
4. Ford AC, et al. Efficacy of pharmacological therapies for the treatment of opioid-induced constipation: Systematic review and meta-analysis. Am J Gastroenterol 2013;108:1566-1574.
5. Cryer B, et al. A randomized study of lubiprostone for opioid-induced constipation in patients with dhronic noncancer pain. Pain Med 2014; Apr 9.
doi: 10.1111/pme.12437. [Epub ahead of print.]