Background & Aims

Spinal Cord Stimulation (SCS) was proposed as a therapeutic modality following the seminal publication of the Gate Control Theory (GCT) of pain processing[1]. However, the GCT does not completely explain the effects of SCS. More importantly, SCS may not fully exploit the therapeutic opportunities offered by the GCT. It is therefore important to understand the mechanism of action (MoA) of SCS to better inform clinicians on proper patient selection and provide a robust scientific basis for the therapy. While pre-clinical SCS models have provided insights into MoAs[2,3], these models have limitations and are lacking consistency. Thus, it may be challenging to translate pre-clinical findings to inform human clinical studies and more than 50 years on from SCS introduction, the MoA of SCS is yet to be fully understood. This study aimed to comprehensively review available SCS pre-clinical models and assessed the effect size of SCS in these models using meta-analysis.

Methods

The systematic review was conducted in line with the PRISMA guidelines[4]. The review searched MEDLINE, EMBASE, Web of Science, and the SCS collection of WikiStim. No limitations were placed on article’s date or language. The review was registered on PROSPERO (ID: CRD42023457443). The meta-analysis investigated the effect size for SCS on paw withdrawal thresholds measured with Von Frey filaments. Hedge’s g for studies that had pre-SCS and during-SCS measurements were calculated. The inverse variance method under a random effects model was used to pool effect sizes.

Results

In total 1617 records were identified: Embase (1054), MedLine (266), Web of Science (264), and WikiStim (33). Following the removal of duplicates (468) and title/abstract screening (1037 removed), 112 reports were retrieved for full-text review. The final review included 78 articles from 22 different laboratories. Sprague Dawley rats were used in 92% of studies, of which 90% were males. Commonly used neuropathic pain models were Spared Nerve Injury model, Seltzer model and Chronic Constriction Injury model that were used in 34%, 29%, and 14% of studies, respectively. Stimulating leads were predominantly implanted spanning T10-T13 (84%). Electrodes were mostly quadripolar (48%) or monopolar (41%). There was a large effect favouring SCS (g=2.04,95% CI: [1.57,2.51]). Subgroup analyses showed similar effect sizes for conventional (?100Hz) (g=1.97,[1.39,2.56]) and non-conventional (g=2.26,[1.33,3.19]) stimulation. There was evidence of publication bias using Egger test (p<0.001).

Conclusions

While there is a healthy body of pre-clinical research on the efficacy and MoA of SCS from diverse institutions, the available evidence has many limitations. For example, there is a preponderance of male animals used in this research reflecting the gender bias previously described in pre-clinical research generally[5], and this warrants deeper consideration in future experiments. In addition, SCS demonstrated efficacy with a large effect size, but there was evidence of publication bias. There was also no significant difference in effect size between conventional vs. non-conventional SCS stimulation. Whilst clinical superiority of novel waveforms over conventional waveforms has been reported[6,7] there is, as yet, no evidence of such superiority in pre-clinical models. In summary, our work helps identify gaps and limitations in pre-clinical SCS models that, when addressed, may improve the translatability of pre-clinical research.

References

[1] Melzack R, Wall PD. Pain mechanisms: a new theory. Science 1965;150:971-979.

[2] Caylor J, Reddy R, Yin S, Cui C, Huang M, Huang C, Rao R, Baker DG, Simmons A, Souza D, Narouze S, Vallejo R, Lerman I. Spinal cord stimulation in chronic pain: evidence and theory for mechanisms of action. Bioelectron Med 2019;5:12.

[3] Sdrulla AD, Guan Y, Raja SN. Spinal cord stimulation: clinical efficacy and potential mechanisms. Pain Practice 2018;18:1048-1067.

[4] Page MJ, McKenzie JE, Bossuyt PM, Boutron I, Hoffmann TC, Mulrow CD, Shamseer L, Tetzlaff JM, Akl EA, Brennan SE, Chou R, Glanville J, Grimshaw JM, Hróbjartsson A, Lalu MM, Li T, Loder EW, Mayo-Wilson E, McDonald S, McGuinness LA, Stewart LA, Thomas J, Tricco AC, Welch VA, Whiting P, Moher D. The PRISMA 2020 statement: An updated guideline for reporting systematic reviews. Int J Surg 2021;88:105906.

[5] Beery AK, Zucker I. Sex bias in neuroscience and biomedical research. Neurosci & Biobeh Rev 2011;35:565-572.

[6] Deer T, Slavin KV, Amirdelfan K, North RB, Burton AW, Yearwood TL, Tavel E, Staats P, Falowski S, Pope J, Justiz R, Fabi AY, Taghva A, Paicius R, Houden T, Wilson D. Success Using Neuromodulation With BURST (SUNBURST) Study: Results From a Prospective, Randomized Controlled Trial Using a Novel Burst Waveform. Neuromod 2018;21:56-66.

[7] Kapural L, Yu C, Doust MW, Gliner BE, Vallejo R, Sitzman BT, Amirdelfan K, Morgan DM, Brown LL, Yearwood TL, Bundschu R, Burton AW, Yang T, Benyamin R, Burgher AH. Novel 10-kHz High-frequency Therapy (HF10 Therapy) Is Superior to Traditional Low-frequency Spinal Cord Stimulation for the Treatment of Chronic Back and Leg Pain: The SENZA-RCT Randomized Controlled Trial. Anesthesiology 2015;123:851-860.

[8] Kemler MA, De Vet HC, Barendse GA, Van Den Wildenberg FA, Van Kleef M. The effect of spinal cord stimulation in patients with chronic reflex sympathetic dystrophy: two years’ follow-up of the randomized controlled trial. Ann Neurol 2004;55:13-18.

[9] Kumar K, North R, Taylor R, Sculpher M, Van den Abeele C, Gehring M, Jacques L, Eldabe S, Meglio M, Molet J, Thomson S, O’Callaghan J, Eisenberg E, Milbouw G, Fortini G, Richardson J, Buchser E, Tracey S, Reny P, Brookes M, Sabene S, Cano P, Banks C, Pengelly L, Adler R, Leruth S, Kelly C, Jacobs M. Spinal Cord Stimulation vs. Conventional Medical Management: A Prospective, Randomized, Controlled, Multicenter Study of Patients with Failed Back Surgery Syndrome (PROCESS Study). Neuromod 2005;8:213-218.

[10] Mekhail N, Levy RM, Deer TR, Kapural L, Li S, Amirdelfan K, Hunter CW, Rosen SM, Costandi SJ, Falowski SM, Burgher AH, Pope JE, Gilmore CA, Qureshi FA, Staats PS, Scowcroft J, McJunkin T, Carlson J, Kim CK, Yang MI, Stauss T, Pilitsis J, Poree L, Evoke Study Group, Brounstein D, Gilbert S, Gmel GE, Gorman R, Gould I, Hanson E, Karantonis DM, Khurram A, Leitner A, Mugan D, Obradovic M, Ouyang Z, Parker J, Single P, Soliday N. Durability of Clinical and Quality-of-Life Outcomes of Closed-Loop Spinal Cord Stimulation for Chronic Back and Leg Pain: A Secondary Analysis of the Evoke Randomized Clinical Trial. JAMA Neurol 2022;79:251-260.

[11] Petersen EA, Stauss TG, Scowcroft JA, Brooks ES, White JL, Sills SM, Amirdelfan K, Guirguis MN, Xu J, Yu C. Effect of high-frequency (10-kHz) spinal cord stimulation in patients with painful diabetic neuropathy: a randomized clinical trial. JAMA Neurol 2021;78:687-698.

[12] Traeger AC, Gilbert SE, Harris IA, Maher CG. Spinal cord stimulation for low back pain. Cochrane Database of Systematic Reviews 2023;2023. doi:10.1002/14651858.CD014789.pub2.

Presenting Author

Dave Mugan

Poster Authors

Dave Mugan

BSc, MBA

Newcastle University & Saluda Medical

Lead Author

Quoc Vuong

PhD

Newcastle University

Lead Author

Birte Dietz (PhD)

Saluda Medical

Lead Author

Ilona Obara (PhD)

Newcastle University

Lead Author

Topics

  • Systematic Reviews/Meta-Analysis