Inhibiting IκB kinase-ß downregulates inflammatory cytokines in injured discs and neuropeptides in dorsal root ganglia innervating injured discs in rats.

STUDY DESIGN: Quantitative and immunohistological analysis of the efficacy of an IκB kinase-ß (IKKß) inhibitor in an injured intervertebral disc (IVD) model. OBJECTIVE: To elucidate the efficacy of an IKKß inhibitor on inflammatory cytokine levels in injured IVDs or on neuropeptide levels in the dorsal root ganglia (DRG) neurons innervating injured IVDs in rats. SUMMARY OF BACKGROUND DATA: Multiple studies have suggested that upregulation of inflammatory cytokines in damaged IVDs causes discogenic low back pain. The efficacy of blocking individual inflammatory cytokines is limited; however, inflammatory cytokine stimuli often require IKKß to activate nuclear factor-k B. METHODS: Sprague-Dawley rats were divided into 3 groups: sham, saline (disc-injury plus saline), and IKKß (disc-injury plus anti-IKKß). To induce injury, IVDs were repeatedly punctured.Experiment 1: Four, 7, and 14 days postinjury, coccygeal (Co) 5/6, Co6/7, and Co7/8 IVDs were resected and tumor necrosis factor-α, interleukin (IL)-1ß, and IL-6 levels were quantified by enzyme-linked immunosorbent assay. Experiment 2: The neurotracer Fluoro-Gold was injected into injured L5-L6 IVDs and uninjured sham group IVDs to detect DRG neurons. One week postsurgery, L1-L6 DRGs were immunolabeled with the neuropeptide calcitonin gene-related peptide. The proportions of Fluoro-Gold-labeled calcitonin gene-related peptide-immunoreactive DRG neurons were assessed. RESULTS: Experiment 1: IVD levels of tumor necrosis factor-α (through 2 wk), IL-1ß (at 4 d), and IL-6 (at 4 d) were significantly higher in the saline group than in the sham group, and significantly lower in the IKKß group than in the saline group (P < 0.05). Experiment 2: The percentage of calcitonin gene-related peptide-immunoreactive Fluoro-Gold-labeled DRG neurons was significantly higher in the saline group than in the sham group, and significantly lower in the IKKß group than in the saline group (P < 0.05). CONCLUSION: Injury-induced upregulation of inflammatory cytokines within IVDs and increased levels of neuropeptides within DRG neurons can be suppressed by inhibiting IKKß. LEVEL OF EVIDENCE: N/A.

Vertebral compression exacerbates osteoporotic pain in an ovariectomy-induced osteoporosis rat model.

STUDY DESIGN: Basic pain study using osteoporotic rodent models. OBJECTIVE: To examine alterations in distribution of pain-related neuropeptides after compressive force on osteoporotic vertebrae and their chronic pain-related properties. SUMMARY OF BACKGROUND DATA: We previously reported significantly increased production of calcitonin gene-related peptide (CGRP), a marker of inflammatory pain, in the dorsal root ganglia (DRG) of vertebrae in osteoporosis-model ovariectomized (OVX) rats. Here, we hypothesized that longitudinal compressive force on vertebrae can affect osteoporotic pain properties, which has not been examined yet. METHODS: OVX rats were used as the osteoporosis model. Female Sprague-Dawley rats were prepared and Fluoro-Gold (FG) neurotracer was applied to the periosteal surface of the Co5 vertebra. After FG labeling, the animals were divided into 4 groups: Control, Control + compression, OVX, and OVX + compression. The Control groups were not ovariectomized. In the compression groups, K-wires were stabbed transversely through Co4 and Co6 with Co5 compressed longitudinally by rubber bands bridged between the 2. One, 2, 4, and 8 weeks after surgery, bilateral S1 to S3 DRGs were excised for immunofluorescence assays. Expression of CGRP and activating transcription factor 3, a marker of neuronal injury, were compared among the 4 groups. RESULTS: Sustained upregulation of CGRP in DRG neurons was observed after compression of the Co5 vertebra, and Co5 compression caused significant increase in CGRP production in DRG neurons, whereas a greater level of activating transcription factor 3 upregulation was observed in DRGs in OVX rats after dynamic vertebral compression 8 weeks after surgery, implying potential neuropathic pain. CONCLUSION: There was sustained upregulation of CGRP and activating transcription factor 3 in DRGs in osteoporotic model rats compared with controls, and levels were further enhanced by dynamic vertebral compression. These findings imply that dynamic compression stress on vertebrae can exacerbate osteoporotic pain by inducing both inflammatory and neuropathic pain mediators. LEVEL OF EVIDENCE: N/A.

The effect of platelet-rich plasma on posterolateral lumbar fusion in a rat model.

BACKGROUND: Our purpose was to examine platelet-rich plasma (PRP) for its effect on bone formation and to follow the immunohistochemical changes in calcitonin gene-related peptide (CGRP) in dorsal root ganglion neurons innervating the discs as a possible index of nociceptive nerve transmission in a rat model. METHODS: A total of seventy rats were used. Ten constituted a non-punctured disc sham group, while another ten rats constituted a group that underwent puncture of the L4-L5 discs. Forty rats were in experimental groups in which the L4-L5 discs were punctured; posterolateral lumbar arthrodesis was performed with PRP (the PRP group) or without the use of PRP (the normal arthrodesis group), with twenty rats in each group. The remaining ten rats were used as blood donors. Four and eight weeks after surgery, microcomputed tomography examinations were done to evaluate the amount of bone and the L4-L5 spines were harvested to evaluate bone union, followed by resection of dorsal root ganglion neurons. The percentages of Fluoro-Gold-labeled and CGRP-immunoreactive neurons were calculated. RESULTS: The platelet count and the concentration of growth factors in PRP were higher than those in blood (p < 0.05). The bone volumes observed in the PRP group were significantly greater than those of the normal arthrodesis group at four and eight weeks (p < 0.05). Three (30%; 95% confidence interval [CI], 6% to 65%) of ten rats in the normal arthrodesis group and eight (80%; 95% CI, 44% to 98%) of ten rats in the PRP group were considered to have bone fusion four weeks after surgery (p < 0.05). At eight weeks, seven (70%; 95% CI, 34% to 94%) of ten rats in the normal arthrodesis group and nine (90%; 95% CI, 55% to 99%) of ten rats in the PRP group were considered to have bone fusion (p = 0.27). The proportion of CGRP-immunoreactive neurons was significantly greater in the punctured group than in the other groups. There were no significant differences between the normal arthrodesis group and the PRP group. CONCLUSIONS: PRP appears to promote bone formation in rats and has a tendency to shorten the period of bone union in this rat model of posterolateral lumbar arthrodesis, but it did not influence the proportion of CGRP-immunoreactive neurons, a likely indicator of inflammatory pain originating from the degenerative intervertebral disc. CLINICAL RELEVANCE: The ability of PRP in this model suggests that it may be able to shorten the period of union and lead to an early return to social activities after treatment.

Comparison of CatWalk analysis and von Frey testing for pain assessment in a rat model of nerve crush plus inflammation.

STUDY DESIGN: Assessment of pain-related behavior and immunohistology of the dorsal root ganglion in a rat model. OBJECTIVE: To investigate pain-related behavior in a rat model of nerve crush plus inflammation using the CatWalk system. SUMMARY OF BACKGROUND DATA: A definitive method for evaluating animal models of lumbar disease has not been established. Von Frey testing has often been used in this type of study, but the reliability remains in question. The CatWalk system is a computer-assisted apparatus for analyzing gait that provides an automated way to assess gait function during pain. However, there have been few reports using this system for models of lumbar disease. METHODS: Fourteen rats were divided into 2 groups: a treatment group and a sham group. For the treatment group, nucleus pulposus was applied to the sciatic nerve and the sciatic nerve was pinched. Two different methods for assessment of pain-related behavior, von Frey testing and CatWalk analysis, were used before surgery and at 4 and 7 days after surgery. Immunohistochemistry was used to examine calcitonin gene-related peptide expression in L4 to L6 dorsal root ganglia. RESULTS: No significant differences were found between the treatment and sham control groups using von Frey testing. However, significant differences in 4 parameters were found between the 2 groups using the CatWalk system (P < 0.05). The proportion of calcitonin gene-related peptide-immunoreactive neurons was higher in the treatment group than in the control group (P < 0.05). CONCLUSION: Our results demonstrate that the CatWalk system is useful for the measurement of pain-related behavioral change in our rat model in which nociception was indicated at a cellular level. Although further studies are needed, we think that this system is a valid alternative method for the evaluation of models of lumbar disease in rodents.

In-vivo transfection of the proopiomelanocortin gene, precursor of endogenous endorphin, by use of radial shock waves alleviates neuropathic pain.

BACKGROUND: Neuropathic pain is difficult to control and patient response to current treatment is often inadequate. Opioids have been widely used to treat a variety of pain states, but have several side effects. Endogenous opioids are clinically safe, but are not used for treatment because of rapid metabolism. However, in-vivo transfection of endogenous opioid genes could have a powerful and safe analgesic effect. The purpose of this study was to investigate the efficacy of proopiomelanocortin (POMC, a precursor of the endogenous opioid peptide ß-endorphin) gene transfer by use of radial shock waves (RSWs) in a rat neuropathic pain model. METHODS: As a neuropathic pain model, we used the Bennett chronic constriction injury (CCI) method. Immediately after CCI induction, POMC plasmid was injected into the rats' gastrocnemius muscle followed by exposure to RSW. Mechanical allodynia was measured for 4 weeks and dorsal root ganglion (DRG) neurons were sectioned and immunostained. RESULTS: ß-Endorphin blood levels and the number of ß-endorphin-immunoreactive (IR) muscle fibers increased over 28 days. ß-Endorphin overexpression caused a decrease in the number of calcitonin gene-related peptide (CGRP)-IR DRG neurons and suppressed neuropathic pain induced by CCI without causing adverse side effects. The size-distribution pattern of CGRP-IR DRG neurons shifted from small to large cells in the CCI group; however, the number of both small and large CGRP-IR cells decreased in the POMC group. CONCLUSION: POMC gene transfection alleviated allodynia and reduced CGRP expression in DRG neurons without adverse effects. CGRP is not produced in large neurons under physiologic conditions; however, in this study CGRP expression was shifted to large neurons after nerve injury. This change in cell-size distribution suggests that CGRP expression in large neurons is related to neuropathic pain. These findings suggest that POMC gene transfection using RSWs is a safe and effective treatment for neuropathic pain.

Additional decompression at adjacent segments leads to adjacent segment degeneration after PLIF.

PURPOSE: Adjacent segment degeneration (ASD) is one of the major complications of lumbar fusion. Several previous retrospective studies reported ASD after PLIF. However, few reports evaluated whether decompression surgery combined with fusion surgery increases the rate of complications in adjacent segments. The purpose of the current study was to investigate the degeneration in decompressed adjacent segments after PLIF. METHODS: A total of 23 patients (12 men, 11 women; average age, 58.6) who underwent PLIF surgery [1 level (n = 9), 2 levels (n = 8), 3 levels (n = 4), 4 levels (n = 2)] were included. Additional adjacent decompression above or below the level of interbody fusion was performed at 25 levels and no adjacent decompression was performed at 15 levels. We retrospectively investigated ASD by X-ray films of all 40 adjacent segments (above and below fusion level) and clinical outcomes of all 23 cases. RESULTS: Of the 40 adjacent segments, 19 (47.5%) showed ASD and 9 (22.5%) showed symptomatic ASD. In the 19 segments with ASD, ASD occurred in 16 of 25 (64.0%) segments at decompressed sites compared with 3 of 15 (20.0%) non-decompressed sites. The ratio of ASD in adjacent segments was significantly higher at decompressed sites than at non-decompressed sites (p < 0.01). CONCLUSION: ASD occurs frequently in association with additional decompression above or below the level of PLIF. In cases in which the adjacent segments require decompression, a surgical strategy that preserves as much of the posterior complex as possible should be selected.

Tumor necrosis factor-α-immunoreactive cells in nucleus pulposus in adolescent patients with lumbar disc herniation.

STUDY DESIGN: Immunohistochemistry for tumor necrosis factor (TNF)-α in nucleus pulposus of adolescent patients with lumbar disc herniation. OBJECTIVE: To examine whether an inflammatory cytokine is expressed in the nucleus pulposus of adolescent patients with lumbar disc herniation. SUMMARY OF BACKGROUND DATA: TNFα is thought to play a crucial role in the radicular pain caused by lumbar disc herniation in adult patients. However, the expression of TNFα in the nucleus pulposus of adolescent patients with lumbar disc herniation has not been explored. METHODS: Five samples of nucleus pulposus from adolescent patients with lumbar disc herniation (age, 12-16 yr; n = 5) or controls requiring surgery for other back problems (age, 12-16 yr; n = 4; nonpainful scoliosis) were harvested during surgery. Nucleus pulposus specimens were immunostained using TNFα antibodies and immunostained cells in the nucleus pulposus were counted. We compared the expression of TNFα between the 2 groups. RESULTS: In patients with lumbar disc herniation, more TNFα-immunoreactive cells were seen in the nucleus pulposus in comparison with patients with nonpainful scoliosis (P < 0.01). CONCLUSION: The results suggest that TNFα may play a role in adolescent patients with lumbar disc herniation. The TNFα expression may be related with disc degeneration and pain in adolescent patients with lumbar disc herniation.

Differences between tumor necrosis factor-α receptors types 1 and 2 in the modulation of spinal glial cell activation and mechanical allodynia in a rat sciatic nerve injury model.

STUDY DESIGN: Immunohistological analysis of spinal glial cells and analysis of pain behavior in the rat neuropathic pain model were investigated to clarify the function of tumor necrosis factor (TNF)-α receptors p55 type 1 and p75 type 2. OBJECTIVE: Our objective was to investigate changes in hyperalgesia and glial cell activation after injection of antibodies to each TNF receptor in a rat sciatic nerve injury model. SUMMARY OF BACKGROUND DATA: Recent research has revealed that activation of spinal glia plays an important role in radicular and neuropathic pain. TNF-α is reportedly a modulator for glial cell activation; however, the precise relationship between TNF-α and its 2 receptors on glial cells has not been fully delineated. METHODS: Chronic constriction sciatic nerve injury and sham-operated rats were used. Antibodies to p55 or p75 or saline were intrathecally injected at the L5 level into rats with chronic constriction injury. Mechanical allodynia was examined for 2 weeks. Spinal cords were removed for immunohistochemical studies of ionized calcium-binding adaptor molecule 1 or glial fibrillary acidic protein. RESULTS: Saline rats showed significantly more mechanical allodynia and the number of ionized calcium-binding adaptor molecule 1--immunoreactive microglia and glial fibrillary acidic protein--immunoreactive astrocytes were significantly increased in the saline rats compared with sham-operated rats during the 2 weeks. Injection of both antibodies significantly reduced pain behavior and anti-p55 caused significantly greater reduction compared with anti-p75. The numbers of microglia in both the antibodies groups were significantly decreased when compared with the saline group. In addition, the anti-p55 antibody suppressed microglial activation more than the anti-p75 antibody. CONCLUSION: These results indicate that the microglial TNF-α p55 pathway played a more important role than the TNF-α p75 pathway in the pathogenesis of peripheral nerve injury pain. This suggests that future studies seeking to clarify neuropathic pain should target TNF-α and p55 receptors in microglia.

Transdermal fentanyl for chronic low back pain.

PURPOSE: Chronic low back pain is a common clinical problem. As medication, non-steroidal anti-inflammatory drugs are generally used; however, they are sometimes non-effective. Recently, opioids have been used for the treatment of chronic low back pain, and since 2010, transdermal fentanyl has been used to treat chronic non-cancer pain in Japan. The purpose of the current study was to examine the efficacy of transdermal fentanyl in the treatment of chronic low back pain. MATERIALS AND METHODS: This study included patients (n=62) that suffered from chronic low back pain and were non-responsive to non-steroidal anti-inflammatory drugs. Their conditions consisted of non-specific low back pain, multiple back operations, and specific low back pain awaiting surgery. Patients were given transdermal fentanyl for chronic low back pain. Scores of the visual analogue scale and the Oswestry Disability Index, as well as adverse events were evaluated before and after therapy. RESULTS: Overall, visual analogue scale scores and Oswestry Disability Index scores improved significantly after treatment. Transdermal fentanyl (12.5 to 50 µg/h) was effective in reducing low back pain in 45 of 62 patients; however, it was not effective in 17 patients. Patients who experienced the most improvement were those with specific low back pain awaiting surgery. Adverse events were seen in 40% of patients (constipation, 29%; nausea, 24%; itching, 24%). CONCLUSION: Transdermal fentanyl significantly improved visual analog scale scores and Oswestry Disability Index scores in 73% of patients, especially those with specific low back pain awaiting surgery; however, it did not decrease pain in 27% of patients, including patients with non-specific low back pain or multiple back operations.

Existence of a neuropathic pain component in patients with osteoarthritis of the knee.

PURPOSE: Pain from osteoarthritis (OA) is generally classified as nociceptive (inflammatory). Animal models of knee OA have shown that sensory nerve fibers innervating the knee are significantly damaged with destruction of subchondral bone junction, and induce neuropathic pain (NP). Our objective was to examine NP in the knees of OA patients using painDETECT (an NP questionnaire) and to evaluate the relationship between NP, pain intensity, and stage of OA. MATERIALS AND METHODS: Ninety-two knee OA patients were evaluated in this study. Pain scores using Visual Analogue Scales (VAS), Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC), painDETECT, duration of symptoms, severity of OA using the Kellgren-Lawrence (KL) system, and amount of joint fluid were evaluated and compared using a Spearman's correlation coefficient by rank test. RESULTS: Our study identified at least 5.4% of our knee OA patients as likely to have NP and 15.2% as possibly having NP. The painDETECT score was significantly correlated with the VAS and WOMAC pain severity. Compared with the painDETECT score, there was a tendency for positive correlation with the KL grade, and tendency for negative correlation with the existence and amount of joint fluid, but these correlations were not significant. CONCLUSION: PainDETECT scores classified 5.4% of pain from knee OA as NP. NP tended to be seen in patients with less joint fluid and increased KL grade, both of which corresponded to late stages of OA. It is important to consider the existence of NP in the treatment of knee OA pain.

Difficulty of diagnosing the origin of lower leg pain in patients with both lumbar spinal stenosis and hip joint osteoarthritis.

STUDY DESIGN: Case series. OBJECTIVE: To present the difficulty of diagnosing the origin of lower leg pain in patients with lumbar spinal stenosis and hip joint arthritis. SUMMARY OF BACKGROUND DATA: Pain arising from a degenerated hip joint is sometimes localized to the lower leg. Patients with lumbar spinal disease may also show radicular pain corresponding to the lower leg area. If patients present with both conditions and only pain at the lower leg, it is difficult to determine the origin of the pain. METHODS: We reviewed 420 patients who had leg pain with lumbar spinal stenosis diagnosed by myelography, computed tomography after myelography, or magnetic resonance imaging. Pain only at the ipsilateral lateral aspect of the lower leg but slight low back pain or pain around the hip joint was shown in 4 patients who had lumbar spinal stenosis and hip osteoarthritis. The symptoms resolved after L5 spinal nerve block, but remained after lidocaine infiltration into the hip joint. We performed decompression and posterolateral fusion surgery for these 4 patients. RESULTS: Leg pain did not resolve after lumbar surgery in all patients. Conservative treatment was not effective from 6 to 12 months, so ultimately we performed ipsilateral total hip replacement for all patients and they became symptom-free. CONCLUSION: It is difficult to determine the origin of lower leg pain by spinal nerve block and hip joint block in patients with lumbar spinal stenosis and hip osteoarthritis. We take this into consideration before surgery.

Platelet-rich plasma combined with hydroxyapatite for lumbar interbody fusion promoted bone formation and decreased an inflammatory pain neuropeptide in rats.

STUDY DESIGN: A prospective interventional trial, using a rat model of lumbar interbody fusion. OBJECTIVE: To examine the potential efficacy of platelet-rich plasma (PRP) for lumbar interbody fusion, using hydroxyapatite (HA). SUMMARY OF BACKGROUND DATA: PRP is an autologous product containing a high concentration of platelets in a small volume of plasma and has osteoinductive effects. HA has osteoconductive ability and has been used in combination with autogenous bone for spine fusion. However, reports using PRP with HA for spine fusion are very few. The purpose of this study was to examine the efficacy of PRP with HA for spinal interbody fusion and at the same time to estimate the change in immunoreactivity of the inflammatory neuropeptide, calcitonin gene-related peptide (CGRP), in dorsal root ganglion (DRG) neurons innervating spinal discs. METHODS: A total of 35 Sprague-Dawley rats were used in this study. Twenty-one rats were used for conducting interbody fusion experiments, 7 rats were used as immunostaining controls, and 7 other rats were used as blood donors for making PRP. L5-L6 interbody fusion was performed on 21 rats using HA + PRP (n = 7), HA + platelet-poor plasma (n = 7), or HA + saline (n = 7). Simultaneously, Fluoro-Gold neurotracer was applied to the intervertebral space to detect DRG neurons innervating the discs. L5-L6 lumbar radiographs were obtained and lumbar DRGs were immunostained for CGRP. The rate of bone union and the change in CGRP immunoreactive DRG neurons innervating the discs were evaluated and compared among groups. RESULTS: All L5-L6 lumbar discs were fused in the PRP + HA group (fused 7/total 7), whereas only 1 case was fused in the platelet-poor plasma group (1 of 7) and no cases in the HA-only group (0 of 7), which was a significant difference. Upon immunohistochemical analysis, CGRP-positive neurons innervated L5-L6 intervertebral discs in nonunion cases, and these were significantly increased compared with those in union cases. CONCLUSION: Our study suggests that using PRP with HA was beneficial for spine fusion. This combination may promote bone union and also decrease inflammatory neuropeptide in sensory neurons innervating the discs.

ISSLS prize winner: disc dynamic compression in rats produces long-lasting increases in inflammatory mediators in discs and induces long-lasting nerve injury and regeneration of the afferent fibers innervating discs: a pathomechanism for chronic discogenic low back pain.

STUDY DESIGN: Animal model of intravertebral disc (IVD) degeneration. OBJECTIVE: To examine production of inflammatory mediators in IVDs and neuropeptides in dorsal root ganglia (DRGs) in rat models of IVD compression and injury. SUMMARY OF BACKGROUND DATA: Sensory nerve fibers in IVDs and inflammatory mediator responses have been verified in animal models of IVD injury. However, the IVD injury in animals incompletely models degenerated human IVDs causing discogenic low back pain, because human IVDs are also subject to compression. METHODS: Experimental groups (controls, IVD injury, IVD compression, and their combination) of Sprague Dawley rats were prepared. Fluoro-Gold (FG; Fluorochrome, Denver, CO) was applied into coccygeal IVDs. Inflammatory mediators in IVDs, including nerve growth factor, tumor necrosis factor α, interleukin 1ß, and interleukin 6, were quantified using enzyme-linked immunosorbent assays. DRGs were immunostained for calcitonin gene-related peptide, activating transcription factor 3, and growth-associated phosphoprotein 43. RESULTS: The upregulation of inflammatory mediators was transient in the IVD injury group but delayed and long-lasting in the IVD compression group. When the IVD injury and compression were combined, the upregulation of inflammatory mediators was long-lasting through 8 weeks. The proportion of calcitonin gene-related peptide-immunoreactive neurons among Fluoro-Gold-labeled neurons remained significantly higher in the IVD injury, compression, and combination groups than in the controls. In contrast, increases in the proportions of activating transcription factor 3-immunoreactive or growth-associated phosphoprotein 43-immunoreactive neurons in the IVD injury group animals were transient but long-lasting in the compression and combination groups compared with controls. CONCLUSION: Disc injury in rats produces persistent increases in neuropeptides in DRGs but only transient increases in inflammatory mediators in IVDs. On the contrary, disc compression in rats produces a long-lasting increase in inflammatory mediators in IVDs and neuropeptides in DRGs. Moreover, disc compression induces persistent nerve injury and regeneration of the afferent fibers innervating IVDs.

Efficacy of epidural administration of anti-interleukin-6 receptor antibody onto spinal nerve for treatment of sciatica.

INTRODUCTION: Interleukin-6 (IL-6) is thought to play a crucial role in the radicular pain caused by lumbar spinal stenosis. However, efficacy of inhibition of IL-6 for sciatica in patients with lumbar spinal stenosis has not been clarified. The purpose of the current study was to examine the effect of the anti-IL-6 receptor monoclonal antibody, tocilizumab, on radicular pain by its epidural administration onto spinal nerves in patients with lumbar spinal stenosis. METHODS: Sixty patients with low back and radicular leg pain caused by spinal stenosis were investigated. In 30 patients, we infiltrated 2.0 mL of lidocaine and 80 mg of tocilizumab onto the affected spinal nerve, and 2.0 mL of lidocaine and 3.3 mg of dexamethasone were used in 30 patients. Low back pain, leg pain, and leg numbness were evaluated during 1 month after spinal nerve infiltration. RESULTS: Infiltration of tocilizumab was more effective than dexamethasone for leg pain (3 days, 1, 2, and 4 weeks), low back pain (3 days, 1, 2 and 4 weeks), and leg numbness (3 days, 1 and 2 weeks). No adverse event was observed in either group. CONCLUSION: Our results indicate that the epidural administration of an anti-IL-6 receptor monoclonal antibody, tocilizumab, onto the spinal nerve produced reduction of radicular leg pain, numbness, and low back pain without adverse event. IL-6 may be one of the inducers of pain caused by spinal stenosis in humans.

Clinical incidence of sacroiliac joint arthritis and pain after sacropelvic fixation for spinal deformity.

PURPOSE: Sacroiliac fixation using iliac screws for highly unstable lumbar spine has been reported with an improved fusion rate and clinical results. On the other hand, there is a potential for clinical problems related to iliac fixation, including late sacroiliac joint arthritis and pain. MATERIALS AND METHODS: Twenty patients were evaluated. Degenerative scoliosis was diagnosed in 7 patients, failed back syndrome in 6 patients, destructive spondyloarthropathy in 4 patients, and Charcot spine in 3 patients. All patients underwent posterolateral fusion surgery incorporating lumbar, S1 and iliac screws. We evaluated the pain scores, bone union, and degeneration of sacroiliac joints by X-ray imaging and computed tomography before and 3 years after surgery. For evaluation of low back and buttock pain from sacroiliac joints 3 years after surgery, lidocaine was administered in order to examine pain relief thereafter. RESULTS: Pain scores significantly improved after surgery. All patients showed bone union at final follow-up. Degeneration of sacroiliac joints was not seen in the 20 patients 3 years after surgery. Patients showed slight low back and buttock pain 3 years after surgery. However, not all patients showed relief of the low back and buttock pain after injection of lidocaine into the sacroiliac joint, indicating that their pain did not originate from sacroiliac joints. CONCLUSION: The fusion rate and clinical results were excellent. Also, degeneration and pain from sacroiliac joints were not seen within 3 years after surgery. We recommend sacroiliac fixation using iliac screws for highly unstable lumbar spine.

Sensory and autonomic innervation of the cervical intervertebral disc in rats: the pathomechanics of chronic discogenic neck pain.

STUDY DESIGN: An immunohistological analysis of the cervical intervertebral disc (IVD). OBJECTIVE: To investigate sensory and autonomic innervation of the rat cervical IVD. SUMMARY OF BACKGROUND DATA: Many clinicians are challenged with treating wide-ranging chronic neck pain. Several authors have reported that sympathetic nerves participate in chronic pain, and various sympathectomy procedures can effectively treat chronic pain. METHODS: The neuro-tracer Fluoro-gold (FG) was applied to the anterior surfaces of C5-C6 IVDs from 10 Sprague-Dawley rats to label the neurons of the innervating dorsal root ganglion (DRG), stellate ganglion (SG; sympathetic ganglion), and nodose ganglion (NG; parasympathetic ganglion). Seven days postsurgery, DRGs from level C1-C8, SG, and NG neurons were harvested, sectioned, and immunostained for calcitonin gene-related peptide (CGRP; a marker for peptide-containing neurons) and isolectin B4 (IB4; a marker for nonpeptide-containing neurons). The proportion of FG-labeled DRG neurons that were CGRP-immunoreactive (CGRP-IR), IB4-binding, and non-CGRP-IR and IB4-binding, and the proportion of FG-labeled SG neurons and NG neurons were calculated. RESULTS: FG-labeled neurons innervating the C5-C6 IVD were distributed throughout the C2-C8 DRGs. The proportions of FG-labeled DRG neurons that were CGRP-IR, IB4-binding, non-CGRP-IR and IB4-binding, as well as SG neurons, and NG neurons were 20.6%, 3.3%, 55.7%, 8.9%, and 11.5%, respectively. The proportion of CGRP-IR FG-labeled DRG neurons was significantly higher than the proportion of IB4-binding FG-labeled DRG neurons at each level (P < 0.05). CONCLUSION: The C5-C6 IVD was innervated multisegmentally from neurons of the C2-C8 DRG, SG, and NG. Overall, 79.6% of the nerve fibers innervating the IVD were sensory nerves and 20.4% were autonomic nerves. Furthermore, 23.9% of the nerve fibers innervating the IVD were afferent sensory pain-related nerves, 8.9% were efferent sympathetic nerves, and 11.5% were efferent parasympathetic nerves. These findings may explain the wide-ranging and chronic discogenic pain that occurs via the somatosensory and autonomic nervous system.

A case of symptomatic extra-foraminal lumbosacral stenosis ("far-out syndrome") diagnosed by diffusion tensor imaging.

STUDY DESIGN: Case report. OBJECTIVE: Diagnosis of symptomatic extra-foraminal lumbosacral stenosis using diffusion tensor imaging (DTI). SUMMARY OF BACKGROUND DATA: Conventional magnetic resonance imaging (MRI) has sometimes proved inadequate for evaluating symptomatic spinal nerve lesions. DTI has been developed to visualize anisotropy of nerve-fiber tracts to evaluate nerve degeneration. We report a case of nerve compression causing a far-out lesion diagnosed using DTI. METHODS: A 68-year-old patient presented with an 8-month history of severe right-sided sciatica. Computed tomography and MRI showed right L5-S1 foraminal stenosis and contact of the L5 transverse process and S1 ala without canal stenosis at the L4-L5 level. We evaluated the fractional anisotropy (FA) of the right L5 spinal nerve and compared it with bilateral L3-S1 spinal nerves to determine the L5 spinal nerve compression site. RESULTS: DTI revealed narrowing of the right L5 spinal nerve between the L5 transverse process and S1 ala. FA was significantly decreased in the right L5 spinal nerve between the L5 transverse process and S1 ala. There was no significant difference in the FA of spinal nerves between the right and left sides at L3, L4, or S1. The right L5 spinal nerve from the central spinal canal to the extra-foraminal lumbosacral lesion was exposed during surgery and found to be severely compressed by the L5 transverse process and S1 ala. Postoperatively, the patient's symptoms disappeared immediately. CONCLUSION: We used DTI to diagnose a symptomatic lesion as an extra-foraminal lumbosacral lesion caused by compression of the L5 spinal nerve at the foramina. Because DTI can quantitatively measure damage to nerve fibers, it may be advantageous for the diagnosis of far-out syndrome.

Lumbar disc degeneration induces persistent groin pain.

STUDY DESIGN: Prospective study of 212 patients with groin pain but without low back pain. OBJECTIVE: To evaluate discogenic groin pain without low back pain or radicular pain. SUMMARY OF BACKGROUND DATA: Patients feel low back pain originating from discogenic disease. It has been reported that the rat lower lumbar discs are innervated mainly by L2 dorsal root ganglion neurons. Thus, it is possible that patients feel referred groin pain corresponding to the L2 dermatome originating from intervertebral discs; however, the referred pain has not been fully clarified in humans. METHODS: We selected 5 patients with groin pain alone for investigation. The patients suffered from groin pain and showed disc degeneration only at 1 level (L4-L5 or L5-S1) on magnetic resonance imaging. Patients did not show any hip joint abnormality on radiography or magnetic resonance imaging. To prove that their groin pain originated in degenerated intervertebral discs, we evaluated changes in groin pain after infiltration of lidocaine into hip joints and examined pain provocation on discography, pain relief by anesthetic discoblock, and finally anterior lumbar interbody fusion surgery. RESULTS: All patients were negative for hip joint block, positive for pain provocation on discography, and positive for pain relief by anesthetic discoblock. Furthermore, bony union was achieved 1 year after anterior interbody fusion surgery in all patients, and visual analogue scale score of groin pain was significantly improved at 1 year after surgery in all patients (P < 0.05). CONCLUSION: In the current study, we diagnosed discogenic groin pain, using magnetic resonance imaging, infiltration of lidocaine into the hip joint, pain provocation on discography, pain relief by anesthetic discoblock, and lumbar surgery. It is important to consider the existence of discogenic groin pain if patients do not show low back pain.

Differences in damage to CGRP immunoreactive sensory nerves after two lumbar surgical approaches: investigation using humans and rats.

STUDY DESIGN: Immunohistochemical study. OBJECTIVE: To evaluate invasive surgical approaches by analyzing the number of sensory nerve fibers at 2 back muscle sites in rats and humans and the number of injured nerve fibers innervating these 2 sites after muscle injury in rats. SUMMARY OF BACKGROUND DATA.: Several minimally invasive approaches have recently become popular in the treatment of lumbar spine disorders. Minimally invasive surgery (MIS) is not invasive to back muscle and is thought to reduce low back pain. Muscle damage has been generally evaluated by magnetic resonance imaging (MRI); however, damage to sensory nerve fibers in and around back muscle that is directly related to pain has apparently not been explored. METHODS: Human muscle at L4-L5 was obtained from the paraspinous process (during a midline approach) and from paraspinal back muscle (during a Wiltse paraspinal approach) (n = 10 each). The muscle was sectioned and immunostained for calcitonin gene-related peptide (CGRP). To detect dorsal root ganglion (DRG) neurons innervating back muscle in rats, Fluoro-Gold (FG) was applied to the same 2 sites on the lower back muscle at L4-L5 (only application, n = 12; application of FG + muscle injury, n = 12). DRGs were harvested and immunostained for CGRP and activating transcription factor-3 (ATF-3: marker for nerve injury). The numbers of FG-labeled CGRP-immunoreactive or FG-labeled ATF-3-immunoreactive DRG neurons innervating the 2 sites were counted and compared. RESULTS: CGRP-immunoreactive sensory nerve fibers were found at the 2 sites. The average number of CGRP-immunoreactive sensory nerve fibers in muscle obtained in a midline approach was significantly higher than that in muscle obtained in a Wiltse paraspinal approach (P < 0.01). The numbers of FG-labeled CGRP- and ATF-3-immunoreactive DRG neurons innervating paraspinous process muscle were significantly greater than those innervating paraspinal back muscle in rats (P < 0.01). CONCLUSION: There are more CGRP-immunoreactive sensory nerve fibers and DRG neurons innervating muscle in the midline approach area than in the Wiltse paraspinal approach area in humans and rats. There are more ATF-3-immunoreactive DRG neurons innervating muscle in the midline approach area than in the Wiltse paraspinal approach area after muscle injury in rats. This result may show the differences in sensory nerve injury during the 2 surgical approaches.

Investigation of dichotomizing sensory nerve fibers projecting to the lumbar multifidus muscles and intervertebral disc or facet joint or sacroiliac joint in rats.

STUDY DESIGN: Immunohistological analysis of dichotomizing sensory nerve fibers projecting to the lumbar multifidus muscles and intervertebral disc (IVD), facet joint (FJ), or sacroiliac joint (SIJ) in rats. OBJECTIVE: To elucidate dichotomizing sensory nerve fibers projecting to the lumbar multifidus muscles and to IVDs, FJs, or SIJs. SUMMARY OF BACKGROUND DATA: Clinically, the origin of low back pain remains unknown. Multiple studies have identified lumbar muscles, IVDs, FJs, and SIJs as sources of low back pain. Pain may originate directly from lumbar muscles or be referred from the spine, or both. Dorsal root ganglion (DRG) neurons with dichotomizing axons have been reported in several species and are thought to be related to referred pain. METHODS: We used 2 neurotracers, 1,1'-dioctadecyl-3,3,3',3'-tetramethyl-indocarbocyanine perchlorate (DiI) and fluorogold (FG), in this double-labeling study involving 30 Sprague Dawley rats. DiI was applied to lumbar multifidus muscles in all rats. Simultaneously, FG was applied to the anterior left portion of L5-L6 IVDs in the IVD group (n = 10), to the left L5-L6 FJs in the FJ group (n = 10), and to the left SIJs in the SIJ group (n = 10). Fourteen days after surgery, left DRGs from L1 to L6 were harvested, sectioned, and observed under a fluorescence microscope. RESULTS: We verified the existence of double-labeled DRG neurons (i.e., dichotomizing sensory nerve fibers) projecting to lumbar multifidus muscles and to IVDs, FJs, or SIJs, depending on the group. The proportion of double-labeled cells in all DiI-labeled DRG neurons was higher in the FJ group (6.8%) and SIJ group (7.1%) than in the IVD group (3.1%) (P < 0.05). CONCLUSION: Our results document the presence of dichotomizing sensory nerve fibers projecting to lumbar multifidus muscles and to IVDs, FJs, and SIJs. Referred low back muscle pain may reflect disorders of lumbar posterior structures, such as FJs and SIJs, rather than disorders of lumbar anterior structures, such as IVDs.