Improving an old tool to treat opioid overdoses | May 16, 2016 Issue - Vol. 94 Issue 20 | Chemical & Engineering News
Volume 94 Issue 20 | pp. 34-38
Issue Date: May 16, 2016

Cover Story

Improving an old tool to treat opioid overdoses

As overdose deaths climb, drugmakers and activists are working to make naloxone easier to use and a staple of medicine cabinets
Department: Science & Technology
News Channels: Biological SCENE, Organic SCENE
Keywords: pharmaceuticals, naloxone, opioid, overdose, Narcan, Evzio
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Credit: John Sommers II/REUTERS/Newscom
A vial of naloxone HCl next to a syringe.
 
Credit: John Sommers II/REUTERS/Newscom

The emergency call came in simply as a person down. It could have meant any number of things, says former Atlanta-area paramedic Kevin Hazzard. The patient might have been a diabetic whose blood sugar was too low or someone who’d had too much to drink. But when Hazzard arrived on the scene, it was clear the young woman had overdosed on heroin.

In brief

Overdose deaths from heroin and prescription opioids have skyrocketed in the U.S. over the past 10 years. But there is a drug that can reverse overdoses in a matter of minutes—the opioid antagonist naloxone. Naloxone has been available to hospitals and emergency medical personnel since the 1970s. Now, there’s a push to make the drug available to anyone who might witness an overdose. Read on to learn how drugmakers are developing naloxone delivery devices that are easier to use.

“She was just lying there,” Hazzard says. “She was blue. Instantly, I realized she was not breathing.” He reached for the naloxone.

It was the first time he’d ever used the opioid overdose antidote, also known by its trade name Narcan. He gave her the full dose all at once. She responded so quickly to the drug—bolting upright, breathing, and then vomiting—that she caused Hazzard and his partner to jump back with fright. It was like waking the dead.

This was in 2004, and the opioid crisis was only just beginning to take hold in the U.S. Overdose calls like these were rare, says Hazzard, who wrote about his experiences as a paramedic in the memoir “A Thousand Naked Strangers.” By the end of his career as a paramedic in 2013, Hazzard says he could expect heroin and opioid overdose calls on a weekly basis.

Even so, he says, naloxone’s power to pull someone back from the brink of death always amazed him. When it comes to treating opioid overdoses, he says, it is “the perfect tool.”

But, unfortunately, Hazzard says there were also many times he and his colleagues got to an overdose victim too late.

In the past 15 years, prescription opioid and heroin overdose deaths have quadrupled in the U.S. According to the National Center for Health Statistics at the Centers for Disease Control & Prevention, heroin overdoses killed more than 10,000 people in 2014, and overdoses from prescription opioids, such as oxycodone (Oxycontin) and hydrocodone (Vicodin), claimed the lives of more than 18,000 that same year.

Consequently, those who work with drug users have pushed to get naloxone into the hands of friends, family members, and other bystanders who might be able to respond to an overdose more quickly than paramedics. There’s also an effort to supply naloxone to patients who take opioids to manage chronic pain. In response, some drugmakers have developed new naloxone delivery systems that are simple enough that anyone can use them. Two new products—an autoinjector and a nasal spray—were approved by the Food & Drug Administration in 2014 and 2015, respectively. The hope is that expanding access to these devices and keeping prices reasonable will encourage more widespread naloxone use in the U.S.

Naloxone is a textbook example of a competitive receptor antagonist. It competes for the same receptors as opioid agonists, such as heroin and fentanyl, pushing those drugs out and taking their place. Naloxone doesn’t turn on opioid receptors when it binds them, so it produces no opioid high. All it does is prevent those other opioids from acting. After taking naloxone, opioid users can experience withdrawal symptoms, but naloxone has no effect on someone who isn’t experiencing an overdose.

FDA approved naloxone for treating opioid overdoses in 1971. Emergency room physicians and paramedics such as Hazzard have used injectable naloxone for decades. And for the past 20 years, community activists have distributed naloxone kits to people who are at risk of an overdose or who might witness an overdose.

“When you have an opioid overdose, it’s really an issue of time,” says Alexander Walley, a physician and medical director of the addiction consultation service at Boston Medical Center. Opioid overdoses slow breathing, resulting in less oxygen getting to the brain. There’s a small window of minutes to hours in which an overdose can be reversed before brain damage or death occurs, he explains.

“Most people aren’t alone when they overdose,” Walley notes. But people who witness an overdose are often hesitant to call for help because they’re worried about being arrested or that the person overdosing will be arrested. And when they finally do call for help, he says, it takes time for emergency medical services to respond. By making naloxone more accessible to people who might be present during an overdose, “we’re really extending the time window in which people can be rescued.”

Even though this has been known for decades, drugmakers have been slow to respond. “Ten years ago, it was very difficult to get drug companies interested in developing new naloxone devices because they didn’t think there was a market,” Walley says. But that has changed because of the opioid epidemic.

“Anyone who has prescription opioids in their house should also have naloxone.”

Janie Simmons, developer of the website GetNaloxoneNow.org

Before 2014, the only FDA-approved way of delivering naloxone was via injection, either into a vein or a muscle. But giving an injection can be daunting for someone without medical training. Also, as overdose victims are often intravenous drug users, giving an injection carries the risk of exposing oneself to blood-borne diseases such as HIV or hepatitis C.

To get around this problem, about 15 years ago, medical personnel and people working with drug users developed an improvised intranasal naloxone delivery system. The improvised device contains a syringe filled with 2 mL of a naloxone solution and an atomizer that allows you to squirt the naloxone solution into someone’s nose. The intranasal kits have been effective at reversing overdoses, but they were never submitted to FDA for approval.

Officials at FDA say these improvised kits have some drawbacks, such as inconsistent dosing and “added assembly time in a situation where seconds count.” People need to be trained to use the improvised devices, adds Phil Skolnick, director of the Division of Therapeutics & Medical Consequences at the National Institute on Drug Abuse (NIDA). “They’re not intuitive, and there’s a high rate of error.”

What’s more, Skolnick explains, the improvised intranasal devices don’t achieve the same blood levels of naloxone that injections do. The problem, he says, is that although the solution in the kits is good for an injection, it’s simply too dilute for intranasal delivery. “Try putting 1 or 2 mL of something up your nose, and see how much actually ends up down your throat.”

In 2012, Skolnick was attending a meeting about the opioid crisis hosted by the National Institutes of Health when he met Roger Crystal, the chief executive officer of Lightlake Therapeutics (now Opiant Pharmaceuticals), and learned the company was interested in developing an intranasal version of naloxone. The two decided that a partnership would be ideal: NIDA would absorb some of the financial risk of the initial research, and Lightlake could use its resources to turn any scientific advances into a commercial product.

“What we wanted to do at NIDA was to try to develop a formulation that gave you something equivalent to an injection,” Skolnick says. That was because FDA required injection-like pharmacokinetic properties for approval of any intranasal version of naloxone.

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Narcan nasal spray
Credit: Adapt Pharma
A photo of the new naloxone nasal spray.
 
Narcan nasal spray
Credit: Adapt Pharma
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Evzio
Credit: Kaléo
A photo of the new naloxone autoinjector.
 
Evzio
Credit: Kaléo

Ideally, Skolnick reasoned, a naloxone nasal spray would deliver a small volume—0.1 to 0.2 mL—of a concentrated naloxone solution to the nose. Skolnick says he called up his colleague Kenner Rice, a chemist at NIDA who has been studying opioids, including the antagonist naloxone, since the 1970s. “I asked him, ‘What’s the solubility of naloxone?’ He said, ‘200 mg/mL.’ Then I said, ‘Thank you,’ and I hung up the phone,” Skolnick recalls. “That really was the essence: understanding that you could make a much more concentrated solution of naloxone.” NIDA scientists ended up going with a solution that was 40 times as concentrated as those in the improvised intranasal devices.

After NIDA scientists found a stable formulation of this concentrated naloxone solution, Lightlake filled their nasal spray devices with it and did a clinical trial that showed the nasal spray had pharmaco­kinetic properties similar to intramuscular injection. After a larger trial, Lightlake partnered with Adapt Pharma to make the product available, and it was approved by FDA last November under the name Narcan nasal spray.

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The human toll
Overdose deaths from prescription opioids and heroin have reached epidemic levels in the U.S.
Source: CDC Wonder
A bar graph showing the steep rise of overdose deaths from prescription opioids and heroin from 1999 to 2014.
 
The human toll
Overdose deaths from prescription opioids and heroin have reached epidemic levels in the U.S.
Source: CDC Wonder
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Expanded access
Thirty-eight states have laws that make it possible for people to get access to naloxone without a personal prescription in some circumstances.
Source: Drug Alcohol Depend. 2015, DOI: 10.1016/j.drugalcdep.2015.10.013
A map showing the 32 states that have standing orders for naloxone.
 
Expanded access
Thirty-eight states have laws that make it possible for people to get access to naloxone without a personal prescription in some circumstances.
Source: Drug Alcohol Depend. 2015, DOI: 10.1016/j.drugalcdep.2015.10.013

The nasal spray is very easy to use, Skolnick says. In fact, in a human use trial that was required for approval, 90% of first-time users were able to use the spray correctly.

It’s the sort of thing anyone who is taking a high dose of narcotics for chronic pain should have around just in case they overdose, Skolnick says. “It’s like a fire extinguisher.”

The other new naloxone product is an autoinjector called Evzio, made by the company Kaléo. Evzio is the company’s second product. Its first was Auvi-Q, an epinephrine autoinjector designed to treat life-threatening allergies. The compact autoinjector has an internal speaker that plays a recording that explains how to use the device. It was conceived by Kaléo’s cofounders, twin brothers Eric and Evan Edwards, who suffer from food allergies.

When searching for another drug to use with its autoinjector technology, Kaléo’s team noticed the growing number of opioid overdoses in the U.S., says the company’s CEO, Spencer Williamson. Using the autoinjector for naloxone seemed like a good fit.

To create Evzio, the company’s scientists went through 22 different naloxone formulations before finding one that had a long shelf life and could withstand high temperatures, Williamson says. They also studied how people interact with Evzio to ensure it was easy to use.

Evzio, which has the footprint of a credit card and is about as thick as a pack of gum, kicks into action when a user pulls off its outer case. A voice from its speaker instructs the user to remove a safety guard and place Evzio on the outer thigh. The device then counts down until it injects the drug. The injection takes about a quarter of a second, and the device then retracts its needle, Williamson says. “The patient never sees the needle, before, during, or after the injection.”

According to data collected by Kaléo from people who have used Evzio, the device has been involved in more than 1,100 overdose reversals since its introduction in 2014.

Such new delivery methods will encourage more widespread use of naloxone, says Sharon Stancliff, medical director for Harm Reduction Coalition, an advocacy organization for people and communities impacted by drug abuse. However, she has some concerns about each product.

She’s tentatively excited about Adapt’s Narcan nasal spray but worries that it might deliver too much naloxone. Such high levels may lead to complications in the field, she says, such as severe withdrawal. “Severe withdrawal can lead to a lot of vomiting, and vomiting is dangerous when you’re not fully awake,” Stancliff says. It could cause someone to choke.

Stancliff calls the Evzio autoinjector “a beautiful little device.” But she says its price puts it out of reach for programs that look to distribute naloxone free of charge.

Williamson acknowledges that the list price of Evzio is high. When it was first introduced in 2014, its wholesale price was $690. Six months ago, the price rose to $900, and at the beginning of February, it had climbed to $4,500.

But the list price is not what consumers pay, Williamson notes. The price to patients with insurance has gone down to $0 in most cases, he says. For people without insurance, Kaléo has a program that provides the product at no cost.

When Adapt introduced its Narcan nasal spray in the U.S. at the end of February, the company said it would make the product available to government agencies, school districts, higher education institutions, and nonprofits for a reduced price of $37.50 per dose. A single dose of naloxone used for injection or in the improvised intranasal device costs about $50—more than double what it cost 18 months ago.

Robert Goldberg, vice president at the Center for Medicine in the Public Interest, a health care policy research organization, attributes the naloxone price spike in part to increased demand and need to expand production. He notes that this has been a trend with injectable generics.

Although increasing prices may be putting up a barrier for some to get naloxone, all but five states have changed their laws to reduce barriers for people looking for access to the drug. Naloxone is only available by prescription, but the law in 38 states now permits a person to receive naloxone from a pharmacy without first receiving a prescription for the medication in some circumstances, says Corey S. Davis, deputy director of the Network for Public Health Law, which provides technical assistance with public health laws.

Most states do this via a standing order, where a doctor writes a prescription that covers a particular facility, such as a drug treatment center. Pharmacy chains, such as Walgreens and CVS, have generally had physicians issue standing orders that cover all of their pharmacists in a particular state.

“I believe that anyone who has prescription opioids in their house should also have naloxone,” says Janie Simmons, an ethnographer who specializes in overdose prevention and the developer of the website GetNaloxoneNow.org, which provides free online overdose-prevention training. Simmons says she’s seeing a sea change in the U.S. with respect to naloxone. As the opioid crisis expands, elected officials are beginning to support efforts to get naloxone into the hands of first responders and bystanders. President Barack Obama’s 2017 budget includes $500 million to expand overdose prevention, including improving access to naloxone.

But not everyone agrees naloxone is beneficial. Last month, Maine Gov. Paul LePage (R) vetoed a bill that would permit pharmacists in the state to dispense naloxone. “Naloxone does not truly save lives; it merely extends them until the next overdose,” LePage wrote. “Creating a situation where an addict has a heroin needle in one hand and a shot of naloxone in the other produces a sense of normalcy and security around heroin use that serves only to perpetuate the cycle of addiction.”

Many disagree with LePage’s assessment. Naloxone, they say, saves lives and offers an opportunity for people with addictions to seek treatment. A study published in 2013 showed that Massachusetts communities with naloxone distribution programs had fewer opioid overdose deaths than those without (BMJ, DOI: 10.1136/bmj.f174). “Naloxone is far from the only answer to putting an end to the opioid crisis,” Stancliff says, “but naloxone keeps an overdose from becoming fatal, so a person has another chance.”  

How chemists synthesized naloxone

The world will likely never know for sure who was the first chemist to synthesize naloxone. On March 14, 1961, Sankyo (now Daiichi Sankyo) applied for a patent on the compound in Japan. On the same day, chemists Mozes Lewenstein and Jack Fishman filed for a U.S. patent on naloxone.

Little is known about the Sankyo work beyond what is described in the patent. But some of Fishman and Lewenstein’s story became known through a trade magazine article written when Fishman and his colleague Harold Blumberg shared the 1982 John Scott Award, which honors “ingenious men and women who make useful inventions,” for their work on naloxone.

The story goes that Lewenstein was the head of Endo Laboratories’ narcotics division but also had a small private lab in New York that was licensed to work on narcotics. Fishman worked in this small private lab, although he was also employed at the Sloan Kettering Institute for Cancer Research.

Fishman synthesized naloxone on the basis of observations chemists had made of other opioids. Chemists knew that nalorphine—which swaps morphine’s methylamine for an allylamine—was a potent opioid antagonist. In fact, in the 1960s, nalorphine was often used to reverse overdoses in newborns of mothers who had been given opioid pain relievers for childbirth. These babies often stopped breathing after birth because of the opioids, and doctors would revive them with nalorphine. But at high doses, nalorphine can cause hallucinations, so it’s no longer used.

Chemists also knew that adding a hydroxyl group to the carbon next to an opioid’s amine, thereby creating a tertiary alcohol, increased the drug’s potency. Oxymorphone has this critical hydroxyl group, and it is 10 times as potent a painkiller as morphine. Fishman and Lewenstein wondered what would happen if they took oxymorphone and replaced its methylamine with an allylamine. The result was naloxone.

When Fishman made the compound, Blumberg was the director of Endo’s biological laboratories. He had been urging chemists to make naloxone’s structure for several years with no luck. But Lewenstein licensed naloxone to Endo, and Blumberg began testing the compound on animals. It was not the great analgesic he had hoped for. Instead, it reversed the effects of every opioid they tested it against and was 15 times as potent as nalorphine.

Lewenstein died in 1966, Blumberg in 1999, and Fishman in 2013. Although Fishman worked in biochemical research for many years, he was never aware of how widespread the drug was used to reverse overdoses, says his widow, Joy Fishman. But Fishman’s invention of the overdose antidote would prove ironic for the family. In 2004, Joy’s son from another marriage died from a heroin overdose. Since 2013, Joy has been working with Drug Policy Alliance to prevent overdose deaths by expanding access to naloxone. “Every mother of every drug addict should have it,” she says. “It should be part of our medicine cabinets and glove compartments.”

 
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Comments
Maxwell (May 25, 2016 2:42 PM)
I'm not sure that quoting Paul LePage, often called "America's craziest governor" for a wide variety of reasons, is a good counterpoint to easy Naloxone access. What about the other states that won't provide it without a prescription?

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