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. Author manuscript; available in PMC: 2019 Sep 1.
Published in final edited form as: Pain. 2018 Sep;159(Suppl 1):S91–S97. doi: 10.1097/j.pain.0000000000001235

Exercise-induced pain and analgesia? Underlying mechanisms and clinical translation

Kathleen A Sluka 1,2,3, Laura Frey Law 1, Marie Hoeger Bement 4
PMCID: PMC6097240  NIHMSID: NIHMS955863  PMID: 30113953

Abstract

An acute bout of physical activity and exercise can increase pain in individuals with chronic pain, but regular exercise is an effective treatment. This review will discuss these two dichotomous findings by summarizing studies in human and animal subjects. We will provide the data that supports the role of physical activity in modulating central nervous system excitability and inhibition, immune system function, and psychological constructs associated with pain. We show evidence that the sedentary condition is associated with greater excitability and less inhibition in both the central nervous system (brainstem inhibitory/facilitatory sites) and the immune system. We further show that exercise and regular physical activity decreases excitability and improves inhibition in both the central nervous system (brainstem inhibitory/facilitatory sites) and the immune system. We will then discuss the clinical implications of these findings, make recommendations for clinical application of exercise, and suggest future research directions.

Keywords: pain, exercise, analgesia, physical activity, immune system, central sensitization, opioid, central inhibition, macrophage

Introduction

Physical inactivity or a sedentary lifestyle is a significant health concern world-wide. The Centers for Disease Control recommends 150 minutes per week of moderate to vigorous activity for health benefits [1]. World-wide the great majority of the population does not meet these physical activity guidelines. Furthermore, physical inactivity is a recognized risk factor for many conditions including cardiovascular disease, diabetes, cancer, dementia, and depression [70](Figure 1). In fact, this has been referred to as the “diseasome of physical inactivity” [70]. Physical inactivity is also a risk factor for development of pain [50–52,90]. The HUNT study performed a population based analysis of 4219 subjects and showed that those with moderate levels physical activity report less musculoskeletal pain [50,51]. Similarly, higher leisure time physical activity is associated with a lower risk of chronic pelvic pain in men [90], and those with a greater number of years of leisure physical activity decreased the risk of low back pain during pregnancy [64]. Thus, physical inactivity may be a risk factor for development of chronic pain, while physical activity reduces this risk.

Figure 1.

Figure 1

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Diagram representing the diseasome of physical inactivity. Physical inactivity is a risk factor for development of a number of diseases including pain. Modified from [70].

Regular physical activity can be achieved through regular lifestyle activity or by structured exercise. In chronic pain, prescribed exercise is an effective treatment for most pain conditions, and use of exercise and physical therapy has long been recognized for its effectiveness in reducing disability and health care costs [40,42,85]. Despite this, an acute bout of exercise can exacerbate pain, in those with chronic pain. As an example we have shown that an upper body fatiguing exercise increases pain by 3 points on a 10 point scale in those with fibromyalgia (Figure 2A)[23], and isometric contractions in individuals with fibromyalgia show no increase in pain thresholds that normally occurs in healthy controls [41,53]. Furthermore, people with chronic pain are generally less active than age-matched healthy controls (Figure 2B,C) [20,29,56,60].

Figure 2.

Figure 2

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A. Graphs showing the increase in pain and physical fatigue in people with fibromyalgia compared to healthy controls after a whole body fatiguing exercise task. *, p<0.05. Data are mean ± S.E.M. Data are regraphed from [23]. FM=fibromyalgia; HC=healthy controls; PF=physical fatigue. B. Graph showing self-reported activity levels in METS*min/week for those with fibromyalgia and healthy controls. *, p<0.05. Data are mean ± S.E.M. Data are graphic representations from tables in [60]. C. Graph showing moderate physical activity levels measured by accelerometry in fibromyalgia compared to healthy controls. *, p<0.05. Data are mean ± S.E.M. Data are graphic representations from tables in [60].

Effects of exercise on the central nervous system

We propose that regular physical activity changes the state of central pain inhibitory pathways and the immune system to result in a protective effect against a peripheral insult. This normal protective state that occurs with regular physical activity is not found in physically inactive individuals and results in a greater risk for development of chronic long-lasting pain.

Figure 3 depicts two states of the nervous system for cells in the brainstem that modulate pain. Brainstem sites, like the rostral ventromedial medulla (RVM), both facilitate and inhibit nociceptive signals [37,71]. We suggest that in the sedentary condition that muscle insult results in increased phosphorylation of the NR1 subunit of the NMDA receptor, which would result in increased facilitation. There is substantial research suggesting that NMDA receptors in the RVM facilitate pain, and phosphorylation of the NMDA receptor enhances channel conductance and increases insertion of NMDA receptors into the synapse [18,21,22,27,82,87,88]. Simultaneously, we propose there is an increased expression of the serotonin transporter (SERT), which would result in reduced inhibition. Classical studies show that injection of serotonin or a SERT inhibitor into the RVM is analgesic, blockade of serotonin receptors prevents analgesia by stimulation of the PAG, and systemic morphine increases serotonin in the RVM [47,48,57,58,79]. Further, in the sedentary condition there is less opioid tone in the nervous system to prevent these excitatory effects upon peripheral nerve damage. In the physically active state we propose that activation of opioid receptors modulates neuron activity so that there is less phosphorylation of the NDMA receptor and less expression of the serotonin transporter. Basic research studies support this hypothesis. We show, in sedentary animals, that there is increased expression of the serotonin transporter and increased phosphorylation of the NR1 subunit of the NMDA receptor in the RVM in animals with nerve injury or chronic muscle pain [3,9,55]. These increases do not occur in physical active animals with nerve injury or chronic muscle pain [3,9,55]. Further blockade of opioid receptors systemically, in the PAG or the RVM prevents the protective effects of regular physical activity, and mu-opioid receptor knockouts do not develop analgesia to regular physical activity [55]. Further we show that naloxone-treated or mu-opioid receptor knockout physically active animals do not show the increases in SERT in the RVM supporting an interaction between endogenous opioids and serotonin [55]. In human studies, greater exercise-induced analgesia was associated with a gene for stronger opioid signaling (OPRM1 G) in combination with weak 5-HT tone (5-HTT low/5-HT1a G), suggesting interactions between opioid and serotonergic mechanisms for exercise-induced analgesia [83]. Thus, regular physical activity prevents hyperalgesia through activation of opioids and serotonin to produce analgesia.

Figure 3.

Figure 3

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A schematic diagram representing the neurons in the brainstem, rostral ventromedial medulla, that facilitate and those that inhibit pain and how sedentary lifestyle or physical activity could modulate their activity. Based on data outlined in the text, we propose that in sedentary conditions there is less opioid tone in the brainstem and overall less inhibition. This results in the neurons showing more facilitation after nociceptive input with increases in phosphorylation of the NR1 subunit of the NMDA receptor and increased expression of the serotonin transporter (SERT). We further propose that regular physical activity increases release of endogenous opioids in the brainstem that inhibit facilitatory neurons to reduce facilitation. This would be associated with less phosphorylation of the NR1 subunit of the NMDA receptor and reduced expression of SERT. Overall, in the physically active condition there would be more inhibition from opioids and serotonin, and less excitation.

In humans, several studies have emerged suggesting greater physical activity is associated with equal or reduced pain sensitivity across a wide range of assessments. Quantitative sensory testing (QST) is increasingly used as an indirect measure of centrally mediated pain processing. Healthy individuals routinely participating in vigorous activity demonstrate enhanced conditioned pain modulation, a measure of central pain inhibition, compared to less active individuals [32,67]. In people with osteoarthritis, a 12-week exercise program increased pain thresholds and decreased temporal summation [38]. However, in one study temporal summation, a measure of central pain facilitation, to cold pain was unchanged [32] whereas temporal summation to heat pain was reduced in the other [67]. Similarly, a meta-analysis of athletes versus normally active adults indicates reduced pain sensitivity overall in athletes [80]. These studies suggest that engagement in regular physical activity is related to decreased pain sensitivity in healthy adults. However, few studies have examined associations between daily lifestyle physical activity and pain sensitivity in FM or other chronic pain populations.

Epidemiological investigations also support the protective nature of physical activity on the development of chronic pain, which may be due to peripheral or central mechanisms. A population-based study from Norway showed chronic musculoskeletal pain incidence was 10 – 38% less in individuals participating in moderate leisure-time activity one to three times per week compared to those with no leisure-time activity [50,51]. However, in patient populations the relationships between regular physical activity and central pain processing is less clear. Increasing physical activity and exercise reduces symptomology in a variety of patient population, and is a first line treatment in a number of chronic pain populations, from fibromyalgia to low back pain [59,72]. Further, non-pharmacological therapies, in general, are considered first-line treatments, with exercise having strong support [59,72]. However, QST and physical activity levels have not been routinely investigated in patient populations. In a small study of 18 women with fibromyalgia, fitness levels, as assessed by cycle ergometry or the six-minute walk test (6MWT), were not associated with pain thresholds or temporal summation assessments [25]. However, this area of study remains sparse and may be limited by the reduced range of lifestyle physical activity levels observed in many chronic pain populations.

Effects of exercise on the immune system

We also propose that regular physical activity modulates the immune system locally at the site of insult, systemically, and in the central nervous system. In the physically inactive condition there are more inflammatory cytokines and less anti-inflammatory cytokines. After regular physical activity this balance shifts to more anti-inflammatory cytokines and less inflammatory cytokines. Inflammatory cytokines activate receptors on nociceptors to produce pain while anti-inflammatory cytokines reduce activity of nociceptors to prevent pain [26,33,46,91]. Figure 4 shows our theory that physical activity levels modulate phenotype of macrophages in muscle. Macrophages are located in muscle and release inflammatory or anti-inflammatory cytokines depending on two relevant phenotypes: classically-activated (M1) macrophages release inflammatory cytokines and regulatory (M2) macrophages release anti-inflammatory cytokines [66]. In support, we show that in uninjured animals physically active animals show an increased proportion of M2 macrophages [54]. Similarly, in animals with nerve injury, sedentary animals show an increased proportion of M1 and less M2 macrophages at the site of injury, while physically active animals show increases in M2 and less M1 macrophages [4]. The analgesia produced by regular physical activity and exercise is prevented by blockade of either IL-10 (muscle insult) or IL-4 (nerve injury) [4,54]. Thus, at the peripheral site of insult there are alterations in macrophage phenotype that underlie the analgesia produced by regular exercise.

Figure 4.

Figure 4

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A schematic diagram representing the interaction between muscle, macrophages, and nociceptors in the peripheral nervous system. Macrophages, found in local tissue, can be polarized to and M1 phenotype that releases pro-inflammatory cytokines which activate nociceptors, or an M2 phenotype that releases anti-inflammatory cytokines which inhibit nociceptors. Our data support that there are greater M1 macrophages at the site of insult or injury in the sedentary state and that regular physical activity increases the proportion of M2 macrophages. Our data further support the notion that regular physical activity changes the state of the immune system so that there is a greater proportion of M2 macrophages and greater anti-inflammatory cytokine that mediate the analgesia of regular physical activity.

In chronic pain conditions, systemic inflammation is suggested as an underlying pathology [61,76,77]. Systemically, immune cells, i.e., peripheral blood mononuclear cells (PBMCs), are highly plastic, can alter levels of cytokines systemically or locally in tissue, and secrete inflammatory or anti-inflammatory cytokines based on their phenotype. In support, people with FM show enhanced circulating inflammatory cytokines and enhanced evoked-release of inflammatory cytokines from circulating monocytes [6,7,30,68,69]. In contrast, a 4- or 8-month aquatic exercise program for individuals with FM decreases circulating and stimulated release from monocytes of inflammatory cytokines of IL-8, IL-1β, and TNF [6,68,69]. In healthy controls, exercise-training also reduces the percentage of inflammatory monocytes in healthy men and women [81]. However, it should be noted that the number of subjects in the majority of these studies was low, and there are mixed results in the literature, likely a result of low sample size, use of mixed populations of immune cells, use of different stimuli to evoke and cytokine release from immune cells [62,77,84]. Thus, preliminary studies show that exercise can alter systemic cytokines, and reduce systemic inflammation, a proposed mechanism of chronic pain.

In the central nervous system, glia cells modulate inflammatory and anti-inflammatory cytokines, and play a significant role in a variety of pain conditions [63]. In animals with nerve injury, there is activation of glial cells, increases in inflammatory cytokines, and decreases in anti-inflammatory cytokines [4,34,63,86]. Regular physical activity and exercise reduce glial cell activation, reduce inflammatory cytokines and increase anti-inflammatory cytokines in the spinal cord dorsal horn [4,34]. Specifically, the enhanced astrocyte (GFAP) and microglial (Iba-1) immunoreactivity produced by nerve injury was significantly reduced by treadmill running [4]. In parallel decreases in the anti-inflammatory cytokines -IL-4, Il-1ra, and IL-5-induced by nerve injury are reversed by treadmill running [4]. On the other hand the increase in inflammatory cytokine IL-1beta is reduced by regular physical activity [34]. Further, there are increases in transcription factors that regulate IL-1β, NFκB and NLRP3 inflammasome, that are also reduced by regular physical activity [34]. Thus, regular exercise normalizes neuroimmune signaling in the central nervous system to prevent and reverse the development of hyperalgesia.

Effects of exercise on psychological co-morbidities

In addition to the beneficial effects of exercise on immune health, people who participate in regular physical activity typically have enhanced mental health and psychological well-being whereas individuals that are physically inactive are more likely to experience depression and anxiety. Specific to chronic pain, individuals that report low levels of physical activity are more likely to report higher kinesiophobia, fear avoidance beliefs, and pain catastrophizing compared with those that report higher physical activity levels [28,49]. However, in a cohort of patients with nonspecific LBP, fear of movement was not associated with subjective and objective (i.e., questionnaire and accelerometry, respectively) measures of physical activity [17]. Therefore, the relation between physical activity and psychological health is less clear for individuals with chronic pain.

Despite the frequent recommendation of exercise in the treatment of depression and anxiety [16,19], the prescription of exercise on improving psychological functioning for individuals with chronic pain is equivocal. In an overview of Cochrane Reviews to determine the effectiveness of physical activity and exercise interventions for adults with chronic pain [31], only five of the twenty-one reviews included psychological well-being (i.e., mental health, anxiety, and depression). Variable effects were reported that included positive and no effects of exercise on psychological health.

The variability in the response may be related to how exercise is incorporated with other interventions in promoting psychological well-being. For example, in a systematic review and meta-analysis, the strongest effects for reducing pain catastrophizing in adults with chronic non-cancer pain was with multimodal treatment that included cognitive behavioral therapy and exercise [75]. The authors propose several explanations such that participating in exercise produces positive benefits that subsequently promotes cognitive restructuring; increases self-efficacy by encouraging self-management; attenuates rumination through increased attentional demands of exercise and decreases pain via activation of descending inhibitory systems. Similarly, in patients with chronic low back pain, a multimodal program that included cognitive behavioral training and exercise produced better effects than exercise alone in improving quality of life and reducing disability and fear avoidance beliefs [65]. It is important to note that improvements occur with exercise alone; participating in regular physical activity that included both aerobic and strength training reduced pain catastrophizing in patients with chronic low back pain which mediated the improvements in disability and depression [78]. Thus, exercise prescription that incorporates a biopsychosocial approach that addresses the multitude of factors that occur with prolonged pain is important to maximize the overall positive effects [5,40].

Clinical Implications

Pain with activity is a significant barrier to activity participation11–13. We routinely show that in sedentary animals there is an increase in hyperalgesia with a single bout of fatiguing exercise [12,35,36,89]. We further show that in human subjects there is a significant increase in pain with fatiguing exercise in people with fibromyalgia [23]. Treatments designed to reduce pain with activity have the potential to improve participation in regular activity. We recently show that application of transcutaneous electrical nerve stimulation (TENS) to the spine in people with fibromyalgia reduces movement-evoked pain, but has no effect on resting pain [24]. Similarly, in people with postoperative pain, Rakel and Frantz applied TENS and showed a reduction in movement-evoked pain but not in resting pain [73]. Thus, TENS may be an effective treatment to reduce movement-evoked pain to encourage activity participation in individuals with chronic pain.

The type of exercise may be less important than the act of doing exercise. Several studies have compared different types of exercise for different types of pain and show no difference between active exercise interventions [15,39,45,74]. For example, in individuals with low back pain, comparison of spinal stabilization exercises to conventional physical therapy which included general exercise showed no differences between groups [14]. For those with neck pain, comparison of proprioceptive training to craniocervical flexion showed no differences in outcomes between groups [45]. Similarly, comparison of graded exercise and graded exposure for those with chronic low back pain showed similar effects [15]. Further, significant effects of strengthening and aerobic exercise are shown in low back pain, osteoarthritis, and fibromyalgia, and are both part of recommended guidelines for these conditions [2,10,11,13,59,72]. In fact, a recent Cochrane review comparing motor control exercise to other forms of exercise for those with chronic low back pain concluded “Given the evidence that MCE [motor control exercise] is not superior to other forms of exercise, the choice of exercise for LBP [low back pain] should probably depend on patient and therapist preferences, therapist training, costs and safety [74].” We suggest this lack of specificity of exercise may be related to the multiple and widespread mechanisms by which exercise works to reduce pain.

Future research directions

Basic science studies have only just begun to examine the underlying mechanisms of exercise. A better understanding of the molecular and cellular mechanisms of exercise can lead increase pain or decrease pain will help to develop novel strategies to address chronic pain and improve implementation and adherence for this important intervention for chronic pain. It is abundantly clear that regular exercise and physical activity are effective for reduction in pain. It has also become increasingly clear that the type of exercise for reduction in pain is less important than doing the exercise. While the Centers for Disease Control (CDC) recommends 150 minutes of moderate physical activity per week and 2 days of strengthening per week for health benefits [1], it is unclear if this dose is needed for pain relief [5]. Indeed multiple clinical trials use less time and lower intensities and still produce clinical effects in those with chronic pain [40]. However, we do not know the most effective dose, or the minimal effective dose. Further, like all interventions, adherence and compliance with the program is extremely important to producing an effect. Barriers to exercise adherence include pain with exercise, low levels of physical activity, low self-efficacy and psychological dysfunction, and poor social support [43]. Supervised exercise, individualized therapy, and self-management techniques may improve adherence; however, the quality of trial assessing these interventions is low [44]. Thus, future clinical studies will need to determine the most effective and minimally effective doses of exercise, if physical activity is equally beneficial to regular prescribed exercise, and develop methods and programs to improve adherence. Lastly, while accepted that exercise is an important intervention for chronic pain, it is often not used as a first-line treatment, relying rather on medication prescriptions. The CDC opioid prescribing guidelines recommend the use of non-pharmacological approaches as the preferred approach to chronic pain (CDC guidelines). As much as 50% of all visits to primary care practitioners is for chronic pain [8], yet non-pharmacological treatments are underutilized. Therefore future studies should develop innovative methods to improve utilization of non-pharmacological treatments by health care practitioners for both acute and chronic pain.

Footnotes

Conflict of Interest: All authors have no conflicts of interest.

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