Theory to Practice: Better Pain Treatment Through Advances in Spinal Stimulation

Utilizing scientific theory for clinical application can lead to breakthroughs for patients. One remarkable example was the gate theory of pain rapidity of translation into a surgical treatment for pain. The description of dual pathways of sensory input to the brain (1) in which small nerve fibers transmit painful stimuli and large fibers transmit vibration, touch and pressure was followed just two years later (1967) by the first report of the use of dorsal column stimulation for the treatment of limb pain (2). These fibers also modulate interneurons such that non-noxious stimuli “distract” from pain by inhibiting transmission of painful stimuli (“closing the gait”) to the brain.

Unfortunately, this pace of advancement was not sustained, as it took 30 years for dorsal column stimulation (more commonly referred to as spinal cord stimulation (SCS)) to earn Food and Drug Administration (FDA) approval for the treatment of chronic intractable trunk or limb pain. Conventional SCS requires inducement of paresthesias in the distribution of the patient’s pain. This is typically accomplished using a low frequency (20-60 Hz) that is shaped by the active electrical contacts and the pulse width of stimulation.

Advancements and Approvals
The science of pain continued, but, following FDA approval, clinical advances focused predominately on device technology. As the initial devices were composed of paddle electrodes requiring surgical placement and large, non-rechargeable generators, improvements included:

  • Paddle configuration including cylindrical percutaneous varieties;
  • Rechargeable pulse generators; and
  • New programming algorithms.

Truly transformative technology breaking through the monotony took another 15+ years capitalizing on new scientific understanding. The key to this advancement is moving beyond the gate theory to incorporate advancement in our understanding of pain circuits.  First among these has been the application of new waveforms of stimulation, which counteract pain circuits without paresthesias.

High frequency stimulation is believed to inhibit firing of wide-dynamic range neurons within the dorsal horn of the lower thoracic spinal cord in response to mechanical and electrical stimuli (3). A specific, proprietary form of high-frequency stimulation, HF10™ (Nevro Corp, Redwood City, Calif.), delivers 10kHz stimulation in charge-balanced, biphasic waveforms without the production of paresthesias. The electrodes are placed anatomically to span the T9 and T10 vertebral bodies, and optimal benefit is achieved by working through a proprietary programming algorithm (4).

The pivotal randomized clinical trial comparing HF10™ stimulation to conventional SCS was remarkable for demonstrating the superiority of HF10™ therapy in all primary and secondary endpoints (5). At 24 months, the percentage of patients achieving greater than 50 percent reduction in pain was 76.5 percent versus 49.3 percent for back pain and 72.9 percent versus 49.3 percent for leg pain (HF10 versus conventional SCS, respectively). Based on this data, the Centers for Medicare & Medicaid (CMS) approved a transitional pass-through payment to support additional reimbursement, considering this to be new technology.

Burst stimulation is another approach. Within the spinal cord and CNS, there are populations of neurons that fire tonically and others that fire in a burst pattern. The burst firing pattern seems to be more efficient in transmitting certain types of information to the cortex, including suppression of nociceptive pain (6,7). BurstDR™ (Abbott -St. Jude Medical, St. Paul, Minn.) capitalizes on this by providing stimulation in “bursts” of ?ve pulses (1 ms pulse width, 500 Hz), each burst delivered at a frequency of 40 Hz. While the final results of their multi-center clinical trial are pending, burst stimulation was statistically superior to tonic or placebo stimulation in reducing pain. Very few patients experienced paresthesias during burst stimulation (8).

Choose the Right Path
A cautionary note should be made with regards to each of these proprietary stimulation paradigms.  Scientists, clinicians and rivals in the SCS field continue to explore which components of these paradigms are critical to achieving pain control. For example, must high-frequency stimulation equal 10 kHz? A small study by North, et al. found improved pain control, as compared to conventional SCS, with sub-perception stimulation at 1 kHz (9). Additional studies have suggested that charge density, not the specific stimulation parameters, are responsible for pain control (10). Furthermore, much work is required to understand how these technologies are best matched with specific patients and pain syndromes.

One final innovative development to discuss bypasses the spinal cord, providing stimulation directly to the dorsal root ganglion (DRG). DRG stimulation provides an option for patients with focal pain distribution that has otherwise been difficult to control with spinal cord stimulation. It is FDA approved for the treatment of complex regional pain syndrome (CRPS) I and II. In addition, its use has been explored for the treatment of phantom limb pain, post-herpetic neuralgia and other indications (11). In a randomized-controlled study comparing DRG to SCS stimulation in patients with CRPS I and II, 81 percent versus 56 percent achieved greater than 50 percent pain relief, respectively (12). Patients report confinement of the stimulation to their painful area and little to no postural changes in their stimulation.  There is the additional advantage that such focal stimulation requires a small charge density – foregoing the need for a rechargeable generator.

After decades of stagnation, advancements in stimulation technology have led to improved outcomes.  The field will undoubtedly continue to grow and force reconsideration of current treatment paradigms.

1. Melzack, R. & Wall, P.D. (1965). Pain mechanisms: a new theory. Science. 150(3699):971-979. 

2. Shealy, C.N., Mortimer, J.T., & Reswick, J.B. (1967). Electrical inhibition of pain by stimulation of the dorsal columns: Preliminary clinical report. Anesthesia & Analgesia. 46(4):489-491. 

3. Arle, J.E., Mei, L., Carlson, K.W., & Shils, J.L. (2016). High-frequency stimulation of dorsal column axons: Potential underlying mechanism of paresthesia-free neuropathic pain relief.Neuromodulation. 19(4):385-397. 

4. Van Buyten, J.P., Al-Kaisy, A., Smet, I., Palmisani, S., & Smith, T. (2013). High-frequency spinal cord stimulation for the treatment of chronic back pain patients: results of a prospective multicenter European clinical study. Neuromodulation. 16(1):59-65-6. 

5. Kapural, L., Yu, C., Doust, M.W., Gliner, B.E., Vallejo, R., Sitzman, B.T., … Burgher, A.H. (2016). Comparison of 10-kHz High-Frequency and Traditional Low-Frequency Spinal Cord Stimulation for the Treatment of Chronic Back and Leg Pain: 24-Month Results From a Multicenter, Randomized, Controlled Pivotal Trial. Neurosurgery. 79(5):667-677. 

6. Crosby, N. D., Weisshaar, C. L., Smith, J. R., Zeeman, M. E., Goodman-Keiser, M. D., & Winkelstein, B. A. (2015). Burst and Tonic Spinal Cord Stimulation Differentially Activate GABAergic Mechanisms to Attenuate Pain in a Rat Model of Cervical Radiculopathy. IEEE Transactions on Biomedical Engineering, 62(6), 1604-1613. 

7. De Ridder, D. & Vanneste, S. (2016) Burst and Tonic Spinal Cord Stimulation: Different and Common Brain Mechanisms. Neuromodulation. 19(1):47-59. 

8. Schu, S., Slotty, P.J., Bara, G., von Knop, M., Edgar, D., & Vesper, J. (2014). A prospective, randomised, double-blind, placebo-controlled study to examine the effectiveness of burst spinal cord stimulation patterns for the treatment of failed back surgery syndrome. Neuromodulation: Technology at the Neural Interface, 17(5):443-450. 

9. North, J.M., Hong, K.S.J., & Cho, P.Y. (2016). Clinical outcomes of 1 kHz subperception spinal cord stimulation in implanted patients with failed paresthesia-based stimulation: Results of a prospective randomized controlled trial. Neuromodulation, 19(7):731-737. 

10. Miller, J.P., Eldabe, S., Buchser, E., Johanek, L.M., Guan, Y., & Linderoth, B. (2016). Parameters of spinal cord stimulation and their role in electrical charge delivery: A review. Neuromodulation, 19(4):373-384. 

11. Eldabe, S., Burger, K., Moser, H., Klase, D., Schu, S., Wahlstedt, A. … Vanderick, B. (2015). Dorsal root ganglion (DRG) stimulation in the treatment of phantom limb pain (PLP). Neuromodulation, 18(7):610-6-7. 

12. Deer, T.R., Levy, R.M., Kramer, J., Poree, L., Amirdelfan, K., Grigsby, E., … Mekhail, N. (2017). Dorsal root ganglion stimulation yielded higher treatment success rate for complex regional pain syndrome and causalgia at 3 and 12 months: A randomized comparative trial. Pain, 158(4):669-681.