Ultrasound can be used to release nerve-blocking agents contained in liposomes and relieve patients from pain. This would be an alternative to opioids and open up the possibility of a safer, on-demand and personalized management of pain.
A departure from opioids
Opioids are frequently prescribed to patients in an attempt to relieve disease- or surgery-related pain. But such drugs carry a high-risk of addiction and overdose that can potentially lead to death. This became a cause of concern over the past decade as official figures revealed an increase in deaths by pain-reliever overdose in America of more than 400% in women and 237% in men between 1999 and 2010.
In response to this problem, researchers from Boston, Madrid and Hong-Kong teamed up to create a safer substitute that would provide instant pain relief at specific locations. They designed a system that uses engineered liposomes containing an anaesthetic agent, and whose outer shell is triggered by ultrasound to burst the liposome open and release its cargo. This strategy provides local anaesthesia where needed (Nature Biomedical Engineering 1 644).
A sono-sensitive drug-delivery system
Ultrasound has been investigated to direct diverse organic vehicles to specific locations. For example, microbubble-induced opening of the blood-brain barrier has reached the human trial stage. The non-invasive and non-ionizing nature of ultrasound makes it a suitable energy source to direct these vehicles, but it is its extended depth of penetration that makes ultrasound the trigger of choice over other techniques such as near-infrared light.
Of all the existing vehicles, liposomes – spherical vesicles with a lipid bilayer shell – were preferred due to their customizable potential and ability to carry tetrodotoxin (TTX), a molecule administered in clinical trials to attenuate cancer pain. FDA-approved protoporphyrin IX (PPIX) was encapsulated between the two layers of the liposome and used as a sonosensitizer to trigger the release of the anaesthetic under the action of the ultrasound energy. The team investigated various combinations of frequencies, intensity, duration and duty cycle of insonation to ensure maximum efficiency in the release of TTX.
Experiments in rats
The researchers conducted experiments in rats to validate the need for PPIX and verify whether TTX was responsible for nerve blockade – the phenomenon responsible for anaesthesia. They injected liposomes directly in the nerve and sonicated, while assessing the status of the nerve by timing how long the rat could stay on a hot plate. The results validated their hypotheses and the group observed that the duration and intensity of anaesthesia were dependent upon the duration and intensity of the ultrasound beam.
After one injection, a 10-minute insonation led to 34 hr of nerve blockade; subsequent insonations with no reinjection of liposomes led to around 1 hr of additional nerve blockade. This result paves the way for personalized narcotic-free pain management. The technique also proved to be safe, as all 20 animals used in the experiments with TTX and PPIX survived.
The future of pain management?
These results are very promising. The fact that the degree of nerve blockade is controlled by the ultrasound duration and intensity allows for customizable pain management. Patients could receive an injection at the hospital and relieve their pain themselves at home, whenever they need, using a small portable ultrasound device. This could potentially help combat opioid addiction, reduce the overall duration of hospitalization and hence alleviate bed blocking.
