Moving from the research laboratory to human clinical trials for chronic pain takes a long time, especially when the basic research focuses on novel ideas, far removed from mainstream thoughts about why chronic pain occurs. It is difficult to convince pharmaceutical companies to gamble on a heretical idea; but it is because mainstream ideas and solutions for chronic pain have failed that novel ideas were explored. This new view of chronic pain puts the blame not on neurons, but rather on immune cells associated with peripheral nerves and immune-like cells in spinal cord called "glial cells."

These are new players in chronic pain, and there is now overwhelming evidence from over a decade of basic research that these non-neuronal cells are importantly involved in both the creation and maintenance of chronic pain. This once heretical idea is becoming mainstream. Now, pharmaceutical companies are finally listening and drug candidates based on this approach are beginning to move to, and through, clinical trials. This is an exciting step forward.

Immune Cells and Immune-like Glial Cells

Traditionally, people think of pain being relayed by a simple chain of neurons. If you step on a nail, for example, nerve endings in your skin create electrical signals that are sent first to your spinal cord, and then to your brain, where pain is perceived. Classically, only nerve endings in your skin, joints, muscles, or internal organs can create the pain message. However, it is now clear that immune cells that live inside of big nerve bundles in your body can "tap in" and cause the creation of pain messages as well, far away from nerve terminals. It took a long time to realize how important these cells are, as mainstream science did not conceive of immune cells being able to "talk to" nerve fibers inside of big nerve bundles. That simply wasn't supposed to happen, but it does. In response to infection, inflammation, or damage to peripheral nerves or nearby tissues, these immune cells become activated. Upon activation, they release excitatory substances, such as proinflammatory cytokines, that cause pain messages to be sent to the spinal cord, and hence to the brain.

Immune-like glial cells within the spinal cord are very importantly involved as well.

They are "immune-like" because they function like immune cells in your body, but live in the spinal cord. Like immune cells, they release excitatory substances, such as proinflammatory cytokines, when they become activated in response to infection, inflammation, or damage to peripheral nerves or nearby tissues. These glial cells are in intimate contact with neurons of the pain pathway. As a result, proinflammatory cytokines and other substances released by activated glial cells can excite pain neurons in the spinal cord, greatly amplifying the pain message that is sent to the brain. In turn, clothing, a warm shower, or a cool breeze is now perceived as pain. In addition, a normally painful stimulus is perceived as more painful than it should be.

Basic research in rats has made tremendous strides in the last few years in understanding how immune cells in peripheral nerves and immune-like glial cells in the spinal cord cause chronic pain. These studies have identified what cells are involved and what substances they release to cause pain amplification; also, they have identified many drugs that can stop immune and glial cell amplification of pain. Most of these compounds are for research purposes only, as they are not appropriate for use in humans.

Enbrel® and Other Drugs that Target Proinflammatory Cytokines

However, there are a few compounds that are intriguing from a clinical perspective. The ones that have the most potential are those that target proinflammatory cytokines because they are key pain-enhancing substances released both by immune cells within peripheral nerves and immune-like glial cells within the spinal cord. Proinflammatory cytokines are extremely powerful substances that evolved to help the immune system kill foreign invaders, such as bacteria or viruses. While they are very important in helping you survive bacterial or viral infections, when they are released by immune cells in nerves or glial cells in the spinal cord, the end result is pain.

So what kinds of drugs that target proinflammatory cytokines might be useful for human chronic pain? One is entanercept (Enbrel), which blocks the function of one of the family of proinflammatory cytokines, called tumor necrosis factor (TNF). While this drug has received attention earlier this year because a celebrity with CRPS attributed pain relief to this drug, there are likely better drugs on the horizon. While entanercept may be effective when only TNF is involved in the creation of pain, typically multiple members of the proinflammatory cytokine family are simultaneously involved. Thus other therapies target all of these pain-inducing substances. For example, thalidomide-like drugs are now in clinical trials for chronic pain. While thalidomide was removed from the market decades ago for causing devastating birth defects, new versions of this drug have been developed which avoid such problems. Indeed, these drugs have had initial success in clinical trials, with reports of resolving chronic pain from CRPS.

However, drugs like entanercept and thalidomide-based compounds are given systemically, i.e., by injection or oral administration, which exposes the entire body to the drug. Thus, they may interfere with the normal function of the entire immune system, not just with the function of immune cells in nerves or glial cells in the spinal cord. Potentially, problems can occur when a person in chronic pain contracts a bacterial or viral infection, since the immune system may be compromised. Patients must use compounds with this potential problem firmly in mind.

Another approach that is nearing clinical trials in early pre-clinical testing at Avigen, Inc. avoids this problem. An injection is given by lumbar puncture into the cerebrospinal fluid that surrounds the spinal cord. This is similar to how pain suppressive drugs are delivered around the spinal cord for pain relief during and after surgery, and for mothers giving birth. To suppress the pain amplifying effects of proinflammatory cytokines, this therapy causes the sustained release of a powerful anti-inflammatory cytokine, called interleukin-10 (IL-10). IL-10 calms down the agitated glial cells and suppresses proinflammatory cytokines that amplify pain.

Taken together, there are new therapies on the horizon for treating chronic pain, including that from CRPS. These novel approaches target immune cells and glial cells instead of neurons. As all currently available therapies that target neurons fail to control chronic pain in the majority of patients, these new therapies are exciting as they provide a whole new approach to clinical pain control

Linda R. Watkins, PhD, is a Professor in the Department of Psychology, a University of Colorado President's Teaching Scholar, and the Director of the Interdepartmental Neuroscience Ph.D. Program, at the University of Colorado, in Boulder. linda.watkins@colorado.edu; Department of Psychology, Campus Box 34, Muen. D457B, University of Colorado at Boulder, Boulder, CO 80309-0345

Updated October 7, 2005