WASHINGTON, D.C.–The experience of pain in patients with rheumatic diseases–and pain in other types of disorders–is much more complex than nerve endings on the skin getting the sensory input from a flame or another stimulus and the nervous system processing it as pain, recent research has shown.
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The central nervous system (CNS) is also heavily involved, and the understanding of this can lead to the treatment of pain that simultaneously resolves other symptoms that are also CNS regulated and that can help determine which drugs work in which people, experts said here at the recent 2012 ACR/ARHP Annual Meeting, held November 9–14.
The traditional notion of pain as just a peripheral, or strictly stimulus-driven, phenomenon is over, said Daniel Clauw, MD, professor of anesthesiology and medicine in the department of rheumatology at the University of Michigan, Ann Arbor. He is also director of the Chronic Pain and Fatigue Research Center there.
“There’s really two different parts of the pain system,” he said. “There’s a part of the pain system that is recognizing nociceptive input in the periphery—the classic sort of pain system that we’ve all learned about—but then the central nervous system can either turn up or turn down the gain and the extent to which the nociceptive input is felt by an individual.”
There can be a low-volume setting, with someone getting what might normally be painful stimuli but not actually feeling pain.
“Or they can have a very high-volume control setting, and they can be experiencing pain in spite of the fact that they don’t have any ongoing peripheral nociceptive input that we can identify by classic mechanisms, i.e., someone with a condition like fibromyalgia,” Dr. Clauw said.
Clifford Woolf, MD, PhD, director of the F.M. Kirby Neurobiology Center at Boston Children’s Hospital and professor of neurobiology at Harvard Medical School in Boston, who is credited with discovering and coining the term “central sensitization,” said that, “what’s fascinating is that many of the mechanisms that operate the human pain system and harness synaptic efficacy are very similar to the ones that operate and enable us to learn [and] retain information with memory.”
But one feature that differentiates central sensitization is “heterosynaptic facilitation.” This involves a “global increase in excitability of the neuron such that an input that was not activated before can now become enhanced.”
A simple example would be applying capsaicin to the skin, then applying secondary stimuli nearby. The capsaicin activates the nociceptors, producing a state of heightened excitability in the CNS, which can lead even a light touch nearby to be experienced as pain.
With CNS involvement, centrally acting analgesics then can have multiple benefits, Dr. Clauw said.
“When someone responds to one of these drugs, they typically have an improvement in more than just pain. If they respond to a serotonin norepinephrine reuptake inhibitor, people will often have improvements in fatigue and in mood,” Dr. Clauw said.
Measuring the Mechanisms of Pain
Understanding the mechanisms of a specific patient’s pain can help direct treatment better, leading to “personalized analgesia,” he said.
Neuroimaging, like functional magnetic resonance imaging (fMRI), is helping in this regard, he said. FMRI allows changes in blood flow to be examined, showing neuronal activation that is associated with various tasks. Positron emitting tomography and H magnetic resonance spectrometry allow the activity of neurotransmitters to be examined.
An emerging interest is the significance of the level of brain “connectivity” among regions not normally connected, Dr. Clauw said.
Experts are now beginning to wonder whether this might be partially responsible for the memory problems and some of the other difficulties seen in people with chronic pain, he said. The pain, it seems, literally might be taking up brain networks needed for executive functions and interfering with those kinds of tasks.
Whether certain therapies work can have everything to do with the mechanism behind the pain, Dr. Clauw said. Opioids, for instance, don’t seem to work very well for centrally regulated kinds of pain.
“This is the reason that we should move towards a mechanistic approach to pain,” Dr. Clauw said. “Because it’s not just academic interest as to what underlying mechanism or mechanisms someone has. It really is going to determine which drugs they’re going to respond to, whether they’re going to respond to very expensive surgical interventions, injections, blocks, and other things that are done to almost everyone with chronic pain right now irrespective of what the underlying mechanism of their pain is.”
Dr. Woolf said another challenge is finding animal models that really reflect how pain is experienced.
“This is a real concern, one that I think anyone working in pain needs to think about,” he said. “We still remain very poor at studying exactly what an animal is feeling.”
An Astounding Finding
It’s not enough to simply apply a stimulus and gauge a reflex response, he said. It’s the voluntary behavior that really matters.
In a recent study by his laboratory, researchers applied a pain stimulus then observed how that affected mice’s natural inclination to run in wheels that were readily available. The amount of running dropped to 40% compared to controls. Interestingly, by the third day after the stimulus was given, the mice were back to normal running in spite of the continued presence of mechanical allodynia.
They also found something even more astounding: The amount of medication needed to produce a reduction in the von Frey threshold—a measure of the response to a pain stimulus—was about 10 times higher than the amount needed to return a mouse to a normal running regimen.
“It turns out that we were measuring the wrong thing—if you measure pain in terms of what the animal chooses to do, the dose becomes spot on,” Dr. Woolf said. “The message here is that if you ask the right question, there’s a chance you may get the right answer.”
Thomas Collins is a freelance medical journalist based in Florida.