Why Generic Naloxone Is Superior to NARCAN®… and Kloxxado®… and Zimhi™

Back in November 2019, I wrote an article called “Why Name Brand NARCAN® Is Worth the Extra Price.” There, I argued name-brand NARCAN® naloxone nasal spray is worth what it costs — on average, one two-dose box costs $132.49 here in Tennessee roughly three to five times the cost of intramuscular (injectable) naloxone kits. And that NARCAN® was the superior formulation of naloxone.

Having distributed thousands of doses of naloxone here in rural/non-Memphis West Tennessee — both NARCAN® and its generic, unpatented, intramuscular counterpart — since writing that article, I’ve changed my mind: NARCAN® isn’t worth the money and we harm reductionists shouldn’t bother buying it.

2019 Daniel Came to Some Poor Conclusions

Here are a couple of assumptions I made about NARCAN®:

#1. It’s Easier to Use Than Intramuscular Naloxone Kits

At the time, I always thought name-brand nasal spray NARCAN® was easier to use than intramuscular naloxone kits, which include a syringe, one or more vials of naloxone, and instructions.

Admittedly, since NARCAN® doesn’t need to be assembled, its design is foolproof, making it easier for beginners to use. However, this comes at a disadvantage — intranasal naloxone takes longer to absorb than injected naloxone; I feel the 15 or 30 seconds needed to prepare an intramuscular injection of naloxone outweighs any ease-of-use benefits offered by NARCAN®.

#2. People Could Accidentally Stab Themselves or Others With the Syringes That Are Part of Intramuscular Naloxone Kits

This is not likely to happen. Although responding to opioid overdose is unquestionably traumatic, even for the most experienced of us, accidentally stabbing yourself or someone else with a syringe used to administer IM naloxone is not a real concern.

As the time of publication, our participants have reversed about 100 overdoses since we began tracking this information in June 2021. Roughly 80% involved injectable naloxone, and accidental stabs haven’t happened once.

Here’s Why NARCAN® Isn’t Worth as Much as It Costs:

#1. IM Naloxone Kits Are Much Cheaper Than NARCAN®

IM naloxone kits are substantially cheaper than NARCAN®. I won’t publish cost data here, as I’m not allowed to share information from the NASEN Buyer’s Club price list, but just know intramuscular kits cost significantly less than their eight-times-U.S.-patented, 28-times-internationally-patented name-brand counterpart: NARCAN®.

As we’ll explain further on, IM naloxone kits contain two or three single-dose vials of naloxone. Even today, during a major, national naloxone shortage, vials of injectable naloxone cost between $30 and $45 at retail, according to a February 2022 brief on naloxone access by the University of Tennessee’s SMART Policy Network.

Note: Before this still-ongoing shortage, which began in early 2021, vials of naloxone cost just $15 at retail.

Harm reduction programs, however, typically source vials of injectable naloxone at much lower rates — as low as $1 per vial, if not for free.

According to a 2020 statewide study by the University of Tennessee Health Science Center College of Pharmacy, the mean retail price of a box-unit of NARCAN® was $132.49 (box-units contain two dose-units).

Using the aforementioned price range of $30 to $40 for a single-dose vial of naloxone, you could buy between three and four vials at retail price with the money you’d spend on NARCAN®.

Accounting for bioavailability differences — again, we go over this later in the article — one NARCAN® dose-unit contains the equivalent of about five vials of injectable naloxone; box-units of NARCAN® (what you’d actually buy at a pharmacy) contain two doses, equating to roughly 10 vials of injected naloxone. Still, that’s only two doses.

Thus, even though you’d get less naloxone by purchasing injectable vials, you stand a very real chance of reversing an opioid overdose with each vial of naloxone you have.

So, even though NARCAN® contains more naloxone — with $132.49 getting you 8 mg of naloxone (roughly equivalent to 4 mg of injected naloxone) — you could save more people with IM naloxone kits. This means that, even at the highly inflated cost of $30 to $45 per vial, injectable naloxone gives you more bang for your buck than NARCAN®.

#2. A Large Pharmaceutical Corporation Benefits Substantially From the Sale of NARCAN®

Emergent BioSolutions bought out Adapt Pharma, the company that originally patented NARCAN® and pushed it through FDA clinical trials. NARCAN® was FDA-approved back in 2015; yes, contrary to popular belief, NARCAN® is very much a new thing (well, it’s a new formulation of naloxone — the drug it contains, naloxone, has been used for decades for reversing opioid overdose, among other things, such as relieving constipation). Emergent acquired Adapt in 2018 for $735 million, which included the patents for NARCAN®. Of course, Emergent didn’t pay the entire $735 million ($635 million cash upfront and up to $100 million for reaching various sales-based milestones through 2022) for the eight U.S. and 28 international patents used to copyright NARCAN® — Emergent got many other assets from the deal — but still, Emergent has to recuperate that cost somehow.

If anything’s for sure, we shouldn’t be paying for it.

Although it’s been done for centuries, profiting from tragedies is not cool. We should not condone Emergent BioSolutions making money off of us. They claim to provide donations (you can read more about this under Community Giving and Corporate Giving on the company’s website) — not that I’m accusing them of lying about donating money, for the record — but fail to list how much money they’ve actually provided to organizations like ours.

Until Emergent BioSolutions donates 100% of their profits from the sale of NARCAN®, we don’t feel comfortable supporting them; since this will never happen, this means we’ll never feel comfortable supporting them and that we’ll never feel comfortable buying name-brand NARCAN® knowing that Emergent is profiting off of us.

#3. Nasal Atomizers Do Just as Good a Job as NARCAN®

First off, I should explain that intramuscular naloxone kits contain three components:

• 1 to 2 intramuscular-use syringes (our kits contain 3-mL Luer-Lok™ syringes)
• 2 to 3 vials of naloxone (our kits contain 3 standard 0.4-mg/mL, 1-mL vials of naloxone hydrochloride solution)
• Instructions for using naloxone in responding to opioid overdose

Intranasal naloxone kits — which are relatively rare, for the record, but are essentially the same thing as IM naloxone kits — contain one additional component: a nasal atomizer. Intranasal naloxone kits are almost the same thing as intramuscular naloxone kits; the only difference is that intranasal kits contain one extra component: a nasal atomizer.

You might be familiar with Luer-Lok™, a patented technology that’s seriously valued by the medical world — and us, ’cause, y’know, we use syringes, too.

If you don’t know what Luer-Lok™ technology is, syringes with Luer-Lok™ technology are threaded (think of a female receptacle for a screw), in turn making it possible to easily, securely screw on attachments such as needles or — in this case — nasal atomizers.

Nasal atomizers are small, screw-on devices made of plastic and foam that screw on the end of Luer-Lok™ syringes. They turn liquid into a fine mist.

Why Are Nasal Atomizers Necessary?

If you were to softly, lazily push liquid — injectable naloxone solution (which is largely water, anyways) or water, for example — out of a syringe without any attachments, it’d more or less dribble out; if you were to push it out with more pressure, it’d squirt out in a solid, unbroken stream — quite a thick stream, too, I might add… it’d be as thick as the opening of the syringe. If squirted into the nose, this liquid would likely run down the throat, bypassing the nasal membranes altogether. Any liquid that remained in the nasal cavity would take a long time to be absorbed.

This is why all nasal sprays are, well, sprays!

Note: Naloxone is very poorly absorbed when ingested — as such, the point of intranasal naloxone administration is to keep the drug in the nasal cavity… not in or down the throat.

Without something to turn the liquid into a fine mist — in this case, nasal atomizers — liquid pushed out of needle-less syringes wouldn’t be ideal for rapid intranasal absorption.

NARCAN® Also Contains a Nasal Atomizer

Although you can’t see it, NARCAN® nasal spray devices contain built-in atomizers. Don’t be confused by this term — “atomizer” is just a fancy word for something that sprays liquid as a fine mist.

Nasal atomizers easily, quickly screw onto Luer-Lok™ syringes and do a fantastic job of spraying liquid in a fine mist, a necessary part of proper intranasal drug administration.

There’s One Potential Downside…

NARCAN® packs 4 milligrams of naloxone into 0.1 mL of fluid. The vials found in IM naloxone kits contain just 0.4 milligrams of naloxone per 1 mL of fluid — making NARCAN®’s naloxone solution 100x more concentrated.

Spraying a full milliliter of fluid into someone’s nose… that’s a lot of liquid. And what if someone needs more than one vial?

If you’re dead-set on intranasal naloxone, I admit: NARCAN® might be your best bet.

However, I can’t think of any situations where intranasal naloxone administration is superior to intramuscular administration — after all, IM works faster and comes with several other benefits (virtually all of which are covered in this article).

#4. NARCAN® Is More Likely to Cause Precipitated Withdrawal…

People who are chemically dependent on drugs (illicit drugs, legal drugs, or prescription medications — all types’a drugs!) get “dopesick” without them, a process known as drug withdrawal syndrome. Although every drug’s withdrawal timeline is different, most opioid users report peak withdrawal symptoms somewhere between three to five days of abstinence.

Rather than sloooooowly being eased into opioid withdrawal over the course of several days, only eventually reaching the worst of the worst, precipitated withdrawal causes opioid-dependent persons to feel maximum withdrawal symptoms within seconds.

So, how is naloxone tied to precipitated withdrawal?

Here’s how it happens: As an opioid antagonist, naloxone works by forcefully ripping opioid agonists off of the brain’s opioid receptors, replacing them, and latching on tight enough to prevent those agonists from reattaching themselves for up to 90 minutes.

This forceful tearing — when opioid antagonists rip opioid agonists off the brain’s opioid receptors — can cause precipitated withdrawal in opioid-dependent persons (opioid-dependent people are those who need to take opioids every day to avoid getting “dopesick”).

Contrary to popular belief, however, naloxone does not always cause precipitated withdrawal — or make people instantly dopesick, in other words.

The more naloxone you administer to an opioid-dependent person, the greater the risk of precipitated withdrawal. The less naloxone you give them, the lower the risk. Also, all opioid overdoses are different — one case might be resolved with a small amount of naloxone, whereas another might require substantially more.

When adjusted for bioavailability differences, NARCAN® (4 mg) contains roughly five times as much naloxone as one 1-mL vial of naloxone (0.4 mg/mL). Although limited, our in-house data shows that over 90% of overdose reversals that involved intramuscular naloxone needed no more than two vials of naloxone (1 mL, 0.4 mg/mL). Less than 6% required three to four vials. None required more than four vials.

Considering that (#1.) one dose of NARCAN® is equivalent to five vials of IM naloxone and (#2.) that people rarely need more than four vials’ worth of IM naloxone to be revived, we can safely assume that the amount of naloxone found in NARCAN® is excessive.

#5. … as a Result, Causing People Who’ve Used Naloxone — or Been Revived by Naloxone — to Be Cautious About Using It in the Future

Similar to how some people ask not to be resuscitated by first responders — even going as far as getting “DNR” tattoos, which stand for “do not resuscitate” — some people who use opioids tell their peers to not revive them with naloxone should they fall out. The idea behind this rationale is that naloxone makes you dopesick upon revival.

Nobody wants to be dopesick, especially if you’re dependent on fentanyl — an opioid that’s known for particularly hellish withdrawal symptoms (sadly, fentanyl absolutely dominates the North American illicit opioid market and has for several years).

Again, naloxone does not always make someone dopesick upon revival… but all it takes is one bad experience to make someone a sworn opponent of naloxone.

Opioid overdose usually kills people by cutting them off from oxygen. Without oxygen, our organs can’t function — the most important of which is our brain. Permanent brain damage can occur in as little as 4 minutes without oxygen. Hypoxia — the state of being without oxygen — can result in death in as little as 8 minutes.

Note: Contrary to common belief, airway obstruction is the number-one means of opioid-related death; respiratory depression, a temporary breathing disorder characterized by slow, ineffective breathing, comes in second place.

We’re Left With a Trade-Off

The moment an opioid overdose occurs, the clock starts ticking. With this in mind, we’re left with a sticky situation: Do we administer more naloxone upfront, knowing the worst that can happen is precipitated withdrawal, or do we start off slow and gradually administer more and more naloxone — one dose every 1 to 2 minutes?

Doesn’t it make more sense to use more naloxone upfront and have a higher chance of saving someone’s life?

I don’t think so. Here’s why:

Reason #1

While I struggled to find hard data on this, personal experience tells me that people who overdose once are highly likely to experience multiple overdoses. The likelihood of experiencing multiple lifetime overdoses is positively correlated with characteristics and behaviors including but not limited to:

• Regularly injecting drugs
• Polydrug use — especially drugs like meth, cocaine, and heroin/fentanyl
• Frequent use of RX opioids without having a legitimate prescription (due to the high prevalence of pressed pills — a.k.a. “bootleg” pills)
• Frequently injection of drug in public places (frequent public injection, as opposed to private [e.g., in-home] injection, is correlated with a much higher risk of overdose)
• Illicit use of buprenorphine (see above-linked study)
• Being injected by someone else within the past month (see above-linked study)

Our in-house data shows that most of our participants who’ve revived someone with naloxone end up reviving the same person more than once.

Due to the high likelihood of people experiencing multiple overdoses, we should avoid doing things that lead to people having bad experiences with overdose reversal. This includes calling the police, threatening someone with legal action, making them feel guilty, and — of course — using too much naloxone (in opioid-dependent persons, at least). All of these things can prevent people from using sensible, evidence-based approaches when handling suspected cases of opioid overdose.

And, as we discussed above, using too much naloxone can bring on precipitated withdrawal, thereby encouraging people to develop a personal no-naloxone policy — and maybe even share that attitude with other people at risk of opioid overdose, in turn leading to more (preventable) drug-related deaths.

You can reliably avoid inducing precipitated withdrawal by using as little naloxone as possible — just one 0.4-mg vial (IM) at a time — and waiting 1-2 minutes between each dose.

Reason #2

It’s generally recommended to wait 1 to 2 minutes after administering the first dose of naloxone before administering another one. You should follow this rule of thumb until the person is conscious.

Let’s think back to hypoxia — the lack of oxygen we discussed earlier — which can cause permanent brain damage in just 4 minutes and lead to death in as little as 8 minutes. What if someone ends up needing four vials of naloxone? At the rate of one dose every 1 to 2 minutes, wouldn’t that put the person being revived at risk of permanent brain damage or death?

Not necessarily.

Here’s an example:

Here’s a More-Detailed Version of the Aforementioned Situation

Assume you’re hanging out with a friend at your house. After returning from the bathroom, you see that your friend is incapacitated. They used opioids within the past hour; although you think they’re experiencing an opioid overdose, you notice your friend exhibits slowed, almost nonexistent breathing, cold and clammy skin, and blue-gray lips and fingernails. Now you’re certain you have an opioid overdose on your hands.

Here’s a timeline of how you respond to their overdose:

• T–0:00 | administer one 0.4-mg vial of naloxone intramuscularly; you start rescue breathing, giving your friend one breath every 5 seconds
• T+0:02 | still unconscious; administer one more vial of IM naloxone; you continue rescue breathing
• T+0:04 | still unconscious; administer one more vial of naloxone, IM; rescue breathing continues
• T+0:06 | still unconscious; administer one more vial of IM naloxone; you’re still giving your friend rescue breaths
• T+0:07 | finally, your friend regains consciousness

Had you not provided rescue breaths, your friend might have suffered severe, permanent brain and organ damage — after all, brain damage can occur within 4 minutes of oxygen loss. They could’ve been close to dying, had you not maintained rescue breathing.

Let’s revisit the question that prompted me to write this example:

What if someone ends up needing four vials of naloxone? At the rate of one dose every 1 to 2 minutes, wouldn’t that put the person being revived at risk of permanent brain damage or death?

Answer: Assuming you follow this naloxone dosing pattern, if the subject struggles to breathe on their own and you don’t perform rescue breathing, you may be placing the subject at risk of organ damage or death.

An important part of responding to opioid overdose is rescue breathing (which includes making sure your subject’s airway is free of obstruction). In simple terms, rescue breathing is like CPR without the chest compressions. While different sources say different things, SAMHSA recommends giving one rescue breath every 5 seconds. Rescue breaths ensure the person experiencing overdose doesn’t run out of oxygen.

Condensed answer: If you perform rescue breathing and ensure the subject’s airway isn’t blocked, NO, using this naloxone dosing strategy will not place the subject at an enhanced risk of permanent organ damage or death.

Reason #3

As we’ve established, reversing an opioid overdose with naloxone doesn’t always lead to precipitated withdrawal.

People who aren’t opioid-dependent don’t have to worry about naloxone-induced opioid withdrawal — at all!

Assume you’re hanging out with a friend or family member and, on that particular day, they use opioids around you. Due to y’all’s relationship, you stand a good chance of knowing whether they’re opioid-dependent (whether they have to take opioids everyday to avoid withdrawal) or not. If you’re confident they’re not opioid-dependent, you could choose to give them a higher dose of naloxone immediately upon responding to their overdose.

However…

Here’s something to think about: No matter how close you are with them, they still might use opioids everyday — just on the down-low. So, if you front-load your overdose response with multiple doses of naloxone — as opposed to just one dose at first, followed by another dose every 1 to 2 minutes — and they happen to be opioid-dependent… you might accidentally make them dopesick.

If this happens, you might feel inclined to ask, “What do you mean you’re dopesick? I thought you didn’t use these things everyday…”

Asking such a question won’t do anything but damage you two’s relationship by making them feel like you’re being too intrusive — like you’re not minding your business. After all, people who use drugs, especially “hard” drugs like illicit opioids, are hard-wired to keep this information on the down-low due to the harsh stigma that we often face.

In Summary…

Since NARCAN® is so much more likely to cause post-revival precipitated withdrawal than injectable, intramuscular (IM) naloxone, it’s more likely to create negative experiences re: overdose reversal. Thus, people brought back to life with NARCAN® are more likely to exercise caution about using naloxone to reverse opioid overdose, in turn making them less likely to even use naloxone in the first place; hesitancy to use naloxone is undoubtedly associated with things like:

• Being unwilling to seek emergency help for life-threatening health concerns, increasing the likelihood of death or permanent injury
• Giving incapacitated people meth or other stimulants without consent in hopes it makes them conscious (and, thus, reverses — or at least improves the prognosis of — opioid overdose)
• Using other potentially dangerous, non-evidence-based approaches in hopes of reversing overdose, such as:
  • Putting people into ice baths or excessively cold showers
    • This can potentially boost the risk of shock, falling, or drowning
  • Injecting people with substances like milk or saltwater (yes, it’s happened…)
  • Trying to induce vomiting in hopes of removing drugs that subjects might have swallowed
    • This can cause choking or force vomit into the lungs, potentially causing a fatal injury
  • Slapping people (instead of lightly pinching them, performing a sternum rub, or shouting) in hopes of making them conscious
    • This, along with otherwise forcefully stimulating subjects, will only cause injury — they carry no upsides

Where Can We Go From Here?

#1. Emergent BioSolutions Should Prioritize the Production, Marketing, and Sale of 2-mg NARCAN®

Although we’re confident that, as a small grassroots nonprofit organization in rural Tennessee, we won’t influence an NYSE-listed pharmaceutical giant’s operations, we urge Emergent BioSolutions to decrease their production of 4-mg NARCAN® in favor of 2-mg NARCAN®.

This way, even though a corporation would still profit from our shared tragedy — the seemingly never-ending rash of opioid-related fatalities — making the 2-mg version more available could lead to fewer people to have negative perceptions of naloxone (because they’d be less likely to experience precipitated withdrawal after being revived), all without damaging the collective life-saving potential of NARCAN® products.

Although the 2-mg version supposedly exists, I’ve never seen it IRL, nor has anyone I know personally. I’d feel much better about keeping NARCAN® around if it were the 2-mg formulation, not the heavy-duty, frankly unnecessary 4-mg version that dominates the market.

#2. Harm Reduction Organizations Should Buy Generic Forms of Naloxone, Not Name-Brand Formulations

We don’t want corporations to profit off of opioid overdose. Further, when harm reduction organizations buy name-brand NARCAN® or other name-brand naloxone formulations in favor of generic forms of naloxone, they’re helping pharmaceutical companies recover their astronomically high research and development costs — in turn affording those harm reduction programs less naloxone.

If at all possible, we believe harm reduction organizations should buy generic forms of naloxone.

#3. Harm Reduction Organizations Should Speak Out Against New Formulations of Naloxone (Kloxxado®, Zimhi™)

Kloxxado®

Kloxxado® is a new nasal-spray formulation of naloxone that was approved by the FDA in April 2021 and hit the U.S. market in August 2021. It’s twice as strong as NARCAN®, holding 8 mg of naloxone.

Kloxxado® nasal spray is even more likely to cause precipitated withdrawal than NARCAN®. As mentioned , this may cause an unintended side effect — people growing averse to naloxone (and any evidence-based overdose response protocol, for that matter) upon experiencing naloxone-induced precipitated withdrawal.

Also, supporting Kloxxado® nasal spray supports Hikma, a pharmaceutical company that’s undeniably hungry to recoup the untold fortunes it spent in research and development to bring Kloxxado® to market — and, I don’t know about you, but we don’t want companies profiting off of our shared tragedy.

Lastly, by using Kloxxado®, you’re supporting the myth that a significant share of opioid overdoses require excessive doses of naloxone — this is totally false! In other words, you’re supporting misinformation just by using this stuff… even by spreading a positive opinion about this stuff. The world of drugs already has enough misinformation — don’t let Hikma, Kloxxado®’s manufacturer, pump more misinformation into our world.

Note: On Kloxxado®’s website, Hikma claims 34% of opioid overdoses required two or more doses of 4-mg NARCAN®; our preliminary data shows that 100% of people revived with IM naloxone needed no more than four-fifths the equivalent naloxone found in one 4-mg NARCAN® nasal spray.

I know Hikma has given away Kloxxado® nasal spray to several harm reduction organizations over the past few months. If your organization can’t otherwise get naloxone, I understand — Kloxxado® is better than nothing.

However, as soon as you can source other types of naloxone, do so. Cut your reliance on Kloxxado® immediately for the sake of harm reduction at large.

Kloxxado® vs NARCAN® – Quick Summary

	Kloxxado®	NARCAN®
# of Varieties	1	2
Amount of Naloxone	8 mg	4 mg, 2 mg
Volume of Liquid	0.1 mL	0.1 mL
# of Sprays/Device	1	1
# of Devices/Box	2	2
Average Retail Price	~$141*	$132.49†
Price w/ GoodRX Discount Card (DC)	≥$123.40	≥$127.18
Generic Available?	No	Yes
Price of Generic	N/A	Unclear
Price of Generic w/ GoodRX DC	N/A	≥$18.87‡
Prescription Required?	No	No

Zimhi™

Although I’ve yet to see Zimhi™ in real life, the FDA approved this formulation of injectable naloxone in October 2021 and, according to its manufacturers, it hit the U.S. market in March 2022. Zimhi™ contains 5 mg of naloxone, 12x as much as a single vial of (1 mL, 0.4 mg/mL) naloxone (like the ones found in IM naloxone kits)! Zimhi™ is 2.5x as strong as NARCAN®, which is already excessively strong.

Zimhi™ is even more likely than Kloxxado® — and NARCAN®… — to cause precipitated withdrawal. This may have the unintended result of leading people who use opioids to develop negative opinions of naloxone, thereby turning drug users away from the evidence-based tools they need to properly respond to opioid overdose.

Also, using Zimhi™ supports two pharmaceutical companies: Adamis and US WorldMeds — the former being a publicly-traded company, listed on the NASDAQ — allowing them to profit from our shared tragedy.

Further, just by using Zimhi™, you’re supporting Adamis’s claims that a significant portion of opioid overdoses require ultra-high doses of naloxone. This is false! Very, very few opioid overdoses need this much naloxone. In other words, just by using Zimhi™, you’re supporting misinformation — and there’s already tons of misinformation floating around the drug-using community as it is.

Note: Zimhi™’s website claims that “50% of opioid reversals are estimated to require more than one dose of naloxone.” This claim was sourced using data from the Connecticut Department of Public Health’s September 2021 Statewide Opioid Reporting Directive Newsletter. The Constitution State utilizes SWORD (Connecticut Statewide Opioid Reporting Directive), wherein all EMS organizations and providers must call the state’s poison control center immediately after dealing with patients suspected of opioid overdose or near-overdose. Per this September 2021 newsletter, the Connecticut Poison Control Center fielded 416 calls in May 2021, which broke down as follows:

• 72 non-fatalities in which no naloxone was administered
• 175 non-fatalities that involved multiple doses of naloxone
• 137 non-fatalities that involved a single doses of naloxone
• 5 non-fatalities in which it wasn’t clear how much naloxone was administered
• 27 fatalities in which:
  1. 10 received m multiple doses of naloxone
  2. 4 received a single dose of naloxone
  3. 12 received no naloxone
  4. In 1 case, it wasn’t known whether naloxone was administered

The aforementioned claim on Zimhi™’s website was calculated as such: 326 total cases involved naloxone; 175 / 326 = 53.68% of cases involved multiple doses of naloxone. This is some of the weakest evidence I’ve ever seen to back up a claim of how X% of opioid overdoses required multiple doses. This data does not prove that those 175 cases actually required more than one dose of naloxone. For example, the EMS who responded to opioid overdoses could have chosen to immediately administer multiple doses of naloxone upon arrival.

To claim that over 50% of cases required multiple doses of naloxone relies on the presumption that EMS waited at least 1 to 3 minutes after administering the first dose of naloxone to administer a second dose. I’m just a grassroots harm reductionist, but even I know there’s no space for presumptions in public health reporting.

It also doesn’t state what type of naloxone was used. Assume many or all of these cases involved single-dose vials of IM naloxone. If EMS administered two doses of IM naloxone, each patient received 0.8 mg of naloxone. Even if some patients required three or four vials — which would total 1.2 mg and 1.6 mg, respectively — there’s a huge gap between 1.6 mg of naloxone and the 5 mg of naloxone that Zimhi™ contains. For clarity, we think this is unfavorable because higher doses of naloxone are more likely to throw people into precipitated withdrawal, in turn potentially making people averse to naloxone and other good opioid overdose reversal practices.

Zimhi™ vs IM Naloxone Kits – Quick Summary

	Zimhi™	IM Naloxone Kits
# of Varieties	1	Potentially Dozens*
Amount of Naloxone	5 mg	0.4 mg/vial
Adjustable Dosing?	No	Yes
# of Shots per Device	1	Multiple, Typically 2-3/kit
# of Devices/Box	2	1-2 Syringes; 2-3 Vials
Average Retail Price	$160.96†	N/A‡
Price w/ GoodRX DC	≥$127.18§	N/A‡
Generic Available?	No	Is Inherently Generic
Prescription Required?	No	No

#4. If You Need a Syringe-Free Formulation of Naloxone, Consider this Alternative to NARCAN® and Kloxxado®

Unfortunately, syringes carry stigma. As such, some people are syringe-averse. I’ve had several people refuse injectable (IM) naloxone kits just because they contained syringes; these people happily accepted NARCAN®, however, because it was syringe-free.

Whenever I come across syringe-averse participants, I spend roughly 15 to 30 seconds educating them about syringes and why people shouldn’t be wary of carrying injectable naloxone kits. Examples of things I might say include:

• “The syringes in these kits are way bigger than the syringes people use to inject drugs.”
• “Syringes aren’t illegal by themselves. You need drugs, drug paraphernalia, or to admit to using syringes for illegal drugs to catch possession of drug paraphernalia charges. I have been pulled over several times with IM naloxone kits and police couldn’t give less of a damn about them.”
• “If you’re still worried about catching a paraphernalia charge, a 2015 state law (T.C.A. § 40-7-124) protects people from being charged with or prosecuted for possession of drug paraphernalia as long as you tell police you’re in possession of syringes before you get searched.”
• “Injectable naloxone is absorbed by the body faster than nasal-spray naloxone (NARCAN®); plus, your nose only absorbs half the naloxone that gets sprayed up there — your body absorbs 100% of the naloxone that’s injected into it.”

After sharing two or more of these facts, I drop the issue and give the participant NARCAN® if I have it — and I almost always have both kinds (IM naloxone kits and NARCAN®). This strategy helps me fight stigma against syringes while still connecting people with the harm-reducing supplies they oftentimes-desperately need.

Still, there’s no guarantee that you’ll make those syringe-averse participants comfortable with injectable naloxone kits. While you — as a harm reductionist — should always share pro-syringe facts and ideas with syringe-averse participants, it’s better to comply with their requests for a non-syringe formulation of naloxone than to leave them empty-handed.

Keep in mind that NARCAN® and Kloxxado® aren’t the only syringe-free formulations of naloxone.

Let’s Not Forget IM Naloxone Kits With Nasal Atomizers

Since we’ve already discussed this option, we won’t cover it twice. Just know that this is an acceptable alternative to these two name-brand, nasal-spray formulations of naloxone (NARCAN®, Kloxxado®).

… and Here Comes Amphastar!

In case you didn’t know, Amphastar makes an intranasal naloxone formulation (which happens to be cheaper than NARCAN® — and Kloxxado®, for that matter).

This two-part device is simple to use; simply take one cap off of each piece (the housing and the naloxone vial), then screw the vial into the housing. Then remove the bright yellow protective tip, and you’re good to go — almost…

Just like IM naloxone kits, Amphastar’s Luer-Jet™ Prefilled Syringes require nasal atomizers — which, inconveniently, are sold separately.

Even with the cost of a nasal atomizer, this naloxone device is cheaper than NARCAN®.

At 2 mg of naloxone in 2 mL of solution, this means it’s got a 1 mg/mL concentration of naloxone — 2.5x as concentrated as the standard, 0.4-mg-per-milliliter, orange-top vials of naloxone found in IM kits, although not as concentrated as NARCAN®, at 4 mg/0.1 mL.

Still, One (Potential) Problem Persists

Amphastar’s Luer-Jet™ Prefilled Syringe contains 2 mg of naloxone, which is suspended in 2 mL of water. This comes out to 1 mg naloxone/1 mL solution — 2.5x as concentrated as the orange-top naloxone vials. Still, this is 40x less concentrated as the naloxone solution in NARCAN®.

Our in-house data on how our participants reverse opioid overdoses indicates that, of all cases that involved naloxone injection, over 50% required one vial (0.4 mg) or less of IM naloxone (the equivalent of 0.8 mg or less of intranasally administered naloxone).

At this device’s concentration of 1 mg naloxone/mL, just 0.8 mL would need to be sprayed into people’s noses to reverse ~50% of all opioid overdoses.

Considering — again, of all cases that involved naloxone injection — that over 85% of cases required two 0.4-mg vials (0.8 mg naloxone in total) or less (the equivalent of 1.6 mg or less of intranasally administered naloxone), you’d need to spray no more than 1.6 mL of fluid into someone’s nose to successfully resolve ~85% of opioid overdose cases. Spread across two doses, if not three or four… that’s no more than 0.8 mL per administration of naloxone.

Per a quick Google search, although nasal sprays tend to average between 0.1 mL and 0.15 mL of liquid per spray, with doses ranging as high as 0.4 mL. While the nose can hold more than that, we still run a risk of having a less-than-ideal amount of naloxone absorbed by using these less-concentrated solutions (e.g., Amphastar’s Luer-Jet™ Prefilled Syringe, the orange-top naloxone vials).

Splitting these intranasal naloxone doses into several smaller ones given more frequently (i.e., every 30 seconds instead of every 2 minutes) will optimize absorption.

Ultimately, I think Amphastar’s Luer-Jet™ Prefilled Syringe is suitable for reversing opioid overdose via intranasal administration. I don’t think the volume of liquid here is much of a concern. This formulation is also unique in that it can be reused — just throw the atomizer away after reviving someone and get a new one, and this device could theoretically be used to reverse as many as three or four overdoses!

Note: If you didn’t know, Amphastar’s Luer-Jet™ Prefilled Syringe is actually popular in the medical field due to its Luer-Lok™ tip, meaning it can easily be used on IVs.

#5. We (Supposedly) Have Access to Two Generics of NARCAN®

After a long, drawn-out lawsuit filed by Emergent BioSolutions was struck dead late last year, Teva and Sandoz both announced their generics of NARCAN® nasal spray on Dec. 21, 2021.

I say “supposedly” because, still, I’ve yet to see either of these generics IRL. Both manufacturers claim that their generic formulations are available in retail pharmacies around the U.S.

The two manufacturers may have been slow to market their generics after Emergent appealed a 2021 decision on its long-running patent lawsuit against Teva, in which Emergent argued for several more years of patent protection for NARCAN®, which the courts denied. The most recent ruling on the case came on Feb. 10, 2022.

According to GoodRX, one box (which contains two dose-units) of generic NARCAN® costs as little as $18.87 as of publication (May 16, 2022). The lowest GoodRX price of name-brand NARCAN® is currently $127.18.

Part of Sandoz’s sales will go to Emergent. Sandoz will also give royalties to Opiant Pharmaceuticals, the original creator of NARCAN®.

Devil’s Advocate — In Defense of NARCAN®

Despite every point I’ve made against NARCAN®, the name-brand nasal spray isn’t all bad…

Pro #1. Requires No Assembly, Easy to Use

Its foolproof design prevents handling mistakes, especially in first-time overdose responders. It’s easy to fumble a syringe, struggle with drawing liquid from a vial, and figuring out how to give the shot. After all, overdoses are nothing short of traumatic; when your adrenaline’s pumping, you’re less likely to do things like read the instructions on naloxone kits or successfully put an intramuscular naloxone kit together.

Pro #2. Syringe Stigma Makes Some People Unwilling to Accept Injectable Naloxone Kits — NARCAN® Is a Suitable Alternative

Although we fight it every day, people have negative attitudes toward syringes — it’s an attitude most harm reduction providers will come across on the daily.

Even if you’re able to successfully assuage the concerns of some syringe-averse participants, you won’t convert everybody. Rather than forcing injectable naloxone kits on these folks, it’s better to give them the type of naloxone they ask for.

And since NARCAN® has become a generic trademark of naloxone (i.e., Q-Tip is a generic trademark of cotton swab), these people will almost always ask for “NARCAN®”; giving participants exactly what they ask for will boost participant satisfaction, increase your harm reduction program’s reputation, and potentially make participants more likely to properly respond to opioid overdose (i.e., not using unsafe responses like submerging incapacitated persons into ice baths).

Pro #3. If You Haven’t Already, Expect to See Generics Soon

Based on conversations I’ve had with other harm reductionists, it seems as if markets where harm reduction is more advanced and widespread — typically densely populated cities, which are traditionally considerably left-leaning (or forward-thinking, in other words); also, more forward-thinking states such as Washington or Portland fit the bill here — have seen more of these generics than the rest of the country.

Although some of the profits from the sale of these generic NARCAN® devices is kicked back to a couple pharmaceutical companies (as detailed in #5 above), I feel much better about using these generics than their much-more-expensive, name-brand counterpart: NARCAN®!

Wrapping Things Up

While the prospect of generic NARCAN® excites me, I still worry about its propensity for putting people into precipitated withdrawal, and thus potentially turning those people away from embracing proper opioid overdose response protocol — including but not limited to the use of naloxone in salvaging the lives of people who use drugs. This concern is even more present with Kloxxado® and Zimhi™.

Also — the more space we give high-dose naloxone formulations, especially new ones like Kloxxado® and Zimhi™, the more incentivized pharmaceutical companies will be to craft new-and-“improved” versions of naloxone — all of which will certainly be high-dose formulations.

The wheel doesn’t need reinventing. We have naloxone. An injectable and a nasal spray version — we’ve got what we need.

And I appreciate innovation. But Kloxxado® and Zimhi™ are far from innovative, as are the rationale for their very existence.