Endogenous Modulation of Pain The Role of Exercise, Stress and Cognitions in Humans

University of Southern Denmark
Endogenous Modulation of Pain

The Role of Exercise, Stress and Cognitions in Humans
Vaegter, Henrik Bjarke; Fehrmann, Elisabeth; Gajsar, Hannah; Kreddig, Nina
Published in:
The Clinical Journal of Pain
DOI:
10.1097/AJP.0000000000000788
Publication date:
2020
Document version:
Accepted manuscript
Citation for pulished version (APA):

Vaegter, H. B., Fehrmann, E., Gajsar, H., & Kreddig, N. (2020). Endogenous Modulation of Pain: The Role of
Exercise, Stress and Cognitions in Humans. The Clinical Journal of Pain, 36(3), 150-161.
https://doi.org/10.1097/AJP.0000000000000788
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The Clinical Journal of Pain Publish Ahead of Print
DOI:10.1097/AJP.0000000000000788
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Endogenous modulation of pain: the role of exercise, stress and cognitions in humans
Special Topical Series in Clinical Journal of Pain: Manuscript 2
Henrik Bjarke Vaegtera,b, Elisabeth Fehrmannc,d, Hannah Gajsare, Nina Kreddige

a
Pain Research Group, Pain Center, Odense University Hospital, Odense, Denmark
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b
Department of Clinical Research, Faculty of Health Sciences, University of Southern Denmark
c
Karl Landsteiner Institute for Outpatient Rehabilitation Research, Austria
d
Department of Psychology, Karl Landsteiner University of Health Sciences, Austria
e
Department of Medical Psychology and Medical Sociology, Faculty of Medicine, Ruhr University
Bochum, Bochum, Germany
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Special Topical Series in Clinical Journal of Pain: based on Approach to Physical Activity in
Pain: From Theory to the Lab, From Clinic to the Patient – Official Satellite of the World Congress
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on Pain, Sept. 11, 2018, Boston, USA

Conflicts of Interest and Source of Funding: There are no actual or potential conflicts of interest
for any of the authors.
Corresponding author:
Henrik Bjarke Vægter, PhD
Pain Research Group, Pain Center, University Hospital Odense, Denmark
Department of Clinical Research, Faculty of Health Sciences, University of Southern Denmark
Heden 7-9, Indgang 200
DK – 5000 Odense C
Tel.: +45 65413869; fax: +45 65415064.
E-mail address: henrik.bjarke.vaegter@rsyd.dk
Copyright © 2019 Wolters Kluwer Health, Inc. Unauthorized reproduction of the article is prohibited.
Abstract
Pain is a complex and highly subjective phenomenon that can be modulated by several factors.
Based on results from experimental and clinical studies, the existence of endogenous pain
modulatory mechanisms that can increase or diminish the experience of pain is now accepted. In
this narrative review, the pain modulatory effects of exercise, stress, and cognitions in humans are
assessed. Experimental studies on the effect of exercise have revealed that pain-free subjects show a
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hypoalgesic response after exercise. However, in some patients with chronic pain this response is
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reduced or even hyperalgesic in nature. These findings will be discussed from a mechanistic point
of view. Stress is another modulator of the pain experience. Although acute stress may induce
hypoalgesia, ongoing clinical stress has detrimental effects on pain in many patients with chronic
pain conditions, which have implications for the understanding, assessment and treatment of stress
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in patients with pain. Finally, cognitive strategies play differing roles in pain inhibition. Two
intuitive strategies, thought suppression and focused distraction, will be reviewed regarding
experimental, acute, and chronic pain. Based on current knowledge on the role of exercise, stress,
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and cognitive pain control strategies on modulation of pain, implications for treatment will be
discussed.
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Keywords: endogenous pain modulation, exercise-induced hypoalgesia, stress, cognition, pain
sensitivity, thought suppression, focused distraction
1. Endogenous modulation of pain
Pain is defined by the International Association for the Study of Pain (IASP) as ‘an unpleasant
sensory and emotional experience associated with actual or potential tissue damage, or described
in terms of such damage’ [1]. As suggested by this definition, several factors can impact on the
experience of pain, and modulation of pain is now a well-established phenomenon in humans. This
phenomenon has for instance been observed during combat in wounded soldiers reporting little or
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no pain [2]. Similarly, there are anecdotes about absence of pain associated with injuries sustained
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during running [3]. Based on the results from several experimental and clinical studies, the
existence of endogenous pain modulatory mechanisms that can increase or diminish the experience
of pain is now generally accepted.
1.1 Role of exercise, stress and cognitions in modulation of pain

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Current evidence support that modifiable lifestyle factors such as exercise, stress and specific pain-
related cognitive strategies can influence prognosis and are thus important components in the
understanding, treatment and rehabilitation of many patients with chronic musculoskeletal pain
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conditions. Some of these factors may even interact such that exercising positively moderates the
negative effects of stress, and use of different cognitive strategies may be more or less helpful in
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coping with stress. In addition, exercise, stress and cognitive strategies are also directly capable of
modulating the experience of pain. In this narrative review we describe the evidence from
experimental and clinical studies on the pain modulatory effects of exercise, ongoing stress and
different cognitive strategies in pain-free subjects and in subjects with chronic pain conditions.
2. Exercise-based modulation of pain in humans
Exercise can reduce the pain sensitivity in pain-free subjects, also known as exercise-induced
hypoalgesia (EIH). However, the influence of exercise on the pain sensitivity in subjects with
different chronic pain conditions is still controversial, since both hyperalgesia [4] and hypoalgesia
[5] have been reported following exercise.
This section will begin with an overview of previous studies investigating acute EIH
in pain-free subjects with a specific focus on how different exercise parameters, including type,
intensity and duration, as well as the methodology used to assess the pain sensitivity, including
modality and assessment site, influence the hypoalgesic response after exercise. Secondly, even
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though the mechanisms underlying EIH are not entirely clear, potential mechanisms involved in the
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EIH phenomenon in humans will be discussed. Thirdly, several studies have indicated that the
response to acute exercise may be different in subjects with chronic pain and these findings will be
discussed from a mechanistic point of view and possible implications for rehabilitation will be
addressed. Finally, recent findings on the reliability of the EIH response after different exercise
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conditions will be presented to facilitate the use of reliable exercise protocols in future EIH studies.
2.1 Exercise-induced hypoalgesia in pain-free subjects
The EIH phenomenon was first described by Black et al. in 1979 [6], when the effect of a 40 min
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run on pressure pain threshold (PPT) and pressure pain tolerance induced by a tourniquet on the arm
was investigated. Across 15 different running sessions, consistently higher PPT and pain tolerance
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were demonstrated after running compared with before running. Since the first investigation by
Black et al., the number of studies on EIH has increased dramatically, likely reflecting the
increasingly recognized role of exercise in the management of several pain conditions.
From a methodological point of view, the results from the earliest EIH studies have
been challenged by the lack of an adequate control group. Padawer and Levine [7] illustrated that
hypoalgesia after exercise was related to the effect of pain sensitivity testing itself and not exercise
per se, by showing that hypoalgesia after exercise was only present when subjects had also been
exposed to the pain sensitivity assessment prior to exercise. However, more recent EIH studies
including adequate control groups have repeatedly shown that the hypoalgesic effect after exercise
is significantly larger than the effect of repeated pain testing itself [8-10]. EIH is also evident from
the latest meta-analysis from 2012 [11] where Naugle and colleagues concluded that aerobic,
isometric and resistance exercise consistently produced an increase in pain thresholds in pain-free
subjects. It is also worth noting that the effect sizes were related to how pain sensitivity was
assessed. The largest hypoalgesic response was consistently found when PPT was used as test
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stimulus, indicating larger hypoalgesic effects on muscle-skeletal structures compared with the skin,
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which may not be subject to as strong pain inhibition as input from deep structure nociceptors [12].
In addition to peripherally derived measures of pain sensitivity (i.e. the pain threshold), exercise
also reduces more spinal and supraspinal mechanisms of pain. Vaegter and colleagues showed a
significantly larger increase in pressure pain tolerance compared with the increase in pressure and
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heat pain thresholds after a 3 min submaximal isometric knee extension exercise [13] and after a 6
min walking condition [14], suggesting that coping with pain may be influenced to an even larger
extent. Moreover, the degree of temporal summation of pain to repeated pressure and heat
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stimulations, which is suggested as a measure of excitability of the central nervous system, is
reduced after one short session of isometric exercise [15, 16]. The duration of the EIH response is
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short-lasting, but the exact duration is somewhat inconsistent with previous studies showing
hypoalgesia from 5 min after exercise [17] to 30 min after exercise [18].
In addition to the modality of the test stimulus and the aspects of pain sensitivity
assessed, several other factors may influence the magnitude of the EIH response. These include the
intensity and duration of the exercise protocol used, whether pain sensitivity is assessed at
exercising or non-exercising muscles, as well as participant-related factors.
For aerobic exercises like bicycling and running, larger EIH responses have
consistently been shown after moderate or high intensity exercises compared with low intensity
exercises both at exercising leg muscles and non-exercising arm and shoulder muscles [17, 19].
Exercise duration seems to be less important for the EIH response after aerobic exercise [19]. For
isometric exercises, the effects of exercise intensity and duration are less clear. A significant
increase in PPT was found in 80 healthy subjects after submaximal isometric knee extensions [19];
however, the magnitude of the hypoalgesic response was not different between low intensity and
high intensity contractions or between contractions of 90 s or 180 s durations. Similar findings were
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demonstrated after isometric hand grip exercises for 1, 3 and 5 mins [20]. In contrast, PPT was
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increased only after low intensity isometric contractions held to exhaustion, but not when the
contraction was held for only 2 min [21], suggesting that duration may be important for very low
intensity isometric contractions.
EIH is often demonstrated at exercising as well as non-exercising muscles, but

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regardless of exercise type, hypoalgesia is consistently more pronounced when assessed at the
exercising muscles as demonstrated by recent studies investigating EIH after bicycling [9, 22] and
isometric wall squat exercise [10].

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Hypoalgesia after exercise may also be influenced by participant-related factors
although findings are somewhat conflicting. Recently, reduced EIH after isometric exercises were
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observed in older adults compared with younger adults [23, 24]. Nevertheless, no significant
difference in the EIH response after isometric exercise between younger and older healthy subjects
has also been demonstrated [25]. Cognitive or psychosocial factors may also influence the
magnitude of EIH. Higher expectations about EIH elicited higher EIH responses [26], whereas
expectations that exercise increases the pain sensitivity can completely abolish the EIH response
[27]. In addition a negative mood state reduced the EIH response [28], but the EIH response was
not related to the degree of fear of movement [29].
Previous studies investigating the role of habitual physical activity and the EIH
response have quite consistently shown that EIH did not differ between different levels of activity
groups [8, 30, 31] indicating that also inactive subjects may experience hypoalgesia after exercise.
2.2 Potential mechanisms of EIH in humans
Several mechanisms potentially responsible for EIH at exercising and non-exercising body sites
have been investigated in humans. Release of endogenous opioids has been hypothesized as a
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primary mechanism responsible for widespread EIH. Exercise activates peripheral and central
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opioidergic systems [32, 33]. The concentration of beta-endorphin in plasma is 5 times higher after
running, and the activity in pain modulatory opioid-related areas in the brain like the PAG is
significantly altered, however the association between this opioid release and PAG activation and
the EIH response is rather weak [34]. First of all, the rise in endorphin concentration in plasma and
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the activation pattern of opioidergic areas in the brain is often observed up to one hour after
exercise [34], which is not the case for EIH that is demonstrated only shortly after exercise [17, 19].
Secondly, several studies investigating the effect of naltrexone, an opioid receptor antagonist on the
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EIH response have not shown consistent effects on the EIH response [6, 32, 35].
Several non-opioidergic mechanisms have also been investigated, including the role of
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proprioceptive input from exercising muscles, release of endocannabinoids, and changes in blood
pressure. The Gate Control Theory [36], which states that limb movement during exercise may
excite large diameter afferent nerve fibers inhibiting nociceptive processes in the dorsal horn, has
been hypothesized as a mechanism responsible for the more localized hypoalgesia in response to
exercise. Local hypoalgesia was observed after 30 minutes of passive knee joint movement by an
electronic bicycle device [37], however, if proprioceptive inputs from exercising body sites were a
main mechanism for the localized EIH response, a significant hypoalgesic response would also be
expected in exercising muscles after performing 20 minutes of low intensity bicycling, which is
often not the case [17, 19]. Aerobic and isometric exercises activate the endocannabinoid system in
an intensity-dependent manner, suggesting a potential role in EIH [38]. In support of this
hypothesis, a previous study showed a small but significant association between the increase in
endocannabinoid-related lipid analogs and the reduction in temporal summation of heat pain after a
3 minutes submaximal isometric exercise; however, there was no significant association between
the increase in endocannabinoid-related lipid analogs and the increase in PPT following exercise,
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questioning the direct relationship with EIH [39]. Exercise causes changes in the cardiovascular
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response, which have been suggested as a possible mechanism due to baroreceptor activation [40].
Even so, there is no consistent dose-response correlation between changes in blood pressure and
pain perception following isometric exercise [20, 41]. However, similar for most of the suggested
opioid and non-opioid substances that can influence nociceptor sensitivity, is the increase in these
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substances in the blood during exercise. Jones and colleagues recently showed that blocking the
blood flow to a non-exercising body site reduced the EIH response in the body site where blood
flow was blocked compared with the EIH response in non-blocked body sites after 5 min intense
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bicycling [42], suggesting that systemic peripheral factors may contribute to the widespread EIH
effects.
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The „pain inhibits pain‟ phenomenon has also been suggested as a potential
mechanism responsible for the widespread hypoalgesic response after exercise. In humans, the pain
inhibits pain phenomenon is often assessed by different paradigms of conditioned pain modulation
(CPM) [43]. CPM is based on mechanisms originally investigated in rats by Le Bars et al., [44, 45].
The painful CPM paradigm, which has also been studied extensively in pain-free subjects [46, 47],
shows similar widespread hypoalgesic manifestations as exercise [8, 19]. Moreover, exercise that
produces hypoalgesia is often perceived as painful with peak pain intensity ratings around 5-6 on a
0-10 numerical rating scale [9, 10]. In addition, several studies have shown a relationship between
the CPM response and the EIH response. Ellingson and colleagues showed a larger hypoalgesic
response after a painful exercise compared with a non-painful exercise [48], and several studies
have demonstrated a significant positive association between the CPM response and the EIH
response, indicating that subjects who have a larger CPM response also have a larger EIH response
[25, 49]. Besides, CPM elicited prior to exercise attenuates the subsequent EIH response [49], and
EIH elicited prior to a cold pressor test attenuates the subsequent CPM response in subjects who
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show a systemic EIH response [50], indicating exhaustion of the pain inhibitory systems, and
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possible shared mechanisms between EIH and CPM. Finally, Fingleton and colleagues
demonstrated that PPT increased after aerobic and isometric exercises in subjects with knee
osteoarthritis who also had a normal CPM response, but not in subjects with an impaired CPM
response, suggesting that patients with impaired CPM have less hypoalgesia after exercise [51].
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Although still speculative, EIH may also be conceived as a form of „embodied
distraction‟ through e.g. focused attention, which is important in cognitive pain inhibition, towards
other non-painful somatic sensations (e.g. increased breathing, heart rate and sweating) induced by
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exercise [52], however this needs further investigation.
2.3 Response to acute exercise in subjects with chronic pain

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Reduced EIH responses or even hyperalgesia after exercise have been demonstrated in some
patients with chronic pain. Hyperalgesia after both aerobic and isometric exercises has been
demonstrated in subjects with fibromyalgia [53-56], painful diabetic neuropathy [57], veterans with
chronic musculoskeletal pain [4], chronic fatigue syndrome [58-60], and chronic whiplash-
associated disorder [61]. Subjects with chronic pain and high widespread pain sensitivity showed
reduced EIH after isometric and aerobic exercises compared with subjects with chronic pain and
low pain sensitivity [62]. Additionally, temporal summation of pressure pain was further increased
after aerobic bicycling exercise [62], indicating a role for facilitated central pain mechanisms in the
pain flare-up after exercise commonly observed in clinical practice. However, EIH responses were
elicited in patients with fibromyalgia after aerobic exercise performed at moderate intensity [5], and
after isometric contractions performed at low intensity [63], suggesting a different or even opposite
dose-response relationship between exercise intensity and hypoalgesia in subjects with chronic pain
compared with pain-free subjects. Interestingly, more intense aerobic exercise induced hypoalgesia
in subjects with more localized back pain conditions [59, 64]. Hypoalgesia after isometric exercise
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was also demonstrated in patients with shoulder myalgia when the exercise was performed by a
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non-painful leg muscle [56], however, no hypoalgesic response was found when exercise was
performed by the painful shoulder muscle, indicating that exercising non-painful muscles can
induce hypoalgesia in subjects with more localized chronic pain. Similar findings have also recently
been demonstrated in subjects with whiplash-associated disorder [65].

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2.4 Reliability of the acute EIH response
In addition to the discriminative value of EIH between pain-free subjects and different chronic pain
manifestations, small studies have suggested that the EIH response may be related to treatment
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outcome [66], indicating some clinical utility. However, to improve the clinical applicability and
interpretation of the EIH response, test-retest reliability of the EIH phenomenon needs to be
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established. Recently, the between-sessions test-retest reliabilities of EIH after 1) 3 minutes
isometric wall squat [10], 2) 20 minutes bicycling in which the intensity was based on subjective
ratings of perceived exertion [9], 3) 20 minutes of bicycling in which the intensity was based on
heart rate [67], and 4) 20 minutes bicycling in which the exercise intensity was based on objective
blood lactate measurements [22] were investigated. Across exercise protocols, some subjects
consistently showed hypoalgesia after exercise in both sessions, some subjects consistently showed
hyperalgesia in both sessions and some subjects had different responses in the two sessions. In
general, the between-subjects reliability based on ICC values, which is a measure of how well the
test differentiates the EIH responses between subjects across sessions, were fair to moderate for the
three exercise protocols. The within-subjects reliability, which is a measure of the agreement
between the EIH responses within individuals across sessions, showed better agreement for
bicycling based on objective lactate threshold compared with subjective ratings of perceived
exertion or heart rate, indicating that strict standardization procedures in relation to the exercise
intensity might improve the within-subject reliability of the EIH response.
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2.5 Summary
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Aerobic and isometric exercises reduce pain sensitivity at exercising and non-exercising muscles in
pain-free subjects with a larger hypoalgesic response at the exercising muscles, suggesting that
responsible mechanisms include local or segmental pain inhibitory mechanisms in concert with
activation of systemic pain inhibitory mechanisms with widespread anti-nociceptive effects, likely
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related to the pain inhibits pain phenomenon, and occurring at both peripheral, spinal, and
supraspinal levels. EIH after aerobic exercise is related to exercise intensity, whereas EIH after low
intensity isometric exercise may be related to exercise duration. In subjects with more localized
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chronic pain conditions, exercising non-painful muscles can reduce pain sensitivity at both painful
and non-painful body sites, whereas exercising painful muscles does not produce acute hypoalgesia.
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In patients with widespread pain, high pain sensitivity or impaired CPM, both aerobic and isometric
exercises may cause a widespread increase in the pain sensitivity.
2.6 Potential treatment implications:
Based on the current understanding of the pain modulatory effect of exercise, specific
recommendations for clinical practice may be premature. However, from a mechanistic point of
view, painful exercises appear to have larger hypoalgesic effects than non-painful exercises,
especially in pain-free subjects who are capable of activating descending inhibitory pain
mechanisms. In addition, hypoalgesic responses are mostly present when exercises are performed in
non-painful body areas, which may be a challenge in subjects with more widespread pain
distributions. Moreover, expectations about a hypoalgesic response from exercise may influence the
response, which indicate that the patient‟s preference and expectations about exercise should be
assessed prior to exercise prescription. Knowledge on how the hypoalgesic response after exercise
is influenced by other factors like use of analgesics [68] and stress [69], which may interact with
pain inhibitory systems and are common in chronic pain conditions is still very limited in humans.
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3. Stress-induced modulation of pain
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Stress can have a profound effect on the experience of pain. Although acute stress can induce
hypoalgesia (see [70] for review), stress often increases the experience of pain in many patients
with chronic musculoskeletal pain conditions. This section will begin with a definition of stress
followed by an overview of the influence of stress on pain in subjects with back pain, and its role in
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pain chronification. Moreover, methods to assess stress and implications for treatment aimed at
stress reduction will be discussed.
3.1 Definition and occurrence of stress

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Selye, known as the „father of stress‟ defined stress in 1936 as „a non-specific response of the body
to any demand‟ [71]. Selye‟s definition allows others to understand that stress is not merely a
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reaction to something bad, but a reaction to a change in situation. However, with the cognitive-
transactional model, Lazarus and Folkman highlighted that only the appraisal of a situation or a
stimulus as something threatening evokes a stress response, which varies by individuals [72].
Therefore, the same fear-based stressor that provokes a stress response in one individual may be
indifferent for another [72, 73].
In a two-way appraisal process, a person first evaluates whether a situation is
dangerous, positive, or neutral (mostly on an unconscious level). Second, the person assesses his or
her internal or external resources (competencies or social support etc.) to cope with the situation.
Only if a situation is assessed as dangerous and the resources are considered insufficient, does the
person feel stressed. A stressor may be a psychological or physical threat to safety, well-being, or
status that exceeds the perceived resources, an inconsistency between expectations and reality, or an
unpredictable change in environment [73]. Stress affects the person as a whole, including physical,
mental, or emotional strain or tension. The bodily adaption processes contain an ennervation of the
sympathicus (fight and flight-reaction), the activation of the hypothalamic–pituitary–adrenal axis
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(HPA axis), the acceleration of heart rate, blood pressure and breathing, and an increased secretion
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of catecholamines (norepinephrine, epinephrine and serotonin) as well as cortisol and
corticosteroids [73].
3.2 Stress and back pain
The World Health Organization claims that stress is the „Health Epidemic of the 21st century“ and
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is responsible for devastating health problems and exorbitant costs [74]. Ongoing stress and intense
stress reactions due to critical life events (hyperstress) are two of the main causes and consequences
of health problems and illnesses, such as cardiovascular [75], and pain diseases [76].
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Regarding pain, pain-related and non-pain-related stressors need to be distinguished.
Importantly, the perception of chronic pain itself could be a potential stressor, and the appraisal of
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pain as something frightening or threatening (e.g. catastrophizing) may evoke an exaggerated
physiological stress response. Whereas non-pain-related stress may distract attention from a
concurrent painful stimulus, pain itself as a stressor may intensify its experience [73, 77]. Persistent
pain can also lead to stressful consequences and an increased exposure to stressful events, such as
job losses, marital disruption, and medical procedures and surgeries [78, 79].
Pain-related and non-pain-related stressors may likely influence the perception of
pain, interfere with treatment, and worsen prognosis [80]. Risk factors for chronification of pain
include psychosocial components, such as psychosocial stressors (e.g. work-related or family
stressors), fear, depressed mood, fear-avoidance and catastrophizing behaviors, passive coping-
strategies or sleeping disorders, which are often interrelated and influence each other [81]. Besides,
endurance behavior is known as a risk factor for pain chronicity, disability, and reduced quality of
life [82, 83]. Exaggerated psychosocial responses to pain are maladaptive and likely to intensify the
pain experience and hamper recovery [76, 84, 85]. On the other hand, exaggerated responses to
non-pain-related stressors may initiate, exacerbate, or prolong the pain experience. However, so far
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less emphasis has been placed on the role of non-pain-related stressors compared to pain-related
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stressors.
Back pain is associated with non-pain related social- and family- stressors [86-89],
and work-related stressors [90-94]. Contextual stressors, family stress and general stressors were
found to provoke negative feelings and an increase of pain in patients with chronic low back pain
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[89]. The general self-reported stress and mental suffering of 15 chronic low back pain patients
compared to 15 healthy controls was significantly higher, and specific familiar problems, such as a
small family-coherence, low autonomy, disorganization, and chronic conflicts were associated with
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back pain [86]. Furthermore, social stressors as well as social problems, sometimes resulting in
isolation, were found to be related to low back pain [87, 88].

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Work-related stressors may also be associated with the occurrence of low back pain
[90-94]. A strong association between low back pain and job stressors, such as poor social support
at work, and low job-satisfaction was shown [92], as well as a strong correlation of back pain with
high working demands, followed by dissatisfaction with the job [93]. However, in another review
back pain could not be clearly associated with job stressors [95].
Increasing evidence also shows that psychological stress or trauma is associated with
persistent pain, and makes the probability of its occurrence higher. Results of meta-analyses support
the evidence that distress and mental suffering [96-98], as well as posttraumatic stress disorders [79,
99] are related to chronic low back pain. Childhood adversities (e.g., family conflict, sexual abuse,
physical abuse, divorce) and conflict and victimization in adulthood are enhanced in people with
various pain conditions, including pelvic pain [100], and fibromyalgia [101]. Furthermore, stress-
intolerance, increased baseline-tension, and pain hypersensitivity syndromes may result from a
chronically overburdened stress response system [102].
3.3 A neurophysiological view on stress and pain
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From a neurophysiological perspective, there is evidence that pain perception and fear involve
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complex, partially overlapping neuronal networks that in principle can be modulated at all synaptic
relay stations involved [103]. Brain areas associated with fear, such as the amygdala, and the medial
and cingulate prefrontal cortices, are also relevant for the emotional/aversive and cognitive aspects
of pain [103]. Pain sensitivity is also increased when people expect pain, and this is accompanied by
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increased neural activity in the anterior cingulate cortex [104, 105]. Currently, emerging concepts
propose that basic neuronal mechanisms of memory formation are relevant for the pathological
forms of chronic pain or chronic fear. Long-term plasticity (LTP) has been characterized most
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extensively at C-fibers synapses at cortical synapses including the anterior cingulate cortex [106], in
the superficial spinal dorsal horn [107], and the amygdala [108]. LTP can thus affect and mutually
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interfere with both fear and pain at some of these relays. LTP at multiple sites in serially connected
pathways (e.g. in spinal cord, and in the anterior cingulate cortex) can function as a “cascade
amplifier” boosting signal amplification at each relay station [103]. Furthermore, memory traces of
excessive fear, as in fear- and anxiety-related disorders, may be linked to a specific aversive
experience in the past and may trigger/facilitate the chronification process of pain [103, 109].
Studies investigating the HPA-axis and involved cortisolism in chronic pain patients
showed that chronic stress-induced changes in cortisolism are linked to several pain diseases, and to
a new onset of musculoskeletal pain [110, 111]. Whereas several studies have reported a
hypocortisolism [110-113] in chronic pain conditions, others reported a hypercortisolism, and
temporal aspects of cortisol dysfunction likely connected to the magnitude and duration of
perceived threats [114, 115]. Cortisol dysfunction itself may result in unmodulated inflammation
and reactivation of the stress response, which may lead to a cycle of inflammation, depression, and
pain [73].
3.4 Stress in subgroups of back pain patients
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As mentioned above, fear-avoidance pain behavior is one well researched risk factor for the
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chronification of pain [76, 84, 85]. The Avoidance-Endurance Model (AEM) defines three
maladaptive pain response patterns, fear-avoidance, distress-endurance and eustress-endurance.
Whereas patients with fear-avoidance behavior tend to employ catastrophizing thoughts, increased
fear of pain and avoidance of specific movements and activity, patients with endurance behavior
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tend to suppress thoughts on pain or distract themselves from pain, which allows them to maintain
their activities despite of pain [82]. Nevertheless, this thought suppression can result in an increase
of thoughts on pain due to a so-called rebound effect, which in turn leads to even more negative
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feelings and feelings of help- and hopelessness especially in patients with distress-endurance
behavior. Patients with eustress-endurance behavior patterns, on the other hand, tend to distract
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themselves from pain and are in a more positive mood despite pain. In comparison to these three
maladaptive pain response patterns, patients with adaptive response patterns are able to deal with
pain in a flexible way, listen to their body and react in an adaptive way neither avoiding nor
persisting too much, which decreases the probability for pain persistence. The pain response
patterns described in the AEM play a role in the association of stress and pain, and include
cognitive strategies with which pain sufferers try to inhibit pain. Therefore, the model is relevant
both in this part of the review, concerning stress, as well as the following part, concerning cognitive
pain inhibition strategies, and will be discussed here as well as in paragraph 4.3.
There are some studies investigating non-pain related stressors in subgroups of
patients with maladaptive pain response patterns. Regarding work-related stress, fear-avoidance
behavior has been associated with work absences and disabilities at work [116, 117]. Studies
concerning endurance behavior found over-activity to be correlated with work-related stress. For
example, in a qualitative study with low back pain patients all of the patients with over-active
behavior reported that they were very active and ambitious even before the pain first occurred, as
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they wanted to avoid to be seen as lazy or useless [118]. In another study, Andrews et al. [119]
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examined over-activity in relation to the attachment styles in adults and found that patients with
over-active behavior showed significantly more anxious-ambivalent or anxious-avoidant attachment
styles. Since other studies found evidence that an anxious-ambivalent and an anxious-avoidant
attachment style is associated with over-commitment at work [120], perfectionism [121, 122], and
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burn-out [123], the authors concluded that overactive patients possess more ambition at work
resulting in a higher work load [119].
Pain response patterns in chronic low back pain patients also influence stress levels
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measured by cortisol. Whereas chronic low back pain patients with endurance behavior showed
higher cortisol levels at the cortisol awakening reaction compared to the other subgroups, patients
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with fear-avoidance behavior showed lower levels of cortisol compared to the other subgroups
[113].
In an recent study conducted by one of the authors, 137 low back pain patients
subgrouped based on the AEM were interviewed on potential stressors and resources in different
areas of life (work, familiy/partnership, health, individual resources) [124]. Patients with fear-
avoidance reported a higher amount of mental suffering compared to the adaptive responders. A
large part of the patients reported work-related stress and family stressors, but there were not any
subgroup-specific differences within the amount of stress. However, the adaptive responders, who
were less at risk for pain chronicity, reported a higher amount of resources compared to the other
subgroups. According to the definition of Lazarus and Folkman [72], stress occurs if one thinks
there are not enough resources to cope with a stressful situation, and the adaptive responders were
more able to cope with stressful situations through the awareness of their resources.
3.5 Therapeutic consequences
Translated into practice, the literature states that interventions that reduce stress or increase
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competences to cope with stress could help patients with pain. Mindfulness-based interventions as
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well as cognitive-behavioral methods, and exercises have been proposed for stress and pain
management, and improvements are thought to be mediated through reappraisal of inappropriate
beliefs and alteration of negative thoughts [78, 125, 126]. Mindfulness-based interventions include
the training of non-judgmental awareness to thoughts, sensations, and emotions, and being present
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in the moment. The effectiveness of the Acceptance Commitment Therapy, where mindfulness is a
key element, has been shown by several randomised controlled trials [127-129]. Next to
acceptance- and mindfulness-based interventions, patients are encouraged to engage in committed,

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values based action [130, 131].
Regarding maladaptive pain response patterns as fear-avoidance and kinesiophobia,

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exposure and exercises in a safe environment is effective in the reduction and alteration of fear-
avoidance behavior [132, 133]. Moreover, patients should be taught about the role of stress in the
pain occurrence and experience [73]. The awareness of external resources (sports, hobbies,
persons), as well as training of internal resources (mind set, setting limits) might help patients cope
with pain or stressful situations. Numerous studies have investigated the role of thoughts in
inhibition of pain. The next part of this review will present the results in experimental, acute, and
chronic pain.
4. Cognitive modulation of pain
In addition to stress and exercise as modulators of pain, cognitive pain inhibition strategies play an
important role as influences on pain-related sensations and emotions. Two prevailing strategies
[134], employed to inhibit pain, thought suppression and focused distraction, are commonly used
with the goal to suppress pain or to distract from it [135]. Their key difference is subtle, but
consequential [136]. In thought suppression, pain is an unwanted thought or sensation, and the
essence is to not think about pain, while focused distraction works by distracting from pain with a
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specific other thought. The next section will give a general overview of the two strategies thought
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suppression and focused distraction, before going into the respective and compared influences they
may have on experimental, acute, and chronic pain.
4.1 Thought suppression and focused distraction
Thought suppression is defined as the effort to “not think” about unwanted thoughts
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and sensations [136]. Paradoxically, it can increase these unwanted thoughts and sensations. The
Ironic Process Theory [137] illustrates this effect: it describes a conscious and effortful search for
distractors, and an automatic and non-conscious target search checking for the unwanted thought
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within the mind, constantly reminding of the unwanted thought. When both processes run smoothly,
suppression appears to be possible for a short time [138-140]. When cognitive demands disrupt the
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effortful distractor search, while the automatic target search keeps running effortlessly, thought
frequency is assumed to increase, which was generally supported [141-145], but not consistently
[146]. There is broad agreement that thought suppression can increase the frequency of unwanted
thoughts, coined the “rebound effect” [147], especially in intangible thoughts, such as pain [140].
Rebound effects have been shown to appear delayed [140], and to last up to a week [145]. In short-
term effects of thought suppression, both increases and decreases in thoughts frequency were
shown. An “immediate enhancement”, increasing unwanted thoughts during suppression, was
assumed [148], but was subsequently rarely found in studies [140]. Other studies observed short-
term benefits of thought suppression [138-140, 149], which may, along with its intuitive appeal,
reinforce its perceived benefit, without taking into account the long-term detrimental effect of the
rebound.
Focused distraction involves thinking about one particular, ideally very concrete,
thought, like a red Volkswagen [147], your home in vivid detail [148, 150-152], or a blue sports car
[153]. This provides an alternative to the unwanted thought, leading to a focused distraction that is
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in contrast to the unfocused and unsuccessful distraction resulting from thought suppression [136].
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Studied in comparison to thought suppression, focused distraction led to less intrusions about
unwanted thoughts, and was accompanied by less anxiety [154]. Focused distraction was related to
less distress than thought suppression in dealing with unwanted thoughts in OCD [151], and was
more effective in managing clinically significant intrusive thoughts. However, it should be noted
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that the thoughts used in focused distraction studies were usually instructed by the experimenter.
Self-generated distractors may vary widely in content, quality, and effect. Exploration of the
characteristics and effects of freely generated distractors seems to be a worthwhile subject for future
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research.
4.2 Thought suppression, focused distraction and pain

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Both thought suppression and distraction are common strategies to cognitively inhibit pain and are
reported frequently. In an effort to inhibit pain, thought suppression [82, 149, 155], and distraction
are commonly used [156, 157]. However, studying them has its complications. It may be difficult
for participants to distract from pain or suppress it, and give pain ratings, or observe a pain
threshold, at the same time [135, 156].
4.2.1 Thought suppression and pain
In experimental pain, thought suppression was observed to increase thought frequency and pain
experience [158], with thought frequency mediating the relationship between thought suppression
and pain. Masedo and Esteve [159] showed that acceptance was superior to suppression and pain
education regarding pain tolerance, pain, distress, and recovery, while suppression was either worse
or equal to pain education.
Regarding clinical pain, Konietzny et al. [160] observed trait thought suppression to
heighten depressive mood in female patients with sub-acute back pain under high stress. Thought
suppression was shown to moderate the relationship between depression and pain in acute and sub-
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acute [161] and in chronic back pain [162]. In chronic low back pain, thought suppression is further
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seen as a risk factor for poorer pain outcomes, heightened pain severity, increased pain interference,
and depressive symptoms [163]. Experiencing pain, many patients show a suppression reaction,
followed by an emergence of different negative consequences, such as distress, depressive moods,
and increased pain [137, 147, 158, 164, 165]. Thought suppression showed a positive correlation
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with pain persistence behavior [155], and is assumed to lead to persistent pain and disability in
chronic pain, as well as slowed recovery [82].
4.2.2 Focused distraction and pain

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In experimentally induced pain, Fernandez and Turk [166] found that imagery strategies
significantly reduced pain. Other studies have also found focused distraction to be helpful, but not
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singularly so: Jackson et al. [167] reported it to be equal to pain education, and inferior to
acceptance. Thompson et al. [168] found focused distraction to be superior to sensory focusing
regarding pain tolerance, but not pain threshold in participants with high anxiety sensitivity.
However, previous findings showed sensory focusing as the more effective strategy, but only in
men [169]. McCaul et al. [170, 171] observed that focused distraction increased pain tolerance and
decreased pain, but was not clearly preferable over attending to pain. In acute pain and medical
procedures, van Ryckeghem et al. [135] note that distraction may also be helpful.
In chronic low back pain, however, focused distraction does not appear to be as
beneficial. While distraction in experiments is usually brief and guided, people with chronic pain
have to be self-reliant and self-engaging in distraction, for an indefinite amount of time [156, 167].
In their meta-analysis, van Ryckeghem et al. [135] found no evidence for distraction and sensory
monitoring to be superior to control groups in altering chronic pain, with a small and insignificant
overall effect size for distraction. Distraction efficacy only differed from the control groups when
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the control group was asked to focus on pain, but not if the control group could choose what to do.
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Of note, it is possible that the control groups chose to distract from the pain as well, or chose other
strategies that were effective, especially as most studies did not check for the use of comparable
strategies in the control condition. While distraction significantly heightened the pain threshold, it
had no significant effect on pain intensity, pain unpleasantness, and pain tolerance. These findings
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did not differ between clinical pain and experimentally induced pain in patients with chronic pain.
As Hasenbring and Verbunt [157], and Johnson [156] note, distraction may even be associated with
more intense chronic pain. Goubert et al. [138] observed no reduction in pain during an activity
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with distraction, and increased pain immediately afterwards. However, other studies found differing
results. Nicholas et al. [172] found that cognitive behavioral therapy either combined with sustained
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attention to pain, or with focused distraction, significantly improved pain, disability, depression,
and medication use. Higher adherence to each strategy was associated with larger effect sizes. Fors
and Götestam [173] found that distraction by imagery and pain education both reduced pain and
anxiety levels. Distraction helped patients with chronic pain carry on with a pain-eliciting exercise
for longer, but the same distractor did not increase their cold pressor pain tolerance time, while it
did for pain-free participants [174]. Van Ryckeghem et al. [135] generally state that distraction does
not appear to be beneficial, neither in chronic nor in experimental pain. Distraction may even be
counterproductive in chronic pain, as chronic pain may already be associated with a heightened
awareness or vigilance for pain and somatic sensations, and distraction may not be helpful in the
alarmed state of chronic pain. Greater pain intensity may mean pain can no longer be easily
excluded from attention, so that distraction becomes ineffective [175]. Alternatively, van
Ryckeghem et al. [135] suggest that chronic pain may be associated with problems in executive
functioning, reducing the ability to inhibit pain (see [176] for a meta-analytical review). However,
as the authors also note, there was substantial heterogeneity in the studies, so moderators may be
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relevant. For example, Hadjistavropoulos et al. [177] found that in patients without health anxiety,
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distraction was superior to sensory monitoring and control, but in patients with health anxiety,
sensory monitoring was superior to distraction and control. Likewise, further emotional and
motivational factors may influence the efficacy of distraction – reducing the threat or introducing a
motivationally relevant distraction task might prove to be analgesic [135].

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4.3 Pain studies directly comparing the effectiveness of thought suppression and focused distraction
in pain inhibition
Several studies explicitly compared the effects of thought suppression and focused distraction on
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pain. In experimental pain, Burns [150] studied thought suppression, focused distraction, and
sensory focus, which was instructed as objectively focusing on the elicited sensations. Patients with
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chronic low back pain and pain-free controls underwent a cold pressor, and a mental stress task. In
patients with pain, but not in pain-free participants, using thought suppression resulted in greater
muscle tension increases, which were hypothesized to aggravate chronic pain, than using any of the
other cognitive strategies in the study. Likewise, thought suppression led to a delayed effect of
greater unpleasantness and arousal during the mental stress task in patients, but not in pain-free
participants. Thus, thought suppression may contaminate the next stressful event, but only in people
already in pain. The effects of focused distraction and sensory focus generally did not differ, as
neither produced a contamination effect, and both appeared to buffer physiological responses in
patients with pain. Burns proposes that focused distraction and sensory focus may both have
prevented an attentional focus on the emotional aspects of pain that may underlie the contamination
effect that was observed in thought suppression. Thus, the attentional strategy that is used to deal
with a painful event may affect the rest of the day for a patient with pain [150]. Cioffi and Holloway
[148] examined suppression, distraction, and monitoring in healthy participants undergoing a cold
pressor test, and a subsequent vibration stimulus. The suppression group showed the slowest
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recovery from pain, and the monitoring group the fastest. The suppression group rated the
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subsequent vibration as significantly more unpleasant than the other groups. This was interpreted as
a contamination effect of thought suppression on a following event. A similar contamination effect
was found by Quartana et al. [178, 179], and Elfant et al. [180]. Burns et al. [181] showed sex
differences in this contamination effect of suppression. Men in the “no suppression” condition
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showed significantly lower pain and unpleasantness than men in the “suppression” condition, who
were equal to women in both conditions.
Wenzlaff and Wegner [143] assumed an automatic direction of attention to result from
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thought suppression. This preferential allocation of attention, when directed towards pain-related
stimuli, is called a pain-related attentional bias, which was shown to predominantly relate to worse
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pain outcomes [182, 183]. As cognitive pain inhibition strategies operate by directing attention,
research on their influence on pain-related attentional biases may elucidate underlying mechanisms
of cognitive pain inhibition. In order to explore the potential effects of cognitive pain inhibition
strategies on a pain-related attentional bias, Kreddig et al. [152] compared the effects of thought
suppression and focused distraction on the development of a pain-related attentional bias in healthy
participants experiencing a cold pressor. Before and after this pain induction, during which the pain
inhibition strategies were employed, the pain-related attentional bias was assessed with a dot-probe
task and an attentional blink task. The results showed that thought suppression and focused
distraction had different influences on the experience of pain, but not on attention towards pain.
Directly after the cold pressor, the thought suppression group reported lower pain intensity and
perceived threat than the focused distraction group, while the two strategies did not yield
differential effects pertaining to a pain-related attentional bias.
Regarding clinical pain, suppression and distraction are assumed to play important
roles in behavioral patterns at risk for exacerbation from acute to chronic pain. As described in
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paragraph 3.4, the Avoidance-Endurance Model [155] states two distinct behavioral groups of
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endurance, both leading to chronic pain. Thought suppression is conceptualized as a part of the
distress-endurance pattern, leading to affective distress and depressive mood in the short term [184],
and increased pain and disability (through pain persistence and resulting overuse) in the long term
[82]. By contrast, focused distraction, and positive mood despite pain, is described in the eustress-
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endurance pattern, which also leads to chronic pain presumably by overuse in the long term, but is
characterized by recovery from pain in the short term [184].
4.4. Summary
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Cognitive pain inhibition strategies, such as thought suppression and focused distraction, have
received a lot of attention in research for their ability to influence pain outcomes. Thought
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suppression is usually seen as a detrimental strategy in the long term, leading to increased thought
intrusions about pain, pain intensity, distress, and disability. However, despite these findings, its
short-term benefits and intuitive appeal of pushing the pain out of the mind may unfortunately
reinforce its popularity in individuals suffering from pain. Focused distraction seems to reduce
experimentally induced pain, and heightens pain tolerance, and has shown some benefit in medical
procedures, but is not always clearly superior to other strategies like monitoring or acceptance. In
chronic pain, however, focused distraction seems less beneficial, and can even be
counterproductive. Studies comparing the two strategies suggest that focused distraction may still
be preferable over thought suppression. In experimental pain, studies suggest better pain-related
outcomes for focused distraction, and harmful contamination effects and heightened attention
towards pain for thought suppression. Regarding the development of chronic pain, the avoidance-
endurance model proposes detrimental roles for both strategies in the long-term, but better
outcomes on mood and performance for distraction.
5. Where to go from here
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When suffering from pain, people may benefit from a strategy they can turn to, to decrease the pain,
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or to feel more in control of it. Ideally, this strategy will be self-determined by the individual, and
able to work adjuvantly in treatment. Finding helpful strategies, or patterns in individuals that
determine strategies to be helpful or not, and teaching them, might be key. Increased self-efficacy
may arise from successful pain inhibition strategies, which vary from increased use of functional
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strategies to cope with stress, and from bodily strategies such as exercises to cognitive attempts of
attention diversion. Recently, results from laboratory research revealed that there further might be
substantial interactions between the pain inhibitory effects of exercise and cognitive inhibition,
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showing for example a positive correlation between habitual modes of distraction from pain during
dynamic exercise and EIH in pain-free adults [185].

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It is however important to note that bodily as well as cognitive strategies of pain
inhibition may also have more or less counterintuitive, detrimental effects, especially in patients
with chronic pain. Thought suppression can easily trigger affective distress, as thought suppression
is highly failure prone [137] and failures can lead to greater distress [135]. Moreover, recent studies
indicated that habitual thought suppression was, when co-occurring with high stress, related to
increased depression in women with sub-acute back pain [160] and also in physically highly active
individuals, such as athletes with back pain [186]. Notably, physical exercise per se may counter-
intuitively increase pain in the short-term, especially in patients with chronic pain.
In light of the fact that exercise is an important component of multimodal treatment programs in the
management of chronic pain, along with beneficial cognitive pain inhibition strategies, there is
currently a need to identify conditions of effective use of bodily and cognitive strategies of pain
inhibition. There is further a need to consider possible interactions between different modes of pain
inhibition such as physical exercise, cognitive attention diversion and stress, in order to optimize the
effects of these strategies within multimodal treatments.
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Endogenous Modulation of Pain The Role of Exercise, Stress and Cognitions in Humans

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Endogenous Modulation of Pain

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Download date: 21. mar. 2022

Special Topical Series in Clinical Journal of Pain: Manuscript 2

Henrik Bjarke Vaegtera,b, Elisabeth Fehrmannc,d, Hannah Gajsare, Nina Kreddige

on Pain, Sept. 11, 2018, Boston, USA

Keywords: endogenous pain modulation, exercise-induced hypoalgesia, stress, cognition, pain

sensitivity, thought suppression, focused distraction

of pain is now generally accepted.

1.1 Role of exercise, stress and cognitions in modulation of pain

2. Exercise-based modulation of pain in humans

[5] have been reported following exercise.

2.1 Exercise-induced hypoalgesia in pain-free subjects

increasingly recognized role of exercise in the management of several pain conditions.

stimulations, which is suggested as a measure of excitability of the central nervous system, is

exercising or non-exercising muscles, as well as participant-related factors.

intensity isometric contractions.

EIH is often demonstrated at exercising as well as non-exercising muscles, but

isometric wall squat exercise [10].

Hypoalgesia after exercise may also be influenced by participant-related factors

not related to the degree of fear of movement [29].

2.2 Potential mechanisms of EIH in humans

an intensity-dependent manner, suggesting a potential role in EIH [38]. In support of this

exercise [52], however this needs further investigation.

2.3 Response to acute exercise in subjects with chronic pain

been demonstrated in subjects with whiplash-associated disorder [65].

established. Recently, the between-sessions test-retest reliabilities of EIH after 1) 3 minutes

intensity might improve the within-subject reliability of the EIH response.

exercises may cause a widespread increase in the pain sensitivity.

2.6 Potential treatment implications:

stress reduction will be discussed.

3.1 Definition and occurrence of stress

indifferent for another [72, 73].

In a two-way appraisal process, a person first evaluates whether a situation is

sympathicus (fight and flight-reaction), the activation of the hypothalamic–pituitary–adrenal axis

3.2 Stress and back pain

Regarding pain, pain-related and non-pain-related stressors need to be distinguished.

pain as something frightening or threatening (e.g. catastrophizing) may evoke an exaggerated

Pain-related and non-pain-related stressors may likely influence the perception of

include psychosocial components, such as psychosocial stressors (e.g. work-related or family

isolation, were found to be related to low back pain [87, 88].

chronically overburdened stress response system [102].

3.3 A neurophysiological view on stress and pain

3.4 Stress in subgroups of back pain patients

maladaptive pain response patterns, fear-avoidance, distress-endurance and eustress-endurance.

over-active behavior showed significantly more anxious-ambivalent or anxious-avoidant attachment

resulting in a higher work load [119].

3.5 Therapeutic consequences

management, and improvements are thought to be mediated through reappraisal of inappropriate

acceptance- and mindfulness-based interventions, patients are encouraged to engage in committed,

values based action [130, 131].

Regarding maladaptive pain response patterns as fear-avoidance and kinesiophobia,

4. Cognitive modulation of pain

may have on experimental, acute, and chronic pain.

4.1 Thought suppression and focused distraction

shown. An “immediate enhancement”, increasing unwanted thoughts during suppression, was

4.2 Thought suppression, focused distraction and pain

threshold, at the same time [135, 156].

4.2.1 Thought suppression and pain

or equal to pain education.