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doi: 10.2522/ptj.20130597
Originally published online July 17, 2014
Published online July 17, 2014PHYS THER.
Kara E. Hannibal and Mark D. Bishop
Management in Pain Rehabilitation
Psychoneuroendocrine Rationale for Stress
Chronic Stress, Cortisol Dysfunction, and Pain: A
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Chronic Stress, Cortisol Dysfunction,
and Pain: A Psychoneuroendocrine
Rationale for Stress Management in
Pain Rehabilitation
Kara E. Hannibal, Mark D. Bishop
Pain is a primary symptom driving patients to seek physical therapy, and its attenu-
ation commonly defines a successful outcome. A large body of evidence is dedicated
to elucidating the relationship between chronic stress and pain; however, stress is
rarely addressed in pain rehabilitation. A physiologic stress response may be evoked
by fear or perceived threat to safety, status, or well-being and elicits the secretion of
sympathetic catecholamines (epinephrine and norepinepherine) and neuroendo-
crine hormones (cortisol) to promote survival and motivate success. Cortisol is a
potent anti-inflammatory that functions to mobilize glucose reserves for energy and
modulate inflammation. Cortisol also may facilitate the consolidation of fear-based
memories for future survival and avoidance of danger. Although short-term stress may
be adaptive, maladaptive responses (eg, magnification, rumination, helplessness) to
pain or non–pain-related stressors may intensify cortisol secretion and condition a
sensitized physiologic stress response that is readily recruited. Ultimately, a pro-
longed or exaggerated stress response may perpetuate cortisol dysfunction, wide-
spread inflammation, and pain. Stress may be unavoidable in life, and challenges are
inherent to success; however, humans have the capability to modify what they
perceive as stressful and how they respond to it. Exaggerated psychological
responses (eg, catastrophizing) following maladaptive cognitive appraisals of poten-
tial stressors as threatening may exacerbate cortisol secretion and facilitate the
consolidation of fear-based memories of pain- or non–pain-related stressors; however,
coping, cognitive reappraisal, or confrontation of stressors may minimize cortisol
secretion and prevent chronic, recurrent pain. Given the parallel mechanisms under-
lying the physiologic effects of a maladaptive response to pain and non–pain-related
stressors, physical therapists should consider screening for non–pain-related stress to
facilitate treatment, prevent chronic disability, and improve quality of life.
K.E. Hannibal, PT, DPT, Rehabilita-
tion Science Doctoral Program,
University of Florida, PO Box
100154, Gainesville, FL 32610-
0154 (USA). Address all corre-
spondence to Dr Hannibal at:
hannibal@ufl.edu.
M.D. Bishop, PT, PhD, Depart-
ment of Physical Therapy, Univer-
sity of Florida, Gainesville.
[Hannibal KE, Bishop MD. Chronic
stress, cortisol dysfunction, and
pain: a psychoneuroendocrine
rationale for stress management in
pain rehabilitation. Phys Ther.
2014;94:xxx–xxx.]
© 2014 American Physical Therapy
Association
Published Ahead of Print:
July 17, 2014
Accepted: July 6, 2014
Submitted: December 9, 2013
Perspective
Post a Rapid Response to
this article at:
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Pain is a leading cause of disabil-
ity, decreases in work produc-
tivity, poor quality of life, and
rising medical expenses.
1,2
Pain is
also a primary symptom driving
patients to seek physical therapy,
and its attenuation commonly
defines a successful outcome.
3,4
Patient evaluation and differential
diagnosis require clinicians to differ-
entiate among a broad range of
potential sources of pain. To simplify
this process, physical therapists are
trained to identify and rule out “red
flags” and “yellow flags” prior to ini-
tiating treatment. Although red flags
generally refer to symptoms of non-
musculoskeletal origin (eg, visceral
pain), yellow flags are used to signify
psychosocial components such as
fear and catastrophizing behav-
iors.
5,6
Similarly, although red flags
warrant referral, yellow flags are
meant to warn clinicians that treat-
ment is likely to be complicated by
psychological variables and progno-
sis may be fair.
5,6
Physical therapists
are becoming increasingly proficient
in the identification and treatment of
yellow flags; however, outcomes
vary by individual, and the influence
of non–pain-related stress is worthy
of consideration.
A pain-induced stress response is
elicited by a magnified perception of
pain as threatening or dangerous
(catastrophizing) and often mani-
fests as fear and avoidance of pain-
provoking stimuli.
2,7,8
The overall
literature suggests that exaggerated
psychosocial responses to acute
pain are maladaptive and likely to
intensify the pain experience and
impede recovery.
2,7–10
A large num-
ber of studies examining risk fac-
tors for pain report an association
between musculoskeletal pain and
pain-related psychosocial stress,
such as fear, catastrophizing, and
negative coping.
1,2,7–9
The fear-
avoidance model (FAM) describes 2
alternative responses to the experi-
ence of pain; a fear-avoidance or
catastrophizing response may pro-
long the pain experience and aug-
ment a cycle of chronic pain and
disability, whereas confrontation
may break the pain-fear-avoidance
cycle and promote recovery.
2,7–9
This approach to chronic pain man-
agement is occasionally used by
physical therapists with techniques
such as graded exercise and graded
exposure.
11
Although these methods
may be used to promote confron-
tation of pain-related fears, similar
exaggerated responses to non–pain-
related stressors may initiate, exac-
erbate, or prolong the pain experi-
ence. A greater understanding of
the detrimental role of an exagger-
ated response to pain or non–pain-
related stressors in perpetuating
chronic pain and disability requires a
broad understanding of the underly-
ing sympathetic and neuroendocrine
mechanisms involved.
The first aim of the current article is
to review the physiologic stress
response and convey the parallel
mechanisms underpinning maladap-
tive responses to pain and non–pain-
related stressors. The second aim is
to underscore the role of the physi-
ologic stress response in exacerba-
tion of the pain experience and the
development of chronic symptoms.
Finally, the overarching goal of this
article is to highlight the importance
of addressing and managing the fear-
based perception of potential stres-
sors as threatening for the effective
and long-term treatment of pain.
Although life-threatening psycholog-
ical symptoms may warrant referral,
patient education regarding the jux-
taposed psychological and physio-
logic relationship between pain and
stress, in addition to coping skills,
may be utilized to minimize pain and
disability and maximize quality of
life.
The Stress Response—the
Hypothalamic-Pituitary-
Adrenal (HPA) Axis and
Cortisol
Neurologically, humans function on
a continuum between sympathetic
(fight or flight) and parasympathetic
(rest and digest). The sympathetic
nervous system promotes catabolic
tissue breakdown and fat metabo-
lism to mobilize glucose for energy
and promote arousal, alertness, moti-
vation, and goal-directed behavior.
12
At the other end of the spectrum, the
parasympathetic nervous system
promotes healing, repair, immunity,
and the anabolic growth required for
restored energy reserves and longev-
ity.
12
Needless to say, a delicate bal-
ance between sympathetic and para-
sympathetic activity is critical for
long-term physical and psychological
health.
Cortisol is a vital catabolic hormone
produced by the adrenal cortex of
the kidney.
13
It is released in a diur-
nal fashion, with blood levels peak-
ing in the morning to facilitate
arousal and steadily declining there-
after.
14,15
Throughout the day, cor-
tisol maintains blood glucose and
suppresses nonvital organ systems
to provide energy to an actively
functioning brain and neuromus-
cular system.
16
Cortisol is also a
potent anti-inflammatory hormone;
it prevents the widespread tissue
and nerve damage associated with
inflammation.
16
In addition to its paramount role in
normal daily function, cortisol is a
key player in the stress response. In
the presence of a physical or psycho-
logical threat, cortisol levels surge to
provide the energy and substrate
necessary to cope with stress-
provoking stimuli or escape from
danger.
13,17
However, although a
stress-induced increase in cortisol
secretion is adaptive in the short-
term, excessive or prolonged corti-
Chronic Stress, Cortisol, and Pain
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sol secretion may have crippling
effects, both physically and
psychologically.
16–18
The Acute Stress Response
A “stressor” is any stimulus or event
that evokes a physiologic stress
response, commonly referred to as a
state of “stress” or “anxiety.” A stres-
sor may be a physical or psycholog-
ical threat to safety, status, or well-
being; physical or psychological
demands that exceed available
resources; an unpredictable change
in environment; or an inconsistency
between expectations and out-
comes.
7,19,20
Whether the stressor is
pain or non–pain-related (eg, work
overload, financial troubles, social
embarrassment), the perception of
uncontrollable or unpredictable
environmental demands that exceed
coping resources is likely to evoke a
physiologic stress response, mani-
festing as a feeling of uneasiness or
impending doom, rumination or
worry, and avoidance of stress-
provoking stimuli.
1,2,7,20
However,
the perception of environmental
stimuli as threatening or frightening
varies by individual; therefore, the
same fear-based stressor that evokes
a stress response in one individual
may be innocuous to another. Fear of
the worst possible outcome (eg,
unemployment, bankruptcy), fear of
social embarrassment, fear of pain,
or fear of failure activates the
amygdala, a portion of the brain’s
limbic system.
21
The amygdala
responds to fear or danger by initiat-
ing an immediate sympathetic
response, followed shortly thereafter
by a neuroendocrine response, in an
instinctive attempt to restore homeo-
stasis and promote survival.
13,15,22,23
Maladaptive cognitive appraisals or
beliefs regarding the threatening
nature of potential stressors may pro-
mote an exaggerated physiologic
stress response that is likely to initi-
ate, exacerbate, or prolong the pain
experience.
20,24,25
Importantly, pain
itself is a potential stressor, and a
maladaptive perception of pain as
threatening or frightening may
evoke an exaggerated physiologic
stress response, thereby perpetuat-
ing chronic pain and disability.
In the initial stage of the acute stress
response, the amygdala signals the
brain stem to release sympathetic
adrenergic catecholamines, norepi-
nephrine and epinephrine.
15,26
Once
released into the blood flow, cate-
cholamine neurotransmitters increase
heart rate, blood pressure, and res-
piration; vasoconstrict arterioles;
and stimulate sweat secretion and
pupillary dilation.
12
Importantly,
this short-term sympathetic response
is proinflammatory, functioning to
destroy antigens, pathogens, or for-
eign invaders; adrenoreceptor antag-
onists have been shown to inhibit
stress-induced inflammation and
cytokine production by blocking the
proinflammatory effects of norepi-
nepherine.
13,26,27
Although the role
of the sympathoadrenal medullary
response in chronic pain is impor-
tant to consider, the details are
beyond the scope of this article.
While sympathetic neurotransmitters
regulate the initial stage of the acute
stress response, a neuroendocrine
response follows in a delayed but
prolonged and gene-mediated fash-
ion.
26,28
Upon the perception of
stress, the amygdala activates the
HPA axis by signaling the hypo-
thalamus to release corticotropin-
releasing hormone (CRH).
17
This
hormone then triggers the release of
adrenocorticotropic hormone (ACTH)
from the anterior pituitary, and
ACTH stimulates the release of cor-
tisol from the adrenal cortex.
14
Approximately 15 minutes after the
onset of stress, cortisol levels rise
systemically and remain elevated
for several hours.
13,22
Increased lev-
els of cortisol mobilize glucose
and tissue substrates for fuel, sup-
press nonvital organ systems, and
decrease inflammation to allow for
the effective management of stress.
16
The critical anti-inflammatory role
of cortisol may be emphasized by
the countless inflammatory disor-
ders commonly treated with its syn-
thetic pharmaceutical replacement,
corticosteroids.
29
The Chronic Stress
Response
Stressful events are inevitable in
daily life, and overcoming obstacles
is inherent to success. Although it
may not be realistic to live and work
in a world free of stressors, humans
have the capacity to control what
they perceive as stressful and how
they respond to it.
20
A short-term
stress response to pain or non–pain-
related stressors may serve an adap-
tive function to promote survival
or motivate success; however, a
chronic stress response may be cat-
astrophic.
15,17
Exaggerated or recur-
rent negative cognitions, rumination
or worry, magnification, and help-
lessness are all maladaptive cata-
strophizing responses to pain or
non–pain-related stress that may pro-
long cortisol secretion.
30–33
Similar
alterations in cortisol levels have
been reported following laboratory-
induced stress, self-reported stress,
and a catastrophizing response to
pain.
20,30,31,34,35
Whether the stress-
provoking stimulus is pain or non–
pain-related, chronic reactivation of
the stress response and repeated
surges of cortisol result in cortisol
dysfunction.
The overall literature suggests sev-
eral possible neuroendocrine alter-
ations underlying cortisol dysfunc-
tion: depletion of cortisol,
insufficient free (unbound) cortisol,
impaired cortisol secretion or CRH
function, glucocorticoid receptor
(GR) resistance or down-regulation,
or hypersensitivity of the negative
feedback system.
18,36–39
Therefore,
although cortisol depletion follow-
ing prolonged or excessive secretion
may contribute to its dysfunction,
Chronic Stress, Cortisol, and Pain
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there are additional explanations to
consider.
Under normal conditions, cortisol
binds to the GR and acts as an anti-
inflammatory.
15,36
However, pro-
longed or excessive cortisol secre-
tion may result in a compensatory
down-regulation or resistance of the
GR that blocks cortisol binding, sim-
ilar to the mechanism underlying
insulin-resistant diabetes.
28,36
It also
has been suggested that extreme
surges in cortisol may increase its
affinity for the mineralocorticoid
receptor (MR), and when bound to
the MR, cortisol has proinflamma-
tory effects.
26
In either case, elevated
inflammatory by-products may dam-
age the GR, thereby compounding
cortisol dysfunction.
39
Additionally,
impaired binding to the GR may
disrupt the negative feedback mech-
anism by which cortisol normally
inhibits the continued release of
CRH when its levels are sufficient.
36
Corticotropin-releasing hormone has
been reported to activate inflamma-
tory mast cells, stimulate the release
of norepinepherine (a proinflamma-
tory sympathetic neurotransmitter)
from the locus coeruleus, and up-
regulate glutamate and N-methyl-D-
aspartate (NMDA) in the amygdala
to condition a fear-based stress
response.
15,36,38,40
It also has been
reported that non–pain-related acti-
vation of CRH receptors in the
amygdala may trigger pain in the
absence of tissue damage and
increased excitatory input may
hyperpolarize postsynaptic poten-
tials, rendering the amygdala resis-
tant to inhibitory input from the
prefrontal cortex.
35,40
Although
research has yet to identify exactly
which mechanisms underlie the pro-
cess of stress-induced cortisol dys-
function, its etiology is likely a com-
bined, multifactorial, and cyclical
process that may be tissue specific
and vary by individual and environ-
mental factors.
Regardless of the neuroendocrine
mechanisms involved, the long-term
effect of chronic stress remains the
same: cortisol fails to function. In an
animal model, blunted corticoste-
rone (equivalent to cortisol in a rat)
levels were observed after 2 weeks
of repeated restraint stress, and the
constant stress of morphine with-
drawal produced hypocortisolism
after 8 days.
36
In humans, stress-
induced inflammation has been
implicated in diseases such as osteo-
porosis, rheumatoid arthritis, myop-
athy, fibromyalgia, chronic fatigue
syndrome, chronic pelvic pain, tem-
poromandibular joint dysfunction,
chronic low back pain, sciatica, and
more.
14,31,36,41,42
Cortisol is a potent
anti-inflammatory, and its failure to
function results in an unmodulated
inflammatory response to physical
pathogens, unrecognized proteins,
or psychological stressors.
15,36
Inflammation induces oxidative and
nitrosative stress, free radical dam-
age, cellular death, aging, and sys-
temic tissue degeneration.
43,44
Signs
and symptoms of stress-induced
cortisol dysfunction include bone
and muscle breakdown, fatigue,
depression, pain, memory impair-
ments, sodium-potassium dysregula-
tion, orthostatic hypotension, and
impaired pupillary light reflex.
36
Furthermore, stress-induced wide-
spread inflammation may be the
final straw in a multifactorial chain
of events contributing to hundreds
of idiopathic inflammatory autoim-
mune diseases.
15,36
The HPA Axis and Cortisol:
Influences on Pain
A large body of evidence is dedicated
to elucidating the relationship
between pain and stress. Numerous
prospective studies have reported
baseline anxiety scores to be signifi-
cant predictors of pain, depression,
and a reduced quality of life.
1,41,45–48
Importantly, pain itself is a stressor,
and a maladaptive response to acute
pain may intensify the pain experi-
ence and condition a sensitized
physiologic stress response to pain-
provoking stimuli.
21,24,25,49
Exagger-
ated, prolonged, or recurrent activa-
tion of a sensitized stress response to
pain or non–pain-related stressors
may initiate or exacerbate pain and
disability.
16,41,45
Although the rela-
tionship between pain and stress is
widely accepted, the underlying neu-
roendocrine mechanisms involved
are less understood.
The Acute Stress Response:
Influences on Pain
Under normal conditions, cortisol
secretion during an acute stress
response serves to mobilize glucose
reserves for energy, inhibit pain
and non–vital organ systems, and
promote an adaptive fight-or-flight
response.
16
Additionally, stress-
induced cortisol secretion may facil-
itate the formation of a fear-based
memory conditioned to elicit a sen-
sitized fight-or-flight response to
promote survival and avoidance
of future threat.
50
However, these
effects may be specific to the fear
or stress-provoking stimuli. For
example, whereas cortisol secretion
during a non–pain-related stress
response (eg, public speaking) may
distract attention from a concurrent
painful stimulus, thereby inhibiting
pain, cortisol secretion in response
to pain (where pain is the stressor)
may intensify its experience and
condition a fear-based memory of
pain.
24,25,49
Whatever the perceived
threat or focus of attention may be,
excessive cortisol secretion is likely
to intensify its experience, facilitate
the formation of a fear-based mem-
ory, and condition a sensitized phys-
iologic stress response.
20
The amygdala regulates the percep-
tion of fear and the conditioning of a
learned physiologic stress response
to negatively appraised emotional
stimuli.
21,50,51
Numerous studies
have shown associations between
cortisol and increased levels of activ-
Chronic Stress, Cortisol, and Pain
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ity in the amygdala during states of
anxiety and fear.
23,35,40,51–54
Animal
studies have demonstrated that cor-
tisol promotes dendritic growth
and strengthens synaptic connectiv-
ity in the amygdala to facilitate the
formation of fear-based emotional
memories by increasing glutamate
levels, up-regulating NMDA recep-
tors, potentiating prolonged calcium
uptake, and increasing levels of
brain-derived neurotrophic factor
(BDNF).
23,35,40,51,55
It also has been
reported that lesions of the amygdala
block the conditioning of a fear-
based stress response and inhibit the
progression from acute to chronic
pain (ie, chronic reactivation of a
fear-based memory of pain).
23,40,56
In a systematic review of 48 human
functional magnetic resonance imag-
ing (fMRI) studies examining brain
regions involved in fear condition-
ing, the amygdala was reported to be
the most consistently activated
across all studies.
54
Although the role
of the amygdala in the fear response
is widely accepted, the additional
brain regions involved are less
agreed upon. The hippocampus, cin-
gulate cortex, insula, caudate, and
dentate gyrus have all been consid-
ered to play a role in the formation of
fear-based memories.
22,52–54
How-
ever, some fMRI studies in humans
have shown that during an acute
stress response, a decrease in
amygdala-hippocampal connectivity
was associated with elevated salivary
cortisol.
53,57
While the hippocampus
is a key player in the encoding and
retrieval of long-term memory under
normal conditions, recent studies
hypothesized that humans utilize
alternative pathways to consolidate
emotional fear-based memories dur-
ing episodes of acute stress.
23
Fur-
thermore, under normal conditions,
the hippocampus may tonically
inhibit the amygdala and hypothala-
mus, thereby reducing hyperactivity
of the HPA axis.
15,17
It has been sug-
gested that decreased hippocampal
activity during acute stress, and long-
term hippocampal atrophy following
chronic stress, may disinhibit the
amygdala and disrupt the balance
between hippocampal and amygda-
loid regulation of the HPA axis.
22,51
To summarize, the amygdala inter-
prets a potential stressor as threaten-
ing or frightening and elicits cortisol
secretion; cortisol facilitates the for-
mation of a fear-based memory by
conditioning maladaptive emotional
responses in the amygdala, thereby
increasing HPA axis activation.
24,25,49
Importantly, cortisol-induced mem-
ory formation may be specific to the
focus of attention during an acute
stress response, and the prefrontal
cortex may exacerbate or attenuate
amygdala activity and cortisol
secretion.
17,20
Human studies have demonstrated
that cortisol levels rise in anticipa-
tion of a stressful event and eleva-
tions vary by magnitude of perceived
threat.
13,20,22
A verbally induced
nocebo effect (whereby negative
expectation enhances the pain expe-
rience) was shown to elicit an
increase in pain intensity and corti-
sol secretion during laboratory-
induced ischemic pain, and nocebo-
induced pain (but not ischemic pain
alone) was successfully reversed
with diazepam, a common antianxi-
ety medication.
24
Similarly, attention
to a stressor before or during its
occurrence is likely to elevate corti-
sol secretion and condition a sensi-
tized, fear-based stress response.
20,58
Magnification, helplessness, and
rumination are 3 catastrophizing
responses whereby attention to
pain as a stressor, in addition to
worry and passive coping, prolong
the stress response and elevate cor-
tisol secretion.
30–33
Similar alter-
ations in cortisol have been dem-
onstrated in studies examining a
catastrophizing response to pain,
negative cognitive appraisals or pes-
simistic beliefs about life events, pre-
examination stress in medical stu-
dents, and work overload in hospital
employees.
20,30–32,58
Whether the
stressor is pain or non–pain-related,
cortisol secretion is likely to contrib-
ute to the consolidation of fear-based
emotional memories that are readily
recruited by nonthreatening stimuli
and conditioned to reactivate the
stress response.
The Chronic Stress
Response: Influences on
Pain
Chronic reactivation of a sensitized
stress response exhausts the HPA
axis, and cortisol dysfunction is
commonly implicated in idiopathic
pain and inflammation.
14,16,32,36,41
Chronic stress-induced hypocortiso-
lism has been well documented and
linked to pain somatization disor-
ders, such as fibromyalgia, chronic
fatigue syndrome, chronic pelvic
pain, and temporomandibular disor-
der.
14,15,41
Long-term stress has been
shown to attenuate the cortisol
awakening response and contribute
to morning fatigue, pain, and inflam-
mation.
59,60
In a study of 121 middle-
aged adults, a blunted cortisol awak-
ening response was predictive of
pain and fatigue later that day.
41
Sim-
ilarly, hypocortisolism has been asso-
ciated with low back pain, and a low
cortisol awakening response was
associated with leg pain intensity,
pain catastrophizing, and low coping
scores in 42 patients diagnosed with
lumbar disk herniations.
33,61
Further-
more, long-term follow-up investiga-
tions have suggested a predictive
relationship between hypocortiso-
lism and new-onset musculoskeletal
pain.
38,41
Acute pain is a stressful stimulus that
is likely to elicit cortisol secretion
and is commonly associated with
hypercortisolism, whereas repeated
or magnified cortisol secretion fol-
lowing maladaptive responses to
acute pain or a non–pain-related
stressor is likely to perpetuate hypo-
Chronic Stress, Cortisol, and Pain
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cortisolism and chronic, recurrent
pain (Figure).
14,15,36,41
Although the
overall evidence suggests an associa-
tion between hypocortisolism and
chronic pain, several studies have
reported hypercortisolism in chronic
pain conditions, and the temporal
aspects of cortisol dysfunction may
depend on the magnitude and dura-
tion of perceived threat.
13,20,22,25
For
example, short-term exaggerated
responses to daily stressors may
cause repeated short-term surges
of cortisol secretion that rapidly
exhaust cortisol levels, presenting as
recurrent episodes of hypercortiso-
lism followed by hypocortisolism
and pain.
13,16,36
Alternatively, a pro-
longed or constant low-amplitude
stress response may perpetuate con-
stant pain and prolonged hypocorti-
solism.
62
Additionally, the varying
temporal aspects of the relationship
between cortisol dysfunction and
pain may be attributed to different
underlying mechanisms of cortisol
dysfunction (previously discussed).
For example, depletion of circulating
free (unbound) cortisol may cause
short-term hypocortisolism, whereas
inflammatory damage to the GR
receptor may cause more long-term
effects. To summarize, the temporal
aspects of the relationship between
pain and cortisol dysfunction may
vary based on the specific parame-
ters of the individualized stress
response (duration and magnitude of
perceived threat), the varying mech-
anisms of cortisol dysfunction (eg,
sufficient free cortisol levels, GR
receptor dysfunction), and countless
environmental or situation-specific
factors. Although these inconclusive
hypotheses require clarification by
future study, it is reasonable to con-
clude that cortisol dysfunction is
likely to contribute to the develop-
ment of chronic pain.
Recovery
Rapid Return to Baseline
Adaptive
Response
Confrontation
Coping
Physiologic
Stress Response
(E/NE and
Cortisol Secretion)
STRESSOR
Fear-Based Threat
(Pain or Non–Pain-Related)
Maladaptive
Response
Catastrophizing:
Rumination
Helplessness
Magnification
Sensitized
Fear-Based
Memory
Prolonged or Excessive
HPA Axis Activation
Cortisol Dysfunction
Inflammation
PainDepression
}
}
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T
E
C
H
R
O
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I
C
Figure.
Proposed role of stress-related hypothalamic-pituitary-adrenal (HPA) axis activation in the transition from acute to chronic pain. Acute
stress response: pain or non–pain-related stressor activates a normal physiologic stress response (short-term sympathetic release of
epinepherine and norepinepherine [E/NE] followed by secretion of the anti-inflammatory hormone, cortisol). An adaptive coping
response permits the return to normal levels of E/NE, cortisol, and inflammation; a maladaptive response causes excessive or
prolonged cortisol secretion and creates a fear-based memory of the stressful stimulus that is sensitized and readily reactivated by
future stressors. Chronic stress response: prolonged cortisol secretion (due to maladaptive coping response to acute stress) results in
cortisol dysfunction. Cortisol dysfunction results in unmodulated inflammation following reactivation of the stress response, which
may contribute to a cycle of inflammation, depression, and pain; pain is a stressor that may reactivate a proinflammatory stress
response, now unmodulated due to cortisol dysfunction.
Chronic Stress, Cortisol, and Pain
6fPhysical Therapy Volume 94 Number 12 December 2014
at APTA Member on November 11, 2014http://ptjournal.apta.org/Downloaded from
Cortisol is a potent anti-inflammatory
hormone, and its dysfunction is
likely to result in widespread inflam-
mation following the reactivation of
an acute proinflammatory stress
response. Studies have shown asso-
ciations among inflammatory cyto-
kines, stress-related chronic pain,
and salivary hypocortisolism.
26,63
There are countless mechanisms by
which widespread inflammation
may contribute to pain, as pain is a
definitive component of the inflam-
matory response. Reactivation of a
sensitized stress response in the
presence of physical or psychologi-
cal threat or fear elicits the release
of proinflammatory sympathetic cat-
echolamines, and the impaired anti-
inflammatory function of cortisol
may intensify and prolong a formerly
short-term inflammatory response.
17
Similarly, following physical injury
under normal conditions, localized
secretion of inflammatory cytokines
initiates the healing process and
lowers nociceptor thresholds to
elicit a protective pain response.
However, physical injury during a
state of stress-induced hypocorti-
solism may result in a persistent
inflammatory response that impairs
healing. Additionally, prolonged ele-
vation of inflammatory cytokines
sensitizes nociceptors, manifesting
as an increase in pain sensitivity. Fur-
thermore, continuous reactivation of
the stress response by unmodulated
inflammatory mediators and condi-
tioned emotional hyper-responsive-
ness may compound the effects of
inflammation, reinforce a condi-
tioned stress response, and amplify
the cycle of stress, inflammation, and
pain.
15,36
Inflammation produces free radical
byproducts, and oxidative and nitro-
sative stress damage healthy tis-
sue.
43,44
Accumulation of free radi-
cals over time underlies the aging
process, and oxidative stress may be
responsible for widespread tissue
degeneration. Osteoporosis, myopa-
thies, and idiopathic neuropathies
are common manifestations of wide-
spread inflammation, and pain is a
common side effect of these condi-
tions.
13–16
To complicate the pro-
cess, inflammation widens gap junc-
tions in the blood brain barrier and
intestinal lining, allowing for harmful
toxins and large foreign bodies
(unrecognized by the immune sys-
tem) to breach the protective barri-
ers and exacerbate the inflammatory
response.
26
Furthermore, wide-
spread inflammatory hypersensitivi-
ties to unrecognized proteins may
give rise to autoimmunity, whereby
the immune system mistakenly
attacks healthy tissue.
15,16
Addition-
ally, widespread inflammation and
free radical binding to healthy cells
may create abnormal growths or can-
cerous cells.
64
Low cortisol awaken-
ing responses have been associated
with poor overall health, acquired
immunodeficiency syndrome, and
cancer.
64
Ultimately, the damaging
effects of widespread inflammation
may contribute to the multifactorial
etiology of countless patholo-
gies.
43,64,65
Although genetics and
environmental exposures may be
unavoidable, a conditioned physio-
logic response to a maladaptive psy-
chological perception of threat may
be a modifiable contributing factor.
Low levels of serotonin have been
widely implicated in the etiology
of pain and impaired inhibition
of nociceptive transmission in the
spinal cord.
66
Selective serotonin
reuptake inhibitor antidepressant
medications are frequently pre-
scribed for pain relief.
66
Serotonin
is synthesized from the amino
acid, tryptophan, and inflamma-
tory activation of the indoleamine
2,3-dioxygenase enzyme activates
tryptophan breakdown into kyneu-
rine and quinolinic acid (trypto-
phan catabolites [TRYCATs], or
by-products of tryptophan catabo-
lism).
43,44
Activation of the TRYCAT
pathway depletes tryptophan avail-
ability for serotonin synthesis and
has been associated with depression,
anxiety, and pain.
43,44
Additionally,
quinolinic acid is a strong NMDA
agonist with neurotoxic effects that
may exacerbate pain via hippocam-
pal degeneration.
43,44
Reduced hip-
pocampal volume has been reported
to be directly correlated with self-
reported pain intensity and chronic
stress.
55,67
Therefore, chronic stress
and inflammation may contribute to
pain and depression by TRYCAT-
induced serotonin depletion and hip-
pocampal degeneration.
Chronic stress and lack of control
over life experiences when out-
comes fail to meet expectations may
manifest as a sense of helplessness or
hopelessness.
19
After repeated disap-
pointments and failures to achieve
success, humans are likely to give up
when they feel a loss of control.
Although chronic fears, challenges,
and unexpected events define anxi-
ety, repeated failures, giving up,
helplessness, and hopelessness are
all characteristics of depression.
68
Similarly, chronic pain and repeated
failures in pain management are
likely to be perceived as a lack of
control over health and may manifest
as depression. In either case, the
transition to depressive symptoms
should be addressed and prevented
by modifying the way pain or non–
pain-related stressors are perceived
and managed.
Clinical Implications:
Assessment and Treatment
Pain is a leading cause of disability
and the number one symptom driv-
ing patients to seek physical ther-
apy. Although faulty ergonomic
practices, postural strain, and repet-
itive overuse microtrauma must be
addressed for the effective treat-
ment of musculoskeletal pain, indi-
viduals in the same environment
with equivalent ergonomic and pos-
tural demands do not all experience
pain, and a dysfunctional HPA axis
Chronic Stress, Cortisol, and Pain
December 2014 Volume 94 Number 12 Physical Therapy f7
at APTA Member on November 11, 2014http://ptjournal.apta.org/Downloaded from
may mediate this discrepancy.
Although the factor initiating treat-
ment may be musculoskeletal in
origin, a chronic stress response
(to pain or non–pain-related stres-
sors), cortisol dysfunction, and
widespread inflammation may initi-
ate, exacerbate, or prolong the pain
experience, impair healing, and per-
petuate chronic disability. Screening
tools such as the Pain Catastrophiz-
ing Scale and the Fear-Avoidance
Beliefs Questionnaire are becoming
increasingly common in clinical
practice and utilized to identify mal-
adaptive responses to pain.
5,6,9
How-
ever, in the physical therapy setting,
there is less emphasis on the role of
non–pain-related stress in the pain
experience.
Prior to addressing non–pain-related
stress in pain management, it is
important to identify patients most
likely to benefit from stress manage-
ment. Objective measures of cortisol
may be obtained from blood, saliva,
urine, or hair; however, laboratory
tests may not be appropriate for the
physical therapy setting, and each
test has specific limitations. Alterna-
tively, there are a multitude of sub-
jective measures of self-reported
stress that may be easily integrated
into the screening process. The Per-
ceived Stress Scale, the Impact of
Events Scale, the Daily Stress Inven-
tory, and the State-Trait Anxiety
Inventory are reliable and valid mea-
sures of stress that have demon-
strated varying associations with
objective measures of cortisol.
69–72
However, different scales measure
different components of stress; for
example, the Perceived Stress Scale
is a measure of chronic stress (within
the previous 30 days),and the State-
Trait Anxiety Inventory is a measure
of current stress-related symptoms
(state) and characteristics of an anx-
ious personality type (trait).
70,72
Cop-
ing scales also have been created to
identify patients with poor stress
management skills. The Connor-
Davidson Resilience Scale, the Resil-
ience Scale for Adults, and the Brief
Resilience Scale received the best
psychometric ratings in a review of
resilience scales for adaptive cop-
ing styles.
73
There is a plethora of
stress-related outcome measures and
screening tools, each with unique
advantages and disadvantages.
Following the identification of stress
or maladaptive coping skills during
initial screening, educating patients
about the role of stress in the pain
experience may allow for cortical
inhibition of emotional fear-based
responses to nonthreatening stim-
uli.
20,24,25
Additionally, awareness
of the influence of non–pain-related
stress in the pain experience may
allow patients to address non–pain-
related stressors, thereby facilitating
pain rehabilitation. Physical thera-
pists also may address musculo-
skeletal or ergonomic contributions
to pain that may be exacerbated
by aberrant posture associated with
psychological stress (eg, stress-
related postural dysfunction with
prolonged computer use at work).
However, in cases of severe stress
or mental illness, the physical thera-
pist should refer patients to the
proper health care provider for
a multidisciplinary team approach
to rehabilitation. In a recent case
report of multidisciplinary stress
management interventions, biofeed-
back administered by a physical ther-
apist and psychotherapy adminis-
tered by a clinical psychologist were
successfully implemented to facili-
tate the long-term resolution of neck
pain and disability.
74
Mindfulness-based interventions and
cognitive-behavioral therapy have
been suggested for pain or stress
management, and improvements
are thought to be mediated by pre-
frontal modulation of amygdala activ-
ity with reappraisal of faulty beliefs
and restructuring of negative cogni-
tions.
75
However, although correct-
ing maladaptive responses to non-
threatening stimuli is important to
minimize stress, it may only apply
if individuals are falsely appraising
nonthreatening stimuli as threaten-
ing. The function of the physiologic
stress response is to promote sur-
vival, and when a real threat exists,
fear induces a stress response to
motivate survival, success, or goal
achievement. Therefore, if the stres-
sor or threat is real, such as a quar-
relsome coworker or financial trou-
bles, the optimal solution may be
confrontation to address the under-
lying cause of stress (rather than
reappraisal). Although the achieve-
ment of success and avoidance of
danger are not always possible or
optimal, managing failure and unex-
pected events, accepting challenges,
and confronting fears may drive suc-
cess and prevent an overactive stress
response. Ultimately, to effectively
manage chronic stress and prevent
its debilitating long-term effects,
individuals must identify the fear that
underlies the stress response (be it
physical, psychological, social, or
environmental), assess its rationality
(threatening or nonthreatening), and
address it (confrontation or cogni-
tive reappraisal).
Conclusion
Although stressful events may be
an inevitable part life, a prolonged
or exaggerated response to pain
or non–pain-related stressors may
intensify sympathetic and neuroen-
docrine activity, exhaust cortisol,
and perpetuate widespread pain
and inflammation. Elevated cortisol
levels following acute stress may
facilitate the consolidation of fear-
based emotional memories and con-
dition a sensitized physiologic stress
response. Negative appraisals or
maladaptive beliefs, a hypervigilant
response to stressful stimuli, cog-
nitive inflexibility, and passive or
avoidant coping may contribute to
prolonged or frequent activations of
the HPA axis. Following chronic
Chronic Stress, Cortisol, and Pain
8fPhysical Therapy Volume 94 Number 12 December 2014
at APTA Member on November 11, 2014http://ptjournal.apta.org/Downloaded from
reactivation of the HPA axis, cortisol
dysfunction and inflammation may
directly facilitate pain transmission
via impaired modulation or repeated
nociceptor activation by inflam-
matory mediators. Secondary effects
of widespread inflammation may
include autoimmune hypersensitivi-
ties, inflammation-induced wide-
spread oxidative or free radical dam-
age, and idiopathic inflammatory
tissue degeneration. Serotonin deple-
tion and hippocampal degeneration
are likely to compound the effects of
inflammation on pain and depres-
sion. However, there are a multitude
of mechanisms by which inflamma-
tion, stress, and pain are related
and the underlying processes are
likely multidirectional and cyclical in
nature. Future study is needed to
identify patients most likely to bene-
fit from stress management and
those most appropriate for referral.
Ultimately, the early identification
of stress and the incorporation of
stress management education into
pain rehabilitation may facilitate
effective pain management, prevent
the transition to chronic and depres-
sive symptoms, minimize disability,
and improve quality of life.
Dr Hannibal provided concept/idea and
writing. Dr Bishop provided fund pro-
curement (NIH, NCAAM, AT006334) and
assisted with concept development.
DOI: 10.2522/ptj.20130597
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Chronic Stress, Cortisol, and Pain
10 fPhysical Therapy Volume 94 Number 12 December 2014
at APTA Member on November 11, 2014http://ptjournal.apta.org/Downloaded from
doi: 10.2522/ptj.20130597
Originally published online July 17, 2014
Published online July 17, 2014PHYS THER.
Kara E. Hannibal and Mark D. Bishop
Management in Pain Rehabilitation
Psychoneuroendocrine Rationale for Stress
Chronic Stress, Cortisol Dysfunction, and Pain: A
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