Comparison of the effects of treatment with celecoxib, loxoprofen, and acetaminophen on postoperative acute pain after arthroscopic knee surgery: A randomized, parallel-group trial.

BACKGROUND: Selective cyclooxygenase-2 (COX-2) inhibitors, conventional non-selective nonsteroidal anti-inflammatory drugs (NSAIDs), and acetaminophen have been adopted for the relief of mild to moderate acute and chronic pain. However, it remains unclarified whether the therapeutic differences in pain sensation exist among these agents. The aim of this study was to compare the efficacy of different types of analgesic agents for postoperative acute pain management. METHODS: A single-center, randomized, controlled study was performed in consecutive patients who underwent the second-look procedure with removal of internal fixation after anterior cruciate ligament reconstruction or arthroscopic meniscal repair/meniscectomy. Celecoxib (400 mg for the first dose and then 200 mg), loxoprofen (60 mg), or acetaminophen (600 mg) was orally administered from postoperative 3 h. The pain intensity on a 100-mm VAS scale and subjective assessment of therapeutic pain-relief were compared among these three treatment groups until postoperative 2 days. The acquired data were analyzed according to the per-protocol analysis principle. RESULTS: A total of 432 patients were screened, and 160 were enrolled. The VAS score tended to decrease over time in all groups. There was a significant improvement in the pain score both at rest and on movement, and subjective impression in the celecoxib-treated group compared with acetaminophen at postoperative 2 days. On the other hand, loxoprofen resulted in the benefit only in the pain score at rest in comparison with acetaminophen. Any comparisons between celecoxib and loxoprofen showed insignificant differences throughout observations. No adverse effects were confirmed in each group. CONCLUSIONS: These obtained findings in our dose setting conditions suggest that celecoxib and loxoprofen treatments were superior to acetaminophen in pain-relief, though the superiority of loxoprofen over acetaminophen was modest. Overall, selective COX-2 inhibitors including conventional NSAIDs seem to have a possible advantage in acute pain management of relatively less invasive surgery.

Mid-term and long-term follow-up data after placement of the Graf stabilization system for lumbar degenerative disorders.

OBJECT: The Graf pedicle screw and ligament device is designed to provide flexible stabilization to prevent abnormal spinal movement. The purpose of this study was to investigate radiographic and clinical outcomes during a minimal 5-year follow-up period. METHODS: Between 1991 and 1997, 43 consecutive patients (whose mean age was 61 years) with lumbar degenerative disease underwent decompression and stabilization in which the Graf system was placed. Data were available for 31 patients who attended follow up for the minimal 5-year period. In a retrospective review, the authors assessed measurements on radiographs, clinical results (using Japanese Orthopaedic Association [JOA] Scale scores), and low-back pain (using a visual analog scale [VAS] score), preoperatively and postoperatively at 1, 3, 5, and/or 10 years. Radiographic measurements included sagittal and frontal range of motion (ROM), regional lordosis, and posterior disc height as well as the extent of degenerative spondylolisthesis. Final follow-up JOA and VAS scores were significantly better than preoperative scores. Sagittal and frontal ROM was significantly reduced at 1 and 5 years, respectively, compared with preoperative values, and a gradual reduction persisted throughout the follow-up period. Compared with its preoperative status, the disc height ratio (adjacent segments to the operated level) was reduced 5 years after surgery. A significant inhibition of the vertebral slippage was detected only in the flexion position. CONCLUSIONS: Analysis of these data indicated that the Graf system eventually leads to successful fusion, suggesting the presence of stability in all three dimensions. The use of the Graf system should continue to be evaluated as an alternative device in the treatment of lumbar degenerative disease.

Changes in pain behavior and histologic changes caused by application of tumor necrosis factor-alpha to the dorsal root ganglion in rats.

STUDY DESIGN: Histologic changes in the dorsal root ganglion (DRG) and the nociceptive stimulation thresholds were studied in rats. OBJECTIVE: To examine the effects of tumor necrosis factor-alpha (TNF) with special reference to pain behavior and histology of the DRG. SUMMARY OF BACKGROUND DATA: Recently, it was reported that local application of nucleus pulposus induces a characteristic tissue reaction at the surface of the DRG. However, to our knowledge, there have been no previous reports about the relationship between the histologic changes and pain behavior caused by cytokines. METHODS: Recombinant TNF was applied to the L4 DRG. Mechanical and thermal nociceptive thresholds were tested. The L4 DRG was sectioned and observed by light microscopy. RESULTS: After the application of 5 ng/microL TNF, significant differences were observed in mechanical and thermal stimulation thresholds. At the site of application of TNF, a characteristic a semilunar-shaped enlargement was observed. The average width of the part was significantly larger in the 5 ng/microL TNF application, as compared to the 0.5-ng/microL TNF application. CONCLUSIONS: The higher concentration of TNF used induced allodynia and hyperalgesia responses. Because the region showing the histologic changes was significantly larger after application of the higher concentration of TNF, the reaction of the DRG may be related to pain.

Nerve growth factor content in dorsal root ganglion as related to changes in pain behavior in a rat model of experimental lumbar disc herniation.

STUDY DESIGN: The time courses of nerve growth factor content and pain-related behavior were examined using experimental disc herniation models. OBJECTIVES: To investigate a relationship between nerve growth factor level and pain behavior. SUMMARY OF BACKGROUND DATA: An induction of nerve growth factor in the periphery is regarded as a major contributor of inflammatory hyperalgesia and neuropathic pain. However, it has not been clarified quantitatively whether disc herniation induces changes in nerve growth factor levels in the dorsal root ganglion in relation to pain-related behavior. METHODS: A total of 140 rats were used in this study. The animals had their left L4 nerve roots and associated dorsal root ganglion exposed and were equally divided into 4 groups: L4-L5 disc puncture, displacement of L4 nerve roots/dorsal root ganglion, the combination of disc puncture and displacement, and sham exposure. The content of nerve growth factor in the affected dorsal root ganglion was assessed by enzyme-linked immunosorbent assay as well as pain behavior during a postoperative 21-day period. RESULTS: Disc puncture resulted in nerve growth factor induction at postoperative day 3, but not apparent behavioral changes. Mechanical displacement induced nerve growth factor at postoperative day 1 and mechanical allodynia at postoperative day 3, respectively (P < 0.05). In the combination model, there were more pronounced changes in nerve growth factor induction and both mechanical and thermal threshold during 7 days after surgery (P < 0.05). CONCLUSIONS: These data suggest the possibilities that elevated nerve growth factor level is partly involved in pain behavior and further the combined model mimicking the clinical situation, which causes the marked neuronal responses, is helpful to advance the understanding of the mechanisms underlying sciatica due to lumbar disc herniation.

Infliximab attenuates immunoreactivity of brain-derived neurotrophic factor in a rat model of herniated nucleus pulposus.

STUDY DESIGN: The effect of infliximab, a chimeric monoclonal antibody to TNF-alpha, on induction of brain-derived neurotrophic factor (BDNF) was examined using an experimental herniated nucleus pulposus (NP) model. OBJECTIVES: To investigate whether treatment of infliximab could attenuate an induction of BDNF, which functions as a modulator of pain, following NP application to the nerve root. SUMMARY OF BACKGROUND DATA: Evidence from basic scientific studies proposes that TNF-alpha is involved in the development of NP-induced nerve injuries. However, the therapeutic mechanisms of infliximab against pain have not been elucidated experimentally. METHODS: Twenty rats were used in this study. In the test groups, the animals underwent application of NP to the L4 nerve roots and received a single systemic (intraperitoneal) injection of infliximab at the time of surgery (Infli-0 group, n = 5) or at 1 day after operation (Infli-1 group, n = 5). As a control treatment, sterile water was administered intraperitoneally to 5 rats with NP application (NP group) and to 5 sham-operated rats (sham group). On day 3 after surgery, the L4 dorsal root ganglion (DRG) and L4 spinal segment were harvested and assessed regarding BDNF immunoreactivity. RESULTS.: Application of NP induced a marked increase of BDNF immunoreactivity in number in the DRG neurons and within the superficial layer in the dorsal horn compared with the sham group (P < 0.01). Infliximab treatment in the Infli-0 and Infli-1 groups reduced the BDNF induction in both DRG and spinal cord (P < 0.05). CONCLUSION: These findings indicate that infliximab attenuates the elevated BDNF levels induced by NP. The present study therefore further indicates the importance of TNF-alpha in sciatica due to disc herniation and the possible therapeutic use of a TNF-alpha inhibitor for this condition.

Selective inhibition of tumor necrosis factor-alpha prevents nucleus pulposus-induced histologic changes in the dorsal root ganglion.

STUDY DESIGN: The possibility to prevent nucleus pulposus-induced structural changes of the dorsal root ganglion (DRG) by selective tumor necrosis factor-alpha (TNF-alpha) inhibition was assessed in an experimental model in the rat spine. OBJECTIVES: To evaluate the role of TNF-alpha in the mediation of nucleus pulposus-induced structural changes by using selective inhibition and to confirm the effect of TNF-alpha inhibitor at the point of histologic findings. SUMMARY OF BACKGROUND DATA: TNF-alpha is known to be released from the nucleus pulposus, and has been suggested to play a key role in chemical damage of the adjacent nerve tissue. The TNF-alpha inhibitor prevents the reduction of nerve conduction velocity and may limit the nerve fiber injury, intracapillary thrombus formation, and intraneural edema formation caused by nucleus pulposus. However, there is no report on the effect of the inhibitor regarding histologic findings and the appearance of the TNF-alpha in the DRG exposed to nucleus pulposus. METHODS: 1) Rats were treated with an intraperitoneal injection of infliximab. Nucleus pulposus from the disc was obtained 1, 3, 7, 14, and 21 days after the injection. The TNF-alpha-positive cells were observed using immunohistochemistry. 2) Disc herniation of the nucleus pulposus was made on the L4-L5 disc in rats. Two groups were treated with selective TNF-alpha inhibitor 1 day before or 3 hours after surgery. The other group received no TNF-alpha inhibitor. The L4 DRG was resected 1, 3, 7, 14, and 21 days after surgery. The specimens were processed for hematoxylin and eosin staining and immunohistochemistry using rabbit antisera to TNF-alpha. The histologic findings and TNF-alpha-positive cells were observed by light microscopy. RESULTS: 1) While positively stained immunoreactive TNF-alpha appeared between 7 and 21 days, no immunoreactive TNF-alpha was observed 1 and 3 days after injection in the nucleus pulposus. 2) The histologic changes of the DRG caused by nucleus pulposus were smaller in the infliximab treatment group than those in the nontreatment group. The number of immunoreactive TNF-alpha cells was high 1 and 3 days after surgery in the DRGs of disc herniation rats that were treated without an injection of the inhibitor, low on day 7 and 14, and very low on day 21 after surgery. No immunoreactive TNF-alpha was observed in the DRGs of the TNF-alpha inhibitor treatment groups on day 1, 3, and 21 after surgery. Weakly stained cells were sometimes observed in rats at day 7 and 14 after surgery. CONCLUSIONS: Infliximab may prevent the histologic damage induced by nucleus pulposus. When rats were given a single intraperitoneal injection of infliximab at the beginning of disc herniation, the histologic damage seemed to be reduced in comparison with the nontreated rats.

Distribution and appearance of tumor necrosis factor-alpha in the dorsal root ganglion exposed to experimental disc herniation in rats.

STUDY DESIGN: Distribution and appearance of tumor necrosis factor-alpha (TNF-alpha) in the dorsal root ganglion (DRG) exposed to experimental disc herniation were investigated using an immunohistochemical method in rats. OBJECTIVES: To study the distribution and appearance of TNF-alpha in the DRG following experimental disc herniation in rats. SUMMARY OF BACKGROUND DATA: Nucleus pulposus in the epidural space induces spinal nerve root injury not only by mechanical but also chemical mechanisms. Cytokines may play a key role in the chemical damage. There is, however, no report on the distribution and appearance of TNF-alpha in the DRG exposed to nucleus pulposus. METHODS: Nucleus pulposus from the discs was smeared on the glass slides and processed for immunohistochemistry by the avidin-biotinylated peroxidase complex technique using rabbit antisera to TNF-alpha in rats. A herniation of the nucleus pulposus was made by incision of the L4-L5 disc in rats. The L4 and L5 DRGs were resected 1, 3, 7, 14, and 21 days after surgery. The specimens were processed for immunohistochemistry using rabbit antisera to TNF-alpha. The TNF-alpha-positive cells were observed and counted using light microscopy. Distribution of the TNF-alpha products was compared on each day after surgery. RESULTS: A positive staining was seen in the cell bodies and in the matrix between the cells in the smeared nucleus pulposus. In the L4 DRG sections, the number of positive cells was significantly higher in the disc incision group than in the sham group at 1, 3, 7, and 14 days after surgery (P < 0.05). The positive cells showed a decrease in number day by day after surgery. On the contrary, in the L5 DRG, only a few positive cells were observed in the disc incision group after surgery. There was no statistically significant difference between disc incision and the sham groups at each day after surgery for the L5 DRGs. CONCLUSIONS: The immunoreactivity of TNF-alpha in the DRG directly exposed to nucleus pulposus increases during 2 weeks. A collapse of the positive cells was seen in the DRG directly exposed to the nucleus pulposus.

Effects of neutralizing antibodies to tumor necrosis factor-alpha on nucleus pulposus-induced abnormal nociresponses in rat dorsal horn neurons.

STUDY DESIGN: The effect of an anti-tumor necrosis factor alpha (anti-TNFalpha) antibody on abnormal discharges caused by application of nucleus pulposus to the nerve root was investigated in an electrophysiologic study. OBJECTIVES: To assess whether inhibition of TNFalpha can reduce nucleus pulposus-induced abnormal discharges. SUMMARY OF BACKGROUND DATA: It has been shown that TNFalpha, a proinflammatory cytokine, is a key pathogenic factor in the development of nucleus pulposus-induced abnormal discharges as a pain sensation. However, the electrophysiologic mechanisms involved in sciatica after disc herniation still have not been elucidated. METHODS: Extracellular activities of wide-dynamic-range neurons were assessed in 21 rats. Autologous nucleus pulposus harvested from the tail was applied to the L5 nerve root. The animals were simultaneously treated with antibodies to TNFalpha (anti-TNF + nucleus pulposus group) and with phosphate-buffered saline (nucleus pulposus group). As a control (control group), a similar volume of muscle was applied to the nerve root with phosphate-buffered saline. Responses of wide-dynamic-range neurons to noxious and innocuous stimuli were examined for 2 hours. RESULTS: Discharges evoked during noxious stimulation and discharges after withdrawal of stimulation in the nucleus pulposus group were significantly higher than those in the control group (P < 0.05). In the anti-TNF + nucleus pulposus group, discharges after withdrawal of stimulation were remarkably inhibited, as compared with those of the nucleus pulposus group (P < 0.05). However, evoked discharges during stimulation apparently were not inhibited. Responses to innocuous stimulation did not change throughout the measurements. CONCLUSIONS: These data indicate that application of TNFalpha antibodies to the nerve root partially prevents the nucleus pulposus-induced abnormal nociresponses. Therefore, anti-TNFalpha treatment may have a therapeutic effect on sciatica after lumbar disc herniation.

Exogenous tumor necrosis factor-alpha induces abnormal discharges in rat dorsal horn neurons.

STUDY DESIGN: An electrophysiologic study to examine effects of exogenous application of tumor necrosis factor-alpha (TNF-alpha ) activities and nociresponses of dorsal horn neurons in the spinal cord at L5. OBJECTIVES: To investigate the role of TNF-alpha in the induction and development of hyperalgesia in neural mechanisms responsible for a radicular pain. SUMMARY OF BACKGROUND DATA: TNF-alpha is found in the herniated disc and known to play a pivotal role in the development of inflammatory hyperalgesia; however, it is not known whether TNF-alpha causes abnormal discharge in the dorsal horn neurons and enhances nociresponse. METHODS: Single-unit activities of neurons in the L5 superficial dorsal horn were extracellularly recorded, using 28 urethane-anesthetized rats. The wide dynamic range and nociceptive-specific neurons activated by stimulation of the hind paw were selected. Effects of exogenous TNF-alpha were examined regarding 1) spontaneous discharges of wide dynamic range and nociceptive-specific neurons, 2) responses of wide dynamic range neurons to noxious stimulation, and 3) morphologic changes in the dorsal root ganglion. RESULTS: Application of TNF-alpha to the nerve root induced 1) a significant increase in spikes/sec in spontaneous discharges of wide dynamic range and nociceptive-specific neurons, 2) enhanced responses of wide dynamic range neurons to noxious stimulation, and 3) inflammatory changes in the ganglion. CONCLUSION: These results suggest the possibility that TNF-alpha produced in the vicinity of nerve roots due to disc herniation might cause ectopic discharges in primary afferent fibers and thereby induce the prolonged excitation in pain-processing neurons responsible for radicular pain.