Characterisation of the effects of pulsed radio frequency treatment of the dorsal root ganglion on cerebrospinal fluid cellular and peptide constituents in patients with chronic radicular pain: A randomised, triple-blinded, controlled trial.

INTRODUCTION: Chronic radicular neuropathic pain is a major clinical problem with a life time prevalence of more than 50%. Pulsed radiofrequency (PRF) treatment is a recognised therapy. However, the pathophysiology of chronic neuropathic pain (CNP) and the mechanism of action of PRF remains ill-defined. Improving our knowledge of the mechanisms of CNP and PRF action will enhance our ability to treat patients with this common debilitating problem more effectively. This study aims to characterise the CSF cellular and peptide constituents in patients with CNP and the effect of pulsed radiofrequency (PRF) on these constituents and reported pain. MATERIALS AND METHODS: Prospective randomised tripled-blinded control trial of patients receiving PRF treatment versus sham for radicular pain. All patients received local anaesthetic to the appropriate dermatome to confirm diagnosis. Clinical assessment using standard clinical assessment tools and examination of CSF using flow cytometry and ELISA for cellular and peptide constituents was carried out before and 3 months after treatment. RESULTS: Ten patients were randomised to PRF (n = 5) or Sham (n = 5) treatment. PRF resulted in a significant reduction in pain score (NRS) at 3 months (6.8 to 2.6, p < .05). PRF reduced the TNF-α concentration and CD3+ count in CSF. CD4/CD8 ratio of patients with CNP was lower than historical controls (1.4 versus 3.0-4.2). The majority of CD3+ cells in the CNP patients were activated effector memory cells (80%) versus the surveillance central memory cells (85%) seen in healthy controls. CONCLUSIONS: PRF is superior to local anaesthetic administration for the management of radicular pain and is associated with CSF constituent modulation in vivo. Patients with CNP have lymphocyte characteristics which suggest immune activation.

An investigation into the modulation of T cell phenotypes by amitriptyline and nortriptyline.

Amitriptyline is prescribed for treating the symptoms of neuroinflammatory disorders including neuropathic pain and fibromyalgia. As amitriptyline has evidence of modulating the neuroimmune interface; the effects of amitriptyline treatment on T-cell phenotype and function were examined in vitro. Peripheral blood mononuclear cells(PBMCs) were isolated and treated with amitriptyline, nortriptyline and a combination of both drugs. Toxicity for T-cells was assessed by Annexin V/Propidium Iodide staining. Activation status and cytokine expression by T-cells post treatment was assessed by flow cytometry. The levels of secreted cytokines, chemokines and neurotrophins were measured by ELISA in the supernatants. There was no significant increase in T-cell death following 24 or 48 h compared to controls. There were significantly lower frequencies of CD8+ T-cells after treatment with amitriptyline, nortriptyline and a combination of both compared to a Vehicle Control(VC)(p<0.001). The frequencies of naive CD8+CD45RA+ cells were significantly lower after amitriptyline, nortriptyline and a combination of both (p<0001). The frequencies of CD27+CD4+(p<0.05) and CD27+CD8+(p<0.01) T-cells were also significantly lower following combination drug treatment. Significantly lower frequencies of IFN-γ-producing CD8+ T-cells were observed with all treatment combinations(p<0.05) and frequencies of IL-17-producing CD4+ and CD8+ T-cells were significantly lower following amitriptyline treatment (p<0.05). Frequencies of Natural Killer T-cells were significantly higher following treatment with nortriptyline (p<0.05). Significantly higher levels of IL-16 (p<0.001) and lower levels of TNF-ß (p<0.05) were observed in supernatants. This data indicates that both amitriptyline and nortriptyline modulate the phenotype and function of T-cells and this may have clinical relevance in the pathologies of its off-label applications.

Dorsal root ganglion pulsed radiofrequency treatment for chronic cervical radicular pain: a retrospective review of outcomes in fifty-nine cases.

Pulsed radiofrequency treatment adjacent to the cervical dorsal root ganglion is used to treat persistent cervical radicular pain that has not responded to conservative therapies. This technique has gained popularity in years for both cervical and lumbosacral radicular pain. The evidence to support its use is still evolving. METHODS: We performed a retrospective review of outcomes in 59 patients who underwent this therapy over a 3-year period in our institution. We evaluated a reduction in pain, duration of pain relief, reduction in use of analgesics and progression to surgery. RESULTS: Our results demonstrated 49 patients experienced some relief. Forty patients of the 59 experienced an improvement in pain of 50% or more. The mean duration of relief in this group was 37 weeks. Seven patients experienced complete resolution of their pain. In this group, the mean duration of relief was 39 weeks. Regarding the 53 patients who were taking medication for pain prior to the procedure, 37 patients reduced or discontinued their usage after the procedure. CONCLUSION: Despite the limitations of a retrospective study, we feel our study adds to the growing evidence base that pulsed radiofrequency treatment adjacent to the cervical dorsal root ganglion has a role in the treatment of chronic cervical radicular pain.

Human dorsal root ganglion pulsed radiofrequency treatment modulates cerebrospinal fluid lymphocytes and neuroinflammatory markers in chronic radicular pain.

Radicular pain is a common cause of disability. Traditionally treatment has been either epidural steroid injection providing short-term relief or surgery with associated complications. Pulsed radiofrequency (PRF) applied to the dorsal root ganglion (DRG) is a minimally invasive day-care treatment, which is gaining significant clinical acceptance in a selective group of patients with pure radicular pain. Greater insights into the immunomodulatory effects of this procedure may help to further optimise its application and find alternative treatment options. We have examined it's effect on lymphocyte frequencies and secreted inflammatory markers in the cerebrospinal fluid (CSF) and correlated this with clinical outcome to identify clinical markers of chronic radicular pain. Ten patients were recruited for the study. CSF lymphocyte frequencies and levels of cytokines, chemokines and growth factors were quantified using flow cytometry and enzyme-linked immunosorbent assay (ELISA), respectively. Clinical assessment utilised Brief Pain Inventory scores. Nine out of ten patients (90%) demonstrated significant reduction in pain severity (p = 0.0007) and pain interference scores (p = 0.0015) three months post-treatment. Our data revealed significant reductions in CD56+, CD3-, NK cell frequencies (p = 0.03) and IFN-γ levels (p = 0.03) in treatment responders, while CD8+ T cell frequencies (p = 0.02) and IL-6 levels were increased (p = 0.05). IL-17 inversely correlated with post-treatment pain severity score (p = 0.01) and pre and post-treatment pain interference scores (p = 0.03, p = 0.01). These results support the concept that chronic radicular pain is a centrally mediated neuroimmune phenomenon and the mechanism of action of DRG PRF treatment is immunomodulatory.

Spinal cord stimulation for FBSS and CRPS: A review of 80 cases with on-table trial of stimulation.

BACKGROUND: Spinal cord stimulation (SCS) is used for the treatment of chronic neuropathic pain, a notoriously difficult condition to treat. Failed Back Surgery Syndrome (FBSS) and Complex Regional Pain syndrome (CRPS) remain the strongest indications. Funding remains a difficult issue and the use of trial of stimulation is the traditional method of ensuring best outcomes from implantation. METHODS: A retrospective and consecutive review of 80 cases of spinal cord stimulation for patients with a diagnosis of FBSS and CRPS having undergone prior comprehensive medical management and interventional treatment with no sustained benefit. Trial of stimulation was performed on-table and if acceptable coverage was achieved, the case proceeded to full implantation. RESULTS: The mean patient age was 50.08 years (range 28-80 years). At 12 months follow-up, thirty two patients (40%) no longer required analgesic medication. Thirty patients (37.5%) reported their pain was manageable with first line analgesics. Fourteen (17.5%) reported their pain was manageable first line analgesic and occasional tramadol or codeine. Four (5%) reported that their pain was manageable with NSAID's, paracetamol, amitriptyline, and regular codeine or tramadol. Seventeen out of eighty patients (21.25%) were unemployed before SCS implant, and at 12 months follow up eight of these patients (47.05%) had returned to work. There was no infective complications or explants. Two patients (2.53%) required one lead revision, which was successful. CONCLUSION: SCS is the most effective treatment for FBSS and CRPS, which is proven resistant to medical management. On-table trial and implantation is easy to perform with good success rate and low morbidity and if successful will reduce complication rates, especially infection.

Central and systemic inflammatory responses to thoracotomy - potential implications for acute and chronic postsurgical pain.

Chronic postsurgical pain (CPSP) may affect up to 70% of patients after surgery. Glial and immune mediators have been implicated in the pathogenesis of chronic postsurgical pain. Our objective was to study cerebrospinal fluid (CSF) and serum concentrations of IL-1ß, IL-6, IL-8, IL-10, IFNγ and TNFα over a 72-hour period in patients undergoing a thoracotomy and oesophagectomy. Despite adequate pain control, thoracotomy was still associated with significant central and peripheral inflammation. This must be taken into consideration in planning future strategies to prevent CPSP.

Cerebrospinal fluid levels of vascular endothelial growth factor correlate with reported pain and are reduced by spinal cord stimulation in patients with failed back surgery syndrome.

OBJECTIVES: Spinal cord stimulation (SCS) is an efficacious therapy for chronic neuropathic pain whose precise mechanism of action is unclear. Mediators produced by glial and immune cells are now believed to modulate neuronal transmission and promote chronic neuropathic pain. We postulated a relationship between cerebrospinal fluid (CSF) concentrations of neuroimmune mediators and SCS. MATERIALS AND METHODS: We measured CSF concentrations of the chemokine, monocyte chemotactic protein-1 (MCP-1), and the growth factors, brain-derived neurotrophic factor (BDNF), and vascular endothelial growth factor (VEGF) and tested for relationships with stimulation parameters and clinical response in nine patients with failed back surgery syndrome (FBSS). RESULTS: Patients with FBSS had higher CSF concentrations of BDNF (p = 0.01) and MCP-1 (p = 0.0001) than matched controls. CSF concentrations of BDNF and VEGF correlated with reported pain (p = 0.04). Five minutes of SCS resulted in a reduction in median VEGF concentrations (p = 0.01). CONCLUSIONS: Patients with FBSS have altered CSF levels of BDNF and MCP-1. CSF VEGF correlates with pain and is reduced by SCS. This may offer novel insights into both the mechanism of action of SCS in FBSS and the variation in clinical response that may be encountered.

Surgery induces cyclooxygenase-2 expression in the rat cervical spinal cord.

BACKGROUND AND OBJECTIVES: Nonsteroidal anti-inflammatory drugs with a selective cyclooxygenase-2 (COX-2) inhibitory profile are effective analgesics in the postoperative period. This implies that surgery induces COX-2 biosynthesis. We examined whether peripheral surgical trauma can induce COX-2 expression in the rat cervical spinal cord. METHODS: Sprague-Dawley rats were divided into 2 groups. The control group underwent general anesthesia but had no surgery. The surgical group underwent general anesthesia and surgical exposure of neck structures. After 14 days, the animals were euthanized, and a section of cervical spinal cord was taken to identify COX-1 and COX-2 expression by immunohistochemical analysis. Two independent blinded observers analyzed the slides. RESULTS: Analysis of COX-1 protein expression revealed homogenous staining in glial cells in all regions of the cervical spinal cord examined. There was no difference in expression between the control and surgical groups. However, whereas the control group demonstrated minimal COX-2 expression, the surgical group showed extensive neuronal and glial cell cytoplasmic COX-2 expression. CONCLUSIONS: This study demonstrates that surgery induces COX-2 expression in the rat cervical spinal cord. This could provide a scientific rationale for the use of selective COX-2 inhibitors as analgesics in the postoperative period.

The use of pulsed radiofrequency treatment for chronic benign pancreatitis pain.

Current analgesic strategies for the management of pain caused by chronic benign pancreatitis are poorly defined and frequently unsuccessful. Strategies have included pharmacotherapy, surgery, and interventional pain techniques such as celiac plexus blockade. Persistent quality analgesia with acceptable side effect profiles is difficult to achieve. Pulsed radiofrequency treatment is a minimally neurodestructive technique that may alter nerve conduction and offer a reduction in pain perception. We describe our experience with this technique in two patients with pain secondary to chronic benign pancreatitis.

Nimesulide 90 mg orally twice daily does not influence postoperative morphine requirements after major chest surgery.

BACKGROUND: Cyclooxygenase 2 inhibition has proven analgesic efficacy in a variety of surgical procedures. We postulated that perioperative cyclooxygenase 2 inhibition significantly reduces postoperative morphine requirements after major thoracic surgery and investigated the site of this potential analgesic effect. METHODS: Ninety-two patients participated in this single-center, double-blind, randomized, placebo-controlled, parallel-group trial. Patients between the ages of 18 and 80 yr undergoing a thoracotomy or median sternotomy were randomized to receive either nimesulide or placebo in combination with a standard analgesic regimen perioperatively. Nimesulide was administered orally the evening before surgery and at 12-h intervals for 5 days postoperatively. The primary efficacy variables were morphine consumption and pain scores for the first 48 h postoperatively. The secondary efficacy variable was the effect of nimesulide on cyclooxygenase activity in cerebrospinal fluid (CSF). RESULTS: Pain scores at rest or with movement, and total morphine consumption for the first 48 h postoperatively, were not statistically different between the groups. The mean difference in total morphine consumption up to 48 h postoperatively between the nimesulide and placebo group was a 9.0 mg reduction (95% CI: -28.9 to 10.9 mg) (P = 0.37). Adjusted mean (se) CSF 6-keto-PGF1alpha (6-keto-PGF1alpha) concentrations increased by 54.7 (25.7) pg/mL from preoperatively to Day + 2 postoperatively in the placebo group, whereas adjusted mean (se) CSF 6-keto-PGF1alpha concentration decreased by 0.6 pg/mL (18.2 pg/mL) in the nimesulide group. These changes were not statistically different between the groups (P = 0.095). CONCLUSION: Nimesulide, at a dose of 90 mg twice daily in combination with a standard analgesic regimen, does not influence pain scores, morphine requirements, or CSF prostaglandin levels after major thoracic surgery.

Management strategies for neuropathic pain in different European countries.

Many healthcare professionals are aware of the management protocols for nociceptive pain. However, the diagnosis and management of neuropathic pain remains, for many. a confusing and uncertain topic. This paper looks at neuropathic pain management in two countries, Poland and the Republic of Ireland, and discusses the analgesic strategies for the management of this common type of pain.

Spinal prostaglandin formation and pain perception following thoracotomy: a role for cyclooxygenase-2.

STUDY OBJECTIVE: Prostaglandins (PGs) generated in the spinal cord may play a major role in pain perception. Consequently, the suppression of spinal cyclooxygenase (COX) and PG formation may contribute to the analgesic effect of nonsteroidal anti-inflammatory drugs (NSAIDs) in pain following surgery. Which isoform of COX is responsible for postsurgical pain and, consequently, should be targeted, is unclear. DESIGN: Prospective randomized blinded study. SETTING: University teaching hospital. PATIENTS: Thirty patients undergoing thoracotomy for lobectomy were recruited. INTERVENTIONS: Patients were randomized to receive the COX-2 selective inhibitor nimesulide, 100 mg orally twice daily, or ibuprofen (nonselective), 400 mg orally three times daily, in an open-label study. In addition, there was a randomized control group that received no NSAIDs. Cerebrospinal fluid (CSF) was analyzed for 6-keto-PGF(1)alpha, the principle metabolite of prostacyclin. COX-1 and COX-2 activity was determined by measuring serum thromboxane (TX) B(2) and endotoxin-induced PGE(2) generation in whole blood. MEASUREMENTS: Pain perception was measured by visual analog scores, and blinded assessment of opioid analgesic requirements and expiratory peak flow measurements were performed. RESULTS: At the doses used, nimesulide was selective for COX-2, while ibuprofen was nonselective based on serum TXB(2) levels. The mean (+/- SEM) levels of 6-keto-PGF(1)alpha in CSF increased following surgery from 32 +/- 4.9 to 127 +/- 29 pg/mL (p < 0.001), and this was suppressed by nimesulide (49 +/- 9.3 pg/mL; p = 0.0025) but not by ibuprofen (122 +/- 35 pg/mL). Pain scores (p < 0.001), morphine requirement (p = 0.0175), and the fall in peak expiratory flow rate (p < 0.001) were significantly lower in the nimesulide group. CONCLUSIONS: Increases in spinal PG synthesis after thoracotomy are repressed by a selective COX-2 inhibitor. This suggests that the inducible COX-2 mediates central PG synthesis, which may be important in the generation of pain, as the use of nimesulide also resulted in significant decreases in postoperative pain perception.

Comparison between repeat bolus intrathecal morphine and an epidurally delivered bupivacaine and fentanyl combination in the management of post-thoracotomy pain with or without cyclooxygenase inhibition.

OBJECTIVE: To compare the analgesic efficacy of a traditional epidurally delivered bupivacaine/fentanyl combination with a repeat bolus intrathecal morphine technique in the management of post-thoracotomy pain and to assess further the effect of cyclooxygenase (COX) inhibition on both modalities. DESIGN: Prospective, randomized, blinded study. SETTING: University teaching hospital. PARTICIPANTS: Patients having thoracic surgery. INTERVENTIONS: Epidural and intrathecal catheters were inserted. Blood and urine samples were collected for analysis. COX-1 and COX-2 inhibition with ibuprofen and nimesulide (COX-2 selective) was instituted. MEASUREMENTS AND MAIN RESULTS: Pain was assessed at rest and coughing by visual analog scale. Peak expiratory flow rate, patient satisfaction rating, sedation score, analgesic requirements, and preoperative and postoperative urinary creatinine levels were measured. The spinal and nimesulide combination showed the lowest pain scores (p < 0.001), least reduction in peak expiratory flow rate (p < 0.001), and highest patient satisfaction rating (p = 0.02). COX inhibition did not affect analgesic requirements in the epidural group or increase urinary creatinine in any group. CONCLUSION: The intrathecal morphine and nimesulide combination offered significantly better analgesia than any other combination studied. The efficacious interaction between opioids and nonsteroidal anti-inflammatory drugs may be COX-2 mediated.