The latest statistics about America’s opioid epidemic are staggering. The Centers for Disease Control (CDC) estimate an average of 125 deaths from opioid overdoses per day in the United States—that means each month, we’re seeing a tragedy more deadly than September 11th. Between July 2016 and September 2017, hospitalizations from opioid overdoses jumped 30 percent nationwide (70 percent in the Midwest). Data strongly suggest that the rapid rise in opioid addiction, overdose, and death in the last 20 years is largely driven by the increase in prescription of synthetic opioids for pain. As the crisis worsens, pain management options are desperately needed that don’t involve opioids.

Mindfulness practices have shown promise for managing chronic pain since Jon Kabat-Zinn’s pioneering work in the 1980s, when he developed Mindfulness-based Stress Reduction (MBSR) and applied it to various clinical populations. A recent review and meta-analysis found that for chronic pain patients, mindfulness meditation is associated with a decrease in pain compared to all types of controls in 30 randomized trials. Questions remain, however, as to how this effect may be achieved physiologically. Most pain relief is induced through the body’s natural opioid system, or by artificially activating this system through powerful opioid drugs such as morphine, codeine, or fentanyl. Even cognitive methods of pain relief like placebo or attentional control have been shown to act through the body’s natural opioid system. Does meditation use the same pathways?

Several years ago, Mind & Life funded two separate but complementary Varela Grants that sought to address this question using an elegant pharmacological test. The drug naloxone is often used to treat opioid overdose because it potently blocks opioid receptors. When given fast enough to an overdose victim, it can help prevent death because it blocks the receptors that the opioid would normally interact with. This property of naloxone also means it can be helpful in research studies to tease out which pathways might be active in a given condition.

The two Varela grantees—Fadel Zeidan and Lisa May—both used naloxone to see if it would block meditation-induced pain relief. If it did, they would know that meditation was acting through the body’s natural opioid system, just like other methods of pain relief. If naloxone didn’t block the effect, then some other biological pathway must be involved. And if mindfulness does activate the opioid system in our bodies, it might be an even more attractive option for people with chronic pain.

Below, Fadel and Lisa reflect on their projects, how their findings dovetail to expand our understanding of mindfulness and pain, and what this might mean in the midst of the opioid epidemic.

What drove you to undertake this research?

FADEL: One of the fundamental questions in pain research is to identify the biological systems that construct and modulate pain. Naloxone was originally approved by the FDA in the 1970s, and has been used to show that placebo analgesia and other cognitive techniques (acupuncture; distraction) are mediated by natural—or what we call endogenous—opioid systems. We know that one of the most promising applications for mindfulness meditation is to treat pain, but exactly how mindfulness works to reduce pain is still unclear. So, examining if mindfulness engages endogenous opioids to reduce pain was a logical next step.

LISA: Also, from a wider lens, examining the neural mechanisms of pain perception allows us to see the impact of mental processes on the physical body. Most people are used to the idea that we can change our experience with chemicals, but sometimes we forget that we can change the chemical activity of our brains depending on how we use our brains. The way we choose to engage our minds—our thoughts, beliefs, attitudes, and practices—shapes our brain chemistry, our habits, and our future experience. I find that inspiring.

At the Mind & Life Grants Department, we received your two Varela proposals on the same topic a few years ago. Both were rigorous and exciting projects, and the review committee decided to fund them both in the hopes that your research might be mutually informative. We realized that you may not have known each other, or that you were thinking along the same lines, so we put you in touch. Can you describe how your projects complemented each other, and how your experience has been working together?

LISA: When you connected me with Fadel, we quickly discovered that we were planning on tackling the same research question with different designs. Fadel was studying people who hadn’t meditated before, and I was recruiting experienced meditation practitioners. In addition, Fadel was comparing separate groups of people (those who received a brief mindfulness training vs. a control group), and I was using repeated measurements on the same participants. So that enabled a really cool approach, what we call a conceptual replication. In this situation, if our findings agree, their validity is strengthened because we show the same basic idea in different populations and different set-ups. And it was wonderful to be able to consult with each other along the way about logistics and details.

FADEL: We collaborated on our study designs, naloxone dosage, and basic psychophysics. My lab examined the effects of brief mindfulness-based mental training on pain and used naloxone to see if the effect was working through the body’s opioid system. Lisa studied long-term mindfulness practitioners, and used naloxone in a similar way, to learn whether it would interfere with mindfulness-induced pain relief. Interestingly, we both found that naloxone didn’t block the effects of mindfulness meditation, which means that mindfulness does not engage endogenous opioids to reduce pain. Together our work offers a more comprehensive account across the meditative training spectrum—from novice to expert. We even presented our work together at the American Psychosomatic meeting in Denver a couple of years ago. Lisa has been great to work with!

So you both found, in separate studies, that mindfulness meditation reduces pain without activating the body’s natural opioid system. What do you think is most exciting about these combined findings, and how will this be relevant to people’s lives?

LISA: Both Fadel’s and my research suggests that meditation reduces pain via a non-opioid pathway. This means that meditation could represent a promising pain-reducing intervention for people who don’t want to rely entirely (or perhaps at all) on opioids, or those with compromised natural opioid function associated with opioid use/abuse or other disorders. It’s also likely that meditation impacts other health outcomes via this same non-opioid mechanism.

FADEL: Another angle relates to possibilities for integrated pain treatment approaches. We know that opioid and non-opioid mechanisms of pain relief interact in a synergistic manner in the body. This means that combining mindfulness-based approaches with other pain relief strategies that do use opioid signaling may be particularly effective in the treatment of pain.

Overall, the fact that mindfulness seems to bypass the opioid pathway is a critical finding for the millions of chronic pain patients seeking a non-opioid therapy to reduce pain.

Lisa, your study had some additional unique findings. Can you describe those?

LISA: Before this study, we didn’t have any idea of the prevalence of mindfulness-based pain relief in long-term meditation practitioners. We know now that the vast majority of the participants in this study (85 percent) did experience pain reduction during meditation, which means it’s a common and consistent effect. Another finding that was quite unexpected was that for these experienced meditators, giving naloxone actually made the mindfulness-based pain relief even more effective! This is the first study to demonstrate the enhancement of pain relief via a full blockade of opioid receptors, and we’re not quite sure yet how this might be working. This provides new information not just about meditation, but about the function of the brain itself. I’m excited to see how this line of research develops.

Fadel, what are your next steps for this work, and what new questions have been generated?

FADEL: This work has led to a whole new avenue of research for me. We just completed another NIH-sponsored naloxone study where we disentangled the pain-relieving mechanisms underlying mindfulness vs. slow breathing vs. sham mindfulness meditation. Data analysis is still underway, but I can tell you that we’ve replicated our original mindfulness findings and have some more insight into the role (or lack thereof) of endogenous systems in the self-regulation of pain.

We still need to do more research, but what is clear is that mindfulness does not use the body’s natural opioid system to reduce pain. It appears that one of the oldest self-regulatory techniques could be employing an as-yet undiscovered pain relieving mechanism. Pretty cool, right? So much interesting work to do!

We’re so glad to have you both in the Mind & Life community. Any final reflections?

LISA: The Varela grant from Mind & Life was instrumental in funding this project; without it, I would not have been able to complete this important research. There just aren’t that many opportunities for graduate students to gain funding to cover these kinds of projects.

FADEL: Agreed! And to be eligible for a Varela grant, you have to attend the Mind & Life Summer Research Institute (SRI). I really can’t put into words how much attending SRI has impacted me over the years. It gave me the confidence, inspiration, and motivation to continue to study mindfulness by providing a venue to share ideas, learn about emerging evidence and methods, and appreciate the roots of contemplative practices.

I started researching the effects of mindfulness on health outcomes in 2001 as an undergraduate student. At that time, mindfulness was more or less a taboo scientific subject. When I first presented an idea to study the effects of mindfulness on cognition, I remember a professor telling me, “Fadel, this is the psychology department, not the philosophy department.” Amazing how times have changed. From my perspective, the integration of mindfulness into Western culture is due in large part to the Mind & Life Institute, as well as new technologies such as functional neuroimaging that provide objective evidence for mindfulness-based improvements in health.

Without Mind & Life, this work from Lisa’s and my teams would not have been done. And who knows where I would be now if it wasn’t for the enriching, at times enlightening, experiences at the Summer Research Institute and the many opportunities provided by Mind & Life.

Lisa May, Ph.D. earned her doctorate at the Institute for Neuroscience at the University of Oregon. Her research there investigated the neural mechanisms by which gratitude and mindfulness affect the way pain is perceived, and how these relate to negative beliefs and attitudes about pain. She is currently a Project Director at the Social & Affective Neuroscience Laboratory at the University of Oregon.

Fadel Zeidan, Ph.D. is an assistant professor of neurobiology and anatomy at Wake Forest School of Medicine, and a Mind & Life Fellow. His research is focused on determining the neural mechanisms that mediate the relationship between self-regulatory practices and health, with a particular emphasis on the neural mechanisms supporting mindfulness meditation-based pain relief. Learn more about his lab, and watch his presentation to the Dalai Lama on this work.