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Does perispinal etanercept work for stroke recovery?

Medically reviewed by Carmen Pope, BPharm. Last updated on Jan 12, 2023.

Official answer


There is good evidence that perispinal administration of etanercept (Enbrel) works extremely well for stroke recovery, with the publication of the first RCT in 2019 that supported thousands of individual case reports of a beneficial effect. Improvements in chronic post-stroke symptoms with etanercept is usually rapid, within 10 minutes, and long-lasting. Perispinal etanercept was first developed as a treatment for poststroke symptoms by Dr. Edward Tobinick, in 2010.

Perispinal etanercept appears beneficial for most patients, even more than three years after a stroke. Treatment with etanercept for stroke recovery is off-label, which means its use has not been approved by the FDA, although the use of etanercept for other conditions, such as plaque psoriasis, is approved.

What evidence is there to support using etanercept for stroke recovery?

In 2019, a double-blinded RCT (n=80) concluded that perispinal etanercept was effective for central post-stroke pain syndrome (CPSP) with the average daily pain score reducing by 19.5 to 24 points in the group that received etanercept. Nearly 30% of patients reported near complete pain abatement after the first treatment of etanercept. In addition, mean shoulder rotation improved by 55 degrees in the group receiving etanercept.

Over 4000 patients from 91 countries have received perispinal etanercept since 2010. Numerous observational reports of benefits have been reported in the literature and impressive outcomes videoed independently. Rapid improvements in stroke symptoms have been observed and confirmed by non-neurological medical practitioners, nurses, speech pathologists, and neuroscientists.

In addition to several case reports, an observational study of 629 patients was published in December 2012. 617 of these patients had suffered from a stroke a mean of 42 months earlier and 12, a traumatic brain injury. Statistically significant improvements in neurological and cognitive function and pain reduction were reported in the stroke cohort, many occurred rapidly.

What effects does etanercept have on stroke symptoms?

Research has found peri-spinal etanercept results in significant improvements in:

  • Behavior
  • Central post-stroke pain syndrome (CPSP) – A disabling condition characterized by pain and sensory abnormalities in parts of the body supplied by those nerves present in the area of the brain injured by the stroke. Mild sensations on the skin, such as touch, warmth, and cold are misinterpreted and registered by the brain as pain
  • Cognitive function
  • Hand function – stronger grip
  • Hemiparesis – this is the inability to move one side of your body and in stroke patients, it makes everyday activities like eating or dressing, difficult
  • Hemisensory defects (these are altered sensations on one side of the body and could include numbness, tingling, or heaviness)
  • Improvements in swallowing
  • Mood with reductions in depression and anxiety
  • Movement
  • Sensations
  • Shoulder pain and range of movement. Significant, almost instant improvements have been seen regarding shoulder flexion in the paretic arm (the arm that is paralyzed after a stroke)
  • Spatial perception (being aware of your surroundings and your position relative to them)
  • Speech (reduces slurring and increases the speed of speech)
  • The way a person walks (their gait).

Case studies have also reported regained bladder sensation and control and a reduction in excessive emotionalism.

How does etanercept work for stroke recovery?

Etanercept is an anti-tumor necrosis factor (TNF) biologic that works by suppressing the body's natural response to TNF, a protein produced by white blood cells that are involved in early inflammatory events.

TNF is a widespread signaling molecule that is also generated within the brain and acts as a gliotransmitter – a chemical that facilitates communication between neurons and other glial cells. Research has shown that TNF can be problematic if generated excessively.

Research has identified that TNF plays a significant role in the pathophysiology of stroke and chronic brain dysfunction and the pathogenesis of neuropathic pain. Brain imaging after a stroke shows chronic neuroinflammation and intracerebral microglial activation that can persist for years following a stroke. Cerebral TNF generated by a single event has been shown to maintain its production by keeping microglia (the main cells that produce it) in an activated state. Etanercept removes this positive feedback, so its effects are long-lasting.

What are the side effects of perispinal etanercept?

Etanercept is extensively used to treat other inflammatory conditions, such as rheumatoid arthritis, psoriatic arthritis, plaque psoriasis, juvenile idiopathic arthritis, and ankylosing spondylitis, and the product information lists the full range of side effects that have been reported among the millions of people that have used it. But in actual practice, etanercept has a low risk of causing side effects, which is one of the reasons it has become one of the world’s biggest-selling biologics.

When etanercept is given for post-stroke recovery, only 25mg is used as a single dose (which may be repeated after a few weeks). For most approved conditions in adults, etanercept is given as 50mg SC weekly.

How is etanercept given for stroke recovery?

25mg of etanercept is given by injection, directly into the cerebrospinal fluid in the spine by a trained physician. The patient then lies flat on their back and the bed is tilted backward so the patient’s head is below their feet at an angle of roughly 16 degrees for 5 minutes (this is called Trendelenburg Positioning).

Prior research had shown that head-down positioning for short periods made the blood-cerebrospinal fluid barrier more permeable to albumin, which Tobinick later demonstrated in 2009 to also be true for etanercept, despite it being a larger molecule. Trendelenburg positioning allows etanercept to rapidly reach the choroid plexus and the CSF within the cerebral ventricles, bypassing the blood-brain barrier.

The dose of perispinal etanercept can be repeated (in trials this was done after 22 to 26 days).

What is the controversy around giving etanercept for stroke recovery?

Many international experts are confused as to why barriers have been put in place by the American Academy of Neurology (AAN) as well as Big Pharma to prevent clinical trials of perispinal etanercept from being conducted in the United States.

In 2014 a Fellow of the AAN Academy attempted to stop the off-label treatment of perispinal etanercept by Dr. Tobinick through the Court system (California Case No. 04–2012-222007, 22 May 2015). The Fellow lost the case, with the court declaring poststroke etanercept to be within the standard of care, citing that there was enough research about etanercept’s safety and effectiveness to support its use. Despite the Medical Board of California adopting this court decision, the AAN appears to disregard it and has an advisory on its website stating that evidence is insufficient to determine the effectiveness of etanercept treatment and that it may be associated with adverse outcomes and high cost.

Most neurologists in America have ignored invitations to observe or engage in perispinal etanercept, and most have been openly skeptical and scathing of its beneficial effects. Luckily, international interest is exceptionally high, and without unjustified barriers, and in 2019 the first double-blinded RCT of perispinal etanercept for unrelenting central post-stroke pain (CPSP) was published by a Griffith University-led team, using patients from hospitals in Australia and New Zealand. This research was funded by public donations collected from the community-based Stroke Recovery Trial fund based in Australia. CPSP is notoriously difficult to treat and there is a substantial need for effective treatments. Approval of the study was obtained from the Griffith University Human Research Ethics committee (MSC/10/14/HREC).

What are the benefits of using etanercept for stroke recovery?

Increasing life expectancy and the strong correlation between age and stroke incidence means that the number of people having a stroke will only increase in the future. Having a treatment such as etanercept that can restore a person’s ability to walk, talk, move their arm, or live pain-free, even to a small degree, is much needed and welcome.

The perispinal method of drug delivery could also prove to be a game changer with regard to drug delivery for other neurological conditions, such as Alzheimer’s or Parkinson’s disease.

What is the cost of etanercept for stroke recovery?

The cost of perispinal etanercept for stroke recovery is not disclosed on the Institute of Neurological Recovery website but it was reported to be around $4800 U.S in 2012 so is likely to be more expensive now.

  • Institute of Neurological Recovery. Florida,94%20countries%20around%20the%20world.
  • Practice Advisory: Etanercept for Poststroke Disability. AAN Summary of Practice Advisory for Clinicians. American Academy of Neurology. file:///C:/Users/carme/Downloads/Practice%20advisory_%20Etanercept%20for%20poststroke%20disability.pdf
  • Ian A Clark (2020) Randomized controlled trial validating the use of perispinal etanercept to reduce post-stroke disability has wide-ranging implications, Expert Review of Neurotherapeutics, 20:3, 203-205, DOI: 10.1080/14737175.2020.1727742
  • Central Poststroke Pain Syndrome. Published March 17, 2016. U.S. Pharmacist.
  • Ian A. Clark (2017) An unsound AAN Practice Advisory on poststroke etanercept, Expert Review of Neurotherapeutics, 17:3, 215-217, DOI: 10.1080/14737175.2017.1282315
  • Stephen J. Ralph, Andrew Weissenberger, Ventzislav Bonev, Liam D. King, Mikaela D. Bonham, Samantha Ferguson, Ashley D. Smith, Adrienne A. Goodman-Jones & Anthony J. Espinet (2020) Phase I/II parallel double-blind randomized controlled clinical trial of perispinal etanercept for chronic stroke: improved mobility and pain alleviation, Expert Opinion on Investigational Drugs, 29:3, 311-326, DOI: 10.1080/13543784.2020.1709822
  • Ignatowski, T.A., Spengler, R.N., Dhandapani, K.M. et al. Perispinal Etanercept for Post-Stroke Neurological and Cognitive Dysfunction: Scientific Rationale and Current Evidence. CNS Drugs 28, 679–697 (2014).
  • Tobinick E. (2011). Rapid improvement of chronic stroke deficits after perispinal etanercept: three consecutive cases. CNS drugs, 25(2), 145–155. 

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