One may be used to treat opioid use disorder; the other is administered in emergencies as an opioid overdose antidote.

Opioids like prescription oxycodone create a sense of relief from pain—a reaction that people can start to crave over time. Heroin, an illegal opioid, gives users a "rush." In each instance, these sensations can be highly addictive, and use of these drugs can be potentially life-threatening. That's where opioid antagonists, like naltrexone and naloxone, come in.

Whether someone has stopped opioid use or is overdosing, opioid antagonists can help keep them safe and curb cravings—here's how:

opioid antagonist Naloxene Narcan , Hands Holding Syringe and Naloxone Opioid Overdose Medication
Credit: Getty Images

Opioid agonist vs. antagonist—What's the difference?

Before we dive into opioid antagonists, let's discuss its similarly named but very different counterpart: opioid agonists.

When you think of an opioid, it will typically be an opioid agonist. This label covers fentanyl, heroin, and prescription opioids like oxycodone. It also includes two medications doctors prescribe to relieve opioid withdrawal symptoms: methadone and buprenorphine. The latter is a "partial agonist," meaning its effects are weaker, reports the Substance Abuse and Mental Health Services Administration (SAMHSA).

"Agonists bind to opioid receptors to create the euphoric effect," Ashley McGee, RN, the vice president of nursing at Mountainside treatment center, tells Health.

So what do opioid antagonists do? "[They] bind to receptors to block the effects of opioids. Therefore, they are unable to activate and provide a euphoric effect in the brain," McGee explains. Naltrexone and naloxone are the most common opioid antagonists available.

To sum it up: "Opioid antagonists and agonists work on the same part of the brain but create opposite effects," Michael Damioli, LCSW, the clinical director at Colorado Medication Assisted Recovery, tells Health.

Types of opioid antagonist medications

Two drugs, naltrexone and naloxone, are the most commonly prescribed "centrally acting" opioid antagonists, per a 2021 review published by the US National Library of Medicine (NLM). That means they act on opioid receptors in the central nervous system.

Naltrexone

This drug blocks both the euphoric and sedative effects of opioids by binding to and hindering opioid receptors. In doing this, naltrexone works to reduce opioid cravings, reports SAMHSA. It's approved by the US Food and Drug Administration (FDA) for the treatment of opioid use disorder.

As Damioli explains, "If someone takes naltrexone and then uses an opioid such as heroin, the naltrexone will prevent the heroin from binding to receptors in that person's brain and prevents them from experiencing the effects of their drug."

Unlike the agonists methadone and buprenorphine, which may help people wean off opioids, a person can't take naltrexone while using opioids. Individuals can start taking naltrexone once they have been off short-acting opioids for at least seven days and long-acting opioids for 10 to 14 days, according to SAMHSA.

Naltrexone is available in oral form or as a long-acting opioid antagonist by injection. However, the FDA has only approved injections for medication-assisted treatment—a common approach that combines medication and therapy. 

Damioli recommends extended-release options, such as Vivitrol, for people who are at a high risk of relapsing or struggle to take medication every day. The injection, given every four weeks or once a month, per the FDA, slowly and consistently releases naltrexone into the body.

Another critical aspect of preparing to take naltrexone—or any other medication—is understanding the possible side effects.

According to Mayo Clinic, specific naltrexone side effects can include:

  • Stomach pain or cramping
  • Nausea
  • Headaches
  • Muscle pain
  • Anxiety
  • Trouble sleeping

Mayo Clinic reports that, in rare cases, other side effects may occur that require immediate medical attention, such as:

  • Rashes
  • Blurred vision
  • Depression or mood changes
  • Painful urination
  • Fever
  • Ringing sensation in ears
  • Hallucinations

Naloxone (Narcan)

Unlike naltrexone, naloxone is an emergency opioid antagonist taken in cases of an opioid overdose, notes the NLM. Commonly known by the brand name Narcan, it works to temporarily reverse the effects of an opioid overdose by attaching to opioid receptors and blocking the drug's effects. It can also undo an opioid's effects, such as bringing breaths back to normal if they slowed or ceased.

Naloxone lasts for only 30 to 90 minutes, and someone experiencing an overdose may require further treatment or additional doses, reports the National Institute on Drug Abuse (NIDA). As a result, emergency medical care should always be sought in addition to administering naloxone.

While it is available in all states without a prescription, doctors may prescribe naloxone to people at risk of an overdose, reports SAMHSA. These instances can include people who:

  • Take opioids on a regular basis for chronic pain
  • Recently received emergency care due to opioid poisoning or intoxication
  • Receive a mix of opioid medication

Naloxone is also an effective option for an opioid overdose that involved a stimulant or sedative as well, says SAMHSA. It is available as a nasal spray or injection, per the NLM, though the latter is typically reserved for medical professionals. If you or someone you know may be at risk of an opioid overdose, it may be advisable to have a doctor or pharmacist demonstrate how to use it.

According to the NLM, naloxone side effects for either the nasal spray or injection can include:

  • Headaches
  • Muscle pain
  • Congestion
  • Nasal dryness or swelling
  • Pain or redness at the injection site
  • Flushed skin
  • Hot flashes
  • Excessive sweating

The NLM also reports that a person should seek medical attention if they develop a serious side effect such as:

  • Seizure
  • Losing or lost consciousness
  • Irregular heartbeat
  • Hallucinations

Another reason to see doctor? The person may have opioid withdrawal symptoms after taking naloxone, which will require medical help to treat safely.

"If someone is physically dependent on opioids, then taking an opioid antagonist will cause them to quickly enter into opioid withdrawal, which can be an unsettling and scary experience known as precipitated withdrawal," says Damioli. A medical professional can assist in regulating this and monitor a person's health and symptoms.

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