Pain 2007

January, 2007

Pain is a major problem for physicians and the public alike, resulting in nearly $100 billion in lost productivity and health-care costs each year, according to the nonprofit Partners Against Pain. In 2006 general pain researchers around the globe advanced understanding of what underlies acute and chronic pain, as well as ways to alleviate it.

One study identified a “master switch” for the development of neuropathic pain, a chronic form of pain quite different from the acute pain of an injury. Another found that simply anticipating pain may be worse than actually experiencing it. Researchers looking for pest controls stumbled onto an enzyme blocker that may provide relief from inflammatory pain while decreasing the risk of heart attack associated with drugs such as rofecoxib (Vioxx). Canadian scientists found that mice display empathy and become sensitive to pain while watching another mouse experience pain. And researchers found that the type of placebo and the context in which it is given may enhance the placebo effect on pain perception.

Master Switch Identified for Chronic Pain

Neuropathic pain, from injury to “peripheral” nerves outside the brain and spinal cord, is characterized by a chronic shooting or burning sensation. It responds poorly to treatment with opioid drugs, which are the strongest painkillers and include such drugs as morphine, codeine, and oxycodone (brand name Oxycontin).

In the journal Neuron, researchers at Harvard Medical School reported finding a “master switch” for the development of neuropathic pain.1 This switch, the Runx1 gene, is expressed only in sensory nerve cells called nociceptive cells, which are involved in sensing pain. These cells translate painful stimuli into nerve signals via ion channels, special pores in the nerve cell membrane.

The researchers, led by Qiufu Ma, exposed “knockout” mice (in which the Runx1 gene was removed) to thermal, mechanical, inflammatory, and neuropathic stimuli and measured their reaction to pain by how long they either lifted or licked their paw in response.

Runx1 gene_PR_2007 
Limiting pain: A gene called Runx1 is active in pain receptors for thermal and inflammatory pain, indicated by arrows, and neuropathic pain, indicated by the arrowheads. Mice lacking the Runx1 gene did not react to these types of pain.  (Image courtesy of Qiufu Ma)

While the Runx1–deficient mice responded to the mechanical pain stimulus, they showed no reaction to the painful thermal, neuropathic, or inflammatory stimuli. The development of pain-receptor cells was impaired and the ion channels known to be involved in sensing thermal and neuropathic pain were nonexistent.
The findings could have important implications for developing new, more effective treatment strategies for neuropathic pain, possibly by turning off the expression of the Runx1 gene in patients suffering from chronic pain, the researchers said.

Anticipating Pain May Be as Bad as Pain Itself

Waiting for a shot in the doctor’s office or looking ahead to a painful medical procedure causes some people to think, “Just get it over with. I don’t care how much it hurts!” Scientists may now know why: for some of us, anticipating pain may be as bad as actually experiencing it.

Using brain scans to study the biology of dread, a team of researchers at Emory University School of Medicine found that almost one third of study participants who volunteered to receive an electric shock chose to receive a stronger jolt in exchange for getting the ordeal over with rather than waiting for a weaker one. Volunteers were placed inside a magnetic resonance imaging machine and given a series of 96 electric shocks, of varying intensities, to the foot. Most volunteers chose to receive a stronger electric shock if the waiting time before the shock was shorter.

The findings, reported by Gregory Berns and colleagues in Science, indicate that a majority of individuals in the study dreaded waiting for a shock.2 Those who could not tolerate a delay and chose an immediate and more painful jolt were considered “extreme dreaders,” while “mild dreaders” could endure a delay for a milder shock.

The magnetic resonance scans showed that parts of the brain’s “pain matrix,” a network of brain regions that respond to noxious stimuli including pain, became active even before the study participants were given the shocks. Regions of the brain involving fear and anxiety showed no response prior to the jolt that distinguished the mild from the extreme dreaders. The results demonstrate that the more a person dreads an event, the more attention the brain’s pain-sensing centers pay to the amount of time until the event occurs.  It is not yet clear how these preferences relate to how people deal with events that are known to be unpleasant, such as going to the doctor for a painful procedure, but the neurobiological underpinnings of dread may hold some clues for better pain management in the future.

Pain Control from Pest Control

After the earlier withdrawal of the popular pain reliever Vioxx (rofecoxib) from the market because of safety concerns, researchers at the University of California, Davis, may have stumbled upon a safer way to deliver needed pain relief for people suffering from arthritis or other inflammatory diseases.

The researchers started out with an unrelated goal: to find biological pest controls that would regulate the development of insect larvae. However, in the course of their study they discovered a new human enzyme that indirectly blocks the production of COX2 proteins, which are involved in pain and inflammation.

Using the two therapies in combination may lead to relief of inflammatory pain and decrease the side effects of drugs used to alleviate that pain. In testing on rodents, the researchers found that the enzyme blocker was as potent as low doses of rofecoxib and another COX2 inhibitor, celecoxib (Celebrex), but without producing changes in blood chemistry that were linked to serious cardiovascular complications, including heart attacks, in an earlier study—the finding that led to Vioxx’s removal from the market. The new study was published in Proceedings of the National Academy of Sciences.3
A combination of the two types of COX2 blockers could dramatically reduce the concentrations of Cox-2 inhibitor needed to effectively treat inflammation, the researchers said. This combination apparently changes blood chemistry in a way that reduces the tendency for blood clots to develop, a key feature of heart attacks. Combination therapy such as this may help solve the dilemma of whether to use powerful Cox-2 inhibitors to treat inflammatory pain.

“Emotional Contagion” of Pain

Previous pain research has shown that early-life experiences and certain social factors can make chronic pain worse. For instance, German scientists found that social factors can alter brain function in a way that worsens pain sensations.4 Another study showed that pain experienced early in life can affect how pain is experienced in adulthood.5 A new study, reported in Science, by Jeffrey Mogil and colleagues shows that a mouse’s response to pain is intensified in the presence of another mouse in pain, suggesting that empathy plays a role in pain.6

Using an acetic acid writhing test, which simulates a mild stomachache, the researchers, at McGill University’s Pain Genetics Laboratory, determined that mice that were familiar with one another showed a subclass of empathy called “emotional contagion,” in which one mouse recognizes and adapts to the emotional state of another. The researchers found that a mouse became more sensitive to acetic acid while watching another mouse experience a painful heat stimulus.

Yin Yang Mice 
Your pain and mine: A mouse in pain felt it more intensely when in the presence of another mouse in pain, which suggests that empathy has an effect.  (Image courtesy of Jeffrey Mogil) 

Mice rely on pheromones (chemical substances that transmit messages between members of the same species) to interact with one another. The investigators blocked the rodents’ senses of smell, vision, and hearing and found they could still sense one another’s pain, suggesting that some form of communication among them affected their response to pain.

Because social interaction plays an important role in chronic pain behavior, the McGill findings may be relevant to the study of pain in humans. The findings in the mouse model may be used to study the human brain mechanisms involved in pain, as well the role social factors play in pain management.

Type of Placebo Has an Effect

More than 50 years ago, a Harvard anesthesiologist named Henry K. Beecher first described the role placebos play in medicine. The placebo effect is the phenomenon of a patient’s symptoms being alleviated by an otherwise ineffective treatment because the individual expects or believes it to work.

In two studies, published in the British Medical Journal and the Journal of Neuroscience, a research team led by Ted Kaptchuk of Harvard Medical School’s Osher Institute demonstrated that the placebo effect can be modulated by the type of placebo given, as well as by the context in which it is delivered.7,8

In the first study, Kaptchuk’s group gave sham acupuncture to 135 patients suffering from severe arm pain, while another 135 received an inert pill, to determine which placebo treatment had a greater effect. Neither proved to have a superior effect. In a later study, half of each group remained on their original placebo treatment while the other half received active treatment.

The patients receiving the sham acupuncture reported greater reduction in pain than those taking the inert pills. Kaptchuk says the findings suggest that the “ritual” of receiving treatment with a device such as sham acupuncture may enhance the placebo effect more so than an inert pill, a possibility he and his colleagues continue to study.

The researchers also used functional magnetic resonance imaging to determine the brain networks activated by sham acupuncture during the round of testing that included some patients receiving an active treatment. Building on previous studies that discovered pathways involving the prefrontal cortex, striatum, and brain stem for processing placebos, the researchers found that specific areas of the brain are particularly associated with the placebo effect. One of them is the anterior insular cortex, which activates bodily feelings, including pain. These studies add to the growing body of evidence that the so-called placebo effect has a basis in changed brain functions.