[Show abstract][Hide abstract] ABSTRACT: Osteoarthritic (OA) pain is largely considered to be inflammatory pain. However, during the last stage of knee OA, sensory nerve fibers in the knee are shown to be significantly damaged when the subchondral bone junction is destroyed, and this can induce neuropathic pain. Several authors have reported that tumor necrosis factor-α (TNFα) in a knee joint plays a crucial role in pain modulation. The purpose of the current study was to evaluate the efficacy of etanercept, a TNFα inhibitor, for pain in knee OA.
Thirty-nine patients with knee OA and a 2-4 Kellgren-Lawrence grading were evaluated in this prospective study. Patients were divided into two groups; hyaluronic acid (HA) and etanercept injection. All patients received a single injection into the knee. Pain scores were evaluated before and 4 weeks after injection using a visual analogue scale (VAS) and the Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC), and they were compared between the groups.
Before injection, VAS and WOMAC scores were not significantly different between the groups (p>0.05). Significant pain relief was found in the etanercept group at 1 and 2 weeks by VAS, and at 4 weeks by WOMAC score, compared with the HA group (p<0.05). No adverse events were observed in either group.
Direct injection of etanercept into OA knee joints was an effective treatment for pain in moderate and severe OA patients. Furthermore, this finding suggests that TNFα is one factor that induces OA pain.
Yonsei medical journal 09/2015; 56(5):1379-83. DOI:10.3349/ymj.2015.56.5.1379 · 1.29 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: To examine the analgesic effect of intradiscal administration of a tumor necrosis factor-αα (TNF-α) inhibitor in patients with discogenic low back pain (LBP).
Prospective, randomized study.
Department of Orthopaedic Surgery, Chiba (Japan) University Hospital.
Seventy-seven patients diagnosed with discogenic LBP.
Discogenic LBP patients were randomly assigned to the etanercept (n = 38; bupivacaine [2 mL] with etanercept [10 mg]) or control (n = 39; bupivacaine [2 mL]) groups. Patients received a single intradiscal injection. Numerical rating scale (NRS) scores for LBP at baseline, 1 day, and 1, 2, 4, and 8 weeks after the injection were recorded. The Oswestry disability index (ODI) scores at baseline and at 4 and 8 weeks after injection were evaluated. Postinjection complications were recorded and evaluated.
In the etanercept group, the NRS scores were significantly lower than in the control group at every time point after the injection for 8 weeks (P < 0.05). Similarly, 4 weeks after the injection, the ODI score was lower in the etanercept group than in the control group (P < 0.05). However, the ODI scores were not significantly different at 8 weeks. Complications were not observed.
Single intradiscal administration of a TNF-α inhibitor can alleviate intractable discogenic LBP for up to 8 weeks. TNF-α may be involved in discogenic pain pathogenesis. This procedure is a novel potential treatment; longer-term effectiveness trials are required in the future.
Wiley Periodicals, Inc.
Pain Medicine 08/2015; DOI:10.1111/pme.12892 · 2.30 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Surgery for lumbar spinal degeneration disease is widely performed. While posterior decompression and fusion are popular, anterior lumbar interbody fusion (ALIF) is also used for treatment. Extreme lateral interbody fusion (XLIF) is commonly used for noninvasive ALIF; however, several complications, such as spinal nerve and psoas muscle injury, have been reported. In the current study, we examined the clinical efficacy and complications of oblique lateral interbody fusion (OLIF) for lumbar spinal degeneration disease.
Thirty-five patients with degenerated spondylolisthesis, discogenic pain, and kyphoscoliosis were examined. All patients underwent OLIF surgery (using a cage and bone graft from the iliac crest) with or without posterior decompression, without real-time electromyography monitoring. Posterior screws were used in all patients. Visual analog scale (VAS) score and Oswestry Disability Index (ODI) were evaluated before and 6 months after surgery. Surgical complications were also evaluated.
Pain scores significantly improved after surgery, compared to those before surgery (p<0.05). There was no patient who underwent revision surgery. There was no spinal nerve, major vessel, peritoneal, or urinary injury. Few patients showed symptoms from psoas invasion.
OLIF surgery produced good surgical results without any major complication.
Yonsei medical journal 07/2015; 56(4):1051-1059. DOI:10.3349/ymj.2015.56.4.1051 · 1.29 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Nuclear factor-κB (NF-κB), receptor activator of NF-κB (RANK), and RANK ligand (RANKL) are transcriptional regulators of inflammatory cytokines. RANKL expression in dorsal root ganglion (DRG) neurons is elevated in animal models of pain or intervertebral disc herniation. We sought to evaluate the effect of anti-RANKL antibodies on sensory nerves innervating injured intervertebral discs.
We labeled DRG neurons innervating L5-6 discs with FluoroGold (FG). The L5-6 discs of 36 rats were punctured using a 23-gage needle and 18 rats underwent sham surgery without disc puncture. The puncture group was evenly subdivided into a group in which 10 μl saline was administered to the injured disc and a group in which 10 μl of anti-RANKL antibody was administered. Seven and 14 days postsurgery, DRGs at L2 level were harvested, sectioned, and immunostained for calcitonin gene-related peptide (CGRP). The proportion of CGRP-immunoreactive (IR) DRG neurons of all FG-positive neurons was determined. Amount of tumor necrosis factor (TNF)-α and interleukin(IL)-6 was measured within the intervertebral discs in each group at 7 and 14 days after surgery using an enzyme-linked immunosorbent assay (ELISA).
The proportion of CGRP-IR DRG neurons to total FG-labeled neurons innervating injured intervertebral discs and amount of TNF-α and IL-6 in the injured discs in the saline control group was significantly increased compared with that found in rats from the sham surgery group (P < 0.05). However, application of anti-RANKL antibody to the injured discs significantly decreased the proportion of CGRP-IR DRG neurons to total FG-labeled neurons and amount of TNF-α and IL-6 in the injured discs (P < 0.05).
TNF-α and IL-6 in the injured discs increased and CGRP expression increased in DRG neurons innervating injured discs, and antibodies to RANKL could suppress this increased TNF-α, IL-6, and CGRP expression. RANKL may be a therapeutic target for pain control in patients with lumbar disc degeneration.
European Spine Journal 06/2015; 24(9). DOI:10.1007/s00586-015-4058-z · 2.07 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Retrospective study.
We conducted a study to investigate the time course changes in bone metabolic markers after the administration of the anti-receptor activator of nuclear factor-kappa B ligand (RANKL) antibody and to assess drug compliance among osteoporotic patients.
The anti-RANKL antibody is expected to provide an improvement in those with a bone metabolism disorder. However there are only a few clinical reports available on the effect of treatment.
We included 40 post-menopausal osteoporotic patients who received the anti-RANKL antibody. To determine the time course changes in the bone metabolic markers, we measured the serum tartrate-resistant acid phosphatase 5b (TRACP 5b; a bone resorption marker) and the serum N-terminal propeptide of type 1 collagen (P1NP; a bone formation marker) levels prior to and 1 month after administrating the anti-RANKL antibody. To evaluable drug compliance, we assessed the dropout rate during treatment and at 6 months after treatment.
The average TRACP 5b level significantly decreased from 574.8 mU/dL before treatment to 153.2 mU/dL 1 month after treatment (p<0.05). There was no significant difference in the average P1NP level, which was 56.9 µG/L and 35.1 µG/L before and 1 month after treatment, respectively (p>0.05). As for drug compliance, we did not have any dropouts during the treatment or after 6 months (dropout rate: 0%).
Our study suggests that anti-RANKL antibody treatment suppresses bone resorption and maintains bone formation.
Asian spine journal 06/2015; 9(3):338-343. DOI:10.4184/asj.2015.9.3.338
[Show abstract][Hide abstract] ABSTRACT: The pathological mechanism of intractable low back pain is unclear. However, intervertebral disc (IVD) degeneration is a primary cause of low back pain, and pain-related mediators, such as interleukin-6 (IL-6), have been correlated with discogenic pain. The objective of this study is to elucidate the mechanism of local IL-6 and IL-6 receptor (IL-6R) expression after IVD injury as well as determine the involvement of IL-6/IL-6 signaling in discogenic pain. To do this, quantitative and immunohistological analyses in a mouse model of IVD injury were performed. Firstly, we measured the local expression levels of IL-6 and IL-6R in IVDs by enzyme-linked immunosorbent assay (ELISA). Secondly, we immunohistochemically confirmed their localization in injured IVDs. Lastly, we evaluated the effects of intradiscal injection of an IL-6 inhibitor by evaluating pain-related protein, calcitonin gene-related peptide (CGRP), expression in dorsal root ganglia (DRG) neurons that innervate IVDs. Injured IVDs showed increased production of IL-6 and IL-6R. IL-6 and IL-6R expression in the injured IVD were predominantly localized in the annulus fibrosus and endplate, and intradiscal injection of the IL-6 inhibitor suppressed CGRP expression in the DRG neurons. These results show that IL-6 and IL-6R expression levels are responsive to IVD injury and that inhibition of IL-6/IL-6R signaling may be a promising analgesic treatment for degenerative disc diseases. This article is protected by copyright. All rights reserved.
This article is protected by copyright. All rights reserved.
Journal of Orthopaedic Research 05/2015; 33(10). DOI:10.1002/jor.22925 · 2.99 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Muscle injury is common and is thought to account for 10%-50% of all sports-related injuries. The use of rest, ice, compression, and elevation is common in clinical practice, but many treatments over a long period are required to produce a therapeutic effect. We evaluated the utility of photodynamic therapy as a new treatment option for the acute stage of muscle injury.
Twenty 8-week-old Sprague-Dawley male rats underwent experimental injury of the right gastrocnemius muscle with a drop-mass method. After muscle injury was induced, a liposomally formulated indocyanine green derivative (7 mg/kg) near-infrared laser irradiation was performed at 18 h after injury. Local time-dependent changes in the treatment (n = 14) and no treatment (n = 14) groups were evaluated with in vivo imaging, histologic examination, and enzyme-linked immunosorbent assay methods.
In vivo imaging fluorescence values were significantly higher in the no treatment group, whereas interleukin-6 and tumor necrosis factor-α levels were significantly higher in the treatment group at 18 h after injury. Histologic examination results revealed that the treatment group had less bleeding and more degeneration repair processes than the no treatment group at 24 h and 1 week after muscle injury.
These findings suggest that photodynamic therapy promotes a tissue-repairing effect during the early stage of muscle injury.
Journal of Orthopaedic Surgery and Research 04/2015; 10(1):50. DOI:10.1186/s13018-015-0193-9 · 1.39 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: This study aimed to evaluate the time course of local changes during the acute phase of gastrocnemius muscle strain, in a rat model, using an in vivo imaging system. Thirty-eight, 8-week-old Sprague-Dawley male rats were used in our study. Experimental injury of the right gastrocnemius muscle was achieved using the drop-mass method. After inducing muscle injury, a liposomally formulated indocyanine green derivative (LP-iDOPE, 7 mg/kg) was injected intraperitoneally. We evaluated the muscle injuries using in vivo imaging, histological examinations, and enzyme-linked immunosorbent assays. The fluorescence peaked approximately 18 h after the injury, and decreased thereafter. Histological examinations revealed that repair of the injured tissue occurred between 18 and 24 h after injury. Quantitative analyses for various cytokines demonstrated significant elevations of interleukin-6 and tumor necrosis factor-α at 3 and 18 h post-injury, respectively. The time course of fluorescence intensity, measured using in vivo imaging, demonstrated that the changes in cytokine levels and histopathologic characteristics were consistent. Specifically, these changes reached peaked 18 h post-injury, followed by trends toward recovery. This article is protected by copyright. All rights reserved.
This article is protected by copyright. All rights reserved.
Journal of Orthopaedic Research 03/2015; 33(7). DOI:10.1002/jor.22832 · 2.99 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Case series.
To determine the utility of "PainVision" apparatus for the assessment of low back pain.
A newly developed device, the PainVision PS-2100 (Nipro, Osaka, Japan), has been used to assess the perception of pain in a quantitative manner. In the current study, we aimed to evaluate the efficacy of PainVision for the assessment of low back pain.
We assessed 89 patients with low back pain. The numeric rating scale (NRS) score, McGill Pain Questionnaire (MPQ) score and the degree of pain calculated by PainVision were measured twice at 4-week intervals in each patient. An electrode was patched on the forearm surface of the patients and the degree of pain was automatically calculated (degree of pain=100×[current producing pain comparable with low back pain-current at perception threshold/current at perception threshold]). Correlations between NRS and MPQ scores and the degree of pain were determined using Spearman's rank correlation test.
There was a strong correlation between the NRS and MPQ scores at each time point (rs =0.60, p<0.0001). The degree of pain also showed a moderate correlation with NRS and MPQ scores at each time point (rs =0.40, p<0.03). The change in the degree of pain over 4 weeks showed a moderate correlation with changes in the NRS and MPQ scores (rs =0.40, p<0.01).
PainVision as self-reported questionnaires is a useful tool to assess low back pain.
Asian spine journal 12/2014; 8(6):793-8. DOI:10.4184/asj.2014.8.6.793
[Show abstract][Hide abstract] ABSTRACT: Purpose
Transient receptor potential vanilloid 1 (TRPV1) is a ligand-gated nonselective cation channel, which can be activated by capsaicin and other noxious stimuli. Recently, an association between bone pain and TRPV1 has been reported. However, the influence of osteoporosis on TRPV1 in the sensory system innervating the femur has not been reported.
Materials and Methods
TRPV1-immunoreactive (ir) in dorsal root ganglia (DRG) neurons labeled with neurotracer [Fluoro-Gold (FG)] innervating the femurs of Sprague Dawley rats were examined in control, sham, and ovariectomized (OVX) rats. We evaluated osteoporosis in the femurs and compared the proportion of TRPV1-ir DRG neurons innervating femur between the 3 groups of rats.
OVX rats showed osteoporotic cancellous bone in the femur. FG labeled neurons were distributed from L1 to L6 DRG, but there was no significant difference in the proportion of labeled neurons between the 3 groups (p>0.05). The proportions of FG labeled TRPV1-ir DRG neurons were 1.7%, 1.7%, and 2.8% of DRG neurons innervating the femur, in control, sham-operated, and OVX rats, respectively. The proportion of TRPV1-ir neurons in DRG innervating the femur in OVX rats was significantly higher than that in control and sham-operated rats (p<0.05).
Under physiological conditions, DRG neurons innervating femurs in rats contain TRPV1. Osteoporosis increases the numbers of TRPV1-ir neurons in DRG innervating osteoporotic femurs in rats. These findings suggest that TRPV1 may have a role in sensory perception of osteoporotic femurs.
Yonsei Medical Journal 11/2014; 55(6):1600-5. DOI:10.3349/ymj.2014.55.6.1600 · 1.29 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Study Design
Experimental animal study.
To evaluate pain-related behavior and changes in nuclear factor-kappa B (NF-kB), receptor activator of NF-kB (RANK), and ligand (RANKL) in dorsal root ganglia (DRG) after combined sciatic nerve compression and nucleus pulposus (NP) application in rats.
Overview of Literature
The pathological mechanisms underlying pain from lumbar-disc herniation have not been fully elucidated. RANKL are transcriptional regulators of inflammatory cytokines. Our aim was to evaluate pain-related behavior and RANKL expression in DRG after sciatic-nerve compression and application of NP in rats.
Mechanical hyperalgesia and RANKL expression were assessed in three groups of rats: NP+sciatic nerve compression (2 seconds), sham-operated, and controls (n=20 each). Mechanical hyperalgesia was measured every other day for 3 weeks using von Frey filaments. RANKL expression in L5 DRGs was examined at five and ten days after surgery using immunohistochemistry.
Mechanical hyperalgesia was observed over the 12-day observation period in the NP+nerve compression group, but not in the control and sham-operated animal groups (p<0.05). RANKL immunoreactivity was seen in the nuclei of L5 DRG neurons, and its expression was significantly upregulated in NP+nerve compression rats compared with control and sham-operated rats (p<0.01).
The exposure of sciatic nerves to mechanical compression and NP produces pain-related behavior and up-regulation of RANKL in DRG neurons. RANKL may play an important role in mediating pain after sciatic nerve injury with exposure to NP.
Asian spine journal 10/2014; 8(5):557-64. DOI:10.4184/asj.2014.8.5.557
[Show abstract][Hide abstract] ABSTRACT: Study Design
Experimental animal study.
To evaluate pain-related behavior and changes in glial activity in the spinal dorsal horn after combined sciatic nerve compression and nucleus pulposus (NP) application in rats.
Overview of Literature
Mechanical compression and inflammation caused by prostaglandins and cytokines at disc herniation sites induce pain. Structural changes and pain-associated cytokines in the dorsal root ganglia and spinal dorsal horn contribute to prolonged pain. Glial cells in the spinal dorsal horn may also function in pain transmission.
The sciatic nerve was compressed with NP for 2 seconds using forceps in the NP+nerve compression group; the sham-operated group received neither compression nor NP; and the control group received no operation. Mechanical hyperalgesia was measured for 3 weeks using von Frey filaments. Glial activity in the spinal dorsal horn was examined 7 days and 14 days postsurgery using anti-glial fibrillary acidic protein and anti-Ionized calcium binding adaptor molecule-1 antibodies to detect astrocytes and microglia, respectively.
Mechanical hyperalgesia was detected throughout the 14-day observation in the NP+nerve compression group, but not in control or sham-operated groups (p<0.05). Both astrocytes and microglia were significantly increased in the spinal dorsal horn of the NP+nerve compression group compared to control and sham groups on days 7 and 14 (p<0.05).
Nerve compression with NP application produces pain-related behavior, and up-regulates astrocytes and microglia in the spinal dorsal horn, suggesting that these glia may be related to pain transmission.
Asian spine journal 10/2014; 8(5):549-56. DOI:10.4184/asj.2014.8.5.549
[Show abstract][Hide abstract] ABSTRACT: Purpose
Opioids improve pain from knee and hip osteoarthritis (OA) and decrease the functional impairment of patients. However, there is a possibility that opioids induce analgesia and suppress the physiological pain of OA in patients, thereby inducing the progression of OA changes in these patients. The purpose of the current study was to investigate the possibility of progressive changes in OA among patients using opioids.
Materials and Methods
Two hundred knee or hip OA patients were evaluated in the current prospective, randomized, active-controlled study. Patients were randomized 1:1:1 into three parallel treatment groups: loxoprofen, tramadol/acetaminophen, and transdermal fentanyl groups. Medication was administered for 12 weeks. Pain scores and progressive OA changes on X-ray films were evaluated.
Overall, pain relief was obtained by all three groups. Most patients did not show progressive OA changes; however, 3 patients in the transdermal fentanyl group showed progressive OA changes during the 12 weeks of treatment. These 3 patients used significantly higher doses than others in the transdermal fentanyl group. Additionally, the average pain score for these 3 patients was significantly lower than the average pain score for the other patients in the transdermal fentanyl group.
Fentanyl may induce progressive changes in knee or hip OA during a relatively short period, compared with oral Non-Steroidal Anti-Inflammatory Drugs or tramadol.
Yonsei Medical Journal 09/2014; 55(5):1379-85. DOI:10.3349/ymj.2014.55.5.1379 · 1.29 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Study DesignProspective study.PurposeTo examine the long-term effects of interspinous ligament injections of local anesthetics and steroids for the treatment of Baastrup's diseases.Overview of LiteratureBaastrup's disease is associated with axial low back pains. Baastrup's disease has been more recently described as the "kissing spinous processes" disease. Several authors have reported methods for the diagnosis and treatment of the disease. However, there has been only one report of patients receiving interspinous ligament injections of agents for the treatment of Baastrup's disease.MethodsSeventeen patients showed severe low back pains between spinous processes at L3-L4 or L4-L5. X-ray imaging, computed tomography, and magnetic resonance imaging revealed kissing spinous processes, consolidation of spinous process, or inflammation of an interspinous ligament. Pain reliefs after lidocaine and dexamethasone administration into interspinous ligament as therapy for low back pains were being examined and followed up.ResultsLow back pain scores significantly improved immediately after injection of the agents into interspinous ligaments. At final follow-up (1.4 year), low back pain scores significantly improved as compared with before the treatment.ConclusionsFindings from the current study indicate that lidocaine and dexamethasone administration into interspinous ligament in patients diagnosed with Baastrup's disease is effective for managing the pain associated with this disease.
Asian spine journal 06/2014; 8(3):260-6. DOI:10.4184/asj.2014.8.3.260