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Perspective

A Mechanism-Based Approach to
Physical Therapist Management of Pain
Ruth L. Chimenti, Laura A. Frey-Law, Kathleen A. Sluka
R.L. Chimenti, PT, PhD, Department
of Physical Therapy and Rehabilitation
P
  ain reduction is a primary goal of physical therapy for patients who present with acute or
Science, University of Iowa, Iowa City,
persistent pain conditions. The purpose of this review is to describe a mechanism-based
Iowa.
approach to physical therapy pain management. It is increasingly clear that patients need
L.A. Frey-Law, PT, PhD, Department to be evaluated for changes in peripheral tissues and nociceptors, neuropathic pain signs
of Physical Therapy and Rehabilitation and symptoms, reduced central inhibition and enhanced central excitability, psychosocial
­Science, University of Iowa. factors, and alterations of the movement system. In this Perspective, 5 categories of pain
K.A. Sluka, PT, PhD, Department of Phys- mechanisms (nociceptive, central, neuropathic, psychosocial, and movement system) are
ical Therapy and Rehabilitation Science, defined, and principles on how to evaluate signs and symptoms for each mechanism are
1-242 MEB, University of Iowa, provided. In addition, the underlying mechanisms targeted by common physical therapist
Iowa City, IA 52242 (USA). ­ Address treatments and how they affect each of the 5 categories are described. Several different
correspondence to Dr Sluka at: mechanisms can simultaneously contribute to a patient’s pain; alternatively, 1 or 2 primary
­kathleen-sluka@uiowa.edu. Dr Sluka is mechanisms may cause a patient’s pain. Further, within a single pain mechanism, there are
a Catherine W
­ orthingham Fellow of the
likely many possible subgroups. For example, reduced central inhibition does not neces-
American Physical Therapy Association.
sarily correlate with enhanced central excitability. To individualize care, common physical
[Chimenti RL, Frey-Law LA, Sluka KA. therapist interventions, such as education, exercise, manual therapy, and transcutaneous
A mechanism-based approach to phys- electrical nerve stimulation, can be used to target specific pain mechanisms. Although
ical therapist management of pain. the evidence elucidating these pain mechanisms will continue to evolve, the approach
Phys Ther. 2018;98:302–314.] outlined here provides a conceptual framework for applying new knowledge as advances
© 2018 American Physical Therapy are made.
­Association

Accepted: February 12, 2018


Submitted: June 13, 2017

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Mechanism-Based Approach to Pain Management

W hether acute or chronic,


pain is a leading reason for
patients to seek physical
therapy. Approximately 100 million
­Americans suffer from persistent pain.1
diagnosis could have different under-
lying mechanisms contributing to their
pain. Accordingly, a mechanism-based
approach requires evaluating specific
pain mechanisms as well as prescrib-
approach to pain management, includ-
ing several evaluation and treatment
options, and facilitate an appreciation
for how these mechanisms may over-
lap and interact. Throughout this article
The cost of persistent pain in Ameri- ing the appropriate treatments to target the reader is referred to other sources
ca, including decreased productivity altered mechanism(s). Although each providing detailed information on how
at work and health care, is estimated pain mechanism can be addressed in- to identify, evaluate, and treat individ-
between $560 and $635 billion, which dividually, the efficiency of an interven- ual pain mechanisms. Benefits of a
is greater than cardiovascular disease, tion may be maximized when multiple mechanism-based approach are that it
cancer, and diabetes combined.2 The pain mechanisms are targeted simulta- expands physical therapist practice to
Department of Health and Human Ser- neously. include latest research from a number
vices recently published a National Pain of fields and enables the use of target-
Strategy,3 highlighting the insufficient This mechanism-based approach to ed interventions with the goal of opti-
training in pain assessment and treat- care is common in pharmaceutical mizing outcomes. However, methods of
ment for many clinicians. The National pain management. People with neuro- pain mechanism assessment continue
Institutes of Health and the Interagency pathic pain are often prescribed gab- to evolve for clinical use and it is often
Pain Research Coordinating Commit- apentinoids because of their ability difficult to differentiate between pain
tee also recently published the Federal to block calcium channel activity that mechanisms. With time, clinical tools
Pain Research Strategy, which identified is enhanced in this condition5; people will continue to develop to advance the
as a top priority the need to develop, with inflammatory nociceptive pain mechanism-based approach. This ap-
evaluate, and improve models of pain are often prescribed anti-inflammato- proach is also open to the integration
care.4 Accordingly, the purpose of this ry ­medications (eg, nonsteroidal anti-­ of additional pain mechanisms as they
article is to provide an overview of a inflammatory drugs and tumor necrosis are identified with future research.
mechanism-based approach to physical factor inhibitors)6; and those with noci-
therapy pain management that includes plastic pain are often prescribed reup- Overview of Pain Mechanisms
the evaluation and treatment of 5 pain take inhibitors to modulate central inhi- The initiation, maintenance, and per-
mechanisms: nociceptive, central, neu- bition.6 On the other hand, in physical ception of pain is influenced by bio-
ropathic, psychosocial, and movement therapy, many treatments evolved and logical, psychosocial, and movement
system. Recently, the International As- were used clinically before we under- system factors (Fig. 1). Biological pain
sociation for the Study of Pain (www. stood how they produced their effects. mechanisms can be categorized into 3
iasp-pain.org) released a new term, For example, initial clinical studies used classes, including nociceptive (periph-
nociplastic, designed to be a third de- transcutaneous electrical nerve stim- eral), nociplastic (nonnociceptive), and
scriptor to be used instead of “central” ulation (TENS) to reduce pain in the neuropathic (Fig 1A).39,43,44 Pain often
or “central sensitization.” Nociplas- 1960s, but we did not fully understand originates in the peripheral nervous
tic pain is defined as pain that arises the mechanisms for how TENS reduc- system when nociceptors are activated
from altered nociception despite no es pain until this century.7–19 What has due to an injury, inflammation, or me-
clear evidence of actual or threatened emerged in recent years is the knowl- chanical irritant. Nociceptive signals are
tissue damage causing the activation of edge that many physical therapist in- relayed to the spinal cord and up to the
peripheral nociceptors or evidence for terventions have multiple mechanisms cortex through ascending nociceptive
disease or lesion of the somatosensory of action and are thus considered mul- pathways resulting in the perception
system causing the pain. timodal pain treatments. For example, of pain. Peripheral sensitization of no-
research shows that exercise can alter ciceptive neurons can enhance or pro-
A mechanism-based approach to pain all 5 pain mechanisms: nociceptive, long the pain experience, even without
management incorporates and builds neuropathic, nociplastic, psychosocial, sensitization of central neurons (Fig. 2).
on the biopsychosocial model by de- and movement system.20–38 Accordingly, nociceptive pain is primar-
fining specific pathobiology in pain ily due to nociceptor activation, albeit
processing, pain-relevant psychologi- We have expanded the mecha- processed through the central nervous
cal factors, and movement system dys- nism-based approach from the patho- system (CNS), typically resulting in
function. The term “pain mechanisms” biological processes only (ie, biomed- acute localized pain, such as an ankle
is used to delineate factors that can ical model) to include psychological sprain. Within the CNS, nociceptive
contribute to the development, main- and movement system dysfunction. signals are under constant modulation
tenance, or enhancement of pain. Fur- Recognizing the importance of pain by cortical and brain-stem pathways,
ther, these pain mechanisms can also mechanisms for individualizing care is which can be facilitatory or inhibitory,
occur in a cyclical manner in reaction not novel,39–42 but has not been wide- and modulate both emotional and sen-
to the pain. A patient may have multiple ly implemented in physical therapist sory components of pain.45 Nociplastic
pain mechanisms occurring simultane- practice. This article will provide a pain c­onditions are due to alterations
ously, and 2 individuals with the same brief overview of a mechanism-based of nociceptive processing, most l­ikely

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Mechanism-Based Approach to Pain Management

Figure 2.
Diagram illustrating how peripheral and
central sensitization can lead to pain. (A)
Condition with no pain. Normal nociceptor
activity and central neuron activity usually
do not produce pain. (B) Condition with pe-
ripheral sensitization. Enhanced nociceptor
activity activates nonsensitized central noci-
ceptive neurons to result in pain. (C) Con-
dition with central sensitization but without
peripheral sensitization. Normal activation
of nociceptors activates sensitized central
neurons to result in pain. (D) Condition
with both peripheral sensitization and cen-
tral sensitization contributing to pain. Treat-
ments aimed at peripheral nociceptive input
would be effective in people with peripheral
sensitization but would have minimal effects
in people with central sensitization and par-
tial effects in people with both peripheral
sensitization and central sensitization.

pain.12,39 Neuropathic pain occurs when


there is a lesion or disease within the
somatosensory system.39 This could
occur due to direct injury to the nerve,
such as carpal tunnel syndrome, or due
to metabolic diseases, such as diabetes.
Nociceptive, nociplastic, and neuro-
pathic pain may not respond equally
Figure 1.
well to various treatments, thus, the un-
Schematic diagrams representing a mechanism-based approach to pain management. (A) De-
scription and examples of 3 pain mechanisms (nociceptive, nociplastic, and neuropathic) that
derstanding of underlying mechanisms
contribute to pain, as previously outlined by Phillips and Clauw.39 People with pain can have 1 will help to guide treatment choices
or a combination of mechanisms contributing to their pain. (B) Schematic representation of 3 aimed at these mechanisms.
pain mechanisms occurring within the context of movement system and psychosocial factors.
These 3 biological pain processes
can be influenced by, as well as di-
rectly influence, psychosocial factors
­ithin the CNS, such as enhanced
w central sensitization) to varying degrees (Fig. 1B).39,46 Addressing maladaptive
central excitability and/or dimin- along a continuum, such as low back psychosocial factors can maximize
ished central inhibition, often r­eferred pain or knee osteoarthritis (Fig. 3).39 therapy effectiveness for acute and
to as central sensitization (Fig. 2). Pain conditions with enhanced pe- chronic pain conditions.46,47 Negative
Nociplastic pain is typically chronic
­ ripheral and central sensitization may ­emotionality factors, such as depression
and more widespread than n ­ ociceptive respond well to removal of only the or fear avoidance beliefs, may augment
pain, with ­ fibromyalgia as the classic peripheral input, which can eliminate other pain mechanisms and contribute
­example.12 Nociplastic pain can occur central sensitization in some cases (eg, to the maintenance of a painful condi-
­independently of ­peripheral nociceptor total knee replacement). However, re- tion.47,48 Psychological factors are hy-
activity; however, some conditions in- moval of the peripheral input may pothesized to be critical in the transition
volve both nociceptive and nociplastic only have a partial effect with residual from acute to chronic pain and predic-
pain mechanisms (eg, peripheral and central sensitization causing ­continued tive of the development of ­chronic pain

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Mechanism-Based Approach to Pain Management

interventions to the primary pain mech-


anism(s).

Evaluation of biological pain mech-


anisms is informed through patient-­
reported history, questionnaires,
and potentially quantitative sensory
testing (QST). Unfortunately, identi-
­
Figure 3. fication of nociceptive, nociplastic,
In pain conditions, peripheral sensitization and central sensitization vary across a continuum. and ­ neuropathic pain mechanisms
Sensitization of the peripheral nervous system contributes to a large proportion of pain with are not ­directly measurable, but must
an acute localized injury, whereas sensitization of the central nervous system contributes to be ­inferred from indirect assessments.
a large proportion of pain with chronic widespread pain conditions, such as fibromyalgia Nociceptive pain is indicated by pain
­
(FM). For other diagnoses, depicted in the midrange as low back pain (LBP), osteoarthritis localized to the area of tissue i­njury
(OA), rheumatoid arthritis (RA), Achilles tendinopathy (AT), and temporomandibular joint within normal tissue healing time.
disorder (TMD), people can have high levels of peripheral sensitization, high levels of central Peripheral factors can also contrib-
­
sensitization, or both.
ute to chronic musculoskeletal pain,
but are more challenging to discern.
Enhanced ­
­ peripheral sensitivity, such
­ ostoperatively.46,49–51 Therefore, thera-
p toward providing precision medicine to as primary hyperalgesia, can be detect-
peutic interventions often benefit from patients with pain. The use of anatomic ed by ­ lowered pressure pain thresh-
considering these psychosocial factors. or radiographic diagnoses alone (ie, olds at the site of injury compared to
medical model) without consideration the ­ contralateral side.60,61 However,
As physical therapists, evaluation and of the underlying pain mechanism(s) interpretation of this test may be con-
treatment of the movement system is a (ie, enhanced biopsychosocial model) founded by the presence of secondary
key component of our care for patients is insufficient to guide rehabilitative hyperalgesia on the contralateral side,
with pain.52 Clearly, we recognize “an- care. Although peripheral pathology indicating the need for established
talgic gait” patterns as movement influ- is linked to musculoskeletal pain,57 norms in a pain-free population. No-
enced by pain; overuse syndromes as symptom severity can be modulated ciplastic pain conditions include more
painful conditions induced by repetitive by central processing, psychosocial diffuse symptoms such as widespread
movement; and the nociceptive with- factors, and the movement system. The pain, fatigue, sleep dysfunction, and
drawal reflex as a well-characterized common mismatch between tissue pa- cognitive disturbances, but can also
link between afferent pain pathways thology and pain is supported by find- involve relatively isolated pain due to
and the efferent motor system. Howev- ings among asymptomatic 80-year-olds, altered CNS processing, such as sec-
er, the relationships between pain and where 96% have signs of disk degen- ondary hyperalgesia or referred pain.62
the movement system are complex and eration and 62% have rotator cuff tears Researchers use several QST measures
often highly variable between individu- on imaging.58,59 In order to apply a to identify altered pain processing,60,63
als.53 Pain can produce increased mus- mechanism-based approach, one must which may have clinical utility once
cle contraction, tone, or trigger points54; first evaluate for signs and symptoms further developed and characterized.
it can result in muscle inhibition or suggestive of changes in peripheral tis- Enhanced central excitability can be as-
fear-avoidance behaviors resulting in sues and nociceptors, reduced central sessed by enhanced pain response to
disuse and disability,55 or both facilita- inhibition and/or enhanced central ex- a repetitive noxious stimulus (eg, von
tion and inhibition in opposing muscle citability, neuropathic pain signs and Frey filament for 10–30 s), referred to
groups.56 Thus, targeted interventions symptoms, psychosocial factors, and as temporal summation of pain.60,64
may help reduce motor responses that altered movement patterns. Once the However, temporal summation is also
exacerbate pain or improve function by primary pain mechanism(s) are identi- a normal response to repetitive nox-
minimizing the motor effects of pain. fied, then a clinician can be more spe- ious stimulation,64 and as yet we do not
The integration of physical therapists’ cific with their overall assessment. For have normative values to indicate an
expertise in the movement system with example, with patient referred for low enhanced response for clinical popula-
the other pain mechanisms has the po- back pain (anatomic region), the phys- tions. Pain inhibition is evaluated using
tential to elevate our level of care to ical therapist may identify pain associ- a conditioned pain modulation (CPM)
more effectively evaluate and treat pain ated with fatigue and sleep dysfunction test, which employs a “pain i­nhibits
conditions. (central indicators), high kinesiophobia pain” modulation. CPM measures pain
(psychosocial factor), and abdominal thresholds at a distant site during/after
muscle weakness (movement system a conditioning noxious stimulus (eg,
Evaluation of Pain Mechanisms
factor). By defining the mechanisms pressure pain threshold of leg during
Evaluation of pain mechanisms can
contributing to a patient’s pain, a cli- immersion of hand in ice-cold water).65
help individualize care to a patient
nician can prioritize and target specific Most pain-free individuals exhibit
rather than a diagnosis, and is a step

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Mechanism-Based Approach to Pain Management

Figure 4.
Four continua of movement system adaptations to pain and how they can affect an exercise program.

i­ncreased pain thresholds (less sensitiv- the biopsychosocial approach versus a assuming any particular pain mecha-
ity), whereas in chronic pain ­conditions multidisciplinary team with a clinical nism(s) to be associated with certain
there are often reduced or no change psychologist.75-77 diagnoses, is improved personalized
in pain thresholds.63 Currently, limita- treatment. Pain processing physiology,
tions to using QST as a clinical indica- Physical therapists have unique skills psychological states, and movement
tor are the lack of both norms to aid to evaluate patient-specific movement function can vary widely within a single
in the interpretation of findings and dysfunction. In people with pain, move- diagnosis.62 For example, people with
established test metric standards. Fi- ment system changes are unique to fibromyalgia demonstrate d ­ ysfunctional
nally, neuropathic pain is evidenced by each individual, can be task dependent, central inhibition, based on lowered
positive neural symptoms such as tin- and can range from subtle to severe.12,78 inhibitory CPM, compared to healthy
gling, burning, and dysesthesia, and/or Several considerations for evaluation of controls. Yet, some individuals with fi-
negative neural symptoms, such as loss movement system function in relation to bromyalgia have normal CPM respons-
of sensation. These symptoms can be pain are outlined in Figure 4. For some es, while some healthy controls exhibit
evaluated using sensory testing and/or patients, pain can cause motor inhibi- reduced CPM inhibition (Fig. 5A).12 Fur-
the painDETECT questionnaire.66 tion (eg, weakness79), whereas others ther, not all individuals with pain ex-
have motor facilitation (eg, increased hibit elevated psychosocial factors. For
Based on a patient’s self-reported histo- muscle tension80). It is important to de- example, in an ongoing clinical trial,82
ry, a clinician may choose to screen for termine if the motor dysfunction is a di- only 26% of women with fibromyalgia
ongoing psychological factors contrib- rect result of pain, or a more long-term had high pain catastrophizing and 51%
uting to pain. Psychological factors can adaptation that is volitional or reflexive. had high fear of movement (Fig. 5B).
be assessed clinically using 1 or more If it is a direct result of pain, reducing Although these percentages are high-
instruments available to screen for de- the pain will likely restore the move- er than those of healthy controls (1.1%
pression,67,68 anxiety,68,69 pain catastro- ment pattern.79 The phase of healing with high pain catastrophizing), many
phizing,70 fear of movement or reinju- is also relevant for determining how a women with fibromyalgia did not re-
ry,71,72 or pain self-efficacy.73 The use motor adaptation should be addressed port these ­ psychological c­onstructs.
of abbreviated screening tools, such as in physical therapy. For someone with a Finally, movement patterns in individ-
a 2-item depression screening test, re- recent hip fracture, assistive devices are uals with low back pain can vary sub-
quire little time and have greater accu- initially used to help reduce the load on stantially, with either increased or de-
racy than a physical therapist’s personal the injured limb, but, with time, patients creased extensor muscle activation.53
assessment.74 There are also screening may need help restoring nonprotective Together these research findings illus-
tools available to help determine the motor adaptations to avoid prolonged trate that heterogeneity in pain mecha-
appropriate level of care for patients loading imbalances.81 nisms can be substantial between indi-
with psychosocial concerns, such as viduals within the same pain diagnosis
pursuing an intervention implemented The value of identifying pain mecha- (eg, high variability in central pain pro-
solely by physical therapists trained in nisms for each individual, rather than cessing measures or p ­sychological

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Mechanism-Based Approach to Pain Management

Mechanisms Underlying ment may be most effective. Although


we provide only a partial list of all pos-
Physical Therapist sible interventions for pain, our inten-
Interventions tion is to demonstrate how the mech-
Once pain mechanisms are identi- anism-based approach may be applied
fied, the second phase of the mech- when attempting to match treatments to
anism-based approach is to provide underlying pain mechanisms.
treatment(s) targeting these mecha-
nisms. Outlined below are brief summa- Nociceptive Mechanisms
ries of how several potential therapies Exercise therapy.  Basic science
(exercise, manual therapy, TENS, and evidence shows that exercise reduces
patient education) can alter individu- nociceptor activity by decreasing ion chan­
al pain mechanisms, but is not an ex- nel expression, increasing expression
haustive list. Although the underlying of endogenous analgesic sub­ stances
mechanisms of several treatments have in exercising muscle (neurotrophins),
been well documented, our mechanistic and altering local immune cell function
understanding of many other treatment (increased anti-inflammatory cytokines).20–27
options remains incomplete. These 4 Further, exercise restores normal move­
treatments were chosen for their com- ment of joint and tissue,87 which could
mon use and documented effective- hypothetically remove a mechanical
ness for pain treatment. Each type of irritant to a nociceptor. Thus, exercise
intervention can involve v ­ arious forms, decreases nociceptor excitability, inc­
which we do not ­ specifically address. reases peripheral inhibition, and pro­
Figure 5. For ­ example, studies on ­ exercise can
(A) Scatterplot showing the variability in motes healing of injured tissues, which
include aerobic and/or strengthening. makes exercise particularly useful to
conditioned pain modulation (CPM) in
people with fibromyalgia and healthy con-
Manual therapy can include soft-tissue those with nociceptive pain.
trols, represented as the percent change massage, stretching, or joint mobili-
in pressure thresholds before and after the zation. Pain education and cognitive-­
Manual therapy.  Basic science
CPM test. In a comparison of people with behavioral therapy–informed tech-
evidence shows that joint manipulation
fibromyalgia and healthy controls, although niques used by physical therapists
activates analgesic systems peripherally
there was an overall decrease, on average encompass a wide range of topics,
(cannabinoid, adenosine) in several
there were clearly people with fibromyal- ­including education, coping strategies,
gia who presented with normal CPM and animal models of pain.88 In animal
problem solving, pacing, relaxation
healthy controls who presented with re- models, stretching increases expression
and imagery.47,63,83–85 TENS can be used
duced CPM. (B) Analysis of data from an and release of mediators that reduce
with a variety of settings, such as low
ongoing fibromyalgia activity study with inflammation, such as resolvins to
transcutaneous electrical stimulation (n =
or high frequency. Figure 6A summariz-
promote healing and reduce pain.89,90
172) revealed the variability in psychologi- es potential mechanisms, also further
Additionally, massage therapy reduces
cal measures in people with fibromyalgia82; described below, with more extensive
expression of inflammatory genes and
26% had high scores on the Pain Catastro- reviews available elsewhere.12
cytokines that activate nociceptors,
phizing Scale (> 30/52), and 51% had high
and increases the tissue repair genes.91
scores on the Tampa Scale of Kinesiophobia Although a pain mechanism-based Further, manual therapy techniques
(> 37/68). approach may be novel for physical restore normal movement of joint
therapy, pharmacology has long used and connective tissue,92 which could
treatments targeting a specific pain hypothetically remove a mechanical
a­ ssessments), that patients may present mechanism to maximize therapeutic irritant to a nociceptor. Thus, manual
with only certain components of a pain benefit (Fig. 6B). For example, a ran- therapy can target nociceptive pain
mechanism (eg, high fear of movement domized double-blind placebo-con- because it increases peripheral
but no pain catastrophizing or depres- trolled trial in patients with peripheral in­hibition, promotes healing of
sion), and that patients can present with neuropathic pain found treatment re- injured/inflamed tissues, and may
multiple pain mechanisms (eg, cen- sponse differed based on nociceptor reduce mechanical activation of a
tral sensitization and heightened psy- phenotype. Oxcarbazepine, a sodium nociceptor.
chosocial factors). Although physical channel blocker that reduces nocice-
therapists routinely assess a variety of ptor activity, had a larger effect in the
TENS.  Application of TENS can target
outcomes for sensory, motor, function, “irritable nociceptor” group than the
distinct nociceptive pain mechanisms.7–11
and emotional/affective components of “nonirritable nociceptor” group (num-
TENS can alter sympathetic activity
pain, we suggest adding assessments ber needed to treat = 4 vs 13).86 Thus,
to reduce pain through activation of
from a mechanistic standpoint as the the knowledge of nociceptor pheno-
local a2A-noradrenergic receptors,7,8
next step in advancing optimal pain type in this patient population helps
activate peripheral inhibitory m-opioid
care. inform which pharmacological treat-

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Mechanism-Based Approach to Pain Management

Figure 6.
(A) Diagram illustrating sites of action, based on currently available mechanistic data, of common physical therapist treatments on the 5
mechanistic categories for pain. Exercise works to modify all 5 mechanisms and can be considered a multimodal therapy. Currently known
mechanisms of action of common physical therapist treatments on pain are outlined in detail in the text. TENS = transcutaneous electrical
nerve stimulation. (B) Diagram illustrating sites of action, based on currently available mechanistic data, of common pharmacological treat-
ments on the 5 mechanistic categories for pain. Many physical therapist treatments target multiple mechanisms, whereas most pharmaceu-
tical agents target a single mechanism.

receptors,9 and reduce the excitatory chronic pain.28,94–97 Mechanistically, Manual therapy.  There is growing
neurotransmitter, substance P, which regular exercise reduces central evidence that massage and joint
normally increases in injured excitability and expression of excitatory manipulation modulate central pain
animals.10,11 Thus, TENS would be useful neurotransmitters in spinal cord, brain mechanisms.87,99–106 Massage activates
for those with enhanced sympathetic stem, and cortical nociceptive sites.28 In descending inhibitory pathways, using
activity and nociceptor sensitization. animal models of pain, regular aerobic oxytocin to produce analgesia,99,100
exercise increases release of endogenous whereas joint mobilization uses
Central Mechanisms opioids in the midbrain and brain stem, serotonin, noradrenaline, adenosine,
Education.  Educating patients about specifically the periaqueductal gray and cannabinoid receptors in the spinal
pain mechanisms and challenging and rostral ventromedial medulla.28,29,31 cord to produce analgesia.87,101,102 Joint
maladaptive pain cognitions/behaviors In the serotonergic system there is mobilizations can also reduce glial
can alter central pain processing.63,83 In decreased expression of the serotonin cell activation in the spinal cord.103 In
people with chronic pain, an increased transporter and increased release of the people, manipulation reduces central
understanding of pain using the “explain neurotransmitter serotonin in the rostral excitability as measured by reduced
pain”93 paradigm corresponds to an ventromedial medulla that leads to temporal summation, in the region of
increase in pain threshold83 and increases enhanced analgesia.28–30,98 Additionally, primary hyperalgesia,107 and reduced
in CPM (central inhibition).63 Thus regular exercise reduces glial cell secondary hyperalgesia in those with
education may be useful for those with activation, increases anti-inflammatory chronic pain.106,108 Thus, manual therapy
maladaptive cognitions and behaviors cytokines, and decreases inflammatory techniques activate central inhibitory
associated with altered CNS processing. cytokines in the spinal cord.24,94 In mechanisms and reduce central
parallel, QST in healthy adults shows excitability to produce analgesia in both
Exercise therapy.  The most studied, greater levels of exercise are associated people and animal models of pain.
and well-accepted, central mechanism with lower central excitability (ie,
to produce analgesia by exercise temporal summation), greater pain TENS.  TENS works primarily through
involves activation of descending thresholds, and greater inhibition central mechanisms by increasing
inhibitory systems with increases (CPM).28,96,97 Thus, regular exercise can central inhibition and reducing central
in endogenous opioids and altered modulate pain sensitivity by altering excitability.12–19 Studies in animal
serotonin function.28–31 Studies in central nociceptive processing and models of pain show that high and
animals and people have shown increasing central inhibition in both low-frequency TENS analgesia activates
that regular exercise can prevent animals and people, making it an ideal multiple central pathways, including
or reduce the risk of developing choice for those with nociplastic pain. the spinal cord, rostral ventromedial

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Mechanism-Based Approach to Pain Management

medulla, periaqueductal gray, and techniques, like those used in neural also reduces stress and anxiety in
multiple cortical sites.13,14,19 The central mobilization, could ameliorate nerve people without pain.130–132 However, the
inhibitory neurotransmitters involved compression as cadaver studies show effects of manual therapy, particularly
in the analgesia include m-opioid and dispersal of intraneural fluid with mobilizations, on other pain-related
serotonin receptors (low frequency) neural mobilization.114,115 Thus, manual psychological constructs is not well
and delta-opioid receptors (high therapy has the potential to improve characterized.
frequency),14,15 which have been healing and reduce nerve compression
confirmed in people with chronic in neuropathic pain; however, these Movement System
pain.16,17 TENS also produces analgesia effects need to be confirmed in future Education. Educational techniques for
through activation of GABAA receptors studies. altering the movement system are often
and muscarinic receptors (M1, M3) in given in combination with an exercise
the spinal cord.18,109 In parallel, TENS Psychosocial Mechanisms program, making it difficult to assess the
also reduces central sensitization Education. Education and cognitive- effect of education alone. For example,
measured directly in nociceptive behavioral therapy–informed tech­ there was a greater improvement in
dorsal horn neurons,110 and reduces niques are aimed at changing beliefs performance of a straight leg raise and
release and expression of excitatory and behaviors that contribute to forward bend after pain education with
neurotransmitters (glutamate and distress, fear, catastrophizing, and exercise compared with an anatomy
substance P), glial cell activation, and anxiety. For example, patients with education with exercise,117 suggesting
inflammatory cytokines and mediators acute low back pain educated using that pain education with exercise
in the dorsal horn.10,11,111 In individuals a fear-avoidance model and graded has the potential enhance changes
with fibromyalgia, high-frequency exercise (see home study course116) in movement patterns. Additionally,
TENS restores central inhibition (CPM), had lower fear-avoidance beliefs.47 Pain relaxation techniques, biofeedback and
and increases pressure pain thresholds education reduces pain catastrophizing cognitive-behavioral therapy–informed
at the site and outside the site of and negative pain cognitions, but may techniques can reduce motor facilitation
stimulation, supporting a modulation not directly affect pain scores.117–119 or muscle spasm.133 Thus, neuroscience
of central nociceptive processing in education may be particularly useful to
humans.112 Thus, TENS activates central Exercise therapy.  Exercise is a well- help improve general function, whereas
inhibitory pathways and reduces central accepted means to improve a number biofeedback and relaxation techniques
sensitization simultaneously to reduce of negative psychological factors could be more useful for those with
pain and hyperalgesia. that are related to pain, including enhanced motor facilitation.
catastrophizing, depression, and
Neuropathic Mechanisms cognitive dysfunction.33,34 Exercise Exercise therapy.  The type of
Exercise therapy. Regular aerobic also improves learning, memory, exercise prescribed will depend on
exercise increases anti-inflammatory and neurogenesis.120,121 In mice, the movement system dysfunction
cytokines (eg, interleukin 4) and the voluntary exercise reduces depressive found in the assessment (Fig. 4). For
expression of M2 macrophages, which behaviors with concomitant increases example, strengthening may be optimal
secrete anti-inflammatory cytokines at in brain-derived neurotrophic factor if weakness and motor inhibition are
the site of injury.24,32 Regular aerobic and opioid receptor expression in present,36 but may be less effective if
exercise can also decrease expression the hippocampus.122,123 Although the muscle spasm or motor facilitation is
of M1 macrophages and inflammatory neurobiological mechanisms in humans present.134 Stretching may be effective
cytokine production at the site of are less clear, Cochrane reviews for tight or limited joint range of
injury.24,32 These effects on cytokines indicate exercise reduces depressive motion, thereby normalizing movement
and macrophages promote nerve symptoms124 and improves cognitive and subsequently reducing pain.135,136
healing and analgesia in animal models function.125 Pain catastrophizing can Graded exercise or graded exposure
of neuropathic pain.24,32 In people also decline with exercise,126 and is may be useful for patients with volitional,
with diabetic neuropathy, a decrease negatively correlated with the magnitude nonprotective movement system
in pain is associated with increased of exercise-induced analgesia.127 Thus, adaptations that interfere with activity
growth of epidermal nerve fibers after exercise reduces negative psychological participation.37,38 Further, as mentioned
a regular exercise program.113 Thus, factors associated pain, and can improve above, neuromuscular reeducation can
exercise can be considered a disease- cognitive and social factors. help normalize movement patterns,
modifying treatment in neuropathic resulting in reduced pain with
pain conditions by promoting healing Manual therapy.  There are a number activity.87 A systematic review showed
of injured tissues. of studies suggesting that massage that strengthening and strengthening
reduces psychological distress. Massage combined with aerobic exercise
Manual therapy. In animal models decreases cortisol in the blood in people demonstrated moderate or large effect
of neuropathic pain, mobilization with a wide range of pain conditions, sizes on pain and function in women
promotes healing by increasing myelin including juvenile rheumatoid with fibromyalgia, whereas aerobic
sheath thickness in peripherally injured arthritis, burn injury, migraines, and alone resulted in no effect or small
nerves.103 Theoretically, manual therapy autoimmune disorders.128,129 Massage effect sizes.35 Although more research

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Mechanism-Based Approach to Pain Management

is needed to determine adequate dose, may benefit more from a generalized (eg, simple modulated pulse mode)
timing, and combinations of exercise strengthening or an aerobic condition- prevents tolerance.147 Exercise, which
types, exercise can alter the movement ing program aimed at altering central uses serotonergic mechanisms, could
system in order to improve function inhibition and excitation. In addition, produce longer-lasting effects in those
and disability. as people with chronic pain often have taking reuptake inhibitors. Alternative-
movement-evoked pain, the addition of ly, negative interactions between treat-
Manual therapy.  Manual therapy can an adjunct treatment, such as TENS,112 ments may also occur. For example, in
be used to relieve pain, increase joint may be useful to improve exercise tol- mice and people with opioid tolerance,
range of motion, and improve function erance. For patients with fear of move- low-frequency TENS does not produce
for a variety of musculoskeletal pain ment, graded-exposure to exercise, analgesia.16,146 Thus, understanding the
conditions.91,108,137 Spinal manual where exercises are progressed based mechanisms will help to make better
therapy techniques ranging in force on the patient’s level of fear, may work individualized treatment choices based
from manipulation with high velocity to increase function while also decreas- the patient’s current treatment program.
thrust to a nonthrust mobilization ing pain-related fear.37,38,47 Further, the
technique decrease motor neuron intensity of exercise needed to reduce Although we have a fairly strong under-
excitability.138,139 On the other hand, pain and improve function is likely standing of underlying mechanisms for
manipulation increases activity of much less than intensities typically rec- physical therapist interventions, and un-
the oblique abdominal muscles in ommended for health benefits of phys- derstand conceptually how individual
those with low back pain.140 Thus, ical activity.77 In fact, as shown by a treatments might affect different types
manipulation may be useful to help wide range of clinical trials (see table of of pain mechanisms, there are limited
normalize motor function; however it systematic reviews on exercise-induced studies using these nonpharmacolog-
is unclear at present which techniques analgesia),12 just 2 or 3 times per week ical treatments in a mechanism-based
work best for increasing versus for 20 to 30 minutes is adequate to pro- manner. Most clinical studies compare
decreasing motor activity. duce pain relief and improve function 2 treatments, such as 2 different exer-
in a variety of painful conditions. cise programs, in a recruited popula-
TENS.  The use of a pain-relieving tion without considering the underlying
modality, such as TENS, may normalize Although nearly all patients receive mechanisms, with mixed results.86,92 We
movement if pain is reflexively causing some education about their pain condi- suggest that future studies should be
abnormal motor activation or if there tion, the type of education may be dis- designed to identify treatments based
is increased pain with activity since tinctly different depending on the eval- on underlying mechanisms, and test if
it works best to reduce movement- uation. Individualized patient education targeted treatments produce improved
evoked pain.112 Although TENS may based on pain-mechanisms could range outcomes. Future studies should also
not directly target the movement from focusing on modification of mala- investigate the multimodal effects of
system, this, and any pain relieving daptive beliefs for those with high pain combining multiple physical therapist
technique, may be used to target pain- catastrophizing to education of underly- interventions, as well as combining
induced nonvolitional abnormal motor ing central mechanisms for those with physical therapy and pharmaceutical
patterns, or increase patient tolerance nociplastic pain. In patients with chron- treatments targeting underlying mech-
for exercise. ic low back pain, exercise combined anisms to provide clinicians with the
with targeted pain education, was more most effective treatment programs for
effective at reducing pain and disabili- pain.
Implementation of ty compared to exercise with a biome-
the Mechanism-Based chanical pain education approach.141,142 Conclusion
Approach Sociocultural factors may be addressed Although there is much we have yet
Although each pain mechanism can by encouraging family members and to learn about underlying pain mech-
be addressed individually by the treat- physicians to emphasize active patient anisms and optimal interventions,
ments discussed above, the efficiency participation in exercise prescription, significant advances have occurred in
­
of an intervention can be maximized which also improves intervention ad- the science of pain that are clinically
when considering multiple pain mech- herence.143,144 relevant to physical therapists. Pain is
anisms might be addressed simultane- now recognized as more than a periph-
ously. Physical therapists routinely pre- Based on known underlying mecha- erally driven symptom; it is a multidi-
scribe exercise to address alterations in nisms, physical therapist interventions mensional construct that can become a
the movement system, and the choice of may produce additive or even syner- disease itself when chronic.1 Whether
exercise type is informed by concurrent gistic interactions with pharmaceutical patients present to therapy for acute
pain mechanisms when using a mecha- agents, or enhance effectiveness of mul- or persistent pain conditions, the goals
nism-based approach. For example, for tiple physical therapist interventions. of therapy are often aimed at reduc-
patients with a nociceptive-driven pain For example, repeated application of ing pain and restoring function. The
condition, a region-specific ­ exercise a single frequency of TENS produces mechanism-based approach provides
program may be most effective. In ­analgesic tolerance.145,146 However, com- an additional conceptual framework for
contrast, patients with nociplastic pain bining low- and high-frequency TENS physical therapists to make e ­ducated

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treatment decisions that incorporate 5 Dworkin RH, O’Connor AB, Back- 18 Radhakrishnan R, Sluka KA. Spinal
known basic science and clinical evi- onja M, et al. Pharmacologic man- muscarinic receptors are activated
agement of neuropathic pain: evi- during low or high frequency TENS-in-
dence with individualized assessments dence-based recommendations. Pain. duced antihyperalgesia in rats. Neu-
to optimize patient care and clinical 2007;132:237–251. ropharmacology. 2003;45:1111–1119.
effectiveness. Although the evidence 6 Scholz J, Woolf CJ. Can we conquer 19 Xiang XH, Chen YM, Zhang JM, Tian
elucidating these pain mechanisms will pain? Nat Neurosci. 2002;5(sup- JH, Han JS, Cui CL. Low- and high-fre-
pl):1062–1067. quency transcutaneous electrical acu-
continue to evolve, the approach out- point stimulation induces different
7 King EW, Audette K, Athman GA,
lined here provides a conceptual frame- effects on cerebral mu-opioid receptor
Nguyen HO, Sluka KA, Fairbanks CA. availability in rhesus monkeys. J Neu-
work to apply new knowledge as ad- Transcutaneous electrical nerve stim- rosci Res. 2014;92:555–563.
vances are made. ulation activates peripherally located
alpha-2A adrenergic receptors. Pain. 20 Shankarappa SA, Piedras-Renteria
2005;115:364–373. ES, Stubbs EB Jr. Forced-exercise de-
Author Contributions lays neuropathic pain in experimental
8 Nam TS, Choi Y, Yeon DS, Leem JW, diabetes: effects on voltage-activat-
Paik KS. Differential antinociceptive
Concept/idea/research design: R.L. Chimenti, ed calcium channels. J Neurochem.
effect of transcutaneous electrical stim- 2011;118:224–236.
L. Frey-Law, K.A. Sluka ulation on pain behavior sensitive or
Writing: R.L. Chimenti, L. Frey-Law, K.A. ­Sluka insensitive to phentolamine in neuro- 21 Gandhi R, Ryals JM, Wright DE. Neu-
pathic rats. Neurosci Lett. 2001;301:17– rotrophin-3 reverses chronic mechan-
20. ical hyperalgesia induced by intra-
Funding muscular acid injection. J Neurosci.
9 Sabino GS, Santos CM, Francischi JN, 2004;24:9405–9413.
The writing of this article was supported by de Resende MA. Release of endoge-
National Institutes of Health grants (ref nos. nous opioids following transcutaneous 22 Sharma NK, Ryals JM, Gajewski BJ,
electric nerve stimulation in an exper- Wright DE. Aerobic exercise alters an-
NIH R01 AR061371, NIH UM1 AR063381, imental model of acute inflammatory algesia and neurotrophin-3 synthesis
NIH NIAMS R03 AR065197). R.L. Chimen- pain. J Pain. 2008;9:157–163. in an animal model of chronic wide-
ti’s time spent writing was supported by a spread pain. Phys Ther. 2010;90:714–
10 Rokugo T, Takeuchi T, Ito H. A histo-
postdoctoral fellowship in pain research
­ 725.
chemical study of substance P in the
(ref no. T32 NS045549-12) and K99 rat spinal cord: effect of transcutane- 23 Leung A, Gregory NS, Allen LA, Sluka
AR0715170. The funding sources played no ous electrical nerve stimulation. J Nip- KA. Regular physical activity prevents
pon Med Sch. 2002;69:428–433. chronic pain by altering resident mus-
role in the writing of this manuscript. cle macrophage phenotype and in-
11 Chen YW, Tzeng JI, Lin MF, Hung CH, creasing interleukin-10 in mice. Pain.
Disclosure Hsieh PL, Wang JJ. High-frequency 2016;157:70–79.
transcutaneous electrical nerve stim-
Dr Chimenti and Dr Frey Law completed ulation attenuates postsurgical pain 24 Bobinski F, Teixeira JM, Sluka KA,
and inhibits excess substance P in rat Santos ARS. Interleukin-4 mediates
the ICJME Form for Disclosure of Poten- dorsal root ganglion. Reg Anesth Pain the analgesia produced by low-in-
tial C ­ onflicts of Interest and reported no Med. 2014;39:322–328. tensity exercise in mice with neuro-
­conflicts of interest. Dr Sluka serves as a con- pathic pain. Pain. 2017 November 15
12 Sluka KA. Mechanisms and Manage-
sultant for Novartis Consumer H ­ ealthcare/ [E-pub ahead of print]. doi: 10.1097/j.
ment of Pain for the Physical Thera- pain.0000000000001109.
GSK ­ Consumer Healthcare, receives a pist. 2nd ed. Seattle, WA: IASP Press;
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physical activity on serum IL-6 and IL-
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