Continuing Education Activity

Opioid receptor antagonists block one or more of the opioid receptors in the central or peripheral nervous system. Opioid receptors are specific transmembrane neurotransmitter receptors that couple G-proteins, which upon stimulation by endogenous or exogenous opioids, lead to the intracellular process of signal transduction. The two most commonly used centrally acting opioid receptor antagonists are naloxone and naltrexone. Naloxone comes in intravenous, intramuscular, and intranasal formulations and is FDA-approved for use in opioid overdose and the reversal of respiratory depression associated with opioid use. Naltrexone is available in both oral and long-acting injectable formulations and is FDA-approved to treat opioid and/or alcohol maintenance treatment. The most commonly used peripheral opioid receptor antagonist is methylnaltrexone, which is a potent competitive antagonist acting in the digestive tract and is also FDA-approved for the treatment of opioid-induced constipation. This activity outlines the indications, mechanism of action, methods of administration, important adverse effects, contraindications, monitoring, and toxicity of opioid antagonists, so providers can direct patient therapy to optimal outcomes to combat opioid overdose, misuse, or adverse effects.

Objectives:

• Identify the mechanism of action of various opioid antagonist medications.
• Summarize the different indications for the various opioid antagonist agents.
• Review the adverse event profile of opioid antagonists.
• Outline the importance of collaboration and communication among interprofessional team members to improve outcomes and treatment efficacy for patients who might benefit from therapy with opioid antagonists, especially in light of the ongoing opioid crisis.

Indications

Opioid receptor antagonists block one or more of the opioid receptors in the central or peripheral nervous system. Opioid receptors are specific transmembrane neurotransmitter receptors that couple G-proteins, which upon stimulation by endogenous or exogenous opioids, lead to the intracellular process of signal transduction.

The most recent classification scheme identifies three major classes of opioid receptors, with several minor classes. The three most clinically relevant opioid receptors are the mu, kappa, and delta receptors. Stimulation of central mu receptors causes respiratory depression, analgesia (supraspinal and peripheral), and euphoria.[1] Peripheral mu receptors are tissue-specific, with higher concentrations in bronchial smooth muscle and the digestive tract. This is the reason for opioids suppressing the cough reflex and causing constipation.[2]  Kappa and delta-opioid receptors also have potent analgesic effects; kappa receptors are known to cause disassociation, hallucinations, and dysphoria, and delta receptors also modulate mu receptors.[3][4]

The two most commonly used centrally acting opioid receptor antagonists are naloxone and naltrexone. Naloxone comes in intravenous, intramuscular, and intranasal formulations and is FDA-approved for use in opioid overdose and the reversal of respiratory depression associated with opioid use. Naltrexone is available in both oral and long-acting injectable formulations and is FDA-approved to treat opioid and alcohol use disorders as a maintenance treatment. The most commonly used peripheral opioid receptor antagonist is methylnaltrexone, which is a potent competitive antagonist acting in the digestive tract and is also FDA-approved for the treatment of opioid-induced constipation.[5] Methylnaltrexone comes in oral tablets and as a subcutaneous injection. Nalmefene is another opioid antagonist. Its affinity for mu and kappa receptors is similar to naltrexone, though its affinity for delta receptors is greater than naltrexone. In the United States, it is approved for the reversal of Mu receptor agonist effects by parenteral routes. Nalmefene has a more extended duration of action than naloxone and has increased bioavailability. Nalmefene has approval in some European countries as an oral formulation to treat alcohol use disorder. 

Opioid antagonists such as naloxone have come into the public spotlight with the emergence of the opioid epidemic and the need for readily accessible reversal agents in the setting of an acute opioid overdose. Various communities have experimented with naloxone dispensaries or over-the-counter availability at pharmacies without the need for a prescription. These communities have shown promising results in lives saved.[6] There is also a national movement to arm law enforcement officers, first responders, and schoolteachers with specific training in recognizing an opioid overdose and the knowledge and confidence to administer a reversal agent such as naloxone correctly.

Mechanism of Action

Centrally acting opioid receptor antagonists are potent competitive inhibitors with the highest affinity for the mu receptor. Naloxone is the most common choice in opioid overdose emergencies, and naltrexone is utilized primarily in opioid and alcohol use disorders to help maintain abstinence primarily by decreasing cravings. The competitive antagonism of the central mu receptors stimulates the respiratory drive, increases alertness, terminates analgesia and euphoria, and causes mydriasis.[1]

Peripherally acting opioid receptor antagonists do not readily cross the blood-brain barrier but are potent competitive inhibitors at the mu receptor, which are found in high concentration at peripheral nerve terminals in bronchial smooth muscle and the digestive tract. Antagonism of these peripheral mu receptors can lead to intestinal hypermotility.[5] Some studies suggest that up to 60% of opioid analgesia originates from the peripheral opioid receptors and that antagonizing through pharmacologic means may lead to an acute pain crisis.[7]

Administration

A precipitated withdrawal from opiates, whether caused by naloxone in the pre-hospital or emergency department setting or by naloxone or naltrexone during a medically supervised withdrawal treatment, can lead to hospital admission or even require intensive care. There are rare, isolated reports of stress-induced cardiomyopathy and organic delusional disorder.[8][9] More commonly, the implementation of intravenous hydration and electrolyte replacement is in order due to significant nausea, vomiting, and diarrhea.

During a medically supervised withdrawal, often great care is taken in increasing the naltrexone dose gradually over a period of 3-7 days resulting in opiate “washout.” This naltrexone-accelerated withdrawal has high complication rates and almost certainly requires the addition of an alpha-2 agonist (like clonidine and lofexidine, which requires less concern for hypotensive effects.) and comfort medications such as benzodiazepines, antiemetics, and muscle relaxers.[10]

Adverse Effects

Accelerated protocols for medically supervised management of withdrawal aim to reduce the transition time to naltrexone treatment, thereby reducing patient inconvenience, lengths of inpatient or residential stay, and treatment costs. This method has not found widespread use. During a supervised naltrexone-accelerated withdrawal, a “naloxone challenge” can be performed to ensure a complete system depletion of exogenous opioids prior to full-dose oral naltrexone or extended-release intramuscular naltrexone (Vivitrol). A low naloxone starting dose of just 0.1 mg intravenous is given, and the patient is monitored for up to 30 minutes for signs of withdrawal. Typically, symptoms present within 1-5 minutes. A doubled dose of 0.2 mg follows, and the patient undergoes observation. Thirty minutes following, a final dose of 0.4 mg is given, and if the patient is asymptomatic, the assumption is that the patient can safely receive naltrexone without fear of withdrawal symptoms. The extended-release injectable version of naltrexone has found increased favor among practitioners for opiate maintenance treatment as it only needs dosing every four weeks.[11]

Buprenorphine, a partial mu agonist and kappa antagonist, can be combined with naloxone for effective therapy in medically supervised opioid withdrawal. Naloxone, when combined with buprenorphine, has poor oral availability,[12] but when crushed and intravenously injected, can precipitate opioid withdrawal symptoms. This can act as a deterrent for opioid users who are physiologically dependent. To begin buprenorphine-naloxone therapy during induction, the patient must have a mild-to-moderate withdrawal (Clinical Opioid Withdrawal Scale [COWS] of greater than 10 or 12) to receive a net benefit for the opioid agonist component and relief from withdrawal symptoms. The time it takes to be in mild-to-moderate withdrawal (COWS > 10 or 12) is dependent on the half-life of the opioid used by the patient. Methadone, for example, has a half-life greater than 24 hours.[13] Buprenorphine can be started for maintenance therapy if the patient has not used opiates for a while but still has a craving (after completing rehab or release from prison). On the whole, starting buprenorphine should only take place when there are no signs of opioid intoxication or sedation or some observable signs of opioid withdrawal.

Contraindications

Opioid receptor antagonists block one or more of the opioid receptors in the central or peripheral nervous system. Stimulation of central mu receptors causes respiratory depression, analgesia, and euphoria.

• Naloxone comes in intravenous, intramuscular, and intranasal formulations and is FDA-approved for use in opioid overdose and the reversal of respiratory depression associated with opioid use.
• Naltrexone is available in both oral and long-acting injectable formulations and is FDA-approved for the treatment of opiate and alcohol use disorder (mainly maintenance treatment).
• A precipitated withdrawal from opiates, whether caused by naloxone in the pre-hospital or emergency department setting or by naloxone or naltrexone during a medically supervised management of opioid withdrawal, can lead to hospital admission or even require intensive care.
• Some studies have shown a dose-dependent relative risk reduction on the amount of naloxone distributed in the community, whether by prescription or community dispensaries, versus opioid-related overdose mortality.

Enhancing Healthcare Team Outcomes

The 2016 CDC Guideline for Prescribing Opioids for Chronic Pain specifically recommends incorporating strategies to mitigate risks, such as prescribing naloxone in patients with a history of substance use disorder, high risk and/or history of overdose, higher opioid dose (>50 morphine milligram equivalent daily dosing), patients at risk of returning to a high dose to which they are no longer tolerant (e.g., patients recently released from prison), or concurrent benzodiazepine use.[14] Some studies have shown a dose-dependent relative risk reduction on the amount of naloxone distributed in the community, whether by prescription or community dispensaries, versus opioid-related overdose mortality.[6] 

There has also been legislation passed providing legal protection to laypersons attending to a suspected opioid overdose and/or initiating early activation of the emergency response system. All interprofessional healthcare team members (MDs, DOs, NPs, PAs) who prescribe opioids should be familiar with current guidelines for pain management; failure to do so may result in patient harm and loss of prescribing privileges for certain controlled substances. Nurses and pharmacists also have a role to play in these cases because they often are the first contact points for patients with the medical system. Pharmacists can see the patient's prescription history, and nursing staff can provide counsel and ask questions. Working as an interprofessional team is necessary when using opioid antagonist therapy to achieve optimal patient results and prevent adverse events, both from the antagonist medication as well as the opioid itself. [Level 5]

Mainstreaming Addiction Treatment (MAT) Act

The Mainstreaming Addiction Treatment (MAT) Act provision updates federal guidelines to expand the availability of evidence-based treatment to address the opioid epidemic. The MAT Act empowers all health care providers with a standard controlled substance license to prescribe buprenorphine for opioid use disorder (OUD), just as they prescribe other essential medications. The MAT Act is intended to help destigmatize a standard of care for OUD and will integrate substance use disorder treatment across healthcare settings. 

As of December 2022, the MAT Act has eliminated the DATA-Waiver (X-Waiver) program. All DEA-registered practitioners with Schedule III authority may now prescribe buprenorphine for OUD in their practice if permitted by applicable state law, and SAMHSA encourages them to do so. Prescribers who were registered as DATA-Waiver prescribers will receive a new DEA registration certificate reflecting this change; no action is needed on the part of registrants.

There are no longer any limits on the number of patients with OUD that a practitioner may treat with buprenorphine. Separate tracking of patients treated with buprenorphine or prescriptions written is no longer required. 

Pharmacy staff can now fill buprenorphine prescriptions using the prescribing authority's DEA number and does not need a DATA 2000 waiver from the prescriber. However, depending on the pharmacy, the dispensing software may still require the X-Waiver information in order to proceed. Practitioners are still required to comply with any applicable state limits regarding the treatment of patients with OUD.  Contact information for State Opioid Treatment Authorities can be found here: https://www.samhsa.gov/medicationassisted-treatment/sota. 

Review Questions

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References

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Disclosure: Jonathan Theriot declares no relevant financial relationships with ineligible companies.

Disclosure: Sarah Sabir declares no relevant financial relationships with ineligible companies.

Disclosure: Mohammadreza Azadfard declares no relevant financial relationships with ineligible companies.