Improvements in Intractable Lumbar and LowerExtremity Symptoms after Systemic Administration of Tocilizumab, an Anti-interleukin-6 Receptor Antibody.

STUDY DESIGN: Prospective cohort study (open-label, single-arm, and non-blinded). PURPOSE: This study aims to determine the effects of systemic administration of tocilizumab, an anti-interleukin-6 (IL-6) receptor antibody on refractory low back pain and leg symptoms. OVERVIEW OF LITERATURE: IL-6 overexpression is associated with neuropathic pain pathogenesis, which is potentially followed by chronic low back pain, including leg pain and numbness. This finding suggest that inhibition of IL-6 at the site of pain or in the transmission pathway could provide novel therapeutic targets for chronic low back pain. METHODS: This prospective, single-arm study included 11 patients (eight men; mean age, 62.7 years) with ≥3-months' chronic pain history due to lumbar disease. Subcutaneous TCZ injections were administered twice, at a 2-week interval. We evaluated low back pain, leg pain, and leg numbness using numeric rating scales and the Oswestry Disability Index (ODI; baseline and 6 months postinjection); serum IL-6 and tumor necrosis factor-α levels (baseline and 1 month postinjection); and clinical adverse events. RESULTS: Intractable symptoms reduced after TCZ administration. Low back pain improved for 6 months. Improvements in leg pain and numbness peaked at 4 and 1 month, respectively. Improvements in ODI were significant at 1 month and peaked at 4 months. Serum IL-6 was increased at 1 month. IL-6 responders (i.e., patients with IL-6 increases >10 pg/mL) showed particularly significant improvements in leg pain at 2 weeks, 1 month, and 2 months compared with nonresponders. We observed no apparent adverse events. CONCLUSIONS: Systemic TCZ administration improved symptoms effectively for 6 months, with peak improvements at 1-4 months and no adverse events. Changing serum IL-6 levels correlated with leg pain improvements; further studies are warranted to elucidate the mechanistic connections between lumbar disorders and inflammatory cytokines.

Platelet-rich plasma enhances bone union in posterolateral lumbar fusion: A prospective randomized controlled trial.

BACKGROUND CONTEXT: Platelet-rich plasma (PRP) accelerates bone union in vivo in a rodent model of spinal fusion surgery. However, PRP's effect on bone union after spinal surgery remains unclear. PURPOSE: The objective of this study was to evaluate the efficacy of PRP after posterolateral lumbar fusion (PLF) surgery. STUDY DESIGN/SETTING: Single-center prospective randomized controlled clinical trial with 2-year follow-up. PATIENT SAMPLE: The patient sample included a total 62 patients (31 patients in the PRP group or 31 patients in the control group). OUTCOME MEASURES: The outcome measures included the bone fusion rate, the area of bone fusion mass, the duration of bone fusion, and the clinical score using the visual analog scale (VAS). MATERIALS AND METHODS: We randomized 62 patients who underwent one- or two-level instrumented PLF for lumbar degenerative spondylosis with instability to either the PRP (31 patients) or the control (31 patients) groups. Platelet-rich plasma-treated patients underwent surgery using an autograft bone chip (local bone), and PRP was prepared from patient blood samples immediately before surgery; patients from the control group underwent PLF without PRP treatment. We assessed platelet counts and growth factor concentrations in PRP prepared immediately before surgery. The duration of bone union, the postoperative bone fusion rate, and the area of fusion mass were assessed using plain radiography every 3 months after surgery and by computed tomography at 12 or 24 months. The duration of bone fusion and the clinical scores for low back pain, leg pain, and leg numbness before and 3, 6, 12, and 24 months after surgery were evaluated using VAS. RESULTS: Data from 50 patients with complete data were included. The bone union rate at the final follow-up was significantly higher in the PRP group (94%) than in the control group (74%) (p=.002). The area of fusion mass was significantly higher in the PRP group (572 mm2) than in the control group (367 mm2) (p=.02). The mean period necessary for union was 7.8 months in the PRP group and 9.8 months in the control group (p=.013). In the PRP, the platelet count was 7.7 times higher and the growth factor concentrations were 50 times higher than those found in plasma (p<.05). There was no significant difference in low back pain, leg pain, and leg numbness in either group at any time evaluated (p>.05). CONCLUSIONS: Patients treated with PRP showed a higher fusion rate, greater fusion mass, and more rapid bone union after spinal fusion surgery than patients not treated with PRP.

Longitudinal Evaluation of the Histological Changes in a Rat Model of Paravertebral Muscle Injury.

INTRODUCTION: Thus far, few reports have described the time series histological variations in injured paravertebral muscle tissues for long durations, considering the type of pain. The purpose of this study is to evaluate histological changes in injured paravertebral muscles and dominant nerves considering the type of pain. METHODS: We used 59 eight-week-old male Sprague-Dawley rats. A 115-g weight was dropped from a height of 1 m on the right paravertebral muscle. Fluoro-Gold (FG), a sensory nerve tracer, was injected into this muscle. Hematoxylin and eosin (HE) staining and nerve growth factor (NGF) immunostaining of the muscle were performed for histological evaluation. L2 dorsal root ganglia (DRG) on both sides were resected, and immunohistochemical staining was performed for calcitonin gene-related peptide (CGRP, a pain-related neuropeptide) and for activating transcription factor 3 (ATF3, a neuron injury marker). Each examination was performed at 3 days, 1-3 weeks, and 6 weeks after injury. RESULTS: HE staining of the paravertebral muscle indicated infiltration of inflammatory cells and the presence of granulation tissue in the injured part on the ipsilateral side at 3 days and 1 week after the injury. Fibroblasts and adipocytes were present at 2-3 weeks. At 6 weeks, the injured tissue was almost completely repaired. NGF was detected at 2-3 weeks post injury and appeared to colocalize with fibroblasts, but was not observed at 6 weeks post injury. The percentage of cells double-labeled with FG and CGRP in FG-positive cells of the primary muscle was significantly higher in the injured side at 3 days and 1-3 weeks post injury (P < 0.05). However, at 6 weeks, no significant difference was observed. No significant expression of ATF3 was observed. CONCLUSIONS: These results suggest that sensitization of the dominant nerve in the DRG, in which NGF may play an important role, can protract pain in injured muscles.

Vascular endothelial growth factor in degenerating intervertebral discs of rat caudal vertebrae.

INTRODUCTION: Discogenic back pain remains poorly understood with respect to etiopathogenesis, despite being a considerable burden. We sought to examine the expression of vascular endothelial growth factor in injured intervertebral discs in rat caudal vertebrae. METHODS: Forty-eight male Sprague Dawley rats were assigned to 2 groups according to disc puncture injury: puncture (n = 32) or non-puncture (n = 16). Disc puncture was performed percutaneously such that the incision would be in the primary plane of motion for the coccygeal discs 5-6, 6-7, and 7-8. A 26-gauge needle was used to puncture each disc 10 times. Punctured discs were examined histologically by hematoxylin and eosin staining at 1, 7, 14, and 28 days post-injury. RESULTS: Vascular endothelial growth factor was localized immunohistochemically, and determined quantitatively using an enzyme-linked immunosorbent assay. Peak inflammation occurred on the 7th day post-injury, but tissue degeneration continued until day 28. Local expression of vascular endothelial growth factor tended to be highest in the annulus fibrosus on the 7th and 14th days after puncture injury. The level of vascular endothelial growth factor was highest 1-day post-injury, and then gradually decreased thereafter. Furthermore, vascular endothelial growth factor levels in the puncture group were significantly higher than those in the non-puncture control group (p < 0.05). CONCLUSIONS: We found increased expression of the inflammatory cytokine vascular endothelial growth factor in injured intervertebral discs, suggesting that vascular endothelial growth factor may be clinically important in discogenic back pain.

Efficacy of nerve growth factor antibody in a knee osteoarthritis pain model in mice.

BACKGROUND: Nerve growth factor (NGF) is not only an important factor in nerve growth but also a major contributor to the production of inflammation. It has been reported that inhibiting NGF could reduce several types of pain in several animal models. Here, we aimed to clarify the efficacy of NGF antibody in a knee osteoarthritis (OA) pain model in mice. METHOD: Six-week-old male C57BR/J mice were used (n = 30). Ten mice comprised the control group, which received saline injection into the right knee joints; the other 20 mice comprised the experimental group, which received monoiodoacetate (MIA) injection into the right knee joints. Three weeks after surgery, the 20 experimental mice were randomly placed into treatment groups which received either sterile saline (non-treat group: 10 mg/kg, i.p.) or an anti-NGF antibody (anti-NGF group: 10 mg/kg, i.p.). Simultaneously, all mice received fluorogold (FG) retrograde neurotracer injection into their right joints. In a behavioral study, we evaluated gait using the CatWalk quantitative gait analysis system before surgery, 3 weeks after surgery (before treatment), 4 weeks after surgery (one week after surgery), and 5 weeks after surgery (2 weeks after surgery). In immunohistochemical analysis, the right dorsal root ganglia (DRGs) from the L4-L6 levels were resected 5 weeks after surgery (2 weeks after surgery). They were immunostained for calcitonin gene-related peptide (CGRP), and the number of FG-labeled or CGRP-immunoreactive (IR) DRG neurons was counted. RESULTS: On gait analysis using the CatWalk system, duty cycle, swing speed, and print area were decreased in non-treat group compared with those in control group and improved in the anti-NGF group compared with those in non-treat group. CGRP expression in DRGs was up-regulated in non-treat group compared with that in control group and suppressed in the anti-NGF group compared with that in non-treat group (both p < 0.05). CONCLUSIONS: MIA injection into the knee joint induced gait impairment and the up-regulation of CGRP in DRG neurons in a knee OA pain model in mice. Intraperitoneal injection of anti-NGF antibody suppressed this impairment of gait and up-regulation of CGRP in DRG neurons. These finding suggest that anti-NGF therapy might be valuable in the treatment of OA pain in the knee.

Inhibiting Vascular Endothelial Growth Factor in Injured Intervertebral Discs Attenuates Pain-Related Neuropeptide Expression in Dorsal Root Ganglia in Rats.

STUDY DESIGN: An experimental animal study. PURPOSE: To evaluate effects of anti-vascular endothelial growth factor (VEGF) on the content and distribution of the calcitonin gene-related peptide (CGRP) in the dorsal ganglia in a rat model. OVERVIEW OF LITERATURE: Increased expression of VEGF in degenerative disc disease increases the levels of inflammatory cytokines and nerve ingrowth into the damaged discs. In animal models, increased levels of VEGF can persist for up to 2 weeks after an injury. METHODS: Through abdominal surgery, the dorsal root ganglia (DRG) innervating L5/L6 intervertebral disc were labeled (FluoroGold neurotracer) in 24, 8-week old Sprague Dawley rats. The rats were randomly allocated to three groups of eight rats each. The anti-VEGF group underwent L5/6 intervertebral disc puncture using a 26-gauge needle, intradiscal injection of 33.3 µg of the pegaptanib sodium, a VEGF165 aptamer. The control-puncture group underwent disc puncture and intradiscal injection of 10 µL saline solution, and the sham-surgery group underwent labeling but no disc puncture. Two rats in each group were sacrificed on postoperative days 1, 7, 14, and 28 after surgery. L1-L6 DRGs were harvested, sectioned, and immunostained to detect the content and distribution of CGRP. RESULTS: Compared with the control, the percentage of CGRP-positive cells was lower in the anti-VEGF group (p<0.05; 40.6% and 58.1% on postoperative day 1, 44.3% and 55.4% on day 7, and 42.4% and 59.3% on day 14). The percentage was higher in the control group compared with that of the sham group (p<0.05; sham group, 34.1%, 40.7%, and 33.7% on postoperative days 1, 7, and 14, respectively). CONCLUSIONS: Decreasing CGRP-positive cells using anti-VEGF therapy provides fundamental evidence for a possible therapeutic role of anti-VEGF in patients with discogenic lower back pain.

Correlation among Inflammatory Cytokine Expression Levels, Degree of Disk Degeneration, and Predominant Clinical Symptoms in Patients with Degenerated Intervertebral Discs.

STUDY DESIGN: Observational study. PURPOSE: To assess the correlation among inflammatory cytokine expression levels, degree of intervertebral disk (IVD) degeneration, and predominant clinical symptoms observed in degenerative disk disease (DDD). OVERVIEW OF LITERATURE: Low back pain (LBP) is associated with inflammatory cytokine expression levels, including those of tumor necrosis factor-alpha (TNF-α), interleukin 6 (IL-6), and nerve growth factor (NGF). However, the association between cytokine expression levels and the physiological mechanisms of disk degeneration and clinical pain remain controversial. METHODS: Using the enzyme-linked immunosorbent assay, TNF-α, IL-6, and NGF expression levels were analyzed in 58 IVD samples that were harvested from patients with lumbar DDD. Patient samples were grouped according to the degree of IVD degeneration using the Pfirrmann grading system and magnetic resonance imaging, and the correlations between the disease groups and each cytokine expression level were assessed. In addition, on the basis of their predominant preoperative symptoms, the patients were assigned to either an LBP or leg pain group to determine the correlation among these disease manifestations and individual cytokine expression levels. RESULTS: A gradual increase in TNF-α (R=0.391) and IL-6 (R=0.388) expression levels correlated with the degree of IVD degeneration, whereas NGF (R=0.164) expression levels exhibited a minimal decrease with disease progression. Regarding the predominant clinical manifestation, only the LBP group exhibited a significant increase in TNF-α expression levels (p=0.002). CONCLUSIONS: These results suggested that TNF-α and IL-6 play an important role in the pathophysiology of IVD degeneration at any stage, whereas NGF plays an important role during the early disease stages. Moreover, because TNF-α expression levels were significantly high in the LBP group, we propose that they are involved in LBP onset or progression.

Long-Term Outcomes of In Situ Fusion for Treating Dysplastic Spondylolisthesis.

STUDY DESIGN: Retrospective, observational, single-center study. PURPOSE: To investigate the long-term outcomes of in situ fusion procedures for treating dysplastic spondylolisthesis. OVERVIEW OF LITERATURE: In situ fusion performed in patients with dysplastic spondylolisthesis avoids the development of nerve complications. METHODS: In total, 12 of 28 patients who underwent in situ fusion for treating dysplastic spondylolisthesis at Chiba University Hospital from 1974 to 2004 were followed up in August 2013. Surgical complications were evaluated. Low back pain and leg pain were assessed using a visual analog scale (VAS). Vertebral alignment, including the lumbosacral angle and lumbar lordosis angle measurement on radiographic images (profile view in the neutral standing position), was evaluated during preoperative, postoperative, and final examinations. RESULTS: The mean follow-up duration, patient age at the final examination, and patient age at operation were 20.0±7.2, 42.3±13.3, and 22.3±11.4 years, respectively. No complications were reported. Mean VAS scores for low back pain and leg pain were significantly lower at the final examination than at the preoperative examination (p<0.05). At the preoperative, postoperative, and final examinations, the mean lumbosacral angle was 32.3°±14.2°, 33.7°±11.8°, and 36.5°±16.4°, while the mean lumbar lordosis angle was 51.0°±14.8°, 48.6°±18.8°, and 49.6°±15.5°, respectively. No significant differences were noted among these values across the different time periods (p<0.05). CONCLUSIONS: In situ fusion performed in patients with dysplastic spondylolisthesis avoids the development of nerve complications such as nerve paralysis that may occur after repositioning operation and maintains appropriate long-term sagittal alignment, even 20 years after operation.

Anatomical evaluation of lumbar nerves using diffusion tensor imaging and implications of lateral decubitus for lateral transpsoas approach.

PURPOSE: Recently, lateral interbody fusion (LIF) has become more prevalent, and evaluation of lumbar nerves has taken on new importance. We report on the assessment of anatomical relationships between lumbar nerves and vertebral bodies using diffusion tensor imaging (DTI). METHODS: Fifty patients with degenerative lumbar disease and ten healthy subjects underwent DTI. In patients with lumbar degenerative disease, we studied nerve courses with patients in the supine positions and with hips flexed. In healthy subjects, we evaluated nerve courses in three different positions: supine with hips flexed (the standard position for MRI); supine with hips extended; and the right lateral decubitus position with hips flexed. In conjunction with tractography from L3 to L5 using T2-weighted sagittal imaging, the vertebral body anteroposterior span was divided into four equally wide zones, with six total zones defined, including an anterior and a posterior zone (zone A, zones 1-4, zone P). We used this to characterize nerve courses at disc levels L3/4, L4/5, and L5/S1. RESULTS: In patients with degenerative lumbar disease, in the supine position with hips flexed, all lumbar nerve roots were located posterior to the vertebral body centers in L3/4 and L4/5. In healthy individuals, the L3/4 nerve courses were displaced forward in hips extended compared with the standard position, whereas in the lateral decubitus position, the L4/5 and L5/S nerve courses were displaced posteriorly compared with the standard position. CONCLUSIONS: The L3/4 and L4/5 nerve roots are located posterior to the vertebral body center. These were found to be offset to the rear when the hip is flexed or the lateral decubitus position is assumed. The present study is the first to elucidate changes in the course of the lumbar nerves as this varies by position. The lateral decubitus position or the position supine with hips flexed may be useful for avoiding nerve damage in a direct lateral transpsoas approach. Preoperative DTI seems to be useful in evaluating the lumbar nerve course as it relates anatomically to the vertebral body.

Evaluation of Histological Changes in Back Muscle Injuries in Rats over Time.

STUDY DESIGN: Animal model study. PURPOSE: The purpose of this study was to evaluate the histological variation in the injured muscle and production of calcitonin gene-related peptide in rats over time. OVERVIEW OF LITERATURE: Vertebral surgery has been reported to cause atrophy of the back muscles, which may result in pain. However, few reports have described the time series histological variation in the injured muscle and changes in the dominant nerve. METHODS: We used 30 male, 8-week-old Sprague-Dawley rats. The right and left sides of the paravertebral muscle were considered as the injured and uninjured sides, respectively. A 115 g weight was dropped from a height of 1 m on the right paravertebral muscle. Hematoxylin and eosin (H&E) staining of the muscle was performed 1-3 weeks after injury for histological evaluation. Fluoro-Gold (FG) was injected into the paravertebral muscle. The L2 dorsal root ganglia on both sides were resected 1, 2, and 3 weeks after injury, and immunohistochemical staining for calcitonin gene-related peptide was performed. RESULTS: H&E staining of the paravertebral muscle showed infiltration of inflammatory cells and the presence of granulation tissue in the injured part on the ipsilateral side 1 week after injury. Muscle atrophy occurred 3 weeks after injury, but was repaired via spontaneous replacement of muscle cells/fibers. In contrast, compared with the uninjured side, the percentage of cells double-labeled with FG and calcitonin gene-related peptide in FG-positive cells in the dorsal root ganglia of the injured side was significantly increased at each time point throughout the study period. CONCLUSIONS: These results suggest that sensitization of the dominant nerve in the dorsal root ganglia, which may be caused by cicatrix formation, can protract injured muscle pain. This information may be helpful in elucidating the underlying mechanism of persistent pain after back muscle injury.

Oriented collagen tubes combined with basic fibroblast growth factor promote peripheral nerve regeneration in a 15 mm sciatic nerve defect rat model.

We developed a new scaffold material-oriented collagen tubes (OCT)-and evaluated the potential of OCTs combined with basic fibroblast growth factor (bFGF) to repair of a 15 mm sciatic nerve defect in rats. The treatment groups consisted of OCT with adsorbed bFGF (OCT/bFGF group), OCT in phosphate-buffered saline (PBS) (OCT/PBS group), and a no-treatment group (Defect group). Functional evaluation of nerve regeneration was performed using the CatWalk system, and histological analyses of the defect sites were also performed. In rats treated with either OCT/bFGF or OCT/PBS, the walking function parameter of max contact area returned to normal levels by 4 weeks after grafting, and the regeneration of myelinated fibers was detected after 8 weeks. However, more regenerated myelinated fibers were observed in the OCT/bFGF group compared with the OCT/PBS group at 4 weeks. In addition, the max contact area and swing speed in the OCT/bFGF group were significantly recovered compared to the OCT/PBS and Defect groups at 8 weeks. Although the combination of bFGF and OCT was superior to OCT alone for nerve regeneration and functional recovery, the present findings demonstrate that OCT alone or in combination with bFGF accelerates nerve repair in a large peripheral nerve defect in rats. © 2016 Wiley Periodicals, Inc. J Biomed Mater Res Part A: 105A: 8-14, 2017.

Dose Optimization for Single Intradiscal Administration of the Tumor Necrosis Factor-α Inhibitor, Etanercept, in Rat Disc Injury Models.

STUDY DESIGN: Experimental animal study. PURPOSE: We aimed to determine the optimal dose of a single direct injection of the tumor necrosis factor (TNF)-α inhibitor, etanercept, by using the rat model of degenerative intervertebral disc from injury. OVERVIEW OF LITERATURE: The pain-related peptide expression was suppressed in the etanercept (100 µg and 1,000 µg)-administered groups in a dose-dependent manner. METHODS: The neurotracer FluoroGold (FG) was applied to the surfaces of L4/5 discs to label their innervating dorsal root ganglion (DRG) neurons (n=50). Ten rats were included in the nonpunctured disc sham surgery control group, whereas the other 40 were included in the experimental group in which intervertebral discs were punctured with a 23-gauge needle. Saline or etanercept (10 µg, 100 µg, or 1,000 µg) was injected into the punctured discs (n=10 for each treatment). After 14 days of surgery, DRGs from L1 to L6 were harvested, sectioned, and immunostained for calcitonin gene-related peptide (CGRP). The proportion of FG-labeled CGRP-immunoreactive DRG neurons was evaluated in all the groups. RESULTS: There were no significant differences between the puncture+saline group and the puncture+10-µg etanercept group (p >0.05). However, a significant decrease in the percentage of FG and CGRP double-positive cells in FG-positive cells was observed in the etanercept (100 µg and 1,000 µg)-administered groups in a dose-dependent manner (p <0.05). CONCLUSIONS: When a low dose of the TNF-α inhibitor (10 µg of etanercept) was directly administered to the rat intervertebral disc in the rat model of degenerative intervertebral disc from injury, no suppressive effect on the pain-related peptide expression was observed. However, when a higher dose of etanercept (100 µg and 1,000 µg) was administered, the pain-related peptide expression was suppressed in a dose-dependent manner.

Low-Dose Tramadol and Non-Steroidal Anti-Inflammatory Drug Combination Therapy Prevents the Transition to Chronic Low Back Pain.

STUDY DESIGN: Retrospective study. PURPOSE: To determine whether low-dose tramadol plus non-steroidal anti-inflammatory drug combination therapy could prevent the transition of acute low back pain to chronic low back pain. OVERVIEW OF LITERATURE: Inadequately treated early low back pain transitions to chronic low back pain occur in approximately 30% of affected individuals. The administration of non-steroidal anti-inflammatory drugs is effective for treatment of low back pain in the early stages. However, the treatment of low back pain that is resistant to non-steroidal anti-inflammatory drugs is challenging. METHODS: Patients who presented with acute low back pain at our hospital were considered for inclusion in this study. After the diagnosis of acute low back pain, non-steroidal anti-inflammatory drug administration was started. Forty patients with a visual analog scale score of >5 for low back pain 1 month after treatment were finally enrolled. The first 20 patients were included in a non-steroidal anti-inflammatory drug group, and they continued non-steroidal anti-inflammatory drug therapy for 1 month. The next 20 patients were included in a combination group, and they received low-dose tramadol plus non-steroidal anti-inflammatory drug combination therapy for 1 month. The incidence of adverse events and the improvement in the visual analog scale score at 2 months after the start of treatment were analyzed. RESULTS: No adverse events were observed in the non-steroidal anti-inflammatory drug group. In the combination group, administration was discontinued in 2 patients (10%) due to adverse events immediately following the start of tramadol administration. At 2 months, the improvement in the visual analog scale score was greater in the combination group than in the non-steroidal anti-inflammatory drug group (p<0.001). CONCLUSIONS: Low-dose tramadol plus non-steroidal anti-inflammatory drug combination therapy might decrease the incidence of adverse events and prevent the transition of acute low back pain to chronic low back pain.

Pregabalin for Refractory Radicular Leg Pain due to Lumbar Spinal Stenosis: A Preliminary Prospective Study.

We investigated the efficacy of pregabalin (PGB) for neuropathic leg pain in lumbar spinal stenosis (LSS) patients with disturbed activities of daily living (ADL)/quality of life (QOL) in a prospective observational study. Subjects were a total of 104 LSS patients with neuropathic pain (NeP) in leg and neurological intermittent claudication (IMC) refractory to nonsteroidal anti-inflammatory drugs (NSAIDs) for at least a month. NeP was identified using screening tool, Pain DETECT questionnaire. Visual analog scale (VAS) scores and responses to the Japanese Orthopaedic Association Back Pain Evaluation Questionnaire (JOABPEQ) were assessed before and 6 weeks after PGB treatment initiation. Changes in IMC distance and adverse events were also recorded. PGB significantly improved their VAS scores for pain and sleep quality (P < 0.001). With respect to JOABPEQ, significant improvements were observed with regard to the following dimensions: pain-related disorders (P < 0.01), lumbar spine dysfunction (P = 0.031), gait disturbance (P = 0.028), and psychological disorders (P = 0.014). The IMC distance showed an improvement tendency after PGB treatment, albeit with no significance (P = 0.063). Minor adverse events such as dizziness were observed. PGB can be effective for neuropathic leg pain refractory to NSAIDs in LSS patients, resulting in not only pain control but also improving lower back pain-related ADL/QOL scores.

The efficacy of nerve growth factor antibody in a mouse model of neuropathic cancer pain.

Neuropathic cancer pain is caused by tumors compressing the spinal nerve roots and is usually difficult to treat. The aim of current study was to determine the influence of NGF antibody on pain-related markers and behavior in a mouse model of neuropathic cancer pain. Twenty mice were used to model neuropathic cancer pain by applying murine sarcoma cells to their left sciatic nerve. Ten mice were sham operated. Two weeks after surgery, the murine sarcoma-affected mice were allocated randomly into treatment groups receiving either sterile saline (saline group) or an anti-nerve growth factor antibody (anti-NGF group). Three weeks after surgery (a week after treatment), the pain-related behavior of mice was evaluated using a CatWalk system. Subsequently, bilateral dorsal root ganglia (DRGs) from the L4-L6 levels and spinal cords at L4-L6 levels were resected. DRGs were immunostained for calcitonin gene-related peptide (CGRP) and activating transcription factor 3 (ATF-3), and spinal cords were immunostained for ionized calcium-binding adaptor molecule-1 (iba-1). Mechanical allodynia was observed in mice from the saline group and was improved in mice from the anti-NGF group. CGRP and ATF-3-immunoreactivity in DRGs and microglia expression in the spinal dorsal horn were upregulated in the saline group compared with the sham group, and they were suppressed in the anti-NGF group compared with the saline group (P<0.05). These findings suggest that anti-NGF therapy might be valuable for treating neuropathic cancer pain.

One-Year Prospective Evaluation of the Technique of Percutaneous Cortical Bone Trajectory Spondylodesis in Comparison with Percutaneous Pedicle Screw Fixation: A Preliminary Report with Technical Note.

Background and Objective Cortical bone trajectory (CBT) spondylodesis is a novel screw fixation method in which screws are inserted through the pedicle in a caudal-medial to cephalad-lateral direction, providing a similar or more rigid spinal fixation compared with traditional pedicle screws. However, the traditional CBT technique requires invasive detaching and opening of the paraspinal muscle. In a small clinical prospective study we introduced a percutaneous CBT fixation technique by modifying the percutaneous pedicle screw (PPS) technique and evaluated the short-term outcome. Materials and Methods We enrolled 40 patients with lower back pain (LBP) and limb r;adicular pain with a diagnosis of spondylolisthesis who underwent transforaminal lumbar interbody fusion surgery. The patients were divided into two groups according to screw trajectory: the percutaneous CBT (pCBT) and the traditional PPS arms (20 patients in each). A consecutive group of 20 patients underwent traditional PPS, and the other underwent pCBT; dorsal spondylodesis was combined with transforaminal lumbar interbody fusion (TLIF) in both groups. Perioperative data such as operative time, blood loss, duration of fluoroscopy, and total incision length were investigated. Postoperative outcomes were evaluated using the visual analog scale (VAS) for LBP and leg pain at baseline, 1, 6, and 12 months. A p value < 0.05 was considered statistically significant. Results We observed no significant disadvantages in pCBT patients in perioperative and postoperative data compared with the PPS group. There were no complications. The pCBT patients showed a significantly shorter total incision length (p < 0.01) with a significantly shorter duration of fluoroscopy (p < 0.05). The postoperative VAS score was significantly improved in the pCBT group, especially 6 months after the surgery (p < 0.05). Conclusion The pCBT spondylodesis provided an outcome comparable with PPS fixation with a tendency for improvement 1 year postsurgery. This technique can be used in appropriate cases, combined with lumbar interbody fusion.

Efficacy of Anti-NaV1.7 Antibody on the Sensory Nervous System in a Rat Model of Lumbar Intervertebral Disc Injury.

PURPOSE: The pathophysiology of discogenic low back pain is not fully understood. Tetrodotoxin-sensitive voltage-gated sodium (NaV) channels are associated with primary sensory nerve transmission, and the NaV1.7 channel has emerged as an analgesic target. Previously, we found increased NaV1.7 expression in dorsal root ganglion (DRG) neurons innervating injured discs. This study aimed to examine the effect of blocking NaV1.7 on sensory nerves after disc injury. MATERIALS AND METHODS: Rat DRG neurons innervating the L5/6 disc were labeled with Fluoro-Gold (FG) neurotracer. Twenty-four rats underwent intervertebral disc puncture (puncture group) and 12 rats underwent sham surgery (non-puncture group). The injury group was divided into a saline infusion group (puncture+saline group) and a NaV1.7 inhibition group, injected with anti-NaV1.7 antibody (puncture+anti-NaV1.7 group); n=12 per group. Seven and 14 days post-surgery, L1 to L6 DRGs were harvested and immunostained for calcitonin gene-related peptide (CGRP) (an inflammatory pain marker), and the proportion of CGRP-immunoreactive (IR) DRG neurons of all FG-positive neurons was evaluated. RESULTS: The ratio of CGRP-IR DRG neurons to total FG-labeled neurons in the puncture+saline group significantly increased at 7 and 14 days, compared with the non-puncture group, respectively (p<0.05). Application of anti-NaV1.7 into the disc significantly decreased the ratio of CGRP-IR DRG neurons to total FG-labeled neurons after disc puncture at 7 and 14 days (40% and 37%, respectively; p<0.05). CONCLUSION: NaV1.7 antibody suppressed CGRP expression in disc DRG neurons. Anti-NaV1.7 antibody is a potential therapeutic target for pain control in patients with lumbar disc degeneration.

Muscle injury in rats induces upregulation of inflammatory cytokines in injured muscle and calcitonin gene-related peptide in dorsal root ganglia innervating the injured muscle.

INTRODUCTION: In this study we evaluated the relationships among the behavioral changes after muscle injury, histological changes, changes in inflammatory cytokines in the injured muscle, and changes in the sensory nervous system innervating the muscle in rats. METHODS: We established a model of muscle injury in rats using a dropped weight. Behavior was assessed using the CatWalk system. Subsequently, bilateral gastrocnemius muscles and dorsal root ganglia (DRGs) were resected. Muscles were stained with hematoxylin and eosin, and inflammatory cytokines in injured muscles were assayed. DRGs were immunostained for calcitonin gene-related peptide (CGRP). RESULTS: Changes of behavior and upregulation of inflammatory cytokines in injured muscles subsided within 2 days of injury. Repaired tissue was observed 3 weeks after injury. However, upregulation of CGRP in DRG neurons continued for 2 weeks after injury. CONCLUSION: These findings may explain in part the pathological mechanism of persistent muscle pain. Muscle Nerve 54: 776-782, 2016.