The mechanisms and pathways on the origin of chronic low back pain associated with degenerative changes in the intervertebral disc have been studied for more than half a century. Unlike etiologies with a clear pathological cause, such as disc herniation, spondylolisthesis or spinal stenosis, CLBP appears to arise in part following disc and endplate degeneration with subsequent changes in the endplate morphology and biology. Inflammatory mediators have been shown to be expressed following disc injury, leading to a cascade of further inflammatory response via cytokine production .
Direct evidence supporting the vertebral body as a source of clinical pain was provided by Kuslich et al. who reported on a series of patients during laminectomy using local anesthesia only. They reported that direct intraoperative mechanical stimulation of the endplates of these awake patients consistently provoked significant pain response . Additional evidence for the endplate’s role in generation of pain signals was provided by Lotz et al., who performed a histomorphological study of human vertebral bodies which documented endplate nociceptor densification with increased disc degeneration .
Heggeness et al. observed that injection into the disc, as during discography, caused the endplates to deform and hypothesized that this deformation could account for the pain experienced during a discogram in some patients . After hypothesizing that increased physical activity could instigate disc degeneration, Adams et al. showed that minor damage to the vertebral endplates could lead to structural changes in the adjacent intervertebral discs [21, 22]. Carragee et al. determined that vertebral body and endplate MRI signal changes, indicative of intraosseous edema or inflammation, were well correlated with clinical low back pain .
Further correlation between vertebral body pathology and CLBP was described by Modic et al. who described intraosseus MRI changes adjacent to the vertebral endplates in patients with CLBP . Weishaupt et al. reported 100% specificity to pain in patients with Type 1 and Type 2 Modic changes and furthermore observed strong and very similar positive predictive values and specificity associated with both Type 1 (88%) and Type 2 (96%) Modic changes . Kuisma et al. found a 2.28 odds ratio for the presence of Modic changes at L5–S1 in patients with CLBP . Although Rahme and Mossa found that low back pain is more commonly associated with Type I Modic changes, they also noted that this association was sometimes made based on relatively small sample sizes, and that other studies showed correlation between both Type 1 and Type 2 Modic changes and low back pain . Schroeder et al. recently observed cytokine elevation in patients with Modic Type 2 MR signals treated with anterior lumbar fusion, indicating that both Type 1 and Type 2 changes may be associated with low back pain .
In longitudinal studies, a change in Modic presentation from Type 1 to Type 2 has been observed, with the concomitant observation that pain was more likely associate with Type 1 presentation [24, 29]. In the present study, approximately 68% of patients reported experiencing low back pain for more than 5 years, suggesting that the higher baseline incidence of Modic Type 2 changes observed may reflect the transition of Modic Type 1 findings to Type 2 over time. Kjaer et al. have observed that Type 1 Modic changes are correlated with more recent low back pain, which may in part explain the higher prevalence of Type 2 findings in the SMART patient population who were symptomatic for over half a decade [30, 31]. Note that during the course of the SMART study itself, only a single instance of Type 1 to Type 2 conversion was observed. No statistical difference was observed in outcome between patients presenting with Type 1 versus Type 2 Modic changes.
The SMART trial was designed to test the hypothesis that the BVN plays an important role in the transmission of pain signals in patients with CLBP. The data showed that ablation of the BVN in the treatment arm decreased patients’ mean ODI by more than twice the MCID. The magnitude of the decrease was in line with decreases in ODI previously observed following fusion and total disc replacement (TDR) surgery. Two common TDRs, the Charité and the ProDisc, report an average percent improvement in ODI of 42.0% at 3 months, which compares favorably with the 48.5% improvement at 3 months observed in the treatment arm of the present study [32, 33]. These TDR studies were controlled against fusion; the average percent improvement in ODI of the patients receiving fusion was 35.0%. However, the patients in these TDR studies were permitted to enroll with conditions other than just isolated back pain, including stenosis or disc herniation. Studies looking at strictly chronic low back patients report lower percentage improvements in ODI. For example, Fritzell et al. reported a 25% improvement in ODI in their CLBP patients surgically treated with fusion, whereas Brox et al. reported a 37% improvement in ODI in fused CLBP patients [1, 34]. Thus, the improvement in patient outcome observed in the treatment arm of the SMART study was comparable to that observed following TDR and fusion procedures for similar etiologies.
The mean improvement in ODI in the ITT sham arm was 15.4 points at 3 months, and was durable at 6 and 12 months. Positive responses to placebo or sham treatments are well-recognized, especially in chronic pain populations, where the degree and duration of sham effectiveness often approaches that of active treatment [35, 36, 37, 38]. Furthermore, multiple studies evaluating medical devices against sham interventions also suggest a correlation between the magnitude of the sham response and the invasiveness of the treatment [39, 40, 41, 42, 43, 44, 45].
The cognitive perception of chronic pain is a function of peripheral nociceptor input and complex central neurobiological modulation. Historically, clinical placebo or sham effects were attributed to statistical and not biological factors. Placebos were included in trials to statistically filter out the “noise” not associated with the mechanism of action of the proposed pharmacological or surgical treatment itself. In such a model, the total treatment effect is a linear superposition of the placebo effect and the interventional effect. A high placebo response in such a linear model is interpreted to indicate that the treatment effect is minimal and the procedure or drug is not particularly effective. However, newer models, particularly when studying pain, recognize that modulation of the central brain response through modification of expectations is an integral part of the patient’s response to any treatment. These models incorporate the sham response as part of the overall treatment effect, and have been developed to the point where they can distinguish which patients are going to have a higher central brain response (sham response) as opposed to peripheral response (intervention response).
Supporting this neurobiological basis for a placebo or sham response, Tétreault et al. performed an elegant study where they first confirmed brain activity associated with a placebo response, and then a priori predicted which patients in a subsequent study would show a placebo response . The ability to predict, opposed to just document, a placebo response and to map areas of the brain associated with that response suggests that in a given population there exist a range of patient responses to a specific pain alleviation therapy, from almost pure central brain placebo response to nearly pure peripheral stimulatory inhibitory response. Treatments may act on one or the other response in varying degrees, but the documentation through randomized controlled study of the ability to relieve both peripheral and central pain is important to the adoption of a new surgical therapy. The ability in the SMART trial to distinguish the active treatment from the sham treatment suggests that ablation of the BVN has therapeutic value, although the overall pain response in a given patient is a complex function of the combined effects of placebo and treatment.
Radiofrequency ablation of the BVN for the relief of chronic low back pain represents a new treatment modality and is distinct from other RF ablation therapies used in the spine such as facet ablation. BVN ablation is technically and scientifically distinct from facet ablation because it uses a transpedicular approach into the vertebral body to access the BVN directly to alleviate vertebrogenic pain, and furthermore mandates strict patient selection criteria. Note that facet ablation may have varying effectiveness as a function of patient selection, as recently reported by Juch et al. .
In the present study, using a 10-point ODI improvement as a threshold, 75.6% of treatment arm patients as opposed to 55.3% of sham arm patients were characterized as responders. In addition, the treatment group reported statistically significant improved outcomes compared to the sham group. Comparison of the difference in outcome score between the sham and treatment groups does not represent the clinical utility of the Intracept Procedure because a sham treatment is not a clinically acceptable treatment for CLBP, nor is a sham response likely to occur in an open label setting. The overall therapeutic value of the procedure should be viewed through its safety profile and observed improvements from patient baseline, which are the same filters applied to other more invasive procedures which have not been compared to sham treatment. The results of this study support BVN ablation as a minimally invasive treatment for relief of chronic low back pain.