Chronic pain affects 1 in every 4 adults in the United States, many of whom are resistant to pharmacotherapy.1 It is a significant burden to both individuals and healthcare systems, affecting mental health, cognitive function, and promoting opioid dependency.2 However, researchers are hot on the heels of discovering new ways to treat the condition — including via deep brain stimulation (DBS).

What is DBS?

DBS has the potential to treat a variety of neurological diseases by the implantation of electrical leads into specific areas of the brain’s cortex or subcortex, linking the leads to an implanted electrical stimulator.3 The appropriate areas of the brain are then stimulated with electrical current to ease or eliminate certain symptoms. While this treatment strategy is approved for motor diseases like essential tremors, dystonia, and Parkinson’s disease, it is gaining increasing interest for pain relief in therapy-resistant individuals.4

DBS for the treatment of chronic pain


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Since the 1950s, researchers have investigated DBS for the treatment of individuals with incurable, pain-inducing disorders.5 These investigations involved a variety of intractable pain syndromes, ranging from brachial plexopathy, injury of the spinal cord, and thalamic pain syndrome, to accident-related pain and mechanical lower back pain.6 Success has also been reported for incurable facial pain, although subsequent studies targeting different chronic pain disorders demonstrated inconsistent efficacy.5,6 Consequently, DBS is still considered investigational and “off-label” for chronic pain treatment today.

This “off-label” status has not hindered research, however. One study reported the results of 59 patients with a diverse range of chronic pain syndromes, who received DBS in the periventricular grey (PVG) area of the brain and/or the thalamus.7 In comparison to pre-operative levels, results indicated a drastic improvement, with more than half of patients, regardless of pain etiology, reporting pain relief by 50 percent.

Another study involved performing DBS on the periaqueductal grey (PAG) or PVG area, along with the sensory region of the thalamus or internal capsule, on patients with a variety of pain etiologies. Pain reduction exceeded 50 percent.8

Interestingly, some patients who fail to meet the 50 percent pain reduction criteria so often used in research testify to being greatly satisfied with any amount of pain reduction as it significantly improves their quality of life.9 This means that many patients are documented to have failed DBS treatment regardless of a partial, but notable, improvement.

Identifying novel target sites for chronic pain therapy

According to Prasad Shirvalkar, pain physician and Assistant Professor at the University of California, “Historically, DBS has overwhelmingly targeted two brain regions: the ventral thalamus and the PAG areas. Thalamic DBS was hypothesized to work consistent with the Gate Control Theory of pain. It is believed that stimulating the thalamus produces ‘tingling’ or other paraesthesia that effectively block pain-related transmission from fibers that provide input from the periphery and spinal cord. The Gate Control Theory posits that ascending fibers/inputs to the brain have limited bandwidth, and that providing some additional input may interfere with pain signal transmission.  The PAG DBS may help by boosting the body’s endogenous opioid system, but there is some controversy over this.”3

According to research, a low frequency below 50 Hz is presumed to have an analgesic effect upon thalamus and PAG stimulation, while higher frequencies above 70 Hz are presumed to increase pain sensitivity. Additionally, stimulation of the ventral posterolateral (VPL) and ventral posteromedial (VPM) nuclei causes a pleasant sensation that overrides pain, while stimulation of PVG and PAG areas triggers analgesia and a warm sensation over the painful region.9

“More recently, a team at Oxford has introduced DBS of the anterior cingulate cortex (ACC), which may dampen the ‘unpleasantness’ or ‘bothersomeness’ of pain without affecting the somatosensory component of pain,” says Shirvalkar. Patients have reported that even though pain was not totally relieved, it was less irritating or felt distant from them, demonstrating the emotional or affective aspect of the ACC.9

Overcoming barriers to the effective use of DBS

DBS currently involves a constant flow of electrical current and does not adjust to changes in brain activity.1 According to Shirvalkar, “One of the biggest obstacles with DBS for pain is that no matter which target is stimulated, DBS often loses effect in the long term over 1-2 years for many patients. That is, the brain seems to adapt to the stimulation and ‘ignores’ it. We are trying to figure out how to overcome such adaptation.”3

“It is more likely that multiple brain regions conspire over a network to produce and perpetuate chronic pain states,” Shirvalkar explains. “We are conducting a clinical trial that incorporates a novel trial period, where patients temporarily have electrodes placed in their brain for a period of 10 days. We then work very hard over 10 days to record brain activity and stimulate multiple regions that we believe are important for chronic pain. This way, we can determine which sites or ‘nodes’ are most pain-relieving when stimulated for that individual person.” By performing a comprehensive trial period, Shirvalkar and his team can learn more about the network behavior of chronic pain in the brain and maximize the probability of finding an efficacious therapy for each patient. Importantly, Shirvalkar says, “This way, patients are not implanted with a permanent device when there is a low chance of long-term benefit.”

Any emerging research findings could advance treatment for other conditions too. “Other brain diseases that are treated with brain stimulation such as epilepsy, Parkinson’s disease, and depression (although experimentally) could also benefit from developing technology where stimulation responds to ongoing neural activity,” says Shirvalkar. “Many of my colleagues are working on developing adaptive DBS for these other medical conditions.”

The future of DBS for chronic pain

Going forward, Shirvalkar believes that there is the need for advancement in two key scientific areas. “The first is understanding basic brain mechanisms that underlie these diseases so that we can better understand what effect stimulation is actually having on the disease itself,” he says. “The second is figuring out how we can modulate the key brain circuits non-invasively, using transcranial magnetic stimulation or scalp stimulation. I think the future is moving away from stimulating ‘single brain regions’ and towards networks, ultimately with the goal of doing this without invasive implants.”

References

1. Miller, JA. Tailoring deep brain stimulation to treat chronic pain. UC San Francisco. Published February 3, 2020. Accessed December 20, 2020. https://www.ucsf.edu/news/2020/02/416601/tailoring-deep-brain-stimulation-treat-chronic-pain.

2. Dydyk AM, Yarrarapu SNS, Conermann T. Chronic Pain. StatPearls; 2020. Updated November 8, 2020. https://www.ncbi.nlm.nih.gov/books/NBK553030/

3. Shirvalkar P, Sellers KK, Schmitgen A, et al. A Deep Brain Stimulation Trial Period for Treating Chronic Pain. J Clin Med. 2020;9(10):3155. doi:10.3390/jcm9103155

4. Lozano AM, Lipsman N, Bergman H, et al. Deep brain stimulation: current challenges and future directions. Nat Rev Neurol. 2019;15(3):148-160. doi:10.1038/s41582-018-0128-2

5. Frizon LA, Yamamoto EA, Nagel SJ, Simonson MT, Hogue O, Machado AG. Deep Brain Stimulation for Pain in the Modern Era: A Systematic Review. Neurosurgery. 2020;86(2):191-202. doi:10.1093/neuros/nyy552

6. Ben-Haim S, Mirzadeh Z, Rosenberg WS. Deep brain stimulation for intractable neuropathic facial pain. Neurosurg Focus. 2018;45(2): E15. doi:10.3171/2018.5.FOCUS18160

7. Boccard SGJ, Pereira EAC, Moir L, Aziz TZ, Green AL Long-term outcomes of deep brain stimulation for neuropathic pain. Neurosurgery. 2013; 72:221-230. doi:10.1227/NEU.0b013e31827b97d6

8. Kumar K, Toth C, Nath RK Deep brain stimulation for intractable pain: A 15-year experience. Neurosurgery. 1997; 40:736-746. doi:10.1097/00006123-199704000-00015

9. Farrell SM, Green A, Aziz T. The Current State of Deep Brain Stimulation for Chronic Pain and Its Context in Other Forms of Neuromodulation. Brain Sci. 2018;8(8):158. doi:10.3390/brainsci8080158

This article originally appeared on Neurology Advisor