CATR: Welcome, Dr. Coffin. Tell us what you do.
Dr. Coffin: I’m a physician boarded in addiction medicine, infectious disease, and internal medicine. I am the director of substance use research at the San Francisco Department of Public Health, and on faculty at UCSF. My research is mainly in substance use, and I have various projects dealing with treatments for stimulant and alcohol use disorders, as well as HIV and hepatitis C prevention. A large focus of my work has been the development of opioid overdose prevention programming.

CATR: Which patients should be receiving naloxone prescriptions?
Dr. Coffin: We should think about prescribing naloxone to three broad patient groups. The first and most important group is people using drugs purchased outside of the health care industry: that is to say, anybody using drugs purchased on the street.

CATR: You recommend prescribing naloxone to people using any street drugs, not just those who use opioids?
Dr. Coffin: Fentanyl is changing the way we think about overdose prevention. It is taking over the illicit drug supply and is often being sold as something else. Someone who uses only cocaine has a reasonable chance of inadvertently exposing themselves to fentanyl. I should also mention that fentanyl is increasingly being smoked instead of injected. In general, opioid overdose is uncommon when not injecting; however, fentanyl seems to be different. People who smoke or sniff fentanyl, some of whom have never injected, are now experiencing overdoses. That is why we recommend prescribing naloxone to anyone who uses any street drugs—they’re the same people who are most likely to be present when an overdose happens.

CATR: What is the second group that should have access to naloxone?
Dr. Coffin: The second group is a subset of patients who have been prescribed opioid analgesics, as set forth in the 2016 CDC guidelines (Dowell D et al, MMWR Recomm Rep 2016;65(1):1–49). This includes anyone prescribed opioids at a dose of 50 milligram morphine equivalents (MME) or greater, anyone taking benzodiazepines along with opioids, anyone with a history of a substance use disorder or opioid overdose, and anyone with medical comorbidities that increase overdose risk. The guidelines are complicated, but basically, anyone who is prescribed opioids in any significant amount or who has additional risk factors should get naloxone.

CATR: And the third group?
Dr. Coffin: The third group is people who are likely to witness an opioid overdose. This includes parents, friends, and roommates. We call this “third-party prescribing,” and while it’s not universally authorized, most states allow for it. There are far too many stories out there about a family member finding their loved one who just overdosed, calling the ambulance, and simply having to wait too long for it to arrive. Third-party prescribing allows for a life-saving intervention without reliance on the immediate availability of health care professionals.

CATR: What forms of naloxone are available? What are their advantages and disadvantages?
Dr. Coffin: The IM injection is the most basic, consisting of a vial and a syringe—just like those used by patients to self-administer insulin years ago. Some patients may be hesitant using needles, but people who use drugs by injection will likely be comfortable with them. An advantage of the IM is that you know exactly how much naloxone the patient is getting, and it acts almost immediately. There is an auto-injector, which is a self-contained device that delivers naloxone with a needle. It’s a fantastic device. It talks to you and walks you through naloxone administration in real time. The needle is robust and will go through a pair of jeans, but the cost is unwieldy for most settings and I believe it is no longer being produced.

CATR: And then there is the ubiquitous nasal spray.
Dr. Coffin: The nasal spray is the most commonly prescribed because it’s very easy to administer, but it is important to be aware that people can have quite different absorption through the nasal mucosa. The dose for the nasal spray is 10 times higher than the IM injection in order to account for this difference, and that means people who absorb the medication readily will get a pretty steep dose of naloxone. Some recipients of the nasal spray therefore report headaches, which isn’t typically seen with other forms of naloxone. Interestingly, we see headaches with the buprenorphine/naloxone co-formulated product (brand name Suboxone) in around 10%–15% of patients, but very few headaches in patients taking buprenorphine alone (brand name Subutex). Given that the nasal spray is easy to administer, reliable, and widely available, it is usually the preferred formulation for prescribing naloxone. (Editor’s note: See News of Note on page 9 for more information about a new high-dosage naloxone formulation, KLOXXADO.)

CATR: I’ve heard concern from patients and providers alike that nasal congestion might interfere with the effective delivery of naloxone when given intranasally. Are there any data behind that?
Dr. Coffin: I don’t believe so. The IM injection is generally 0.4 mg, and that dose works reliably even in the setting of fentanyl. The nasal spray is 4 mg, which is approximately bioequivalent to 2 mg of IM. So even if full absorption doesn’t occur, the nasal spray should be more than sufficient to revive an overdose victim. I’m not particularly concerned about nasal congestion or anatomical abnormalities.

CATR: And what do these different formulations cost?
Dr. Coffin: The nasal spray cost, while not trivial, is covered by many insurance plans and is within reach of some people paying out of pocket. The brand-name Narcan is around $150 per two-pack; a generic has been approved but is not yet available. I’d love to see the price go down, but given the manufacturing costs, I don’t think it’s possible to get it under $30. The auto-injector has recently gone out of production (though there is still some backlog availability) but it was always priced high, anywhere from several hundred to several thousand dollars. The IM injection is the most economical; with contracts, it’s inexpensive enough to be distributed by many naloxone distribution programs. The IM injection is rarely prescribed on an individual basis, with the exception of some Medicare Part D plans that don’t cover the nasal spray.

CATR: Can you tell us what you mean by naloxone distribution programs?
Dr. Coffin: There are two models of getting naloxone into the hands of those who need it. One is prescription, which is what most of us in the medical system are used to. The other is distribution, in which an organization purchases naloxone in bulk and gives it out to large numbers of patients. The most common setting for this model is syringe exchange programs; these organizations are able to get naloxone cheaply enough that they can hand out thousands of doses to the people who are around overdoses all the time. Individual prescribing is important, but the distribution model is the real harm reduction workhorse; most overdose reversals in the community come from naloxone obtained through the distribution model, namely via a standing order.

CATR: And can you explain what a standing order is?
Dr. Coffin: Essentially, a standing order allows a physician to write a naloxone order in such a way that the medication can be dispensed under their license to a large group of people, without the physician needing to directly see individual patients and write individual scripts. Naloxone is not a controlled substance, so most states have passed standing order laws of some kind, with the exception of Idaho, Nebraska, and Oregon (SAFEProject, 2021). This is important information to communicate to patients who can’t or don’t want to see a prescriber.

CATR: Where does a standing order allow naloxone to be dispensed from?
Dr. Coffin: A standing order is generally used to allow naloxone to be dispensed from a place like a syringe exchange or a pharmacy. For example, I issue the standing order for the Drug Overdose Prevention and Education Project in San Francisco, and the naloxone finds its way to the staff at the syringe exchange programs, who then dispense it directly to the clients. This is not billed through insurance; it is done outside of what we think of as the traditional health care system.

CATR: So should providers refer their patients to needle exchange programs or have them go to their local pharmacy to get naloxone?
Dr. Coffin: If you are a prescriber seeing a patient who warrants a naloxone prescription, I generally recommend just prescribing it to the patient. But you can also take steps to make sure people in the community know that naloxone is widely available. You can list the places that dispense naloxone so clients know they can ask for it, or you can put a flyer in the waiting room for people who don’t want to talk to you about their substance use.

CATR: What about patients who aren’t injecting drugs and who do not go to syringe exchange programs? How might they find where naloxone is available under these standing orders?
Dr. Coffin: Accessing naloxone can be a little bit trickier for these patients, and that’s part of the reason it’s important to prescribe naloxone directly to patients whenever you can. Some states have great web-based resources for naloxone as well, which will typically list pharmacies in the area that have standing orders. SAFEProject, which stands for Stop the Addiction Fatality Epidemic, has an online compilation of state-specific information with links to each state’s online resources (www.safeproject.us/naloxone-awareness-project/state-rules/). Another resource is a summary of state naloxone access laws put out by the Legislative Analysis and Public Policy Association (www.legislativeanalysis.org/wp-content/uploads/2020/10/Naloxone-summary-of-state-laws-FINAL-9.25.2020.pdf).

CATR: Naloxone is unusual in that, unlike other medications, patients do not typically administer it to themselves. Providers therefore have to educate patients on how to use naloxone and make them into naloxone educators themselves. Can you give us some specific language to use with patients?
Dr. Coffin: Sure. First, consider the term “overdose”; we use it all the time, but it can be problematic. Many people, especially those taking prescription opioids, only think of an overdose as an intentional act—like swallowing a whole bottle of pills. They don’t think of the term as simply having too much opioid in your body at a given moment. So instead of using the word “overdose,” I’ll explain naloxone like this: “Opioids can cause a bad reaction where you stop breathing, and that can be fatal. Naloxone is a medication that can reverse that.” In fact, we interviewed patients prescribed opioids and found that almost half of those who had overdosed denied having an “overdose,” but described a “bad reaction” where they couldn’t be woken up without assistance such as being revived by paramedics (Behar E et al, Ann Fam Med 2016;14(5):431–436).

CATR: What are other key points that you emphasize when prescribing naloxone?
Dr. Coffin: The most important thing to do when you’re prescribing naloxone is to make sure that patients let those around them know where the naloxone is located. This holds for third-party prescribing as well; you want to make sure that everyone in the household knows where the naloxone is kept and that it is easily accessible. The nasal spray and auto-injector don’t need much instruction in terms of use. But be sure to explain to your patient that if they see somebody not breathing, they should administer naloxone right away, call 911, and attempt whatever type of resuscitation they are comfortable providing—such as rescue breathing or chest compressions. It’s not complicated, but all the pieces need to be there. The Substance Abuse and Mental Health Services Administration, commonly called SAMHSA, has a free downloadable resource called Opioid Overdose Prevention Toolkit that lays out how to recognize and respond to an overdose (www.store.samhsa.gov/product/Opioid-Overdose-Prevention-Toolkit/SMA18-4742).

CATR: What are some important risk factors for opioid overdose?
Dr. Coffin: There are two main modifiable risk factors that practitioners can easily focus on. The first is consumption of other drugs, particularly depressants like alcohol and benzodiazepines. The other is tolerance, which can be lost in as little as 3 days of abstinence. Some patients taking buprenorphine might stop the medication in order to use opioid agonists, and those few days are enough to have a loss of tolerance. More commonly, people being released from prison and leaving abstinence-based treatment programs have sky-high mortality for the first 48 hours. Patients being tapered off opioids also lose tolerance toward the end of the taper.

CATR: How should clinicians stay up to date regarding federal and local regulations, both pertaining to opioid use disorder treatments in general and to naloxone specifically?
Dr. Coffin: Again, many regulations are state specific, but I would recommend that anyone treating patients with opioid use disorder be aware of a few local laws that are on the books in most states. First, multiple states now have co-prescribing mandates that require a naloxone prescription for patients who are receiving opioids or who have certain risk factors. Most, but not all, states have third-party prescription laws and standing order protocols. There are also Good Samaritan laws that give some protection against low-level drug violations for people who report an overdose. That said, these laws are complex; no one can realistically keep track of all of them. I recommend a website through Temple University called LawAtlas (www.lawatlas.org), which maintains a registry of laws relevant to the psychiatric practitioner. They have a section devoted to naloxone prescribing (www.pdaps.org/datasets/laws-regulating-administration-of-naloxone-1501695139).

CATR: Thank you for your time, Dr. Coffin.