Title: Evaluation of the analgesic efficacy of spinal cord stimulation for patients with treatment-resistant failed back surgery syndrome, and associated gene expression changes in peripheral blood lymphocytes.
Introduction: Failed back surgery syndrome (FBSS) has been defined as a chronic radicular pain of unknown origin that has recurred or persists in the same distribution despite anatomically satisfactory previous spinal surgery. Pharmacological treatment according to the three-step pain relief guidelines developed by the World Health Organization (WHO) could be therapeutically useful for most patients depending on their analgesia requirements. However, between 10-30% of patients suffering from FBSS do not achieve the required pain relief and alternative therapies are necessary. Among them, the spinal cord stimulation (SCS) appears to be one of the most effective therapies for resilient patients, although the underlying mechanisms involved in its efficacy are poorly understood. Thus, the present study was aimed to evaluate gene expression changes of targets closely related with pain modulation, in the peripheral blood lymphocytes of patients diagnosed with FBSS and treated with SCS.
Material and methods: A total of 10 patients (7 male and 3 female, mean age 49,5 ± 11,4 years) with the diagnosis of pharmacological treatment-resistant FBSS were recruited, according to certain inclusion and exclusion criteria, in the Pain Unit of the University General Hospital of Valencia to initiate a SCS treatment. All patients were evaluated with specific pain screening questionnaires (visual analogue scale (VAS), painDETECT) to gather clinical data regarding the pain sensation at different time points in a total of five visits (1 week before (T0) and 1 day (T1), 5 days (T2), 15 days (T3), 2 months after (T4), all respect the neurostimulator implant surgery). In addition, peripheral blood samples were obtained in each visit and lymphocytes isolation was performed with a density gradient protocol employing Ficoll. Finally, real time PCR analyses were carried out to analyze gene expression variations of interleukin 1 beta (IL1β), proenkephalin (PENK) and cannabinoid receptors 1 and 2 (CB1r, CB2r). All the procedures were reviewed and approved by the University General Hospital of Valencia and Miguel Hernandez University IRBs.
Results: The evaluation of pain sensitivity through the VAS clearly showed a progressive and statistically significant amelioration of pain sensation. When comparing starting and final evaluation time points, the mean score at T0 was 8.65 while at T4 was 4.94 (p<0.05). Furthermore, similar results were also obtained with the painDETECT questionnaire, in which the mean score at T0 was 22.3 (high probability (>90%) of neuropathic pain presence) and at T4 was 9.1 (low probability (<15%) of neuropathic) (p<0.05). Gene expression studies revealed that IL1β and PENK mRNA levels were significantly up-regulated in lymphocytes at T4 time point with respect to T0 (p<0.05). Interestingly, CB1r and CB2r were also significantly up-regulated at T3 (p<0.05) but not at T4.
Discussion: Clinical data from the present study demonstrates that the management of treatment-resistant FBSS patients with SCS is highly effective, with a significant and progressive reduction of the pain sensitivity at different evaluation time points after surgery. In addition, interesting gene expression changes in lymphocytes are present in targets related with pain modulation. Nevertheless, further studies with a higher number of patients are required to improve our knowledge about the mechanisms of action involved in SCS effectiveness.