Masashi Takaso

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.

Efficacy of Epidural Administration of Anti-Interleukin-6 Receptor Antibody onto Spinal Nerve for Treatment of Sciatica

IntroductionInterleukin-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.MethodsSixty patients with low back and radicular leg pain caused by spinal stenosis were investigated. In 30 patients, we infiltrated 2.0xa0mL of lidocaine and 80xa0mg of tocilizumab onto the affected spinal nerve, and 2.0xa0mL of lidocaine and 3.3xa0mg of dexamethasone were used in 30 patients. Low back pain, leg pain, and leg numbness were evaluated during 1xa0month after spinal nerve infiltration.ResultsInfiltration of tocilizumab was more effective than dexamethasone for leg pain (3xa0days, 1, 2, and 4xa0weeks), low back pain (3xa0days, 1, 2 and 4xa0weeks), and leg numbness (3xa0days, 1 and 2xa0weeks). No adverse event was observed in either group.ConclusionOur 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.

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.

Single-level instrumented posterolateral fusion of the lumbar spine with a local bone graft versus an iliac crest bone graft: a prospective, randomized study with a 2-year follow-up

The iliac crest bone grafting (ICBG) technique for lumbar posterolateral fusion surgery is widely used; however, donor site problems such as pain and sensory disturbance have been reported. Local bone is available for fusion surgery, but its reliability as a graft has not been fully reported. In the current study, we examined single-level instrumented posterolateral fusion with a local bone graft versus an ICBG in a prospective randomized study. Eighty-two patients diagnosed with L4 degenerated spondylolisthesis were divided into two groups at random. Forty-two patients underwent instrumented posterolateral fusion with a local bone graft (L4–L5 level), and 40 patients underwent instrumented posterolateral fusion with an ICBG (L4–L5 level). Rate and duration of bone union, visual analog scale (VAS) score, Japanese orthopedic association score (JOAS), Oswestry Disability Index (ODI), and complications were evaluated before and 2xa0years after therapy. VAS score, JOAS, and ODI were not significantly different between the two groups before and after surgery (Pxa0>xa00.05). Rate and average duration of bone union were 90% and 8.5xa0months in the local bone graft group, and 85% and 7.7xa0months in the ICBG group, but without significant difference (Pxa0>xa00.05). Prolonged surgical time and complications such as donor site pain (8 patients) and sensory disturbance (6 patients) were observed in the ICBG group. If single-level posterolateral fusion was performed, local bone graft technique has the same bone union rate compared with ICBG, requires less surgical time, and has fewer complications.

Nuclear factor-kappa B decoy suppresses nerve injury and improves mechanical allodynia and thermal hyperalgesia in a rat lumbar disc herniation model

Nuclear factor-kappa B (NF-κB) is a gene transcriptional regulator of inflammatory cytokines. We investigated the transduction efficiency of NF-κB decoy to dorsal root ganglion (DRG), as well as the decrease in nerve injury, mechanical allodynia, and thermal hyperalgesia in a rat lumbar disc herniation model. Forty rats were used in this study. NF-κB decoy–fluorescein isothiocyanate (FITC) was injected intrathecally at the L5 level in five rats, and its transduction efficiency into DRG measured. In another 30 rats, mechanical pressure was placed on the DRG at the L5 level and nucleus pulposus harvested from the rat coccygeal disc was transplanted on the DRG. Rats were classified into three groups of ten animals each: a herniationxa0+xa0decoy group, a herniationxa0+xa0oligo group, and a herniation only group. For behavioral testing, mechanical allodynia and thermal hyperalgesia were evaluated. In 15 of the herniation rats, their left L5 DRGs were resected, and the expression of activating transcription factor 3 (ATF-3) and calcitonin gene-related peptide (CGRP) was evaluated immunohistochemically compared to five controls. The total transduction efficiency of NF-κB decoy–FITC in DRG neurons was 10.8% in vivo. The expression of CGRP and ATF-3 was significantly lower in the herniationxa0+xa0decoy group than in the other herniation groups. Mechanical allodynia and thermal hyperalgesia were significantly suppressed in the herniationxa0+xa0decoy group. NF-κB decoy was transduced into DRGs in vivo. NF-κB decoy may be useful as a target for clarifying the mechanism of sciatica caused by lumbar disc herniation.

Inhibiting Nerve Growth Factor or Its Receptors Downregulates Calcitonin Gene-Related Peptide Expression in Rat Lumbar Dorsal Root Ganglia Innervating injured Intervertebral Discs

Nerve growth factor (NGF) and its dual structurally unrelated receptors, tropomyosin‐related kinase A (TrkA) or p75 neurotrophin receptor (p75NTR), cause the pathogenesis of discogenic pain. To investigate the sensory innervation of injured rat lumbar intervertebral disc (IVD), we examined the expression of neuropeptides such as calcitonin gene‐related peptide (CGRP) at dorsal root ganglia (DRG) by inhibiting NGF or its dual receptors. Sprague–Dawley rats with multiply punctured L5–L6 IVD were used. Six experimental groups were prepared: naïve, sham control, and four agent‐treated groups with punctured IVD (vehicle, anti‐NGF antibody, anti‐TrkA antibody, and anti‐p75NTR antibody). Retrograde neurotracer Fluoro‐Gold (FG) was applied together except for the naïve group. Their lumbar DRG were harvested and immunolabeled for CGRP. FG‐labeled DRG neurons were most prevalent at L1 and L2 DRG, and the proportion of FG‐labeled CGRP‐immunoreactive DRG neurons in the vehicle group was significantly elevated (pu2009<u20090.05) compared with the sham group, while those of antibody‐treated groups, especially in the anti‐p75NTR group, significantly decreased compared with the vehicle group (pu2009<u20090.05). Direct intradiscal application of antibody to NGF or its receptors suppressed CGRP expression, and p75NTR antagonism induced the most profound suppression.

Single-level instrumented posterolateral fusion versus non-instrumented anterior interbody fusion for lumbar spondylolisthesis: a prospective study with a 2-year follow-up

BackgroundSurgery for lumbar spondylolisthesis is widely performed. However, there have been no reports comparing posterolateral and anterior interbody fusion prospectively. We compared instrumented posterolateral fusion with anterior interbody fusion for L4 spondylolisthesis in a prospective study.MethodsForty-six patients diagnosed with L4 degenerated spondylolisthesis were divided into two groups. Twenty-two consecutive patients underwent non-instrumented anterior interbody fusion using an iliac bone graft (ALIF; L4–L5 level), and 24 consecutive patients underwent instrumented posterolateral fusion with local bone (PLF; L4–L5 level). The rates of bone union, visual analog scale (VAS) score, Japanese Orthopedic Association (JOA) score, Oswestry Disability Index (ODI), surgical invasion, and complications were evaluated before and 2xa0years after surgery.ResultsAge, VAS score, JOA score, and ODI were not significantly different between the two groups before surgery (Pxa0>xa00.05). Success of bone union between the two groups was not significantly different (Pxa0>xa00.05). Blood loss during surgery was significantly less; however, periods of bed rest and hospital stay were significantly longer in the ALIF group (Pxa0<xa00.05). Overall patient satisfaction, and low back and leg pain in both groups were significantly improved after surgery; however, low back pain showed greater improvement in the ALIF group compared with the PLF group (Pxa0<xa00.05). Complications such as donor site pain (4 patients in the ALIF group) and dural tearing (3 patients in the PLF group) were observed.ConclusionsIf single level fusion for L4 spondylolisthesis is performed, both anterior and posterior methods reduce patients’ low back and leg pain. Improvement of low back pain was significantly greater after ALIF; however, periods of hospital stay and of bed rest were significantly longer.

Proinflammatory cytokines in the cerebrospinal fluid of patients with lumbar radiculopathy

In pathologic radicular pain of lumbar spinal stenosis, cytokines such as tumor necrosis factor-alpha (TNF-α) and interleukins (ILs) play a crucial role in the pathogenesis of nerve degeneration and pain. We investigated TNF-α and IL-6 levels in the cerebrospinal fluid (CSF) of patients with radicular pain caused by lumbar spinal stenosis (LSS). A total of 30 LSS patients and 10 age-matched controls were examined. CSF samples were obtained adjacent to the level of stenosis in 30 LSS patients, and at the L4–L5 level in the 10 control patients. TNF-α and IL-6 levels in the samples were analyzed using enzyme-linked immunosorbent assays (ELISA). We compared the amounts of TNF-α and IL-6 with severity of pain (low back and leg pain), walking ability, and severity of stenosis (cross-sectional area of dural space). The concentration of IL-6 was significantly higher in LSS patients than in controls, but TNF-α levels were beneath the limit of detection. There was no correlation between IL-6 levels and severity of pain or walking ability (pxa0>xa00.05). However, there was a significant correlation between IL-6 levels and severity of stenosis (pxa0<xa00.05). The current study showed that the increased CSF IL-6 levels in LSS patients with radicular pain were not correlated with pain severity; although not proven in this study, the increase in CSF IL-6 concentration could indicate pathological nerve damage or degeneration of lumbar radiculopathy represented by the severity of stenosis.

Efficacy of combination of meloxicam and pregabalin for pain in knee osteoarthritis.

Purpose Osteoarthritic pain is largely considered to be inflammatory pain. Sensory nerve fibers innervating the knee have been shown to be significantly damaged in rat models of knee osteoarthritis (OA) in which the subchondral bone junction is destroyed, and this induces neuropathic pain (NP). Pregabalin was developed as a pain killer for NP; however, there are no reports on pregabalin use in OA patients. The purpose of this study was to investigate the efficacy of pregabalin for pain in OA patients. Materials and Methods Eighty-nine knee OA patients were evaluated in this randomized prospective study. Patients were divided into meloxicam, pregabalin, and meloxicam+pregabalin groups. Pain scores were evaluated before and 4 weeks after drug application using a visual analogue scale (VAS), and Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC). Pain scales among groups were compared using a Kruskal-Wallis test. Results Before drug application, there was no significant difference in VAS and WOMAC scores among the three groups (p>0.05). Significant pain relief was seen in the meloxicam+pregabalin group in VAS at 1, 2, and 4 weeks, and WOMAC score at 4 weeks, compared with the other groups (p<0.05). No significant pain relief was seen in the meloxicam only group in VAS during 4 weeks and WOMAC score at 4 weeks compared with the pregabalin only group (p>0.05). Conclusion Meloxicam+pregabalin was effective for pain in OA patients. This finding suggests that OA pain is a combination of inflammatory and NP.

Low affinity NGF receptor (p75 neurotrophin receptor) inhibitory antibody reduces pain behavior and CGRP expression in DRG in the mouse sciatic nerve crush model

Nerve growth factor (NGF) and its low‐affinity receptor, p75 neurotrophin receptor (p75NTR), are important mediators of pain. To explore further the mechanisms involved, we examined suppression of pain behavior and expression of neuropeptides such as calcitonin gene‐related peptide (CGRP) using a p75 NTR inhibitory antibody, in a mouse sciatic nerve crush model. In the nerve‐injured model, 150 µg of a p75 NTR inhibitory antibody or 10 µl of saline were applied. The sciatic nerve in the sham‐operated group was uninjured. Mechanical allodynia was measured for 2 weeks. CGRP and p75NTR expression in L5 dorsal root ganglions (DRGs) was examined immunohistochemically. Mechanical allodynia was found in the two nerve injured groups, but not in the sham‐operated group (pu2009<u20090.05). However, the magnitude of the mechanical allodynia was significantly decreased after application of p75 NTR inhibitory antibody (pu2009<u20090.05). CGRP and p75NTR immunoreactivity in the L5 DRG neurons was upregulated in the injured nerve groups compared with the sham‐operated group; however, p75 NTR inhibitory antibody decreased the CGRP and p75NTR expression (pu2009<u20090.01). Application of the p75 NTR inhibitory antibody to the pinched sciatic nerve suppressed CGRP and p75NTR expression and pain behavior.