1. 2014;17;E45-E60Anti-Nerve Growth Factor in the Treatment of Low Back Pain and Radiculopathy: A Systematic Review and a Meta-Analysis
   Systematic Review
   Victor F Leite, MD, Anna M Buehler, PharmD, PhD, Omar El Abd, MD, Ramsin M. Benyamin, MD, Daniel C Pimentel, MD, Janini Chen, PT, Wu Tu Hsing, MD, PhD, Danesh Mazloomdoost, MD, and Joao ED Amadera, MD, PhD.

BACKGROUND: Low back pain with or without radiculopathy is an important cause of disability and economic expenditure. However, many patients are not meeting optimal pain control through existing treatments. Recent studies have linked nerve growth factor (NGF) and the pathophysiology of persistent pain. Anti-NGF could be an alternative drug treatment for low back pain.
OBJECTIVE: Systematically review the efficacy and safety of anti-NGF in the treatment of low back pain.
METHODS: A systematic review of the literature with no language, date or publication status restriction, using Medline, EMBASE, Cochrane Library, and the clinicaltrials.gov database. Additional literature was retrieved by conferring with experts in the field or reviewing bibliographies and annals of meetings and congresses. Search terms included “monoclonal antibodies,” “nerve growth factor,” “anti-ngf,” “fulranumab,” “tanezumab,” “sciatica,” “back pain,” and “spine.”
STUDY DESIGN:  Inclusion criteria were observational studies with safety as an outcome and randomized or nonrandomized controlled trials studying the efficacy and/or the safety of anti-NGF drugs on low back pain. Exclusion criteria included patients with autoimmune conditions or osteoporosis. Studies were assessed independently by 2 authors regarding inclusion/exclusion criteria, risk of bias, clinical relevance, and quality of evidence (GRADE approach).
RESULTS: 1,168 studies were retrieved. After excluding duplicates and applying the inclusion/exclusion criteria, 4 RCTs remained (n = 2,109): 2 for tanezumab, one for REGN475, and one for fulranumab. Only the tanezumab studies showed any significant difference over placebo (n = 1,563) for both pain relief and functional improvement. 
CONCLUSIONS: There is very low evidence that systemically administered anti-NGF therapy has a small positive effect compared to placebo for both pain relief (standarized mean difference [SMD] = -0.29, 95% confidence interval [CI] -0.58 to 0.00) and functional improvement (SMD = -0.21, 95%CI -0.37 to -0.05 ) of low back pain. There was low evidence of adverse effects (AEs) compared to placebo and low evidence of neurological AEs than placebo (relative risk = 1.93, 95%CI 1.41 to 2.64).Tanezumab, as a specific anti-NGF treatment, showed low evidence of a small to moderate effect for pain relief of low back pain (SMD = -0.44, 95%CI -0.81 to -0.07); and low evidence of a small effect for functional improvement (SMD = -0.26, 95%CI -0.40 to -0.12) with systemic administration, although not clinically significant. Tanezumab and anti-NGFs overall had, respectively, moderate and low evidence of overall AEs and serious AEs and a higher risk of developing neurological AEs when compared with placebo.
Although anti-NGF, specifically tanezumab, showed a low-to-moderate effect on pain relief and functional improvement, it cannot be recommended for low back pain treatment. Without more research on the pathophysiology of anti-NGFs and adverse effects, its use is not safe in the overall population. However, as corroborated by the US Food and Drug Administration, this meta-analysis underscores a role for greater insight into anti-NGF therapy for painful conditions that are refractory to current drugs, such as oncologic pain, chronic pancreatitis, and phantom-limb pain. Given the pathophysiology of axial pain involving inflammatory mediators and the adverse effects of systemic anti-NGF use, consideration of local therapies may warrant further exploration.