Ultra-marathon participation has increased from 40,783 male and female participants in 2000, to 459,757 participants worldwide over the same distances in 2016 according to results retrieved from DUV Ultramarathon-Statistik at https://statistik.d-u-v.org . The pain-related research for this growing population of veteran and novice ultra-endurance athletes is deficient and more data is needed.
Historically, research investigating the long-term benefits of exercise has focused on the anti-inflammatory responses from a chronic exercise regimen . Those few studies that have examined pain mechanisms during exercise have shown exercise-induced hypoalgesia , , . Similar findings have also been seen both during , and as a result of training for, ultra-endurance events . It is reasonable to conjecture that any anti-inflammatory effect from exercise must have resulted from the negative feedback mechanisms initiated by the pro-inflammatory response in place to maintain homeostasis during that specific bout of exercise , , .
Inflammation is a component of different types and intensities of exercise , , , . It has been well documented that muscle damage and inflammation are components of ultra-endurance exercise as indicated by established inflammatory markers , , , , .
Training and experience in these types of ultra-endurance events impacts the inflammatory response. Noakes and Carter  have shown that novice ultra-marathon runners have a significantly greater CK level after a 56 km ultra-marathon compared to experienced ultra-endurance athletes competing in the same race. Even in a group of well-trained, experienced, ultra-endurance athletes, it has been shown that there is a significant increase in inflammatory biomarkers during an ultra-marathon competition .
Inflammation can lower the receptor potential threshold of nociceptors resulting in a state of hypersensitivity referred to as hyperalgesia. Sensory receptors, not classified as nociceptors, are also affected by inflammation. With inflammation non-nociceptive receptors may now respond to what is normally an innocuous stimulus and produce allodynia , .
Central sensitization has been defined as “an increased response of the central nervous system neurons which inform of pain when faced with inputs coming from low threshold mechanoreceptors” . Inflammation has been suggested to be a cause of central sensitization , .
We speculated that since ultra-marathon competition has been shown to be associated with inflammation , , ,  and that inflammatory biomarkers have been shown to modulate both the peripheral and central pain systems , , the endogenous pain inhibiting pathways may be attenuated during an ultra-marathon. We hypothesized that pressure pain threshold (PPT) and conditioned pain modulation (CPM) may be altered during an ultra-endurance activity such that PPT would be decreased and CPM measures would reflect a decrease in the descending central pain inhibition.
Subjects were recruited over a 3-year period from participants entered into the Wild Sebastian 100 ultra-marathon in Fellsmere, FL; the Saint Sebastian 100 ultra-marathon in Sebastian, FL and during the 2016 and 2017 Keys 100 ultra-marathon run from mile marker 100 in Key Largo to Key West, FL. Male and female subjects provided informed consent to the research protocol reviewed by the Indian River State College Institutional Review Board. Control subjects were recruited from staff personnel working during the race.
All of the ultra-marathon courses were predominantly flat. The Wild Sebastian and the Saint Sebastian races were run over different courses in the Saint Sebastian Preserve but were on very similar soft, sandy trails over either a 25 mile or 10 mile loop. The Keys 100 ultra-marathon is run almost entirely on concrete sidewalks and gravel paths along the road or on the road itself starting in Key Largo and going straight to Key West along route A1A.
Pressure pain threshold (PPT) and conditioned pain modulation (CPM) were assessed prior to the start of the race and again immediately after completion of 25 miles, 50 miles and 100 miles. Control subjects were tested prior to all events always during the general time period the experimental subject data was collected. For the post measurements of the control subjects data was collected at periods of time between the finish of the 50 mile and 100 mile events. In all cases these control subjects had participated either as a research assistants or as a runner support-team assistant; all had experienced the same environmental conditions as the runners and had some degree of sleep deprivation.
A Baseline © dolorimeter with a scale ranging from 0 to 10 kg/cm2, with 0.25 kg increments, was used to assess PPT. These values were later converted to kilopascals for analysis. The dominant arm was used for the PPT measure. The dolorimeter stylus, having a round, blunt surface area of 1.52 cm2, was pressed three separate times onto a location at the distal radius and ulna, equidistant from the medial and lateral styloid processes. The subjects were instructed to signal when the pressure of the dolorimeter changed from a sensation of pressure to what they sensed as pain.
These measurements were blinded. The technician making the dolorimeter measurements did not observe the dial during or after the measurements. Another technician recorded all dolorimeter measurements. After the three consecutive PPT measures, the subjects placed their non-dominant hand into a bath of cold water maintained at 15°C. The PPT measure was then repeated on the dominant hand in the same location at 90 s and again at 120 s, while the non-dominant hand remained in the cold-water bath. The same blinded procedure, described above, was employed.
2.4 Data analysis
These data were analyzed with paired and unpaired t-tests at p<0.05 level of statistical significance.
Six subjects completed 25 miles during the Wild Sebastian ultra-marathon; 22 completed 50 miles during all three ultra-marathons and 16 completed 100 miles during the Saint Sebastian and Keys 100 ultra-marathons. We obtained data on 11 control subjects. Experimental and control subject descriptive statistics are presented in Table 1.
After 25 miles, the runner’s PPT decreased significantly (p<0.05) from a mean of 535.64 kPa pre-race to 451.00 kPa post-race (Fig. 1). The CPM also decreased significantly (p<0.05) from 576.42 kPa pre-race to 463.36 kPa at 25 miles (Fig. 1). In our runners CPM was elevated pre-race relative to PPT: 576.42 vs. 535.64 (p<0.05).
After 50 miles, the runner’s PPT decreased significantly (p<0.05) from a mean of 490.85 kPa pre-race to 398.12 kPa post-race (Fig. 2). The CPM also decreased significantly (p<0.05) from 546.63 kPa pre-race to 431.93 kPa at 50 miles (Fig. 2). CPM was significantly elevated prerace relative to PPT, 546.63 vs. 490.85 (p<0.05).
After 100 miles, the PPT decreased significantly (p<0.05) from a mean of 468.41 kPa pre-race to 362.02 kPa post-race (Fig. 3). The CPM also decreased significantly (p<0.05) from 484.23 kPa pre-race to 351.62 kPa at 100 miles (Fig. 3). CPM was elevated pre-race relative to PPT, 484.23 vs. 468.41, but was not significantly different (p=0.38).
PPT, CPM and control data is included in Table 2.
Our control data illustrates that there were no changes in their PPT and CPM due to exposure to the same, or at least very similar, environmental conditions and sleep deprivation, as our runners. The control PPT actually increased, but not significantly (p=0.67) after at least 24 h between measurements from 338.11 kPa initially to 362.73 kPa (Fig. 4). The pre-CPM was 405.75 kPa and the post was 401.18 kPa, virtually the same pre to post (Fig. 4). The pre-CPM of 405.75 kPa was significantly elevated when compared to the pre-PPT of 338.11 kPa (p<0.05) which was expected and was consistent with our runners (Fig. 4).
We present evidence of a decreased pain threshold and loss of descending pain inhibition while running 25 miles, 50 miles and 100 miles. Our data suggests a central and possibly a peripheral sensitization of nociceptors and A-β receptors resulting in hyperalgesia and/or allodynia throughout the course of an ultra-marathon.
4.1 Hypoalgesic effect of exercise
A previous meta-analysis revealed that isometric, aerobic, and dynamic resistance exercises result in exercise-induced analgesia (EIA) in healthy subjects. There was a moderate effect size found for EIA in all aerobic exercises included in this meta-analysis, but it should be noted that the longest duration for the aerobic exercise was only 32 min .
In the current study exercise lasted much longer than 32 min. Ultra-marathons and other ultra-endurance activities can continue for many hours extending to days and even weeks. Our subjects competed over a time range lasting from 5 h to over 31 h for distances between 25 and 100 miles.
High active lifestyles have been shown to be associated with decreased pain sensitivity , , . We agree that high active lifestyles, a category that would include ultra-endurance athletes, induce anti-inflammatory mediators that have a pain-reducing effect possibly mediated by reduced peripheral and central sensitivity. These results should not be misconstrued, however, to suggest that high active lifestyles and exercise training will remove normal inflammatory responses from ultra-endurance competition. We contend that inflammatory mediators have sensitizing effects on central and peripheral pain during sustained exercise especially during ultra-endurance exercise.
Another meta-analysis revealed a definitive difference in pain perception due to regular physical activity. Athletes appear to have greater pain tolerance but the data for differences in pain threshold were much less convincing , .
Results of analgesia studies with different running durations have been conflicting. Two studies showed no analgesic effect of running 40 min , , while others showed decreased ischemic pain . One study revealed an increased dental pain threshold .
Pain perception during the Western States 100-Mile Endurance Run was studied . They found that the faster runners had a modest reduction in their response to their pressure pain perception. The slower runners did not share this reduction in pain perception. This race is one of the most challenging ultra-marathons in the US, if not the world. The faster runners were most likely those runners that are among the best prepared, worldwide, for this type of an event. The slower runners, although surely exceptional, were more comparable to the runners in the present study that ranged from elite to novice.
Noakes investigated the response of novice versus experienced runners during a 56 km race. It was shown that the novice runners had significantly greater CK levels than the experienced runners suggesting greater exercising skeletal muscle stress in these novice runners .
The Western States study utilized a visual analogue scale (VAS) to assess the same pressure placed on their index fingers at points throughout the race. The VAS technique is a subjective assessment of pain that does not measure a mechanical pain threshold. The testing threat to internal validity utilizing the VAS measurement cannot be discounted. The present study used a dolorimeter to assess pressure pain threshold. This technique may offer greater objectivity. The present study extends the findings from the Western States Ultra-marathon by including an assessment of peripheral sensitization with PPT measurements before and immediately after ultra-marathon competition as well as an assessment of descending pain inhibition utilizing CPM.
Pain tolerance and personality traits were studied during the Trans-Europe Foot Race held in 2009 . These runners averaged 70 km daily, over 64 days, covering a total of 4,487 km. It was found that the participants had a higher pain tolerance to a cold pain tolerance test. The authors concluded that this high pain tolerance seen in the ultra-marathon runners may be a factor that predisposes these athletes to greater success in ultra-endurance events. They could not conclude, however, that the training for this type of an event caused the changes in pain tolerance.
Muscle soreness was studied in relation to inflammatory response during a relay event over 894 km . Teams of runners ran various legs throughout the event ranging from 9 km to 24.5 km, with a mean total distance of 119.5 km, over 95 h. These relay runners were able to recover between their individual legs of the race and were likely able to run at a greater intensity than if running the total distance all at once. These authors found large increases in inflammation biomarkers, including TNF-α, CK and IL-6, and showed correlations between these inflammatory biomarkers and increased muscle soreness throughout the race.
4.2 Inflammation of exercise
One very important pain-modulating component of all types of exercise is the inflammation of exercise. Inflammatory responses to exercise, both pro-inflammatory and anti-inflammatory, have been studied . The study of pain modulation resulting from pro-inflammatory and anti-inflammatory responses to exercise, however, has been given relatively little attention.
The emphasis of the anti-inflammation research is often focused on the health benefits derived from an exercise regimen. Although the positive relation between anti-inflammatory, myokine-induced hypoalgesia and the intensity and duration of exercise has often been inferred, there is little evidence of this when extended to ultra-endurance conditions in the current literature .
Research on pro-inflammatory responses to exercise is substantial. The emphasis of this research is typically focused on the inflammatory and immune responses to exercise as well as muscle damage. Inflammation during exercise has been shown to occur in a wide variety of types of exercise but it has been more thoroughly studied in endurance activities , .
The effect of inflammatory mediators on nociceptors, referred to as peripheral sensitization  and heterosensitization  together with the inflammatory effect on the nociceptor synapse at the dorsal horn, referred to as central sensitization, are well known , . The effect of inflammation on sensory afferents is to reduce the action potential threshold for both noxious and non-noxious stimuli resulting in hyperalgesia and allodynia, respectively. As a result of inflammation it has been shown that this same change occurs in sensory afferents in areas of the body removed from the site of injury .
Our interest was to investigate the changes in endogenous inhibition and/or accentuation of pain detected by changes in PPT and CPM during an ultra-marathon event. Our data suggests both nociceptor sensitization either due to or in combination with central sensitization during an ultra-marathon that has an onset as early as 25 miles into the race and continues through 100 miles.
4.3 Hyperalgesic effect of ultra-endurance exercise
A recent review of nociceptor sensitization by Gold and Gebhart  and the work from others, over the past five decades, reveals that nociceptor plasticity may result from inflammation , , . Gold and Gebhart, also point out that there are distinct nociceptors derived from different tissues . When considering the results of this present study we must keep in mind that the changes in PPT reflect the composite response from a variety of tissues at the distal arm with distinct afferents that combine for the measured threshold response of our subjects.
The inflammatory response to ultra-endurance exercise, both pro and anti-inflammatory, has been well described , , , , . Based upon previous research we suggest that the significant decrease we observed (p<0.05) in PPT occurring from 25 to 100 miles during an ultra-marathon result from the inflammatory cascade and/or the cytokines and myokines involved in this inflammatory response to ultra-endurance exercise. This may manifest as nociceptor plasticity, central sensitization causing decreased descending inhibition to nociceptors, deficit in descending inhibition or a combination of all the above.
We have seen decreases in CPM beginning at 25 miles and continuing throughout 100 miles in our ultra-marathon subjects. This suggests either a deficit in descending pain modulation or central sensitization. There is a distinction between these mechanisms that result in a reduced descending pain inhibition. A spatial summation technique has been employed to differentiate a deficit in descending pain inhibition versus central sensitization . This technique revealed that fibromyalgia patients lacked the “normal” recruitment of endogenous pain inhibitory responses to cold-water immersion. The fibromyalgia group was differentiated from a low back pain group with the latter group having decreased endogenous inhibition of pain from a lack of “peripheral nociceptor activity and/or central sensitization” . Our subjects demonstrated an intact CPM pre-race but a decreased CPM after 25, 50 and 100 miles. This suggests a central sensitization instead of a deficit in descending inhibition as seen in chronic pain conditions such as fibromyalgia .
In conclusion we provide the first data that indicates a decreased PPT and CPM during an ultra-marathon. This suggests either peripheral and/or centralized sensitization from ultra-endurance running. Further research, in general, is necessary to define the physiological responses to the rigors of this type of activity in this growing population of ultra-endurance athletes. Additional research is especially necessary on the inflammatory effects to pain mechanisms during endurance exercise, explicitly during ultra-endurance exercise, given the paucity of data currently available in the peer-reviewed literature on this growing population of athletes.
We would like to acknowledge the crucial contributions from the student members of the Indian River State College Florida Ultra-Endurance Academic Research Club. Without their help in data collection during this paper would not have been possible.
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About the article
Published Online: 2018-07-12
Published in Print: 2018-10-25
Research funding: There were no grant monies used in this research. This research is partially funded by the general education budget of the Indian River State College Biology Department.
Conflict of interest: There is no conflict of interest as there is no funding from any commercial organization for this research.
Informed consent: The informed consent document was approved by the Indian River State College Institutional Review Board prior to conducting this research and was provided to all subjects used in this study.
Ethical approval: This study was approved by the Indian River State College Institutional Review Board prior to collecting data.
Citation Information: Scandinavian Journal of Pain, Volume 18, Issue 4, Pages 703–709, ISSN (Online) 1877-8879, ISSN (Print) 1877-8860, DOI: https://doi.org/10.1515/sjpain-2018-0079.