Editor’s note: This article is part of PRF’s featured content series “Investigating Virtual Reality for Pain Management: Past, Present, and Future,” which has been made possible thanks to a generous grant from the MAYDAY Fund.
Luana Colloca, MD, PhD, is an MPower Distinguished Professor at the University of Maryland, Baltimore, and the Director of the Placebo Beyond Opinion Center at the University of Maryland School of Nursing. Luana has conducted studies on the behavioral, neural, and pharmacological mechanisms of pain modulation related to placebo and nocebo effects. Her lab has also developed an interest in virtual reality as a non-pharmacological approach to relieving pain and other symptoms.
Transcribed below, IASP’s former Associate Director of Publications, Gregory Carbonetti, PhD, speaks with Luana about her background in placebo research, how it influences her recent work with virtual reality, and the story behind her feature in a 2020 cover story for National Geographic.
Can you tell us a bit about yourself and your broader research interests?
I have a background in medicine, neuroscience, and neuroethics, and I started working in science almost two decades ago. I started my research primarily with placebo effect expectations and how our mindset can influence clinical outcomes.
A few years ago, when I was based at the University of Maryland, we submitted a grant for social learning and placebo effects. Leadership came back to me and said, “Well, we can fund you if you started to do virtual reality (VR) within this arena of placebo effects. And you would need to collaborate with this engineer, with this surgeon, [etc.]” And my first reaction was, why? I never [did this kind of] research. Virtual reality was something that I had not been taught at all. Today, I’m very thankful to the leadership in my campus because it really envisioned something that was going to explode. Now, seven years later, we have several papers, a lot of new ideas, and federal grants [funding research] on virtual reality.
My approach was very skeptical, like, okay, what is that? Maybe it’s just a placebo effect. And so, we started to work together as a team. I started to explain the science about pain to engineers that didn’t know anything about it. And on the contrary, the surgeon was dealing with pain every day at the Shock Trauma Center, and she was telling me anecdotally, “I put the [headset] onto my patients in the ER, and I reduce opioids. I can handle things better in both adults and kids.”
This motivated me to truly start to research what is beyond virtual reality for pain. And as a placebologist, physician, and scientist, I decided to approach virtual reality from my background, my science on placebo, and truly understand how virtual reality can mitigate pain, and if so, what kinds of a pain. Then, the questions started to multiply.
Currently, I lead a team as MPower Distinguished Professor at the University of Maryland. We have a collaboration across the schools and with University of Maryland College Park and, of course, across labs.
What’s the thing that surprised you the most when you rolled your sleeves up and really started to work with virtual reality and understand what the mechanism is? Was there anything, in particular, that really struck you as you started to really explore the space?
Well, I mentioned to you I was skeptical, so I was listening to my collaborators. For my engineering colleagues, there were components that were extremely important, like the hardware or a device that was not heavy with wonderful resolution and little cyber sickness. On the other hand, when I was listening to my clinician, they said, “Well, it works but needs to be interactive and not passive.” But in some ER settings, interacting and playing with VR, will not work.
On the other hand, we also have a musician on board, so for them the quality of the 3D sound was important. My lab cares about which part of the pain we are going to study: experimental pain, pain threshold, pain tolerance, acute pain related to trauma, chronic pain, etc. That was the main area of research in the lab; the goal was to have an approach that was unbiased, able to listen to everyone, and somehow sort out the gaps in the literature. One of our main questions was: does virtual reality reduce pain, and if so, is it all based on attention/distraction, or is there something beyond that?
You had an article published in our flagship journal, PAIN, titled “Factors Influencing the Hypoalgesic Effects of Virtual Reality.” Can you speak about what went into that work and what some of the major findings were?
This study aimed to understand which factors are relevant in VR, and we were able to create the ideal control that is a “sham” virtual reality where we remove the immersion and still have the participant wearing the goggles. But we also wanted to change the content.
We used a VR space we call “the Ocean” and as part of what they see in the 3D [environment], they follow a jelly fish, a turtle, and so on, while this soothing and very relaxing music plays in the background, accompanying these dynamic figures. For the “sham” condition, what we did was create this identical content on a monitor, as if they were sitting on a couch and watching their TV. We also wanted them to have an imagery task, so we told them, “Now imagine being immersed in the ocean, surrounded by jellyfish, with this nice, soothing sound.”
It really was to understand the difference between the imagined content per se – the ocean – and the content delivered in a high quality, technological approach, where the immersion was effective and pleasant. And we compare that with different, more neutral content that was shown in the lab where they see the VR setup, and so on.
The goal – why we had this multifactorial design in a crossover study with counterbalance conditions – was to understand what is relevant: the immersion, the engagement with the content, or merely thinking about that content, and whether any [of these factors] produce the same effects as VR. And the VR immersion works as if we enhanced the effects of the 2D version. The content also became relevant because we know content works well as long as what is perceived is pleasant and engaging – but the goal is to understand if it’s merely attention or distraction.
If we provide the same task without VR at all, the distraction/attention load can’t explain the effects of VR. This study – conducted in healthy controls – was the continuation of another study that we published in PAIN where the goal was to understand the autonomic responses to VR. We provided the healthy participants again with VR, with different content, replacing the ambient, nature music and the jellyfish, with what we call the Opera – where we had our maestro from College Park, the School of Music recording La clemenza di Tito, from Mozart.
We were also continuously recording heart rate variability, as well as skin sympathetic response. The goal in collecting the heart rate variability data was to have a proxy index for vagal activation, and the skin sympathetic response that many say is the “galvanic response” aimed to understand if they were faking and tolerating more pain or if the body was in actual pain.
We gave them a remote [with which] they were free to self-administer painful stimulation at a level they felt they could tolerate. When they were immersed in the Ocean, they were able to tolerate a much higher level of pain than when they had no VR.
On the other hand, it was interesting, for the Opera, only those who like opera – those who tend to go to the theater, people who enjoy this kind of music – were able to tolerate more pain. For people that [did not enjoy opera]– even the vagal stimulation showed no relaxation – they were not able to tolerate higher level of pain.
That study allowed us to understand that not any content works, but when the content is something that participants perceive as enjoyable, we see higher pain tolerance while they relax. And it seems to us like paradox: how can you self-induce pain and still relax?
And what about the distractions? Using a working memory task to truly measure the impact of distraction, we found that VR with pleasant content is still better than distraction. When we had the distraction, the participants still self-induced pain, but the skin sympathetic response became high and the vagal response showed no relaxation.
We are not saying distraction is not relevant, but there’s more to it than just distraction. We can achieve modulation of the autonomic system, as well as bring more regulation and autonomic relaxation that will further allow us to understand why VR can be very effective with pain.
Do you think there is going to be a personalization of the VR, or what the immersive environment is going to be, as you move into trials?
In fact, the next step for us was to translate this laboratory study into more clinical research. The first thing we did, and this is another study published in PAIN, was to use the identical Ocean, the identical Opera, and some other content to the bedside. We went to Shock Trauma Center and brought, to the drawer closest to the bed, the VR goggles. We had many kinds of trauma patients, including traumatic brain injury (TBI). This time we showed them the Ocean, and then inactive goggles with nothing inside, completely black.
We were truly just trying to see the placebo effects of wearing the goggles with nothing inside or the Ocean, for control group. And we were able to, again, see this relaxation by the patient being continuously monitored. We were able to measure continuous heart rate variability and so on, but also, intake of opioids.
Patients perceived the VR with the Ocean as the most effective, but also wearing the goggles with no content added analgesic effects, allowing us to see their body respond with a reduction of pain. But only the VR with the Ocean content – which we had already learned in the lab was effective in increasing pain tolerance – allowed us to reduce the intake of opioids at the bedside.
There was an impact, clinically speaking, in helping these patients to tolerate their pain through daily events and feel like this treatment was effective. The self-perception was there, and for us, the most interesting thing was the body response that was in line with the reduction of the pain and opioid intake.
You have a recently published manuscript with Nature Publishing Group right now that was published recently. Can you give us a sneak peek as to what we might see in this manuscript?
The next step was to have a trial where we ship the goggles home for a very natural, ecological environment. We never saw participants in the lab – we used e-consent through Zoom – we used ecological momentary assessments for one week before randomizing the patient to either virtual reality, MP3 [i.e., only sound with no visuals], or nothing. The goal was to understand comparative effectiveness.
This time, we don’t have sham VR, we don’t have a control VR group. We now have two treatments that are active, including an MP3 group with cognitive behavioral therapy for pain – where they learn to meditate, to breathe, to accept their pain – that was delivered to their phone. Our goal was to determine the benefit of using VR as a tool to deliver this cognitive behavioral therapy versus the same identical therapy given through MP3.
MP3 can be easy. You can run and listen, but you can’t run with virtual reality. If we think about marketing this tool, of course the goggles can’t be used everywhere, only in a certain context, although it’s exploding with augmented reality where you still see the things around you, so I think that will not even be a limitation soon.
What we saw was that VR enhanced the clinical efficacy of the intervention for pain intensity, pain unpleasantness, and mood regulation. We also measured ability to sleep, and the patients that were using VR also slept better during the trial.
Moreover, we added another component – expectations. We wanted to study expectation because VR is relatively new, and these are chronic pain patients. We thought that maybe what they expect to gain from the trial would be a self-fulfilling prophecy. We asked, “How much do you expect to improve from this virtual reality trial?” But we also introduced a sort of educational tool, where we told them there are studies showing that virtual reality works, and they are likely similar to those patients in terms of clinical phenotype.
We showed them a plot of other patients’ benefits and we reassessed expectations. Everyone was receiving all the treatments, since it was a crossover study. They knew that, for part of the trial, they would receive VR, and for part of the trial, they’d receive MP3 with the identical content. Expectations jumped after our educational session. We were curious, at the end of the trial, to see if there was an improvement of expectation, but for pain intensity and unpleasantness, the expectations had no effects at all, suggesting that the intrinsic action of virtual reality on pain intensity and unpleasantness was independent from what they expect.
Now, the next question is to understand if nociplastic, neuropathic, and musculoskeletal pain respond similarly to VR, along with other mental health comorbidities. Already, we saw that mental health – meaningful, clinical major depression – somehow minimized the effects of VR. We need to be creative somehow and try to understand what kind of content, if any, can help patients who are depressed and dealing with chronic pain. The next step, for us, will be truly to tailor the VR to the patients’ needs and understand different phenotypes of pain and comorbidities that may change the impact of VR.
You were featured in a National Geographic cover story focused on pain in 2020. What do you think has been the biggest change in this space that has happened over the last five years? And then on the other side of the coin, if we have this conversation five years from now, what do you think is going to be the next big advancement in this space?
Well, five years ago, we were just starting. We had just had two papers published in PAIN with virtual reality – and I was kind of disappointed when the reporter came to the lab. I was all ready to talk about placebo effects and they told me, “No, we are not interested.” I felt surprised, I had 200 papers on placebo, two papers on virtual reality, and they wanted to feature me for VR.
At the time, we had started an MPower strategic partnership across University of Maryland campuses. We were passionate and truly interested in understanding VR through the lens of placebo effects. And five years later in the lab, we have been so productive, and now we handle virtual reality with less questions and, I would say, less skepticism. First, we started with healthy, pain-free participants, and the effects were large. Then, the next step was trauma patients, and the effect was there. Then, moving on to the chronic pain patients, seeing them coming back and saying, “I want to buy these goggles. I want to buy this VR.”
We are committed now. We have federal grants; actually, we are just at the beginning of more and more, but we also have interest in optimizing the content and the hardware to fulfill patient needs. Like, who is benefiting most? Can we do something for those who don’t respond? And if we change the content, maybe they will respond? It’s a fast pace.
We are also working on policy and collaboration with other colleagues, so I am looking forward to my plenary at the 2025 USASP meeting that will be covering virtual reality and the mechanism of translation research that we have been conducting in this arena.
It has been super productive, and very good in terms of federal funds. Without federal funds, I doubt we would’ve gained all this knowledge; being funded by NIH has been critical. Of course, the state funds were the beginning for our journey, but without the federal grants, we would not have all the knowledge that we have been producing. I think this is also a call to understand that science can be translated from a laboratory setting to a translational clinical setting and sending patients home.
To people who are skeptical, does science translate? It does.
Gregory Carbonetti, PhD, is the former Associate Director of Publications at IASP and an avid New York Islanders supporter.
Featured Image: Mark Tiessan and National Geographic.