BACKGROUND: Perineural inhibitors of tumor necrosis factor have recently generated intense interest as an alternative to epidural steroid injections for lumbosacral radiculopathy.
OBJECTIVE: To evaluate whether epidural steroids, etanercept, or saline better improves pain and function in adults with lumbosacral radiculopathy.
DESIGN: A multicenter, 3-group, randomized, placebo-controlled trial conducted from 2008 to 2011. Randomization was computer-generated and stratified by site. Pharmacists prepared the syringes. Patients, treating physicians, and nurses assessing outcomes were blinded to treatment assignment. (ClinicalTrials.gov registration number: NCT00733096)
SETTING: Military and civilian treatment centers.
PATIENTS: 84 adults with lumbosacral radiculopathy of less than 6 months' duration.
INTERVENTION: 2 epidural injections of steroids, etanercept, or saline, mixed with bupivacaine and separated by 2 weeks.
MEASUREMENTS: The primary outcome measure was leg pain 1 month after the second injection. All patients had 1-month follow-up visits; patients whose condition improved remained blinded for the 6-month study period.
RESULTS: The group that received epidural steroids had greater reductions in the primary outcome measure than those who received saline (mean difference, -1.26 [95% CI, -2.79 to 0.27]; P = 0.11) or etanercept (mean difference, -1.01 [CI, -2.60 to 0.58]; P = 0.21). For back pain, smaller differences favoring steroids compared with saline (mean difference, -0.52 [CI, -1.85 to 0.81]; P = 0.44) and etanercept (mean difference, -0.92 [CI,-2.28 to 0.44]; P = 0.18) were observed. The largest differences were noted for functional capacity, in which etanercept fared worse than the other treatments: steroids vs. etanercept (mean difference, -16.16 [CI, -26.05 to -6.27]; P = 0.002), steroids vs. saline (mean difference, -5.87 [CI, -15.59 to 3.85]; P = 0.23), and etanercept vs. saline (mean difference, 10.29 [CI, 0.55 to 20.04]; P = 0.04). More patients treated with epidural steroids (75%) reported 50% or greater leg pain relief and a positive global perceived effect at 1 month than those who received saline (50%) or etanercept (42%) (P = 0.09).
LIMITATION: Short-term follow-up, small sample size, and a possibly subtherapeutic dose of etanercept.
CONCLUSION: Epidural steroid injections may provide modest short-term pain relief for some adults with lumbosacral radiculopathy, but larger studies with longer follow-up are needed to confirm their benefits.
PRIMARY FUNDING SOURCE: The John P. Murtha Neuroscience and Pain Institute, International Spinal Intervention Society, and Center for Rehabilitation Sciences Research.
INTRODUCTION: Two subcutaneous injections of adalimumab in severe acute sciatica significantly reduced the number of back operations in a short-term randomised controlled clinical trial.
OBJECTIVE: To determine in a 3-year follow-up study whether the short-term benefit of adalimumab in sciatica is sustained over a longer period of time.
METHODS: The primary outcome of this analysis was incident discectomy. Three years after randomisation, information on surgery could be retrieved in 56/61 patients (92%).A multivariate Cox proportional hazard models, adjusted for potential confounders, was used to determine factors predisposing to surgery.
RESULTS: Twenty-three (41%) patients had back surgery within 3 years, 8/29 (28%) in the adalimumab group and 15/27 (56%) in the placebo group, p=0.04. Adalimumab injections reduced the need for back surgery by 61% (HR)=0.39 (95% CI 0.17 to 0.92). In a multivariate model, treatment with a tumour necrosis factor-α antagonist remained the strongest protective factor (HR=0.17, p=0.002). Other significant predictors of surgery were a good correlation between symptoms and MRI findings (HR=11.6, p=0.04), baseline intensity of leg pain (HR=1.3, p=0.06), intensity of back pain (HR=1.4, p=0.03) and duration of sickness leave (HR=1.01 per day, p=0.03).
CONCLUSION: A short course of adalimumab in patients with severe acute sciatica significantly reduces the need for back surgery.
Objective. Based on several experimental results and on a preliminary study, a trial was undertaken to assess the efficacy of adalimumab, a tumor necrosis factor α inhibitor, in patients with radicular pain due to lumbar disc herniation. Methods. A multicenter, double-blind, randomized controlled trial was conducted between May 2005 and December 2007 in Switzerland. Patients with acute (duration of <12 weeks) and severe (Oswestry Disability Index score of >50) radicular leg pain and imagingconfirmed lumbar disc herniation were randomized to receive as adjuvant therapy either 2 subcutaneous injections of adalimumab (40 mg) at 7-day intervals or matching placebo. The primary outcome was the score for leg pain, based on a visual analog scale (0-100 mm), which was recorded every day for 10 days and at 6 weeks and 6 months. Results. Of the 265 patients screened, 61 were enrolled; 31 patients were assigned to receive adalimumab, and 4 patients in the placebo group were lost to followup. Over time, the course of leg pain was more favorable in the adalimumab group than in the placebo group (P = 0.002). However, the effect size was relatively small, and at the last followup visit the difference was 13.8 (95% confidence interval -11.5, 39.0). Compared with patients in the placebo group, approximately twice as many patients in the adalimumab group fulfilled the criteria for "responders" and for "low residual disease impact" (P < 0.05), and fewer surgical discectomies were performed (6 versus 13 in the placebo group; P = 0.04). Conclusion. The addition of a short course of adalimumab to the treatment regimen of patients experiencing acute and severe sciatica resulted in a small decrease in leg pain and in significantly fewer surgical procedures.
BACKGROUND: Recent evidence implicates the inflammatory cytokine tumor necrosis factor as a major cause of radiculopathy. Yet, whereas open-label studies with systemically delivered tumor necrosis factor inhibitors have yielded positive results, a placebo-controlled study failed to demonstrate efficacy. One variable that may have contributed to poor outcomes is low drug levels at the site of nerve inflammation. To date, no studies have evaluated the efficacy or safety of epidurally administered anti-tumor necrosis factor agents. METHODS: A double-blind, placebo-controlled, dose-response study was conducted to evaluate an epidural tumor necrosis factor inhibitor. Twenty-four patients with subacute lumbosacral radiculopathy were randomly assigned to receive two transforaminal epidural injections of 2, 4, or 6 mg of entanercept 2 weeks apart in successive groups of eight. In each group, two patients received epidural saline. A parallel epidural canine safety study was conducted using the same injection doses and paradigm as in the clinical study. RESULTS: The animal and human safety studies revealed no behavioral, neurologic, or histologic evidence of drug-related toxicity. In the clinical arm, significant improvements in leg and back pain were collectively noted for the etanercept-treated patients, but not for the saline group, one month after treatment. One patient in the saline group (17%), six patients in the 2-mg group (100%), and four patients each in the 4-mg and 6-mg groups (67%) reported at least 50% reduction in leg pain and a positive global perceived effect one month after treatment. Six months after treatment, the beneficial effects persisted in all but one patient. CONCLUSION: Epidural entanercept holds promise as a treatment for lumbosacral radiculopathy.
OBJECTIVE: To evaluate the efficacy of Infliximab, a monoclonal antibody against tumor necrosis factor alpha (TNF), in patients with acute/subacute sciatica secondary to herniated disc at L3/4 or L4/5. DESIGN: A randomized controlled trial. Background: The results from our randomized trial demonstrated no efficacy for Infliximab but the subgroup results suggested that Infliximab may be effective for sciatica induced by herniations at L3/4 or L4/5. METHODS: Inclusion criteria were unilateral moderate-to-severe sciatic pain with an MRI-confirmed disc herniation at L3/4 or L4/5 and candidacy for discectomy. Patients were randomized to receive either a single infusion of Infliximab 5 mg/kg or placebo. Outcomes included intensity of leg and back pain, Oswestry disability, quality-of-life (RAND-36) and straight leg raising (SLR) restriction at week 26. Data between baseline and the six-month follow-up were analyzed using MannWhitney U test. RESULTS: Due to slow recruitment the trial ended prematurely after 15 patients in total were allocated to receive Infliximab (n=7) or placebo (n=8). At week 26, leg pain intensity had decreased by 73% in the Infliximab group compared to 65% in the control group (p=0.52). For all measured variables at 6 months, Infliximab treatment was associated with greater improvements compared to placebo, especially at early time points. Two patients in the Infliximab group and three in the placebo group had a discectomy or caudal injection (p=1.00). CONCLUSIONS: Our results warrant continuation of research on TNF antagonists in sciatica induced by disc herniations at L3/4 or L4/5.
STUDY DESIGN: Prospective, double-blind, reference-controlled, investigator-initiated, single center.
OBJECTIVE: To evaluate the efficacy of Autologous Conditioned Serum (ACS; Orthokine) for the treatment of lumbar radicular compression in comparison to triamcinolone.
SUMMARY OF BACKGROUND DATA: Evidence from animal studies indicates that cytokines such as interleukin-1 play a decisive role in the pathophysiology of lumbar radiculopathy. ACS is enriched in the interleukin-1 receptor antagonist and other anti-inflammatory cytokines.
METHODS: Thirty-two patients were treated by epidural perineural injections with ACS; 27 patients were treated with 5 mg triamcinolone and 25 patients with 10 mg triamcinolone. Treatment was applied once per week for 3 consecutive weeks and followed for 6 months. The Visual Analogue Scale (VAS) of low back pain was the primary outcome measure. The Oswestry Disability Index (ODI) was the secondary endpoint of the study. All statistical analyses were performed in an exploratory manner using SAS for Windows, version 8.2, on a personal computer. Descriptive statistics were calculated for the VAS and ODI by treatment group and time point. The data were submitted to a repeated-measurements analysis of variance with effects on treatment group, time, and treatment group-by-time interaction.
RESULTS: Patients with lumbar back pain who were treated with ACS or the 2 triamcinolone concentrations showed a clinically remarkable and statistically significant reduction in pain and disability, as measured by patient administered outcome measurements. From Week 12 to the final evaluation at Week 22, injections with ACS showed a consistent pattern of superiority over both triamcinolone groups with regard to the VAS score for pain, but statistical significance was observed only at Week 22 in direct comparison to the triamcinolone 5 group. However, there was no statistically significant difference between the 2 triamcinolone dosages during the 6 months of the study.
CONCLUSION: ACS is an encouraging treatment option for patients with unilateral lumbar radicular compression. The decrease in pain was pronounced, clinically remarkable, and potentially superior to steroid injection.
BACKGROUND: In recent years, convincing evidence has emerged implicating tumor necrosis factor alpha as a causative factor in radiculopathy and discogenic back pain. But although preliminary open-label studies demonstrated promising results for the treatment of low back pain with tumor necrosis factor-alpha inhibitors, early optimism has been tainted by a controlled study showing no significant benefit in sciatica. To determine whether outcomes might be improved by a more direct route of administration, the authors evaluated escalating doses of intradiscal etanercept in 36 patients with chronic lumbosacral radiculopathy or discogenic low back pain.
METHODS: A double-blind, placebo-controlled pilot study was conducted whereby six patients received 0.1, 0.25, 0.5, 0.75, 1.0, or 1.5 mg etanercept intradiscally in each pain-generating disc. In each escalating dose group of six patients, one received placebo. A neurologic examination and postprocedure leukocyte counts were performed in all patients at 1-month follow-up visits. In patients who experienced significant improvement in pain scores and function, follow-up visits were conducted 3 and 6 months after the procedure.
RESULTS: At 1-month follow-up, no differences were found for pain scores or disability scores between or within groups for any dose range or subgroup of patients. Only eight patients remained in the study after 1 month and elected to forego further treatment. No complications were reported, and no differences were noted between preprocedure and postprocedure leukocyte counts.
CONCLUSIONS: Although no serious side effects were observed in this small study, a single low dose of intradiscal etanercept does not seem to be an effective treatment for chronic radicular or discogenic low back pain.
STUDY DESIGN: Randomized, controlled study.
OBJECTIVE: To evaluate the effect of infliximab on herniated nucleus pulposus (HNP) resorption.
SUMMARY OF BACKGROUND DATA: Although the effects of tumor necrosis factor alpha (TNF-alpha) on HNP resorption are not fully understood, TNF-alpha appears to be an essential mediator in HNP resorption.
METHODS: As part of a substudy of the FIRST II study, magnetic resonance images (MRIs) were obtained from 21 patients who were candidates for discectomy at weeks 0, 2, 12, and 26 after receiving a single infusion of either 5 mg/kg infliximab (11 patients) or placebo (10 patients). The volume (mm3) of HNP, thickness (mm) and extent (%) of rim enhancement, and presence of nerve root edema were assessed.
RESULTS: HNP volume decreased significantly from baseline to 6 months in both treatment groups (P < 0.01), with no difference noted between the infliximab and placebo groups. By week 2, rim enhancement thickness increased significantly in the infliximab group compared with the placebo group (P = 0.003). Two patients in each group required back surgery before the 6-month assessment.
CONCLUSIONS: Infliximab did not appear to interfere with disc herniation resorption over a 6-month period.
Perineural inhibitors of tumor necrosis factor have recently generated intense interest as an alternative to epidural steroid injections for lumbosacral radiculopathy.
OBJECTIVE:
To evaluate whether epidural steroids, etanercept, or saline better improves pain and function in adults with lumbosacral radiculopathy.
DESIGN:
A multicenter, 3-group, randomized, placebo-controlled trial conducted from 2008 to 2011. Randomization was computer-generated and stratified by site. Pharmacists prepared the syringes. Patients, treating physicians, and nurses assessing outcomes were blinded to treatment assignment. (ClinicalTrials.gov registration number: NCT00733096)
SETTING:
Military and civilian treatment centers.
PATIENTS:
84 adults with lumbosacral radiculopathy of less than 6 months' duration.
INTERVENTION:
2 epidural injections of steroids, etanercept, or saline, mixed with bupivacaine and separated by 2 weeks.
MEASUREMENTS:
The primary outcome measure was leg pain 1 month after the second injection. All patients had 1-month follow-up visits; patients whose condition improved remained blinded for the 6-month study period.
RESULTS:
The group that received epidural steroids had greater reductions in the primary outcome measure than those who received saline (mean difference, -1.26 [95% CI, -2.79 to 0.27]; P = 0.11) or etanercept (mean difference, -1.01 [CI, -2.60 to 0.58]; P = 0.21). For back pain, smaller differences favoring steroids compared with saline (mean difference, -0.52 [CI, -1.85 to 0.81]; P = 0.44) and etanercept (mean difference, -0.92 [CI,-2.28 to 0.44]; P = 0.18) were observed. The largest differences were noted for functional capacity, in which etanercept fared worse than the other treatments: steroids vs. etanercept (mean difference, -16.16 [CI, -26.05 to -6.27]; P = 0.002), steroids vs. saline (mean difference, -5.87 [CI, -15.59 to 3.85]; P = 0.23), and etanercept vs. saline (mean difference, 10.29 [CI, 0.55 to 20.04]; P = 0.04). More patients treated with epidural steroids (75%) reported 50% or greater leg pain relief and a positive global perceived effect at 1 month than those who received saline (50%) or etanercept (42%) (P = 0.09).
LIMITATION:
Short-term follow-up, small sample size, and a possibly subtherapeutic dose of etanercept.
CONCLUSION:
Epidural steroid injections may provide modest short-term pain relief for some adults with lumbosacral radiculopathy, but larger studies with longer follow-up are needed to confirm their benefits.
PRIMARY FUNDING SOURCE:
The John P. Murtha Neuroscience and Pain Institute, International Spinal Intervention Society, and Center for Rehabilitation Sciences Research.
