Article In Brief
Focused high-intensity ultrasound at a low-intensity helped ameliorate peripheral neuropathy associated with the chemotherapy drug vincristine.
Non-invasive, low-intensity focused ultrasound reduces the pain of chemotherapy-induced peripheral neuropathy in a rat model, according to a study in February 4 edition of the journal Neuroscience. The results provide support for clinical development of this noninvasive approach to a debilitating and refractory side effect of successful cancer treatment.
Vincristine is a vinca alkaloid used to treat leukemia, lymphoma, and several other types of cancer. While it is an effective chemotherapeutic agent, about 60 percent of patients treated with it develop painful peripheral neuropathy, said the study's principal investigator Julie Pilitsis, MD, PhD, chair of the department of neuroscience and experimental therapeutics and professor of neurosurgery at Albany Medical College in New York.
The drug damages microtubule networks in the axon, which, through unknown mechanisms, leads to neuropathic pain. Effects of the drug include tactile hypersensitivity, burning sensations, paresthesias, and autonomic symptoms.
“As people are living longer as survivors of cancer, this treatment side effect is becoming much more common. Treatment is not just about survival—it is about treating the aftermath of cancer, so we have to think about quality of life,” Dr. Pilitsis said.
One approach to treating peripheral neuropathy is electrical stimulation of the dorsal root ganglion, which has been shown to be effective, but requires surgical implantation. Dr. Pilitsis and colleagues have been developing an alternative approach, using focused ultrasound.
The mechanical sound waves of ultrasound can be focused onto a small, highly precise location, Dr. Pilitsis said. Early work on the effects of ultrasound on excised nerves indicated that the response was determined by both intensity and pattern of dosing. At high doses, ultrasound heats tissue and causes nerve ablation. Focused high-intensity ultrasound is now being used in treatment of essential tremor, and the current study used the same system.
Ablation has been tried for peripheral neuropathy, Dr. Pilitsis said, and it works for six to 12 months, but then the nerve regrows and the pain returns. But at lower intensities with pulsed stimulation, ultrasound has a modulatory effect, which is not damaging but rather regulating the frequency at which nerves fire.
“That led us to ask whether it could be used to modulate activity of the dorsal root ganglia, the collection of sensory neuron cell bodies just outside the spinal cord, which acts as the main hub of communication between the peripheral and central nervous systems,” Dr. Pilitsis said. “Vincristine's effects may begin as a microtubule dysfunction, but it has upstream effects as well. The way the dorsal root ganglion communicates with the brain changes.”
Study Design, Findings
To explore the ability of low-intensity focused ultrasound to reduce vincristine-induced pain, Dr. Pilitsis and colleagues first tested its effect when the ultrasound-emitting device was surgically placed on the L5 dorsal root ganglion, and then went on to determine if the same benefit could be obtained when ultrasound was delivered from a device applied to the surface of the skin.
Rats received vincristine by injection for five days a week over two weeks, and then were tested to confirm development of neuropathic pain. Testing was performed with Von Frey fibers (VFF), in which a weighted filament is applied to the rat's paw until the filament bends, delivering a known mechanical force. Filaments of increasing thickness are used until the rat withdraws the paw, which is equated to a response to pain. Thermal and locomotion responses were also recorded.
Before vincristine treatment, VFF response was seen at approximately 28 grams of force. After vincristine, response was seen at less than 4 grams.
Dr. Pilitsis then internally delivered a single three-minute treatment with ultrasound, and tested responses at 24, 48, 72, and 120 hours. She found that treatment restored VFF response to 24, 23, 22, and 24 grams, respectively, which was statistically equivalent to pre-vincristine levels. No such benefit was seen in animals receiving sham stimulation. Response on the hot plate also indicated a robust increase in pain threshold in treated animals.
Dr. Pilitsis then applied the ultrasound stimulation externally, so that the treatment traveled through the skin and soft tissue to the L5 dorsal root ganglion. Parameters were set to focus the ultrasound at around 5 millimeters below the surface of the skin. As she saw with the internally applied stimulus, external treatment restored pain thresholds to normal up to 120 hours after a single treatment. There was no difference in the amount of movement between treated and untreated groups, showing that this treatment did not cause damage to the spinal cord. A thermal probe at the level of the dorsal root ganglion indicated a rise in temperature of 1.8 degrees C, which remained elevated for about seven minutes.
“The exciting thing about these results is that externally applied ultrasound can have the same effect as internally applied treatment,” Dr. Pilitsis said. “That could be a gamechanger for treatment of peripheral neuropathy,” she said, adding, that the duration of effect was notable, lasting five days from a three-minute application. “That indicates to me that we are not just changing the way the nerve fires. We are likely having a more circuit-wide effect.”
Surface ultrasound is currently used in physical therapy, where mild heating is meant to stimulate circulation and relax tissue. Temperature rises only about 2 degrees C, Dr. Pilitsis said, “so we are hoping that if we stay within that, it will be well within people's comfort range.”
The depth at which ultrasound waves can be effectively focused is a hurdle the team is currently working on. They have begun testing in pigs (using a different pain model), whose skin-to-dorsal root ganglion distance is much closer to that of humans, and those tests appear successful. Having made the adjustments to the delivery device to go from less than 1 centimeter for the rat to 6 centimeters for the pig, “I think we can make further adjustments to get to the 6 to 7 centimeters needed for humans,” she said.
Protocols for clinical trials are also being developed. “We won't know until we try it in humans whether we can effectively blind patients” to sham stimulation, Dr. Pilitsis added.
She is also hoping to test the treatment is other forms of neuropathy, including diabetic neuropathy, which affects more than 13 million Americans.
“This approach to neuropathic pain is really provocative, and potentially has a lot of value,” said Jeffrey Elias, MD, associate professor of neurosurgery and neurology at University of Virginia, Health Sciences Center in Charlottesville, who was not involved with the study. “This is a first step to being able to noninvasively modulate the nervous system for neuropathic pain, and I commend them.”
Dr. Elias has developed ablative ultrasound as a treatment for essential tremor and headed the clinical trial that led to its approval.
One of the most intriguing possibilities for this approach to peripheral neuropathy, he said, was the likelihood that it could be portable. “I'm sure it will start off in the clinic, but you could easily imagine it becoming a wearable device for at-home use, and possibly rather rapidly. That is the potential power of it.”
Safety will be an important consideration as clinical trials are developed, he added, “but it is pretty well accepted that low-intensity ultrasound is safe. There are certain limits already defined by the FDA, and the treatment here is well below that. The challenge is to develop enough preclinical evidence to design a good clinical study, and these results are a big step forward in that direction.”
Nir Lipsman, MD, PhD, assistant professor of surgery at University of Toronto and scientist at the Sunnybrook Research Institute, added: “Studies like this are critical to advance the field, and to view ultrasound not only as a powerful diagnostic tool, but as a therapeutic tool for difficult-to-treat conditions. There is an urgent need to develop safe and effective ways to control pain, and peripheral neuropathy in particular. Work like this will lead to the development of such therapies that are focal and informed by sound science and experience.”
Dr. Pilitsis had no financial disclosures directly related to the publication of this work. She is a consultant for Boston Scientific, Nevro, Jazz Pharmaceuticals, and Abbott and receives grant support from Medtronic, Boston Scientific, Abbott, Nevro, Jazz Pharmaceuticals, GE Global Research, and NIH. She is medical advisor for Aim Medical Robotics and Karuna and has stock equity. Dr. Elias received research funding from Insightec, the device manufacturer for FUS, which goes to the University of Virginia.