Naloxegol (

INN Inns are generally establishments or buildings where travelers can seek lodging, and usually, food and drink. Inns are typically located in the country or along a highway; before the advent of motorized transportation they also provided accommo ...

; PEGylated naloxol; trade names Movantik and Moventig) is a peripherally acting μ-opioid receptor antagonist developed by

AstraZeneca AstraZeneca plc () is a British-Swedish multinational pharmaceutical and biotechnology company with its headquarters at the Cambridge Biomedical Campus in Cambridge, England. It has a portfolio of products for major diseases in areas includi ...

, licensed from Nektar Therapeutics, for the treatment of

opioid Opioids are substances that act on opioid receptors to produce morphine-like effects. Medically they are primarily used for pain relief, including anesthesia. Other medical uses include suppression of diarrhea, replacement therapy for opioid use ...

-induced

constipation Constipation is a bowel dysfunction that makes bowel movements infrequent or hard to pass. The stool is often hard and dry. Other symptoms may include abdominal pain, bloating, and feeling as if one has not completely passed the bowel movement ...

. It was approved in 2014 in adult patients with chronic, non-cancer pain. Doses of 25 mg were found safe and well tolerated for 52 weeks. When given concomitantly with opioid analgesics, naloxegol reduced constipation-related side effects, while maintaining comparable levels of analgesia. The most common side effects are abdominal pain, diarrhea, nausea, flatulence, vomiting and headache. Patients often describe the above side effects to be similar to an instant withdrawal state brought on quickly rather than the 24 hours it may take to occur naturally. As a pure

opioid antagonist An opioid antagonist, or opioid receptor antagonist, is a receptor antagonist that acts on one or more of the opioid receptors. Naloxone and naltrexone are commonly used opioid antagonist drugs which are competitive antagonists that bind to the ...

Naloxegol has no potential for abuse. Naloxegol was previously a Schedule II drug in the United States because of its chemical similarity to opium alkaloids. It was officially decontrolled on 23 January 2015. It was reclassified as a prescription drug after the

FDA The United States Food and Drug Administration (FDA or US FDA) is a federal agency of the Department of Health and Human Services. The FDA is responsible for protecting and promoting public health through the control and supervision of food ...

and

DEA The Drug Enforcement Administration (DEA; ) is a United States federal law enforcement agency under the U.S. Department of Justice tasked with combating drug trafficking and distribution within the U.S. It is the lead agency for domestic en ...

concluded that the impermeability of the blood–brain barrier to this compound made it non-habit-forming, and so without the potential for abuse.

Medical use

Naloxegol is indicated for the treatment of opioid-induced constipation (OIC) in patients with chronic non-cancer pain. It is recommended that any maintenance

laxative Laxatives, purgatives, or aperients are substances that loosen stools and increase bowel movements. They are used to treat and prevent constipation. Laxatives vary as to how they work and the side effects they may have. Certain stimulant, lubri ...

be discontinued before starting naloxegol or be held for at least 3 days. Naloxegol should be taken on an empty stomach at least two hours after the last meal.

Side effects

The most common side effects for naloxegol include: *

Abdominal pain Abdominal pain, also known as a stomach ache, is a symptom associated with both non-serious and serious medical issues. Common causes of pain in the abdomen include gastroenteritis and irritable bowel syndrome. About 15% of people have a m ...

Diarrhea Diarrhea, also spelled diarrhoea, is the condition of having at least three loose, liquid, or watery bowel movements each day. It often lasts for a few days and can result in dehydration due to fluid loss. Signs of dehydration often begin w ...

Nausea Nausea is a diffuse sensation of unease and discomfort, sometimes perceived as an urge to vomit. While not painful, it can be a debilitating symptom if prolonged and has been described as placing discomfort on the chest, abdomen, or back of the ...

* Flatulence *

Vomiting Vomiting (also known as emesis and throwing up) is the involuntary, forceful expulsion of the contents of one's stomach through the mouth and sometimes the nose. Vomiting can be the result of ailments like food poisoning, gastroenteri ...

* Headache

Pharmacodynamic properties

Naloxegol inhibits opioid binding in

μ-opioid receptor The μ-opioid receptors (MOR) are a class of opioid receptors with a high affinity for enkephalins and beta-endorphin, but a low affinity for dynorphins. They are also referred to as μ(''mu'')-opioid peptide (MOP) receptors. The prototypical � ...

s in the gastrointestinal tract, thus decreasing the constipating effects (slowing of gastrointestinal motility and transit, hypertonicity, increased fluid reabsorption) associated with

s. If naloxegol is coadministered with other

s, there is a potential for additive effect and increased risk of

opioid withdrawal Opioid withdrawal is a set of symptoms (a syndrome) arising from the sudden withdrawal or reduction of opioids where previous usage has been heavy and prolonged. Signs and symptoms of withdrawal can include drug craving, anxiety, restless legs, ...

Mechanism of action

Chemically, naloxegol is a

pegylated PEGylation (or pegylation) is the process of both covalent and non-covalent attachment or amalgamation of polyethylene glycol (PEG, in pharmacy called macrogol) polymer chains to molecules and macrostructures, such as a drug, therapeutic protein ...

(polyethylene glycol-modified)

derivative In mathematics, the derivative of a function of a real variable measures the sensitivity to change of the function value (output value) with respect to a change in its argument (input value). Derivatives are a fundamental tool of calculus. ...

of α- naloxol. Specifically, the 6-α-hydroxyl group of α- naloxol is connected via an

ether In organic chemistry, ethers are a class of compounds that contain an ether group—an oxygen atom connected to two alkyl or aryl groups. They have the general formula , where R and R′ represent the alkyl or aryl groups. Ethers can again be ...

linkage to the free hydroxyl group of a monomethoxy-terminated n=7 oligomer of PEG, shown extending at the lower left of the molecule image at right. The "n=7" defines the number of two-carbon ethylenes, and so the chain length, of the attached PEG chain, and the "monomethoxy" indicates that the terminal hydroxyl group of the PEG is "capped" with a

methyl group In organic chemistry, a methyl group is an alkyl derived from methane, containing one carbon atom bonded to three hydrogen atoms, having chemical formula . In formulas, the group is often abbreviated as Me. This hydrocarbon group occurs in ma ...

.Technically, the molecule that is attached via the ether link is ''O''-methyl-heptaethylene glycol hat is, methoxyheptaethylene glycol, CH₃OCH₂CH₂O(CH₂CH₂O)₅CH₂CH₂OH molecular weight 340.4,

CAS number A CAS Registry Number (also referred to as CAS RN or informally CAS Number) is a unique identification number assigned by the Chemical Abstracts Service (CAS), US to every chemical substance described in the open scientific literature. It inclu ...

4437-01-8. See The pegylation of the 6-α- hydroxyl side chain of naloxol prevents the drug from crossing the blood–brain barrier (BBB). As such, it can be considered the antithesis of the peripherally-acting opiate

loperamide Loperamide, sold under the brand name Imodium, among others,Drugs.co Page accessed September 4, 2015 is a medication used to decrease the frequency of diarrhea. It is often used for this purpose in inflammatory bowel disease and short bowel syn ...

which is utilized as an opiate-targeting anti-diarrheal agent that does not cause traditional opiate side-effects due to its inability to accumulate in the central nervous system in normal subjects.

References

{{Opioid receptor modulators Allyl compounds Daiichi Sankyo 4,5-Epoxymorphinans AstraZeneca brands Mu-opioid receptor antagonists Peripherally selective drugs Synthetic opioids

Medical use

Side effects

Pharmacodynamic properties

Mechanism of action

See also

References