The Baby and the Bathwater

by James Cavuoto, editor

Much of the need for neurotechnology devices and therapies has arisen because of pain. In the early days of this industry, it was chronic low back pain that drove sales of spinal cord stimulation systems—still the largest product category in the global neuromodulation market.

But newer devices and therapies are targeting other forms of pain, including the intense psychic pain that accompanies major depression and other neuropsychiatric disorders. No matter the type or source of pain that a patient is suffering from, the experience is subjective—unlike diabetes or hypertension, we’ve yet to come up with a reliable and quantifiable physiological measure of pain that is not derived from the patient’s own account.

One of the greatest challenges confronting clinical trial sponsors investigating new neuromodulation therapies is proving that their therapy does not benefit from the placebo effect. Many a startup firm in this space has gone by the wayside because their therapy does not produce results that are significantly better than what’s obtained by some form of “sham” stimulation.

Regulators and payers take it for granted that the placebo effect should be eliminated from a clinical trial. It seems that nobody cares about benefiting from the placebo effect or incorporating it into their therapy.

But what if there is an identifiable and repeatable physiological basis for the placebo effect and what if that mechanism actually plays a role in neuromodulation therapies that does not exist in other forms of pain relief? In other words, what if a clinical trial is treating signal as noise—in effect, throwing the baby out with the bathwater?

A recent research article published in the journal Nature suggests that there is indeed a neural circuit basis for the placebo effect in pain relief. The article, written by a team from the University of North Carolina, Stanford, and Harvard among others, reports that analgesia from the expectation of pain relief is mediated by rostral anterior cingulate cortex neurons that project to the pontine nucleus—a precerebellar nucleus with no established function in pain. The authors created a behavioral assay that generates placebo-like anticipatory pain relief in mice

“This study reveals circuit, cellular, and synaptic mechanisms that underlie placebo analgesia and, more broadly, the cognitive-evaluative dimension of pain, bridging the gap with our more advanced understanding of the sensory-discriminative and affective-motivational dimensions of pain,” they write.

This is not the first body of work to suggest a neural basis of the placebo effect. In a well documented talk at the recent meeting of the International Neuromodulation Society, journal editor Robert Levy recounted numerous studies that showed a physiological basis for placebo. “The fact that we don’t include placebo in our model of the mechanism of action of neuromodulation therapies appears to be a profound mistake,” he said.

There’s more at stake here than just a lack of understanding of mechanisms of action. If our process of developing and approving a new therapy discards rather than includes a key element that actually makes the patient feel better, then we are in violation of the axiom that says, “First, do no harm.”

If indeed neuromodulation therapies for pain and mood disorders work in part because of the placebo effect, and if that effect is not produced as prominently in existing therapies, than any clinical trial that discards the placebo effect is flawed. As we’ve argued in the past, a more relevant clinical trial design would be a non-inferiority trial of a neuromodulation therapy vis-a-vis a drug therapy, for example.

Clinical trials—and indeed all of modern medicine—should be geared toward making patients get better, not by preventing them from benefiting from a stigmatized mechanism of action.