A Phase I/II Double-Blinded Randomized Prospective Study of Sterile Amniotic Fluid Filtrate Epidural Injection for the Treatment of Lumbosacral Radicular Pain Due to Spinal Stenosis: Improving Safety and Outcomes in the Treatment of Pain and Disability Related to Spinal Stenosis.

Lumbar spinal stenosis is a common cause of chronic pain and disability in older adults and is the leading reason for spinal surgery in older adults. In this condition, degenerative changes in intervertebral discs and osseous anatomy of the spine result in narrowing of the spinal canal and neuroforamen in close proximity to the traversing spinal nerve roots, causing back and radicular leg pain, paresthesias and weakness. In the absence of a progressive neurologic deficit, initial treatment of lumbosacral radicular pain includes physical therapy, activity modification, and oral neuropathic or analgesic medications. If this conservative approach fails to relieve pain, an image guided epidural steroid injection (ESI) is the second-line treatment. Surgical decompression may be a treatment option for some patients who fail conservative therapy, but it is not uniformly effective and is associated with substantial direct and indirect risks. Further, some patients are unwilling to undergo invasive surgical treatments, and in others, surgery is contraindicated due to medical co-morbidities.

Epidural steroid injections are widely used for the treatment of spinal stenosis. Over 25% of all epidural steroid injection in the Medicare population are administered for the treatment of pain associated with spinal stenosis, accounting for more than 500,000 injections per year. When performed with sterile technique and fluoroscopic-guidance, epidural spine injections of steroid are safe. However, steroid use in the epidural space is associated with rare but catastrophic sequelae including paraplegia due to spinal cord infarction. The larger size or aggregation of particulate steroids likely obstructs arteriolar blood flow to the spinal cord if inadvertently injected into radicular arteries during TFESI. In addition, epidural steroid use is associated with common immediate/short-term adverse events such as facial flushing, headache, insomnia, transient hypertension, increased blood glucose in patients with diabetes. Injections must often be repeated when administered for chronic radicular pain given a typical natural history of life-long pain associated with this condition, which increases the risk of long-term sequelae including osteoporosis, adrenal suppression, hypertension, cataracts, gastrointestinal bleeding, and immune system dysfunction among many others.

Furthermore, the injection treatment paradigm for patients with spinal stenosis has not been optimized. While transforaminal epidural steroid injection appears to be superior to both placebo saline injection and lidocaine injection at short-term to intermediate follow-up when performed for the indication of radicular pain due to acute disc herniation, the highest quality evidence to date suggests a lesser degree of efficacy for the indication of leg pain due to spinal stenosis This is particularly problematic given that radicular pain related to disc herniation is self-limited, whereas spinal-stenosis related radicular pain does not tend to improve over time. Thus, there is a large group of patients with spinal stenosis who fail to respond to physical therapy and oral medication management, yet either wish to avoid spinal surgery or are not eligible, and suffer from chronic pain and debility given the poor treatment options. Clearly, better treatments with more optimal safety and side-effect profiles compared to epidural corticosteroids must be investigated in this context.

There is therefore a critical need to identify safe and effective treatments for this common clinical condition, which would allow for improved patient function and pain relief. Amniotic Fluid (AF) is a promising new biologic treatment with neuro-protective and regenerative properties. Early after conception and until the mother's water breaks for the delivery of their infant, the fetus is bathed in amniotic fluid. AF functions as a supportive cushion to the fetus and provides a protective environment. AF is a rich source of nutrients, cytokines and growth factors that are required for fetal development and maturation. AF also contains multiple cell types with the potential to differentiate along multiple cell lineages. The protective and regenerative properties of AF are achieved via the exchange of water and solutes with surrounding tissues. This is accomplished via the utilization of different pathways during the course of a pregnancy that likely contribute to changes in the composition of AF with gestational age.

Early evidence demonstrates that concentrates of AF inhibit the development of peritonitis and accelerate defense-repair mechanisms within damaged joints, demonstrating protective biological properties. Since these early publications, more sophisticated evaluations have revealed the presence of antimicrobial, immunomodulatory, and growth-promoting activities of AF. For example, low AF antimicrobial activity is associated with a high incidence of an infectious syndromes in pregnant women. Components with antimicrobial, antiviral and antifungal activity that are present in AF include lysozyme, peroxidase, transferrin, beta-lysin, immunoglobulins and zinc-peptide complexes. Immunomodulatory properties of AF are evident from studies showing that enteral feeding of AF suppresses the pro-inflammatory responses in preterm pigs with necrotizing enterocolitis. Further, growth-promoting activities of AF are supported by both animal studies and in vitro studies, showing that AF can enhance neochondrogenesis, regenerate peripheral nerves and bone, accelerate re-epithelialization in corneas, and promote healing of human skin wounds. Some of the factors that are found in AF that may contribute to these activities include inflammatory mediators such as TNF-a, IL-6, IL8, and IL-1048 trophic factors that include EGF, IGF-1, FGF, HGF and TGF-a, and hyaluronic acid, an important factor in promoting re- epithelialization in human skin wounds.