Patients with chronic pain often have limited treatment options. Drugs such as opioids can provide relief; however, they come with dangerous side effects and a high risk of addiction. Now, a new study in mice suggests there is a way to harness the placebo effect for chronic pain — a tantalizing finding that could pave the way for better treatments.
By activating a key group of neurons — already known to be switched on by anesthetic drugs — whenever mice entered a distinctive box, the researchers taught the rodents to associate that environment with a reduction in pain. The animals then continued to experience pain relief in this environment even without the neural stimulation, the authors report in Current Biology. Other studies have managed to create a temporary placebo effect in mouse models of acute pain; however, this is the first to show sustained relief from chronic pain.
The findings “support the emerging concept that drugs and placebos share a common mechanism of action,” says Neuroscientist Fabrizio Benedetti, a placebo expert at the University of Turin Medical School who was not involved in the new study. That discovery, he adds, could guide our understanding of how placebos work in humans.
Fan Wang, a Neuroscientist at the Massachusetts Institute of Technology (MIT) and Senior Author of the new study, has spent the past two (2) decades investigating the neural circuits that underlie touch, pain, and anesthesia. Back in 2020, she and colleagues at Duke University discovered a cluster of neurons in the central amygdala that “turn off” pain when activated by anesthesia. Stimulating these neurons in mice relieved both acute and chronic pain, whereas suppressing them made the animals extremely sensitive to even gentle touch.
Wang was curious to know whether that same neural circuitry could be tapped to “reverse engineer” the placebo effect, using the activity of these neurons to create an association between a specific context and pain relief.
Wang’s team used mice that, because of treatment with chemotherapy, had chronic neuropathic pain. The researchers introduced the animals to a pair of boxes — one decorated with vertical stripes, the other with horizontal ones. When a mouse entered one of the chambers, researchers used light to activate neurons in its central amygdala until, after a few training sessions in each box, it was conditioned to associate that chamber with pain relief. Even when the researchers stopped stimulating, the mice exhibited far fewer pain-related behaviors — such as grooming and licking — when they entered the chamber for several days afterward.
Surprisingly, even though the rodents showed a marked reduction in pain, their pain-suppressing neurons did not reactivate. This suggests they experienced a genuine placebo effect, the researchers explain, driven by the expectation of pain relief, and working through a separate brain mechanism that has yet to be identified. The mice also exhibited signs of a placebo effect — albeit a weaker one — if they received morphine instead of neural stimulation while in one of the boxes.
Benedict Alter, an Anesthesiologist and pain researcher at the University of Pittsburgh who was not involved in the new study, sees a parallel between Wang’s research and work being done with so-called open-label placebos. In these cases, patients are aware they are receiving a placebo pill; however, may still experience benefits due to conditioning, such as the simultaneous administration of an active drug. A 2021 study showed, for example, that if patients took placebo pills alongside opioids while recovering from surgery, continuing the pills helped reduce their pain once the opiods were stopped.
However, Alter also notes that the placebo effect in rodents is not necessarily comparable to that in humans, for whom “social interactions and personal experiences also play a large role.” Jiang Kong, an expert in pain perception and modulation at Harvard Medical School, agrees “there’s still a long way to go” before these findings can be translated to develop strategies for helping humans. In the meantime, however, animal models can help scientists “fill the gap” in their knowledge of the placebo effect, he says, and experiment with ways of further boosting it.
Ultimately, Wang hopes a better understanding of the placebo effect will change the way researchers and physicians approach chronic pain and addiction. In the future, doctors could potentially enhance the effectiveness of traditional pain treatments by pairing them with activities or contexts that trigger the placebo effect. “There should be awareness of how remarkable the brain-body interaction is,” she says. “We should find a way to tap into this power.”
REFERENCE: Science (News/Brain & Behavior); 05 SEP 2024; Phie Jacobs