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NALOXEGOL

Naloxegol is a peripherally acting mu-opioid receptor antagonist designed to treat opioid-induced constipation (OIC) without affecting pain relief. Clinical trials have investigated naloxegol in various patient populations receiving opioid therapy, including those with chronic non-cancer pain, cancer-related pain, and post-surgical patients. These studies have examined naloxegol’s effectiveness in improving bowel function, its safety profile, and its pharmacokinetic properties. This article provides an overview of key clinical trials that have evaluated naloxegol’s efficacy, safety, and patient outcomes in treating opioid-induced constipation.

Table of Contents

What is Naloxegol?

Naloxegol (also known by brand names Movantik or Moventig) is a medication specifically designed to treat opioid-induced constipation (OIC) in patients who take opioid pain medications. It belongs to a class of drugs called peripherally acting mu-opioid receptor antagonists (PAMORAs)[1]. Unlike other constipation treatments, naloxegol targets the root cause of opioid-induced constipation while allowing opioids to continue providing pain relief.

Naloxegol is a PEGylated derivative of naloxone (a well-known opioid antagonist). The PEGylation (addition of polyethylene glycol) is a key feature that limits naloxegol’s ability to cross the blood-brain barrier, meaning it works primarily in the digestive system without affecting pain control in the brain[2].

How Naloxegol Works

Opioid medications relieve pain by binding to opioid receptors in the brain, but they also bind to receptors in the digestive tract. When opioids activate these gut receptors, they slow down bowel function, leading to constipation. This is why constipation is such a common side effect of opioid pain medications.

Naloxegol works by blocking the mu-opioid receptors in the gastrointestinal tract. By doing this, it prevents opioids from slowing down bowel function while allowing them to continue providing pain relief through their action in the brain[3]. This targeted approach makes naloxegol different from standard laxatives, which don’t address the specific mechanism of opioid-induced constipation.

Once in the body, naloxegol is absorbed rapidly, with peak concentrations achieved in less than 2 hours. It’s primarily processed by the liver and reaches steady levels in the body within 2-3 days of once-daily administration[4].

Medical Conditions Treated with Naloxegol

Naloxegol is FDA-approved specifically for the treatment of opioid-induced constipation (OIC) in adult patients with chronic non-cancer pain. OIC is defined as constipation that develops as a direct result of opioid use and is characterized by:

  • Reduced bowel movement frequency
  • Development or worsening of straining during bowel movements
  • Sense of incomplete evacuation
  • Harder stool consistency

OIC is different from regular constipation because it’s caused by the specific action of opioids on the digestive system and often doesn’t respond well to traditional laxatives[5].

While initially approved for patients with non-cancer pain, clinical studies are investigating naloxegol’s effectiveness for cancer patients experiencing opioid-induced constipation as well[6]. Some studies have shown promising results in this population, though research is ongoing.

Additionally, researchers are studying naloxegol’s potential uses in other conditions affected by opioid-related bowel dysfunction, such as post-operative ileus (a temporary cessation of normal bowel function after surgery) and opioid-related esophageal disorders[7][8].

Effectiveness of Naloxegol

Clinical trials have demonstrated that naloxegol is effective in treating opioid-induced constipation. In Phase III clinical studies, significantly more patients taking naloxegol (particularly at the 25 mg dose) experienced relief from constipation compared to those taking a placebo[9].

Key measures of effectiveness include:

  • Response rate: More patients achieved at least 3 spontaneous bowel movements per week, with an increase of at least 1 bowel movement per week over baseline[5].
  • Time to first bowel movement: Patients taking naloxegol typically had their first post-dose bowel movement faster than those taking placebo[10].
  • Stool consistency: Improvement in stool consistency as measured by the Bristol Stool Scale[10].
  • Straining: Decreased straining during bowel movements[10].
  • Complete bowel movements: Increased frequency of complete bowel movements (feeling of complete emptying)[9].

Studies have shown that naloxegol works regardless of patient characteristics such as age, gender, race, body mass index, region, type of opioid, or dose of opioid[11]. This makes it a versatile option for diverse patient populations.

Importantly, naloxegol’s effectiveness is not diminished by previous laxative use or response, making it suitable for patients who haven’t found relief with traditional constipation treatments[5].

Dosage Information

The standard recommended dose of naloxegol for most adult patients is 25 mg taken once daily on an empty stomach. This typically means taking it at least 1 hour before the first meal of the day or 2 hours after a meal[12].

For patients with renal impairment (kidney problems) where creatinine clearance is less than 60 mL/min, the recommended dose is reduced to 12.5 mg once daily[13].

Dosage considerations:

  • Naloxegol is available as 12.5 mg and 25 mg tablets.
  • The tablet should ideally be swallowed whole and not crushed or chewed. However, for patients who cannot swallow the tablet whole, it can be crushed and mixed with water for oral administration or given through a nasogastric tube in certain circumstances[14].
  • Patients should discontinue all maintenance laxative therapy before starting naloxegol, though rescue laxatives can be used if needed after starting treatment[1].

It’s important to note that naloxegol usually begins working within 24-48 hours for most patients, though individual response times may vary[10].

Side Effects

Like all medications, naloxegol can cause side effects, though not everyone experiences them. The most common side effects include:

  • Abdominal pain (21% of patients versus 7% on placebo)[8]
  • Diarrhea (9% versus 5%)
  • Nausea (8% versus 5%)
  • Flatulence (gas) (6% versus 3%)
  • Vomiting (5% versus 4%)
  • Headache (4% versus 3%)
  • Excessive sweating (3% versus <1%)

Most gastrointestinal side effects occur within the first few days of treatment and tend to resolve with continued use[15].

Serious but rare side effects may include:

  • Opioid withdrawal symptoms: Although naloxegol is designed to work primarily in the gut, some patients may experience symptoms of opioid withdrawal, especially if they take higher than recommended doses[16].
  • Gastrointestinal perforation: There’s a very small risk of tears in the intestinal wall, particularly in patients with certain conditions like cancer, peptic ulcer disease, or those taking medications that may increase this risk[16].

Naloxegol is contraindicated (should not be used) in patients with known or suspected gastrointestinal obstruction and in patients who are taking strong CYP3A4 inhibitor medications (such as clarithromycin or ketoconazole)[17].

Use in Special Populations

Elderly Patients: Clinical studies have included patients over 65 years old, with no significant differences in safety or effectiveness compared to younger patients. No dosage adjustment is required based on age alone[18].

Patients with Kidney Impairment: For patients with moderate to severe renal impairment (creatinine clearance less than 60 mL/min), the recommended dose is reduced to 12.5 mg once daily. The dose can be increased to 25 mg if well tolerated[13].

Patients with Liver Impairment: For patients with mild to moderate hepatic (liver) impairment, no dosage adjustment is necessary. Naloxegol has not been studied in patients with severe hepatic impairment and is not recommended for these patients[19].

Cancer Patients: While initially approved for non-cancer pain, studies are evaluating naloxegol’s use in cancer patients with opioid-induced constipation. Early research suggests it may be effective and safe in this population as well[1].

Pediatric Patients: The safety and effectiveness of naloxegol in pediatric patients under 18 years of age have not been established. Some studies are underway to assess its pharmacokinetics in pediatric patients with opioid-induced constipation[18].

Pregnant and Breastfeeding Women: There are no adequate studies of naloxegol in pregnant women to determine its safety. Use during pregnancy should only be considered if the potential benefit justifies the potential risk to the fetus. It’s unknown whether naloxegol is excreted in human milk, so caution should be exercised when used by breastfeeding women[16].

Drug Interactions

Naloxegol can interact with several other medications, potentially affecting its effectiveness or increasing the risk of side effects:

  • Strong CYP3A4 inhibitors (such as ketoconazole, clarithromycin, ritonavir): These medications can significantly increase naloxegol levels in the blood, increasing the risk of side effects. Concomitant use is contraindicated[17].
  • Moderate CYP3A4 inhibitors (such as diltiazem, erythromycin, verapamil): These can increase naloxegol levels moderately. The recommended dose of naloxegol should be reduced to 12.5 mg once daily when used with moderate CYP3A4 inhibitors[17].
  • Strong CYP3A4 inducers (such as rifampin, carbamazepine, St. John’s wort): These medications can decrease naloxegol levels, potentially reducing its effectiveness. Their concurrent use is not recommended[20].
  • Other opioid antagonists: Using naloxegol with other opioid antagonists should be avoided due to the potential for additive effects and increased risk of opioid withdrawal[16].

Additionally, because naloxegol is a substrate of the P-glycoprotein transporter, medications that inhibit P-glycoprotein may increase naloxegol exposure[21].

It’s important to tell your healthcare provider about all medications you’re taking, including prescription drugs, over-the-counter medications, vitamins, and herbal supplements, to avoid potential drug interactions.

Impact on Quality of Life

Opioid-induced constipation can significantly impact patients’ quality of life, sometimes to the point where patients reduce or stop their pain medication, compromising pain control. Studies have shown that naloxegol can improve quality of life for patients suffering from OIC in several ways:

  • Symptom improvement: Clinical trials have demonstrated significant improvements in constipation symptoms as measured by validated tools like the Patient Assessment of Constipation Symptoms (PAC-SYM) questionnaire[10].
  • Quality of life measures: Improvements in the Patient Assessment of Constipation Quality of Life (PAC-QOL) scores, particularly in the satisfaction domain, indicate better overall well-being[10].
  • Patient preference: In comparative studies between naloxegol and other treatments for OIC, many patients reported a preference for naloxegol, citing factors such as effectiveness, predictability, and convenience[12].
  • Maintained pain control: Unlike some other approaches to managing OIC, naloxegol allows patients to continue their opioid pain medication at effective doses without compromising pain control[10].

By addressing the constipation that often accompanies opioid therapy, naloxegol helps patients maintain their pain management regimen while improving digestive comfort and overall quality of life[4].

Ongoing Research

Research on naloxegol continues to explore its potential benefits in various clinical scenarios:

  • Cancer-related pain: Studies are investigating naloxegol’s efficacy and safety in patients with cancer pain who experience opioid-induced constipation[22].
  • Postoperative settings: Research is examining naloxegol’s potential to prevent or treat constipation in postoperative patients receiving opioids, including after cardiac surgery and spinal surgery[7][14].
  • Intensive care patients: Studies are looking at naloxegol’s effectiveness for refractory constipation in intensive care unit patients and those with brain injuries receiving opioid medications[23][24].
  • Pediatric populations: Research is assessing the pharmacokinetics and safety of naloxegol in pediatric patients ages 6 months to under 18 years who receive treatment with opioids[18].
  • Esophageal disorders: Investigations are examining naloxegol’s potential to improve opioid-related esophageal motility disorders[8].
  • Colonic motor patterns: Research is studying how naloxegol affects colonic motor patterns and how it may reverse opioid effects on the colon[2].

These ongoing studies may expand our understanding of naloxegol’s benefits and potentially lead to new approved uses for this medication in the future.

Clinical Trial Type Key Findings Patient Population Dosages Studied
Efficacy Trials – Significantly improved spontaneous bowel movements
– Faster time to first post-dose bowel movement
– Better stool consistency
– Improved quality of life measures		 – Chronic non-cancer pain patients
– Cancer pain patients
– Post-surgical patients		 12.5 mg and 25 mg daily
Safety Studies – Generally well-tolerated
– Most common side effects: abdominal pain, diarrhea, nausea
– No significant impact on pain control
– Cardiovascular safety profile being monitored		 – Various patient populations
– Including renal and hepatic impairment
– Elderly patients		 12.5 mg to 25 mg daily
Pharmacokinetic Studies – Rapid absorption (peak concentrations within 2 hours)
– Drug interactions with CYP3A inhibitors/inducers
– Dosage adjustments needed for renal impairment
– Limited crossing of blood-brain barrier		 – Healthy volunteers
– Patients with renal impairment
– Patients with hepatic impairment		 8 mg to 1000 mg (dose-finding)
Special Population Studies – Effective in cancer patients with OIC
– Pediatric studies ongoing (ages ≥6 months)
– Preventive effect in post-surgical settings
– Potential benefits for esophageal disorders		 – Cancer patients
– Pediatric patients
– Post-surgical patients
– Patients with esophageal disorders		 Varies by population
Gastrointestinal Motility Studies – Reverses opioid-induced slowing of colonic transit
– Improved colonic motor patterns
– Potential for preventing postoperative ileus
– May improve esophageal motility disorders		 – Healthy volunteers
– Surgical patients
– Patients with esophageal disorders		 25 mg daily
Patient Preference Studies – Patient preference compared to other treatments
– Improved treatment satisfaction
– Better quality of life scores
– Reduction in constipation-related symptoms		 – Chronic non-cancer pain patients
– Patients with inadequate response to laxatives		 25 mg daily

FAQ

  • What is naloxegol and how does it work? Naloxegol (brand names Movantik, Moventig) is a peripherally acting mu-opioid receptor antagonist (PAMORA) specifically designed to treat opioid-induced constipation. It works by blocking opioid receptors in the digestive tract without crossing the blood-brain barrier, which means it can reduce constipation caused by opioids without interfering with pain relief. Naloxegol is a PEGylated derivative of naloxone, which helps prevent it from entering the central nervous system.
  • What doses of naloxegol are commonly used in clinical trials? Most clinical trials have studied naloxegol at doses of 12.5 mg and 25 mg once daily. The 25 mg dose has generally shown better efficacy in treating opioid-induced constipation, though the 12.5 mg dose may be used for patients with renal impairment (creatinine clearance <60 mL/min) or those who experience side effects at the higher dose. Some trials have also examined lower or higher doses to establish the optimal therapeutic range.
  • What are the common side effects of naloxegol observed in clinical trials? Common side effects of naloxegol observed in clinical trials include abdominal pain (reported in up to 21% of patients), diarrhea (9%), nausea (8%), flatulence (6%), vomiting (5%), headache (4%), and hyperhidrosis (sweating, 3%). These gastrointestinal side effects were generally more common with naloxegol than with placebo. Most adverse events were mild to moderate in severity and often occurred early in treatment.
  • Is naloxegol effective for cancer patients with opioid-induced constipation? Several clinical trials have investigated naloxegol specifically in cancer patients with opioid-induced constipation. These studies suggest that naloxegol can be effective in this population. For example, one trial (NCT04173858) evaluated quality of life outcomes in cancer patients with OIC under naloxegol treatment, while another study (NCT02745353) compared naloxegol to usual care for OIC in cancer patients. A real-world observational study (NCT03638440) also assessed naloxegol's safety and efficacy in cancer patients with OIC.
  • Can naloxegol be used to prevent constipation after surgery? Yes, some clinical trials have investigated the preventive use of naloxegol for post-surgical constipation. For example, study NCT02946580 examined naloxegol for preventing constipation after spinal surgery, and NCT04433390 studied its effect on postoperative ileus in cardiac surgery patients. Another trial (NCT03316859) evaluated adding naloxegol to the pre-operative regimen for cardiac surgery patients. These studies suggest that naloxegol may help prevent or reduce the duration of opioid-induced constipation in post-surgical settings.

Ongoing Clinical Trials on NALOXEGOL

  • Study on the Effects of Naloxegol and Codeine on Opioid-Induced Constipation in Healthy Volunteers

    Not recruiting

    1 1 1
    Investigated diseases:
    Investigated drugs:
    Belgium

Glossary

  • Opioid-Induced Constipation (OIC): A common side effect of opioid medication where opioids bind to mu-receptors in the gastrointestinal tract, resulting in decreased bowel motility, harder stools, and less frequent bowel movements. OIC is one of the most common reasons patients stop taking prescribed opioid medications.
  • Peripherally Acting Mu-Opioid Receptor Antagonist (PAMORA): A class of medications that block opioid receptors specifically in the digestive system without affecting the pain-relieving effects of opioids in the brain. Naloxegol belongs to this class of drugs.
  • PEGylation: A process where polyethylene glycol (PEG) chains are attached to a molecule (in this case naloxegol). This modification helps prevent the drug from crossing the blood-brain barrier, allowing it to work peripherally without affecting central pain relief.
  • Spontaneous Bowel Movement (SBM): A bowel movement that occurs naturally without the use of rescue laxatives or manual disimpaction within the previous 24 hours. SBMs are commonly used as outcome measures in OIC clinical trials.
  • Rescue-Free Bowel Movement (RFBM): A bowel movement that occurs without the use of rescue medication (additional laxatives beyond the study medication). This is often a primary endpoint in OIC treatment studies.
  • Bowel Function Index (BFI): A clinical assessment tool that measures constipation severity based on three components: ease of defecation, feeling of incomplete bowel evacuation, and personal judgment of constipation. The scale ranges from 0 to 100, with higher scores indicating worse constipation.
  • Patient Assessment of Constipation Symptoms (PAC-SYM): A validated questionnaire that evaluates the severity of constipation symptoms in three domains: abdominal symptoms, rectal symptoms, and stool symptoms. It uses a 5-point scale from 0 (absent) to 4 (very severe).
  • Patient Assessment of Constipation Quality of Life (PAC-QOL): A 28-item self-report instrument that evaluates how constipation affects a patient's quality of life, including physical discomfort, psychosocial discomfort, worries/concerns, and satisfaction with treatment.
  • Bristol Stool Scale (BSS): A diagnostic medical tool used to classify the form of human feces into seven categories, ranging from type 1 (separate hard lumps) to type 7 (entirely liquid). Types 3 and 4 are considered normal, while types 1 and 2 indicate constipation.
  • Laxative Inadequate Response (LIR): A condition where patients continue to experience constipation despite using conventional laxative treatments. Many clinical trials of naloxegol specifically included patients with LIR to assess its effectiveness in this difficult-to-treat population.
  • Bioequivalence: A term used to describe when two drug formulations release the active ingredient at the same rate and extent, resulting in identical blood concentrations over time. This is important when comparing different formulations of naloxegol.
  • Pharmacokinetics (PK): The study of how drugs move through the body, including absorption, distribution, metabolism, and excretion. PK studies of naloxegol examine how quickly it's absorbed, how long it stays in the body, and how it's eliminated.
  • Geometric Center (GC): In colonic transit studies, the geometric center is a weighted average of counts in different colonic regions. It's used to measure how quickly material moves through the colon, with higher values indicating faster transit.
  • Major Adverse Cardiovascular Events (MACE): A composite endpoint in cardiovascular safety studies that typically includes cardiovascular death, non-fatal myocardial infarction (heart attack), and non-fatal stroke. MACE was monitored in some naloxegol safety studies.
  • High-Resolution Esophageal Manometry (HREM): A diagnostic procedure that measures pressures within the esophagus to evaluate motility disorders. Some studies examined naloxegol's effects on opioid-induced esophageal motility disorders using this technique.

References

  1. https://clinicaltrials.gov/study/NCT03638440
  2. https://clinicaltrials.gov/study/NCT05770960
  3. https://clinicaltrials.gov/study/NCT02737059
  4. https://clinicaltrials.gov/study/NCT04173858
  5. https://clinicaltrials.gov/study/NCT01323790
  6. https://clinicaltrials.gov/study/NCT02745353
  7. https://clinicaltrials.gov/study/NCT04433390
  8. https://clinicaltrials.gov/study/NCT02998606
  9. https://clinicaltrials.gov/study/NCT01309841
  10. https://clinicaltrials.gov/study/NCT02839889
  11. https://clinicaltrials.gov/study/NCT02813148
  12. https://clinicaltrials.gov/study/NCT03060512
  13. https://clinicaltrials.gov/study/NCT01372826
  14. https://clinicaltrials.gov/study/NCT02946580
  15. https://clinicaltrials.gov/study/NCT01395524
  16. https://clinicaltrials.gov/study/NCT02813369
  17. https://clinicaltrials.gov/study/NCT01594619
  18. https://clinicaltrials.gov/study/NCT02099591
  19. https://clinicaltrials.gov/study/NCT01392807
  20. https://clinicaltrials.gov/study/NCT01533870
  21. https://clinicaltrials.gov/study/NCT01348724
  22. https://clinicaltrials.gov/study/NCT01384292
  23. https://clinicaltrials.gov/study/NCT02705378
  24. https://clinicaltrials.eu/trial/study-on-naloxegol-to-prevent-constipation-in-patients-with-brain-injury-and-opioid-use/