Neuroinflammation and Peripheral Inflammation—A Big Difference
The discovery that microglial cells can create neuroinflammation in the central nervous system (CNS) is perhaps the scientific breakthrough that will most change the way we treat chronic pain in the years ahead.1-3 This statement alone suggests that neuroinflammation isn’t peripheral inflammation. While the microglial cell is an immunologic or mast cell, it is not a lymphocyte, which produces peripheral inflammation, as seen in joints and muscle.
This memo points out some of the differences that have emerged as pain practitioners have begun to tackle neuroinflammation in an effort to improve pain treatment.2 The major practical difference between neuroinflammation and peripheral inflammation is that most of the pharmaceutical agents used to effectively treat peripheral inflammation are seldom effective against neuroinflammation. For example, the old standby, nonsteroidal anti-inflammatory drugs, such as ibuprofen and naproxen, do not do much clinically to reduce centralized pain and neuroinflammation. Just why is unclear. Perhaps it is due to some characteristic of neuroinflammation, perhaps the activation of the microglial cell, or perhaps these agents simply fail to cross the blood-brain barrier?
Interestingly, an odd array of drugs has been shown by in-vitro studies to suppress the microglial cell and subdue neuroinflammation.3 These agents include minocycline, metformin, low-dose naltrexone, and pentoxifylline. Alendronate, a bisphosphonate that inhibits bone absorption, has recently been shown to attenuate microglial cells.4
Conversely, I have not found the new biologics, infliximab (Remicade) and adalimumab (Humira), which effectively treat peripheral inflammation of rheumatoid and psoriatic arthritis, to be effective in treating neuroinflammation.
Interestingly, both neuroinflammation and peripheral inflammation will respond to corticosteroids. I have found, however, only the corticosteroids dexamethasone and methylprednisolone to be very effective in the treatment of centralized pain and inflammation. Again, just why is unclear. Do most corticosteroids fail to cross the blood-brain barrier, or is there an intrinsic mechanism in the microglial cell that only allows some corticosteroids to be therapeutic? Receptors on microglial cells seem to be critical, as they attach to therapeutic agents.
A most important clinical finding is that neuroinflammation appears to be present regardless of the underlying etiology of the pain. For example, neuroinflammation is present in complex regional pain syndrome (CRPS), arachnoiditis, Lyme disease, and post-viral syndromes—among other causes of centralized pain. Clinically, patients express symptoms of periodic heat and sweating. Elevated serum markers of neuroinflammation, such as tumor necrosis factor a, interleukins, myeloperoxidase, and even C-reactive protein, may be found. It appears that neuroinflammation is a root cause of many central pain syndromes, and attempts to control or suppress it may be treating the underlying cause of pain rather than simply providing symptomatic care. Also, early clinical experience with serum testing of inflammatory markers suggests that both neuroinflammation and peripheral inflammation may go into suppression or convalescence only to flare at some point in the future.5 Just as with rheumatoid arthritis, a total cure may not be possible.
Another factor in treating neuroinflammation is the spinal fluid. Treatment agents for peripheral inflammation are carried to the target solely by arterial blood. Agents that target neuroinflammation may arrive at the pathologic site by arterial blood as well as by spinal fluid whose physiologic purposes include lubrication, waste removal, and nutrition. It may be that agents that effectively treat neuroinflammation need not only to cross the blood-brain barrier but also to enter the spinal fluid to be transported to the inflamed tissue site.
Our future looks bright. Regimens and protocols to treat neuroinflammation are being developed by a number of researchers and clinicians. It’s quite rewarding to see severe pain patients improve without the necessity of our usual symptomatic agents, including the opioids and neuropathic (antiseizure) medications. Practical Pain Management is eager to publish clinical experiences involving control and suppression of neuroinflammation.
Genetic Research in Pain
Also featured in this issue are two articles examining the growing body of research into genetic influences in pain perception and processing. In the first article, Don L. Goldenberg, MD, reviews the genetic factors that influence the development of chronic widespread pain, including fibromyalgia. Twin studies have been instrumental in helping researchers better understand the genetic underpinning of pain. In the second article, John L. Lee, MD, and Steven H. Richeimer, MD, examine what genetic testing is now available to help target pain therapies and screen for personality traits that may influence pain perception and addiction risk.
Also in this issue, John Claude Krusz, PhD, MD, provides his protocol for treating centralized pain and headache in his clinic. Dr. Krusz is a pioneer in the use of subanesthetic dosages of intravenous agents—ketamine, lidocaine, propofol, and magnesium sulfate—for the management of chronic headaches and pain.