February 15, 1999
A team of neuroscientists at Johns Hopkins offers the first concrete evidence of what's behind some of the most incapacitating pain syndromes people can suffer, a move suggesting immediate strategies for treatment.
The syndromes, part of a larger category called neuropathic pain, can occur after the most transient or insignificant injury to a nerve. Over time, pain from the injury extends to nearby skin, which becomes exquisitely sensitive to touch and temperature change. "A mere breeze can trigger severe burning pain, as does going outside on a hot summer day," says neurosurgeon James Campbell, M.D., one of the research team. Changes in skin texture, bone loss or contraction of nearby joints may follow. Neuropathic pain isn't as common as headache or arthritis pain, but neurologists estimate costs worldwide in medical treatment and disability pay run in the millions. The biology of the problem has eluded scientists since it was first well- described a century ago (see enclosed description).
Working with animals, the Hopkins team clearly showed pain signals can originate in nerves not directly at the site of injury. The study, led by Hopkins neurosurgery professor Richard Meyer, M.S., appears in this month's Journal of Neurophysiology. The scientists partially severed a single pain nerve -- a step known to produce signs of neuropathic pain -- and then looked at electrical activity in nearby, undamaged nerves leading to the skin.
In the model animals, the researchers report, branches of the damaged nerve completely disappeared. Nearby undamaged nerves were intact, but they now showed abnormal and spontaneous activity -- telegraphing a message of pain.
In a second part of the study, the researchers added adrenalin-like chemicals to the skin to mimic conditions of a specific type of neuropathic pain called sympathetically maintained pain (SMP). In this least well-understood syndrome, a person's adrenalin-releasing sympathetic nervous system -- one involved in "fight or flight" -- somehow links injured pain nerves with noninjured ones. Things that stimulate this nervous system, like temperature changes, also seem to trigger the pain. "In the study, undamaged nerves not only become active," says Meyer, "but they also fired in response to our adrenalin mimic, something you'd expect in human SMP."
"What we're seeing here," he says, "is a biological change in the innocent' pain nerves whose territory overlaps that of injured nerves. Something makes them newly receptive to, say, adrenalin or, perhaps, to other stimuli such as pressure. Knowing this," he adds, "also suggests treatment."
Existing therapy for neuropathic pain centers on drugs such as opiates that affect the brain's perception of pain, but the cost runs high in side effects. Surgery is an option in some patients, "but results are often disappointing," says Campbell. "These new studies, however, show a basis for targeting the skin -- specifically the skin originally served by the injured nerve. The significance," he adds, "is that pain may arise from the affected skin and that therapy directed there may be quite effective."
The research team is already testing ways to block activity in the activated nerves, such as destroying their sensitive endings via large doses of the chili pepper derivative capsaicin, applied to a patient's skin under anesthesia. Also, ointments containing clonidine, which locally blocks the sympathetic nervous system, might take away the trigger for SMP and other kinds of pain.
The research was supported by grants from the National Institute of Neurological Disorders and Stroke.
Other researchers were Zahid Ali, Ph.D., Matthias Ringkamp, M.D., Timothy Hartke, Philip Chien, and Nicholas Flavahan, Ph.D.
The following is excerpted from a story which appeared in the Johns Hopkins Medical Institutions' publication, Brainwaves, and was written by Janet Worthington. It's an account of one type of neuropathic pain, as described by a physician at the time of the Civil War:
"Under such torments, the temper changes, the most amiable grow irritable, the soldier becomes a coward, and the strongest man is scarcely less nervous than the most hysterical girl."
S. Weir Mitchell, M.D., a 19th century neurologist, was as perplexed by the phenomenon of sympathetically maintained pain (he called it causalgia), as his modern counterparts. In his 1872 book, "Injuries of Nerves and Their Consequences," he carefully documented case after case in which injuries resulted in "the most terrible of all the tortures which a nerve wound may inflict."
Most of his patients were Civil War veterans, otherwise healthy men whose lives had been forever changed by this peculiar, burning pain, described by one as a "red-hot file rasping the skin." In many, pain was associated with a mysterious glossiness in the skin. "The burning comes first, the visible skin-change afterwards," Mitchell reported.
"Of the special cause which provokes it, we know nothing, except that it has sometimes followed the transfer of pathological changes from a wounded nerve to unwounded nerves, and has then been felt in their distribution, so that we do not need a direct wound to bring it about."
The pain's location varied from patient to patient, but "its favorite site is the foot or hand...the palm of the hand or palmar face of the fingers, and on the dorsum of the foot; scarcely ever on the sole of the foot or the back of the hand. When it first existed in the whole foot or hand, it always remained last in the parts referred to...if it lasted long it was finally referred to the skin alone. The part itself is not alone subject to an intense burning sensation, but becomes exquisitely hyperaesthetic, so that a touch or a tap of the finger increases the pain."
Patients took obsessive lengths to avoid exposing the area to the air, Mitchell wrote. "Most of the bad cases keep the hand constantly wet, finding relief in the moisture rather than in the coolness of the application."
And the pain took its toll. "As the pain increases, the general sympathy becomes more marked. The temper changes and grows irritable, the face becomes anxious, and has a look of weariness and suffering. The sleep is restless, and the constitutional condition, reacting on the wounded limb, exasperates the hyperaesthetic state, so that the rattling of a newspaper, a breath of air...the vibrations caused by a military band, or the shock of the feet in walking, gives rise to increase of pain. At last...the patient walks carefully, carries the limb with the sound hand, is tremulous, nervous, and has all kinds of expedients for lessening his pain."