Epidural Posterior Insular Stimulation Alleviates Neuropathic Pain Manifestations in Rats With Spared Nerve Injury Through Endogenous Opioid System.

OBJECTIVES: Neuropathic pain (NP) is defined as constant disabling pain secondary to a lesion or disease of the somatosensory nervous system. This condition is particularly difficult to treat because it often remains resistant to most treatment strategies. Despite the recent diversification of neurostimulation methods, some patients still suffer from refractory pain syndromes. The central role of the posterior insular cortex (PI) in the modulation of pain signaling and perception has been repeatedly suggested. The objective of this study is to assess whether epidural insular stimulation (IS) could reverse NP behavior. MATERIALS AND METHODS: A total of 53 adult Sprague-Dawley rats received left-sided spared nerve injury (SNI) or Sham-SNI to induce NP symptoms. Afterward, epidural electrodes were implanted over the right PI. After two weeks of postoperative recovery, three groups of SNI-operated rats each received a different stimulation modality: Sham-IS, low-frequency-IS (LF-IS), or high-frequency-IS (HF-IS). Behavioral and functional tests were conducted before and after IS. They comprised the acetone test, pinprick test, von Frey test, and sciatic functional index. An additional LF-IS group received a dose of opioid antagonist naloxone before IS. Intergroup means were compared through independent-samples t-tests, and pre- and post-IS means in the same group were compared through paired t-tests. RESULTS: We found a significant reduction of cold allodynia (p = 0.019), mechanical hyperalgesia (p = 0.040), and functional disability (p = 0.005) after LF-IS but not HF-IS. Mechanical allodynia only showed a tendency to decrease after LF-IS. The observed analgesic effects were reversed by opioid antagonist administration. CONCLUSION: These results suggest a significant reversal of NP symptoms after LF-IS and offer additional evidence that IS might be beneficial in the treatment of resistant NP syndromes through endogenous opioid secretion. Relying on our novel epidural IS model, further fine tuning of stimulation parameters might be necessary to achieve optimal therapeutic effects.

Somatosensory Thalamic Activity Modulation by Posterior Insular Stimulation: Cues to Clinical Application Based on Comparison of Frequencies in a Cat Model.

BACKGROUND: The posterior insula (PI) has been proposed as a potential neurostimulation target for neuropathic pain relief as it represents a key-structure in pain processing. However, currently available data remain inconclusive as to efficient stimulation parameters. OBJECTIVE: As frequency was shown to be the most correlated parameter to pain relief, this study aims to evaluate the potential modulatory effects of low frequency (LF-IS, 50 Hz) and high-frequency (HF-IS, 150 Hz) posterior insular stimulation on the activity of somatosensory thalamic nuclei. MATERIALS AND METHODS: Epidural bipolar electrodes were placed over the PI of healthy adult cats, and extracellular single-unit activities of nociceptive (NS), nonnociceptive (NN), and wide dynamic range (WDR) thalamic cells were recorded within the ventral posterolateral nucleus and the medial division of the thalamic posterior complex. Mean discharge frequency and burst firing mode were analyzed before and after either LF-IS or HF-IS. RESULTS: LF-IS showed a significant thalamic modulatory effects increasing the firing rate of NN cells (p ≤ 0.03) and decreasing the burst firing of NS cells (p ≤ 0.03), independently of the thalamic nucleus. Conversely, HF-IS did not induce any change in firing properties of the three recorded cell types. CONCLUSION: These data indicate that 50 Hz IS could be a better candidate to control neuropathic pain.

Intrathecal Baclofen Therapy for Refractory Spasticity: A Case Series.

BACKGROUND: Management of refractory spasticity symptoms remains a challenging task for clinicians. Intrathecal baclofen (ITB) therapy has emerged as a promising option for treating this condition. This study evaluates the effectiveness of ITB therapy in managing refractory spasticity symptoms. METHODS: A retrospective chart review was conducted on 34 patients with refractory spasticity symptoms who underwent ITB therapy at a single institution. The patients' demographics, clinical characteristics, and dosages were recorded. The primary outcome measures were the reduction in pain, improvement in mobility, decrease in spasm frequency, and alleviation of spasticity. RESULTS: ITB therapy successfully reduced pain, improved mobility, decreased spasm frequency, and alleviated spasticity. The mean daily administered dose was 245 µg (range: 88-510 µg, standard deviation:104). However, it was observed that the appropriate dosage of ITB therapy was patient-specific and time-sensitive. Moreover, side effects were observed when an incorrect dose was administered. CONCLUSIONS: ITB therapy is an effective and safe option for managing refractory spasticity symptoms. However, the appropriate dosage should be individualized and monitored closely to avoid side effects. This study highlights the importance of carefully considering the potential risks and benefits of ITB therapy for each patient.

Pentoxifylline significantly reduces radicular pain secondary to lumbar disc hernia: A prospective, randomized crossover, single-blind controlled pilot study.

BACKGROUND AND OBJECTIVES: Optimal medical treatment for low back pain, sometimes associated to radicular pain, has yet to be established. Herniated nucleus pulposus has been found to release TNFα, a pro-inflammatory cytokine involved in radiculopathy. Interestingly, Pentoxifylline (PTX), a phosphodiesterase inhibitor, blocks the activity of TNFα. The aim of this study is to assess the effectiveness of PTX when added to the treatment protocol of radiculopathy in lumbar disc herniation. METHODS: Fifty-eight patients with radicular pain secondary to a lumbar disc hernia were included in this prospective, randomized crossover, single-blind controlled study. PTX was added randomly to the same treatment protocol (ibuprofen + paracetamol + pregabalin) either during the first or the second 15 days of treatment. Patients' pain was assessed at day 15 via the Numeric Rating Scale (NRS) and the Patient's Global Impression of Change score (PGIC). D15 NRS value was considered as the primary outcome measure. RESULTS: Mean D15 NRS score was 3.2 ± 0.84 during the 15-days treatment with PTX, and 5,1 ± 0.97 during the 15-days treatment without PTX (p < 0.0001). During the 15 days treatment period with/without PTX, PGIC score was (7) in 19/3 patients, (6) in 30/10 patients, (5) in 7/27 patients and (4) in 2/18 patients respectively, difference being highly significant (p < 0.0000). CONCLUSION: Adjunction of PTX to the standard medical treatment of radicular pain associated with lumbar disc hernia seems to significantly decrease patients' pain intensity in addition to improving their global satisfaction with treatment.

Outcome and Prognosis of Microsurgical Decompression in Idiopathic Severe Common Fibular Nerve Entrapment: Prospective Clinical Study.

OBJECTIVE: Compression of the common fibular nerve at the level of the fibular neck is considered to be the most frequent lower limb entrapment syndrome, which can be either idiopathic or secondary. Decompressive surgery is indicated only after failure of conservative treatment and/or severe neurologic deficit. The effectiveness of microsurgical decompression has been established only for secondary entrapment syndrome. The aim of this study is to assess the results of microsurgical decompression and establish the prognosis of idiopathic severe common fibular nerve entrapment. METHODS: Fifteen patients were included in this prospective clinical study and were followed at day 1 after surgery and later at 1, 6, and 12 months. More than half (64.3%) of patients had a total motor deficit (0/5). The median motor function preoperatively was 0/5. The average time of conservative treatment before surgery was 25.7 days (range 5-110 days). One patient refused surgical management. RESULTS: Thirteen out of 14 patients who underwent surgery showed significant motor function improvement. The median motor strength at 12 months was 4.5/5. Half of the patients regained normal motor function. The only patient who did not improve had the longest time to surgery interval (110 days). The patient who refused surgery showed no improvement (0/5 at 12 months). CONCLUSIONS: Microsurgical decompression should be considered early in the context of severe idiopathic common fibular nerve entrapment in order to get a favorable outcome.

Motor Cortex Stimulation Regenerative Effects in Peripheral Nerve Injury: An Experimental Rat Model.

BACKGROUND: Immediate microsurgical nerve suture remains the gold standard after peripheral nerve injuries. However, functional recovery is delayed, and it is satisfactory in only 2/3 of cases. Peripheral electrical nerve stimulation proximal to the lesion enhances nerve regeneration and muscle reinnervation. This study aims to evaluate the effects of the motor cortex electrical stimulation on peripheral nerve regeneration after injury. METHODS: Eighty rats underwent right sciatic nerve section, followed by immediate microsurgical epineural sutures. Rats were divided into 4 groups: Group 1 (control, n = 20): no electrical stimulation; group 2 (n = 20): immediate stimulation of the sciatic nerve just proximal to the lesion; Group 3 (n = 20): motor cortex stimulation (MCS) for 15 minutes after nerve section and suture (MCSa); group 4 (n = 20): MCS performed over the course of two weeks after nerve suture (MCSc). Assessment included electrophysiology and motor functional score at day 0 (baseline value before nerve section), and at weeks 4, 8, and 12. Rats were euthanized for histological study at week 12. RESULTS: Our results showed that MCS enhances functional recovery, nerve regeneration, and muscle reinnervation starting week 4 compared with the control group (P < 0.05). The MCS induces higher reinnervation rates even compared with peripheral stimulation, with better results in the MCSa group (P < 0.05), especially in terms of functional recovery. CONCLUSIONS: MCS seems to have a beneficial effect after peripheral nerve injury and repair in terms of nerve regeneration and muscle reinnervation, especially when acute mode is used.

Differential effect of motor cortex stimulation on unit activities in the ventral posterior lateral thalamus in cats.

Although motor cortex stimulation (MCS) is being increasingly used to treat chronic refractory neuropathic pain in humans, its mechanisms of action remain elusive. Studies in animals have suggested the involvement of subcortical structures, in particular, the thalamus. Most of these studies have been performed in rats, a species presenting significant differences in thalamic anatomy and function relative to primates, in particular, a very limited number of thalamic GABA interneurons. The aim of this study was to investigate the effects of MCS on single-unit activities of the thalamic ventral posterior lateral (VPL) nucleus in cats, which contains substantial numbers of GABA interneurons. Spontaneous and evoked activities of VPL units were studied before and after MCS. Motor cortex stimulation induced significant depression of the wide-dynamic-range (WDR) cells' firing rate, concomitant with activity enhancement of nonnociceptive (NN) units. More than half of WDR cells showed a significant decrease in the firing rate, while a similar proportion of NN units exhibited the opposite after-effect. Maximal firing attenuation of WDR cells occurred when the MCS location matched somatotopically their receptive field. Repetition of MCS runs led to an accentuation of WDR depression. After peripheral stimulation, evoked activity in each cell showed MCS effects similar to those observed in spontaneous activity. These data demonstrate a selective top-down inhibition by MCS of nonspecific nociceptive (WDR) cells, enhanced by somatotopic concordance and stimulation repetition, in parallel to facilitation of NN cells. These 2 outcomes may play a role in the complex analgesic effect of MCS observed in neuropathic pain conditions.

Bupivacaine Field Block With Clonidine for Postoperative Pain Control in Posterior Spine Approaches: A Randomized Double-Blind Trial.

BACKGROUND: The synergistic effect of clonidine with bupivacaine, well established in peripheral nerve blocks, remains controversial in local field block for postoperative analgesia. OBJECTIVE: To investigate the potential analgesic benefit of adding clonidine to bupivacaine during preincisional field block in posterior approaches for spine surgeries. METHODS: Two hundred twenty-five patients were enrolled in this study and underwent lumbar spinal fusion (n = 80), lumbar laminectomy (n = 25), lumbar microdiscectomy (n = 94), or cervical laminectomy (n = 26). In each surgical subgroup, patients were randomly assigned in a double-blinded fashion to receive either 20 mL of 0.25% bupivacaine alone (control group, n = 109) or with 150 µg clonidine (clonidine group, n = 116) in the form of a preincisional field block. Outcome parameters included area under the curve of pain from postoperative day D0 to D8 and rescue morphine consumption from D0 to D3. RESULTS: The area under the curve was reduced in the clonidine group, particularly in the microdiscectomy subgroup, and without reaching statistical significance in the cervical laminectomy subgroup. Total rescue morphine consumption was reduced in the clonidine group, particularly at D1-D2, a benefit that was exclusive to the lumbar stenosis and lumbar fusion subgroups. Field block with clonidine, surgical subgroup, and the presence of preoperative spinal pain were factors independently influencing postoperative wound pain in multivariate analysis. CONCLUSION: The addition of clonidine to local preincisional field block with bupivacaine resulted in better and prolonged postoperative analgesia in posterior lumbar spine surgeries, an effect that was more pronounced in patients with no preoperative spinal pain.

Radiofrequency ablation of spinal osteoid osteoma: a prospective study.

OBJECTIVE Surgery has been considered the standard treatment for spinal osteoid osteomas that are refractory to analgesic agents. Radiofrequency ablation (RFA) is a less invasive technique with established efficiency for the treatment of peripheral osteoid osteomas. The main objectives of this study are to evaluate the safety of RFA based on the results of a previous experimental study in rats conducted in the authors' laboratory and to identify its short- and long-term efficiency in the treatment of spinal osteoid osteomas. METHODS Between March 2009 and July 2016, 8 consecutive patients with spinal osteoid osteomas were enrolled in the study and underwent 9 CT-guided RFA procedures. All patients presented with spinal pain (median preoperative visual analog scale [VAS] score 7.55, range 6-8.8) predominantly during the night, and they all had normal neurological examination results before the procedure. Pain (according to the VAS score) and neurological status were reassessed immediately before discharge, with further follow-up at 1, 6, and 12 months after the procedure. At the final follow-up, VAS score, neurological examination, patient satisfaction, and a radiological control (CT scan) were documented (median 48 months, range 12-84 months). VAS scores before and after the procedure were compared during the 3 days before surgery (D0), on the day of the surgery, Day 1 (D1), and at the final follow-up. RESULTS No neurological deficit was documented following the procedure or at the final follow-up. A statistically significant reduction in the VAS score was observed on Day 1 (mean 2.56 ± 0.68, p = 0.005) compared with D0. At the final follow-up, all patients reported a VAS score of 0 and a satisfaction rate of 100%. Only 1 patient had recurrent symptoms (pain, VAS score 8.1) 6 months after the initial RFA. A second procedure was performed, and the patient was subsequently symptom free at the final follow-up. CT scanning performed in all patients (12-84 months post-RFA) showed residual sclerosis in 4 patients and complete resolution of the radiological lesion in the remaining 4 patients. CONCLUSIONS CT-guided RFA appears to be a safe and effective method for the management of spinal osteoid osteoma and can be safely performed for lesions close to the dura or exiting nerve root based on the motor response threshold testing performed during the procedure. It should be considered the treatment of choice for spinal osteoid osteomas refractory to conservative treatment, thus avoiding more aggressive spinal approaches with subsequent potential morbidity.

Stereotactic functional mapping of the cat motor cortex.

Epidural motor cortex stimulation is an increasingly used method to control refractory neuropathic pain although its mechanisms of action remain poorly understood. Animal models are currently developed that allow reproducing the conditions of this neurosurgical approach and clarifying its mechanisms. In this study we validate a new stereotactic functional map of the cat motor cortex carried out in epidural conditions, thus allowing future experimentations that closely mimic the technique used in humans.

Pathological effects and motor response threshold changes following radiofrequency application at various distances from the L-5 nerve root: an experimental study.

OBJECT: Radiofrequency (RF) ablation is a minimally invasive technique often used percutaneously in the treatment of many conditions such as spasticity, pain, and osteoid osteoma. The purpose of this study was to assess the value of motor response threshold (MRT) as an indirect indicator of the RF generator's electrode to nerve distance, and to evaluate the effects of RF at various distances from a nervous structure. METHODS: The L-5 nerve root was studied in 102 Sprague-Dawley rats (sham contralateral side). Motor response thresholds at 0, 2, 4, 5, and 6 mm from the nerve root were assessed before and after RF application for 2 minutes at 80° C on Days 0 and 7. Radiofrequency was applied 0, 2, 4, 5, and 6 mm away from L-5 and with the addition of interposed cortical bone. The effects of RF application on MRT were studied, and subsequent nerve injury was evaluated using light microscopy pathological examination. RESULTS: There is a significant correlation between MRT and the distance between the electrode tip and L-5, with MRT less than 0.5 V when the electrode was in direct contact with the root. Electrical and pathological changes following RF application were more pronounced at 0 mm, with worsening seen on Day 7. Radiofrequency at 2 and 4 mm produced fewer electrical and histological deleterious effects on the nerve on Days 0 and 7, with an obvious improvement on Day 7. At 5 mm, electrical and histological abnormalities were minimal on Day 0 and were fully reversible on Day 7. At 6 mm and with interposed cortical bone, MRT and pathological findings were unchanged on Days 0 and 7. CONCLUSIONS: The MRT proved to be a useful and reliable tool in decreasing nerve morbidity following RF ablation in animals and may be used in humans for the same purpose. It serves as an indirect indicator of the proximity of the RF generator's electrode tip to any adjacent motor nervous structure. A minimum safe distance of 5 mm between the electrode tip and the nerve is required to avoid irreversible nerve injury, unless a bony wall is interposed between them, thus serving as a nerve shield. In medical conditions that require RF ablation of the nerve, such as spasticity and pain, the MRT must be lower than 0.5 V. When a nerve lesion is to be avoided such as in cases of osteoid osteoma, an MRT higher than 2.5 V is considered safe, reflecting a distance greater than 5 mm.