Luana Colloca

(above) Luana Colloca, MD, PhD, MS, associate professor, presents a TEDx Talk exploring the role of the placebo reflex in the neurobiology of pain.

On the Virtual Road to Pain Relief

Our Researcher: Luana Colloca, MD, PhD, MS

By Dan Mezibov
(from the spring 2022 issue of Nursing For/um magazine)

illustration of girl wearing a VR headset and woman holding a balloonWhat if relief for your debilitating chronic pain was, quite literally, just within sight?

Only about a decade old, research that immerses patients in a 360-degree, 3D world of soothing sight and sound has transformed virtual reality (VR) from a booming entertainment experience into a promising tool for managing pain. 

Recent studies have shown VR’s effectiveness in reducing several types of acute pain, such as from dental procedures or during bandage changes in patients suffering severe burns. However, using VR to alleviate chronic pain remains a subject of investigation.

In a novel $3.5 million collaboration, investigators at UMSON and at the University of Maryland, College Park (UMCP) are examining VR’s potential to increase tolerance to chronic facial pain from temporomandibular disorders (TMD), a set of conditions associated with pain and inflammation in the face and neck. Funded by the National Center for Complementary and Integrative Health, the five-year study is following 300 patients to explore how VR’s visual and auditory stimulation in the brain affects long-term improvements in tolerating pain.

This pioneering work is one of several VR and placebo studies taking place at UMSON in the research laboratory of Luana Colloca, MD, PhD, MS, professor, who is among eight faculty from the University of Maryland, Baltimore (UMB) and UMCP selected as inaugural MPower Professors in 2021; the accompanying $150,000, three-year awards are intended to quicken the pace of discovery through collaborative research between the two institutions. The selected faculty have demonstrated collaboration on strategic research that would be unattainable or difficult to achieve by UMB or UMCP acting independently of one another and have embraced the
mission of the two universities’ MPowering the State program – to strengthen and serve Maryland and its citizens.

Colloca’s interdisciplinary lab, which involves experts from nursing, medicine, psychology, physics, music, and engineering, was among the first to discover that simply anticipating a therapy’s benefit – a phenomenon known as the “placebo effect” – generates “real neurobiological responses and not merely biases,” she explains.

Using an app and VR experiences developed by co-investigator Amitabh Varshney, PhD, dean of the UMCP College of Computer, Mathematical, and Natural Sciences, and his team, Colloca’s TMD patients are fitted with headsets and digital goggles that transport them to an assortment of calming environments, such as swimming undersea with marine life or being on stage during an opera performance. Weekly sessions in the lab and at home last for 6 - 20 minutes, include guided instructions on relaxation and meditation, and continue for up to six months. For their in-home VR experiences, patients wear wrist monitors to capture their heart rates and other physiological responses and then log into an online portal to record their mood, anxiety level, and resilience to pain.

The investigation is still ongoing, and Colloca and her team are establishing whether it is VR alone or VR with guided instructions that increases someone’s tolerance to pain. However, the study builds on her previous research examining VR’s impact on heat sensitivity, which suggested that “VR immersion affects multiple sensorial systems” and improves mood, reduces situational anxiety, and eases pain unpleasantness “when patients perceive the VR experience as enjoyable,” she points out.

Given the country’s ongoing opioid public health emergency, “finding low-risk, noninvasive, nonpharmacological interventions that can effectively reduce the use of pain medication is of the utmost importance,” Colloca says. Leveraging VR’s immersion technology “might empower TMD patients with new, accessible, and affordable therapeutic solutions.

More Highlighted Research

Exploiting Placebo Effects

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."