What are Naloxone and Naloxegol?

These are opioid antagonists – they block the effects of opioids. Opioids are drugs that bind the opioid receptor and relieve pain.

There is one key difference between Naloxone vs Naloxegol. AstraZeneca specifically developed Naloxegol to relieve constipation because it only blocks opioid receptors peripherally. Naloxone by contrast blocks opioid receptors everywhere in the body.

It makes intuitive sense that an opioid blocker would relieve constipation because an opioid will induce constipation.

Location, Location, Location

Naloxone can enter the brain, but Naloxegol can’t.

Naloxegol only blocks opioid receptors in the periphery. In other words, naloxegol blocks opioid receptors in the gastroinestinal tract but never enters the brain!

Naloxone on the other hand is a full-fledged opioid blocker (antagonist). So it blocks these receptors in the brain in addition to the periphery (e.g., gastrointestinal tract).

For these reasons, Naloxone is used to treat opioid overdose, which can be life-threatening! Since Naloxegol blocks opioids in the rest of the body (not the brain) it isn’t useful for opioid overdose.

Opioid-Induced Constipation

Chronic pain affects approximately 15% of adults. It decreases quality of life, is notoriously difficult to treat and predisposes to depression.

While opioids are effective pain-relievers, they are not without serious side effects. Opioid induced constipation (OIC) or opiate bowel dysfunction (OBD) is one such undesirable side effect.

Drug Cocktails

Doctors use drugs like Naloxegol along with prescription opiates like oxycodone. Why the cocktail? Because Naloxegol can offset some of the constipation.

OIC and OBD affect a whopping 41% of patients taking oral opioids!

This leaves many patients in an unfortunate situation. They must choose between chronic pain and bowel discomfort. Doctors can prescribe laxatives to relieve constipation. But laxatives are often become less effective over time and lead to bloating and acid reflux.

Opioids: How Do They Work?

opioid antagonists mechanism

Opiates work by activating opioid receptors. Sorry if that answer was underwhelming and overly simplistic!

Opioid receptors live in the nervous system and intestines. By activating receptors in both tissues, opioids impede bowel function. Opioids also impair contraction of the stomach and movement of food through the GI tract.

Blocking gut motility prolongs the time food spends in the intestines. This intestines are where water is continuously removed from food during digestion. When the intestines remove too much moisture constipation ensues.

Opioids also activate receptors in the GI tract to stimulate a reflex that further increases absorption. The combination of these effects leads to constipation and other bowel issues.

Doctors have adopted different approaches to relieve OIC. One strategy doctors use is to treat pain patients with an opioid blocker plus an opioid. Doesn’t that sound paradoxical? Wouldn’t the opioid blocker (antagonist) just cancel each other out?

Naloxone is an opioid antagonist derived from oxymorphone. This drug is marketed under these brand names:

  • Evzio
  • Narcan
  • Novaplus
  • Naloxone HCl
  • PremierPro Rx
  • Nalozone HCl

It competes with other opioids, both those that occur naturally in the body as well as those taken by the user, for opioid receptors.

Naloxone’s primary use is to treat an opioid emergency typically resulting from overdose. Opioid overdose symptoms include:

  • hypoventillaion (slow, shallow breathing)
  • extreme sleepiness
  • slow heart beat
  • loss of consciousness

Naloxone for Opioid-Induced Constipation

Naloxone was originally considered a viable option for treating OIC. That’s because treatment with the drug does indeed improve OIC symptoms.

Drawback #1 – Rapid Half-Life

Yet there are many drawbacks to using Naloxone to relieve constipation.

Naloxone may act quickly but its effects usually last less than one hour. In other words, it has a rapid half-life (pharmacokinetics). Pharmacologists now aim to design drugs to last long enough in the body to be effective.

Naloxone is also broken down quickly when ingested – so little remains once it passes through the liver (hepatic first-pass effect).

Because of its rapid breakdown it is injected intravenously, under the skin, or in the muscle (intramuscularly) to treat opioid emergencies. Sometimes it is even administered a as a spray.

Drawback #2 – Narrow Therapeutic Window

Another issue with naloxone is that it has a very small therapeutic dose range where it can relieve bowel dysfunction without reversing the analgesic effects of the opioid.

Doesn’t it sound crazy to give a patient an opioid to relieve pain, and then give them an opioid blocker to reverse the side effects of the opioid? The idea is that you can strike the perfect balance where the opioid inhibits pain and just enough opioid blocker to limit side effects.

To summarize: Naloxone’s therapeutic effects are very short lived and so it may need to be taken several times a day to manage OIC symptoms.

Drawback #3 – It Gets Into The Brain!

Naloxone crosses the blood brain barrier and therefore enters the central nervous system.

This can induce opioid withdrawal in dependent individuals. Since opioid users have different levels of tolerance to opioids, the dose required to reverse hypoventilation can vary, making it hard to get the dose right.

Naloxegol Comes Onto The Scene

To enhance the therapeutic window for naloxone while reducing its side effects, a peripherally acting μ-opioid receptor antagonist or PAMORA was created from naloxone. PAMORAs is a class of drugs that block opioid interaction with their receptors but also have limited access to the brain. This naloxone derivative PAMORA is called naloxegol!

Similar to naloxone, Naloxegol (Brand names include Movantik and Moventig) blocks opioid binding in the GI tract (μ-opioid receptors). The net result? This effectively improves bowel dysfunction in patients with chronic pain.

Rational Drug Design

But Naloxegol is PEGylated (in other words, has a large molecule called polyethylene glycol attached to it). This means it has a configuration that makes it more difficult for the drug to cross the blood brain barrier compared to naloxone. So it can’t enter the brain and is significantly less likely to cause opioid withdrawal symptoms.

Naloxegol is orally bioavailable. It can be ingested in solid or liquid form. This makes it more convenient than daily injections or taking multiple tablets a day, as is the case with naloxone.

Naloxegol also binds 20x more strongly to the opioid receptors in the GI tract than naloxone. It has a specific affinity to this subtype of opioid receptor so less drug is needed elicit the same effect. In fact, the recommended dose of naloxegol is 25mg taken orally once a day.

For comparison: about 30-40mg of oral naloxone must be taken three times a day. Like naloxone, naloxegol is rapidly absorbed and reaches its maximum concentration within 2 hours. However, it has a much longer half-life of 6-11 hours compared to 31-81 minutes for naloxone.

Still, there are some side effects associated with naloxogel. These include diarrhea, nausea, vomiting, and abdominal pain at the recommended dose. But these effects are usually mild to moderate and are signs that the drug is working.

The Long and Short of The Matter

While opioids are effective for chronic pain in non-cancer patients they cause constipation.

The opioid antagonist naloxone does relieve some bowel dysfunction. Yet because of its narrow therapeutic window, small effective dose range, and potentially severe withdrawal side-effects related to its CNS permeability, it is not the most practical option for OIC.

But its PEGylated derivative (Naloxogel) is a robust alternative. Because Naloxogel is unlikely to induce withdrawal symptoms it provides a long lasting, effective alternative to naloxone for OIC and IBD relief for patients with chronic pain.