Opioid Antagonists: Treatment Considerations and Updates

The burgeoning drug overdose epidemic in the United States led to more than 100,000 deaths in 2021, which were mostly related to opioid toxicity, according to the Centers for Disease Control and Prevention (CDC).¹ The majority of these deaths have been attributed to synthetic opioids such as fentanyl and its analogs, which caused more than 80% of opioid-related deaths in 2020 — an 18-fold increase since 2013.² While the short-acting opioid antagonist naloxone has become the standard treatment for suspected or known opioid overdose, certain situations may call for additional therapies, such as longer-acting opioid antagonists.
 
Adam Bisaga, MD, professor of psychiatry at the Columbia University Irving Medical Center in New York City, New York, and research scientist at the New York State Psychiatric Institute, discussed various clinical considerations in the treatment of opioid overdose. Among the topics of his research in the area of opioid use disorder (OUD), Dr Bisaga has investigated treatment outcomes associated with long-acting opioid antagonists. He has also been involved in various substance abuse training programs and public health projects on the local, national, and international levels.

Are there any notable updates in the field of opioid antagonists? What should clinicians know about the more recently introduced higher-dose formulations of naloxone?

Naloxone is a widely used, first-line opioid receptor antagonist medication for treating opioid overdose and is administered by medical professionals, first responders, and bystanders in the general public. Its safety and efficacy have been well established. Naloxone is currently available as an intranasal spray (2 or 4 mg) or injection (0.4 or 2 mg). In 2021, the US Food and Drug Administration (FDA) approved a higher strength (8 mg) intranasal spray and a 5-mg injection preparation.^3,4 Naloxone has historically only been available by prescription, but just recently, the FDA announced that some versions of the drug are safe for over-the-counter use.⁵
 
Most of the evidence for the effectiveness and safety of naloxone has come from work with prescription opioid or heroin users. One of the main problems that we are facing right now is how to best approach reversal of overdoses from “street drugs” containing highly potent synthetic opioids, such as nonpharmaceutical fentanyl and its analogs. It is not clear whether the current naloxone formulations are as effective for fentanyl as they have been proven to be for heroin and other opioids. This is because the effects on the body from a fentanyl overdose are different from heroin; in addition to the central decrease of the respiratory drive, fentanyl overdose can include a constriction of respiratory muscles and vocal cords — ie, “wooden chest syndrome” — which is not present during overdoses from other opioids.⁶ Naloxone has very limited to no effect on muscle constriction, which is primarily mediated via the adrenergic system rather than the opioidergic system. Anecdotal reports suggest that multiple doses of naloxone in succession are needed to revive individuals who overdose from fentanyl. The most important factor for reversing fentanyl overdoses is to deliver naloxone as soon as possible, as its onset of action on respiration is much shorter than for other opioids.
 
However, a problem arises when giving a higher initial naloxone dose, as it may cause precipitated withdrawal. Opioid withdrawal symptoms can show up as hyperalgesia, anxiety, nausea, hypertension, and tachycardia. This may develop gradually or suddenly, precipitated by administration of an opioid antagonist or partial agonist.⁷ One of the reasons precipitated withdrawal can be dangerous is that it includes an adrenergic surge, which can further constrict the laryngeal and chest wall muscles, thereby restricting respiration. Therefore, giving several smaller doses of naloxone may be actually safer in patients who are still breathing. If there is no breathing detected, then a higher initial dose would be necessary.

The American Heart Association (AHA) recommends, after initiation of CPR, the use of intranasal or intramuscular naloxone with repeat dosing as needed for acute life-threatening opioid overdose.⁸ Can you discuss naloxone dosing in specific settings to avoid acute opioid withdrawal? If there are concerns regarding concurrent stimulant overdose, what should clinicians be aware of? Can you discuss dose re-administration according to opioid type and duration of action?

A standard approach to an opioid overdose includes protection of the airways and administration of a standard naloxone dose, preferably a 0.4- to 0.8-mg intramuscular or intravenous (IM/IV) injection, or a 2-mg intranasal dose if injection is not available. Higher initial doses of 1- to 2-mg IM/IV should be given to patients with apnea or in cardiorespiratory arrest.⁹ A respiratory support — assisted breathing, with supplemental oxygen if available — is also recommended after naloxone is administered. The clinical response (ie, increase in respiratory rate and pupil dilation) should occur within 2 to 3 minutes following IM/IV administration, but if no response is seen during this time, higher (1- to 2-mg IM/IV, or 4- to 8-mg intranasal) repeated doses should be given at 2- to 3-minute intervals while ventilation and oxygenation are maintained.⁶
 
Naloxone only works for 1 to 2 hours after each dose, whereas it can take 8 to 12 hours for the toxic effects of fentanyl or methadone to start resolving. Therefore, a short-acting agent like naloxone needs to be re-administered several times, or given as an IV infusion, to successfully reverse and prevent the recurrence of the overdose. Redosing of naloxone should be guided by clinical parameters. The primary goal of naloxone administration is to restore ventilation to more than 10 respirations per minute and oxygenation above 92% rather than full alertness, as higher doses of naloxone can precipitate opioid withdrawal and may cause difficulty with controlling agitation. An acute lung injury with hypoxia, rales, and mouth frothing can be seen in rapid overdose reversals in patients with marked hypoventilation.¹⁰

Ideally, all individuals who were found overdosed on opioids would be brought in and observed in the hospital for at least 8 to 12 hours to determine if additional doses of an opioid antagonist medication might be needed. This is particularly important because many individuals have an overdose with multiple sedative or stimulant substances, which may cause unpredictable clinical outcomes. The possible synergistic toxic and lethal respiratory and cardiac effects of polysubstance overdose are best assessed and managed with close monitoring.

What is the clinical utility of long-acting opioid antagonists in acute opioid overdose?

Nalmefene is a long-acting opioid receptor antagonist. As compared with naloxone, nalmefene is more potent and approximately 4 times longer acting, which means it has a particular advantage for reversing overdoses from long-acting opioids such as fentanyl or methadone.¹¹
 
Since naloxone only works for 1 to 2 hours after each dose and the toxic effects of fentanyl or methadone can take 8 to 12 hours to start resolving, a short-acting agent like naloxone needs to be re-administered several times to successfully reverse and prevent the recurrence of the overdose. With nalmefene, however, only 1 dose can have the same effect as multiple consecutive doses of naloxone, which is important in the case of a patient who is revived and does not want to go to the hospital, as is often the case. Additionally, nalmefene is more effective at removing fentanyl from the opioid receptors of the brain as compared with naloxone, producing faster and more complete reversal of the overdose.¹²
 
One of the downsides to nalmefene is that if the dose is too high, the precipitated withdrawal that can follow may take longer to resolve than in situations where a short-acting medication like naloxone was used. However, considering how lethal fentanyl is, it appears that nalmefene might be a more effective intervention for fentanyl overdose. Although precipitated withdrawal symptoms are extremely unpleasant, they are not life threatening. The effectiveness and safety of nalmefene in the clinical setting of fentanyl overdose reversals has not been studied.

Can you review reversal of respiratory depression associated with partial opioid agonists such as buprenorphine?

Buprenorphine is a partial agonist at the opioid receptors, which means that the opioid effect it exerts is limited to approximately only 50% of the maximum effect that heroin or methadone can produce.¹³ Moreover, there is a “ceiling” on the respiratory depression buprenorphine may produce, even if very high doses are taken. Because of these properties, buprenorphine is considered to be relatively safe if taken in an overdose. The 2 exceptions are overdoses in the pediatric population or if buprenorphine is taken as a high-dose IV injection in combination with other agents that can reduce respiration, such benzodiazepines or alcohol.⁸
 
Because buprenorphine binds very strongly with the opioid receptor, naloxone has a limited effect to reverse buprenorphine-induced overdose, though it is usually administered in such cases. It is not clear if nalmefene might be more effective for reversal of buprenorphine overdose. Interestingly, buprenorphine can be used to reverse overdose from long-acting opioids such as fentanyl or methadone because it can out-compete those agents at the receptor site while having less opioidergic activity, therefore reducing the overall net opioid effect, such as respiratory depression.⁸ This approach, though effective in anecdotal reports, has not been formally tested.

What are remaining gaps in terms of clinician knowledge regarding the opioid overdose strategies?

The emergence of fentanyl contamination has been linked to a massive increase in the risk for overdose in individuals using “street” opioids and stimulants.⁶ Therefore, all medical practitioners should be familiar with strategies to prevent opioid overdose and provide them to all patients for the greatest public health impact. This primarily includes a prescription for naloxone with instructions on when and how to use it or a link to services providing mail-delivered naloxone and overdose education. In addition, these efforts should include information on harm-reduction interventions such as low-barrier treatment with buprenorphine, syringe exchange programs, services or take-home strips that can test the drug supply for fentanyl, and education on decreasing overdose risk in active drug users.

This Q&A was edited for clarity and length.

Disclosures

Adam Bisaga, MD, reported affiliations with Alkermes, plc.

References

1. Spencer MR, Miniño AM, Warner M. Drug overdose deaths in the United States, 2001-2021. NCHS Data Brief. 2022;(457):1-8. doi:10.15620/cdc:122556
 
2. Centers for Disease Control and Prevention. Synthetic opioid overdose data. Updated June 6, 2022. Accessed January 10, 2023. https://www.cdc.gov/drugoverdose/deaths/synthetic/index.html
 
3. FDA approves higher dosage of naloxone nasal spray to treat opioid overdose. News release. US Food and Drug Administration. May 11, 2021. Accessed January 20, 2023. https://www.fda.gov/news-events/press-announcements/fda-approves-higher-dosage-naloxone-nasal-spray-treat-opioid-overdose
 
4. FDA approves naloxone injection to counteract opioid overdoses. US Food and Drug Administration. October 18, 2021. Accessed January 20, 2023. https://www.fda.gov/drugs/news-events-human-drugs/fda-approves-naloxone-injection-counteract-opioid-overdoses
 
5. FDA announces preliminary assessment that certain naloxone products have the potential to be safe and effective for over-the-counter use. News release. US Food and Drug Administration. November 15, 2022. Accessed January 10, 2023. https://www.fda.gov/news-events/press-announcements/fda-announces-preliminary-assessment-certain-naloxone-products-have-potential-be-safe-and-effective  
 
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8. Dezfulian C, Orkin AM, Maron BA, et al. Opioid-associated out-of-hospital cardiac arrest: distinctive clinical features and implications for health care and public responses: a scientific statement from the American Heart Association. Circulation. 2021;143(16):e836-e870. doi:10.1161/CIR.0000000000000958
 
9. Tylleskar I, Gjersing L, Bjørnsen LP, et al. Prehospital naloxone administration – what influences choice of dose and route of administration? BMC Emerg Med. 2020;20(1):71. doi:10.1186/s12873-020-00366-3
 
10. Jordan MR, Morrisonponce D. Naloxone. In: StatPearls. StatPearls Publishing; 2022.
 
11. Edinoff AN, Nix CA, Reed TD, et al. Pharmacologic and clinical considerations of nalmefene, a long duration opioid antagonist, in opioid overdose. Psychiatry Int. 2021;2(4):365-378. doi:10.3390/psychiatryint2040028
 
12. Krieter P, Gyaw S, Crystal R, Skolnick P. Fighting fire with fire: development of intranasal nalmefene to treat synthetic opioid overdose. J Pharmacol Exp Ther. 2019;371(2):409-415. doi:10.1124/jpet.118.256115
 
13. Lutfy K, Cowan A. Buprenorphine: a unique drug with complex pharmacology. Curr Neuropharmacol. 2004;2(4):395-402. doi:10.2174/1570159043359477

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