Exercise-induced hypoalgesia (EIH) in response to different exercise intensities

In healthy, pain-free populations and also in patients suffering from chronic pain, physical activity can lead to exercise-induced hypoalgesia (EIH) (Vaegter and Jones 2020; Koltyn 2000). EIH describes an acute reduction in pain and pain sensitivity following exercise. It is thought to last for up to 30-min post-exercise and consent exists that this phenomenon occurs in healthy people following different types of exercise modalities (Rice et al. 2019). Yet, EIH is more variable in chronic pain patients where pain sensitivity may remain unchanged or even increase in response to exercise (Vaegter and Jones 2020). The physiological mechanisms underlying EIH are currently incompletely understood, but most likely include the endogenous opioid system (Koltyn 2000) as well as the endocannabinoid (Dietrich and McDaniel 2004) and serotonergic (Lima et al. 2017) system, the autonomic nervous system, and cerebral blood flow (Malfliet et al. 2018).

It was demonstrated that aerobic exercise, isometric exercise, and dynamic resistance exercise produce hypoalgesic effects (Naugle et al. 2012). However, these different exercise types seem to induce EIH in a different magnitude. A recent meta-analysis revealed that EIH is most robust and shows the largest effects when preceded by aerobic exercise. Dynamic resistance exercise induced small EIH effects, and this meta-analysis showed that isometric exercise did not induce any hypoalgesic effects (Wewege and Jones 2021).

Yet, when observing studies that evaluated the EIH effects in response to aerobic exercise, it becomes evident that results are mixed and show different effect magnitudes. One possible explanation suggested is that different exercise intensities lead to a different magnitude of hypoalgesic effects. It is generally believed that a dose–response relationship exists between the intensity of aerobic exercise and resulting EIH, and research suggests that higher intensities lead to a higher EIH response (Naugle et al. 2012; Micalos and Arendt-Nielsen 2016; Hoffman et al. 2004). However, despite the fact that many studies examined the phenomenon of EIH, there is limited understanding of the optimal intensity of aerobic exercise to induce hypoalgesia by pain-inhibitory systems (Naugle et al. 2012). A dose–response relationship using several different intensities was not evaluated in one study, but is rather based on the comparison between different studies using different methods. Hence, the aim of the present study is to compare the different effects of acute 30-min bicycle ergometer exercises on EIH employing four different intensities.

25 subjects successfully finished the study and conducted all exercise sessions. All subjects were able to finish the exercise sessions with 60 and 80% of the IAT, respectively. Five subjects did not finish 30 min of the exercise session consisting of 100% IAT. Therefore, the subjects finished this session after a total mean time of 27.6 (± 5.0) min. Besides, 16 subjects did not finish the 110% IAT session and the participants finished this session after a mean time of 22.5 (± 9.0) min. The time span between two sessions was 7.8 days (± 5.6) and ranged between 2 and 24 days.

Statistical analyses employing a two-way ANOVA with ‘protocol’ and ‘time point’ as factors revealed no significant effect for the ‘protocol’ × ‘time point’ interaction of PPT of the forehead, sternum, left and right elbow, left and right knee, and left and right ankle. However, a significant main effect for the factor ‘time point’ was observed at the landmarks sternum, left and right elbow, left and right knee, and left and right ankle (see Table 2). Post hoc analyses revealed for each of these landmarks that PPT at T0 were significantly lower compared to T1 (p < 0.01) and T2 (p < 0.01), respectively. On the forehead, no main effect was observed for the variable ‘time point’. Means of PPT in response to all exercises are presented as one mean value in Fig. 2. Results of the subsequent post hoc tests employed for the respective landmarks and intensities revealing a main effect for the factor ‘time point’ are presented in Fig. 3 and Supplementary material 1. Coefficient of variance calculation revealed mean values ranging from 0.03 to 0.10 for the entire study. Further coefficient of variance values are provided in Supplementary material 2.

Statistical analyses with protocol and time point as factors revealed no significant effect of the protocol × time point interaction of CPM. Further, no main effect was observed for the variable time point alone (Fig. 4 and Table 2).

This study’s primary objective was to evaluate the effects of four different aerobic exercise intensities on EIH measured using PPT. The results show a main effect over time indicating that EIH occurred at the landmarks of the joints and the sternum. Yet, no interaction effects were observed and, hence, a specific dose–response relationship cannot be established based on the results obtained. However, the results of the post-hoc calculations reveal that EIH seems to be more present in response to higher intensive exercise, i.e. 100 and 110% sessions, respectively (Fig. 3). Several studies investigated the effects of bicycle exercises on EIH using PPT measurements and employing certain intensities. The results of these studies predominantly show that the used exercises led to hypoalgesic effects on certain body sites after bicycle ergometer training. Hoffman et al. compared the effects of three exercise interventions on pain ratings of a 2-min pressure stimulus before and 5 min and 30 min after exercise. The interventions were performed on a treadmill and consisted of a 10-min exercise at 75% of maximal oxygen uptake (VO2max), a 30-min exercise at 50% VO2max, and a 30-min exercise at 75% VO₂max. Pain ratings were significantly decreased 5-min post-exercise at 75% VO2max, while the other two interventions showed no effect. The authors concluded that there might be thresholds for intensity (> 50% VO₂max) and duration (> 10 min) for aerobic exercise to induce acute hypoalgesia (Hoffman et al. 2004). Further, Naugle et al. showed that 20 min of vigorous exercise at 70% of HR reserve increased PPT, whereas PPT was unaltered after moderate exercise at 50% of HR reserve (Naugle et al. 2014). A study by Vaegter et al. also revealed that a high-intensity bicycle exercise at a calculated intensity of 75% VO₂max led to a larger EIH response compared to a low-intensity exercise conducted at 50% VO₂max (Vaegter et al. 2014) supporting the results presented herein with EIH effects observed primarily in the 100 and 110% sessions. Acute exercise most likely reduces pain sensation due to the release of analgetic endogenous opioid-related substances which are expressed centrally in the nervous system and, in addition, locally close to the contractile musculature attenuating nociceptive signalling (Micalos and Arendt-Nielsen 2016). This leads to the assumption that the magnitude of EIH is highest in body parts near the exercising musculature and weaker at remote body parts (Rice et al. 2019). This assumption is also observed in the present study with the highest EIH effects observed at the ankle joints (Fig. 3).

Some studies also demonstrate that acute bicycle exercise results in hyperalgesia, i.e. increase in pain sensitivity, following bicycle exercise. Krüger et al. demonstrated that an incremental bicycle ergometer session up to exhaustion resulted in hyperalgesia at the sternum and forehead. Neither hypo- nor hyperalgesic effects were observed at the elbow, knee, and ankle joints measured via PPT (Krüger et al. 2016). One might argue that the nature of the incremental bicycle session in which a high-intensity and anaerobic demand only occurs for the last 5–6 min is too short to induce hypoalgesic effects. Hyperagesic effects measured via PPT at local and remote musculature were also observed in the study by Micalos and Arendt-Nielsen after participants conducted a 30-min bicycle exercise at 30% of their VO₂max. The authors state the theory that low-intensity exercise might increase the sensitivity of noxious stimuli by facilitating ascending afferent signalling (Micalos and Arendt-Nielsen 2016). However, studies also show that acute bicycle exercises might neither lead to hypo- nor hyperalgesia when measuring pain at the index finger after a 30-min steady-state cycling test at 75% of the VO₂max (Monnier-Benoit and Groslambert 2006) supporting the above-mentioned assumption that hypoalgesia occurs more prominently at body parts close to the exercising muscles. The results of the present study reveal that all intensities induced hypoalgesia with a main effect observed at the joints and sternum. Compared to other studies that tried to examine the effects of exercise intensity on hypoalgesia, we chose the intensities ranging from 60% up to 110%. Hence, our lowest intensity is still higher compared to, for instance, the lowest intensity used in the above-mentioned study by Micalos and Arendt-Nielsen, who explored exercise-induced analgesia employing cycling exercises of 30 min at an intensity of 70 and 30% of peak oxygen uptake (VO₂peak). They found that exercising at 70% of VO₂peak attenuated pressure pain sensitivity locally at the rectus femoris compared to the hyperalgesic effects observed at 30% of VO₂peak (Micalos and Arendt-Nielsen 2016). Higher-intensity exercise might influence the midbrain periaqueductal grey (PAG) and the rostral ventromedial medulla (RVM) network by modulating central pain transmission, which is associated with central endogenous release of inhibitory neurotransmitters in the central nervous system, such as GABA, leading to an inhibition of pain signalling (Micalos 2014; Micalos and Arendt-Nielsen 2016). This theory is supported by animal models showing that GABA increases in response to exercise in rats (Hill et al. 2010). Our lowest intensity exercise of 60% VO₂max for 30 min might still be high enough to induce, at least to a certain degree, these proposed physiological reactions. Our results further indicate that the higher intensive protocols led to a broader EIH effect, as EIH is observed at more landmarks in the 100 and 110% sessions, respectively (Fig. 3).

The present study revealed that EIH occurred at the joints and the sternum. Yet, no change in exercise-induced analgesia occurred at the forehead. Our results show that EIH is higher, in terms of effect sizes, at landmarks near the musculature that is primarily engaged in the exercise supporting previous research (Vaegter et al. 2014). EIH effects may be less pronounced and may occur less consistently depending on the distance to the primary exercising body parts and musculature (Gomolka et al. 2019). Accordingly, the results of our study regarding hypoalgesia measured at the knee and ankle joints support this theory. Yet, a main time effect was also observed at the elbow joints and the sternum. One might argue that bicycle exercise also goes along with contractile activity in the arm and chest musculature. However, these muscle sites are by far less engaged in the total force production compared to the lower extremity musculature. Krüger et al. observed that an incremental bicycle exercise test up to exhaustion led to hyperalgesic effects measured by PPT at the sternum and forehead whilst no differences were observed at the same joint landmarks used in our present study (Krüger et al. 2016). Interestingly, our study revealed that neither hypo- nor hyperalgesic effects occur in response to any of the exercise intensities used at the forehead. The reasons for this observed phenomenon remain elusive; yet, it might be explained by the above-mentioned observation as the head is the most remote body part from the exercising musculature. To the best of our knowledge, only very little research was conducted using the forehead as landmark for hypoalgesic testing and more research is needed to further elaborate this observation.

Decreased pain sensitivity was observed 5-min post-exercise lasting up to 45-min post-exercise. It is generally believed that EIH effects employing PPT last up to 30 min (Rice et al. 2019). Our results indicate that the EIH time span might be even longer than generally believed, which is in contrast to previous research showing that EIH is only observed 5-min post, but not 30-min post-exercise (Hoffman et al. 2004). In another study, EIH was observed 5-min post, but not 15-min post-exercise (Micalos and Arendt-Nielsen 2016). Gomolka et al. conducted a study to evaluate the test–retest reliability of EIH using two 15-min exercise sessions. PPT were measured before, immediately after, and 15 min after at, among others, the leg. Results show that EIH occurred 5-min post in both sessions. Interestingly, 15-min post-exercise, EIH was only observable in one of the two tests (Gomolka et al. 2019). Yet, these studies mentioned are only comparable to a limited extent with each other and with the study presented herein as they differed in the methodological approach chosen. Differences in the exercise type (i.e. treadmill running, bicycle riding) as well as duration (i.e. 30, 15 min) and intensity (i.e. 75% VO₂max, 70% VO₂peak, or heart rate of 85.9% of age-related maximum) need to be considered. Further, experimental pain measurements employed were different with different methods (PPT or NRS response to a 2-min pressure pain stimulus to the finger) and body sites (finger, rectus femoris, or biceps femoris) used making it difficult to compare the results (Hoffman et al. 2004; Gomolka et al. 2019; Micalos and Arendt-Nielsen 2016). Results of the present study reveal that EIH occurs even after 45 min particularly after the highly intensive protocols (i.e. 100 and 110%). Hence, the intensity might also be a decisive variable that mediates the duration of EIH. Yet, concluding from these conflicting results, future studies should also implement pain sensitivity measurements not only immediately after the exercise, but also somewhat afterwards, e.g. 15, 30, 45, and 60-min post-exercise.

The present study further evaluated the effect of the different exercise session on CPM to investigate the endogenous pain-inhibitory system by determining the suppressive influence of a painful conditioning stimulus on a pre-applied painful test stimulus. Results indicate that none of the exercise sessions induced any change in CPM, leading to the assumption that endogenous inhibitory processes were only active to a limited degree to explain the hypoalgesia observed. This in line with existing literature stating that CPM cannot be seen as a primary mechanism of EIH (Ellingson et al. 2014). However, some influencing factors need to be discussed in this context. First, the exercises led to an increase in body temperature, which might have blurred the CPM results as for the test and conditioned stimuli thermal stimuli were employed. Second, sensitivity of CPM might be limited to yield statistically significant differences within the recruited subject sample of this study as healthy and young subjects often reach maximum values (Hackett et al. 2020), which is also observed in our study.

This study for the first time investigated the effects of a 30-min bicycle ergometer exercise comparing four different exercise intensities (60, 80, 10, and 110% of the IAT) on EIH. A main time effect was observed for PPT measured at the elbow, knee, and ankle joints, as well as the sternum with higher values observed 5 min and 45 min post-exercise, respectively. This observation might be explained by local pain-inhibiting pathways and to limited degree by central mechanisms as no such effect was observed for the forehead. However, no interaction effects were observed indicating that no intensity-specific “dose–response effects” with respect to EIH occurred in this study. Besides, none of the exercises altered CPM indicating that the central endogenous pain-inhibitory system does not reveal any acute exercise effects for any intensity used.Author: Please check the edit to the sentence ‚ A main time effect was observed for PPT measured at both elbow,…’This sentence was adjusted. As "Conflict of interest" statement is mandatory for this journal, please provide the same.Dear Sir or Madam, tank you for this advice. Please add the following statement: "Conflict of interest: The authors declare no potential conflicts of interest with respect to the research, authorship, and/or publication of this article."