What is an Opioid Antagonist, and How Does it Work?

Drug misuse leads to over 500,000 deaths yearly. In 75% of these cases, opioid overdose is a factor. Specifically, according to recent estimates, 68,630 Americans lost their lives to opioid overdose in 2020. 

Research suggests timely treatment — with opioid antagonists — can prevent opioid overdose deaths. A multi-site community study demonstrated increased survival rates in cases of opioid overdose treated with opioid antagonists. Similarly, in another study, naloxone (an opioid antagonist) reversed opioid overdose in 93.5% of cases.

This article discusses what an opioid antagonist is, how it works and how it can help you. Read on to learn more.

What is an Opioid Antagonist?

The term 'antagonist' refers to any substance that interferes or inhibits the action of another chemical. Thus, opioid antagonists are medications that prevent opioid activity in the body.

Opioid Antagonists, Agonists, Partial Agonists, and Mixed Agonists/Antagonists: What Are Their Differences? 

Biochemists classify opioids (and related medications) into four groups based on how they interact with opioid receptors:

• Full agonists: These are potent activators of opioid receptors. Examples include fentanyl, heroin, morphine, and oxycodone.
• Partial agonists: These only partially activate opioid receptors. Buprenorphine is an example.
• Antagonists: These bind opioid receptors but do not activate them. Examples include naloxone and naltrexone.
• Mixed agonists/antagonists: These function as antagonists for some opioid receptors and as agonists for others. Examples include butorphanol, nalbuphine, and pentazocine.

How do Opioid Antagonists work?

Opioids work by binding to specific receptors in the body in the brain (central receptors) and the nervous system (peripheral receptors). Opioid antagonists block opioid function by occupying opioid receptors. This prevents the body from responding to endorphins and opioids.

Understandably, opioid antagonists only work if an individual already has opioids in their system. This is because while opioid antagonists occupy opioid receptors, they do not activate them.

Types of Opioid Antagonists

Researchers classify opioid antagonists into two categories — central and peripheral — based on the receptors they bind.

Central opioid antagonists occupy opioid receptors in the brain. These include:

• Naloxone
• Naltrexone

Peripheral opioid antagonists preferentially bind to opioid receptors outside the brain — mainly in the lungs and the gastrointestinal tract. This is because peripheral opioid antagonists can not easily cross the blood-brain barrier. Examples include:

• Methylnaltrexone
• Naldemedine
• Naloxegol
• Alvimopan

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How are Opioid Antagonists Administered?

What are Opioid Antagonists Used For?

Doctors prescribe opioid antagonists for many conditions. Here we discuss the evidence supporting their use. 

Opioid Overdose

The American Society of Health-System Pharmacists (ASHP) recommends naloxone for opioid overdose. This is because studies show naloxone use reduces overdose deaths among individuals that inject opioids. In addition, according to other studies, naloxone can reverse an opioid overdose in 93.5% of cases. Thus, unsurprisingly, naloxone is part of all first responder kits.

Opioid-Use Disorder (OUD)

Suboxone (a combination of naloxone and buprenorphine) and naltrexone are FDA-approved treatments for OUD. Research shows that medication-assisted treatment for OUD can increase user compliance, lower the risk of relapse and reduce the incidence of suicide. It also decreases the risk of opioid overdose-related deaths.

Alcohol-Use Disorder

Naltrexone is FDA-approved for alcohol-use disorder. Researchers believe alcohol interacts with the brain similarly to opioids. Thus, naltrexone, an opioid antagonist, can reduce alcohol cravings and intake. 

Studies show treatment with naltrexone enables 86% of alcohol-dependent individuals to reduce their alcohol intake. In addition, alcohol-dependent naltrexone users report a more positive social outlook and an increased ability to hold down a job.

Obesity

Naltrexone binds to and prevents opioids from binding to pro-opiomelanocortin (POMC) opioid receptors. This inhibits the body's hunger signaling pathway reducing cravings for food. Thus, naltrexone can help overweight individuals lose weight. Participants of a randomized controlled trial reported significant weight loss with naltrexone over 52 weeks. 

Similarly, a metanalysis of overweight users on naltrexone reported up to a 10% weight loss among participants.

Opioid-induced Constipation

Constipation can affect up to 81% of opioid users. This is because by binding to receptors in the gut, opioids delay gastric emptying and reduce fluid absorption. Fortunately, opioid antagonists such as naloxone and methylnaltrexone can relieve opioid-induced constipation.

In a controlled study including twenty-two individuals with opioid constipation, naloxone was able to ease symptoms and reduce the need for laxatives. Similarly, in another study, methylnaltrexone relieved symptoms in 52% of patients with opioid-induced constipation.

Clonidine Overdose

Emergency care doctors use clonidine to treat sudden elevations in blood pressure. However, given its narrow dosing range, clonidine overdose can occur in up to 57% of cases. Clonidine overdose can lead to very low blood pressure and slow heart rhythm.

Isolated studies show naloxone is effective at reversing clonidine overdose. The mechanism by which naloxone achieves this remains unknown.

Shock

Shock is a life-threatening condition where the body's circulation can not keep up with the oxygen demand. This leads to tissue death and organ damage. 

Some researchers have used naloxone to treat shock with promising results. 

Cholestatic Pruritus

Studies show naltrexone can reduce symptoms of cholestatic pruritus in 50% of patients. 

Congenital Anhidrosis

Congenital anhidrosis is a rare condition associated with an impaired ability to feel pain. Researchers are currently evaluating opioid antagonists as a potential treatment option.

What are Opioid Antagonist Side Effects?

Researchers classify the side effects of opioid antagonists into two categories:

1. Adverse Effects Due to Direct Action on the Central Nervous System

These include:

• Diarrhea
• Headache
• Abdominal pain
• Skin rashes

2. Side Effects Due to Opioid Reversal

These are more serious and include:

• Cardiac arrest
• Hypotension (low blood pressure)
• Arrhythmias
• Respiratory arrest
• Pulmonary edema

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Why are Opioid Antagonists Combined with Other Medications?

To enhance treatment effectiveness, pharmacists combine opioid antagonists with other drug categories such as:

• Partial opioid agonists: Opioid antagonists help prevent agonist misuse.
• Dopamine reuptake inhibitors: Studies show dopamine and opioid receptor antagonists can reduce impulsive behaviors in humans. Thus, combining the two categories lowers food cravings and can help individuals lose weight.

Do Opioid Antagonists Help With Pain?

Research suggests opioid antagonists — in particular naloxone and naltrexone — in low doses can relieve pain. This is because opioid antagonists reduce the production of inflammatory substances while increasing the release of endorphins (feel-good hormones).

Frequently Asked Questions (FAQs):

Is Morphine an Opioid Antagonist?

Morphine is a potent full opioid agonist (not an ANTAgonist)

Is Suboxone an Opioid Antagonist?

Suboxone is the trade name containing two active ingredients:

• Buprenorphine (a partial opioid agonist)
• Naloxone (an opioid antagonist)

In other words, it contains both an opioid agonist and antagonist.

Opioid Antagonists Can Help You Take Back Control of Your Life

Opioid antagonists are a diverse medication category that can help you overcome substance misuse disorder. At Confidant Health, we combine medication-assisted treatments (such as opioid antagonists) with behavioral therapies to help you regain control of your life.

Reach out to us today!