Neural Mechanisms of Discogenic Back Pain: How Does Nerve Growth Factor Play a Key Role?

Yasuchika Aoki,Seiji Ohtori,Koichi Nakagawa,Arata Nakajima,Gen Inoue,Masayuki Miyagi,Kazuhisa Takahashi 대한척추신경외과학회 2011 Neurospine Vol.8 No.2

It was reported that nerve fibers were present in the inner part of lumbar intervertebral discs from patients with discogenic pain. Because there are no nerve fibers in the inner part of annulus fibrosus in normal condition, this finding suggests nerve ingrowth into the disc may be a cause of discogenic pain. Disc degeneration is often asymptomatic, thus, to understand the differences between symptomatic and asymptomatic disc, it is necessary to understand the pathogenesis of discogenic pain. We recently revealed that over 90% of the nociceptive dorsal root ganglion (DRG) neurons innervating the disc are sensitive to nerve growth factor (NGF), which is related to inflammatory pain. This indicates that discogenic pain is closely related to inflammation and NGF may play a key role. The increase of inflammatory mediators in symptomatic discs has been reported; we therefore studied the effects of disc inflammation and found that it induces sensitization of disc-innervating neurons and nerve ingrowth into the disc. More recently, it was shown that annular rupture induces nerve ingrowth, an increase of inflammatory mediators in the disc, and upregulation of calcitonin gene-related peptide, a pain-related molecule in DRGs. These findings led us to believe that annular rupture triggers inflammation and nerve ingrowth, inflammatory mediators then further promote nerve ingrowth into the disc and sensitization of disc-innervating neurons, and discogenic pain finally becomes chronic. NGF, found in symptomatic discs, may act as a key factor in generating chronic discogenic pain by sensitizing disc-innervating neurons and stimulating nerve ingrowth into the disc.

Up-Regulation of Pain Behavior and Glial Activity in the Spinal Cord after Compression and Application of Nucleus Pulposus onto the Sciatic Nerve in Rats

Masaki Norimoto,Yoshihiro Sakuma,Miyako Suzuki,Sumihisa Orita,Kazuyo Yamauchi,Gen Inoue,Yasuchika Aoki,Tetsuhiro Ishikawa,Masayuki Miyagi,Hiroto Kamoda,Gou Kubota,Yasuhiro Oikawa,Kazuhide Inage,Takesh 대한척추외과학회 2014 Asian Spine Journal Vol.8 No.5

Study Design: Experimental animal study. Purpose: 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. Methods: The sciatic nerve was compressed with NP for 2 seconds using forceps in the NP+nerve compression group; the shamoperated 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. Results: 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). Conclusions: 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.

More than 6 Months of Teriparatide Treatment Was More Effective for Bone Union than Shorter Treatment Following Lumbar Posterolateral Fusion Surgery

Seiji Ohtori,Sumihisa Orita,Kazuyo Yamauchi,Yawara Eguchi,Nobuyasu Ochiai,Kazuki Kuniyoshi,Yasuchika Aoki,Junichi Nakamura,Masayuki Miyagi,Miyako Suzuki,Gou Kubota,Kazuhide Inage,Takeshi Sainoh,Jun Sa 대한척추외과학회 2015 Asian Spine Journal Vol.9 No.4

Study Design: Retrospective case series. Purpose: To examine the most effective duration of teriparatide use for spinal fusion in women with postmenopausal osteoporosis. Overview of Literature: We reported that daily subcutaneous injection of teriparatide (parathyroid hormone) significantly improved bone union after instrumented lumbar posterolateral fusion (PLF) in women with postmenopausal osteoporosis when compared with oral administration of bisphosphonate. However, the most effective duration of teriparatide use for spinal fusion has not been explored. Methods: Forty-five women with osteoporosis diagnosed with degenerative spondylolisthesis from one of the three treatment groups were evaluated based on: short-duration treatment (average, 5.5 months; n=15; daily subcutaneous injection of 20 μg teriparatide), long-duration treatment (average, 13.0 months; n=15; daily subcutaneous injection of 20 μg teriparatide), and bisphosphonate treatment (average, 13.0 months; n=15; weekly oral administration of 17.5 mg risedronate). All patients underwent PLF with a local bone graft. Fusion rate and duration of bone union were evaluated 1.5 years after surgery. Results: Bone union rate and average duration for bone union were 92% and 7.5 months in the long-duration treatment group, 80% and 8.5 months in the short-duration treatment group, and 70% and 10.0 months in the bisphosphonate treatment group, respectively. Results of bone union rate and average duration for bone union in the teriparatide treatment groups were significantly superior to those in the bisphosphonate treatment group (p <0.05); whereas, significantly superior results were observed in long-duration treatment group when compared with short-duration treatment group (p <0.05). Conclusions: Daily injection of teriparatide for bone union was more effective than oral administration of bisphosphonate. Furthermore, a longer period of teriparatide treatment for bone union was more effective than a shorter period of same treatment.

Does Discontinuing Teriparatide Treatment and Replacing It with Bisphosphonate Maintain the Volume of the Bone Fusion Mass after Lumbar Posterolateral Fusion in Women with Postmenopausal Osteoporosis?

Seiji Ohtori,Sumihisa Orita,Kazuyo Yamauchi,Yawara Eguchi,Yasuchika Aoki,Junichi Nakamura,Miyako Suzuki,Gou Kubota,Kazuhide Inage,Yasuhiro Shiga,Koki Abe,Kazuki Fujimoto,Hirohito Kanamoto,Masahiro Ino 대한척추외과학회 2017 Asian Spine Journal Vol.11 No.2

Study Design: Retrospective case series. Purpose: The purpose of this study was to determine whether discontinuing teriparatide treatment and replacing it with bisphosphonate treatment maintains the volume of the fusion mass after posterolateral fusion (PLF) in women with postmenopausal osteoporosis. Overview of Literature: Clinical data support the efficacy of parathyroid hormone (PTH) for lumbar PLF. However, the use of PTH is limited to 2 years. Methods: We treated 19 women diagnosed with osteoporosis and degenerative spondylolisthesis with teriparatide (20 μg daily subcutaneously). All patients underwent one-level instrumented PLF. Teriparatide was used during 2 months prior to surgery and more than 8 months after surgery. After discontinuing teriparatide treatment, all patients used bisphosphonate (17.5 mg risedronate weekly, oral administration). Area of the fusion mass across the transverse processes at one segment was determined on an anteroposterior radiograph at 1, 2, and 3 years after surgery. Results: We followed 19 patients for 3 years. The average duration of teriparatide treatment was 11.5 months. The bone union rate was 95%. The average area of the bone fusion mass was not significantly different between the right and left sides at 1, 2, or 3 years after surgery (p >0.05). Conclusions: This study showed that replacing teriparatide treatment with bisphosphonate maintained the bone fusion mass volume after PLF in women with postmenopausal osteoporosis.

Do Physical Symptoms Predict the Outcome of Surgical Fusion in Patients with Discogenic Low Back Pain?

Seiji Ohtori,Sumihisa Orita,Kazuyo Yamauchi,Yawara Eguchi,Yasuchika Aoki,Junichi Nakamura,Masayuki Miyagi,Miyako Suzuki,Gou Kubota,Kazuhide Inage,Takeshi Sainoh,Jun Sato,Yasuhiro Shiga,Koki Abe,Kazuki 대한척추외과학회 2016 Asian Spine Journal Vol.10 No.3

Study Design: Retrospective case series. Purpose: To determine whether symptoms predict surgical outcomes for patients with discogenic low back pain (DLBP). Overview of Literature: Specific diagnosis of DLBP remains difficult. Worsening of pain on flexion is a reported symptom of DLBP. This study sought to determine whether symptoms predict surgical outcomes for patients with DLBP. Methods: We investigated 127 patients with low back pain (LBP) and no dominant radicular pain. Magnetic resonance imaging was used to select patients with disc degeneration at only one level. If pain was provoked during discography, we performed fusion surgery (87 patients). Visual analogue scale score and responses to a questionnaire regarding symptoms including worsening of pain on flexion or extension were assessed. Symptom sites before surgery were categorized into LBP alone, or LBP plus referred inguinal or leg pain. We followed 77 patients (average 3.0 years) and compared symptoms before surgery with surgical outcome. Results: Sixty-three patients with a good outcome showed postsurgical pain relief (≥60% pain relief) and 14 patients with a poor outcome did not (<60% pain relief). In patients with good outcomes, worsening of LBP was evident in 65% of cases on flexion and in 35% on extension. However, these findings were not significantly different from those in patients with poor outcomes. The percentage of patients with LBP alone was significantly lower and the percentage of patients with LBP plus referred inguinal or leg pain was significantly higher in the group with good surgical outcome compared with patients in the group with poor surgical outcome (p <0.05). Conclusions: Worsening of pain on extension may be a symptom of DLBP. Surgical outcomes were superior in patients with both LBP and either referred inguinal or leg pain compared with those having LBP alone.

Change of Lumbar Ligamentum Flavum after Indirect Decompression Using Anterior Lumbar Interbody Fusion

Seiji Ohtori,Sumihisa Orita,Kazuyo Yamauchi,Yawara Eguchi,Yasuchika Aoki,Junichi Nakamura,Masayuki Miyagi,Miyako Suzuki,Gou Kubota,Kazuhide Inage,Takeshi Sainoh,Jun Sato,Kazuki Fujimoto,Yasuhiro Shiga 대한척추외과학회 2017 Asian Spine Journal Vol.11 No.1

Study Design: Retrospective case series. Purpose: The purpose of this study was to examine changes in the ligamentum flavum thickness and remodeling of the spinal canal after anterior fusion during a 10-year follow-up. Overview of Literature: Extreme lateral interbody fusion provides minimally invasive treatment of the lumbar spine; this anterior fusion without direct posterior decompression, so-called indirect decompression, can achieve pain relief. Anterior fusion may restore disc height, stretch the flexure of the ligamentum flavum, and increase the spinal canal diameter. However, changes in the ligamentum flavum thickness and remodeling of the spinal canal after anterior fusion during a long follow-up have not yet been reported. Methods: We evaluated 10 patients with L4 spondylolisthesis who underwent stand-alone anterior interbody fusion using the iliac crest bone. Magnetic resonance imaging was performed 10 years after surgery. The cross-sectional area (CSA) of the dural sac and the ligamentum flavum at L1–2 to L5–S1 was calculated using a Picture Archiving and Communication System. Results: Spinal fusion with correction loss (average, 4.75 mm anterior slip) was achieved in all patients 10 years postsurgery. The average CSAs of the dural sac and the ligamentum flavum at L1–2 to L5–S1 were 150 mm2 and 78 mm2, respectively. The average CSA of the ligamentum flavum at L4–5 (30 mm2) (fusion level) was significantly less than that at L1–2 to L3–4 or L5–S1. Although patients had an average anterior slip of 4.75 mm, the average CSA of the dural sac at L4–5 was significantly larger than at the other levels. Conclusions: Spinal stability induced a lumbar ligamentum flavum change and a sustained remodeling of the spinal canal, which may explain the long-term pain relief after indirect decompression fusion surgery.

Time-Course Changes in Bone Metabolism Markers and Density in Patients with Osteoporosis Treated with Romosozumab: A Multicenter Retrospective Study

Kazuhide Inage,Sumihisa Orita,Yawara Eguchi,Yasuhiro Shiga,Masao Koda,Yasuchika Aoki,Toshiaki Kotani,Tsutomu Akazawa,Takeo Furuya,Junichi Nakamura,Hiroshi Takahashi,Miyako Suzuki-Narita,Satoshi Maki,S 연세대학교의과대학 2021 Yonsei medical journal Vol.62 No.9

Purpose: In this multicenter retrospective observational study, we examined the early effects of romosozumab in patients with severeosteoporosis in terms of time-course changes in bone metabolism marker, improvement in bone density, and adverse effects. Materials and Methods: Patients with severe osteoporosis were included. We investigated the progress of TRACP 5b and P1NPbefore and 1–2 months after the administration of romosozumab. We also investigated the bone density of lumbar spine, femoralneck, and the entire femur, measured by the DXA method, before and 5–7 months after the administration of romosozumab. Results: A total of 70 patients (7 males and 63 females, age 75.0±3.6 years) participated in this study. Significant improvements inTRACP 5b and P1NP levels were observed before and 1–2 months after romosozumab administration. The average bone densityof lumbar spine, femoral neck, and the entire femur were measured before and 5–7 months after romosozumab administration;and a significant increase only observed in the lumbar spine. Conclusion: Consistent with the findings of previous clinical studies, romosozumab has both bone formation-enhancing andbone resorption effects (dual effect). In addition, romosozumab also demonstrated improvement in bone density from the earlyphase after the administration, though the result was only seen in the lumbar spine.

Classification of Chronic Back Muscle Degeneration after Spinal Surgery and Its Relationship with Low Back Pain

Seiji Ohtori,Sumihisa Orita,Kazuyo Yamauchi,Yawara Eguchi,Yasuchika Aoki,Junichi Nakamura,Tetsuhiro Ishikawa,Masayuki Miyagi,Hiroto Kamoda,Miyako Suzuki,Gou Kubota,Kazuhide Inage,Takeshi Sainoh,Jun Sa 대한척추외과학회 2016 Asian Spine Journal Vol.10 No.3

Study Design: Retrospective case series. Purpose: To classify back muscle degeneration using magnetic resonance imaging (MRI) and investigate its relationship with back pain after surgery. Overview of Literature: Back muscle injury and degeneration often occurs after posterior lumbar surgery, and the degeneration may be a cause of back pain. However, the relationship between back muscle degeneration and back pain remains controversial. Methods: A total of 84 patients (average age, 65.1 years; 38 men, 46 women) with lumbar spinal stenosis underwent posterior decompression surgery alone. MRI (1.5 tesla) was evaluated before and more than a year after surgery in all patients. Muscle on MRI was classified into three categories: low intensity in T1-weighted imaging, high intensity in T2-weighted imaging (type 1), high intensity in both T1- and T2-weighted images (type 2), and low intensity in both T1- and T2-weighted imaging (type 3). The prevalence of the types and their relationship with back pain (determined on a visual analog scale) were evaluated. Results: MRI revealed muscle degeneration in all patients after surgery (type 1, 6%; type 2, 82%; and type 3, 12%). Type 2 was significantly more frequent compared with types 1 and 3 (p <0.01). Low back pain was significantly improved after surgery (p <0.01). Low back pain was not associated with any MRI type of muscle degeneration after surgery (p >0.05). Conclusions: Various pathologies of back muscle degeneration after posterior lumbar surgery were revealed. Type 2 (fatty) change was most frequent, and other patients had type 3 (scar) or type 1 (inflammation or water-like) changes. According to the Modic classification of bone marrow changes, Modic type 1 change is associated with inflammation and back pain. However, no particular type of back muscle degeneration was correlated with back pain after surgery.

PainVision Apparatus Is Effective for Assessing Low Back Pain

Seiji Ohtori,Hiroshi Kawaguchi,Tsuneo Takebayashi,Sumihisa Orita,Gen Inoue,Kazuyo Yamauchi,Yasuchika Aoki,Junichi Nakamura,Tetsuhiro Ishikawa,Masayuki Miyagi,Hiroto Kamoda,Miyako Suzuki,Gou Kubota,Yos 대한척추외과학회 2014 Asian Spine Journal Vol.8 No.6

Study Design: Case series. Purpose: To determine the utility of “PainVision” apparatus for the assessment of low back pain. Overview of Literature: 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. Methods: 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. Results: 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). Conclusions: PainVision as self-reported questionnaires is a useful tool to assess low back pain.

Evaluation of Behavior and Expression of Receptor Activator of Nuclear Factor-Kappa B Ligand in Dorsal Root Ganglia after Sciatic Nerve Compression and Application of Nucleus Pulposus in Rats

Yoshiyuki Matsuyama,Yoshihiro Sakuma,Miyako Suzuki,Sumihisa Orita,Kazuyo Yamauchi,Gen Inoue,Yasuchika Aoki,Tetsuhiro Ishikawa,Masayuki Miyagi,Hiroto Kamoda,Gou Kubota,Yasuhiro Oikawa,Kazuhide Inage,Ta 대한척추외과학회 2014 Asian Spine Journal Vol.8 No.5

Study Design: Experimental animal study. Purpose: 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. Methods: 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. Results: 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). Conclusions: 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.