Yawara Eguchi

Pain-related sensory innervation in monoiodoacetate-induced osteoarthritis in rat knees that gradually develops neuronal injury in addition to inflammatory pain

BackgroundThe exact mechanism of knee osteoarthritis (OA)-associated pain is unclear, whereas mixed evidence of inflammatory pain and neuropathic pain has been noted. We aimed to investigate pain-related sensory innervation in a monoiodoacetate (MIA)-induced model of OA.MethodsSixty of seventy female Sprague Dawley rats of six week-old underwent intra-articular MIA and fluorogold (FG) retrograde neurotracer injection into their right (ipsilateral) knee, while their left knees were treated with FG in saline as a control (contralateral knee). Other rats were treated with FG only bilaterally, and used as controls. Rats were evaluated for tactile allodynia using von Frey hairs. Proinflammatory mediators in the knee soft tissues, including tumor necrosis factor (TNF)-α, interleukin (IL)-6, and nerve growth factor (NGF), were quantified using ELISAs to evaluate inflammation in the knee after 1, 4, 7,14,21, and 28 days post injection:. Dorsal root ganglia (DRG) were immunostained for three molecules after 7,14,21, and 28 days post injection: calcitonin gene-related peptide (CGRP), a marker of inflammatory pain; and activating transcription factor-3 (ATF3) and growth associated protein-43 (GAP43), as markers for nerve injury and regenerating axons. The distribution of microglia in the spinal cord were also evaluated, because they have been reported to increase in neuropathic pain states. These evaluations were performed up to 28 days postinjection. P < 0.05 was considered significant.ResultsProgressive tactile allodynia and elevated cytokine concentrations were observed in ipsilateral knees. CGRP-immunoreactive (-ir) ipsilateral DRG neurons significantly increased, peaking at 14 days postinjection, while expression of FG-labeled ATF3-ir or ATF3-ir GAP43-ir DRG neurons significantly increased in a time-dependent manner. Significant proliferation of microglia were found with time in the ipsilateral dorsal horn.ConclusionsPain-related characteristics in a MIA-induced rat OA model can originate from an inflammatory pain state induced by the local inflammation initiated by inflammatory cytokines, and that state will be followed by gradual initiation of neuronal injury, which may induce the neuropathic pain state.

Associations between proinflammatory cytokines in the synovial fluid and radiographic grading and pain-related scores in 47 consecutive patients with osteoarthritis of the knee

BackgroundOne of the sources of knee pain in osteoarthritis (OA) is believed to be related to local chronic inflammation of the knee joints, which involves the production of inflammatory cytokines such as tumor necrosis factor alpha (TNFα), interleukin (IL)-6, and nerve growth factor (NGF) in the synovial membrane, and these cytokines are believed to promote pathological OA. In the present study, correlations between proinflammatory cytokines in knee synovial fluid and radiographic changes and functional scores and pain scores among OA patients were examined.MethodsSynovial fluid was harvested from the knees of 47 consecutive OA patients, and the levels of TNFα, IL-6, and NGF were measured using enzyme-linked immunosorbent assays. Osteoarthritic knees were classified using Kellgren-Lawrence (KL) grading (1-4). The Western Ontario and McMaster University Osteoarthritis Index (WOMAC) was used to assess self-reported physical function, pain, and stiffness.ResultsTNFα and IL-6 were detectable in knee synovial, whereas NGF was not. TNFα was not correlated with the KL grade, whereas IL-6 had a significantly negative correlation. We observed differences in the correlations between TNFα and IL-6 with WOMAC scores and their subscales (pain, stiffness, and physical function). TNFα exhibited a significant correlation with the total score and its 3 subscales, whereas IL-6 exhibited a moderately significant negative correlation only with the subscale of stiffness.ConclusionsThe present study demonstrated that the concentrations of proinflammatory cytokines are correlated with KL grades and WOMAC scores in patients with knee OA. Although TNFα did not have a significant correlation with the radiographic grading, it was significantly associated with the WOMAC score. IL-6 had a significant negative correlation with the KL grading, whereas it had only a weakly significant correlation with the subscore of stiffness. The results suggest that these cytokines play a role in the pathogenesis of synovitis in osteoarthritic knees in different ways: TNFα is correlated with pain, whereas IL-6 is correlated with joint function.

Comparison of teriparatide and bisphosphonate treatment to reduce pedicle screw loosening after lumbar spinal fusion surgery in postmenopausal women with osteoporosis from a bone quality perspective.

Study Design. Prospective study. Objective. To examine the efficacy of teriparatide or bisphosphonate treatment to reduce pedicle screw (PS) loosening after instrumented lumbar posterolateral fusion in postmenopausal women with osteoporosis. Summary of Background Data. Failure of fixation caused by loosening of PSs in osteoporosis is a problem in spinal surgery. Oral administration of bisphosphonate or intermittent injection of parathyroid hormone treatment increases bone mass and reduces the risk of osteoporotic vertebral fractures. Although these treatments may be factor in improving bone quality, a clinical study of the efficacy of bisphosphonate or parathyroid hormone for reducing PS loosening that addresses the quality of the bone marrow and pedicle cortex has not yet been reported. Methods. Sixty-two women with osteoporosis diagnosed with degenerative spondylolisthesis were divided into 3 groups: a teriparatide group (daily subcutaneous injection of 20 &mgr;g of teriparatide, n = 20), a bisphosphonate group (daily oral administration 2.5 mg of risedronate, n = 20), and a control group (without medication for osteoporosis, n = 22). All patients underwent decompression and 1- or 2-level instrumented posterolateral fusion with a local bone graft. Loosening of PSs and surgical outcome were evaluated radiographically, clinically, and by computed tomography 12 months after surgery. Results. At 12-month follow-up, the incidence of PS loosening was 7% to 13% in the teriparatide group, 13% to 26% in the risedronate group, and 15% to 25% in the control group. The incidence of PS loosening in the teriparatide group was significantly lower than that in the risedronate or the control group (P < 0.05). In contrast, the extent of PS loosening in the risedronate group was not significantly different from that in the control group (P > 0.05). Conclusion. Our findings suggest that administration of teriparatide increased the quality of the lumbar spine bone marrow and pedicle cortex. Level of Evidence: 3

Epidural administration of spinal nerves with the tumor necrosis factor-alpha inhibitor, etanercept, compared with dexamethasone for treatment of sciatica in patients with lumbar spinal stenosis: a prospective randomized study.

Study Design. Prospective randomized trial. Objective. To examine the effect of the tumor necrosis factor alpha (TNF-&agr;) inhibitor, etanercept, on radicular pain by its epidural administration onto spinal nerves in patients with lumbar spinal stenosis. Summary of Background Data. TNF-&agr; is thought to play a crucial role in the radicular pain caused by lumbar disc herniation and spinal stenosis. Intravenous infusion of infliximab for sciatica has been examined in 2 studies; however, the results were equivocal. Methods. Eighty patients with low back and radicular leg pain were investigated. We diagnosed the patients by physical examination, and X-ray and magnetic resonance imaging. In 40 patients, we epidurally administered 2.0 mL of lidocaine and 10 mg of etanercept onto the affected spinal nerve, and 2.0 mL of lidocaine and 3.3 mg of dexamethasone was used in 40 patients. Low back pain, leg pain, and leg numbness were evaluated using a visual analogue scale (VAS) and Oswestry Disability Index (ODI) score before and for 1 month after epidural administration. Results. Low back pain, leg pain, and leg numbness in the 2 groups were not significantly different before epidural administration. Epidural administration of etanercept was more effective than dexamethasone for leg pain (3 days, and 1, 2, and 4 weeks: P < 0.05), low back pain (3 days, and 1 and 2 weeks: P < 0.05), and leg numbness (3 days, and 1 and 2 weeks: P < 0.05). No adverse event was observed in either group. Conclusion. Our results indicate that epidural administration of a TNF-&agr; inhibitor onto the spinal nerve produced pain relief, but no adverse event. TNF-&agr; inhibitors may be useful tools for the treatment of radicular pain caused by spinal stenosis.

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 Spearmans 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.

Results of surgery for discogenic low back pain: a randomized study using discography versus discoblock for diagnosis.

Study Design. Randomized, controlled study. Objective. To evaluate the diagnosis of discogenic low back pain (LBP) with discography and discoblock. Summary of Background Data. Discogenic LBP is usually diagnosed by magnetic resonance imaging and discography. However, the reliability of discography is controversial. Previously, we reported the usefulness of discoblock with bupivacaine for diagnosis, and discoblock improved the results of anterior interbody fusion surgery. However, that study was not a randomized, controlled study. Therefore, the purpose of the current study was to compare the results of surgery after diagnosis of LBP by discography and discoblock. Methods. Patients (n = 42) with severe LBP showing L4–L5 or L5–S1 disc degeneration on magnetic resonance imaging were evaluated by discography (1.5 mL of contrast medium) or discoblock (intradisc injection of 0.75 mL of 0.5% bupivacaine). We randomized the patients in turn. Anterior discectomy and interbody fusion were performed in patients who responded to the diagnostic procedures. The visual analogue scale score (0, no pain; 100, worst pain), Japanese Orthopedic Association Score (0, worst pain; 3, no pain), Oswestry Disability Index, and patient satisfaction before and 3 years after surgery were recorded and compared between groups. Results. Twelve patients did not show pain provocation by discography or pain relief by discoblock and were excluded. Fifteen patients who showed pain provocation by discography and 15 patients who experienced pain relief with discoblock were evaluated. Rates of improvement in the visual analogue scale score, Japanese Orthopedic Association Score, and Oswestry Disability Index score in the discoblock group were significantly higher than those in the discography group (P < 0.05) from baseline to 3 years after surgery. Three patients were dissatisfied with surgery after discography compared with one patient after discoblock. Conclusion. Pain relief after injection of a small amount of bupivacaine into the painful disc was a useful tool for the diagnosis of discogenic LBP compared with discography.

Teriparatide accelerates lumbar posterolateral fusion in women with postmenopausal osteoporosis: prospective study.

Study Design. Prospective trial. Objective. To examine the clinical efficacy of teriparatide for bone union after instrumented lumbar posterolateral fusion using local bone grafting in women with postmenopausal osteoporosis. Summary of Background Data. Intermittent parathyroid hormone (PTH) treatment increases bone mass and reduces the risk for osteoporotic vertebral fractures. Recombinant human PTH (1–34) has already been approved as a treatment for severe osteoporosis. Preclinical data support the efficacy of PTH for lumbar spinal fusion. However, clinical results of PTH for spinal fusion have not yet been reported. Methods. Fifty-seven women with osteoporosis diagnosed with degenerative spondylolisthesis were divided into 2 treatment groups, a teriparatide group (n = 29; daily subcutaneous injection of 20 &mgr;g of teriparatide) and a bisphosphonate group (n = 28; weekly oral administration of 17.5 mg of risedronate). All patients underwent decompression and 1- or 2-level instrumented posterolateral fusion with a local bone graft. Fusion rate, duration of bone union, and pain scores were evaluated 1 year after surgery. Results. Pain scores improved after surgery; however, no significant difference was noted between the groups after surgery. The rate of bone union was 82% in the teriparatide group and 68% in the bisphosphonate group. Average duration of bone union was 8 months in the teriparatide group and 10 months in the bisphosphonate group. The rate of bone union and average of duration of bone union in the teriparatide group patients were significantly superior to those in the bisphosphonate group. Conclusion. Daily subcutaneous injection of teriparatide for bone union using local bone grafting after instrumented lumbar posterolateral fusion in women with postmenopausal osteoporosis was more effective than oral administration of bisphosphonate.

Disk injury in rats produces persistent increases in pain-related neuropeptides in dorsal root ganglia and spinal cord glia but only transient increases in inflammatory mediators: pathomechanism of chronic diskogenic low back pain.

Study Design. Immunohistological analysis in an injured intervertebral disk (IVD) model. Objective. To elucidate and compare in rats the behavior of the sensory nervous system and inflammatory mediators in experimentally injured IVDs. Summary of Background Data. Multiple human and animal studies have verified the presence of sensory nerve fibers in IVDs or investigated the behavior of inflammatory mediators in injured IVDs, but no in vivo study to date has examined the relationship between the 2. Methods. Eight-week-old female rats were used. In the disk-injured group, L5/L6 disks were injured with a 24-gauge needle; simultaneously, the neurotracer Fluoro-gold was injected into the L5/L6 IVD. The L5/L6 IVD dorsal root ganglia (DRGs) from the L1 to L6 levels, and the spinal cord was resected at several time points after surgery. Nerve growth factor, tumor necrosis factor (TNF)-&agr; and interleukin (IL)-6 production in the IVDs were quantified using enzyme-linked immunosorbent assay. DRGs were immunostained for calcitonin gene-related peptide, and spinal cord sections were immunostained for ionized calcium-binding adaptor molecule-1 and glial fibrillary acidic protein. Results. Nerve growth factor, and TNF-&agr; levels (through 1 week) and IL-6 levels (through 4 days) were significantly higher in the disk-injured group than in the noninjured group (P < 0.05). However, starting at 2 weeks (nerve growth factor and TNF-&agr;) or 1 week (IL-6), the differences in inflammatory mediator levels between the 2 groups no longer were significant. In contrast, the percentage of calcitonin gene-related peptide-immunoreactive neurons among Fluoro-gold–labeled DRG neurons, and the numbers of ionized calcium-binding adaptor molecule-1-immunoreactive microglia and glial fibrillary acidic protein-immunoreactive astrocytes in the spinal dorsal horn remained significantly higher in the injured group than in the noninjured group at all-time points (P < 0.05). Conclusion. Disk injury in rats produces persistent increases in neuropeptides in DRGs and glia in the spinal cord, but only transient increases in inflammatory mediators in IVDs.

Risedronate decreases bone resorption and improves low back pain in postmenopausal osteoporosis patients without vertebral fractures.

Elderly postmenopausal women who have osteoporosis sometimes experience low back pain, however, the relationship between low back pain and osteoporosis in the absence of vertebral fractures remains unclear. We examined the relationship between bone mineral density (BMD), bone resorption and low back pain in elderly female patients who did not have osteoporotic vertebral fractures. The average BMD was 0.675 g/cm(2) when assessed by dual-energy X-ray absorptiometry (DEXA). Patients were excluded from the study if they had vertebral fractures revealed by radiography, CT scans or MRI. Bisphosphonate (risedronate) was administered for 4 months. The visual analogue scale (VAS) pain score, Roland Morris Disability Questionnaire (RDQ), Short Form-36 (SF-36) questionnaire, BMD and N-terminal telopeptide of type I collagen (NTx; a marker for bone resorption) were examined before and after treatment. DEXA did not increase significantly, but serum and urinary NTx were decreased (-51.4% and -62.0%, respectively) after 4 months of risedronate treatment (p<0.01). The assessment was repeated using the VAS score, RDQ and SF-36, which revealed an improvement after risedronate treatment (p<0.01). A decrease in serum and urinary NTx was associated with improvement of low back pain, suggesting that despite the absence of vertebral fractures, bone resorption due to osteoporosis may cause low back pain.

Diffusion magnetic resonance imaging to differentiate degenerative from infectious endplate abnormalities in the lumbar spine.

Study Design. A retrospective observational study of healthy volunteers and patients with degenerative and infectious endplate abnormalities in the lumbar spine. Objectives. Our purpose was to evaluate the usefulness of diffusion-weighted imaging (DWI) for the differentiation of degenerative and infectious endplate abnormalities using 1.5-T magnetic resonance imaging (MRI). Summary of Background Data. DWI can provide valuable structural information about tissues that may be useful for clinical applications in differentiation between degenerative and infectious endplate abnormalities. Methods. Sixteen consecutive patients with endplate abnormalities that was detected by MRI of the lumbar spine, and 15 healthy volunteers were studied. DWI was performed using whole-body imaging with background body signal suppression with a b value of 1000 s/mm2. Apparent diffusion coefficient values of normal and abnormal vertebral bone marrow were calculated. Results. Twenty-nine vertebral abnormalities were found in 16 patients. Nine vertebral abnormalities in 5 patients were because of infections and 20 vertebral abnormalities in 11 patients were because of degenerative changes; 7 levels were classified as Modic type 1, 7 levels as type 2, and 6 levels as type 3. DWI showed hyperintensity in all patients with infection, similar to that used in positron emission tomography, but not in the intervertebral spaces of any patients with degenerative disease. Apparent diffusion coefficient values of infectious bone marrowwere significantly higher than normal and degenerative bone marrow. Conclusion. DWI is useful for differentiation of degenerative and infectious endplate abnormalities. Moreover, MRI is widely used clinically because of the lack of ionizing radiation, low cost, and fast imaging time as compared with positron emission tomography. Therefore, DWI has the potential to be used as a screening tool.