Naloxegol
Peripheral opioid receptor antagonist for opioid induced constipation
Naloxegol (brand name Moventig in Europe, Movantik in the United States) is an oral peripherally acting μ opioid receptor antagonist, colloquially known as a PAMORA. The European Commission granted marketing authorisation in 2014 on the recommendation of the EMA, and the FDA approved the compound in the United States in late 2014. Naloxegol is indicated for the treatment of opioid induced constipation in adult patients who respond inadequately to conventional laxatives.
Long term opioid therapy, for example in chronic tumour pain or severe non cancer pain, causes constipation in up to 80 percent of patients. The mode of action differs fundamentally from classical laxatives because it targets the cause directly: the μ opioid receptors in the gut. Naloxegol blocks these peripheral receptors without compromising the analgesic action of the opioid in the central nervous system.
Mechanism of Action
Naloxegol is a PEGylated derivative of the classic opioid antagonist naloxone. Covalent attachment of a polyethylene glycol chain decisively alters the physicochemical properties of the molecule: it becomes a substrate of the P glycoprotein efflux pump system and is practically unable to cross the blood brain barrier. As a result, its action is confined to the peripheral gastrointestinal tract.
In the gut, naloxegol binds competitively to the μ opioid receptors of the myenteric and submucosal plexuses. Opioids normally inhibit propulsive peristalsis at these sites, increase the tone of the circular muscles, reduce intestinal secretion and delay gastric emptying. Naloxegol reverses this inhibition. Bowel transit normalises, stool consistency and frequency improve, typically within six to twelve hours after intake.
Because the central opioid system is not reached, analgesia from morphine, oxycodone, fentanyl or hydromorphone remains fully intact. A classical opioid withdrawal reaction with restlessness, sweating or pain exacerbation does not occur at the recommended dose. This is the decisive difference from systemically acting antagonists such as naloxone itself.
Indications
- Opioid induced constipation (OIC): in adult patients with an inadequate response to laxatives (macrogol, sodium picosulfate, bisacodyl)
- Chronic pain therapy: during long term therapy with morphine, oxycodone, hydromorphone, tapentadol, fentanyl or buprenorphine
- Palliative care: for tumour pain patients whose quality of life is impaired by therapy resistant constipation
- Non cancer chronic pain: for example in severe back pain, neuropathic syndromes or rheumatological conditions that require opioids
Dosage and Administration
Standard dose: 25 mg once daily, in the morning, at least 30 minutes before the first meal or no earlier than two hours afterwards. Grapefruit and grapefruit juice must be avoided during therapy because they inhibit CYP3A4 and raise plasma concentrations.
Reduced starting dose: 12.5 mg once daily in patients who develop typical gastrointestinal side effects on 25 mg. A 12.5 mg tablet is available in the EU. Renal impairment: in moderate and severe impairment (eGFR below 60 ml/min) therapy is initiated at 12.5 mg daily. Hepatic impairment: use in severe impairment is not recommended, clinical data are lacking. Concomitant laxatives should be paused three days before starting therapy and resumed only if required.
Side Effects
Very common and common (over 1 percent): abdominal pain, diarrhoea, nausea, flatulence, vomiting, headache, nasopharyngitis. Gastrointestinal symptoms usually occur during the first days of treatment and often subside spontaneously with continued use.
Uncommon (0.1 to 1 percent): hyperhidrosis, opioid withdrawal syndrome (especially at high opioid doses or in patients with presumed central opioid tolerance at the blood brain barrier), allergic skin reactions.
Important: cases of gastrointestinal perforation have been observed, predominantly in patients with known diverticulitis, gastrointestinal malignancies or peritoneal metastases. In these groups a careful benefit risk assessment is essential. In acute abdominal pain with peritonism therapy must be stopped immediately and a surgical evaluation initiated.
Interactions
- Strong CYP3A4 inhibitors (ketoconazole, itraconazole, clarithromycin, ritonavir): contraindicated, naloxegol plasma levels rise sharply
- Moderate CYP3A4 inhibitors (diltiazem, verapamil, erythromycin, fluconazole): consider dose reduction to 12.5 mg
- Strong CYP3A4 inducers (rifampicin, phenytoin, carbamazepine, St John's wort): not recommended, efficacy is lost
- Other opioid antagonists (naloxone, naltrexone, methylnaltrexone): additive effects, combination should be avoided
- Grapefruit and grapefruit juice: avoid due to inhibition of gastrointestinal CYP3A4
Special Notes
Pregnancy: no controlled human studies are available. Because of a theoretical risk of inducing fetal opioid withdrawal, use is contraindicated. Breastfeeding: passage into breast milk is possible, breastfeeding during therapy is not recommended.
Blood brain barrier disruption: in patients with advanced multiple sclerosis, traumatic brain injury or brain metastases the efflux protection may be impaired. The risk of central opioid withdrawal is then increased, the benefit risk assessment must be individualised.
Monitoring: document stool frequency and monitor gastrointestinal symptoms clinically. Persistent severe abdominal pain or bloody stool requires immediate medical evaluation.
You might also be interested in
- Oxycodone, a widely used strong opioid with typical OIC risk
- Hydromorphone, a potent opioid in tumour pain therapy
- Lactulose, an osmotic laxative as addition or alternative
- Bisacodyl, a stimulant laxative for acute constipation
Frequently Asked Questions
Will naloxegol weaken my pain therapy?
No. At the recommended dose naloxegol practically does not cross the blood brain barrier and acts only peripherally in the gut. The analgesic action of opioids in the central nervous system is fully preserved. That is the decisive difference from systemically acting antagonists such as naloxone.
When does the effect start?
In many patients a bowel movement occurs within six to twelve hours after the first dose. Full stabilisation of bowel function typically develops during the first two weeks. A lack of response after four weeks suggests that the therapy should be changed.
Why must I avoid grapefruit juice while taking naloxegol?
Grapefruit inhibits the intestinal enzyme CYP3A4 that metabolises naloxegol. Without this breakdown the plasma concentration rises, which can trigger stronger gastrointestinal side effects and, in the worst case, central opioid withdrawal. Please avoid grapefruit completely during therapy.
What is the difference between naloxegol and methylnaltrexone?
Both are peripherally acting μ opioid receptor antagonists for OIC. Methylnaltrexone (Relistor) is given subcutaneously, naloxegol is taken orally as a tablet. Oral administration is often more convenient in ambulatory long term therapy, while the subcutaneous form offers a faster onset in acute situations.
Sources
- EMA, Moventig (Naloxegol) EPAR
- AWMF, Guidelines on Tumour Pain and Palliative Medicine
- Gelbe Liste, Naloxegol active substance profile
- BfArM, Federal Institute for Drugs and Medical Devices
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