Cost-effectiveness of Transforaminal epidural steroid injections for patients with ACUTE sciatica: a randomized controlled trial.

BACKGROUND: Transforaminal epidural injections with steroids (TESI) are increasingly being used in patients sciatica. The STAR (steroids against radiculopathy)-trial aimed to evaluate the (cost-) effectiveness of TESI in patients with acute sciatica (< 8 weeks). This article contains the economic evaluation of the STAR-trial. METHODS: Participants were randomized to one of three study arms: Usual Care (UC), that is oral pain medication with or without physiotherapy, n = 45); intervention group 1: UC and transforaminal epidural steroid injection (TESI) 1 ml of 0.5% Levobupivacaine and 1 ml of 40 mg/ml Methylprednisolone and intervention group 2: UC and transforaminal epidural injection (TEI) with 1 ml of 0,5% Levobupivacaine and 1 ml of 0.9% NaCl (n = 50). The primary effect measure was health-related quality of life. Secondary outcomes were pain, functioning, and recovery. Costs were measured from a societal perspective, meaning that all costs were included, irrespective of who paid or benefited. Missing data were imputed using multiple imputation, and bootstrapping was used to estimate statistical uncertainty. RESULTS: None of the between-group differences in effects were statistically significant for any of the outcomes (QALY, back pain, leg pain, functioning, and global perceived effect) at the 26-weeks follow-up. The adjusted mean difference in total societal costs was €1718 (95% confidence interval [CI]: - 3020 to 6052) for comparison 1 (intervention group 1 versus usual care), €1640 (95%CI: - 3354 to 6106) for comparison 2 (intervention group 1 versus intervention group 2), and €770 (95%CI: - 3758 to 5702) for comparison 3 (intervention group 2 versus usual care). Except for the intervention costs, none of the aggregate and disaggregate cost differences were statistically significant. The maximum probability of all interventions being cost-effective compared to the control was low (< 0.7) for all effect measures. CONCLUSION: These results suggest that adding TESI (or TEI) to usual care is not cost-effective compared to usual care in patients with acute sciatica (< 8 weeks) from a societal perspective in a Dutch healthcare setting. TRIAL REGISTRATION: Dutch National trial register: NTR4457 (March, 6th, 2014).

Ultrasound-guided versus fluoroscopy-guided lumbar selective nerve root block: a retrospective comparative study.

The purpose of this study is to compare the accuracy and effectiveness of ultrasound-guided and fluoroscopy-guided lumbar selective nerve root block (SNRB), and to explore the feasibility of ultrasound-guided methods. This retrospective study included patients with lumbar radicular pain who underwent ultrasound-guided and fluoroscopy-guided selective nerve root block at Honghui Hospital Affiliated to Xi'an Jiaotong University from August 2020 to August 2022. Patients were divided into U-SNRB group and F-SNRB group according to ultrasound-guided or fluoroscopy-guided selective nerve root block. There were 43 patients in U-SNRB group and 20 patients in F-SNRB group. The pain visual analogue scale (VAS) scores, Japanese Orthopaedic Association (JOA) scores, related indexes and complications were recorded and compared between the two groups before, 30 min, 1 month and 6 months after block. To evaluate the feasibility, accuracy and effectiveness of ultrasound-guided selective nerve root block. There were no complications in the process of selective nerve root block in both groups. The operating time and the times of closing needle angle adjustment in U-SNRB group were better than those in F-SNRB group, and the difference was statistically significant (P < 0.05). The VAS score and JOA score of patients in the two groups were significantly improved 30 min after block, 1 month and 6 months after block, and the difference was statistically significant (P < 0.05). There was no significant difference between the two groups (P > 0.05). The accuracy of ultrasound-guided selective nerve root block and the degree of pain relief of patients were similar to those of fluoroscopy guidance, but the operation time and needle angle adjustment times were significantly less than that of fluoroscopy, and could effectively reduce radiation exposure. Therefore, it can be used as a better way to guide for choice.

Treatment method selection for sleep quality due to lumbar DISC herniation: Early surgery or others?; A single center clinical trial.

BACKGROUND/AIM: Sleep deprivation may lead to individual and social insufficiency associated with many physiological and psychological pathologies. This study is reported to investigate sleep quality and the relationship between treatment modalities of lumbar disc herniation, which is the most common cause of chronic lower back pain and sciatica. MATERIALS AND METHODS: This present study was conducted on 249 cases with chronic lower back pain and sciatica caused by a single- level lumbar disc herniation diagnosed after lumbar MRI (Magnetic Resonance Imaging) between June 2017 and September 2019. Cases were divided into three groups according to the treatment modalities: early surgical treatment (n:80), extended conservative treatment (n:142), and medical treatment only (n:27). VAS (Visual Analog Scale) and PSQI (Pittsburgh Sleep Quality Index) data before the treatment and 6 months after the treatment were statistically analyzed. RESULTS: It was determined that post-treatment VAS and PSQI scores were significantly reduced in all cases, regardless of the differences in treatment modalities (p < 0.05). In the early surgical treatment group, VAS score was improved by 69% and PSQI score was improved by 63.8%. These values were 28.5% and 38.6% in the extended conservative treatment. However, VAS score was increased by 27% in the patients who received only medical treatment. Statistical analysis of the treatment modalities showed that early surgical treatment was superior to the other treatment modalities (p < 0.05). CONCLUSIONS: It was determined that early surgical treatment of lumbar disc herniation was superior to other treatment methods in terms of maintaining the sleep quality impairments associated with deterioration in sleep quality.

Full endoscopic versus open discectomy for sciatica: randomised controlled non-inferiority trial.

OBJECTIVE: To assess whether percutaneous transforaminal endoscopic discectomy (PTED) is non-inferior to conventional open microdiscectomy in reduction of leg pain caused by lumbar disc herniation. DESIGN: Multicentre randomised controlled trial with non-inferiority design. SETTING: Four hospitals in the Netherlands. PARTICIPANTS: 613 patients aged 18-70 years with at least six weeks of radiating leg pain caused by lumbar disc herniation. The trial included a predetermined set of 125 patients receiving PTED who were the learning curve cases performed by surgeons who did not do PTED before the trial. INTERVENTIONS: PTED (n=179) compared with open microdiscectomy (n=309). MAIN OUTCOME MEASURES: The primary outcome was self-reported leg pain measured by a 0-100 visual analogue scale at 12 months, assuming a non-inferiority margin of 5.0. Secondary outcomes included complications, reoperations, self-reported functional status as measured with the Oswestry Disability Index, visual analogue scale for back pain, health related quality of life, and self-perceived recovery. Outcomes were measured until one year after surgery and were longitudinally analysed according to the intention-to-treat principle. Patients belonging to the PTED learning curve were omitted from the primary analyses. RESULTS: At 12 months, patients who were randomised to PTED had a statistically significantly lower visual analogue scale score for leg pain (median 7.0, interquartile range 1.0-30.0) compared with patients randomised to open microdiscectomy (16.0, 2.0-53.5) (between group difference of 7.1, 95% confidence interval 2.8 to 11.3). Blood loss was less, length of hospital admission was shorter, and timing of postoperative mobilisation was earlier in the PTED group than in the open microdiscectomy group. Secondary patient reported outcomes such as the Oswestry Disability Index, visual analogue scale for back pain, health related quality of life, and self-perceived recovery, were similarly in favour of PTED. Within one year, nine (5%) in the PTED group compared with 14 (6%) in the open microdiscectomy group had repeated surgery. Per protocol analysis and sensitivity analyses including the patients of the learning curve resulted in similar outcomes to the primary analysis. CONCLUSIONS: PTED was non-inferior to open microdiscectomy in reduction of leg pain. PTED resulted in more favourable results for self-reported leg pain, back pain, functional status, quality of life, and recovery. These differences, however, were small and may not reach clinical relevance. PTED can be considered as an effective alternative to open microdiscectomy in treating sciatica. TRIAL REGISTRATION: NCT02602093ClinicalTrials.gov NCT02602093.

Predicting conservative treatment failure in patients with lumbar disc herniation. Single center, case-control study.

OBJECTIVES: The aim of this study was to identify independent predictors of conservative treatment failure in patients presenting due to lumbar disc herniation-associated low back pain and sciatica. PATIENTS AND METHODS: This is a single institution, case-control study including 240 patients that were selected for microsurgical or conservative treatment due to lumbar disc herniation in a 2,5-year period. Bivariate and multivariate analyses were performed in order to identify independent predictors among demographic, clinical and radiographic factors. RESULTS: Statistically significant differences were observed between conservatively and surgically managed groups in bivariate analysis. Logistic regression models further revealed that leg paresthesia (p =  0,003; OR = 5,136) and percentage of spinal canal stenosis ratio (p < 0,001; OR = 1,055) had the strongest, independent correlation with conservative treatment failure in our cohort. Back-to-leg ratio did not reach statistical significance although it proved a strong correlation in bivariate analysis (p < 0,001, Cramér's V = 0,53). CONCLUSION: Increasing % canal compromise ratio (cut-off value 23%) and co-occurrence of leg paresthesia were the most important risk factors for surgery in our series of patients.

Contribution of dorsal root ganglion octamer transcription factor 1 to neuropathic pain after peripheral nerve injury.

Neuropathic pain genesis is related to gene alterations in the dorsal root ganglion (DRG) after peripheral nerve injury. Transcription factors control gene expression. In this study, we investigated whether octamer transcription factor 1 (OCT1), a transcription factor, contributed to neuropathic pain caused by chronic constriction injury (CCI) of the sciatic nerve. Chronic constriction injury produced a time-dependent increase in the level of OCT1 protein in the ipsilateral L4/5 DRG, but not in the spinal cord. Blocking this increase through microinjection of OCT1 siRNA into the ipsilateral L4/5 DRG attenuated the initiation and maintenance of CCI-induced mechanical allodynia, heat hyperalgesia, and cold allodynia and improved morphine analgesia after CCI, without affecting basal responses to acute mechanical, heat, and cold stimuli as well as locomotor functions. Mimicking this increase through microinjection of recombinant adeno-associated virus 5 harboring full-length OCT1 into the unilateral L4/5 DRG led to marked mechanical allodynia, heat hyperalgesia, and cold allodynia in naive rats. Mechanistically, OCT1 participated in CCI-induced increases in Dnmt3a mRNA and its protein and DNMT3a-mediated decreases in Oprm1 and Kcna2 mRNAs and their proteins in the injured DRG. These findings indicate that OCT1 may participate in neuropathic pain at least in part by transcriptionally activating Dnmt3a and subsequently epigenetic silencing of Oprm1 and Kcan2 in the DRG. OCT1 may serve as a potential target for therapeutic treatments against neuropathic pain.

Epidemiology and etiology of secondary piriformis syndrome: A single-institution retrospective study.

Piriformis syndrome (PS) is a rare etiology of extra-spinal sciatica in which pathologies associated with or around the piriformis muscle (PM) irritate the adjacent sciatic nerve (SN), however, there is scarcity in the literature regarding its exact etiologies, thus, we performed a retrospective study to elucidate the epidemiology of PS and assess various causes of the syndrome. Our study included patients assessed at our institution who presented with sciatica of non-spinal origin between May 2014 and December 2015. Radiology reports of all patients who received pelvic MRI were examined for positive findings involving PM and SN. Of the 143 patients recognized with sciatica and negative lumbar pathology, 24 patients (17%) exhibited positive PM and SN findings. Average patient age was 50.0 ±â€¯15.1 years (range: 21-75), and 17 were female. Seven patients (5%; 4M/3F) presented with tumor, seven patients (5%) had chronic inflammatory changes, one patient had SN adhesions to obturator muscle, three patients (2%, 3F) had aberrant anatomy, and the remaining patients had positive MRI findings, such as nerve atrophy or PM hypertrophy without identifiable cause. Seven patients received steroid injections in the peri-sciatic fossa, and four displayed poor response. Our findings suggested possible trends in extra-spinal sciatica. Affected males appeared more likely to present with tumor, while affected females were more likely to present younger, but with aberrant anatomy. Steroid injections appeared to be suboptimal in most cases. Pelvic MRI is helpful in patients with sciatica and negative spine imaging to rule out neoplastic involvement.

18F-FDG PET/MRI in Chronic Sciatica: Early Results Revealing Spinal and Nonspinal Abnormalities.

Chronic sciatica is a major cause of disability worldwide, but accurate diagnosis of the causative pathology remains challenging. In this report, the feasibility of an 18F-FDG PET/MRI approach for improved diagnosis of chronic sciatica is presented. Methods:18F-FDG PET/MRI was performed on 9 chronic sciatica patients and 5 healthy volunteers (healthy controls). Region-of-interest analysis using SUVmax was performed, and 18F-FDG uptake in lesions was compared with that in the corresponding areas in healthy controls. Results: Significantly increased 18F-FDG uptake was observed in detected lesions in all patients and was correlated with pain symptoms. 18F-FDG-avid lesions not only were found in impinged spinal nerves but also were associated with nonspinal causes of pain, such as facet joint degeneration, pars defect, or presumed scar neuroma. Conclusion: The feasibility of 18F-FDG PET/MRI for diagnosing pain generators in chronic sciatica was demonstrated, revealing various possible etiologies.

Prenatal alcohol exposure is a risk factor for adult neuropathic pain via aberrant neuroimmune function.

BACKGROUND: Clinical studies show that prenatal alcohol exposure (PAE) results in effects that persist into adulthood. Experimental animal models of moderate PAE demonstrate that young adults with PAE display potentiated sensitivity to light touch, clinically termed allodynia, following sciatic nerve chronic constriction injury (CCI) that coincides with heightened spinal glial, spinal macrophage, and peripheral immune responses. However, basal touch sensitivity and corresponding glial and leukocyte activation are unaltered. Therefore, the current study explored whether the enduring pathological consequences of moderate PAE on sensory processing are unmasked only following secondary neural insult. METHODS: In middle-aged (1 year) Long Evans rats that underwent either prenatal saccharin exposure (control) or moderate PAE, we modified the well-characterized model of sciatic neuropathy, CCI, to study the effects of PAE on neuro-immune responses in adult offspring. Standard CCI manipulation required 4 chromic gut sutures, while a mild version applied a single suture loosely ligated around one sciatic nerve. Spinal glial immunoreactivity was examined using immunohistochemistry. The characterization and functional responses of leukocyte populations were studied using flow cytometry and cell stimulation assays followed by quantification of the proinflammatory cytokines interleukin-1beta (IL-1ß) and tumor necrosis factor-alpha (TNF-α). Data were statistically analyzed by ANOVA and unpaired t tests. RESULTS: The current report demonstrates that mild CCI generates robust allodynia only in PAE rats, while the pathological effects of PAE following the application of a standard CCI are revealed by enhanced allodynia and elevated spinal glial activation. Additionally, mild CCI increases spinal astrocyte activation but not microglia, suggesting astrocytes play a larger role in PAE-induced susceptibility to aberrant sensory processing. Leukocyte populations from PAE are altered under basal conditions (i.e., prior to secondary insult), as the distribution of leukocyte populations in lymphoid organs and other regions are different from those of controls. Lastly, following in vitro leukocyte stimulation, only PAE augments the immune response to antigen stimulation as assessed by heightened production of TNF-α and IL-1ß. CONCLUSIONS: These studies demonstrate PAE may prime spinal astrocytes and peripheral leukocytes that contribute to enduring susceptibility to adult-onset neuropathic pain that is not apparent until a secondary insult later in life.

MRI-detection rate and incidence of lumbar bleeding sources in 190 patients with non-aneurysmal SAH.

BACKGROUND: Up to 15% of all spontaneous subarachnoid hemorrhages (SAH) have a non-aneurysmal SAH (NASAH). The evaluation of SAH patients with negative digital subtraction angiography (DSA) is sometimes a diagnostic challenge. Our goal in this study was to reassess the yield of standard MR-imaging of the complete spinal axis to rule out spinal bleeding sources in patients with NASAH. METHODS: We retrospectively analyzed the spinal MRI findings in 190 patients with spontaneous NASAH, containing perimesencephalic (PM) and non-perimesencephalic (NPM) SAH, diagnosed by computer tomography (CT) and/or lumbar puncture (LP), and negative 2nd DSA. RESULTS: 190 NASAH patients were included in the study, divided into PM-SAH (n = 87; 46%) and NPM-SAH (n = 103; 54%). Overall, 23 (22%) patients had a CT negative SAH, diagnosed by positive LP. MR-imaging of the spinal axis detected two patients with lumbar ependymoma (n = 2; 1,05%). Both patients complained of radicular sciatic pain. The detection rate raised up to 25%, if only patients with radicular sciatic pain received an MRI. CONCLUSION: Routine radiological investigation of the complete spinal axis in NASAH patients is expensive and can not be recommended for standard procedure. However, patients with clinical signs of low-back/sciatic pain should be worked up for a spinal pathology.

Causal effect estimation strategies in a longitudinal study with complex time-varying confounders: A tutorial.

The Dutch Sciatica Trial represents a longitudinal study with complex time-varying confounders as patients with poorer health conditions (e.g. more severe pain) are more likely to opt for surgery, which, in turn, may affect future outcomes (pain severity). A straightforward classical as-treated comparison at the end point would lead to biased estimation of the surgery effect. We present several strategies of causal treatment effect estimation that might be applicable for analyzing such data. These include an inverse probability of treatment weighted regression analysis, a marginal weighted analysis, an unweighted regression analysis, and several propensity score-based approaches. In addition, we demonstrate how to evaluate these approaches in a thorough simulation study where we generate various realistic complex confounding patterns akin to the sciatica study.

SOCS1 regulates neuropathic pain by inhibiting neuronal sensitization and glial activation in mouse spinal cord.

Neuropathic pain is still a basic science and clinical challenge now, the neuronal sensitization and glial activation in the spinal cord (SC) level are more far-reaching for contributing to pain hypersensitivity following chronic constriction injury (CCI). Accumulating evidence indicates that astrocytes and microglia are activated in the spinal cord dorsal horn (SCDH) after CCI. Suppressor of cytokine signaling 1 (SOCS1) plays an important role in regulating of neuronal inflammation. Here, we investigated the role of SOCS1 in SC played in neuropathic pain. We find SOCS1 was persistently downregulated in the spinal neurons after CCI in mice. On the contrary, overexpression of SOCS1 in the SC reversed CCI-induced pain behavioral, activation of neurons, astrocytes, microglia, and the expression of proinflammatory cytokines including tumor necrosis factor α (TNF-α), interleukin 1ß (IL-1ß) and IL-6. Over all, these results demonstrate that downregulation of SOCS1 contributed to the development and maintenance of neuropathic pain via activating of neurons, astrocytes, microglia, and proinflammatory cytokines. SOCS1 may be developed into a potential target for treating neuropathic pain.

Resolvin D1 Inhibits Mechanical Hypersensitivity in Sciatica by Modulating the Expression of Nuclear Factor-κB, Phospho-extracellular Signal-regulated Kinase, and Pro- and Antiinflammatory Cytokines in the Spinal Cord and Dorsal Root Ganglion.

BACKGROUND: Accumulating evidence indicates that spinal inflammatory and immune responses play an important role in the process of radicular pain caused by intervertebral disk herniation. Resolvin D1 (RvD1) has been shown to have potent antiinflammatory and antinociceptive effects. The current study was undertaken to investigate the analgesic effect of RvD1 and its underlying mechanism in rat models of noncompressive lumbar disk herniation. METHODS: Rat models of noncompressive lumber disk herniation were established, and mechanical thresholds were evaluated using the von Frey test during an observation period of 21 days (n = 8/group). Intrathecal injection of vehicle or RvD1 (10 or 100 ng) was performed for three successive postoperative days. On day 7, the ipsilateral spinal dorsal horns and L5 dorsal root ganglions (DRGs) were removed to assess the expressions of tumor necrosis factor-α (TNF-α), interleukin-1ß (IL-1ß), IL-10, and transforming growth factor-ß1 (TGF-ß1) and the activation of nuclear factor-κB (NF-κB)/p65 and phospho-extracellular signal-regulated kinase (p-ERK) signaling (n = 30/group). RESULTS: The application of nucleus pulposus to L5 DRG induced prolonged mechanical allodynia, inhibited the production of IL-10 and TGF-ß1, and up-regulated the expression of TNF-α, IL-1ß, NF-κB/p65, and p-ERK in the spinal dorsal horns and DRGs. Intrathecal injection of RvD1 showed a potent analgesic effect, inhibited the up-regulation of TNF-α and IL-1ß, increased the release of IL-10 and TGF-ß1, and attenuated the expression of NF-κB/p65 and p-ERK in a dose-dependent manner. CONCLUSIONS: The current study showed that RvD1 might alleviate neuropathic pain via regulating inflammatory mediators and NF-κB/p65 and p-ERK pathways. Its antiinflammatory and proresolution properties may offer novel therapeutic approaches for the management of neuropathic pain.

Does Serum Visfatin Represent a Biochemical Marker to an Experimental Peripheral Neuropathic Pain in Mice.

The effects of pregabalin on neuropathic pain relief and the serum visfatin level were assessed using an experimental model of neuropathy in a study conducted on 40 male mice with sciatic nerve constriction. The mice were randomly assigned to 4 groups, each with 10 mice. The mice were subjected to experimental chronic partial constriction of the sciatic nerve and compared to sham-operated, saline-treated control mice (group I). The experimental groups (II-IV) were subjected to partial constriction of the left sciatic nerve. A series of behavioral tests, electrophysiological studies and biochemical measures were performed after 3 weeks of daily oral treatment with pregabalin (20 and 40 mg/kg in groups III and IV, respectively). The study revealed the actions of pregabalin against the nociceptive effects of chronic sciatic nerve constriction in mice (p < 0.01), including replenishment of the glutathione level (p < 0.05) and reduction of the serum visfatin level. No significant effect on the tissue malondialdehyde level was found for any of the pregabalin doses. The percentage differences in the maximum tetanic force between the ipsilateral and contra lateral legs were significant in both pregabalin-treated groups (p < 0.05). We concluded that pregabalin reduced the serum visfatin level and produced a dose-dependent antinociceptive antioxidant effect.

Engagement of the GABA to KCC2 signaling pathway contributes to the analgesic effects of A3AR agonists in neuropathic pain.

More than 1.5 billion people worldwide suffer from chronic pain, yet current treatment strategies often lack efficacy or have deleterious side effects in patients. Adenosine is an inhibitory neuromodulator that was previously thought to mediate antinociception through the A1 and A2A receptor subtypes. We have since demonstrated that A3AR agonists have potent analgesic actions in preclinical rodent models of neuropathic pain and that A3AR analgesia is independent of adenosine A1 or A2A unwanted effects. Herein, we explored the contribution of the GABA inhibitory system to A3AR-mediated analgesia using well-characterized mouse and rat models of chronic constriction injury (CCI)-induced neuropathic pain. The deregulation of GABA signaling in pathophysiological pain states is well established: GABA signaling can be hampered by a reduction in extracellular GABA synthesis by GAD65 and enhanced extracellular GABA reuptake via the GABA transporter, GAT-1. In neuropathic pain, GABAAR-mediated signaling can be further disrupted by the loss of the KCC2 chloride anion gradient. Here, we demonstrate that A3AR agonists (IB-MECA and MRS5698) reverse neuropathic pain via a spinal mechanism of action that modulates GABA activity. Spinal administration of the GABAA antagonist, bicuculline, disrupted A3AR-mediated analgesia. Furthermore, A3AR-mediated analgesia was associated with reductions in CCI-related GAD65 and GAT-1 serine dephosphorylation as well as an enhancement of KCC2 serine phosphorylation and activity. Our results suggest that A3AR-mediated reversal of neuropathic pain increases modulation of GABA inhibitory neurotransmission both directly and indirectly through protection of KCC2 function, underscoring the unique utility of A3AR agonists in chronic pain.

MMPIP, an mGluR7-selective negative allosteric modulator, alleviates pain and normalizes affective and cognitive behavior in neuropathic mice.

This study investigated the effects of a single administration of 6-(4-methoxyphenyl)-5-methyl-3-pyridinyl-4-isoxazolo[4,5-c]pyridin-4(5H)-one (MMPIP), a negative allosteric modulator (NAM) of metabotropic glutamate receptor 7 (mGluR7), on pain and on affective and cognitive behavior in neuropathic mice. The activity of pyramidal neurons in the prelimbic cortex (PLC), which respond to stimulation of the basolateral amygdala (BLA) with either excitation or inhibition, was also investigated. The spared nerve injury (SNI) of the sciatic nerve induced, 14 days after surgery, thermal hyperalgesia and mechanical allodynia, reduced open-arm choice in the elevated plus-maze, increased time of immobility in the tail suspension, and increased digging and burying in the marble burying test. Cognitive performance was also significantly compromised in the SNI mice. Spared nerve injury induced phenotypic changes on pyramidal neurons of the PLC; excitatory responses increased, whereas inhibitory responses decreased after BLA stimulation. mGluR7 expression, mainly associated with vesicular glutamate transporter, increased in the hippocampus and decreased in the BLA, PLC, and dorsal raphe in SNI mice. MMPIP increased thermal and mechanical thresholds and open-arm choice. It reduced the immobility in the tail suspension test and the number of marbles buried and of digging events in the marble burying test. MMPIP also improved cognitive performance and restored the balance between excitatory and inhibitory responses of PLC neurons in SNI mice. 7-hydroxy-3-(4-iodophenoxy)-4H-chromen-4-one, XAP044, another selective mGluR7 NAM, reproduced the effects of MMPIP on thermal hyperalgesia, mechanical allodynia, tail suspension, and marble burying test. Altogether, these findings show that mGluR7 NAMs reduce pain responses and affective/cognitive impairments in neuropathic pain conditions.

Peripheral interleukin-4 ameliorates inflammatory macrophage-dependent neuropathic pain.

There is increasing evidence that inflammatory (M1-polarized) macrophages drive the nonresolving neuroinflammation that causes neuropathic pain after nerve injury. As interleukin-4 (IL-4) promotes the suppressive (M2-polarized) state in macrophages, we examined whether exploiting an IL-4-mediated pathway could ameliorate M1 macrophage-dependent neuropathic pain. The mRNA and protein expression of IL-4 receptor α chain (IL-4Rα) were upregulated in accumulating F4/80 macrophages in injured sciatic nerve (SCN). In mouse macrophage cell line J774A.1, IL-4 downregulated the mRNA expression of M1 macrophage-specific molecules (IL-1ß, CC chemokine ligand 3, and CD86) normally provoked by lipopolysaccharide, while increasing the mRNA expression of M2 macrophage-specific molecules (arginase-1, IL-10, and CD206) through a STAT6-mediated pathway. In ex vivo SCN culture, M1 molecules were highly expressed in the injured SCN on day 7 after partial SCN ligation (PSL) but were decreased by IL-4 treatment. In contrast, M2 molecules were upregulated by IL-4. IL-4 also increased phosphorylated STAT6 (pSTAT6) expression and shifted IL-1ß M1 macrophages toward a CD206 M2 phenotype. Perineural administration of IL-4 in mice subject to PSL ameliorated development and maintenance of tactile allodynia and thermal hyperalgesia. These effects of IL-4 were based on that IL-4 treatment increased the proportions of pSTAT6 and CD206 macrophages in injured SCN on day 14 after PSL. We found that neuropathic pain can be ameliorated by IL-4 treatment, which exerts its therapeutic effect on accumulating macrophages through a STAT6-dependent pathway. A shift in macrophage phenotype from the inflammatory to the suppressive phenotype, driven by IL-4R signaling, may have benefits in the treatment of neuropathic pain.

A randomized clinical trial comparing the effectiveness of ultrasound guidance versus nerve stimulation for lateral popliteal-sciatic nerve blocks in obese patients.

OBJECTIVES: Ultrasound guidance may decrease the procedural time for many peripheral nerve blocks compared to nerve stimulation, but these studies have generally excluded obese patients. This single-blinded randomized clinical trial was designed to compare procedural times and related outcomes for ultrasound- versus nerve stimulation-guided lateral popliteal-sciatic nerve blockade specifically in obese patients. METHODS: With Institutional Review Board approval and informed consent, patients with a body mass index greater than 30 kg/m(2) who were scheduled for foot/ankle surgery and desiring a peripheral nerve block were offered enrollment. Study patients were randomly assigned to receive a lateral popliteal-sciatic nerve block under either ultrasound or nerve stimulation guidance. The patient and assessor were blinded to group assignment. The primary outcome was procedural time in seconds. Secondary outcomes included number of needle redirections, procedure-related pain, patient satisfaction with the block, success rate, sensory and motor onset times, block duration, and complication rates. RESULTS: Twenty-four patients were enrolled and completed the study. All patients had successful nerve blocks. The mean procedural times (SD) were 577 (57) seconds under nerve stimulation and 206 (40) seconds with ultrasound guidance (P< .001; 95% confidence interval for difference, 329-412 seconds). Patients in the ultrasound group had fewer needle redirections and less procedure-related pain, required less opioids, and were more satisfied with their block procedures. There were no statistically significant differences in other outcomes. CONCLUSIONS: The results of this study show that, for obese patients undergoing lateral popliteal-sciatic nerve blocks, ultrasound guidance reduces the procedural time and procedure-related pain and increases patient satisfaction compared to nerve stimulation while providing similar block characteristics.

Influence of low back pain and prognostic value of MRI in sciatica patients in relation to back pain.

BACKGROUND: Patients with sciatica frequently complain about associated back pain. It is not known whether there are prognostic relevant differences in Magnetic Resonance Imaging (MRI) findings between sciatica patients with and without disabling back pain. METHODS: The study population contained patients with sciatica who underwent a baseline MRI to assess eligibility for a randomized trial designed to compare the efficacy of early surgery with prolonged conservative care for sciatica. Two neuroradiologists and one neurosurgeon independently evaluated all MR images. The MRI readers were blinded to symptom status. The MRI findings were compared between sciatica patients with and without disabling back pain. The presence of disabling back pain at baseline was correlated with perceived recovery at one year. RESULTS: Of 379 included sciatica patients, 158 (42%) had disabling back pain. Of the patients with both sciatica and disabling back pain 68% did reveal a herniated disc with nerve root compression on MRI, compared to 88% of patients with predominantly sciatica (P<0.001). The existence of disabling back pain in sciatica at baseline was negatively associated with perceived recovery at one year (Odds ratio [OR] 0.32, 95% Confidence Interval 0.18-0.56, P<0.001). Sciatica patients with disabling back pain in absence of nerve root compression on MRI at baseline reported less perceived recovery at one year compared to those with predominantly sciatica and nerve root compression on MRI (50% vs 91%, P<0.001). CONCLUSION: Sciatica patients with disabling low back pain reported an unfavorable outcome at one-year follow-up compared to those with predominantly sciatica. If additionally a clear herniated disc with nerve root compression on MRI was absent, the results were even worse.

Caudal vs transforaminal epidural steroid injections as short-term (6 months) pain relief in lumbar spinal stenosis patients with sciatica.

OBJECTIVE: The aim of this study is to evaluate prospectively the efficacy of caudal epidural steroid injection (CESI) and transforaminal epidural steroid injection (TFESI) in lumbar spinal stenosis patients with sciatic pain. DESIGN: Prospective clinical study. SETTING AND PATIENTS: Thirty-one patients (average age 62 years) from two hospitals, with single dermotomal distribution of sciatic pain due to spinal stenosis were included in the study. INTERVENTIONS: Patients underwent epidural steroid injections done by the same injectionist. Eleven patients from one hospital were included in the CESI group, while the TFESI group consisted of 20 comparable patients from the second site. OUTCOME MEASURES: Primary outcome measure was the complete relief or at least 50% reduction of pain (visual analog scale [VAS]) at 6 months postinjection. Secondary outcome measures were the improvement of function (of at least 15 points of Oswestry Disability Index [ODI]) at 6 months and the changes of VAS and ODI and at 2 weeks, at 3 months, and at 6 months postinjection. RESULTS: A significantly greater number of stenosis patients showed pain relief at 6 months postinjection with TFSI (90%) than with CESI (54.54%). All patients with TFSI showed improvement of function at 6 months while only three (27.27%) patients with caudal epidural improved functionally. Out of the total 31 patients, two patients from group A underwent a second CESI at 15 days postinjection and decompressive spine surgery between 3 and 6 months postinjection. CONCLUSIONS: The effectiveness of transforaminal steroid injection for the stenosis patients with sciatica was superior to caudal at 6 months postinjection.