AANS Neurosurgeon | Volume 28, Number 3, 2019

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Hit the Reset Button: Deep Brain Stimulation for Chronic Pain

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The efficacy of deep brain stimulation (DBS) in the treatment of movement disorders is well established, with emerging indications for a variety of novel pathologies, such as epilepsy, dementia and neuropsychiatric disorders. However, the earliest use of DBS was in the treatment of pain, predating the discovery of dorsal column stimulation and even the “gate control” theory of pain by more than a decade. Although early success was seen in small case series, the structured clinical trials that followed were marred by low patient enrollment, high attrition and poor overall efficacy1, which led to the FDA conferring “off-label” status for the use of DBS for chronic pain. Despite these challenges, there has been early success targeting the affective component of pain, with renewed enthusiasm in designing more well-structured trials focused on homogenous pain diagnoses2.


Conventional DBS Targets for Chronic Pain

In the 1950s, Heath and Mickle observed that septal stimulation alleviated intractable pain related to cancer or rheumatoid arthritis. 3 This work was followed by additional small case series investigating septal stimulation4 and other mesolimbic pathway targets5, though further research was quiescent until the 1970s. These subsequent studies targeted the sensory thalamus6,7 and periaqueductal-periventricular gray (PAG/PVG)8, which continue to be commonly targeted in current clinical practice. Indications for treatment often include centrally-mediated pain syndromes, such as those resulting from phantom limb pain, spinal cord injury and thalamic pain syndrome, also known as central post-stroke pain (CPSP).

Stimulation of the sensory thalamus is the preferred DBS target for the treatment of neuropathic pain of the face and/or body, producing paresthesia overlapping the painful area. Some of the earliest studies6,7 reported show benefit in the treatment of:

  • Facial anesthesia;
  • Dolorosa, phantom limb pain; and
  • CPSP.

However, pain almost invariably recurred, leading to the suggestion that much of the early therapeutic effect may have been related to the lesional effect of electrode insertion. In contrast, PAG/PVG stimulation produces a sensation of warmth and is considered preferential in the treatment of nociceptive pain; this has been hypothesized to be mediated by endogenous endorphin release8. PAG/PVG stimulation appears particularly susceptible to tolerance, with the need for higher stimulation parameters over time to achieve the same therapeutic effect9. Often, electrodes targeting both the thalamus and PAG/PVG will be implanted in the same patient, contralateral to the side of pain (Figure 1).

Figure 1. Coronal (left) and axial (right) T1-weighted MRI demonstrates planned trajectories for electrodes targeting the left ventral posterolateral nucleus of the thalamus (lateral) and periventricular gray matter (medial) in a patient with a previous left middle cerebral artery infarction and central post-stroke pain.

Treatment Challenges

Despite initial enthusiasm and significant reported rates of success, the clinical efficacy of DBS as a pain treatment modality has not held up to scrutiny1. These early studies have been limited by:

  • Retrospective or open-label design
  • Low patient enrollment
  • High attrition

There is tremendous clinical heterogeneity present in the literature, with multiple pain syndromes combined with multiple stimulation targets within the same study. This makes it difficult to draw meaningful conclusions2. However, these study designs reflect the relative rarity of these pain syndromes in the general population and the low number of patients referred for consideration of DBS.

Another recognized challenge is the lack of consensus regarding patient selection when treating pain with DBS. Patients with chronic pain tend to be considered due to the failure of medications or less invasive modalities. DBS is more commonly employed in central neuropathic pain syndromes or pain related to central sensitization, which include CPSP and spinal cord injury. These pain syndromes are distinctly less common than peripheral neuropathic pain; our understanding is limited regarding the natural history and optimal treatment paradigms. These patients respond poorly to multimodal, non-surgical management10, which places them at a disadvantage when pursuing invasive treatment options and may be partially responsible for the low efficacy of DBS reported in the literature.

Evaluating treatment success presents one more hurdle, as improvements in pain quality may not necessarily correlate with improvements in quality of life (QOL). Pain is comprised of sensory, affective and cognitive dimensions, whereas traditional pain assessment scales, such as the Visual Analog Scale, Numerical Rating Scale and Brief Pain Inventory, predominantly measure only the sensory component of pain.

New Directions

Interestingly, recent research has focused on modulating the affective or “unpleasant” perception of pain to improve disability. The first randomized, placebo-controlled study of DBS in patients with CPSP targeted the bilateral ventral striatum/anterior limb of the internal capsule, an area thought to be involved in affective pain processing.11 Although the primary endpoint was not met (greater than or equal to 50% improvement of pain disability in 50% of patients), significant improvements were observed regarding QOL metrics.

Targeting the anterior cingulate cortex (ACC), a region that was historically lesioned for pain control and involved in affective pain processing12 has also been studied. Electrodes were implanted into the bilateral ACC, with significant improvements in QOL metrics that were sustained up to 42 months in some patients.13 In both studies, there was a latency period until clinical improvement was observed, compared to the “immediate” effects or either sensory thalamus or PAG/PVG stimulation.

Both of these studies saw several patients develop recurrent seizures, an unexpected complication. This raises ethical concerns regarding the uncertain risk profile regarding the implementation of innovative or novel DBS therapies, which must be addressed by an augmented consent and a close therapeutic relationship between the patient and physician.14

Yes, No, Yes

The rise and fall of DBS for pain is typical of neurosurgical interventions. Given the promising early results of targeting the affective sphere of pain, more studies are necessary to increase patient enrollment and identify new stimulation targets. It is essential that high quality data be generated from randomized, placebo-controlled trials so that meaningful conclusions can be drawn regarding specific stimulation targets or pain syndromes.

References

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1. Coffey, R. J. (2001). Deep Brain Stimulation for Chronic Pain: Results of Two Multicenter Trials and a Structured Review. Pain Medicine, 2(3), 183-192.

2. Frizon, L. A., Yamamoto, E. A., Nagel, S. J., Simonson, M. T., Hogue, O., & Machado, A. G. (2019). Deep Brain Stimulation for Pain in the Modern Era: A Systematic Review. Neurosurgery.

3. Heath, R.G. & Mickle, W.A. Evaluation of seven years’ experience with depth electrode studies in human patients; in Ramey ER, O’Doherty D (eds): Electrical studies on the unanesthetized brain. New York, Harper & Brothers, 1960, 214-247.

4. Gol, A. (1967). Relief of pain by electrical stimulation of the septal area. Journal of the Neurological Sciences. 5(1), 115-120.

5. Ervin, F.R., Mark, V.H. & Stevens, J. (1969). Behavioral and affective responses to brain stimulation in man. Proceedings of the annual meeting of the American Psychopathological Association. 58, 54-65.

6. Hosobuchi, Y., Adams, J. E., & Rutkin, B. (1973). Chronic Thalamic Stimulation for the Control of Facial Anesthesia Dolorosa. Archives of Neurology, 29(3), 158-161.

7. Mazars, G.J. (1975). Intermittent stimulation of nucleus ventralis posterolateralis for intractable pain. Surgical neurology. 4(1), 93-95.

8. Richardson, D. E., & Akil, H. (1977). Long term results of periventricular gray self-stimulation. Neurosurgery, 1(2).

9. Kumar, K., Wyant, G. M., & Nath, R. (1990). Deep brain stimulation for control of intractable pain in humans, present and future. Neurosurgery, 774.

10. Staudt, M. D., Clark, A. J., Gordon, A. S., Lynch, M. E., Morley-Forster, P. K., Nathan, H., . . . Moulin, D. E. (2018). Long-Term Outcomes in the Management of Central Neuropathic Pain Syndromes: A Prospective Observational Cohort Study. Canadian Journal of Neurological Sciences/Journal Canadien Des Sciences Neurologiques, 45(5), 545-552.

11. Lempka, S. F., Malone, D. A., Hu, B., Baker, K. B., Wyant, A., Ozinga, J. G., . . . Machado, A. G. (2017). Randomized clinical trial of deep brain stimulation for poststroke pain. Annals of Neurology, 81(5), 653-663.

12. Boccard, S. G., Fitzgerald, J. J., Pereira, E. A., Moir, L., Hartevelt, T. J., Kringelbach, M. L., . . . Aziz, T. Z. (2014). Targeting the Affective Component of Chronic Pain. Neurosurgery, 74(6), 628-637.

13. Boccard, S. G., Prangnell, S. J., Pycroft, L., Cheeran, B., Moir, L., Pereira, E. A., . . . Aziz, T. Z. (2017). Long-Term Results of Deep Brain Stimulation of the Anterior Cingulate Cortex for Neuropathic Pain. World Neurosurgery, 106, 625-637.

14. Maslen, H., Cheeran, B., Pugh, J., Pycroft, L., Boccard, S., Prangnell, S., . . . Aziz, T. (2017). Unexpected Complications of Novel Deep Brain Stimulation Treatments: Ethical Issues and Clinical Recommendations. Neuromodulation: Technology at the Neural Interface, 21(2), 135-143.

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