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
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Presenting Author
Dave Mugan
Poster Authors
Topics
- Systematic Reviews/Meta-Analysis