Luana Colloca

By Nancy Menefee Jackson 
(from the summer 2016 issue of Nursing For/um magazine)

Luana Colloca, MD, PhD, jokes that she’s a “placebologist.” But studying the neurobiological basis for pain and the placebo and nocebo effects is serious stuff—with tremendous clinical and ethical implications. In fact, the research prompted Colloca, who has a medical degree and a doctorate in neuroscience, to obtain yet another degree—a master’s in bioethics. She approaches the study of pain and the placebo effect not only as a psychological phenomenon, but as a neurobiological phenomenon, and one that has been documented with objective research approaches.

As a newly minted doctor, she wanted to make a difference in medicine and symptom management, and she began working on a research project involving deep brain stimulation in Parkinson’s disease. She started her career studying the changes in human neural activity in response to a pharmacological conditioning. A saline solution given after repetitive injections of apomorphine, an anti-Parkinson’s medication, induced apomorphine-like effects at the level of neural activity recorded from the brain’s subthalamic region.

“This turned me into a placebologist,” Colloca said. “I wanted to know more and more about the mechanisms underlying placebo effects and particularly in the field of pain, an endemic burden.”

One thing research revealed is that a placebo given after a repetitive administration of non-opioid drugs such as aspirin or ketorolac produced aspirin- or ketorolac-like effects. Similarly, a placebo given after repetitive administrations of morphine produced morphine-like effects. That holds considerable promise for reducing pain with lower drug intake.

Colloca, who is an associate professor at the School of Nursing, created a research agenda exploring pain perception, processing, and modulation in which the expectancy of analgesic relief, which can actually activate endogenous systems, is explored from a psychoneurobiological perspective from genetics to brain imaging. Such research raises the possibility of unfolding the mechanisms of expectancy-induced analgesia with potential implications for pain management.

Conditioning and learning studies by Colloca holds promise for understanding pain modulation. Colloca’s team uses brief experimental high pain and low pain stimulations paired with visual cues, with the scope to investigate the role of conditioning on pain processing and perception. After learning the associations, participants perceive less pain when they receive high pain while seeing the visual cue for low pain, and this analgesic experience is linked to specific brain modulatory changes.

Placebo research is rather fascinating. The effect was first realized in the 1950s, when an anesthesiologist, Henri Beecher from Harvard University, was in Italy helping injured soldiers. When they ran out of morphine, the nurse injected a saline solution, and Henri observed the benefits.

One study that compared arthroplasty knee surgery to a sham knee surgery—a surgeon cut the skin but didn’t do anything else—found that up to two years later, the patients who had received the sham surgery were doing just as well as those who had the real surgery.

The use of an “impure” placebo further muddies the waters. An impure placebo is an active medication given in a situation where it is not expected to have efficacy, such as giving antibiotics to someone with a virus. It would be unethical for a practitioner to prescribe a sugar pill, but as most people know, antibiotics don’t cure a virus, although the patient feels better having a prescription. Rather, placebo research suggests that health practitioners should exploit placebo effects depending upon brain modulatory systems. Boosting expectancies of analgesia and conditioning effects might have implications for how painkiller treatment strategies are planned.

At the opposite end of the spectrum is the nocebo effect. A nocebo effect is an adverse event produced by negative expectancies, and it can modulate the outcome of a given therapy in a negative way. Past experiences, social observation, and verbal suggestions can produce that effect.

In an article published in the Journal of the American Medical Association in 2012, Colloca cited a study of women requesting labor epidural analgesia. The women were told either, “We are going to give you a local anesthetic that will numb the area, and you will be comfortable during the procedure” or “You are going to feel a big bee sting; this is the worst part of the procedure.” The phrasing produced different pain outcomes, and the positive framing induced significantly lower pain.

This research has implications on how a nurse at the bedside informs patients about symptoms, pain relief, and procedures. Clinicians and nurses must find a way to balance communicating important clinical information that a patient has a right to know—and it’s critical to be truthful—while minimizing negative instructions and a negative therapeutic context. “It’s not merely policy; we are talking about neurobiology,” Colloca said. “I believe there is a lot that can be taught to students.”

Placebo and nocebo effects have implications beyond pain management. Research in 1962 in Japan found that men who were allergic to lacquer trees reacted to resin from harmless trees when they were told that the resin was from a lacquer tree. Their reactions were severe, including skin rashes that lasted for days. Although that study was not replicated, other studies found that telling asthma patients that they are inhaling an allergen led to bronchoconstriction, even though they were actually given nebulized saline.

The placebo effect got a bad rap with the advent of double-blind placebo-controlled studies, because it was viewed as a nuisance to be controlled for, rather than a neurobiological phenomenon in its own right. Further exploration of placebo and nocebo effects promises exciting findings.

“We have healing processes in our brain, and we don’t use them fully,” Colloca said. “Clinicians and nurses need to be aware that we have these powerful brain modulatory systems, and their impact on health outcomes is long lasting. The ethical and translational implications of this research can be relevant in medicine.”

(above) Colloca is interviewed in a PBS NewsHour segment and web story, "The placebo effect’s role in healing, explained." 

By Erin Merino 
(from the fall 2024 issue of Nursing For/um magazine)

OUR EXPERT
Luana Colloca, MD, PhD, MS  

Most people are familiar with the placebo effect, but there is a rarer, lesser-known phenomenon, the nocebo effect, that can occur in patients dealing with pain, chronic conditions, and cancer, among other conditions, explains Luana Colloca, MD, PhD, MS, professor and director of the Placebo Beyond Opinions (PBO) Center. According to Colloca, nocebos are a negative reaction to a diagnosis or medical treatment because of expectations: “Individuals begin to experience symptoms even in the absence of exposure to the factor that can cause adverse effects,” Colloca states.

Colloca, who has been researching placebos and nocebos for more than two decades, says “negative external and internal factors can trigger an amplification of signaling in the brain that turn into worsening of symptoms.” An external factor may be a difficult relationship between patient and provider, while an internal factor could be a negative outlook. In her research conducted at UMSON, she has demonstrated that “patients who suffer from catastrophizing and negative thoughts tend to experience higher nocebo effects, suggesting that outlook can be critical to our mental and physical well-being,” she explains.”

She offers recommendations for ways clinicians can convey necessary information without inducing nocebo-producing anxiety in patients:

1. Choose Words Carefully

The language used by clinicians can significantly impact patients’ experiences of their symptoms. Avoid negative language or overstatements. “The words that we use can trigger worsening of fatigue, nausea, distress, anxiety, insomnia due to the nocebo effects that can amplify the side effects of medication,” Colloca states.

2. Show Compassion

Focusing on the person in front of you is imperative. “The most concerning issue is that, when seeing patients, instead of making eye contact, we often find ourselves in front of our keyboards, typing while we talk,” Colloca says. Clinicians should ask the patient questions and listen. “Create this space where the patient feels safe to share what they are suffering from,” Colloca explains. Additionally, Colloca suggests asking questions such as “What do you expect to improve with this treatment?” or “How long do you think this disease will be affecting you?” that allows you to understand how the patient is feeling and enables you to discuss ways to handle symptoms with the patient.

3. Balance Truth and Comfort

Provide honest information while also offering reassurance. The conversation should be a “balance between the truthful information that as clinicians we are meant to provide and comfort,” Colloca says. Make time to connect with patients, even during brief visits. “Provide them with resources and tools so that they don't feel abandoned or alone in dealing with the problem,” she explains.

4. Empower Patients

Encourage patients to participate actively in their healing process. “Frame the information in a way that balances empowerment of expectation and the ability to minimize the unwanted side effects, or nocebo effects,” Colloca explains. Patients “are told a lot about all the medical pharmacological approaches and very little about lifestyle changes in behaviors or access to a nonpharmacological approach or the impact of expectation on symptom perception,” she says. You don’t want patients to feel they are “a victim of the diagnosis and the symptoms, but rather have this intentional healing process where they can be part of that journey,” Colloca explains.

Learn more about placebo research by visiting the Placebo Beyond Opinions website.