Treatment for people with substance use disorder (SUD) has changed dramatically over the past fifty years. The same is true for people who experienced heroin or opioid overdose. In 1973, there was no specific heroin overdose treatment aside from standard medical support in an emergency room/hospital setting. Now we have Naloxone – more commonly known as Narcan – which can reverse an opioid overdose quickly.
In the early 1970s, a person with alcohol or drug use problems had few options. Alcoholics Anonymous (AA) existed for people with what we now call alcohol use disorder (AUD). Narcotics Anonymous (NA) existed for people who engaged in what we now call substance use disorder (SUD). In the 1970s we use phrases like heroin addict or junkie to refer to people who engaged in the disordered use of opioids. We’ve since moved past stigmatizing language. In 2023, we use the phrase opioid use disorder (OUD) for people with problem opioid use and heroin use disorder for people with problem heroin use.
For other substances, we use the same pattern. We say cocaine use disorder and methamphetamine use disorder, for instance.
The language we use has changed, and – as we mention above – treatment has changed as well. We now know the best approach to supporting people with SUD is the integrated treatment model. This approach includes therapy, counseling, lifestyle changes, and community support. For people with opioid use disorder (OUD), the gold-standard approach in the 21 century is medication-assisted treatment (MAT). This modality – pioneered in the late 1960s and early 1970s – involves using medications that block the action of opioids in the brain. Medications for opioid use disorder (MOUD) occupy the receptors opioids activate. This prevents their euphoric effect and prevents the onset of withdrawal symptoms.
Now, in 2023, scientists are exploring another approach to treating heroin overdose and heroin use disorder: immunopharmacotherapy.
What is Immunopharmacotherapy?
That word seems intimidating. But if we break it down into its constituent elements, it’s easy to understand.
Immuno- means it’s related to the immune system – think immunity.
Pharmaco- means it’s a medication – think pharmacy.
And therapy means treatment – think physical therapy, psychotherapy, or any other type of therapy for a physical or mental health problem.
Put them together, and we have a medication that relies on the immune system to treat a specific condition.
A peer-reviewed article published in October 2022 explores the use of immunopharmacotherapy to treat heroin use disorder and prevent heroin overdose. When we talk about the immune system, the first thing many of us think about is vaccines. For good reason. Vaccines leverage the immune system by triggering the creation of antibodies. These proteins, created by white blood cells, attach to pathogens and mark them for immune cells to destroy, sequester, and expel from the body. For instance, a flu vaccine stimulates our body to create proteins that recognize and attach to the flu virus. It allows other immune cells to recognize it as a dangerous pathogen they need to isolate, destroy, and/or remove.
Therefore, a vaccine that prevents heroin use disorder would stimulate the body to create antibodies that recognize heroin. The antibodies would prevent it from acting on the brain. They would also ensure it’s removed safely from the body.
That type of immunity is called active immunity. The body actively creates the tools needed to protect itself from a pathogen. That’s how vaccines work, in general. There’s another way to leverage immune cells to offer protection from unwanted chemicals in the body, though. It’s called passive immunity.
Passive immunity is the use of exogenous – meaning from the outside – antibodies to perform the same function as endogenous antibodies.
Passive Immunity and Heroin Overdose Treatment: How It Can Work
The easiest way to understand passive immunity is to learn that it’s the way a mother’s breast milk helps keep an infant healthy before its immune system becomes fully functional. An infant ingests antibodies the mother makes in her immune system. Those antibodies protect the infant while its immune system begins the process of building its own active immunity to common pathogens. It takes years, but eventually, we all develop robust protection against viruses and bacteria that cause illness and disease.
In the meantime, passive immunity works very well.
Another way to understand passive immunity is to use the phrase monoclonal antibody treatment. Many of us may now recognize this because it was one of the therapies used to treat President Trump when he had COVID-19. A monoclonal antibody is the clone of a specific antibody proven to recognize and attach to a specific pathogen. When a person receives a monoclonal antibody treatment, they ingest a lab-created antibody – based on an antibody created in the immune system of an original donor – and that antibody confers temporary protection against that specific pathogen.
That’s how this new approach to treating heroin overdose and heroin use disorder can work. To prevent overdose or intoxication, an individual with heroin use disorder would receive an injection of an antibody that recognizes heroin. That antibody would perform a function analogous to passive immunity. It would prevent heroin from binding to receptors in the brain and block its action. It would keep heroin sequestered until other immune cells either destroy it or remove it from the body.
We say can and would because this approach is currently in the research phase in the rodent model, which means that so far, the researchers have demonstrated their concept is viable in laboratory mice, but not humans – yet.
Finding the Right Molecule for Heroin Overdose Treatment: How They Did It
For decades, researchers looking for a heroin vaccine have examined two metabolites of heroin – morphine and 6-acetylmorphine – because those are the chemicals known to dull pain, cause euphoria, and lead to respiratory depression that can lead to death in the case of heroin overdose.
Metabolites are the products of chemical reactions in the bloodstream. When an outside chemical interacts with chemicals inside our bodies in the process known as metabolism, the result it metabolites. Researchers focused on these metabolites because of their properties. However, this new study revealed something crucial: focusing on the metabolites was a mistake.
How did they figure this out?
In this study, researchers used laboratory mice to create four distinct monoclonal antibodies. They created one for each of the two metabolites commonly studied, one for heroin itself called 11D12, and one for a separate heroin metabolite.
Once they created, cloned, and produced enough of the four antibodies, they inoculated laboratory mice with them and performed a series of tests to determine two things:
- Whether the antibodies prevented properties of heroin associated with pain relief and euphoria, two properties that drive the disordered use of heroin in humans.
- Whether the antibodies prevented properties of heroin associated with respiratory depression, which is the primary cause of death in cases of heroin overdose.
Let’s take a look at what they found.
Monoclonal Antibodies (mAB) to Heroin and Metabolites: Impact on Pain
- mAB 1 (11D12): completely blocked analgesic effect of heroin
- mAB 2 (4G12): moderate prevention of analgesic effect of heroin
- mAB 3 (6E1): moderate prevention of analgesic effect of heroin
- mAB 4 (6B11): mild to nonexistent prevention of analgesic effect of heroin
In addition to assessing the impact of these antibodies on heroin itself, researchers assessed the impact of these antibodies on heroin metabolites and learned that the mAB/11D12 antibody had a more powerful affinity for heroin than any of its associated metabolites. That’s how they figured out that decades of research on metabolites was a mistake: the antibodies had the most robust effect not on metabolites, but on heroin.
They used this information to test mAB/11D2 for its effect on respiratory depression and compare it to the next most effective antibody, mAB/4G12. Here’s what they found.
Monoclonal Antibodies (mAB) to Heroin: Impact on Respiratory Depression
- mAB 1 (11D12): Robust protective effect against seizure and death
- mAB 2 (4G12): No protective effect against seizure and death
That’s important information in the search for heroin overdose treatment and treatment for heroin use disorder using immunopharmacotherapy. An antibody to heroin – not its metabolites – demonstrated a significant effect on analgesia, which is used as a proxy for euphoria, and demonstrated a significant impact on respiratory depression, which is how a heroin overdose results in death.
How This Research Helps
It would be unfair to call this research step one in the search for an immunopharmacotherapeutic approach to preventing heroin overdose and treating heroin use disorder, because it’s taken decades of unsatisfactory results to arrive here. However, researchers obtained these results in laboratory rodents, rather than in humans. In most cases, that would mean we’re years away from practical human application.
With this approach, though, we may be closer than we think.
Why?
The next phase of this research will focus on two things:
- Creating a human version of the mAB/11D2 monoclonal antibody and testing it in humans
- Creating monoclonal antibodies to synthetic opioids like fentanyl and carfentanil, two opioids currently associated with escalating rates of fatal opioid overdose
In fact, the research team – based at the Scripps Research Institute in San Diego, California – has already created both lines of monoclonal antibodies and is in the process of arranging clinical trials. That means clinical trials may begin soon, and depending on the outcome of those trials, we may be on track for an effective immunopharmacotherapy to prevent heroin overdose and treat heroin use disorder.
The exact details of how this would work are in progress. The overall concept is that a person with heroin use disorder would receive an injection of these antibodies – which remain in the body for months – which would then prevent the intoxication associated with heroin misuse and prevent the respiratory depression associated with fatal heroin overdose.
Dr. Kim Janda, a lead author on the study, summarized his work in an interview in the online science publication Science Daily:
“Our findings suggest that a monoclonal antibody-based therapy will be more effective than a vaccine and should be targeted to heroin itself rather than its psychoactive metabolites…our report will reset research in a direction where successful clinical trials should now be achievable.”
If clinical trials in humans yield similar results to those obtained in laboratory subjects, we may be on the verge of a new generation of medication-assisted treatment for heroin use disorder and the disordered use of other opioids, which could help treatment professionals mitigate the ongoing harm caused by the opioid overdose crisis.
That would be a very, very important and welcome development in the heroin overdose treatment, and treatment for opioid use disorder in general.
We’ll keep a close eye on the research, and report any news here as it’s available.
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