Pain from surgical and dental procedures is a common problem, with some studies estimating that up to 41% of patients report moderate or severe pain after surgery. Doctors can inject local anesthetics to block the transmission of nerve impulses that generate pain in such cases. However, these drugs work only for a short time and are often given as a single large dose, which increases the risk of side effects.
But now, new research led by Daniel Kohane, Boston Children’s Hospital, Harvard Medical School, US, pursues a novel approach to overcome these obstacles. The investigators first encapsulate a local anesthetic called tetrodotoxin (TTX) into small sphere-shaped vesicles known as liposomes. These structures are made of the same molecules present in the membrane that surrounds cells.
After injecting the liposomes into rats, the researchers then used sound waves—ultrasound in particular—to trigger release of TTX from the liposomes, which blocked pain in the animals.
The new strategy is a first step towards providing on-demand pain relief enabling patients to control when, how much, and for how long they will receive a drug to alleviate pain.
“The study represents a nice proof of concept of sonosensitization [making the liposome sensitive to ultrasound] for triggerable drug delivery,” says William Schmidt, NorthStar Consulting, Davis, US, an expert on drug development who was not involved in the study.
The right trigger
The idea of using liposomes to deliver drugs for pain relief is not a new one. For instance, liposomes containing the commonly used local anesthetic bupivacaine are currently available for use in patients.
But the importance of the system described in the new study is that, potentially, patients themselves could control the release of a drug from the liposomes simply by applying ultrasound to the site of pain.
In the past, the researchers had created liposomes containing other drugs, but in a way they were too successful—after blocking a nerve to relieve pain, they were unable to turn the nerve block off. This can be an issue especially when patients need to move around in order to aid their recovery, since blocking a nerve for too long can affect movement of the muscles.
Before hitting upon the idea of using ultrasound, the same research group had used infrared light to trigger release of TTX from liposomes. But, infrared light can’t penetrate very deeply through the skin and into the underlying tissues of the body. This means that whether this approach would relieve pain depends on whether the light could reach the target nerve.
Because ultrasound can penetrate deeper into tissues and is commonplace in medicine today, it could be a more effective and safer way to trigger release of TTX from the liposomes.
To allow ultrasound to accomplish just that, the researchers put another molecule called PPIX into the liposomes, which makes them sensitive to ultrasound. Ultrasound causes PPIX to produce molecules called reactive oxygen species, which are natural byproducts of the metabolism of oxygen. The reactive oxygen species then interact with the liposomal membrane and break it down, which then leads to the release of the TTX from the liposomes.
Sounding it out
To test if the system worked, the researchers injected the liposomes near the sciatic nerve of rats. Then they measured the time it took for rats to withdraw their hind paw from a heated surface, a commonly used method to measure pain in laboratory animals.
The team found that the liposomes containing TTX produced an initial nerve block of approximately eight hours, as the rats took longer to remove their paw from the heat because they were now less sensitive to it.
Next, when the time it took to remove the paw returned to baseline levels (of approximately 4 seconds), ten more minutes of ultrasound resulted in a further nerve block of 40 minutes. Another ultrasound exposure produced nerve block lasting only ten minutes, while a final exposure produced no nerve block.
Aiming for a nerve block that lasted longer, the team developed new liposomes that contained a molecule that helps TTX relieve pain for a longer period of time. When they injected these liposomes along with the liposomes containing TTX, they saw an initial nerve block lasting 35 hours. Three additional ultrasound applications produced nerve block lasting two hours, one hour and 30 minutes, respectively. This was an important finding since patients are looking for more prolonged pain relief.
“As a proof of concept it is important work, but certainly there are issues to be addressed,” said Schmidt. In particular, he said it will be important to test whether the approach will work with other drugs that are more commonly used in patients to relieve pain.
In addition, Kohane, the leader of the research team, says that there are some technical issues that still need to be resolved, “but the goal is to move to human studies.”
Pain relief that patients can control with ultrasound would be a highly desirable therapy—especially because ultrasound is already widely and safely used in medicine.
“Imagine if you could ease your pain after a dental filling by applying ultrasound to it. The potential applications of this technology are numerous,” said Kohane.
To read about the research in more detail, see the related IASP Pain Research Forum news story here.
Dara Bree is a postdoctoral fellow at Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, US.