Chronic Neuropathic, 'Phantom' Pain Comes From Affected Nerve And Spinal Cord, Not Brain

Another kind of chronic pain may start with a specific injury, surgery or disease event, but may linger for weeks or even years beyond any useful protective function. Such events range from shingles to open-heart surgery where up to half the patients suffer long-term pain, breast removal (sometimes even lumpectomies), or – in the most drastic cases, spinal injury or amputation.

Such "neuropathic pain" is particularly vexing and difficult to treat because there's no agreed location or physiological mechanism to target for therapy. New research from the University of Alberta, Canada appearing in the Journal of Neurophysiology reported that the place to look is between the nerves that are producing the pain and the spine, rather than from the spine to the brain, according to the senior author, Peter A. Smith.

The paper, "Sciatic chronic constriction injury produces cell-type specific changes in the electrophysiological properties of rat substantia gelatinosa neurons," is in the online Journal of Neurophysiology, published by The American Physiological Society. Research was by Sridhar Balasubramanyan, Patrick L. Stemkowski, Martin J. Stebbing and Peter A. Smith, University of Alberta, Canada; Stebbing is also at RMIT University, Bundoora, Australia.

Importance of identifying peripheral nerves as key target

Marshall Devor, a professor at the Institute of Life Sciences, and at the Center for Research on Pain, Hebrew University, Jerusalem, said "the results reported in this paper are quite optimistic in terms of the prospects for finding future methods of treatment. First," he said, "because if the problem is in the spine or the brain, it's hard to treat. But if the impact is in the nerve, we have a better idea where to look and it's also easier to target therapy there."

Devor added that the Alberta team "didn't prove that the central nervous system isn't involved, but they have shown that the peripheral nerve probably is highly involved." Devor wrote an editorial in the Journal accompanying the Balasubramanyan et al. paper.

Paradoxes abound: role of inflammation, contrary reactions; Iraq casualties

"The subject gets complicated quickly and is full of paradoxes," Smith said: "For instance, in chronic pain there's often an emotional element. If a patient has post-traumatic stress syndrome, that could make the pain worse because there are overlapping disorders."

The war in Iraq has highlighted the issue of chronic neuropathic pain in amputations (called "phantom limb pain") because the rate of amputations is so high compared to previous wars.

Smith said that another "big issue in chronic pain is that two people can have more or less identical injuries, and one gets chronic pain, but the other doesn't. It may have to do with the immune system and inflammation," he said.

Another paradox, he pointed out, is that "most types of pain are associated with tissue damage and inflammation. Because neuropathic pain can go on for years after initial inflammation has subsided, it is defined as 'noninflammatory pain.' Although this definition is accurate, it may have clouded our thinking as to how neuropathic pain is initiated. Current research suggests that an initial transient inflammatory event may set the whole long term pain sequence into motion," he said.

Classic explanation found lacking, though spinal changes identified

In the current study, researchers constricted the sciatic nerve of young rats, then studied what changes had occurred in the substantia gelatinosa. This translucent area of the spinal cord is involved in the processing of unpleasant sensations that can be perceived as painful. According to Devor, much has been made of the theory that neuropathic pain actually "imprints" changes in the spinal column that are responsible for the long-lived chronic pain.

What Balasubramanyan et al. found, however, didn't quite match what they, or others, might have expected. According to their discussion section: "Given the increase in the excitability of dorsal horn neurons that follows peripheral nerve injury in vivo, and the presence of mechanical hypersensitivity (heightened pain responses) in our experimental animals, the observed changes in the properties of substantia gelatinosa neurons at first seem relatively modest." For example, CCI [chronic constriction injury] did not promote the generation of spontaneous action potentials in substantia gelatinosa neurons.

They conclude that CCI indeed produced a certain level of bona fide "centralization" in that it "alters the intrinsic properties of the dorsal horn by exerting both pre- and postsynaptic effects on excitatory synaptic transmission and by attenuating inhibitory transmission." However, the "relative contribution of intrinsic, peripheral and descending mechanisms to nerve injury-induced 'central hypersensitivity' is yet to be determined."

New directions in treating pain

In addition to further studies designed to identify more precisely what changes occur in neuropathic and chronic pain scenarios, Smith said there is still much to be done in determining how to treat such pain, whatever the mechanisms.

For instance, it may be most appropriate to target the initial injury that precipitates the enduring neuropathic pain. In fact, this is already done by the use of pre-emptive anesthesia during surgery. The surgeon uses a local anesthetic to deaden the nerves as well as a general anesthetic to immobilize the patent for surgery. Such procedures should be encouraged, Smith said. Another possibility may be to suppress the immune system for the initial five days after injury. This may curtail the inflammation associated with peripheral nerves that appears to trigger many aspects of neuropathic pain.

• According to lead author Sridhar Balasubramanyan: "Clearly, what needs to be done now is to go back to the periphery and concentrate on finding what physiological mechanisms might be at work closer to the removed part or the original injury site, as in cases of diabetic neuropathy, shingles and surgery."
• The whole issue of treating chronic and neuropathic pain continues to mystify clinicians and researchers, Smith noted. For instance "opiates work well in almost all cases of regular pain, but morphine is of limited use in chronic pain."

A recent article in Psychiatric Times by Steven A. King reported that while the "apparent neuropathic nature of phantom limb pain (PLP) would suggest that antidepressants, anticonvulsants and similar medications would be most efficacious…most (PLP) patients are treated with acetaminophen, nonsteroidal antiinflammatories and opioids." A survey article by M.A. Hanley and associates found that just over half of PLP patients, and over one-third of severe PLSP patients, "had never been treated" at all for their pain.

Source and funding

The paper, "Sciatic chronic constriction injury produces cell-type specific changes in the electrophysiological properties of rat substantia gelatinosa neurons," is in the online Journal of Neurophysiology, published by The American Physiological Society; it will appear in the July issue. Research was by Sridhar Balasubramanyan, Patrick L. Stemkowski, Martin J. Stebbing and Peter A. Smith, Department of Pharmacology and Centre for Neuroscience, University of Alberta, Edmonton, Canada; Stebbing is also at the School of Medical Sciences, RMIT University, Bundoora, Victoria, Australia.

Research supported by the Canadian Institutes for Health Research, the Christopher Reeve Paralysis Foundation and a stipend from the Alberta Heritage Foundation for Medical Research (Balasubramanyan).