8 Exercise Testing and Training in Patients with ...

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Exercise Testing and Training in Patients with (Chronic) Pain Harriët Wittink and Tim Takken CONTENTS Deﬁnition and Background Mechanism of Action Introduction to Exercise Testing Exercise Training and the Patient with Chronic Pain Conclusion

“Those movements which do not alter respiration are not called exercise.” Galen (∼200 A.D.) Summary A vast body of literature supports the idea that exercise training is an important modality in the treatment and rehabilitation of the chronic pain patient. Exercise testing and prescription should therefore be incorporated in the therapeutic armamentarium of health care professionals working with chronic pain patients. In this chapter we present the scientific basis of the positive effects regular exercise can have on pain, mood, sleep, function, and fitness. Moreover, specific guidelines for exercise testing and prescription for the chronic patient are provided.

Key Words: exercise physiology, aerobic capacity, exercise testing, submaximal, aerobic, anaerobic, frequency, intensity, time

1. DEFINITION AND BACKGROUND Exercise physiology arose mainly in early Greece and Asia Minor, although the topics of exercise, sports, games, and health were of interest to even earlier civilizations. The greatest influence on Western medical traditions came from the Greek physicians of antiquity, including Herodicus (fifth century B.C.), Hippocrates (460–377 B.C.), and Claudius Galenus or Galen (A.D. 131–201). Proper diet and physical training has been recommended since Herodicus’s day. Galen wrote descriptions about the forms, kinds, and varieties of “swift” and vigorous exercises, including their proper quantity and duration (1). In the first century A.D., the Roman satirist Juneval famously observed From: Contemporary Pain Medicine: Integrative Pain Medicine: The Science and Practice of Complementary and Alternative Medicine in Pain Management Edited by: J. F. Audette and A. Bailey © Humana Press, Totowa, NJ

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“Orandum est, ut sit mens sana in corpore sano,” or “A sound mind in a sound body is something to be prayed for.” In Venice in 1539, the Italian physician Hieronymus Mercurialis published The Art of Gymnastics Among the Ancients. This text was heavily influenced by Galen and other early Greek and Latin authors and profoundly affected subsequent writings about gymnastics (physical training and exercise), not only in Europe (influencing the Swedish and Danish gymnastics systems), but also in early America (the 19th -century gymnastics-hygiene movement). By the middle of the 19th-century American physicians had the opportunity to either teach in medical school and conduct research, or become associated with departments of physical education and hygiene. There, they would oversee programs of physical training for students and athletes (1). The first formal exercise physiology laboratory in the United States was established in 1891 at Harvard University. Exercise physiology is now defined as the branch of physiology that studies how the body adapts to physical movement. It is “the identification of physiological mechanisms underlying physical activity, the comprehensive delivery of treatment services concerned with the analysis, improvement, and maintenance of health and fitness, rehabilitation of heart disease and other chronic diseases and/or disabilities, and the professional guidance and counsel of athletes and others interested in athletics, sports training, and human adaptability to acute and chronic exercise” (2).

2. MECHANISM OF ACTION The human body is made for movement. This statement is supported by the fact that human movement influences cardiovascular, respiratory, musculoskeletal, renal, gastrointestinal, genitourinary, nervous, lymphatic, endocrine, and immune systems at the cellular, organ, and systemic levels. In fact, not moving enough causes people to become ill. Epidemiological data have established that physical inactivity increases the incidence of at least 17 unhealthy conditions, almost all of which are chronic diseases or considered risk factors for chronic diseases (3). Chronic conditions related to inactivity include coronary heart disease (CHD), hypertension, Type II diabetes, colon cancer, depression and anxiety, osteoporotic hip fractures, and obesity. Increasing adiposity, or obesity, is itself a direct cause of Type II diabetes, hypertension, CHD, gallbladder disease, osteoarthritis, and cancer of the breast, colon, and endometrium (3,4). Exercise is one key management strategy used by physical therapists to address impairments (problems with body function or structure such as pain or weakness), activity limitations (difficulties an individual may have in executing activities such as walking, sitting, and standing), and participation restrictions (problems an individual may experience in life situations such as working, playing sports or socializing) in patients with chronic pain (5). Exercise testing (see Section 3) can identify impairments or deficits in muscle endurance, strength and aerobic capacity as related to the patient’s desired physical activity level in order to target these for treatment. Multiple meta-analyses on the effects of exercise on various painful conditions report exercise to have a positive effect on pain, aerobic capacity and physical function. The mechanisms behind these effects are not completely clear and are most likely due to multiple factors. Exercise may also influence pain in a number of nonspecific ways, e.g., through its influences on body mass, mood, sleep, motivation, deconditioning, skill

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acquisition, self-efficacy, or social contact (6,7). Possible mechanisms that contribute to these effects are discussed below.

2.1. Pain A number of studies have been conducted to examine whether pain perception is altered during and following exercise, and several reviews have been published on this topic (8,9). Most studies have investigated whether decreased sensitivity to pain (hypoalgesia) occurs following aerobic exercise with less research investigating whether hypoalgesia occurs after other modes of exercise (e.g., resistance or isometric exercise). A number of investigators have reported the development of hypoalgesia during and following exercise under experimental and clinical conditions (8). Hypoalgesia occurs consistently following high-intensity exercise (i.e., a high workload > 200 W or 60–75% of maximal oxygen uptake) (9). Most of these studies have used normal (usually college-aged) subjects. Studies on the effects of exercise on pain threshold in patients with chronic pain, however, are scarce. A recent study found that pain ratings from an experimentally induced pressure pain stimulus was reduced after aerobic exercise (25 minutes at 50–70% of peak VO2 ) in patients (N = 8) with minimal to moderate disability from chronic low back pain (10). The analgesic effect lasted for more than 30 minutes following the aerobic exercise intervention. In contrast, pain thresholds were found to decrease in subjects with chronic fatigue syndrome (CFS), while the same exercise intervention caused an increase in the pain threshold of normal control subjects (11). The authors of this study hypothesized that increased perception of pain and/or fatigue after exercise may be indicative of a dysfunction of the central anti-nociceptive mechanism in CFS patients. The mechanisms for analgesia following exercise are poorly understood. The most commonly tested hypothesis to explain exercise-induced analgesia has been that the observed hypoalgesia that results from strenuous exercise is secondary to activation of the endogenous opioid system. However, results from studies that have investigated the role that the endogenous opioid system plays in the analgesic response to exercise are mixed. Hypoalgesia following exercise does appear to be mediated in part by the endogenousopioid system; however, an elevation in pain threshold can also occur following pre-injection with opioid antagonists, providing evidence for a non-opioid based mechanism. The role of the endocannabinoid system as an alternative neuromodulatorysystem in pain perception is currently a topic of much investigation. The endocannabinoid system has been shown to suppress pain at both central and peripheral sites (12). Preliminary evidence shows that exercise of moderate intensity activates the endocannabinoid system (13), suggesting a new mechanism for exerciseinduced analgesia and possibly other physiological and psychological adaptations to exercise.

2.2. Aerobic Capacity Aerobic capacity is a measure of the ability and efficiency of the body to take oxygen up and to use it as a fuel by turning it into energy (adenosine triphosphate or ATP, section 3). The higher the oxygen uptake for a given activity, the higher the aerobic energy output demanded. Aerobic fitness is expressed in liters/minute (L/min) and often adjusted for bodyweight milliliters/kilogram/minute (mL/kg/min). Physical activities are coded in metabolic equivalent (MET) intensity levels. One MET is defined as the

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resting metabolic rate obtained during quiet sitting and equals an oxygen uptake of 3.5 mL/kg/min. The oxygen cost for physical activities ranges from 0.9 MET for sleeping to 18 METs (running at 10.9 mph) (14). The level of a person’s aerobic capacity thus directly affects the amount and intensity of physical activity this individual is able to perform. Practical experience has shown that one cannot tax more than about 30–40% of one’s aerobic capacity during an eight-hour day without developing subjective or objective symptoms of fatigue (15). A common hypothesis is that aerobic capacity is reduced in patients with chronic pain as a result of physical inactivity, although studies on this topic do not consistently support this conclusion (16). Physical inactivity, or disuse, will lead to deconditioning over time. The “deconditioning syndrome” (17,18) was postulated in the mid 1980s to be the primary factor that contributed to a chronic pain patient’s intolerance to physical activity. The theory was that pain leads to inactivity (disuse), which in turn leads to deconditioning, which further contributes to loss of function and activity avoidance, causing greater deconditioning and disability in a downward spiralling, vicious cycle. More recently, disuse has been presented as one factor among many that perpetuates chronic pain in theoretical pain research models (19,20). Reconditioning, to reverse the physiological effects of disuse, is a frequently used approach in pain rehabilitation to increase activity levels and reduce disability. In addition, exercise can provide behavioral cues that physical activity levels can be increased without a concomitant increase in pain. Greater levels of exercise have been associated with improvements in mood and functioning in patients with chronic conditions over a 2-year study period (21).

2.3. Physical Function Aerobic training of sufficient intensity and duration will increase aerobic capacity, and thus the capacity for physical activities. This change may not be sufficient to alter the level of physical function in a particular individual; therefore, other indices of fitness, including muscle strength, endurance, and flexibility that may have a more direct or additive effect on functional capacity should be considered. Matching the body’s capacity to the individual’s need to perform physical activities is important to prevent injury. For example, focused training to develop greater strength of the muscles of the back and trunk could protect from or minimize injury in a work environment that involves heavy lifting. Endurance training may prevent fatigue and maintain motor control in individuals who have jobs that require repetitive activity. In work environments that demand frequent bending, improved flexibility may be the critical factor to reduce injury risk. Often a combination of improved strength, endurance, and flexibility will enhance the capacity of a pain patient’s ability to return to work safely. Strength and flexibility exercises have also been shown to improve circulation to the back structures and mood, which would favorably influence sensitivity to pain (7,22,23).

2.4. Mood Depressed chronic pain patients report greater pain intensity, less life control, and more use of passive–avoidant coping strategies. They also describe greater interference from pain and exhibit more pain behaviors than chronic pain patients without depression (24). The prevalence of major depression in patients with chronic low back pain is


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three to four times greater than in the general population (25,26) Quasi-experimental and randomized controlled trials (RCTs) demonstrate that both resistance training and aerobic exercise can reduce symptoms of depression (27,28), although there is still a lack of good quality research on clinical populations (7). Aerobic exercise is associated with reductions in state anxiety (29). More recent evidence suggests that resistance training may reduce state anxiety, but more so in subjects with a high baseline level of state anxiety (30). Low to moderate aerobic exercise appears to improve mood states in patients with low back pain (31).

2.5. Sleep Sleep disturbance is a prevalent complaint in patients with chronic pain (32). Twenty percent of American adults (42 million people) report that pain or physical discomfort disrupts their sleep a few nights a week or more (33). Epidemiological studies show that exercise is perceived as helpful in promoting sleep and suggest that regular physical activity may be useful in improving sleep quality and reducing daytime sleepiness (34). Although only moderate effect sizes have been noted, meta-analyses have shown that exercise increases total sleep time and delays REM sleep onset (10 min), increases slow-wave sleep (SWS) and reduces REM sleep (2–5 min) (35,36). Menefee et al. (32) found that higher overall sleep quality and lower sleep latency primarily were related to higher ratings of physical functioning and shorter duration of pain in patients with chronic pain. Their data suggest that physical functioning, duration of pain, and age may be more important than pain intensity and depressed mood in contributing to decreased overall sleep quality and sleep latency. The contribution of physical functioning was particularly strong. This suggests that increasing the level of physical functioning may contribute to better sleep quality in patients with chronic pain.

2.6. Exercise and the Brain Regular physical exercise benefits the nervous system, as well as the musculoskeletal and cardiovascular systems. In humans, exercise may improve mood and cognition, and the data suggests that regular exercise can also promote maintenance of cognitive function with aging. When mice are provided access to a running wheel, the amount of neurogenesis in their hippocampi is increased and they exhibit improved performance in learning and memory tasks. Exercise results in an increase in the level of brainderived neurotrophic factor (BDNF) in the hippocampus, suggesting a role for BDNF in the beneficial effects of exercise on brain function and plasticity. BDNF is a member of the structurally and functionally homologous neurotrophin family. It is the most widely distributed trophic factor in the brain, and participates in neuronal growth, maintenance, and use-dependent plasticity mechanisms such as long-term potentiation and learning (37). There is a reciprocal relationship between BDNF and serotonergic signaling, in which BDNF enhances serotonin production and release,and serotonergic signaling stimulates BDNF production (38). Research has also provided evidence that circulating insulin-like growth factor-1 (IGF-1) plays an important role in the stimulation of hippocampal neurogenesis by physical exercise (38). Two additional effects of exercise on the brain that may contribute to its ability to promote neuronal plasticity and ward off neurodegenerative disease are enhancement of serotonergic signaling (39) and stimulation of angiogenesis (40). Different forms of training in rats, e.g., aerobic and motor skill, had differential effects on the vasculature and synaptic

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connectivity of the brain. The aerobic group was found to have a higher density of capillaries in the cerebellum than the animals trained on motor skills or the inactive control animals. The animals in the motor skill group showed a larger number of synapses in the cerebellum than the other groups (41). Subsequent studies have shown that fitness training can also enhance vascularization of other regions of the brain, such as the motor cortex, in primates as well as rats. It has been suggested that increases in vascularization serves an important function in providing a greater reserve capacity to respond in situations requiring increased oxygen (40).

2.7. Exercise and the Immune System Over the past several decades a variety of studies have demonstrated that exercise induces considerable physiological change in the immune system. Various types of psychological and physiological stressors, including physical activity, influence the immune system. It is well known that physical activity can influence neuropeptide levels both in the central nervous system as well as in peripheral blood. The consensus among exercise immunologists is that moderate exercise enhances immune function and may reduce the incidence of infections, while long-term exhaustive endurance exercise results in immunosuppression and an increased susceptibility to infections (42).The reported changes of immune function in response to exercise have been suggested to be partly regulated by the activation of different neuropeptides. The most common neuropeptides mentioned in this context are the endogenous opioids activated by long-term aerobic exercise. Other neuropeptides, such as serotonin, substance P and vasoactive intestinal peptide (VIP), could also be of interest, as well as several neuroendocrine hormones, including growth hormone (GH), prolactin, and adrenocorticotrophin (ACTH) (43). The identification of receptors for neuropeptides and steroid hormones on cells of the immune system has created a new dimension in this endocrine–immune interaction. It has also been shown that immune cells are capable of producing neuropeptides, creating a bidirectional link between the nervous and immune systems (43).

3. INTRODUCTION TO EXERCISE TESTING The maximal oxygen consumption (VO2peak )∗ attained during a graded maximal exercise to volitional exhaustion is considered the single best indicator of aerobic exercise capacity by the World Health Organization (44). VO2peak reflects the maximal oxygen flux through the mitochondria of the exercising muscle. Based on the Fick principle, VO2peak is the product of cardiac output (heart rate x stroke volume) and the mixed arterio-venous oxygen difference (45). Thus VO2peak is dependent on cardiac function and the ability of the muscles to extract (utilize) oxygen from the circulation. However, measurement of VO2peak is not always possible in the clinical setting, because of the need for an expensive respiratory gas analysis system. Other methods of estimating VO2peak include submaximal tests (see Section 3.3) that can be used as viable alternatives to measure change in aerobic capacity with exercise. ∗

Maximal exercise tests in patients are usually terminated when the subject despite strong verbal encouragement from the experimenters, is unwilling or unable to continue. The appropriate term to use is therefore peak oxygen consumption (VO2peak ), which represents the highest oxygen uptake during an exercise test to volitional exhaustion.


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3.1. Energy Pathways Broadly speaking, two general exercise forms can be distinguished: short-term intensive bouts of exercise or anaerobic exercise capacity, and the long-term endurance type of activity or aerobic exercise capacity. All physical activity involves muscular contractions powered by energy. The currency of energy expenditure is adenosine triphosphate (ATP). The phosphorolysis of ATP to adenosine diphosphate (ADP) and inorganic phosphate releases the energy. The amount of ATP stored in muscle at any time is small and must be resynthesized continuously if exercise continues for more than a few seconds. The synthesis of ATP requires a substrate for energy. Carbohydrate and fat act as substrates under usual conditions and in the presence of ADP, adenosine monophosphate (AMP), creatine phosphate (CP), and inorganic phosphate. Synthesis takes place by different aerobic or anaerobic enzyme pathways. Only carbohydrates (glycogen) use the anaerobic pathway for the generation of energy, whereas glycogen, fat, and protein can be used aerobically. These aerobic and anaerobic ATP-production pathways in humans are displayed in Table 1.

3.2. Maximal Exercise Testing in Pain Patients Not much is known about the validity of exercise testing in patients with chronic pain, given that historically, exercise testing was mostly done in athletes, healthy subjects or subjects with cardiac and pulmonary conditions. One study (46) compared treadmill, bicycle, and upper extremity ergometry (UBE) exercise testing in a small (N = 30) sample of patients with chronic low back pain (CLBP). Respiratory gas exchange analysis was used to determine oxygen uptake and a three-lead electrocardiogram Table 1 Pathways for Energy Production in the Muscle Oxidative Phosphorylation: Glycogenn + 6O2 + 37Pi + 37 ADP → glycogenn−1 + 6 CO2 + 42 H2 O + 37 ATP Glucose + 6 O2 + 36 Pi + 36 ATP →6 CO2 + 42 H2 O + 36 ATP C16 H32 O2 (Fatty acids; palmitate) + 23 O2 + 129 (ATP + Pi) → 129 ATP + 16 CO2 + 145 H2 O Glycolysis: Glycogenn + 3 Pi + 3ATP →glycogenn−1 + 2 lactate + 2 H2 O + 2 ATP Glucose + 2ATP + 2 NAD+ + e− + H+ →Pyruvate + NADH + H+ Creatine Kinase reaction ADP + PCr + H+ ↔ ATP + Cr Adenylate kinase / AMP deaminase reactions 2ADP ↔ ATP + AMP / AMP + H2 O → NH3 + IMP + 2 Pi ATP hydrolysis reaction ATP → ADP + Pi + Energy O2 = oxygen, Pi = inorganic phosphate; ADP= adenosine triphosphate; CO2 = carbondioxide; H2 O = water; ATP = adenosinetriphosphate; PCr = creatine phosphate; H+ = hydrogen; Cr = creatine; AMP = adenosinemonophosphate; NH3 = ammonia; IMP = inosinemonophosphate; NAD+ = Nicotinamide adenine dinucleotide; e– = electron. Table modified after reference (3).

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(ECG) was used to determine heart rates at each minute of testing. Subjects were encouraged to “do as much as you can.” The tests that were used were the modified Bruce treadmill test, the Åstrand-Ryhming bicycle test and a UBE test in which the workload was started at 20 W and increased by 10 W every 3 min. Patients were asked to maintain a cycling rate of 60 rotations per minute (rpm) throughout the UBE test. Seventy percent of the patients with CLBP reported that arm fatigue was the reason to stop UBE testing, and leg fatigue was the major reason (56.7%) for the patients to stop bicycle testing. Peripheral fatigue may play an important role in the aerobic testing of patients with CLBP. This peripheral fatigue may be a reflection of a loss of muscle endurance as the result of prolonged inactivity. Despite this, the testing response for patients with CLBP was remarkably similar to that of normal subjects. Peak and predicted VO2peak showed gender differences consistent with published results for normal subjects. Significantly higher heart rates, VO2peak and predicted VO2peak mL/kg/min were achieved by the modified Bruce treadmill test in this sample of patients than with the bicycle or UBE tests, despite pain.

3.3. Submaximal Exercise Testing in Pain Patients It is important to understand that the most accurate way to measure VO2peak in a single individual is through direct measurement of maximal oxygen uptake. In a chronic pain population this is neither practical nor feasible in a clinical setting. A variety of (submaximal) tests have been developed estimating aerobic capacity when direct measurement is not possible [for review see reference (47)]. These tests usually involve running/walking for a given time or distance, such as the 12-min walk/run test (48), the shuttle test (49), various step tests (50,51) and the 2-km walk test (52). Longer distances and shorter test times are associated with higher levels of aerobic fitness. Other tests estimate VO2peak by submaximal testing and extrapolation to maximal heart rate by treadmill walking or bicycling against a predetermined load with measurement of heart rates (53,54). These tests were mostly developed for testing aerobic fitness in healthy people and were validated by comparing actual measured VO2peak to predicted VO2 or to the test performance. The validity of a number of these tests was established for patients with cardiac or pulmonary problems (55,56), but little has been done to validate these tests in patients with chronic pain. Modified versions exist of several exercise tests to accommodate sicker patients (57–59), but little is known about the validity of these tests in patients with pain. 3.3.1. Walking Tests Walking tests have become more popular in clinical settings. Since the introduction of the Balke 15-min walking test in 1963 (60), many investigators have used such tests in research and clinical practice. Cooper originally developed a 12-min run test (61). In the years after Cooper’s publication, a variety of modifications to this test have been made. One of these modifications for patients is the 6-min walk test (62). The 6-min walk test is a simple, relatively quick, inexpensive and safe test (63). The 6-min walk test is used for different purposes. It has been used as a replacement of the symptom-limited cardiopulmonary exercise test for diagnostic purposes (64). Other studies have used it to establish a prognosis for outcome, or used it as an objective measure to evaluate the efficacy of therapy (65,66).


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Solway et al. (67) recommend the 6-min walk test as the test of choice when using a functional walk test for clinical or research purposes. Most of the research with this test has been done in groups of patients with cardiac or chronic obstructive pulmonary disease (63), but there is the suggestion in the literature that the 6-minute walk test might also be a proper instrument to determine the functional capacity of patients with rheumatic disease (68). The 6-min walk test is also gaining in acceptance as a functional test in the assessment of patients with chronic pain (see Table 2). Mannercorpi et al. (69) report excellent intra-rater reliability for the 6-min walk test in patients with fibromyalgia and showed that the 6-min walk test is sensitive enough to detect differences between patients with fibromyalgia and healthy controls. Two studies have examined the relationship between the 6-min walk test and VO2peak in patients with chronic pain. Correlations ranged from r = 0.328 (N = 28) before to r = 0.420 (N = 20) after an exercise program for fibromyalgia patients (70). The Pearson correlation in patients with CLBP (N = 30) of the 6-min walk test was r = 0.46 (p = 0.02) with treadmill VO2peak (mL/kg/min) (71).The correlation of the 6-min walk test was r = 0.62 (p = 0.001), with bicycle VO2peak (mL/kg/min); however, correlations with predicted VO2peak were poor and non-significant. It thus appears that in patients with chronic pain, the 6-min walk test has little relationship with aerobic fitness but has relevance as a physical performance test. This is further underscored by significant correlations of the 6-min walk distance with the Fibromyalgia Impact Questionnaire total (r = -0.494, p < 0.01) and physical impairment (r = –0.403, p