An increasing number of deaths caused by opioid overdose has generated a need for new painkillers. A recent study conducted in rats investigated a new painkiller developed using nanoparticle technology.
In 2017, about 17 Canadians per day were hospitalized due to opioid overdoses. In the United States, over 115 people die from opioid overdose every day. The misuse of morphine and other opioids is a significant national crisis across Canada and the United States. New painkillers with a low potential of causing addiction are necessary.
Pain treatment presents a global challenge. Not only are people living with pain experiencing distress from inefficient therapy, but the broader community is also impacted. Morphine and its derivatives are associated with side effects and a high potential for drug abuse. A safe and effective painkiller capable of targeting painful areas in the body may overcome these challenges.
Enkephalin is a protein made in the body that has effects on pain relief. This protein activates opioid receptors just like morphine does to reduce the feeling of pain. Whereas morphine binds to both mu and delta opioid receptors, enkephalin has a preference for binding to the delta opioid receptor. Activating the delta receptor is associated with a lower potential for abuse as well as reduced side effects.
Injectable protein painkillers are challenging to develop
Protein painkillers are challenging to develop as an injectable drug because they do not remain stable in the blood. Binding the protein to a neutral molecule that increases the stability of a protein drug in the blood and the use of nanoparticle technology are two methods that are currently being explored.
Researchers at the Institut Galien Paris-Sud in France developed a new painkiller that they tested on a rat model of inflammation. The results of this animal study were presented in Science Advances.
The researchers produced three different painkiller molecules. Each molecule consisted of enkephalin attached to squalene. Squalene is a molecule that helps to stabilize enkephalin in the blood once it is injected. Squalene was attached to enkephalin at three different locations on the enkephalin molecule. Lastly, the enkephalin-squalene molecule was converted into a nanoparticle to protect it from rapidly being destroyed by enzymes in the blood.
The first tests on the enkephalin-squalene molecule were conducted in vitro. The researchers tested each enkephalin-squalene molecule for its ability to detach from the squalene group in serum samples. Two of the enkephalin-squalene molecules released the enkephalin protein at different rates. Depending on where the squalene group was attached on the enkephalin protein the bond was easier or harder to break.
Next, the researchers studied the pain relief effect of the molecules in a rat model of inflammation. This rat model had inflammation in the paw caused by the injection of carrageenan. The pain test involved applying heat to the inflamed aw before and after injection of a placebo, morphine, and the enkephalin-squalene molecules and observing the rats reaction.
Nanoparticle technology allowed for long-lasting pain relief
All rats injected with morphine and the enkephalin-squalene molecules had a reduced sensation of pain from the application of heat. This demonstrated that attaching a squalene group to enkephalin did not alter its therapeutic activity. The researchers also noticed that compared with morphine, the pain relief effect of the enkephalin-squalene molecule lasted much longer.
Lastly, the researchers investigated the ability of the enkephalin-squalene molecule to target the inflamed tissue. After the injection of the enkephalin-squalene molecule, the researchers took tissue samples of the rats and used fluorescence studies to visualize the targets of the molecule. The data highlight the ability of the molecule to concentrate on the inflamed tissue in the paw rather than in the central nervous system.
Future studies should test different doses, injection frequencies, and timing
In conclusion, the nanoparticle technology and the attachment of this new painkiller to a squalene group allowed for long lasting pain relief in a local inflamed tissue in rats. In rats, this new painkiller had limited access to the brain and spinal cord which may mean that it would cause fewer side effects. Further studies are required to determine how different doses, injection frequencies, and timing of injection would impact the pain relief effect in animal subjects.
Written by Jessica Caporuscio, PharmD
- Feng J, Lepetre-Mouelhi S, Gautier A, et al. A new painkiller nanomedicine to bypass the blood-brain barrier and the use of morphine. Sci Adv. 2019.
- Canadian Mental Health Association. Overdose prevention. https://cmha.ca/documents/overdose-prevention