What is the recommended treatment for opioid-induced constipation with naloxegol (peripherally acting mu-opioid receptor antagonist) in adults with chronic non-cancer pain?

Naloxegol for Opioid-Induced Constipation

In adults with chronic non-cancer pain and laxative-refractory opioid-induced constipation, naloxegol 25 mg once daily is strongly recommended as an effective treatment that improves bowel function without compromising pain control. 1

Treatment Algorithm

First-Line Management

• Start prophylactic stimulant laxatives (senna) with or without stool softeners when initiating opioid therapy 2
• Titrate laxative dose with goal of one non-forced bowel movement every 1-2 days 2
• If constipation persists, add osmotic laxatives and consider bisacodyl 2

When to Initiate Naloxegol

• Naloxegol is indicated only after inadequate response to conventional laxatives 1, 3
• Discontinue maintenance laxative therapy before starting naloxegol; may resume if OIC symptoms persist after 3 days 4
• Patients receiving opioids for less than 4 weeks may be less responsive to naloxegol 4

Dosing and Administration

Standard Dosing

• Recommended dose: 25 mg once daily in the morning on an empty stomach 5, 4
• Take at least 1 hour before first meal or 2 hours after a meal 4
• If not tolerated, reduce to 12.5 mg once daily 4

Dose Adjustments

• Renal impairment (CrCl <60 mL/min): Start with 12.5 mg once daily; may increase to 25 mg if tolerated while monitoring for adverse reactions 4
• Moderate CYP3A4 inhibitors (diltiazem, erythromycin, verapamil): Reduce to 12.5 mg once daily and monitor for adverse reactions 4
• Severe hepatic impairment: Avoid use 4

Critical Administration Details

• Avoid grapefruit or grapefruit juice consumption 4
• Discontinue if opioid pain medication is discontinued 4
• For patients unable to swallow tablets whole, may crush and administer orally or via nasogastric tube 4

Efficacy Data

Response Rates

• 41.9% of patients on naloxegol 25 mg achieved response versus 29.4% on placebo 5
• Response defined as ≥3 spontaneous bowel movements (SBMs) per week with an increase from baseline of ≥1 SBM/week for at least 9 of 12 weeks 1
• Naloxegol improves SBM frequency and reduces straining during defecation 5

Pain Control Preservation

• Pain scores and opioid doses remain stable with naloxegol use, confirming it does not interfere with centrally-mediated analgesia 2, 6
• Mean changes in pain scores from baseline were minimal across all treatment groups (ranging from -0.3 to +0.2 on 11-point scale) 6
• Mean daily opioid doses remained essentially unchanged (changes of -2.3 to +0.4 morphine equivalent units) 6

Safety Profile

Common Adverse Effects

• Abdominal pain (17.8%), diarrhea (12.9%), nausea (9.4%), headache (9.0%), and flatulence (6.9%) 5
• Most gastrointestinal adverse effects are transient and mild 7
• Adverse events leading to discontinuation occur in approximately 9.4% of patients versus 4.2% on placebo 5

Long-Term Safety

• Naloxegol was generally safe and well tolerated in 12-week extension studies 8
• No important new adverse events emerged with extended use 8
• Improvements in symptoms and quality of life observed in initial trials were maintained throughout extension studies 8

Mechanism of Action

• Naloxegol is a pegylated derivative of naloxone that blocks peripheral μ-opioid receptors in the gut 1
• Pegylation increases oral bioavailability and enhances peripheral selectivity 1
• Acts as substrate for P-glycoprotein transporter, limiting entry into the central nervous system 1
• Does not cross the blood-brain barrier, preserving central opioid analgesia 3

Critical Contraindications and Warnings

Absolute Contraindications

• Known or suspected gastrointestinal obstruction or patients at risk of recurrent obstruction 4
• Concomitant use with strong CYP3A4 inhibitors (clarithromycin, ketoconazole) 4
• Known serious or severe hypersensitivity reaction to naloxegol 4

Important Warnings

• Opioid withdrawal: Consider overall risk-benefit in patients with disruptions to blood-brain barrier; monitor for withdrawal symptoms 4
• Severe abdominal pain/diarrhea: Monitor after initiating treatment; discontinue if severe symptoms develop 4
• GI perforation risk: Consider risk-benefit in patients with known or suspected GI tract lesions; monitor for severe, persistent, or worsening abdominal pain 4
• Pregnancy: May precipitate opioid withdrawal in pregnant women and fetus 4

Common Pitfalls to Avoid

• Never initiate naloxegol without first ruling out mechanical bowel obstruction 2, 3
• Do not use as first-line therapy—it is indicated only after laxative failure 2, 3
• Do not use concomitantly with strong CYP3A4 inhibitors—this is an absolute contraindication 4
• Do not use concomitantly with other opioid antagonists—potential for additive effect and increased risk of opioid withdrawal 4
• Do not use strong CYP3A4 inducers (rifampin) concomitantly—decreases naloxegol concentrations 4
• Do not forget to assess for other causes of constipation (hypercalcemia, hypokalemia, hypothyroidism, diabetes) before attributing symptoms solely to opioids 3

FDA Approval Status

• Naloxegol was FDA-approved in 2014 as the first oral PAMORA for OIC in adults with chronic non-cancer pain 1
• Also approved for chronic pain related to prior cancer or its treatment in patients who do not require frequent opioid dosage escalation 4
• Not FDA-approved for use in patients with OIC and active cancer pain 1

Comparative Context

• Among PAMORAs, subcutaneous methylnaltrexone shows the highest efficacy 2
• Naldemedine has stronger evidence (high-quality) compared to naloxegol (moderate-quality evidence) 1
• However, naloxegol remains a strong recommendation over no treatment for laxative-refractory OIC 1