Managing Opioid Overdose: Signs, Symptoms, and Reversal Agents

Opioid overdoses remain a leading cause of preventable death - and pharmacy teams are on the front lines of response.

In this episode, TRC Healthcare Associate Editor and Clinical Pharmacist Don Weinberger, PharmD, PMSP, discusses how to recognize opioid overdose, compares naloxone and nalmefene options including the new nalmefene auto-injector, and shares tips for counseling patients and caregivers on using opioid reversal agents effectively.

This is an excerpt from our December 2025 Pharmacy Essential Updates continuing education webinar series.

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CE Information:

TRC Healthcare offers CE credit for this podcast for pharmacist subscribers at our platinum level or higher and pharmacy technician subscribers. Log in to your Pharmacist’s Letter or Pharmacy Technician’s Letter account and look for the title of this podcast in the list of available CE courses. None of the speakers have anything to disclose.

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Clinical Resources from Pharmacist’s Letter, Pharmacy Technician’s Letter, and Prescriber Insights: 

• Article: Boost Access to Naloxone or Nalmefene
• FAQ: Meds for Opioid Overdose
• Toolbox: Appropriate Opioid Use
• Chart: Opioid Reversal Agents Quick Start Guide
• FAQ: Management of Opioid Use Disorder

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Transcript

This transcript is automatically generated. 

00:00:04 Narrator

Welcome to Clinical Capsules from TRC Healthcare, your trusted source for practical, evidence-based updates.

00:00:11 Narrator

On this episode, Associate Editor and Clinical Pharmacist Don Weinberger breaks down how to recognize and respond to an opioid overdose. 

00:00:20 Narrator

He compares naloxone and the newer nalmefene options, along with how to use them, and shares practical tips for expanding access to lifesaving opioid reversal agents… in an excerpt from our popular Pharmacy Essential Updates webinar series.  

00:00:34 Narrator

This podcast offers Continuing Education credit for pharmacists and pharmacy technicians. Please log in to your Pharmacist’s Letter or Pharmacy Technician’s Letter account and look for the title of this podcast in the list of available CE courses.

00:00:46 Narrator

None of the speakers have anything to disclose. 

00:00:49 Narrator

Catch new episodes of Clinical Capsules every 2nd and 4th Tuesday—bringing concise, actionable insights from TRC experts straight to your ears.

00:00:57 Narrator

With that, Let's get started…

00:01:05 Don Weinberger

Okay, so let's get into this topic on how to appropriately manage opioid overdose. And we're talking about this topic today because a new nalmefene auto‑injector will be added to the plethora of different meds for reversing opioid overdose, leaving questions on which works best, if any, and how products really differ. And our December article has great details on this. But let's go through some of that now. Let's warm up our brains with a case.

00:01:32 Don Weinberger

A patient comes to your pharmacy to pick up a new prescription for alprazolam. You pull her patient profile and see she's been diagnosed with chronic back pain, lung cancer, and asthma. She's also currently taking ibuprofen 800 milligrams, fentanyl 25 micrograms per patch, an albuterol inhaler, and the alprazolam 1 milligram she's picking up today. We'll review this case a few times, so stay tuned.

00:01:59 Don Weinberger

When we talk about the history of opioid overdoses, it helps to step back and look at how different types of opioids have contributed to overdose deaths over time, roughly the last two decades. Early on, deaths involving natural and semi‑synthetic opioids, things like oxycodone and codeine, as well as heroin, rise slowly and stay relatively steady. But 10 years later, those trends are slightly elevated, but they really don't change dramatically.

00:02:26 Don Weinberger

But what really stands out is what happens with synthetic opioids, particularly fentanyl. Starting in the later part of 2013, deaths involving synthetic opioids begin to rise sharply. And from there, the increase isn't really gradual. It accelerates quickly and continues climbing year after year, far outpacing the other opioid categories. The shift lines up with the emergence of illicitly manufactured fentanyl and its analogs, which began appearing more widely around that time and have since

00:02:55 Don Weinberger

become the dominant driver of opioid overdose deaths. There is, however, a small but important sign of progress. Since 2023, we've seen a modest decline in opioid‑related overdose deaths. It's a hopeful trend, but it's also a reminder that while we may be moving in that direction, there is significant work to do. Let's refresh on how opioids work in the body and why they become so dangerous. As you know, opioids bind to receptors, help block pain signals,

00:03:24 Don Weinberger

which is why opioids are commonly used for pain relief. But here's the catch. Similar family opioid receptors that help with pain also affect other critical functions like breathing. Opioids activate other opioid‑type receptors that can suppress the body's natural drive to breathe, and that's where the danger comes in. Now, over time, people who use opioids often develop tolerance to the pain‑relieving effects. That means they'll need higher doses to achieve similar levels of pain relief.

00:03:52 Don Weinberger

But tolerance to opioid‑induced respiratory depression, OIRD, can develop more slowly. So as dose goes up, the risk of breathing problems elevates with it. So what are some signs of overdose that patients should be aware of? It's pretty distinct. First is shallow or depressed breathing. It's the most critical warning sign. Also, blue or purple fingernails and lips, a condition called cyanosis, which means oxygen levels are dangerously low. And pinpoint pupils, also known as miosis.

00:04:21 Don Weinberger

See these signs? It's a medical emergency. As I stated, overdose occurs when too much of an opioid binds to the receptors that drive breathing, which may end up resulting in respiratory depression and failure. A medication like an opioid receptor blocker has a higher affinity to the opioid receptors and displaces the opioid at that receptor site, reversing the symptoms of overdoses in the areas of the brain that control breathing. You may have heard these class of medications as opioid receptor blockers,

00:04:51 Don Weinberger

or opioid reversal agents or opioid antagonists. They essentially all mean the same medication class. And I'll refer to them interchangeably throughout our discussion. So let's jump into these classes now. I said earlier there’s a plethora of them, some of which you see and dispense on a regular basis. When we talk about opioid reversal agents, there are really only two generic medications to know, names to know, which are naloxone and nalmefene.

00:05:21 Don Weinberger

But even with these two generics, things can feel confusing because of the number of products, brand names, doses, and routes of administration. Naloxone is available in several forms, including injectable versions, pre‑filled syringes, and intranasal sprays. Nalmefene is also available as an injectable and intranasal spray, and there's now a new nalmefene auto‑injector, which we'll come back to later. One important point to keep in mind is that intranasal naloxone, like Narcan 4 milligram spray,

00:05:50 Don Weinberger

is available in both over‑the‑counter and prescription versions, depending on the product. Overall, there's a lot of similarities between these products, along with some important differences. In terms of use, both naloxone and nalmefene work quickly, with the onset of action within just a few minutes. If there's a response, the patient initially responds, but then slips back into respiratory depression, additional doses can be given every few minutes as needed. Where these two medications differ most is how long they last.

00:06:21 Don Weinberger

Naloxone typically works for about two hours, while nalmefene lasts closer to about six hours. Another difference is age approval. Naloxone can be used in patients of any age, while nalmefene is currently approved only for patients 12 years and older. In theory, nalmefene's longer duration could help reduce the risk of respiratory depression returning, especially with long‑acting opioids. However, evidence shows that there's no clear proof

00:06:46 Don Weinberger

that nalmefene is more effective than naloxone in terms of needing fewer doses or improving survival. Also, it's worth noting that the longer duration of nalmefene may prolong opioid withdrawal symptoms once it's given. So to sum up, there's no good evidence that one opioid reversal agent works better over another for opioid overdose symptoms. So instead, focus on increasing access to what the patient will actually use. So the question is, how do we expand access?

00:07:14 Don Weinberger

Since 2017, expanding access to opioid antagonists has saved at least 100,000 lives. And that number actually may be higher because of underreporting. And that's huge. It shows how powerful this intervention can be. And the good news is that all 50 states now have a way for pharmacists to provide naloxone directly to patients. This can happen through a protocol, standing order, or similar mechanism. And about 16 states have gone even further by allowing pharmacists to provide nalmefene.

00:07:43 Don Weinberger

If cost or insurance coverage is a concern, refer patients to local or state programs, especially around the public health departments. Many communities have initiatives to make these reversal agents available for free or at a reduced cost. Consider keeping an updated list of these sources in your community, what insurance might cover, and manufacturer programs to cover costs. So that you know the mechanisms, signs, and symptoms behind opioid overdose, as well as the meds used, let's jump into who is a candidate for opioid reversal agents.

00:08:13 Don Weinberger

First, anyone with a history of alcohol or other substance abuse. Combining opioids with other substances greatly increases the risk of overdose. Second, people taking high daily doses of opioids, specifically 50 milligrams or more of oral morphine or its equivalents. We'll talk more about this in a moment. Third, those who are switching from one opioid to another. This can be dangerous due to risk of incomplete cross‑tolerance. Fourth, anyone using opioids along with benzodiazepines, like lorazepam, alprazolam,

00:08:41 Don Weinberger

or other sedatives. These combinations can severely depress breathing. Fifth, patients taking opioids with antidepressants. Certain drug interactions can decrease opioid effectiveness, which in turn patients may take more opioids than prescribed for pain relief. Also, individuals with respiratory problems like asthma or COPD. Since opioids can slow breathing, it can make exacerbations for these breathing conditions worse or more likely.

00:09:08 Don Weinberger

Finally, those with renal or liver disease or other serious health conditions. These organs eliminate and metabolize medications, so impairment can lead to dangerous drug levels in the body. The basic idea is to ensure patient profiles are updated with these conditions so risk is assessed properly. So let's go back to what I was referring to with oral morphine equivalents. Some of you may have seen these on adjudication reject screens. Potency refers to how strong an opioid is compared to oral morphine, which is often used as a standard for comparison.

00:09:41 Don Weinberger

If we don't account for potency differences, patients can actually receive a much stronger dose than intended. So I'll actually put this in perspective. So hydrocodone 40 milligrams per day is roughly equal to morphine 40 milligrams per day. So 1 milligram of hydrocodone is about equal to 1 milligram of morphine. But fentanyl 25 micrograms per day is also equivalent to morphine 60 milligrams per day. It's a huge difference. Just a tiny amount of fentanyl can have the same effect as a much larger dose of morphine. So takeaway is this. Potency does matter.

00:10:11 Don Weinberger

Always check equivalencies when switching opioids and use morphine equivalent tools like the CDC calculator to stay safe. Let's get back to the case. Given what we know from the profile, our patient is a candidate for an opioid reversal agent due to the fact she has asthma, there's fentanyl dosing of 25 micrograms. And you know the choices are either naloxone or nalmefene. The technician flags the pharmacist to go over potential concerns, opioid overdoses, and to get details about opioid antagonists.

00:10:40 Don Weinberger

The patient does have questions, though. She's worried that carrying around a med that reverses overdoses will make it seem like she has a drug problem. And she's worried that it will cause harm if it's used and it's not needed. Now, these are definitely some concerns to have. What are the answers? So let's go ahead and put it into Rumor versus Truth, my favorite, since the other podcast I'm on is called just that. And I will name the claim,

00:11:08 Don Weinberger

and you can think about whether it's rumor or truth. So here's the claim. Opioid reversal agents encourage opioid misuse. Is that rumor or truth? What do you think? And the answer is rumor. In communities where naloxone distribution programs exist, opioid overdose deaths decrease and potentially increase interest in treatment. Most patients don't know they're at risk of an opioid overdose, and accidental overdose often occurs in patients who don't intentionally misuse opioids.

00:11:38 Don Weinberger

Okay, let's go into another rumor versus truth. The claim here is opioid antagonists can harm if they're not needed. What do you think? Rumor or truth? Okay, this one's also a rumor. Naloxone or nalmefene work by blocking opioid receptors. If those receptors aren't activated by opioids, the medication has no impact. But patients should be aware that side effects of opioid reversal are consistent with withdrawal. Things like agitation, nausea, and tremors.

00:12:09 Don Weinberger

Okay, so about offering naloxone or nalmefene, key points here. First, continue the conversation with every prescription for opioids and medications for opioid use disorder. Anyone on an opioid can be at risk. So this isn't just for high‑dose patients. It's actually for everyone. Second, think of these agents like a seatbelt. It's not there because we expect an accident, but because it's there to keep you safe if something unexpected does happen.

00:12:35 Don Weinberger

Framing it this way helps patients understand it's a precaution and not a judgment. Also, your language does matter. So try to use non‑stigmatizing terms. For example, instead of saying drug overdose, when speaking to patients, use terms like opioid poisoning, or saying misuse instead of abuse. This reduces shame and makes the conversation easier. Make sure to educate both patients and caregivers on how to use naloxone or nalmefene. Having the medication

00:13:04 Don Weinberger

is only helpful if they know what to do in an emergency. Often the patient themselves can't retrieve or give a dose to themselves if experiencing an opioid overdose, so they may rely on a caregiver for help. And even if the patient lives alone, alert somebody nearby, like a neighbor or a friend, before using opioids so they can check in on the patient. Also consider using smartphone apps or devices that monitor breathing and alert emergency contacts. So,

00:13:35 Don Weinberger

what to do if you think someone has overdosed on opioids? Let's break it down. Number one, call 911 immediately. Then give naloxone or nalmefene as quickly as possible if available. Do not wait for emergency workers to arrive before giving either opioid antagonist. Try to keep the patient awake and breathing. Lay the person on their back to prevent choking and stay with the person until emergency workers arrive.

00:14:01 Don Weinberger

And keep in mind that naloxone or nalmefene is a temporary treatment. More than one dose might be needed under some circumstances, especially if an overdose event involves longer‑acting opioids. Okay, so let's talk about how to actually give it. So first, tilt the head back slightly and insert the entire nozzle into one nostril. Next, use the plunger to spray the contents into the nostril. If necessary, repeat the dose in the other nostril to ensure full absorption.

00:14:29 Don Weinberger

Following these steps helps maximize the efficacy of the medication and ensures patient safety. So what about the injectable agents? First, prepare the device. If it's an auto‑injector, that means twisting the blue cap off, but for a pre‑filled syringe, just simply remove the cap. Once the device is ready, inject the medication into the outer thigh. This can be done through clothing if necessary, which is especially helpful in emergency situations. And hold in place for several seconds.

00:14:58 Don Weinberger

Don't try to recap the needle. Put the used syringe into the blue case, close the case, and give the syringe to the healthcare provider for inspection and proper disposal, but place it away from the scene to avoid needle sticks. Okay, so let's wrap up with some practice pearls for handling naloxone or nalmefene. First, advise patients to keep at least two doses on hand. Well, why two? Because sometimes one dose isn't enough to reverse an overdose, especially with potent opioids.

00:15:26 Don Weinberger

But some patients may think two doses means one dose in one location and one dose in the other, and that's not simply the case. Second, check expiration dates before dispensing. This is easy to overlook, but it's critical. Remind patients to keep an eye on expiration dates and request refills if needed. Replace any med that appears discolored or cloudy. Keep in mind the FDA has information about extended expiration dates for certain products. So search their website for more info.

00:15:54 Don Weinberger

Lastly, store at room temperature whenever possible. Extreme heat or cold can degrade the opioid antagonists, making them less effective when they're needed the most. Get back to our case. The pharmacy was able to get her an opioid reversal agent with a standing order allowed by your state. The pharmacist counseled her and her husband on appropriate use. The patient went home and unfortunately suffered an opioid overdose a week later. But because they had an opioid antagonist available and her husband knew how to use it,

00:16:24 Don Weinberger

she received emergency care and survived. Stories like this happen more often than you might think. So ensuring patients and caregivers receive proper reversal agents and know how to use them means all the difference. So providing opioid reversal agents is an important tool, but it's only one part of a broader strategy to reduce opioid overdose deaths. Real risk reduction comes from combining reversal agents with education, monitoring programs, safer prescribing,

00:16:52 Don Weinberger

and strategies that reduce misuse and exposure in the first place. And we have great clinical resources that address a lot of these. First is our Appropriate Opioid Use Toolbox, and we also have our Meds for Opioid Overdose, and our Opioid Reversal Agents Quick Start Guide, and other resources that cover much of the information you need to help your patients and educate your team.

00:17:17 Narrator

Thanks for listening—we hope today’s episode gave you practical insights you can use right away.

00:17:22 Narrator

Now that you’ve listened, pharmacists and pharmacy technicians can receive CE credit. Just log into your Pharmacist’s Letter or Pharmacy Technician’s Letter account and look for the title of this podcast in the list of available CE courses.

00:17:34 Narrator

We’ve linked the resources we mentioned—and more on today’s topic—right in the show notes. Those links will take you straight to our websites, where you’ll find even more concise, evidence-based charts, articles, and tools.

00:17:46 Narrator

If you’re not yet a subscriber, now’s the time—sign up today to stay ahead with trusted, unbiased insights, and continuing education. Listeners save 10% on a new or upgraded subscription just use code cc1026 at checkout.

00:18:03 Narrator

Looking for more? Check out our other TRC podcasts like Medication Talk and Rumor vs Truth, or dive deeper with our full Pharmacy Essential Updates webinar series.

00:18:12 Narrator

Thanks for listening… stay sharp, stay current—and join us next time on Clinical Capsules!