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Vol. LXV, No. 25
December 6, 2013

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Great Expectations
Colloca Re-Evaluates the Placebo Effect

On the front page...

Dr. Luana Colloca

Dr. Luana Colloca

The placebo effect is surrendering its secrets.

“The placebo effect is a very complex psycho-neurobiological phenomenon wherein humans or animals experience an enhanced benefit via positive expectations,” said Dr. Luana Colloca in her recent lecture at Lipsett Amphitheater.

A research fellow with NCCAM and NIMH, Colloca presented the talk, “Re-evaluating the Placebo Effect in Medicine,” as part of the Grand Rounds for Clinical Fellows lecture series.

“There are many contexts where we are talking about placebo and placebo effects,” Colloca continued. “Randomized clinical trials, experimental research settings and clinical settings or encounters.”


A placebo is a medication or treatment given for its soothing psychological effect. We usually think of it as inert—a sugar pill (“pure placebo”). It can also be an active treatment with efficacy in some conditions, while being used as placebo for another condition, as when antibiotics are given for a viral infection (“impure

The word placebo (“I shall please”) comes from an ancient Latin translation of Psalm 116, while the term nocebo—a negative effect caused by an inert substance—was coined in the 1950s. Placebos are still widely used in medicine. A physician might offer a sugar pill to satisfy the patient and yet not disclose that it lacked any active ingredients. In current clinical practice, such deception, whether or not it is well meant, is deemed unethical.

Yet even if patients are informed, their expectations can still influence pain perception and other biological processes below the level of awareness. This is the placebo effect. It is a neurobiological phenomenon with clinical relevance. The placebo effect is also a critical factor for investigators assessing the efficacy of medical interventions.

Here’s why understanding the mechanisms is crucial. Any experimental and clinical setting has variables that can affect the outcome. These are co-occurring factors that can bias or muddle results and so trialists are keen to tease them out; the placebo effect is among the confounding effects.

“Placebos are used in randomized controlled trials to validate new drugs,” Colloca said. One group receives the drug, the second receives the placebo and the third receives no treatment. Yet even in the most rigorous trial, reduction in symptoms (i.e., pain perception) can be due to the placebo effect.

Colloca reviewed current research, much of it produced by her group, and focused on the psychosocial context around any treatment. The psychosocial context is characterized by three kinds of cues: verbal, conditioning and observation. Here are some highlights:

“We don’t know why some subjects create elevated placebo effects,” Colloca said. The challenge is to find the biomarker—a cellular or molecular indicator. “We want to understand how placebo improves clinical outcomes.”

“We don’t know why some subjects create elevated placebo effects,” Colloca said. The challenge is to find the biomarker—a cellular or molecular indicator. “We want to understand how placebo improves clinical outcomes.”

Photos: Ernie Branson

In one study using a learning model “where we provide an electrical shock, inducing pain, and we inform our participants to expect pain or analgesia,” Colloca’s team used cues of red or green lights in advance of the shock.

One group was conditioned to associate a lack of pain, or a reduced level of pain (analgesia) with the green light. In the next phase, when this group saw the green light, they felt a lower level of pain, even though the pain administered was exactly the same. The placebo effect of the green light had changed their perception of pain. This ability to form a placebo analgesic effect is predictable by activity occurring in the dorsolateral prefrontal cortex of the brain, Colloca said.

“What’s interesting,” she added, “is after about one week, there is still a placebo analgesic effect. That means there is a learning effect.” Thus the memory of analgesia modulated pain perception.

Another study showed how social learning shapes the placebo effect: “We invited an actor to simulate analgesia any time we showed the green light and pain when we would show the red light.”

Subjects observing the actor were told they would receive the same cues for the same stimuli: green for analgesia, red for pain. Instead, both red and green lights were accompanied by exactly the same levels of pain. Yet the participants still perceived the green-light pain as less painful than the red. Observing another person with empathy, Colloca said, can increase placebo effects.

As for the nocebo effect, a simple suggestion of pain can induce long-lasting hyperalgesia (intense pain), she added. This can increase pain faster than the placebo can relieve it.

These findings are relevant for doctor-patient communication, as patients are briefed on procedures, medications, possible side effects, outcomes and how this may affect their expectations and adherence.

For example, if patients are told that injecting a local anesthetic will feel like a bee sting, it may be perceived as quite painful. Yet if they are told that “this is part of a procedure to make them comfortable,” it may be perceived as less painful, more tolerable. To decrease the nocebo effect, we can therefore reframe disclosure to patients in a more positive manner while still honoring the patient’s rights and ethical guidelines.

Patients have the right to be informed, Colloca said, and clinicians and scientists should elicit patients’ points of view and expectations.

Even as the placebo effect surrenders its secrets, it still retains some of its mystery. Colloca explained that the placebo effect is related to endogenous neuropeptides—molecules used by neurons to communicate with each other.

Yet “we don’t know why some subjects create elevated placebo effects,” she continued. The challenge is to find the biomarker—a cellular or molecular indicator. “We want to understand how placebo improves clinical outcomes.”

The videocast is archived at

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