22 April 2014

Pain and ultramarathon running – Exercise induced hypoalgesia and pain perception following acute or chronic running

The sun and warmth came with force to Uppsala this past Easter weekend and it has been temperatures in the mid 60s Fahrenheit (around 18 degrees Celsius) in the shadows. The snow has almost finally disappeared from the local ski piste Sunnerstabacken and I went for this year’s first real hill repeat training. Usually, I try to do these exercises with my trekking poles, as I will use the poles during mountain races where I think they are really beneficial I consider it appropriate to also train with them, but this time I for some reason left them at home. I do not know if it was due to this I experienced quite severe pain in my quadriceps already during the training or if it simply is my lack of serious hill repeat training during the winter. I am now experiencing a rather pleasant delayed onset muscle soreness (DOMS) as well.

Some patches of snow still lingering

As it was the muscle pain rather than my lungs or heart that put the limit on my hill repeats I wondered about how ultramarathon runners perceive pain. Is the sensitivity to pain different among ultramarathon runners in general? What about pain sensitivity during and immediately following races and training? Looking into the literature for studies I found not so many on pain (also called nociception) and ultramarathon running, but more on endurance training and running in general. There is plenty of evidence that exercise not only in itself often is rather painful, but that it also induces a transient decreased sensitivity to pain, so called exercise-induced hypoalgesia (EIH), lasting about half an hour after most types of exercise (reviewed in for instance Dannecker & Koltyn “Pain during and within hours after exercise in healthy adults” Sports Med 2014; Epub ahead of print; Janal “Pain sensitivity, exercise and stoicism” J R Soc Med 1996; 89:376-381). There was recently a meta-analysis published on the subject by Naugle and colleagues (Naugle et al “A meta-analytic review of the hypoalgesic effects of exercise” J Pain 2012; 13: 1139–1150). In this meta-analysis, a total of 25 studies,  consisting of a total of 437 healthy volunteers,  using a repeated measures design to examine the effect of acute isometric, aerobic, or dynamic resistance exercise on pain threshold and pain intensity measures were included were included. The results suggest that all three types of exercise reduce perception of experimentally induced pain in healthy participants, with effects ranging from small to large depending on pain induction method and exercise protocol. The mean effect size for aerobic exercise was moderate, while the mean effect sizes for isometric exercise and dynamic resistance exercise were large.

The mechanism behind EIH is at least partly mediated by endogenous central opioid mechanisms, as some of the effects are reversed by treatment with the opioid agonist naloxone as shown in several studies (see for instance Janal et al “Pain sensitivity, mood and plasma endocrine levels in man following long-distance running: effects of naloxone” Pain 1984; 19: 13-25). A very interesting study by Scheef and colleagues used functional magnetic resonance imaging (fMRI) to study which areas of the brain that were activated and to what degree during a painful thermal heat-pain challenge before and after 2 hours of running or walking in 20 trained athletes. Pain activation levels were elevated after walking, but decreased or unchanged after running, in particular in the periaqueductal grey (PAG) pathway in the brain (Scheef et al “An fMRI study on the acute effects of exercise on pain processing in trained athletes” Pain 2012; 153: 1702-1704). Running, but not walking, also reproducibly elevated beta-endorphin levels in plasma indicating an involvement of the opioidergic system. The interesting with the study by Scheef and colleagues was also that the pain sensitivity was tested after a rather strenuous running bout of two hours, in contrast to most studies which employ much shorter tests for aerobic “endurance” exercise. It is still unclear what the intensity threshold is for aerobic exercise-induced hypoalgesia, although it appears that there might be a dose-response and more vigorous exercise will produce larger EIH (Naugule et al “Intensity thresholds  for aerobic exercise-induced hypoalgesia” Med Sci Sports Exerc 2014; 46: 817-825). This is a controversial issue and some studies indicate that even non-painful exercise can induce EIH and that conditioned pain modulation (CPM) therefore is not the primary mechanism behind EIH (Ellingson et al “Does exercise induce hypoalgesia through condition pain modulation?” Psychophysiology 2014; 51: 267-276).

While it since long has been clear that the pain sensitivity is decreased through EIH immediately following exercise it is more unclear whether pain perception in general is different in athletes compared to normal healthy controls. A recent meta-analysis included fifteen studies, with a total of 899 subjects, where pain perception was compared between athletes and normally active controls following experimentally induced pain (Tesarz et al “Pain perception in athletes compared to normally active controls: a systematic review with meta-analysis” Pain 2012; 153: 1253-1262). The main outcome measures were pain tolerance and pain threshold. The meta-analysis showed that athletes possess higher pain tolerance compared to the controls (Hedges’g =0.87; 95%CI 0.53 -1.21; p < 0.00001), whereas the available data on pain threshold were less uniform.  Looking specifically at running, Scheef and colleagues followed up their study of acute pain modulation with fMRI discussed below with a study of 39 healthy non-trained male volunteers that were assigned to either six-months running exercise or non-exercise controls. 28 individuals completed the study (15 exercise and 13 controls) (Boecker et al “Antinociceptive effects of physical exercise: Inducations for chronic pain modulation in endurance runners” Klin Neurophysiol 2014; 45: P96). Pain related activation was studied with fMRI before and after the 6 months intervention together with pain perception thresholds and physiological variables. The analysis was done with no exercise at least 48 hours prior to the MRI. There were pain related activity in right insula and left mesial/lateral premotor cortex and post-hoc within group analysis revealed relative decreases of insular activity in the exercise group and relative increases of premotor activity in the control group. The findings indicate that there are chronic adaptive changes in the brain function regarding pain processing associated with regular exercise training. These functional brain imaging findings are supported by previous studies of marathon runners showing chronic reduction of pain perception, for instance by Johnson and colleagues (Johnson et al “Marathon runner’s reaction to potassium iontophoretic experimental pain: pain tolerance, pain threshold, coping and self-efficacy” Eur J Pain 2012; 16: 767-774).

But what about ultramarathon runners? First, an interesting study from Martin D. Hoffman’s laboratory of 21 runners finishing the 100-mile mountain trail race Western States Endurance Run (WSER) in 2005, compared with 11 control subjects, looked at acute pressure pain perception after an ultramarathon (Hoffman et al “Pain perception after running a 100-mile ultramarathon” Arch Phys Med Rehab 2007; 88: 1042- 1048). Surprisingly, only the fastest runners in showed a mean reduction in pain ratings after the race (-15±20 mm on a 100-mm visual analogue scale) (p < 0.05), whereas there was no change for the slower runners or controls. The authors speculate that it is possible that an extreme bout of exercise of this nature might “exhaust” the systems responsible for EIH in all but the most well-trained runners, or that these systems were not activated as the slower runners were unable to maintain a high enough exercise intensity during the later stages of the race. From personal experience, not being one of the fastest runners, I clearly believe more in the exhaustion theory.

Secondly, Freund and colleagues looked at cold pressure (CP) pain tolerance in 11 runners completing the 4478 km (2789 mile) long TransEurope FootRace 2009 (TEFR09) and compared them with 11 age, sex and ethnicity matched controls without marathon experience during the past 5 years (Freund et al “Ultra-marathon runners are different: Investigations into pain tolerance and personality traits of participants of the TransEurope FootRace 2009” Pain Practice 2013; 13: 524-532). They also performed the 240 item trait and character inventory (TCI) as well as the general self-efficacy (GSE) test. TEFR09 participants had a highly significant greater cold pain tolerance in the CP test than controls (p < 0.00002). There were no differences in the GSE test, but the TEFR09 participants appared less cooperative and reward dependent, but more spiritually transcendent, than the controls in the TCI test. The authors conclude that low pain perception may predispose an individual to become an ultramarathon runner, however, it remains unclear whether low pain perception is a cause or consequence of continuous extreme running exercise.

From Freund 2013. Time course of mean pain intensity ratings during immersion of left hand in ice water. The x-axis shows the time of immersion, the y-axis the pain rating (NRS from 0 - 10). Error bars denot the SD. Asterixes are placed over measurements with significant differences among the groups.
 
From Freund 2013. Comparison of personality traits between TEFR09 participants and controls using the TCI test and correlation with cold pressor (CP) pain scores  

In summary, ultramarathon running training and racing is clearly associated with pain and it is therefore not surprising that most studies of runners show both acute and chronic decreased sensitivity to pain. This has been found also in other endurance trained athletes, for instance triathletes (Geva et al “Enhanced pain modulation among triathletes: A possible explanation for their exceptional capabilities” Pain 2013; 154: 2317-2323). I think that if you cannot endure, and even in some way thrive on, pain you will not continue run ultramarathons and the first preliminary studies of pain in long endurance running indicate that the positive effects of running, like Runner’s High, might be complemented by enhanced direct pain suppressive mechanisms. I am concerned that the widespread use of non-steroid anti-inflammatory drugs (NSAIDs) in runners, see for instance the widely debated recent study published by Küster and colleagues in British Medical Journal (Kürster et al “Consumption of analgesics before a marathon and the incidence of cardiovascular, gastrointestinal and renal problems: a cohort study” BMJ Open 2013; 3: e002090) might be a dangerous shortcut to replacing these endogenous mechanisms of pain regulation. Not surprisingly, use of NSAIDs was higher among finishers (60.5%) than non-finishers (46.4%) of the 2009 WSER and Vermont 100 Endurance Race (p =0.006) (Hoffman & Fogard “Factors related to successful completion of a 161-km ultramarathon” Int J Sport Physiol Perform 2011; 6: 25-37). I do not think stronger analgesics like some NSAIDs, even though still allowed, has any place in ultramarathon races. Ultramarathon running is really as much about pain management as about lung capacity and muscle strength and endurance.       

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