Scientific Rationale

The off-label use of etanercept for selected neuroinflammatory indications is based upon evidence-based medicine. Please note: results can vary. Treatment is off-label. Please see the Terms of Use. As Sackett et al. explain:

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:

Breschet.copyright2

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 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) (see References below).

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).

References

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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.

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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.

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