In the spring of 2020, a team of colleagues reached out to Alonso Guedes with an interesting request.

The team, part of the University of Minnesota (UMN) Medical School, needed to get lab pigs to react to opioids in ways similar to humans, something they don’t naturally do. As opioid deaths continued to climb, they were racing against the clock to find a way to combat overdoses. 

“Pigs are really similar to people in many ways, especially their immune systems, which makes them a great model to study human medicine. However, pigs are not very sensitive to the respiratory effects of opioids, and that poses a problem when studying interventions for opioid overdoses,” says Guedes, professor of anesthesia and the associate dean for research at the College of Veterinary Medicine (CVM). 

The opioid epidemic in the United States has remained deadly for decades. In 2023, Centers for Disease Control and Prevention data showed deaths from drug overdoses decreased for the first time since 2018 but still accounted for more than 100,000 lives lost—four times the number of overdose deaths 20 years ago. Of these, 70 percent involved opioids, mostly strong synthetic opioids such as fentanyl and carfentanil.  

Guedes, who is also a board-certified specialist in veterinary anesthesia and pain medicine, has shared his method for making pigs more sensitive to opioids with the scientific community, meaning his model can be utilized by researchers around the world. 

Through collaborations between multiple groups from the UMN, Washington State University, Columbia University, and the University of Montana, Guedes’ pig models are helping researchers develop new tools to help save lives in the event of an overdose and prevent one from happening in the first place. 

A vaccine for opioid overdoses

For several years, teams from UMN, the University of Montana, and the University of Washington have been working to design vaccines that could prevent an overdose if someone comes into contact with an opioid. In particular, the vaccine could help prevent overdoses in people who have opioid use disorder (OUD) during vulnerable times.

One challenge with substance use disorders is that even if a person is able to stop using for a period of time, they may relapse—and that relapse is when they are at higher risk for an overdose, Guedes says. 

“The more a person takes opioids, the more tolerant they become, so they need higher and higher doses to get high. But if they go for a period of time without taking opioids, that tolerance reverses back to normal. If they take the same amount then, they overdose,” he explains. 

In these cases, preventative vaccines could be helpful. The challenge is designing them. 

The body does not normally recognize opioids as a foreign substance in the way the immune system recognizes bacteria and viruses as foreign threats and mounts an attack. To design a vaccine against an opioid, the team attached a molecule that the body would recognize as foreign to a specific opioid molecule—the most common being fentanyl. Manipulating the drug molecule in this way prompts the body to start recognizing it as a threat and develop antibodies to the drug. 

“It’s like dressing up fentanyl to stick out in a crowd,” Guedes says. 

The vaccines are specific to different types of opioids, such as heroin or fentanyl, that pose an overdose risk. That way, people do not have this neutralizing reaction to every type of opioid, which could pose a problem if the person needed opioid painkillers during something like a major surgery. 

Given his expertise with animal medicine, Guedes was able to get pigs to respond to an opioid overdose as humans do and serve as a model for how the vaccines may work in humans. It’s a crucial step in the drug development process since the Food and Drug Administration (FDA) requires animal studies to show the drug is safe and effective before being used in humans. 

The initial efficacy studies showed very promising results, and the team is now working on toxicology studies—one of the last steps before the vaccines can go to human trials. So far, there haven’t been any adverse reactions. 

“It’s a painstaking process,” Guedes says. “By the time we start studying it in humans, we know as much as we can about the vaccines, so hopefully it doesn't cause harm afterward.”

Short-acting antibodies

While the goal of vaccination is to provide long-term protection against an overdose, the team of animal and human medical research experts is also working on a solution that would provide temporary immunity against an opioid overdose. 

Monoclonal antibodies are lab-made proteins that mimic the antibodies the immune system creates when a person is exposed to or vaccinated against a pathogen. Essentially, “you cut to the chase,” Guedes says.

“The vaccines are a slower process, you need to expose the body a couple of times to that dressed-up fentanyl. Then the body recognizes it as foreign and starts producing antibodies,” he explains. “For this, you actually produce the antibodies in a lab and if someone is exposed to opioids such as fentanyl and they are having an overdose, you can inject those monoclonal antibodies in the vein and they will very quickly neutralize all the fentanyl.”

The monoclonal antibodies could also be used in a situation in which someone may be exposed to large amounts of opioids in the near future, but they will not experience repeated risk, negating the need for longer-term protection.

Monoclonal antibodies sit between protection from long-acting vaccines and opioid-reversing drugs such as Naloxone, sold as Narcan, which are relatively short-acting.

While Naloxone is still an important tool, its effects can wear off while there is still a high amount of opioids in the body, potentially causing a person to go back into an overdose. The team’s research on monoclonal antibodies to prevent opioid overdoses is in its final stages of animal studies and they are expecting to move to human trials later this year. 

Treating overdoses that do happen

When opioid overdoses do happen, a person stops breathing. 

Guedes and his team are also developing a patch that jump-starts the lungs, much as a defibrillation machine does for the heart. 

“One of the challenges with people who are undergoing an overdose is that a lot of times they are taking a lot of different things,” he says. 

That can make it a challenge to treat an overdose with something that is only effective in reversing an opioid overdose. 

“Having a technology that does not care about what kind of drug someone took that made them stop breathing can be very helpful. That’s where this respiratory device comes into play,” he says. 

The patch, which is attached directly to the skin on a person’s neck, works by stimulating the nerves that cause the respiratory system to breathe. The idea is that by administering a small electrical current to these nerves through wires attached to the patch, a person’s breathing can be restored until they can get proper medical care.

The first round of studies in pigs is complete and the team is getting ready to test and refine the updated design.

“It’s a very iterative process. With every study we do, we learn something that we can refine and then come back with,” Guedes says.

Developing non-opioid pain treatments

The drug pipeline typically goes from humans to animals, that is, a drug that is approved for use in human medicine often turns out to be used off-label in veterinary medicine. But in the case of the non-opioid pain treatment Guedes’ team is developing, animals will likely benefit first.

“Developing medications that are non-addictive is the other slice of the pie that needs to happen, and veterinary knowledge is also really important in this,” he says.

Opioids are not very useful in treating chronic pain in veterinary medicine because animals— including dogs and cats—do not metabolize nor react to opioids in the same way people do. Finding non-opioid treatments for chronic pain in pets could very likely lead to useful treatments for people.

“We are very fortunate in the vet school that we are trained to understand the physiology of many different animals. When you add humans, that’s just one more,” Guedes says.