REVIEW ARTICLE
Effects of Exercise Therapy on Endogenous Pain-relieving
Peptides in Musculoskeletal Pain
A Systematic Review
Jorge P. Fuentes C, Bsc PT, MSc RS,*w z Susan Armijo-Olivo, MSc, PhD,*y
David J. Magee, PhD,J and Douglas P. Gross, PhDJ
Objective: To review the literature regarding the effects of exercise
in patients with musculoskeletal pain on modifying: (1) the plasma
or cerebral spinal fluid concentrations of pain-relieving peptides
and (2) changing the cerebral activity of areas linked with pain
processing and modulation systematically.
Methods: An extensive search of bibliographic databases including
MEDLINE, EMBASE, EBM Reviews-Cochrane Central Register
of Controlled Trials, ISI Web of Science, Scopus, PeDro, AMED,
and CINAHL was made. Two independent investigators screened
the titles of publications and completed quality assessment of the
selected studies.
Results: The search of the literature resulted in a total of 1819
published studies. Of these only 1 study of low methodological
quality was considered to be relevant. The agreement between
reviewers to select the articles was k=1. The agreement for the
methodological quality evaluation was k=0.9.
Discussion: Given the small number of studies identified and the
low quality of research, no firm conclusions could be reached about
the impact of therapeutic exercise on modifying concentrations of
pain-relieving peptides or its effect on changing the cerebral activity
of areas linked with pain processing in patients with musculoskeletal
pain. There is a clear need for well-designed trials examining
exercise therapy interventions and their effect on both pain-relieving
peptides and cerebral activity in patients with musculoskeletal pain.
Key Words: exercise therapy, pain, peptides opioids, serotonin,
systematic review
(Clin J Pain 2011;27:365–374)
P hysical exercise represents a relevant component of
rehabilitation for patients with musculoskeletal pain.
Exercise therapy is a management strategy that includes
Received for publication October 6, 2009; revised November 5, 2010;
accepted December 28, 2010.
From the JDepartment of Physical Therapy; wRehab Research Centre;
*Faculty of Rehabilitation Medicine; yAlberta Research Centre for
Health Evidence (ARCHE) Faculty of Medicine and Dentistry,
University of Alberta, Alberta, Canada; and zDepartment of
Physical Therapy, Catholic University of Maule, Talca, Chile.
Support was provided from the following agencies: Alberta Provincial
CIHR Training Program in Bone and Joint Health (Alberta,
Canada), Izaak Walton Killam scholarship from the University of
Alberta (Alberta, Canada), Canadian Institutes of Health Research
(Canada), Government of Chile (MECESUP Program), University
Catholic of Maule (Talca, Chile), and Physiotherapy Foundation
of Canada through an Ann Collins Whitmore Memorial Award
(Alberta, Canada).
Reprints: Jorge P. Fuentes C, Bsc PT, MSc RS, Faculty of Rehabilitation
Medicine, University of Alberta, 3-50 Corbett Hall, Alberta, Canada
T6G 2G4 and Department of Physical Therapy, Catholic University of
Maule, Talca, Chile (e-mail: jorgef@ualberta.ca)
Copyright r 2011 by Lippincott Williams & Wilkins
Clin J Pain  Volume 27, Number 4, May 2011
several interventions such as aerobic exercise, muscle
strengthening, flexibility and stretching techniques. Although
the effects of therapeutic exercise on pain are not fully
understood, its application is widely used in a variety of
painful musculoskeletal conditions such as low back
pain (LBP), shoulder pain, neck pain, patellofemoral pain
syndrome, and osteoarthritis. Besides its effects on function
and health, therapeutic exercise is known to have some
pain-relieving effects. Most systematic reviews carried out
involving patients with musculoskeletal conditions have
shown that exercise therapy does both, decreases pain and
increases functionality.1–4
Exercise-induced hypoalgesia (EIH) is characterized
by a diminished sensitivity to noxious stimulation or a
decrease in pain perception as a result of exercise, possibly
due to stimulating release of pain-relieving peptides.5–7
Pain-relieving peptides include nonopioid compounds (eg,
serotonin, norepinephrine) and endogenous opioid sub-
stances. In the central nervous system, serotonin and
norepinephrine have been shown to have widespread
influence on cell bodies throughout multiple areas of the
brain and the spinal cord. These pain-relieving peptides
have been implicated in the analgesic response after muscle
contraction.8 In addition, it has been shown that serotonin
is involved in descending pain inhibition.9 Endogenous
peptides with opiate activity (eg, endogenous opioids) can
roughly be subdivided into 3 categories: endorphins,
enkephalins, and dynorphins, stemming from 3 precursor
molecules. Among the final active peptides generated from
these precursors are b-endorphin, the met-enkephalins and
leu-enkephalins, and the dynorphins. These peptides are
produced by neurons scattered throughout the nervous
system.10 For example, endogenous opioid peptide contain-
ing neurons have been found in regions involved in the
nociceptive response. Zones with peptide opioid receptors
that are especially active include the midbrain periaque-
ductal gray, the nucleus raphe magnus, limbic system, and
the rostral ventral medulla. These are part of the descend-
ing inhibitory system that modulates pain transmission at
the spinal cord level.11 Thus, it is believed that opioid
peptides act as neurotransmitters and neuromodulators to
induce analgesia.10,11
It is generally accepted that the overall action of pain-
relieving peptides is to inhibit the nerve cell or the synapse
on which they act by means of presynaptic or postsynaptic
inhibition. At the presynaptic level, peptides decrease
calcium ion entry resulting in a decrease in presynaptic
neurotransmitter release. Peptides also enhance potassium
ion efflux resulting in the hyperpolarization of postsynaptic
neurons and a decrease in synaptic transmission.11 As a
result of these cellular mechanisms, a partial or complete
www.clinicalpain.com | 365
Fuentes C et al
block of synaptic transmission of nociceptive impulses in
the neuronal pathway is produced.12
The action of pain-relieving peptides has been
documented in various physical therapy interventions in
both clinical and experimental settings. For example,
massage of connective tissue has been found to be
associated with an increase in plasma b-endorphin in
patients with myalgia.13 In addition, in patients with spinal
cord injury, an increase of b-endorphin was also reported
after the application of muscle electrostimulation.14 Similar
responses in b-endorphin peptide have been reported in
patients with postoperative pain receiving transcutaneous
electrical nerve stimulation (TENS)15 and patients with
rheumatoid arthritis being treated with cryotherapy.16 In
experimental settings (ie, healthy participants), the applica-
tion of spinal manipulation17 and TENS18,19 have been also
associated with an increase of b-endorphin levels.
Even if exercise therapy has been widely used for
treating pain in musculoskeletal conditions, the mechan-
isms supporting its effectiveness are not well studied. Most
of the information evaluating the impact of exercise on
releasing pain-relieving peptides comes from studies using
healthy participants and athletes. For example, in a study
examining analgesia after strenuous physical activity in
healthy athletes, Droste et al20 reported that both experi-
mental pain thresholds and plasma b-endorphin levels were
increased. In addition, Di Luigi et al21 showed that 30
minutes of treadmill exercise induced a significant increase
of b-endorphin in twin male athletes. This same pattern of
response in b-endorphin has been documented in marathon
runners22 and Nordic cross-country skiers.23
However, other data suggest no correlation between
the hypoalgesic effect of exercise and the increase of
b-endorphin, and also no association between the peak
release of peptides and the decrease of pain has been
reported.20 Thus, it seems that an increase of peptides is not
necessarily accompanied by a decrease in pain. In addition,
substantial intraindividual and interindividual variations
among healthy participants may influence the release of
pain-relieving peptides.24,25
As pain is a complex, multifactorial entity and highly
individualized perception patients with clinical pain
differ from healthy participants in many aspects of pain
perception and pain modulation. For example, descending
control mechanisms are affected in patients with chronic
musculoskeletal disorders when compared with healthy
participants.26,27 In addition, the amount and the intensity
of exercise that patients with clinical pain can endure are
different when compared with healthy participants, which
precludes extrapolation to the clinical situation. Although
some positive findings28–35 regarding the analgesic effect of
exercise in patients with clinical conditions (eg, LBP, neck
pain) have been reported, the evidence examining the
mechanism of pain modulation by exercise therapy has yet
to be synthesized.
OBJECTIVE
Although high-intensity aerobic exercise has been
shown to stimulate release of pain-relieving peptides in
healthy people, little is known about the analgesic effect of
high, moderate, and low intensity exercise, including the
analgesic effect of concentric, eccentric, and resistance
exercise in people with actual musculoskeletal pain.
Therefore, the primary objectives of this review were to
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Clin J Pain  Volume 27, Number 4, May 2011
review the current scientific literature regarding patients
with musculoskeletal pain to assess: (1) whether exercise
modifies plasma or cerebral spinal fluid concentrations
of pain-relieving peptides and (2) whether therapeutic
exercise changes cerebral activity of areas linked with pain
processing and pain modulation systematically.
METHODS
Criteria for Considering Studies for This Review
Design
Clinical trials, controlled trials, and randomized
controlled trial designs comparing exercise therapy to a
placebo/control intervention, or standard care (ie, treat-
ment that normally is offered), or any trial evaluating the
effect of exercise pre intervention and post intervention36
were considered eligible for inclusion in this review. Studies
with an additional treatment arm or combined intervention
were included if the effect of the exercise therapy interven-
tion could be separately identified.
Participants
Inclusion in this review was restricted to trials with
participants meeting the following criteria: (1) a diagnosis of
a painful localized musculoskeletal condition such as LBP,
neck pain, shoulder pain, knee pain, thoracic pain, hip pain,
ankle pain, and (2) adults (>18 y old).
Interventions
Studies were required to examine an exercise therapy
intervention such as aerobic exercise, muscle strengthening,
endurance training, flexibility or stretching techniques
aimed at managing painful musculoskeletal conditions.
Outcomes
Very often studies evaluating EIH use indirect
methods such as pain thresholds, intensity ratings, or pain
tolerance. A concern with these is that they do not represent
an objective measure of the pain sensation as they rely on
the personal reports of the participants. In addition, pain
thresholds represent a limited measure of central pain
processing.37,38 Furthermore, outcomes such as pain ratings
and pain tolerance are more likely to interpret favorable
reports in EIH when compared with pain thresholds.39 An
alternative manner to evaluate effect of exercise on the
painful response, which is likely less prone to bias as it does
not rely on the personal reports of the participants, is to
assess changes of pain-relieving peptides such as nonopioid
compounds (eg, serotonin, norepinephrine) and endogen-
ous opioids (eg, b-endorphins, met-enkephalins and leu-
enkephalins, and dynorphins) in the blood stream and
cerebral spinal fluid as a result of exercise. In addition,
changes in the cerebral activity of areas linked with pain
processing and pain modulation as a result of the exercise
therapy intervention evaluated through positron emission
tomography (PET) and functional magnetic resonance
imaging (fMRI) were also of interest.
Search Strategy
For this review, the literature was searched for
published studies dealing with the effect of exercise therapy
interventions on pain-relieving peptides and changes in the
cerebral activity of areas linked with pain processing and
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Clin J Pain  Volume 27, Number 4, May 2011 Effects of Exercise Therapy on Musculoskeletal Pain

pain modulation. A literature search of studies was done

according to the search strategy of Dickersin et al.40 No TABLE 1. Search Strategy
restrictions were made regarding the language of publication. No. Search Strategy
An extensive search of bibliographic databases included 1 Exp exercise therapy or exp exercise or exp exercise
MEDLINE (1950 to April week 4, 2009), EMBASE (1988 to movement techniques
April 2009), EBM Reviews-Cochrane Central Register of 2 Physical activity.mp
Controlled Trials (1991 to April 2009), ISI Web of Science 3 Movement therapy.mp
(1965to April week 4, 2009), Scopus (April week 4, 2009), 4 Aerobic exercise.mp
PeDro (April week 4, 2009), AMED (1985 to April 2009), 5 Isometric exercise.mp.
and CINAHL (1982 to April week 4, 2009). Key words and 6 Concentric exercise.mp.
medical subject headings related to exercise therapy inter- 7 Static muscle contraction.mp.
8 Exp isometric contraction or exercise induced hypoalgesia.mp
ventions and pain-relieving peptides were identified before
9 Exercise analgesia.mp.
initiating the search. The key words regarding exercise 10 Exp shoulder pain or exp low back pain or exp neck pain or
therapy included were: exercise(s), physical activity, activity, pain.mp or myofascial pain syndrome or exp back pain or
movement, aerobic, isometric, concentric, anaerobic, exp facial pain or exp patellofemoral pain syndrome or exp
and static muscle contraction. Key words related to pain- pain or exp pelvic pain
ful musculoskeletal conditions were as follows: pain, 11 Musculoskeletal pain.mp.
musculoskeletal pain, knee pain, neck pain, LBP, shoulder 12 Exp analgesia
pain, thoracic pain, hip pain, ankle pain, facial pain, 13 Hypoalgesia.mp.
patellofemoral pain syndrome, myofascial pain syndrome, 14 1 or 2 or 3 or 4 or 5 or 6 or 7 or 8 or 9
15 10 or 11 or 12 or 13
and pelvic pain among others. Key words for pain-relieving
16 14 and 15
peptides were: serotonin, norepinephrine, b-endorphin, en- 17 Exp serotonin
dorphin, encephalin/enkephalin, and opioid*. Two additional 18 Exp b-endorphin/
categories were incorporated to the search. The first category 19 Exp endorphins
involved the combination of pain inhibition and exercise 20 Exp analgesics, opioid or exp neuropeptides or exp receptors
analgesia. The key words used were: EIH, exercise analgesia, or exp enkephalin, leucine or encephalin.mp or exp
modulation, pain control, inhibition, endogenous pain enkephalins
inhibition. The second category included the combination 21 Opioid*mp.
of exercise analgesia and cerebral activity. The key words 22 17 or 18 or 19 or 20 or 21
23 16 and 22
used were: exercise, analgesia, exercise analgesia, exercise
24 Exp tomography, emission-computed or exp radioisotopes or
therapy, PET, fMRI, cerebral activity, and cerebrovascular exp positron-emission tomography or exp cerebrovascular
circulation. For details about the search strategy see Table 1. circulation
Two independent investigators screened the titles of 25 Functional MRI. mp or fMRI
publications found in the databases, and if available, the 26 23 and 24
abstract of the publication was screened as well. If either
Exp indicates explode; fMRI, functional magnetic resonance imaging;
investigator felt that any published studies potentially met mp, multiple parameters.
the inclusion criteria, or if there was inadequate informa-
tion to make a decision, a copy of the article was obtained.
The next phase of the search strategy involved
searching for unpublished studies and for studies poten- methodological quality in physical therapy trials (ie, Jadad,
tially overlooked or absent from the databases. This Maastricht, Delphi list, Van Tulder, Maastricht-Amster-
involved hand searching the references of all retrieved dam, PEDro, and Bizzini scales). These scales evaluate 5
articles for potential studies. Citation indexing was used to general categories: Patient selection, blinding, interven-
track referencing of key investigators in the field. tions, outcomes, and statistics. As each scale gives priority
A rating form was developed based on the inclusion to different items when evaluating the quality and no single
criteria listed above to determine eligibility of the retrieved scale covers all the relevant aspects of methodological
articles. Each criterion was graded on a yes/no basis (ie, the quality, the investigators decided to use all of these scales to
published study had to provide enough information to have a more comprehensive overview of the quality of the
adequately meet the criterion). For studies to be included in analyzed studies.43 The 2 investigators independently
the review, the study had to meet all criteria on the rating reviewed each study. The individual items and total scores
form. When discrepancies occurred between reviewers in were compared. Discrepancies in item scoring were settled
the overall rating of an article, the rating forms were through discussion.
compared, reasons for the discrepancies were identified,
and a consensus was reached. All disagreements were
resolved by consensus. k statistics were calculated using RESULTS
Stata 9.0 to determine the level of agreement between raters The search of the literature resulted in a total of 1817
on both trial inclusion and quality score. On the basis of the published studies (Fig. 1 and Table 2). Of the 1817 published
criteria described by Landis et al41,42 an agreement score studies in the databases, only 1 study was considered to be
above 0.61 was considered acceptable. potentially relevant based on our inclusion criteria.44 Another
5 studies45–49 were selected by hand search as potentially
useful studies; however, they were all finally excluded. The
Quality Assessment specific reasons for exclusion of the potentially selected
Assessments of quality were completed independently studies were: 3 studies45,48 did not include a control/com-
by the 2 independent reviewers. Each study was evaluated parison group and 1 of these 3 studies46 did not provide a
using all of the current scales used for evaluating the clear explanation of study results as well; the fourth study47

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Fuentes C et al Clin J Pain  Volume 27, Number 4, May 2011

et al,44 reported an increase in the plasma concentration of

serotonin after application of low-intensity exercise (ie,
lumbar stabilization) in patients with LBP. These findings
contrast with much of the literature using healthy
participants regarding the intensity of exercise required to
elicit a hypoalgesic response mediated by pain-relieving
peptides. For example, results of studies using an exercise
protocol with elevated intensity (ie, 75% VO2max) indicated
that both hypoalgesia50,51 and release of opioid peptides20
occur consistently only at higher-exercise intensities as
measured through VO2max (ie, higher workloads). Poten-
tially, the intensity of exercise required to activate the
release of peptides may differ for healthy individuals and
for patients experiencing musculoskeletal pain. This notion
was confirmed by preliminary experimental evidence in an
animal model in which the opioid system was activated by
low-intensity exercise in a chronic muscle pain model.52
FIGURE 1. Flow diagram of the literature search. Thus, patients with chronic pain may show a different
threshold in response to exercise when compared with
did not involve patients with clinical pain (ie, it only included healthy participants. Therefore, the application of low-
healthy participants); and the fifth study49 was excluded intensity exercise (eg, lumbar stabilization exercises) might
because the analysis of the results of the trial was restricted provide an adequate stimulus to trigger the release of pain-
only to participants receiving exercise training (there was no relieving peptides to produce the EIH phenomenon in these
analysis between training group and nonexercising control individuals. Alternatively, different pain-relieving peptides
group). Thus, only 1 study44 was finally included for critical (ie, endorphins, enkephalins, dynorphins, and serotonin)
appraisal and analysis. The agreement between reviewers to could be triggered under different conditions (ie, different
select the articles was k=1. The agreement for the critical exercise intensity, different type of contractions, and recruit-
appraisal evaluation was k=0.9. Critical appraisal of the ment of global or specific muscles). Thus, as shown by
selected study indicated it was of low methodological quality Sokunbi et al44 the serotonin compound may be released in
(Table 3). Specific characteristics of this study are outlined in less stressful conditions (ie, low-intensity exercise) when
detail in Table 4. compared with opioid peptides (ie, b-endorphin), which
require a higher intensity of exercise to be released
in humans.20,51 This suggests that a potentially different
DISCUSSION mechanism could operate for the serotonin neurotransmitter
when compared with opioid peptides in clinical conditions.
Despite the fact that in this review an exhaustive
Although the lack of consistent evidence renders these
process of literature searching and identifying relevant
statements as merely speculative, some evidence exists
studies was carried out, few studies were found of potential
regarding the pain-relieving effect of low-intensity exercise.
interest and only 1 study met the inclusion criteria. One
For example, exercise used for therapeutic purposes in
potential reason for this lack of research could be the
patients with LBP and neck pain are often low intensity (eg,
logistical difficulties associated with the standardized pro-
stabilization isometric contraction) but have shown some
cesses and techniques used to measure pain-relieving peptides
positive effects.2,33,53 Potentially, the mechanism behind the
(eg, needles, blood samples), analysis of antigens, and the
analgesia is not biomechanical as originally supposed but
expensive imaging technologies required such PET and
due to the release of pain-relieving substances. Further
fMRI. However, additional research in human participants
research investigating the effects of different types, inten-
with painful clinical conditions is clearly needed.
sities, and dosages of exercise on the release of pain-
In this review, only 1 relevant study with poor
relieving peptides is warranted.
methodological quality was found. In this study, Sokunbi
As mentioned earlier, the fact that we found just 1
relevant study after an exhaustive search process is
remarkable. Although exercise constitutes a core compo-
TABLE 2. Abstract Result From Different Electronic Databases nent of rehabilitation, and is often applied as part of a pain
Database Results management program, the results of this study highlight
that a scarce amount of research has been conducted
Medline 203
examining the mechanisms underlying the EIH phenomen-
Embase 258
Cinahl 619 on in patients with musculoskeletal clinical pain. Thus, the
Cochrane 33 hypoalgesic mechanisms of exercise in clinical pain still
Web of science 535 remain unclear.
Scopus 43
PeDro 119
AMED 7 Mechanisms of EIH
Manual search 5 The mechanisms underlying the EIH phenomenon are
Total 1822 not well understood. Different structures and substances
Potentially selected 6
have been involved. For example, the increase of plasma
Selected 1
Final included 1 b-endorphins,20–23 enkephalins, and other nonopioid me-
chanisms such as serotoninergic and norepinephrine

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TABLE 3. Methodological Quality Assessment

Items Included in the Scales Yes No Unclear N/A
Patient selection
Inclusion and exclusion criteria clearly defined/eligibility criteria specified X
Study described as randomized X
Randomization method performed X
Method of randomization described and appropriate X
Method of randomization concealed X
Baseline comparability (group equivalence, homogeneity) X
regarding the most important prognostic indicators
Blinding
Study described as double blind X
Method of blinding described and appropriate X
Blinding of investigator/assessor X
Blinding of participants/patients X
Blinding of therapists/care provider X
Blinding of the outcome (results) X
Interventions
Treatment protocol adequately described for the treatment X
and control groups (eg, frequency, intensity)
Control and placebo adequate X
Cointerventions avoided or comparable X
Cointerventions reported for each group separately X
Control for cointerventions in design X
Testing of participants compliance to treatment protocol X
Compliance acceptable in all groups X
Description of withdraws and dropouts X
Withdrawal/dropouts rate describe and acceptable X
Reasons for dropouts X
Adverse effects described X
Patient follow-up details reported X
Follow-up period adequate X
Short follow-up measurement taken X
The timing of the outcome assessment was comparable in all groups X
Outcomes
Description of outcome measures X
Relevant outcomes were used X
Validity reported for main outcome measures X
Responsiveness reported for main outcome measures X
Reliability reported for main outcome measures X
Use of objective outcome measures X
Statistics
Descriptive measures (point estimates and measures of variability) X
identified and reported for the primary outcome
Appropriate statistical analysis used X
Sample size calculation done before initiation of the study X
Adequate sample size X
Sample size described for each group X
Intention to treat analysis used X
Sokunbi et al.44
Total score=18/39=0.46 poor quality.

neurotransmitters have been implicated.8,54,55 In the same
way, sensory modulation,56 afferent inhibition,38 and
central pain inhibitory mechanisms20 activated by the
stimulation of afferent nerve endings (group III and IV)
in the skeletal muscle have also been suggested.
An emergent line of evidence suggests the role of
systems involved with cardiovascular regulation (blood
pressure) during exercise. Neuroanatomic evidence has
determined a close integration (adaptation and survival
network) between pain modulation areas and cardiovas-
cular regulation.57 Some evidence indicates an interaction
between increased blood pressure and a reduction of pain
sensitivity associated with aerobic51,58,59 and resistance
exercise.60 However, the precise mechanisms underlying
the interaction between exercise, hypoalgesia and blood
pressure are not entirely clear. Although animal and human
research suggests that endogenous opioids may be in-
volved,61–64 the human evidence is limited and inconsistent.
For example, although hypertensive men have elevated
levels of b-endorphin compared with normotensive men,61
a blockade with naloxone did not affect the relationship
between blood pressure and pain perception.62–64
It is well known that isometric contractions are a
powerful stimulus for increased blood pressure and this is
proportional to the percentage of maximum voluntary
contraction.65 A reduction of muscle sensitivity along with
an increase of the blood pressure as a result of isometric
exercise has been reported.66–68 Other recent evidence,

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Fuentes C et al Clin J Pain  Volume 27, Number 4, May 2011

TABLE 4. Study Characteristics

Methods/Primary
End Points
(Outcomes
Measurement)/
Reported Validity Strength and
Type Study Objectives Sample and Reliability Results Weakness
Randomized To investigate the A convenience Methods: Spinal stabilization Strengths
clinical trial changes in the sample participants exercise training Eligibility
plasma levels of of 22 participants randomly significantly criteria
serotonin in (11 males, 11 allocated to the increased the Randomization
response to spinal females) with control group (no plasma level of Baseline
stabilization chronic low back exercise) or the serotonin by 18% comparability
exercises in pain. Control exercise group (P=0.01) when Truly control
patients with low group mean age (stabilization compared with group
back pain was 42.5±7.16 y exercise) preexercise plasma Weaknesses
and the Apparently level values. One session of
experimental participants had Control group intervention
group mean age received a single showed a (exercise)
was 46.8±11.52 y exercise treatment nonstatistically No additional
session significant decline information
Plasma levels were in the plasma regarding
measured before serotonin level treatment
and after 30 min of after 30 min of protocol was
exercise therapy supine resting reported
No additional No blinding
information No
regarding psychometric
treatment protocol properties
was reported reported
Outcome: analysis No follow-up
of plasma level of considered
serotonin by the No clinical
ELISA technique significance
Neither validity calculation
nor reliability No confidence
reported for the interval
outcome reported
A sensitivity of No sample size
the used kit was estimation
5 ng/ml Possibly
underpowered
trial

however, does not support this association for isometric
exercise69 or resistance exercise70 and the modification in
pain perception (ie, pressure pain threshold) in healthy
participants. These data provide equivocal evidence for
cardiovascular-pain interactions and exercise. Therefore,
additional research is warranted to make definitive conclu-
sions.
In the 1 study analyzed in this review various possible
mechanisms, along with the increase of plasma serotonin,
may have been involved. On the basis of the type of exercise
(ie, low-intensity isometric contraction) carried out by the
patients, a sensory modulation was possibly involved
during the task. It is probable that exercise could have
been stimulating low-threshold afferents that inhibited
high-threshold afferents through the Gate Control Theory
proposed by Melzack and Wall.56
Thus, it is plausible that the EIH phenomenon may be
mediated by different determinants instead of a single
mechanism. These factors (opioid and nonopioid mechan-
isms) would not be mutually exclusive and probably would
operate in combination to elicit the hypoalgesic response.
However, this notion is merely speculative and additional
research in human patients with painful clinical conditions
is clearly needed to make definitive conclusions about the
exact nature of this interaction.
Systemic Versus Local Pain Inhibitory
Mechanisms in EIH
Regarding the pain-inhibitory effects of exercise,
consistent evidence supports both a local37,38,71 and a
systemic37,38,72,73 response as hypoalgesia is obtained not only
in the contracting muscle but also in remote areas. Recently,
Koltyn and Umeda73 found that nonexhaustive isometric
contraction was associated with reduced muscle pain sensitiv-
ity and pain reduction in both the exercised (ipsilateral) and
nonexercised (contralateral) hands. In addition, submaximal
isometric contractions reduced mechanical sensitivity of
quadriceps and infraspinatus muscles not only in the
contracted or contralateral muscles but also in distant muscles.
Similar responses have also been shown in chronic painful
conditions.74 It has been theorized that isometric exercise could
activate some generalized endogenous pain-modulatory effects

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Clin J Pain  Volume 27, Number 4, May 2011
such as “activation of the diffuse noxious inhibitory control,
hypoalgesia linked to an increased blood pressure, exercise/
stress induced hypalgesia, and attentional factors (p. 255).”38
However, other investigators proposed that a different central
widespread inhibitory mechanism, different from diffuse
noxious inhibitory control, could occur.37
The latter studies support the notion that EIH is
mediated by changes in the central nervous system
(systemic effects), along with peripheral mechanisms (circu-
lating b-endorphin), and both could explain the systemic
effects of exercise. However, it seems that the complete
mechanisms are not clearly understood and the data
suggest that a complex mechanism may be operative.
Clinical Implications of the Effect of Exercise
on Musculoskeletal Pain
The application of exercise therapy is widely accepted
in physical therapy when treating musculoskeletal condi-
tions.28–35 Therefore, the phenomenon of EIH has potential
clinical relevance for individuals with pain. Exercise has
been recognized as being able to increase flexibility,
strength, mobility, proprioception, and result in many
other improvements in biomechanical tissues.75–80 Thus,
the positive effects of exercise in achieving decreased pain
outcomes may be the result of these indirect effects.
The hypoalgesic effect of high-intensity aerobic ex-
ercise (>70% of maximal capacity) in healthy participants has
been well documented.7,51,81,82 However, some issues regarding
experimental research with healthy participants need to be
addressed. First, the release of pain-relieving peptides may be
subject to considerable intraindividual and interindividual
variation and may differ in individuals with health pro-
blems.24,25 In addition, it has been shown that the hypoalgesic
effect of exercise did not correlate with the increase of b-
endorphin and no association was found between the peak
release of peptides and the decrease of pain.20
Second, changes in pain perception are dependent on
the type of experimental model used.39 It has been shown
that the same type of exercise (ie, aerobic at 75% VO2)
produced a decrease in pressure pain thresholds but a
different response in thermal pain stimulus.82,83 In addition,
a consistent pattern in the hypoalgesic response is shown by
both the mechanical37,38,68,71,73,84,85 and ischemic86 com-
pared with thermal or cold-pressor models of experimental
pain. Third, most of the experimental studies in EIH have
been carried out in a specific population (ie, young, active
male participants).20–23,86 Therefore, the clinical application
of these results (ie, experimental studies) in patients with
musculoskeletal pain is certainly limited.
Clinically more relevant, recent evidence has shown that
in the presence of injury and inflammation of peripheral
tissues (eg, skin, muscle, joints), endogenous opioids can
produce, as a result of a cascade of physiological and
pathophysiological interactions, potent analgesia by activat-
ing opioid receptors on peripheral sensoryneurons.87 This
effect becomes more noticeable in later stages of inflamma-
tion (several days) when endogenous analgesia is predomi-
nantly mediated by peripheral opioid receptors.88 It is
interesting to note that as noninflamed tissue does not hold
opioid-producing cells, this peripherally acting opioid inhibi-
tion seems to occur only in damaged cells.89 Thus, this
phenomenon will operate differently in patients with actual
pain compared with healthy participants.
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Effects of Exercise Therapy on Musculoskeletal Pain
The interaction of the peripheral opioid system and
inflammatory processes and exercise may have clinical
implications. For example, in early stages of musculoskel-
etal painful conditions, exercise may be used as a vehicle to
possibly augment opioid peptide release. Thus, the periph-
erally acting opioid inhibition and the pain-relieving effect
could theoretically be enhanced. During their rehabilitation
process, many patients with acute musculoskeletal pain
are not capable of performing high-intensity dynamic tasks
(eg, >70% of maximal capacity). Therefore, a different type
of exercise and hypoalgesic effect is required for patients
with these clinical conditions. Although still not con-
clusive, the growing experimental evidence supporting the
hypoalgesic effects of the application of low-intensity or
moderate-intensity exercises such as isometric,37,38,68,73,84,85
eccentric,71 and resistance60,70 may have significant clinical
relevance. The application of submaximal (ie, 30% to 50%)
and short duration (ie, 90 to 120 s) isometric exercise has
been associated with an increase of pain thresholds and a
decrease of pain intensity in pressure and thermal experi-
mental pain in healthy participants.37,68,73 This evidence is
important as in other studies the hypoalgesic response
occurred as a result of the application of exhaustive
isometric contraction38,84,85,90 instead of nonexhaustive
exercise. Similarly, it has been shown that repeated bouts
of low load eccentric and concentric exercise in lateral
elbow musculotendinous pain increased pressure thresholds
(mechanical hypoalgesia) in healthy participants.71 Thus, in
acute musculoskeletal pain the application of low-intensity
and moderate-intensity exercises by means of short dura-
tion submaximal isometric, eccentric, or resistance exercises
could be a more realistic modality for reducing pain
sensitivity in these patients. However, a limitation of these
experimental findings is their low applicability to actual
clinical scenarios. As an individual’s response to exercise
can be different in experimental and clinical pain, the use of
isometric, concentric, and eccentric exercises as therapeutic
tools needs to be evaluated in trials with patient popula-
tions.
Compared with studies investigating the effect of EIH
in healthy individuals, little is known about its effects in
people with musculoskeletal painful conditions. Some
evidence shows that exercise by the means of isometric
contractions produces hyperalgesia (decrease in pain
threshold effects in patients with altered central pain
mechanisms such as fibromyalgia).37,85 Conversely, in
chronic shoulder pain, Persson et al74 found that isometric
contraction was associated with decreased sensitivity in
both the ipsilateral and contralateral side. In addition,
results from recent systematic reviews have concluded that
different exercise programs including motor control2,91 and
extensor strengthening exercises92 have comparable bene-
ficial effects in the management of LBP. However, the
underlying hypoalgesic mechanisms are unknown.
The limited evidence found in this systematic review
prevented the authors from making conclusions regarding
the effect of exercise on the increase in pain-relieving
peptides under different exercise protocols. Since Sokunbi
et al,44 apparently used only 1 session of stabilization
exercise, it is unknown whether there is an accumulative
effect of exercise or a series of exercise (ie, >1 session)
stimulating the release of pain-relieving peptides in the long
term. Considering the role of exercise as part of pain
management in rehabilitation, empirical mechanistic sup-
port is imperative. A good understanding of how exercise
www.clinicalpain.com | 371
Fuentes C et al
modulates pain and the processes associated with the EIH
phenomenon in a clinical scenario could translate into
better clinical outcomes. In addition, determining what
substances may be implicated (eg, b-endorphin, serotonin),
the intensity of exercise associated (eg, low, moderate) with
their release, and the association between nature of the
exercise (continuous in aerobic and intermittent in iso-
metric or resistance) and the hypoalgesic response will
hopefully contribute to more effective rehabilitative exercise
prescription resulting in enhanced therapeutic usefulness.
Limitations of This Systematic Review
To the best of the authors knowledge, this systematic
review is the first investigating the effect of exercise therapy
interventions on pain-relieving peptides in painful musculo-
skeletal conditions. This review does have some limitations.
As with any systematic review, there was the potential for
selection bias, however, a comprehensive search strategy was
used and included publications in any language. In addition,
the authors attempted to contact investigators to obtain
relevant information; however, no response from any
investigators was received.
The evidence accumulated from this review about the
effect of exercise in modifying the plasma/cerebral spinal
fluid concentrations or changing the cerebral activity of
areas linked with pain modulation is scarce and limited to
only 1 musculoskeletal condition (LPB). Therefore, more
research investigating different musculoskeletal painful
conditions is necessary to allow for more conclusive
recommendations.
CONCLUSIONS
No conclusive recommendations of the effect of
exercise therapy in modifying the plasma or cerebrospinal
fluid concentrations of pain-relieving peptides in patients
with musculoskeletal pain could be reached. In addition,
the potential effect of therapeutic exercise in changing the
cerebral activity of areas linked with pain processing and
pain modulation in patients suffering from musculoskeletal
pain remains unknown. There is a clear need for well-
designed trials examining exercise therapy interventions
and their effect on pain-relieving peptides and cerebral
activity in patients with musculoskeletal pain.
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