“Evidence based medicine is the conscientious, explicit, and judicious use of current best evidence in making decisions about the care of individual patients. The practice of evidence based medicine means integrating individual clinical expertise with the best available external clinical evidence from systematic research. By individual clinical expertise we mean the proficiency and judgment that individual clinicians acquire through clinical experience and clinical practice. Increased expertise is reflected in many ways, but especially in more effective and efficient diagnosis and in the more thoughtful identification and compassionate use of individual patients’ predicaments, rights, and preferences in making clinical decisions about their care.”
Sackett, D.L., W.M. Rosenberg, J.A. Gray, R.B. Haynes, and W.S. Richardson, Evidence based medicine: what it is and what it isn’t. BMJ, 1996. 312(7023): p. 71-2.
The evidence-based use of etanercept for selected neuroinflammatory indications is supported by current best evidence, including not only the the peer-reviewed Scientific Publications of INR medical providers and their colleagues, but also the peer-reviewed publications of independent academic scientists, including the scientific publications enumerated on this webpage (references 1-60 and below), and the additional scientific publications referenced on this website.
Please see Perispinal Etanercept for Post-Stroke Neurological and Cognitive Dysfunction: Scientific Rationale and Current Evidence. Ignatowski TA, Spengler RN, Dhandapani KM, Folkersma H, Butterworth RF, Tobinick E. CNS Drugs 2014 August, 28(8):679-697. The full-text of the article is available without charge by clicking here.
The INR utilizes etanercept delivered via the cerebrospinal venous system. Dr. Tobinick’s review of the anatomy and physiology of the cerebrospinal venous system in 2006 has been referenced and cited by multiple academic neurosurgeons (e.g. Nathoo, N., E.C. Caris, J.A. Wiener, and E. Mendel, Neurosurgery, 2011. 69(5): p. 1007-14; see also Blaylock, R.L., Surg Neurol Int, 2013. 4: p. 118 (download full free text PDF). The cerebrospinal venous system was first accurately detailed in 1819 by Gilbert Breschet:
Etanercept works by blocking the effects of excess amounts of a protein called tumor necrosis factor (TNF). TNF is an immune signaling molecule that is centrally involved in the initiation and amplification of the inflammatory response. Blocking TNF reduces inflammation. TNF-mediated inflammation, however, is not limited to the joints. TNF-mediated inflammation also occurs in the skin, the gastrointestinal tract, the eyes, the lungs, the kidneys and the brain, spinal cord, and spinal nerve roots; in fact, TNF-mediated inflammation is a generalized phenomenon that may occur in every organ system. Since etanercept has been established to be useful for a wide variety of inflammatory disorders in multiple organ systems it should come as no surprise to any scientist who conducts a diligent search of the medical and scientific literature that substantial scientific evidence suggests that etanercept has potential utility for a variety of neuroinflammatory conditions.
In fact, as of April 2014, there is substantial scientific evidence, in both the basic science and clinical medical literature, that suggests the potential utility of etanercept for a variety of neurological disorders. There are multiple scientific studies that have specifically tested etanercept in animals or humans(1-44):
1.Ye J, Jiang R, Cui M, Zhu B, Sun L, Wang Y, et al. Etanercept reduces neuroinflammation and lethality in mouse model of Japanese encephalitis. The Journal of infectious diseases. 2014.
2.Topdag M, Iseri M, Topdag DO, Kokturk S, Ozturk M, Iseri P. The Effect of Etanercept and Methylprednisolone on Functional Recovery of the Facial Nerve After Crush Injury. Otology & neurotology : official publication of the American Otological Society, American Neurotology Society [and] European Academy of Otology and Neurotology. 2014.
3.Tobinick E, Rodriguez-Romanacce H, Levine A, Ignatowski TA, Spengler RN. Immediate neurological recovery following perispinal etanercept years after brain injury. Clinical drug investigation. 2014;34(5):361-6.
4.Ekici MA, Uysal O, Cikriklar HI, Ozbek Z, Turgut Cosan D, Baydemir C, et al. Effect of etanercept and lithium chloride on preventing secondary tissue damage in rats with experimental diffuse severe brain injury. European review for medical and pharmacological sciences. 2014;18(1):10-27.
5.Coelho SC, Bastos-Pereira AL, Fraga D, Chichorro JG, Zampronio AR. Etanercept reduces thermal and mechanical orofacial hyperalgesia following inflammation and neuropathic injury. Eur J Pain. 2014.
6.Shi X, Zhou W, Huang H, Zhu H, Zhou P, Zhu H, et al. Inhibition of the inflammatory cytokine tumor necrosis factor-alpha with etanercept provides protection against lethal H1N1 influenza infection in mice. Critical care. 2013;17(6):R301.
7.Sainoh T, Orita S, Yamauchi K, Suzuki M, Sakuma Y, Kubota G, et al. Intradiscal Administration of Tumor Necrosis Factor-Alpha Inhibitor, Etanercept, Clinically Improves Intractable Discogenic Low Back Pain: A Prospective Randomized Study. International Society for the Study of the Lumbar Spine 40th Annual Meeting; Scottsdale, Arizona 2013.
8.Iwatsuki K, Arai T, Ota H, Kato S, Natsume T, Kurimoto S, et al. Targeting anti-inflammatory treatment can ameliorate injury-induced neuropathic pain. PLoS One. 2013;8(2):e57721.
9.Freeman BJ, Ludbrook GL, Hall S, Cousins M, Mitchell B, Jaros M, et al. Randomized, Double-blind, Placebo-Controlled, Trial of Transforaminal Epidural Etanercept for the Treatment of Symptomatic Lumbar Disc Herniation. Spine (Phila Pa 1976). 2013;38(23):1986-94.
10.Chio CC, Chang CH, Wang CC, Cheong CU, Chao CM, Cheng BC, et al. Etanercept attenuates traumatic brain injury in rats by reducing early microglial expression of tumor necrosis factor-alpha. BMC Neurosci. 2013;14(1):33.
11.Cheong CU, Chang CP, Chao CM, Cheng BC, Yang CZ, Chio CC. Etanercept attenuates traumatic brain injury in rats by reducing brain TNF- alpha contents and by stimulating newly formed neurogenesis. Mediators Inflamm. 2013;2013:620837.
12.Boivin N, Menasria R, Piret J, Rivest S, Boivin G. The combination of valacyclovir with an anti-TNF alpha antibody [etanercept] increases survival rate compared to antiviral therapy alone in a murine model of herpes simplex virus encephalitis. Antiviral research. 2013;100(3):649-53.
13.Tobinick E, Kim NM, Reyzin G, Rodriguez-Romanacce H, Depuy V. Selective TNF Inhibition for Chronic Stroke and Traumatic Brain Injury : An Observational Study Involving 629 Consecutive Patients Treated with Perispinal Etanercept. CNS Drugs. 2012;26(12):1051-70.
14.Tobinick E. Deciphering the physiology underlying the rapid clinical effects of perispinal etanercept in Alzheimer’s disease. Curr Alzheimer Res. 2012;9(1):99-109.
15.Roh M, Zhang Y, Murakami Y, Thanos A, Lee SC, Vavvas DG, et al. Etanercept, a widely used inhibitor of tumor necrosis factor-alpha (TNF-alpha), prevents retinal ganglion cell loss in a rat model of glaucoma. PLoS One. 2012;7(7):e40065.
16.Ohtori S, Miyagi M, Eguchi Y, Inoue G, Orita S, Ochiai N, et al. Epidural administration of spinal nerves with the tumor necrosis factor-alpha inhibitor, etanercept, compared with dexamethasone for treatment of sciatica in patients with lumbar spinal stenosis: a prospective randomized study. Spine (Phila Pa 1976). 2012;37(6):439-44.
17.Haji N, Mandolesi G, Gentile A, Sacchetti L, Fresegna D, Rossi S, et al. TNF-alpha-mediated anxiety in a mouse model of multiple sclerosis. Experimental neurology. 2012;237(2):296-303.
18.Christianson CA, Fitzsimmons BL, Shim JH, Agrawal A, Cohen SM, Hua XY, et al. Spinal matrix metalloproteinase 3 mediates inflammatory hyperalgesia via a tumor necrosis factor-dependent mechanism. Neuroscience. 2012;200:199-210.
19.Watanabe K, Yabuki S, Sekiguchi M, Kikuchi S, Konno S. Etanercept attenuates pain-related behavior following compression of the dorsal root ganglion in the rat. European spine journal : official publication of the European Spine Society, the European Spinal Deformity Society, and the European Section of the Cervical Spine Research Society. 2011;20(11):1877-84.
20.Tobinick E. Rapid improvement of chronic stroke deficits after perispinal etanercept: three consecutive cases. CNS Drugs. 2011;25(2):145-55.
21.Shen CH, Tsai RY, Shih MS, Lin SL, Tai YH, Chien CC, et al. Etanercept restores the antinociceptive effect of morphine and suppresses spinal neuroinflammation in morphine-tolerant rats. Anesth Analg. 2011;112(2):454-9.
22.Gottlieb AB, Gordon K, Giannini EH, Mease P, Li J, Chon Y, et al. Clinical trial safety and mortality analyses in patients receiving etanercept across approved indications. J Drugs Dermatol. 2011;10(3):289-300.
23.Dogrul A, Gul H, Yesilyurt O, Ulas UH, Yildiz O. Systemic and spinal administration of etanercept, a tumor necrosis factor alpha inhibitor, blocks tactile allodynia in diabetic mice. Acta diabetologica. 2011;48(2):135-42.
24.Tobinick E. Perispinal etanercept: a new therapeutic paradigm in neurology. Expert Rev Neurother. 2010;10(6):985-1002.
25.Kato K, Liu H, Kikuchi S, Myers RR, Shubayev VI. Immediate anti-tumor necrosis factor-alpha (etanercept) therapy enhances axonal regeneration after sciatic nerve crush. Journal of neuroscience research. 2010;88(2):360-8.
26.Fioravanzo L, Venturini M, Di Liddo R, Marchi F, Grandi C, Parnigotto PP, et al. Involvement of rat hippocampal astrocytes in beta-amyloid-induced angiogenesis and neuroinflammation. Curr Alzheimer Res. 2010;7(7):591-601.
27.Chio CC, Lin JW, Chang MW, Wang CC, Kuo JR, Yang CZ, et al. Therapeutic evaluation of etanercept in a model of traumatic brain injury. Journal of neurochemistry. 2010;115(4):921-9.
28.Bassi E, De Filippi C. Beneficial neurological effects observed in a patient with psoriasis treated with etanercept. American journal of clinical dermatology. 2010;11 Suppl 1:44-5.
29.Aden U, Favrais G, Plaisant F, Winerdal M, Felderhoff-Mueser U, Lampa J, et al. Systemic inflammation sensitizes the neonatal brain to excitotoxicity through a pro-/anti-inflammatory imbalance: key role of TNFalpha pathway and protection by etanercept. Brain, behavior, and immunity. 2010;24(5):747-58.
30.Tobinick E. Perispinal etanercept for neuroinflammatory disorders. Drug Discov Today. 2009;14(3-4):168-77.
31.Marchand F, Tsantoulas C, Singh D, Grist J, Clark AK, Bradbury EJ, et al. Effects of Etanercept and Minocycline in a rat model of spinal cord injury. Eur J Pain. 2009;13(7):673-81.
32.Kato K, Kikuchi S, Shubayev VI, Myers RR. Distribution and tumor necrosis factor-alpha isoform binding specificity of locally administered etanercept into injured and uninjured rat sciatic nerve. Neuroscience. 2009;160(2):492-500.
33.Cohen SP, Bogduk N, Dragovich A, Buckenmaier CC, 3rd, Griffith S, Kurihara C, et al. Randomized, double-blind, placebo-controlled, dose-response, and preclinical safety study of transforaminal epidural etanercept for the treatment of sciatica. Anesthesiology. 2009;110(5):1116-26.
34.Zanella JM, Burright EN, Hildebrand K, Hobot C, Cox M, Christoferson L, et al. Effect of etanercept, a tumor necrosis factor-alpha inhibitor, on neuropathic pain in the rat chronic constriction injury model. Spine (Phila Pa 1976). 2008;33(3):227-34.
35.Tobinick EL, Gross H. Rapid cognitive improvement in Alzheimer’s disease following perispinal etanercept administration. J Neuroinflammation. 2008;5:2.
36.Tobinick EL, Gross H. Rapid improvement in verbal fluency and aphasia following perispinal etanercept in Alzheimer’s disease. BMC Neurol. 2008;8:27.
37.Tobinick E. Perispinal etanercept produces rapid improvement in primary progressive aphasia: identification of a novel, rapidly reversible TNF-mediated pathophysiologic mechanism. Medscape J Med. 2008;10(6):135.
38.Griffin WS. Perispinal etanercept: potential as an Alzheimer therapeutic. J Neuroinflammation. 2008;5:3.
39.Tobinick E. Perispinal etanercept for treatment of Alzheimer’s disease. Curr Alzheimer Res. 2007;4(5):550-2.
40.Tobinick E, Davoodifar S. Efficacy of etanercept delivered by perispinal administration for chronic back and/or neck disc-related pain: a study of clinical observations in 143 patients. Curr Med Res Opin. 2004;20(7):1075-85.
41.Tobinick EL. Targeted etanercept for treatment-refractory pain due to bone metastasis: two case reports. Clinical therapeutics. 2003;25(8):2279-88.
42.Tobinick EL. Targeted etanercept for discogenic neck pain: uncontrolled, open-label results in two adults. Clinical therapeutics. 2003;25(4):1211-8.
43.Sommer C, Schafers M, Marziniak M, Toyka KV. Etanercept reduces hyperalgesia in experimental painful neuropathy. J Peripher Nerv Syst. 2001;6(2):67-72.
44.Detrait ER, Danis B, Lamberty Y, Foerch P. Peripheral administration of an anti-TNF-alpha receptor fusion protein counteracts the amyloid induced elevation of hippocampal TNF-alpha levels and memory deficits in mice. Neurochemistry international. 2014.
45.Stellwagen D, Malenka RC. Synaptic scaling mediated by glial TNF-alpha. Nature. 2006;440(7087):1054-9.
46.Santello M, Volterra A. TNFalpha in synaptic function: switching gears. Trends Neurosci. 2012;35(10):638-47.
47.Faingold CL. Chapter 7: Network Control Mechanisms: Cellular Inputs, Neuroactive Substances, and Synaptic Changes. In: Faingold CL, Blumenfeld H, editors. Neuronal Networks in Brain Function, CNS Disorders, and Therapeutics: Elsevier; 2014.
48.Clark IA, Chaudhri G. The balance of useful and harmful effects of TNF, with special reference to malaria. Ann Inst Pasteur Immunol. 1988;139(3):305-6.
49.Clark IA, Rockett KA, Cowden WB. Role of TNF in cerebral malaria. Lancet. 1991;337(8736):302-3.
50.Sherman ML, Spriggs DR, Arthur KA, Imamura K, Frei E, 3rd, Kufe DW. Recombinant human tumor necrosis factor administered as a five-day continuous infusion in cancer patients: phase I toxicity and effects on lipid metabolism. Journal of clinical oncology : official journal of the American Society of Clinical Oncology. 1988;6(2):344-50.
51.Spriggs DR, Sherman ML, Michie H, Arthur KA, Imamura K, Wilmore D, et al. Recombinant human tumor necrosis factor administered as a 24-hour intravenous infusion. A phase I and pharmacologic study. Journal of the National Cancer Institute. 1988;80(13):1039-44.
52.Tarkowski E, Andreasen N, Tarkowski A, Blennow K. Intrathecal inflammation precedes development of Alzheimer’s disease. J Neurol Neurosurg Psychiatry. 2003;74(9):1200-5.
53.Tobinick E, Gross H, Weinberger A, Cohen H. TNF-alpha modulation for treatment of Alzheimer’s disease: a 6-month pilot study. MedGenMed. 2006;8(2):25.
54.Tobinick E. Tumour necrosis factor modulation for treatment of Alzheimer’s disease: rationale and current evidence. CNS Drugs. 2009;23(9):713-25.
55.Clark IA, Alleva LM, Vissel B. The roles of TNF in brain dysfunction and disease. Pharmacol Ther. 2010;128(3):519-48.
56.Clark IA, Vissel B. Treatment implications of the altered cytokine-insulin axis in neurodegenerative disease. Biochem Pharmacol. 2013;86(7):862-71.
57.Works MG, Koenig JB, Sapolsky RM. Soluble TNF receptor 1-secreting ex vivo-derived dendritic cells reduce injury after stroke. Journal of cerebral blood flow and metabolism : official journal of the International Society of Cerebral Blood Flow and Metabolism. 2013.
58.Lei B, Dawson HN, Roulhac-Wilson B, Wang H, Laskowitz DT, James ML. Tumor necrosis factor alpha antagonism improves neurological recovery in murine intracerebral hemorrhage. Journal of neuroinflammation. 2013;10(1):103.
59.King MD, Alleyne CH, Jr., Dhandapani KM. TNF-alpha receptor antagonist, R-7050, improves neurological outcomes following intracerebral hemorrhage in mice. Neurosci Lett. 2013;542:92-6.
60.Butterworth RF. The liver-brain axis in liver failure: neuroinflammation and encephalopathy. Nat Rev Gastroenterol Hepatol. 2013;10(9):522-8.
Additional Scientific Discussion
- Section 1: TNF Brain Syndrome
Increasing scientific evidence suggests that excess (pathologic) levels of TNF, if present in the brain, may impair brain function. Physiological levels of TNF are involved in the regulation of normal brain processes, such as the regulation of synaptic function(45-47). In the 1980’s Clark and his colleagues suggested that excess TNF was involved in the pathophysiology of brain dysfunction associated with malaria(48, 49). In 1988, the clinical results of the initial human trials of recombinant TNF for use in oncology gave a further clue to the essential role of TNF in brain physiology, as three of the initial clinical trial participants demonstrated transient focal neurological dysfunction after TNF infusion(50, 51). More than a decade later researchers discovered that TNF levels 25 times normal were present in the cerebrospinal fluid of patients with Alzheimer’s disease(52). INR medical providers have published clinical evidence suggesting that excess TNF is a mediator of brain dysfunction in a variety of brain disorders(3, 14, 20, 24, 30, 35-37, 39, 53, 54). The accumulating evidence suggests the existence of a “TNF brain syndrome”, defined as “a shared phenotype of brain dysfunction induced by excess TNF in brain disorders of diverse aetiology.(20)”(55, 56) In 2013-2014, increasing evidence of the favorable effects of TNF inhibitors in ameliorating brain dysfunction or mortality in clinical and basic science models suggest the validity of such a concept(1, 3-6, 10-12, 44, 57-60).
- Section 2 – Sciatica
Sciatica and other related forms of intervertebral disc-related pain
Dr. Tobinick was the first to report the favorable clinical effects of etanercept for sciatica and other forms of disc-related pain, more than a decade ago. He filed U.S. patent 6,419,944, on April 5, 2001 describing epidural and other local methods of administration of etanercept for treating sciatica. He and his colleagues were the first to report that perispinal administration of etanercept in humans may result in rapid improvement in pain that had failed to adequately respond to other forms of treatment (Tobinick, E.L., Targeted etanercept for discogenic neck pain: uncontrolled, open-label results in two adults. Clin Ther, 2003. 25(4): p. 1211-8; Tobinick, E.L. and S. Britschgi-Davoodifar, Perispinal TNF-alpha inhibition for discogenic pain. Swiss Med Wkly, 2003. 133(11-12): p. 170-7; Tobinick, E. and S. Davoodifar, Efficacy of etanercept delivered by perispinal administration for chronic back and/or neck disc-related pain: a study of clinical observations in 143 patients. Curr Med Res Opin, 2004. 20(7): p. 1075-85). Dr. Tobinick and his colleagues have extensive positive clinical experience using etanercept for sciatica, cervical radiculopathy and other forms of intractable intervertebral disc-related neuropathic pain, administered to more than 3,000 patients over the course of more than a decade (Tobinick, E., Perispinal etanercept: a new therapeutic paradigm in neurology. Expert Review of Neurotherapeutics, 2010. 10(6): p. 985-1002).
Today, nearly a decade and a half after Dr. Tobinick’s pioneering work began, the use of etanercept for treating intractable sciatica has multi-center scientific support. This independent scientific support now includes four randomized, controlled clinical trials:
Cohen, S.P., et al., Randomized, double-blind, placebo-controlled, dose-response, and preclinical safety study of transforaminal epidural etanercept for the treatment of sciatica. Anesthesiology, 2009. 110(5): p. 1116-26:
“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.”
Ohtori, S., et al., Epidural administration of spinal nerves with the tumor necrosis factor-alpha inhibitor, etanercept, compared with dexamethasone for treatment of sciatica in patients with lumbar spinal stenosis: a prospective randomized study. Spine (Phila Pa 1976), 2012. 37(6): p. 439-44:
“Low back pain, leg pain, and leg numbness in the 2 groups were not significantly different before epidural administration. Epidural administration of etanercept was more effective than dexamethasone for leg pain (3 days, and 1, 2, and 4 weeks: P < 0.05), low back pain (3 days, and 1 and 2 weeks: P < 0.05), and leg numbness (3 days, and 1 and 2 weeks: P < 0.05). No adverse event was observed in either group.”
Freeman, B.J., et al., Randomized, Double-blind, Placebo-Controlled, Trial of Transforaminal Epidural Etanercept for the Treatment of Symptomatic Lumbar Disc Herniation. Spine (Phila Pa 1976), 2013. 38(23): p. 1986-94:
“…Fifty percent of these subjects reported a 100% reduction in WLP[worst leg pain] 4 weeks post-treatment compared with 0% of subjects in the placebo cohort ….Two transforaminal injections of etanercept provided clinically significant reductions in mean daily WLP and worst back pain compared with placebo for subjects with symptomatic LDH[lumbar disc herniation].”
Sainoh, T., et al., Intradiscal Administration of Tumor Necrosis Factor-Alpha Inhibitor, Etanercept, Clinically Improves Intractable Discogenic Low Back Pain: A Prospective Randomized Study, in International Society for the Study of the Lumbar Spine 40th Annual Meeting. 2013: Scottsdale, Arizona.
“More recently Sainoh et al. (2013) [Id.] have presented a paper at the 40th ISSLS on intradiscal injection of anti TNF-alpha in a randomized study of 30 patients that echoed the finding of Tobinick et al. [Tobinick, E.L. and S. Britschgi-Davoodifar, Perispinal TNF-alpha inhibition for discogenic pain. Swiss Med Wkly, 2003. 133(11-12): p. 170-7.] At the 4-week time point it was shown that TNF-alpha provided patients with a statistically significant relief of pain (p<0.005) according to the ODI.” (Kaufman, E.L. and A. Carl, Biochemistry of Back Pain. The Open Spine Journal, 2013. 5: p. 12-18).