Opioid antagonists: Uses, common brands, and safety info

Opioids, like oxycodone, are commonly prescribed for pain relief. An estimated 11% of adult Americans experience daily pain, and millions are treated with prescription opioids for chronic pain. 

Unfortunately, opioids also carry the potential to inadvertently cause issues like slowing of breathing and sedation, as well as a sensation of euphoria through the release of endorphins that might contribute to abuse or misuse. Those taking opioids for analgesia specifically may also develop a tolerance to doses that once gave them relief, causing them to experiment with higher doses to achieve the same level of relief. This also increases the risk of side effects.

In 2018, 9.9 million Americans reported misuse of prescription opioid analgesics, and clinicians are increasingly becoming more concerned and aware of the propensity for patient addiction. Between 1999-2019, almost 500,000 people died from an overdose involving any opioid—including both prescription and illicit opioids—which includes both intentional and unintentional overdoses. In 2017, the economic impact of opioid use disorder and fatal opioid overdose exceeded $1 trillion. 

Opioid antagonists can be used to reverse overdoses or unintended serious side effects sometimes observed with even low doses of opioids, like sedation or slowed breathing. They can also be used in the management and prevention of opioid dependence and detoxification. Common opioid antagonists include naloxone and naltrexone, which reverse and/or block the central nervous system effects of opioid misuse or overdose. Opioid partial agonists, which are a combination of agonist/antagonist, include buprenorphine. Buprenorphine, and other opioids such as methadone, can actually be employed in the treatment of opioid addiction. 

Even the correct use of opioids come with unwanted side effects. Methylnaltrexone is an example of another opioid antagonist that acts mostly in the gastrointestinal tract versus the brain and can be used to reverse some of these more specific side effects. Here we will discuss the pharmacology of opioid antagonists, their side effects, and their safety.

What are opioid antagonists?

Opioid antagonists block one or more of the opioid receptors in either the central or peripheral nervous systems. They essentially compete with and then block the agonist effects of opioids at the same receptors. Opioid receptor antagonists are generally given to reverse different effects of opioids, or in some circumstances to prevent a person from experiencing opioid intoxication.

How do opioid antagonists work?

The three most relevant opioid receptors in the body are the mu, kappa, and delta receptors. Activation of central mu receptors by opioids crossing the blood brain barrier lead to some problematic side effects associated with opioid agonists, such as slowed breathing, in addition to their analgesic effects. Activation of peripheral mu receptors by opioids, mostly in certain lung tissues and in the digestive tract, can also explain some of the other side effects of opioids such as decreased cough and constipation. The kappa and delta receptors are known for their potent pain relief effects. Opioid antagonists work by blocking these various receptors from opioids and have the highest affinity for the mu receptor. Blocking these receptors can reverse the effects of opioids, either centrally or peripherally depending on which opioid antagonist is administered. These medications generally take effect very quickly, so should always be used under the guidance of a medical professional.

What are opioid antagonists used for?

Opioid antagonists can be used for the following conditions:

• Reversal of serious adverse effects related to exogenous opioid use, such as difficulty or slowed breathing

• As part of a maintenance regimen for opioid addiction, and sometimes alcohol addiction, to prevent a relapse

• Management of other side effects with opioids, like constipation

Types of opioid antagonists 

There are two main types of opioid antagonists – those which block the central nervous system effects of opioids, and those which block the peripherally acting side effects of opioids. 

Centrally acting opioid antagonists

Centrally acting opioid antagonists, depending on route of administration, can reverse the mechanism of action of opioids within minutes. Those administered by the intravenous route will generally reverse the effects quickly. The centrally acting antagonists have really come into the spotlight with the emergence of the opioid epidemic and the need for quick-acting antagonistic effects in the setting of an overdose. They can also be used as part of a long-acting management routine in patients undergoing treatment for opioid dependence to prevent a relapse.

The following medications are centrally acting opioid antagonists:

• Kloxxado (naloxone)

• LifEMS (naloxone)

• Narcan (naloxone)

• Vivitrol (naltrexone)

Peripherally acting opioid antagonists

Peripherally acting opioid antagonists also work quickly, with reversal of opioid-induced constipation within four hours of a single dose of a specific agent in 50-60% of patients. Sometimes, these agents are used to reverse other opioid-related side effects, such as nausea and vomiting, or pruritus (severe itching of the skin).

The following medications are peripherally acting opioid antagonists:

• Relistor (methylnaltrexone)

• Movantik (naloxegol)

• Symproic (naldemedine)

• Entereg (alvimopan)

Who can take opioid antagonists?

Adults

Centrally acting opioid antagonists, such as naloxone and naltrexone, are approved by the Food and Drug Administration (FDA) for use in adults as a reversal to opioid overdose as well as to reverse effects of opiate toxicity, such as respiratory depression, from treatment with opioid use. They also may be used to reverse itching associated with opioid use.

Peripherally acting opioid antagonists are FDA approved for use in adults in the management of opioid-induced constipation, except for Entereg which may be used off-label for this indication.

Children

Centrally acting opioid antagonists, such as naloxone and naltrexone, are FDA approved for use in children as a reversal to opioid overdose as well as to reverse effects of opiate activity, such as respiratory depression, from treatment with opioid use. They also may be used to reverse itching associated with opioid use.

Peripherally acting opioid antagonists are not FDA approved for use in children, and evidence to use these agents in this population is very limited.

Seniors

There are no limitations for centrally acting opioid antagonists in senior patients. These patients typically exhibit altered pharmacokinetics, like decreased kidney and liver function, but neither naloxone nor naltrexone require dose adjustments if such conditions are present.

Some peripherally acting opioid antagonists do require dose adjustments in either compromised kidney and/or liver function, so dosages may need to be altered in senior patients.

Can you take opioid antagonists while pregnant or breastfeeding?

The use of centrally acting opioid antagonists while either pregnant or breastfeeding should always be discussed with a medical professional, and risk versus benefit must be weighed carefully. Naloxone and naltrexone both cross the placenta, yet opioid use disorders are associated with adverse outcomes during pregnancy–both to the developing fetus and the mother. 

The use of naltrexone and naloxone for opioid use disorder during pregnancy is limited, so the risk of true withdrawal and abuse should be weighed against the risk of unwanted outcomes to the fetus or mother by the use of these medications. There is a growing body of evidence that demonstrates safety with these agents in a medication-assisted treatment option for opioid abuse during pregnancy, but current guidelines still recommend against their use. Safer and better-studied alternatives exist. In emergency situations, such in the setting of opioid overdose, The American College of Obstetricians and Gynecologists recommend that naloxone be used in pregnant women in order to save the mother’s life, despite the possibility of fetal distress.

In breastfeeding, centrally acting naltrexone is present in breast milk, while it remains unknown if naloxone is present. Therefore, the decision to continue or discontinue breastfeeding during therapy should take into consideration the risk to the infant if exposed, the benefits of breastfeeding, and the benefit of their use to the mother.

The decision to use peripherally acting opioid antagonists during pregnancy or while breastfeeding should be made in conjunction with a medical professional. While no adverse events have been observed in animal reproduction studies, the use of these agents may cause opioid withdrawal in the fetus during pregnancy. During breastfeeding, it is generally recommended to avoid the use of these agents, but ultimately the risk of exposure versus the benefit of continued breastfeeding should be weighed on a case-by-case basis.  

Are opioid antagonists safe?

Opioid antagonists should always be used under the guidance of a medical professional.

Centrally acting opioid antagonists are often used in emergency situations, such as an opioid overdose, so those administering these medications should be prepared for further medical complications which may be associated with acute opioid withdrawal. In patients with certain underlying medical conditions, such as a history of seizures and/or cardiovascular conditions, administration of opioid antagonists may exacerbate these underlying conditions.

Peripherally acting opioid antagonists are generally considered safe, but also have the potential to reverse the central effects of opioids so should be used with caution as they may potentiate opioid withdrawal.

Black Box Warnings

The only opioid antagonist with a black box warning is Entereg (alvimopan). The use of Entereg resulted in a greater incidence of myocardial infarction (MI) compared to those patients which received placebo in a clinical trial over a 12-month period. In trials over shorter periods of time with Entereg, there was no increased risk of MI observed.

Recalls

There are no current recalls for specific opioid antagonists.

Restrictions

Because of Entereg’s black box warning, it is available only through a restricted program for short-term use (15 doses) under a Risk Evaluation and Mitigation Strategy (REMS) called the Alvimopan REMS Program.

Relistor is contraindicated to be used in patients with a GI obstruction. Movantik is known to have several drug interactions, so concurrent medications should be reviewed by a healthcare professional prior to initiation. Entereg should not be used in patients that have received therapeutic doses of opioids for more than seven consecutive days just before Entereg.

Some opioid antagonists require Medication Guides to be dispensed with the medication, which contain specific information about how to safely use the medication. Those that require a Medication Guide include Vivitrol, Relistor, Movantik, and Symproic.

Are opioid antagonists controlled substances?

No, opioid antagonists are not controlled substances.

Common opioid antagonists side effects

The most common side effects of opioid antagonists include:

• Diarrhea

• Abdominal pain

• Headache

• Skin rash

• Acute opioid withdrawal symptoms, including agitation, body pain, confusion, disorientation, hallucination, irritability

How much do opioid antagonists cost?

Opioid antagonists vary in price depending upon the specific medication. Overall, these medications are moderately expensive. Naloxone or naltrexone formulations can range from over a hundred dollars to thousands of dollars per course. Peripherally acting opioid antagonists range in the several-hundreds of dollar range per course. Using a prescription discount card from SingleCare may help reduce the costs of opioid antagonists.