Does exercise increase or decrease

pain?
Underlying mechanism and clinical
implications
Angela BM Tulaar
 Exercise
• Exercise: any bodily activity that enhances or maintains physical fitness and
overall health and wellness
• Therapeutic Exercise: motions of the body or its parts to relieve symptoms
or to improve function (Sydney Licht, 1965)

Kylasov A, Gavrov S (2011). Diversity Of Sport: non-destructive evaluation. Paris: UNESCO: Encyclopedia of Life
Support Systems. pp. 462–91. ISBN 978-5-89317-227-0
• Remember that
'Exercise is Medicine!’
... Stretch to cool down,
not warm up, and do
short bursts of exercise,
not long stretches.
It is important to start slowly
when beginning an
exercise program, and avoid
pushing into stronger pain.
It is often useful to use the 0-10
scale to monitor pain levels
while exercising.
PAIN-FREE LIVING. Your guide to leading a healthier life
• Recent studies show tai chi can reduce arthritis pain and help
with energy, flexibility and balance, while yoga has been shown
to ease joint pain, increase joint flexibility and improve sleep.
Water walking warms the muscles, reduces inflammation and
increases range of motion.
JoAnn Stevelos. Exercise 101: Finding the Right Exercises for Pain Relief. Jan 22, 2019

• Exercise helps ease arthritis pain and stiffness. ... It increases

strength and flexibility, reduces joint pain, and helps combat
fatigue. When stiff and painful joints are already bogging down,
the thought of walking around the block or swimming a few laps
might seem overwhelming.
 rostral ventromedial medulla (RVM)

• Exercise reduces pain through a

peripheral mechanism in healthy
adults. It is well demonstrated that
a single bout of exercise can acutely
reduce pain (Naugle et al., 2012),
• a phenomenon known as exercise-
induced hypoalgesia. However,
the mechanisms of pain reduction
after exercise are not clear.
(Mar 30, 2017)
Why exercise is vital
• Strengthen the muscles around the joints
• Help maintain bone strength
• Give more energy to get through the day
• Make it easier to get a good night's sleep
• Help control body weight
• Enhance quality of life
• Improve balance
 Computational predictions of the effects of exercise,
immobilization, and remobilization on
tendon or ligament structural
properties compared with the
schematic proposed by Woo et al.
(21). Taking normal growth and development
as the control, the effects are essentially
the same for the immature and mature
cases. Exercise leads to a moderate
increase in the stiffness and failure
force. Immobilization leads to a
significant decrease in these
properties, which rapidly return to
normal with remobilization.
Tishya A. L. Wren, PhD; Gary S. Beaupré, PhD; Dennis R. Carter. Tendon and ligament adaptation to exercise, immobilization,
and remobilization. Journal of Rehabilitation Research & Development, Vol. 37 No. 2, March/April 2000, pp 217 - 224
 Effects of exercise training
(ET) on muscle proliferation
and apoptosis in 40‐week‐old
mice. (A) Representative
PCNA immunostaining with
the mouse mAb used to
assess the content of
proliferated cells.
(B,C) Quantitative data for
PCNA‐positive cells. (E)
Representative TUNEL
staining used to assess the
Inoue A, Xian Wu Cheng, Zhe Huang, et.al. Exercise restores muscle content of apoptotic cells.
stem cell mobilization, regenerative capacity and muscle metabolic (F,G) Quantitative data for
alterations via adiponectin/ AdipoR1 activation in SAMP10 mice. J
Cachexia Sarcopenia Muscle. 2017 Jun; 8(3): 370–385) TUNEL‐positive cells.

A schematic diagram describing the homeostatic
responses of ligaments and tendons in response to
different levels of stress and motion
Woo SL-Y, Gomez MA, Akeson WH: The time and
history-dependent viscoelastic properties of the
canine medical collateral ligament. J Biomech
Eng. 1981, 103: 293-298.
a few weeks of immobilization can severely
increase joint stiffness as well as significantly
decrease the structural properties and the
mechanical properties of the tissue.
Remobilization could reverse these negative
changes, but would require up to one year
before these biomechanical properties could
return to near normal levels. On the other
hand, exercise and training could only result in
marginal increases in the biomechanical
properties of ligaments and tendons. Based on
these studies, a highly nonlinear curve could
be drawn to represent the relationship
between levels of stress and motion with the
changes in properties for ligaments and
tendons.
 Overtraining
• Overtraining (OT) is characterized by a continuous
process of intensified physical training without adequate
recovery, which may induce changes in the activation and
regulation pattern of the inflammatory process
• According to the European College of Sport Science, in
2006, OT can culminate in two different states in relation to
performance:
- short-term overreaching (functional overreaching - FOR)
- extreme overreaching (non-functional overreaching -
NFOR)
The FOR (functional overreaching) state is
characterized by a rapid drop in performance
followed by an eventual improvement, in a process
that resembles the super compensation theory .
In the NFOR (non-functional overreaching) state, the
drop in performance has more prolonged recovery.
In general, it is followed by fatigue and biochemical,
immunological and physiological alterations, and
even by behavioral disorders. The NFOR state can
lead to overtraining syndrome (OTS), which as the
name implies, has features even more diffuse,
negatively affecting various systems, presenting a
very slow recovery feature
Anatomical considerations
• Centrally, the rostral ventromedial medulla (RVM) is a key relay for
pain modulation, playing a major role in exercise‐induced pain and
analgesia (Sluka & Rasmussen, 2010; Stagg et al. 2011;
Sluka et al. 2012, 2013).
• Within the caudal brainstem, the nucleus raphe magnus (NRM),
nucleus raphe obscurus (NRO) and nucleus raphe pallidus (NRP)
are involved in modulation of both pain and motor outputs
(Fields et al. 1995; Porreca et al. 2002; Zhuo et al. 2002; Da
Silva et al. 2010a), making these nuclei potential links between
physical activity and pain perception.
• Other pain‐processing areas such as the periaqueductal grey (PAG)
(Mathes & Kanarek, 2006; Stagg et al. 2011) and cortical areas (de
Oliveira et al. 2010) have been implicated in exercise‐induced pain
and analgesia.
Biochemical considerations
• N‐Methyl‐D‐aspartate (NMDA) glutamate receptors in the RVM
also play a key role in chronic muscle pain, including
exercise‐induced pain (Da Silva et al. 2010a; Sluka et al. 2012).
• Phosphorylation of the NR1 subunits of NMDA receptors in the
caudal brainstem mediates the hyperalgesia in animal models
of chronic musculoskeletal pain and exercise‐induced pain
(Sluka et al. 2012).
• On the other hand, opioidergic and serotonergic neurons are
both expressed in the RVM (Basbaum & Fields, 1984)
and there is recent evidence for the involvement of these
systems in the analgesia induced by exercise
(Stagg et al. 2011; Bobinski et al. 2015).
Increases in serotonin and
opioids, and activation of
μ‐opioid (MOR) and
cannabinoid‐1 (CB1) receptors
are implicated in the
exercise‐induced analgesia.
Further, the normally increased
phosphorylation of the NR1
subunit of the NMDA receptor
and the increased expression of
serotonin transporter (SERT)
that is increased by acute
exercise are reduced by regular
physical activity.
Pain and Fatique Interactions
Clinically, physical fatigue is a common complaint in chronic
musculoskeletal pain conditions, while chronic pain is common in
chronic fatigue conditions
(Vierck et al. 2001; Whiteside et al. 2004; Staud et al. 2005; Kadetoff & Kosek, 2007).
The overlap between muscle fatigue and pain syndromes
suggests an interaction between fatigue and pain such that
fatigue may enhance pain. Pain may be a factor in reducing
adherence to regular exercise and rehabilitation, leading the
patient to a sedentary life (Damsgard et al. 2010).
It is proposed that muscle fatigue promotes changes in central
nervous system function that cannot be explained only in the
muscle itself (Davis & Bailey, 1997).
Fatiguing exercise‐induced pain models
When an acute bout of running wheel activity (2 h) was combined
with intramuscular doses of saline of different pH (pH 4.0, 5.0, 6.0
or 7.2), enhanced hyperalgesia developed bilaterally when the
pH 5.0 injections were combined with the fatigue task – no
cutaneous hyperalgesia developed with pH 5.0 injections without
fatigue
(Yokoyama et al. 2007).
Isometric fatiguing task favours a peripheral mechanism that
results in release of fatigue metabolites like acidic pH in muscle
that subsequently activate acid sensing ion channels (ASICs).
(Gregory et al. 2013).
Central mechanisms of fatiguing exercise‐induced hyperalgesia
• C‐fos immunostaining, as a marker of neuron activation, in the caudal
brainstem was investigated. C‐fos immunoreactivity showed an increase in the
number of cells in the NRM, NRO and NRP after a 2 h running‐wheel task,
suggesting the caudal raphe might be involved in the development of
exercise‐induced hyperalgesia (Sluka et al. 2012).
• Since NMDA receptors in the RVM are involved in pain facilitation. NMDA
receptors were blocked in the NRO/NRP during the fatiguing task when
combined with 0.03% carrageenan. NMDA receptor blockade during the
fatiguing task prevented the development of exercise‐induced hyperalgesia.
(Sluka & Rasmussen, 2010)
• Over‐expression of the NR1 subunit of the NMDA receptor in the RVM, using a
feline immunodeficiency virus expressing the complementary DNA to NR1,
produced bilateral mechanical hyperalgesia of the paw and muscle, supporting
a role for NR1 in development of hyperalgesia. (Da Silva et al. 2010b)
Central mechanisms of fatiguing exercise‐induced hyperalgesia
• Since phosphorylation of NMDA receptors can enhance neuron excitability
(Chen & Roche, 2007), the expression of the phosphorylated NR1 subunit
showed:
• In the exercise‐induced pain model induced by whole‐body running wheel
activity combined with 0.03% carrageenan or pH 5.0 injections, there was an
increase in the number of cells stained for phosphorylated NR1 in the NRO,
NRM, and NRP (Sluka et al. 2012; Lima et al. 2016).
• However, there were no differences in the number of p‐NR1 labelled cells in
the electrically stimulated fatigue task combined with two pH 5.0 injections
(Gregory et al. 2013), suggesting different mechanisms in this model.
• Thus, NMDA receptor activation and phosphorylation of NMDA receptors
underlies the development of hyperalgesia from a whole‐body fatiguing task,
but not from a localized fatigue task.
Exercise‐induced analgesia
• High intensity running, or bicycle ergometry produced analgesia that
was reversed by systemic naloxone, suggesting the involvement of
opioids in exercise‐induced analgesia
(Janal et al. 1984; Olausson et al. 1986).
• Using a fatiguing isometric contraction, there were decreases in pain
thresholds that were accompanied by a reduction in cortical
excitability and motor evoked potentials assessed by transcranial
magnetic stimulation
(Bement et al. 2009).
• High levels of physical activity correlate with greater conditioned pain
modulation, which is thought to measure central inhibition, in healthy
controls
(Geva & Defrin, 2013).
Exercise‐induced analgesia
• In people with osteoarthritis, there were significant increases
in pressure pain thresholds in those with normal conditioned
pain modulation, and decreases in pressure pain thresholds
in those with reduced conditioned pain modulation,
suggesting exercise and conditioned pain modulation use
similar mechanisms
(Fingleton et al. 2017).
• Further, both conditioned pain modulation and
exercise‐induced hypoalgesia predict greater pain relief
6 months after total knee replacement
(Vaegter et al. 2017).
• Several studies show a reduction in temporal summation, a measure
of central excitability, in healthy subjects and patient populations
following aerobic and isometric exercise protocols
(Koltyn et al. 2013; Henriksen et al. 2014; Naugle & Riley, 2014;
Lemley et al. 2015; Stolzman & Bement, 2016; Vaegter et al. 2017).
• Thus, in human subjects there is evidence to support modulation of
central nervous system function with enhanced inhibition and
reduced excitation. A number of chronic pain conditions are
associated with a loss of conditioned pain modulation and increased
temporal summation, and thus lack of immediate effects of exercise,
or even increases in pain with acute exercise, could be explained by
this lack of inhibition and enhanced excitability.
• It is further likely that repeated regular exercise could restore the loss
of conditioned pain modulation.
Central mechanisms involved in exercise‐induced analgesia
• The RVM comprises, with the PAG and dorsal
horn, a descending pain inhibitory system that
both facilitates and inhibits noxious stimuli
(Porreca et al. 2002).
Within the RVM, NRM, NRO and NRP are nuclei
known to be involved in pain modulation but are
also involved in modulation of motor responses,
making them potential key areas involved in
exercise‐induced analgesia mechanisms
(Fields et al. 2006).
Three types of cells exist in the RVM: ON‐cells
promote nociception when activated, OFF‐cells
inhibit nociception when activated, and neutral
cells do not respond to noxious stimuli
(Fields et al. 2006).
Central mechanisms involved in exercise‐induced analgesia
• a shift in the balance between ON‐ and OFF‐cell
activation defines hyperalgesia or analgesia from
an exercise task.
• NMDA receptors in the RVM play a role in
facilitation of nociception with an increase in
phosphorylation of the NR1 subunit playing a
critical role
(Da Silva et al. 2010a, b; Sluka et al. 2012).
• Exercise‐induced analgesia promotes the
opposite response.
• Thus, regular physical activity and exercise
use central opioid receptors to produce
analgesia.
• Serotonin (5‐HT) has also been implicated in exercise‐induced
analgesia. One hour of swimming increases 5‐HT levels in the
brainstem and hypothalamus, while 4 weeks of swimming
extended this increase to the cerebral cortex (Dey et al. 1992).
• Similarly, 8 weeks of treadmill running showed increased levels
of 5‐HT in the midbrain and cortex (Brown et al. 1979),
• 4 weeks of treadmill running increases 5‐HT expression in the
RVM (Korb et al. 2010).

Thus, there is emerging evidence that increases in supraspinal

serotonin release, along with reductions in the serotonin
transporter, play a significant role in the analgesia produced by
regular exercise.
ENDOCANNABINOIDS
• Endocannabinoids in the central nervous system also play a
role in exercise‐induced analgesia (Dietrich & McDaniel, 2004).
• Endocannabinoid receptors are present in pain‐modulating
areas of the brain and spinal cord and activation of
endocannabinoid receptors produces analgesia
(Dietrich & McDaniel, 2004).
Further, exercise increases circulating levels of the
endocannabinoid N‐arachidonylethanolamine in healthy human
subjects (Koltyn et al. 2014).

After both aerobic and resistance exercise tasks, there is an

increased expression of the cannabinoid receptor CB1 in the
brain, including the PAG, in healthy uninjured animals.
 SUMMARY
A single bout of fatiguing exercise in the presence of a chronic pain
condition can exacerbate pain that is characterized by increased
phosphorylation of NMDA receptors in the RVM, suggesting enhanced
central facilitation.
Regular exercise promotes pain relief and is characterized by reduced
NMDA receptor phosphorylation, suggesting reduced central
facilitation. Further regular exercise reduces serotonin transporter
expression, increases serotonin levels, and increases opioids in
central inhibitory pathways including the PAG and RVM, suggesting
exercise utilizes our endogenous inhibitory systems to reduce pain.
There is a balance between inhibition and excitation in the central nervous
system that determines whether exercise will promote analgesia or
promote pain. Fitness level, physical activity levels, and state of the injury
or pain condition influence this balance.
 Which Exercises ?
• Cochrane Data Base 2005:
• Both high intensity and low intensity aerobic exercise
appear to be equally effective in improving a patient's
functional status, gait, pain and aerobic capacity for
people with OA of the knee
• Land-based therapeutic exercise was shown to
reduce pain and improve physical function for people
with OA of the knee. There were insufficient data to
provide useful guidelines on optimal exercise type or
dosage.
• Supervised exercise classes appeared to be as
beneficial as treatments provided on a one-to-one
basis.
• Multiple studies have
demonstrated that quadriceps
strengthening exercises can
increase strength and;
• Decrease dependency
• Improve function with ADLs
• Increase walking speed
• Decrease pain.

(Tulaar, ABM, 2004)

Yoga for pain management
• “According to Iyengar, ‘The body is the bow, the asana is the arrow, and the soul is the target,’” says
Mazabow. “If we feel that our lives are becoming unmanageable, the practice of yoga helps us to
pause and drop into peace — giving us a chance to self-correct.” In India, she notes, yoga isn’t
usually practiced simply for fitness as it is in western countries. Instead, a person with a particular
ailment will go to a yoga master to be given specific asanas to help with his or her problem.
• “The Zen masters teach that pain is unavoidable but suffering is optional,” says Mazabow. “In other
words, at some point in our lives we will have pain, whether physical or emotional. It is how we deal
with pain that matters; we can choose to hang on to it or we can let it go.” By choosing to practice
yoga, you can work on the physical aspects of pain through poses, as well as the mental aspects
through breathing techniques, bringing you into a space of quiet meditation.
• Pain is, in fact, relative. A person with an X-ray showing fairly extensive osteoarthritic damage might
not be in pain, whereas someone with a far lesser degree of damage may experience more severe
pain. Yoga helps change your relationship with pain, increases your ability to get
through daily activities, and improves your energy levels. Indeed, Mehta says, “There are
research studies published in peer-reviewed science journals clearly showing how when pain
decreases, there is a decrease in the consumption of pain medication and improved mobility.”
• Water workouts can help relieve pain. Water
compresses the body, which helps reduce
swelling and fluid buildup, relieving
inflammation of the joints. For people who
live with joint pain, reduced gravity in water
assists with mobility and lessens joint impact
during exercise.
• Aquatic exercises include water aerobics,
deep-water movements, yoga, tai chi, and
swimming; often referred to as vertical
workouts because most water exercises are
done standing up; you do not need to know
how to swim or go under water to participate.
 Physical activity and exercise for chronic pain in adults:
an overview of Cochrane Reviews
Louise J Geneen,1 R Andrew Moore,2 Clare Clarke,3 Denis Martin,4 Lesley A Colvin,5 and Blair H Smith1

• Chronic pain is defined as pain lasting beyond normal tissue healing time,
generally taken to be 12 weeks. It contributes to disability, anxiety, depression,
sleep disturbances, poor quality of life, and healthcare costs. Chronic pain has a
weighted mean prevalence in adults of 20%.
• For many years, the treatment choice for chronic pain included recommendations
for rest and inactivity. However, exercise may have specific benefits in reducing
the severity of chronic pain, as well as more general benefits associated with
improved overall physical and mental health, and physical functioning.
• We extracted data for (1) self-reported pain severity, (2) physical function
(objectively or subjectively measured), (3) psychological function, (4) quality of
life, (5) adherence to the prescribed intervention, (6) healthcare use/attendance,
(7) adverse events, and (8) death.
Physical activity and exercise for chronic pain in
adults: an overview of Cochrane Reviews
Louise J Geneen,1 R Andrew Moore,2 Clare Clarke,3 Denis Martin,4 Lesley A Colvin,5 and Blair H Smith1

• We included 21 reviews with 381 included studies and 37,143

participants. Of these, 264 studies (19,642 participants) examined
exercise versus no exercise/minimal intervention in adults with chronic
pain and were used in the qualitative analysis.
• Pain conditions included rheumatoid arthritis, osteoarthritis, fibromyalgia,
low back pain, intermittent claudication, dysmenorrhoea, mechanical
neck disorder, spinal cord injury, postpolio syndrome, and patellofemoral
pain. None of the reviews assessed 'chronic pain' or 'chronic widespread
pain' as a general term or specific condition. Interventions included
aerobic, strength, flexibility, range of motion, and core or balance training
programmes, as well as yoga, Pilates, and tai chi.
 Physical activity and exercise for chronic pain in
adults: an overview of Cochrane Reviews
Louise J Geneen,1 R Andrew Moore,2 Clare Clarke,3 Denis Martin,4 Lesley A Colvin,5 and Blair H Smith1
• According to the available evidence (only 25% of included studies reported
on possible harm or injury from the intervention), physical activity did not
cause harm. Muscle soreness that sometimes occurs with starting a new
exercise subsided as the participants adapted to the new activities. This is
important as it shows physical activity in general is acceptable and unlikely
to cause harm in people with chronic pain, many of whom may have
previously feared it would increase their pain further.
• Future studies should focus on increasing participant numbers, including a
wider range of severity of pain (more people with more severe pain), and
lengthening both the intervention (exercise programme) itself, and the
follow-up period. This pain is chronic in nature, and so a long-term
intervention, with longer periods of recovery or follow-up, may be more
effective.
Cochrane Database Syst Rev. 2017 Apr 24; (4): CD011279. Published online 2017 Apr 24. doi: 10.1002/14651858.CD011279.pub3
 “The goal of Pilates is to
Pilates exercise strengthen the muscles
around the areas that are
arthritic,” said Miller, who
instructs many people living
with different types of
arthritis and chronic pain
conditions. “Working and
strengthening the muscles
through a regular Pilates
program will take the load
and burden off the hips,
Pilates instructor Marilyn Miller has been living with arthritis knees, and feet and produce
for the last 17 years. She developed arthritis in the spine a positive effect.”
following her career as a professional ballet dancer.
Review Duration Frequency Intensity Duration Other
(sessions per (per session) description
day/wk/month)
Bidonde 2014 17 wk (range 4 to 1 to 4/wk Very light (< 57% 45 minutes No minimum
32) HRmax) to (range 30 to 70) requirement for
vigorous (95% inclusion.
HRmax), self- None of the
selected, and not studies met the
specified ACSM exercise
guidelines
specified for
aerobic or
strength training.
Only 1 study met
the ACSM
guidelines for
flexibility
training.

Brown 2010 ≥ 12 wk 3/wk 70% to 85% 1 hour No minimum

HRR requirement for
inclusion.
 Tips for Exercising When You Have Chronic Pain

• Start slowly and gradually increase

efforts as you gain strength,
flexibility, and confidence.
• Move at your own pace. ...
• Exercise every day, if possible.
• Strive for a balanced routine of
cardiovascular, strengthening, and
stretching exercise.