(from Dr. Robbins): The neuroimmune system plays a crucial role in headache and chronic pain. Most(87% or so) of the cells in the brain/spinal cord are neuroglia, not neurons. The drugs developed thus far generally target connections between neurons, such as the neurotransmitters(serotonin, norepinephrine, etc). However, the cells that oversee and regulate the neurons are the neuroglia, a subset of which are microglia. We(the scientific community) used to think that the glia were just supporting cells, the mortar and bricks; it turns out they do far more than that. So, meds/drugs/therapies targeting glia may prove very helpful in headache, as well as depression and other neurologic illnesses.
I started looking at this in 1987, I was convinced that the immune system was crucial in headache etiology/pathogenesis. I looked at different cell types(helper/suppressor: we found the “opposite” of AIDS, where there were more helper to suppressors in headache patients. And, indeed, AIDS patients do get headaches from various reasons, but there pre-existing migraines often decrease).
In 1989 I did a study where people came in and inhaled heparin, which is a blood thinner. They did this for 30 weeks, and many found their headaches were much better. Heparin, besides blood thinning, has a strong effect on the neuro-immune system. It may be one of our only meds that affects these glial cells.
Other possibilities for positively affecting the immune system include LDN(low dose naltrexone), minocycline, and ARBs(a class of blood pressure med, that includes losartan,candesartan,Diovan,Benicar, etc etc.).
For those with NDPH(New Onset Daily Persistent Headache), the action may very well be in the microglia, and targeting the glial cells may help. NDPH occurs after certain triggers, particularly viral illnesses(or Lyme etc.), where someone has been fine, no headache history, and all of a sudden they have headaches for months or years. It appears as if their microglia have been disrupted. Larry Robbins,M.D.

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