Late last year Dr. Dane Cook, along with Dr. Jacob Lindheimer and colleagues, published a systematic review of research looking at pain as a component of post-exertional malaise (PEM) — which is also known as post-exertional symptom exacerbation (PESE).
As seen with other components of PEM/PESE, any pain seemed to be delayed by 8-72 hours after exertion. Interestingly, this finding applied to both myalgic encephalomyelitis /chronic fatigue syndrome (ME/CFS) as well as to fibromyalgia (FM).
I spoke with Dr. Dane Cook to learn more. He is Professor of Kinesiology at the University of Wisconsin in Madison, where he serves as director or co-director of two exercise research laboratories.
Since 2018, he has served on the U.S. National Institute of Neurological Disorders and Stroke’s (NINDS) working group for ME/CFS research. He is also a research physiologist and director of a laboratory at the William S. Middleton Memorial Veterans Hospital.
We discussed his recent systematic review, pain in PEM/PESE, and whether it is possible to link the physiological abnormalities found in exercise to the worsening of symptoms found in PEM/PESE.
Post-exertional malaise is one of the central features of ME/CFS. Yet, it is poorly understood by many health professionals and members of the public. How would you define post-exertional malaise? Can it be scientifically measured?
Dr. Dane Cook:
In our previous interview (2019), I was asked a similar question. We discussed how PEM was poorly defined both clinically and in the literature, that it was highly heterogenous, and the challenge of operationalizing the phenomenon. Our studies have directly addressed this challenge by taking a multi-pronged approach.
First, we determine (or in some cases confirm) the presence of PEM by asking participants whether they experience a worsening of their symptoms after exertion. This first approach dichotomizes PEM as a yes-or-no experience and further confirms whether the participant is cognizant of PEM.
Next, we detail the symptoms of the participant using various validated questionnaires. This allows us to establish both the baseline symptom heterogeneity and the severity of each symptom that the participant is experiencing, [both] in general and on the day of testing.
We then employ a standardized exercise challenge and measure the change in symptoms that occur at various time points post-exercise — e.g. immediately after, 24 hours after, one-week after, etc.
We then operationally define PEM as an increase in disease symptoms compared to baseline. This can occur as one symptom or as various combinations of symptoms.
We consider PEM to be present when symptoms increase significantly either relative to baseline or compared to an otherwise healthy control comparison group. We also detail the types of symptoms that change, their time course, and when peak symptom changes occur.
As to whether it can be scientifically measured — yes. However, symptoms are just one important way to establish PEM.
Our lab also measures the effects of exercise on various biological systems. PEM is clearly a psychobiological phenomenon and exercise has been shown to affect a multitude of physiological processes such as brain, autonomic, immune, and gut function.
The challenge is determining which responses “cause” symptom exacerbation. This is the primary focus of my lab.
“Fatigue” is the symptom most commonly associated with post-exertional malaise. However, musculoskeletal pain can be another component of post-exertional malaise. In your recent paper you noted that there is a knowledge gap when it comes to quantifying the pain-related component of post-exertional malaise.
How did you seek to address this knowledge gap? What did your meta-analysis of the effects of aerobic exercise on clinical pain reveal?
Dr. Dane Cook:
Our recent meta-analysis, lead by my colleague Dr. Jacob Lindheimer, sought to quantify the clinical pain aspects of PEM. The reason for this study was two-fold.
First, fatigue is recognized as a primary component of PEM and a previous meta-analysis had quantified [how much] fatigue changes with exercise — finding small-to-large changes across studies. A similar study for pain was lacking and needed.
Second, pain symptoms [can be] an important aspect of ME/CFS but have received relatively less attention. So Lindheimer and colleagues conducted a systematic review and meta-analysis to quantify the effect of acute exercise on pain symptoms in ME/CFS and FM.
We also examined potential [aspects of PEM and its measurement], such as the time symptoms were measured post-exercise. Similar to fatigue, we found significant small-to-moderate increases in pain symptoms, with larger increases at 8-72 hours post-exercise compared to [those] immediately post-exercise.
We also found that the responses were not significantly different between studies of ME/CFS compared to fibromyalgia (FM). These results show that pain is an important and clinically relevant component of PEM and reveal the need for studies dedicated to understanding the pathophysiology that underlies this response.
The Fibromyalgia Working Group identified fatigue and sleep problems as 2 key associated symptoms. […] These symptoms, along with chronic pain, occur in most patients with FM. […] Physical fatigue may manifest as a complaint of physical exhaustion after physical activity, including an inability to function within normal limits for activities that constitute normal daily activities, and the requirement for rest periods after activity.
—AAPT Diagnostic Criteria for Fibromyalgia
The current diagnostic criteria for fibromyalgia do not explicitly mention PEM, although they do list “physical or mental fatigue” as a core diagnostic symptom of fibromyalgia, cognitive dysfunction (brain fog) as a “major feature” of fibromyalgia, and hypersensitivities to light, sound, odors, etc. as “common complaints.”
Furthermore, they note that “physical fatigue may manifest as a complaint of physical exhaustion after physical activity, including an inability to function within normal limits for activities that constitute normal daily activities, and the requirement for rest periods after activity.”
Does your systematic review or previous work support the idea that fibromyalgia comes with PEM?
Dr. Dane Cook:
I think the literature and our meta-analysis clearly show that FM is associated with PEM. Although our data focused on increased pain post-exercise, other studies have shown multiple symptoms are worsened with physical effort. If we define PEM based on self-reported symptoms, then yes, the data support PEM as an element of FM. A few caveats should be considered though.
First, as our study described, a limitation to this research area has been the lack of direct comparisons between ME/CFS and FM. Because of the substantial overlap between these diseases, it is hard to disentangle whether the current studies include a mix of ME/CFS and FM in their study samples.
We need more research that directly compares the PEM response in well-characterized samples of FM and ME/CFS.
Second, [another caveat concerns] the state of the science in FM. The majority of FM research has focused on pain sensitivity to experimental pain stimuli before and after exercise — determining whether exercise results in an increase in pain sensitivity.
This literature is quite mixed, and it appears that whether a hyperalgesic response occurs is dependent on the intensity and duration of the exercise. Studies that use higher intensity and longer duration exercise appear to show hyperalgesia, while those that use short duration and/or lower intensity exercise do not.
Here in the United Kingdom the National Institute of Clinical Excellence (NICE) updated its guidelines for ME/CFS. These new guidelines rejected the use of graded exercise therapy (GET) as a treatment.
Unfortunately, many of the Royal Colleges have expressed opposition to this aspect of the new guideline and have insisted that there is evidence to support the use of graded exercise therapy as an effective treatment for people with ME/CFS.
Do your years of research into post-exertional malaise support this view that graded exercise therapy is an effective treatment for ME/CFS?
Dr. Dane Cook:
Our studies have focused on the acute effects of exercise, not the chronic effects of exercise training. So, I do not have direct experience with testing exercise as a therapy for treating ME/CFS — and I am not a clinician.
I will comment that as an exercise scientist who studies ME/CFS, I have been dismayed at the conflation of the acute and chronic [effects of] exercise. By this, I mean that researchers and policymakers have tended to treat the acute effects of exercise (from a single bout) the same as the chronic [effects of] exercise (from several bouts delivered in time-specific pattern).
This is a mistake. The acute effects of exercise are often different than the longer-term effects of exercise training, both behaviorally and physiologically.
In our previous interview, I also commented on the unfortunate misconception of ME/CFS as a disease of low fitness, how that was untrue and not supported by credible data, but also that graded exercise therapy (GET) had been siloed into a one-size-fits-all prescription.
There are several clinician experts who use gentle physical activity as part of a multi-pronged treatment approach — which may differ considerably from the oversimplified [approach] of GET.
The challenge [in understanding PEM] is determining whether changes in physiology cause the changes in symptoms. Some studies have shown that the symptoms of PEM are related to the physiological disturbances, but unfortunately, most studies have not determined relationships between symptoms and the biological outcome.
—Dr. Dane Cook
Does the latest research into PEM reveal any understanding of the biological mechanisms of this phenomenon — and by extension the pathophysiology of ME/CFS?
Dr. Dane Cook:
Our understanding of the mechanisms of PEM is advancing. Studies have shown changes in mRNA and microRNA expression during PEM in both blood and spinal fluid. Other studies have shown both functional and structural brain changes during PEM following exercise.
These studies show that acute exercise disturbs multiple physiological systems in ME/CFS and that exercise is a useful model for studying the pathophysiology of ME/CFS.
The challenge is determining whether changes in physiology cause the changes in symptoms. Some studies have shown that the symptoms of PEM are related to the physiological disturbances, but unfortunately, most studies have not determined relationships between symptoms and the biological outcome.
One of our recent studies attempted to address [such a challenge] by testing whether selected cardiopulmonary and perceptual responses [during] exercise [predicted the post-exercise symptoms] in veterans with Gulf War Illness (GWI).
[In this study we] showed that, compared to control veterans, veterans with GWI had [a large worsening of symptoms in response to] exercise, thus demonstrating PEM. We also showed that veterans with GWI had [numerous physiological abnormalities] during exercise.
However, despite these [physiological] differences in exercise responses, our linear model [could not predict the severity of PEM.] Thus, the PEM response was not related to the selected combination of cardiorespiratory and perceptual responses [during] exercise. We are now testing whether other physiological responses can improve this model.
What are the implications of your recent review — either for planning physical activity for people with ME/CFS, or for future research directions into post-exertional malaise?
Dr. Dane Cook:
As stated in our meta-analysis, pain can be a critical consideration within PEM and for planning physical activity in ME/CFS. It is a barrier that, along with other symptoms such as fatigue and cognitive fog, needs to be incorporated into [any activity] prescriptions for those with ME/CFS who wish to increase their physical activity behaviors.
As for future research, understanding the pathophysiology of pain in both PEM and ME/CFS is needed to find those physical activities that may not worsen pain. These studies would advance knowledge of PEM and may reveal how those with ME/CFS can more safely be active.
The publication discussed in this article is the following:
Ellen E Barhorst, Alexander E Boruch, Dane B Cook, PhD, Jacob B Lindheimer, PhD, Pain-Related Post-Exertional Malaise in Myalgic Encephalomyelitis / Chronic Fatigue Syndrome (ME/CFS) and Fibromyalgia: A Systematic Review and Three-Level Meta-Analysis, Pain Medicine, 2021.
Bronc is a former historian who is active in his local ME support group. He enjoys interviewing scientists involved in ME research to help himself and others better understand their illness.
Acknowledgment: The author would like to thank Jody Smith and Eric Pyrrhus for help with editing and preparing this article.