Healing the Hurt

Finding new ways to treat pain

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Illustration by Bartholomew Cooke for TIME

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That's what Dr. David Fink, director of neurology at the University of Michigan, is hoping to show with a gene-therapy study, in which he will inject chronic-pain sufferers with genes coding for natural painkillers, hoping to boost their bodies' levels of those analgesic chemicals. Enkephalins are a type of opiate that the body produces to dull pain sensations, but in cases of chronic pain, these agents appear not to flow in sufficient quantities. So in the first study of its kind, Fink's team is testing whether using a viral vector to inject cancer patients with the gene associated with enkephalins can boost levels of the opiate and address the subjects' pain. "If we could deliver the gene that makes enkephalins," he says, "they could be released from cells directly into the nervous system and potentially reduce pain in a more targeted fashion." As appealing and potent as that strategy is, tapping into the opiate system is also fraught with danger. The analgesic circuits are intricately intertwined with the body's reward-andreinforcement network, meaning that activating it could lead to addictive behaviors. That's what makes prescription opioids and other painkillers so habit-forming.

So identifying other genes — those that regulate the addiction circuits — and finding ways to bypass them could be another avenue to treating chronic pain more effectively with existing opiates. At Stanford University Medical Center, researchers led by Martin Angst, a professor of anesthesia, are studying sets of twins in which one displays a stronger liking for painkilling drugs than the other but both experience the analgesic benefits. The idea is to try to isolate the protein markers, perhaps in the blood, produced by the genes that help one twin resist the habit-forming nature of the drugs. Spotting the protein could help doctors identify those more vulnerable to addiction. "As much as we agree that we need to look for novel pain treatments, we understand narcotics pretty well," Angst says. "And if we had a genetic thumbprint for how likely you are to suffer from drug abuse, how convenient that would be."

Training the Brain
Still, even if such approaches produce new screens for identifying the best responders to painkillers, they won't likely be enough to address the universe of chronic pain with its widely diverse causes. To achieve that, say some researchers, we need to do more than simply muffle the nervous system's false alarms so the brain and body don't hear them. Instead, we have to retrain the brain and find a way to shut that alarm down.

That's where brain imaging — the powerful technology that allows researchers to view the brain at work, nearly in real time — becomes indispensable. What if, for example, pictures of the brain could be used to help people "think" themselves out of pain?

The idea borrows heavily from biofeedback, in which patients use computer screens or other instruments to monitor bodily functions like heart rate or respiration, then dial those functions up or down with just the power of their mind. For pain patients, Dr. Sean Mackey, a professor of anesthesia and pain management at Stanford, has been studying ways to do the same thing with the aid of functional magnetic resonance images (fMRI), which document active regions of the brain at work. "We want to turn the tool that we use to open windows into people's brains and instead use it as a tool to allow people to control their brains," he says.

In Mackey's study, healthy subjects in an fMRI machine were given live access to an image of their brain's activity in a region known as the anterior cingulate cortex — a key regulator of pain signals. Using a heat probe on the arm to cause pain, Mackey and his team asked the volunteers to dial down their level of discomfort when the temperature reached unbearable levels and to dial up their pain sensations when the probe wasn't generating enough heat. They did this not by actually changing the temperature of the probe — that was under the control of the researchers. Rather, they actively refocused their brains either away from or to painful thoughts, depending on the effect they were trying to achieve. To decrease their painful feelings, for example, the subjects were told to distract themselves with thoughts of more-pleasant experiences or events.

Surprisingly, it worked. After the training, the subjects improved their ability to control pain intensity by 23%. And in the ultimate test, when Mackey next trained patients with chronic pain, they reported a 64% reduction in their sensation of pain.

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