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The Journal of Pain, Vol 17, No 9 (September), Suppl. 2, 2016: pp T50-T69
Available online at www.jpain.org and www.sciencedirect.com
Toward a Mechanism-Based Approach to Pain Diagnosis
Daniel Vardeh,* Richard J. Mannion,y and Clifford J. Woolfz
*Division of Pain Neurology, Department of Neurology and Anesthesia, Brigham and Women’s Hospital and Harvard
Medical School, Boston, Massachusetts.
y
Department of Academic Neurosurgery, Cambridge University Hospitals NHS Trust, Cambridge, United Kingdom.
z
FM Kirby Neurobiology Center, Boston Children’s Hospital and Harvard Medical School, Boston, Massachusetts.
Abstract: The past few decades have witnessed a huge leap forward in our understanding of the
mechanistic underpinnings of pain, in normal states where it helps protect from injury, and also in pathological states where pain evolves from a symptom reflecting tissue injury to become the disease itself.
However, despite these scientific advances, chronic pain remains extremely challenging to manage clinically. Although the number of potential treatment targets has grown substantially and a strong case
has been made for a mechanism-based and individualized approach to pain therapy, arguably clinicians
are not much more advanced now than 20 years ago, in their capacity to either diagnose or effectively
treat their patients. The gulf between pain research and pain management is as wide as ever. We are still
currently unable to apply an evidence-based approach to chronic pain management that reflects mechanistic understanding, and instead, clinical practice remains an empirical and often unsatisfactory
journey for patients, whose individual response to treatment cannot be predicted. In this article we
take a common and difficult to treat pain condition, chronic low back pain, and use its presentation
in clinical practice as a framework to highlight what is known about pathophysiological pain mechanisms and how we could potentially detect these to drive rational treatment choice. We discuss how
present methods of assessment and management still fall well short, however, of any mechanismbased or precision medicine approach. Nevertheless, substantial improvements in chronic pain management could be possible if a more strategic and coordinated approach were to evolve, one designed to
identify the specific mechanisms driving the presenting pain phenotype. We present an analysis of such
an approach, highlighting the major problems in identifying mechanisms in patients, and develop a
framework for a pain diagnostic ladder that may prove useful in the future, consisting of successive
identification of 3 steps: pain state, pain mechanism, and molecular target. Such an approach could
serve as the foundation for a new era of individualized/precision pain medicine. The Analgesic, Anesthetic, and Addiction Clinical Trial Translations, Innovations, Opportunities, and Networks (ACTTION)American Pain Society (APS) Pain Taxonomy (AAPT) includes pain mechanisms as 1 of the 5 dimensions
that need to be considered when making a diagnostic classification. The diagnostic ladder proposed in
this article is consistent with and an extension of the AAPT.
Perspective: We discuss how identifying the specific mechanisms that operate in the nervous system to produce chronic pain in individual patients could provide the basis for a targeted and rational
precision medicine approach to controlling pain, using chronic low back pain as our example.
ª 2016 by the American Pain Society
Key words: Diagnosis, low back pain, mechanism, target.
A
mechanistic approach to address chronic pain has
been actively promoted over the past few
decades in an attempt to exploit the growing un-
derstanding of underlying pathological processes as a
means to improve patient management.51,157,158
Medicine is obviously most impactful when defined
The views expressed in this article are those of the authors, none of whom
has financial conflicts of interest relevant to the specific issues discussed.
No official endorsement by the U.S. Food and Drug Administration (FDA)
or the pharmaceutical and device companies that have provided unrestricted grants to support the activities of the ACTTION public-private
partnership with the FDA should be inferred. Financial support for this
supplement and for the development of the AAPT has been provided
by the ACTTION public-private partnership, which has received research
contracts, grants, or other revenue from the FDA, multiple pharmaceutical and device companies, and other sources. A complete list of current
ACTTION sponsors is available at: http://www.acttion.org/partners.
Clifford J. Woolf was supported by the National Institutes of Health
(RO1DE022912; RO1NS038253; R37NS039518; PO1NS072040-01A).
Address reprint requests to Clifford J. Woolf, MD, PhD, FM Kirby Neurobiology Center, Boston Children’s Hospital, 300 Longwood Ave, Boston,
MA 02115. E-mail: [email protected]
1526-5900/$36.00
ª 2016 by the American Pain Society
http://dx.doi.org/10.1016/j.jpain.2016.03.001
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Vardeh, Mannion, and Woolf
mechanisms can be targeted with treatments that act
specifically on those mechanisms. Conditions like
diabetes and peptic ulcer disease were largely tamed
with simple interventions when their mechanisms were
recognized and could be directly addressed. As our
understanding of disease in general has evolved from
systems and organs to subcellular molecular pathways,
opportunities for rational and precise treatment in a
wide variety of conditions have grown substantially. In
chronic pain, identification of molecular mechanisms
has dramatically increased over the past few decades,
however, there still remains a long journey to convert
the effect of these discoveries into improved clinical
practice. Patients are still largely managed on a ‘‘trial
and error’’ basis, more influenced by which physician
they see than any appreciation of underlying ‘pain
mechanisms.’ Diagnostic tools commonly lack specificity
for identifying the ‘‘pain driver’’ defined in terms of
anatomical site, pathology, or pain mechanism, and
treatment rarely targets such drivers. In consequence,
clinical outcomes for chronic pain conditions remain
disappointingly poor, and prevalence and morbidityrelated health care costs are unacceptably high, per
data from the Global Health Data Exchange.77
To illustrate the problem, we take the most common
chronic pain condition—chronic low back pain (cLBP)—
and apply the current understanding of pain mechanisms
to its presentation, diagnosis, and management. By doing
so, we hope to summarize the state of scientific knowledge and also highlight the large discrepancy between
the scientist’s mechanistic and the clinician’s pragmatic
approach to chronic pain. On the basis of this analysis
we introduce a new framework—a pain diagnostic ladder—as a first step toward a more structured and rational
approach to mechanism-based pain medicine.
The Journal of Pain
T51
arthritis, spondyloarthritis, or ongoing nerve compression, which might be amenable to specific diseasemodifying management, even long after pain onset.
Chronic pain conditions include both categories; pain
as a chronic disease of the nervous system and pain as
a symptom of chronic peripheral disease, although distinguishing them is challenging and the 2 may coexist.
In addition, it is becoming clearer that the development
of cLBP may occur because of a combination of
genetically-based susceptibility factors in the nervous
and immune systems as well as local pathological risk
factors; several human genes modifying the risk of
pain chronification have been identified over the past
few years.34 Furthermore, cLBP may not be one but
several distinct conditions, which the commonly used
loose term ‘‘degenerative low back pain’’ does not capture. Certainly the presentation of cLBP is very mixed,
with wide anatomical and qualitative (eg, sharp vs
dull, ongoing vs triggered) variability as well as the relationship to factors such as posture (lying, sitting, standing) and activity. Last, psychosocial factors play an
important role in interindividual differences in chronic
pain perception, and negative affect/depression as
well as pain catastrophizing are thought to be major
contributors to pain-related disability39,154 and are
explored in other review articles in this issue of The
Journal of Pain.40,146
There have been many attempts to classify cLBP to capture its causes; here we have divided cLBP into 3 major
categories: anatomic, pathologic, and mechanistic.
Anatomic
The low back contains a large number of potential pain
generators, including disc and facet joints, vertebral end
The Clinical Challenge of cLBP
Chronic pain is difficult to define—most definitions
have evolved from consideration of pain that persists
beyond the normal time of healing, typically taken as
3 months,107 which may reflect a transition from acute
pathology-driven symptomatic pain to a persistent
and often autonomous pain caused by changes in the
peripheral and central nervous system (CNS). In consideration specifically of cLBP, all moving joints can cause
pain if the joint is inflamed or has degenerated, and
the spine, being a complex articulated structure of
many discovertebral and facet joints is no different.
Because of the increasing mechanical burden of
caudally located vertebrae and discs, lumbar and
lumbosacral elements are particularly prone to the
degenerative changes that occur in all humans over
time.18 However, only a minority of people develop
cLBP, and there is no strong correlation between cLBP
and age or activity,73,77 which would be expected if
degeneration alone were the prime pain driver. Other
factors must be at play.
For one, it is important to consider whether chronic
pain is autonomous of tissue injury or whether it reflects a chronically active disease, such as rheumatoid
Figure 1. Chronic low back pain drivers. An illustration of pain
drivers in chronic low back pain showing their anatomical locus
and associated pathology, and the pain states they produce
(vertebral column drawing done by Simmie Foster MD, PhD).
Abbreviations: i, inflammatory; n, nociceptive; Nep, neuropathic.
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Toward a Mechanism-Based Approach to Pain Diagnosis
The Journal of Pain
plates, nerve roots, ligaments, and spinal muscles (Fig 1).
In practice, it remains a major challenge to identify the
specific contribution of each structure to the clinical presentation. The musculoskeletal clinical examination, with
few exceptions as discussed in this article, has overall poor
localizing value,70 and injections of local anesthetics, as in
intra-articular facet joint injections or medial branch
blocks, as well as provocative discography, remain controversial as diagnostic tools.101,143 In addition, magnetic
resonance spinal imaging findings correlate poorly with
the patient’s reports, and in many cases are unhelpful
to identify a specific source of the pain.79,103 As pain
becomes ‘‘centralized’’ (an initial peripheral trigger
resulting in persistent alterations in the CNS) and in
consequence, more widespread over time, it becomes
increasingly more difficult and less relevant to identify
the initial source.58 In some individuals there may never
have been any peripheral trigger and the pain in these
patients is considered to be an expression of central
amplification because of increased excitation and
reduced inhibition in central nociceptive circuits.
Pathologic
Although cLBP can result from several distinct pathological insults including trauma, infection, inflammation, and systemic disease such as cancer, the most
cLBP sufferers are labeled as having ‘‘degenerative low
back pain.’’ However, none of these pathological descriptors captures the basis of the patient’s pain. Chronic
pain can be classified broadly into 4 pain states: nociceptive, inflammatory, neuropathic, and centralized/
dysfunctional (Table 1). Nociceptive pain reflects activation of nociceptors (high threshold primary sensory neurons) by intense, typically in the case of clinical pain,
mechanical stimuli. Inflammatory pain represents pain
Table 1.
hypersensitivity in the presence of either sterile or
pathogen-driven inflammation, and neuropathic pain
results from damage to the nervous system.106 All 3
can contribute to cLBP and all 3 may occur in the presence of degenerative changes. Dysfunctional or centralized pain represents patients with chronic, often
widespread pain conditions like fibromyalgia, where
there is no noxious stimulus, no detectable inflammation, and no structural damage to the nervous system
or any other tissue, and appears to result from abnormal
pain amplification within the CNS. The contribution of
central pain amplification in cLBP might play an important role in patients with pain disproportionate to minimal peripheral pathology (see Central Sensitivity
Syndromes section), however absence of reliable biomarkers of central pain amplification make this a difficult positive diagnosis, one that is therefore typically
made according to the absence of other positive pathological features.
Mechanistic
The utility in the clinic of a mechanistic classification of
pain currently remains poor and is therefore infrequently used. Mechanistic approaches to the classification of cLBP attempt to highlight cellular mechanisms
working at the level of sensory receptors in target organs, axons, and cell bodies of primary sensory neurons,
or in the spinal cord and brain (Tables 2 and 3).
Identifying such mechanisms, if possible, would provide
an
opportunity
for
specific
targeting
with
pharmacological therapies that act on the identified
mechanisms. Although basic science efforts have made
remarkable progress in identifying some key molecular
targets, a huge clinical challenge remains to identify
these mechanisms from the individual pain patient
Pain States
PAIN STATE
Nociceptive
Inflammatory
Neuropathic
Dysfunctional/centralized
CLINICAL DIAGNOSTIC CRITERIA
Evidence of noxious (mechanical) insult
Symptoms: pain localized to area of stimulus/joint damage
Signs: imaging—mechanical pathology/altered joint architecture such that normal movements
will likely produce excessive forces sufficient to activate nociceptors
Evidence of inflammation
1. Sterile
2. Infectious
Symptoms: redness, warmth, swelling of affected area
Signs: imaging (MRI, SPECT) signs of inflammatory changes, detection of pathogens/response to antibiotics
Evidence of sensory nerve damage
Symptoms: burning, tingling or shock-like, spontaneous pain; paresthesias or dysthesias
Signs: decreased pinprick* or vibration sense, and straight leg raise,* mechanical and cold allodynia
Pain in the absence of detectable pathology
No identifiable noxious stimulus, inflammation or neural damage; evidence of increased
amplification or reduced inhibition.
Abbreviation: SPECT, single-photon emission computed tomography.
NOTE. The 4 categories of nociceptive, inflammatory, neuropathic, and dysfunctional/centralized pain, and their clinical presentation. Note that none of the diagnostic
criteria are highly specific, and there is no gold standard for diagnosing these conditions. Pain states are not mutually exclusive, and coexistence of more than 1 is probably the rule rather than the exception.
*Most specific
General Pain Mechanisms
NONSPECIFIC TREATMENT EXAMPLES
GENERAL PAIN MECHANISM
CLINICAL DIAGNOSTIC CRITERIA
Nociceptive transduction
Proportionate pain in response to identifiable noxious stimulus
Peripheral Sensitization
Primary hyperalgesia due to decreased transduction threshold of
nociceptor terminal
Spontaneous pain in the absence of obvious trigger; relieved
by local nerve block
Secondary hyperalgesia; temporal summation; allodynia
Secondary hyperalgesia; allodynia
Ectopic activity
Central sensitization
Central disinhibition
SPECIFIC TREATMENT EXAMPLES
GABA-PENTINOID
Removing mechanical stimulus
(eg, decompression of nerve)
Anti-inflammatory (eg, NSAID, coxibs);
immunosuppressant
Nav channel blockers
AED
AD
OPIOID
X
X
NMDA antagonists (eg, ketamine)
GABA-A subunit agonists; dual amine
uptake inhibitors
Possibly
X
X
X
X
Some (eg, VA, TPM)
See above
X
Vardeh, Mannion, and Woolf
Table 2.
X
X
X
X
X
Abbreviations: AED, antiepileptic dugs; AD, antidepressants; NSAID, nonsteroidal anti-inflammatory drug; coxib, selective COX-2 inhibitor; VA, valproic acid; TPM, topiramate.
NOTE. More than 1 mechanisms may be at play in any given pain syndrome and no mechanism is specific to a particular pain state. It is currently impossible to distinguish clinically between central sensitization and disinhibition. Several of the
proposed specific treatment examples are not in clinical use (eg, Nav-specific or GABA A receptor-specific antagonists). Note the low specificity of currently used medications for a single mechanism.
Table 3.
Specific Pain Targets
SELECTED SPECIFIC PAIN MECHANISMS
SPECIFIC CLINICAL MANIFESTATION
MOLECULAR TARGET
TrkA (NGF receptor); TRPV1
NMDA receptor phosphorylation
Excitatory transmitter release
Increased postsynaptic activity
Nav1.7 hyperexcitability
Increased nociceptor firing
Spinal interneuron degeneration
Decreased inhibitory
transmission
Increased nociceptor firing
Peripheral sensitization
No specific diagnostic criteria
Pain amplification
No specific diagnostic criteria
Pain amplification No specific
diagnostic criteria
Paroxysmal extreme pain disorder;
primary erythromelalgia
Pain amplification
No specific diagnostic criteria
Familial episodic pain syndrome
TRPA1 sensitization
GENETIC VALIDATION
NMDA receptor
HSAN IV
HSAN V
No
Ca(v)a2d-1
No
Nav1.7
Gaba A receptor
Paroxysmal extreme pain disorder;
primary erythromelalgia
No
TRPA1
Familial episodic pain syndrome
SPECIFIC TREATMENT
anti-NGF AB (phase 3); TrkA R
antagonist (phase 2)
NMDA receptor antagonist
(eg, ketamine)
Gabapentinoids
Nav1.7 antagonist (phase 2)
Gaba A receptor subtype
selective agonist
TRPA1 antagonist
NOTE. Molecular targets identified in preclinical models and sometimes rare human genetic mutations. Clinical identification of these molecular mechanisms remains the most challenging and least developed step on the pain ladder, because
of the absence of any diagnostic tools/biomarkers. Some specific treatment options are available or in clinical development, but identification of these mechanisms in patients to select specific treatments remains the biggest challenge.
The Journal of Pain
PRECLINICAL MANIFESTATION
Nociceptor activation at lowered
heat threshold
Increased postsynaptic activity
Increased NGF synthesis
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The Journal of Pain
phenotype and to then target the molecular mechanism
with a specific treatment. Nevertheless, this strategy
remains as we will argue, the most promising for
individualized diagnoses and treatment, and therefore
continues to deserve attention even if it is not
attainable at present.
Pain States
Pain is a multimodal, complex experience involving
multiple neural sites, including peripheral nerves, the
spinal cord, and higher brain centers. The specific receptive properties of thinly myelinated (A-d fiber) and unmyelinated (C-fiber) nociceptors are determined by
membrane-bound transducing ion channel receptors,
which are gated by temperature, chemical stimuli, or mechanical forces, and upon activation transduce an
external stimulus into a change in membrane potential
by opening a sodium/calcium or closing a potassium
channel.31 Examples of transducer receptors are TRPV1
for heat, acid-sensing ion channels for free protons and
Piezo-type mechanosensitive ion channel component
2 for mechanical sensation.52 The modifiability of the
synaptic contact between nociceptors and spinal cord
dorsal horn neurons, and further modulation of nociceptive signals in the CNS by immune cells, local interneurons, descending pathways from the brain and
brainstem,
and
cognitive/affective
components,
together determine the complex and dynamic, individual pain phenotype.90
The following sections, and Tables 1–3 highlight major
mechanisms underlying nociceptive, inflammatory/
infectious, and neuropathic pain and their known or
postulated occurrence in common clinical scenarios—
with emphasis on cLBP and without inclusion of
psychosocial influences, which are certainly important,
but beyond the scope of this review.
Nociceptive Pain
Nociceptive pain in a clinical setting is the result of activation of high threshold mechanoreceptors by increased
mechanical forces (eg, joint capsule stretch or impingement due to destruction of normal joint architecture).
In the healthy spine, the 2 facet joints carry approximately one-third of the total load at a given spinal level
(the rest going through the disc) but this can increase to
70% in the presence of severely degenerated discs.54 In
an experimental setting, injecting saline into a healthy
lumbar facet joint—thus increasing pressure—causes
pain,83 and neurophysiologic recordings from facet
joints confirm activation of high-threshold fibers upon
joint extension.98 Although joint-associated structures,
including fat pads, ligaments, joint capsules, synovium,
and subchondral bones, are richly innervated by nociceptors, and are therefore all potential pain generators, not
all will be exposed to noxious mechanical forces, even in
cases of severe joint degeneration. Often, however,
degeneration is relatively mild compared with pain
severity, so that local inflammation likely also plays a
major role in the generation of cLBP.
Toward a Mechanism-Based Approach to Pain Diagnosis
Inflammatory Pain
Inflammatory pain results from the activation and
sensitization of nociceptors by inflammatory mediators,
caused for example, by an inflammatory synovial
response to cartilage damage of the facet joint.61
Elevated levels of inflammatory cytokines (eg, interleukin
[IL]-1 or IL-6), as well as increased capsular vascularization
and inflammatory cells are present in degenerate facet
joints.75,96 Because of the close proximity of the facet
joint to the dorsal spinal root and dorsal root ganglion,
local inflammation in the facet could spread from the
joint to directly affect nearby neuronal cells and axons,
causing pain with a radicular distribution.5 For example,
patients with lumbar canal stenosis show higher pain
scores and disability if IL-1b levels are elevated in the facet
joints.75 IL-1b can induce cyclooxygenase (COX)-2 in neurons and the production of matrix metalloproteinases in
synovial fibroblasts, the enzymes responsible for cartilage
degradation,19,160 illustrating a molecular coupling
between
joint
inflammation
and
subsequent
degeneration.
Pain due to degenerative disc disease represents a
quite different process from that in facet joints, because
of the lack of a synovial structure in the disc, which is
necessary to cause the inflammatory picture typical of
osteoarthritis. The fully developed nucleus pulposus
remains vessel-free and isolated from immune exposure,
and therefore is capable of invoking an autoimmune
response and subsequent inflammation upon release
into an immunogenic environment.85,110,117 Several
inflammatory markers (eg, IL-1a, tumor necrosis factor
[TNF]-a, transforming growth factor-b) have been
found in herniated discs, and increased levels of
discogenic cytokines correlate with increased pain
levels.2,153 A distinct but possibly related mechanism is
the ingrowth of nociceptive fibers from the outer ring
of the annulus fibrosis into the inner ring and even
into the nucleus pulposus, which has been reported in
the degenerate disc and is associated with increased
lower back pain.48
Tissue damage or inflammation results in local release
of the intracellular content of injured cells and of inflammatory signaling molecules from immune cells, such as
prostaglandins, growth factors (eg, nerve growth factor
[NGF]) and cytokines (IL-6, IL-1b, TNF-a).59,82 Although
some of these agents directly activate transducer
molecules on nociceptor terminals (eg, ATP acting on
P2X3 receptors), inflammatory mediators also lead to
post-translational and transcriptional changes of transducers (eg, NGF results in decreased threshold and
increased expression of the TRPV1 channel).31,52 When
transducing ion channels are activated by adequate
stimuli, voltage-gated sodium channels expressed by nociceptors, such as Nav1.7, Nav1.8, and Nav1.9, are responsible for amplifying the initial transducer current and
triggering an action potential, and therefore play a key
role in determining the excitability and signaling of sensory neurons. Inflammatory mediators can change the
trafficking, cell surface expression, and gating properties
of these channels, resulting in increased excitability.23
Vardeh, Mannion, and Woolf
Peripheral inflammation induces not only changes in
the nociceptor but also in the CNS. For example, there
is a marked increase of COX-2 in spinal cord neurons after peripheral inflammation in response to systemically
acting cytokines such as IL1-b127 and this seems key to
the development of mechanical hyperalgesia in the inflamed anatomical area, whereas the local expression
of COX-2 at the inflamed site drives heat hypersensitivity.148 COX-2 inhibitors with well documented bloodbrain barrier penetration (eg, celecoxib)33 might therefore be more efficacious in conditions with marked mechanical inflammatory pain hypersensitivity due to such
a central COX-2 induction.
Infection
Infection and the subsequent immune response it generates represent a distinct and important pain mechanism. The local host response to pathogens with
invasion of inflammatory cells and subsequent synthesis
of proinflammatory cytokines like TNF-a, interleukin
IL-1b, and IL-6 can directly activate and sensitize
nociceptors in a fashion similar to that which occurs in tissue damage-associated inflammatory conditions.124
However, only recently has it been shown that gramnegative and gram-positive bacteria directly activate nociceptors, independent of the immune response.27,35,108
Interestingly, 31% of 140 patients with no infectious
symptoms in the previous 6 months and severe sciatica,
tested positive for gram-positive infection on serological
testing, and 53% of 36 patients who underwent microdiscectomy had positive disc cultures, with the most common pathogen being Propionibacterium acnes.139
Similarly, in 61 patients who underwent discectomy,
46% with Modic type I changes on lumbar magnetic
resonance imaging (MRI; implying inflammation/edema
of the vertebral end-plate) were found to have a discogenic infection, and a strong correlation was found between the presence of anaerobic disc infection and
development of Modic type I changes.3 A recent randomized trial of 162 patients with cLBP and Modic type I
changes showed statistically significant improvements
in pain and disability at 1 year when treated with
100 days of amoxicillin versus placebo.4 The surprising
notion that an antibiotic may effectively work as an analgesic in a subgroup of chronic pain patients highlights
the paramount importance of a mechanistic approach
to cLBP. To do this, we need accurate biomarkers of
mechanisms, including those for detection of the presence of ongoing pathogen infection.
Neuropathic Pain
Peripheral nerve damage can result either from systemic diseases causing polyneuropathy and mononeuritis multiplex or to a local insult such as trauma,
compression, and inflammation causing mononeuropathy or radiculopathy. For classic lumbar or cervical radiculopathy (clinically defined as pain, weakness, or
numbness in a myotomal/dermatomal distribution), our
understanding is shifting from an etiology defined simply according to the degree of mechanical root compres-
The Journal of Pain
T55
sion (eg, from a herniated disc or hypertrophied facet
joint), to recognition of a more complex interplay between a mechanical compressive insult and its associated
inflammatory phenomenon, such as chemical factors
released from injured disc material or an inflamed facet
joint. This insight derives from several clinical observations: relief of mechanical compression using discectomy
or laminectomy does not always result in immediate
symptom relief120; the degree of mechanical compression does not correlate well with the severity of clinical
symptoms79,103; conservative therapies targeted at
reducing
inflammation
and
musculoskeletal
remodeling can be successful even when radiological
compression persists110; direct nerve root stimulation
can cause dysesthesia, numbness, and motor loss, but
not pronounced pain91; and nucleus pulposus material,
introduced into the epidural space at a distance from
the nerve root, can induce nerve fiber degeneration
without any compression.29,117
In recognition of the prominent inflammatory component in neuropathic pain, several inflammatory markers
have been identified as potential therapeutic targets.
As an example, TNF-a is elevated in the periradicular
epidural fat in patients with radiculopathy from herniated disc disease55 and infusion with a TNF-a neutralizing
antibody is reported to result in pain reduction for up
to 3 months in patients with severe sciatic pain due to
disc herniation.84 In a randomized trial of patients with
acute radicular leg pain due to disc herniation, 2 subcutaneous treatments with the anti-TNF-a antibody
showed a small but significant improvement in leg pain
over 6 months, favorable outcomes regarding back
pain and disability,57 and a decreased rate of surgery at
a 3-year follow-up.56 Although the long-term benefit
of TNF-a antibodies remains controversial87 and this
treatment has not entered common clinical practice
yet, these data suggest that chronic inflammation may
be an important component for development of cLBP
or radiculopathy.
Nevertheless, radiculopathy does not generally occur
in the complete absence of mechanical compression, so
that there is likely a complex interplay between mechanical and inflammatory factors needed to cause the clinical syndrome.110 In cases of mechanical compression
causing severe pain unresponsive to conservative therapy, if additional signs of neural compression occur,
such as bowel or bladder impairment or an evolving
neurological deficit—such as worsening weakness of
the affected area, surgical decompression may be vital
to functional recovery and pain reduction.88
Central Sensitivity Syndromes
Central sensitivity syndromes (CSS), in which no well
defined peripheral or central disease process can be
found are thought to represent a primary dysregulation
of the CNS leading to pain amplification, and are sometimes termed centralized pain or central sensitization.
Examples include somatic pain syndromes such as fibromyalgia and temporomandibular disorder, as well as
visceral pain syndromes like interstitial cystitis and
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The Journal of Pain
irritable bowel syndrome, and possibly cognitive impairments such as chronic fatigue syndrome.104 Attempts to
diagnose these disorders on the basis of their ‘‘central’’
component include self-reported symptom questionnaires such as the Central Sensitization Inventory104,112
and Fibromyalgia Criteria and Severity Scales,155 which
have the patient evaluate and grade a wide array of
symptoms, including somatic and visceral pain, mood,
energy, sleep, and cognitive function, among others.
Although some of the pain symptoms occurring in
these conditions can likely be explained by the
physiologically well-defined phenomenon of activitydependent central sensitization described in the Spinal
Mechanisms: Sensitization and Disinhibition section
(that is an increased responsiveness of CNS nociceptive
neurons to afferent input due to increased excitation
and reduced inhibition in defined circuits), the diffuse
cognitive and affective symptoms that are part of CSS
are difficult to explain by a unified disease process/mechanism. Nevertheless, CSS for somatic and for visceral pain
seem to be at least partially dependent on continuous
peripheral input, as shown by the effects of injection of
local anesthetic, which can reduce remote pain sensitivity (secondary hyperalgesia, see below) in fibromyalgia patients,135 as well as visceral and cutaneous
hypersensitivity in irritable bowel syndrome patients.122
In contrast, the conditions of low back pain, neck pain,
and radiculopathy, most if not all appear to have an
initial peripheral disease process, which over time can
result in a more widespread pain phenotype outside of
the damaged area.64 The extent to which cLBP includes
an element of mechanistic overlap with CSS is unknown
because there is no specific biomarker or treatment for
CSS, but this is an area of growing interest.
Although much work is required to understand the
pathophysiology of these widespread pain conditions,
the most clinically relevant aspect might be that the
response generally of these patients to treatment is
poorer and they have worse surgical outcomes,69,99,138
perhaps because the wrong drug target or pathological
locus is selected.
Pain Mechanisms
Nociceptive Transduction
Nociceptive transduction represents the physiological
conversion of an intense (noxious) thermal, mechanical,
or chemical stimulus into activity in a nonsensitized nociceptor.13 Although this mechanism can contribute to
chronic pain in specific settings (eg, damage to a joint resulting in abnormal mechanical forces), it rarely is the
sole contributor in chronic pain states.
Peripheral Sensitization
Peripheral sensitization constitutes a decreased
threshold and increased responsiveness of nociceptors
as a result of post-translational changes in and altered
trafficking of transducer receptors (eg, TRPV1) and ion
channels (eg, Nav channels). This is caused by local inflammatory mediators, and results in pain hypersensitiv-
Toward a Mechanism-Based Approach to Pain Diagnosis
ity symptoms confined to the site of the inflamed tissue
(zone of primary hyperalgesia).31,156
Spontaneous Neuropathic Pain
Spontaneous neuropathic pain is a debilitating and
common symptom feature of neuropathic pain,
including some forms of cLBP. Spontaneous pain and dysesthesia after nerve injury are driven by the ectopic firing
of sensory neurons, in injured and perhaps also in uninjured neighboring sensory fibers,36 and from the DRG
itself.6 This is caused by changes in the expression, distribution, and phosphorylation of membrane ion channels,
triggered by the major alterations in neuronal metabolism, and transcription resulting from peripheral
axonal injury (eg, downregulation of potassium channels30,145 membrane depolarization, and modulation of
sodium channels like Nav1.7, Nav1.8, and Nav1.9,
resulting in hyperexcitability31,150). Carbamazepine,
which stabilizes the inactivated state of voltage-gated
sodium channels, is the first-line treatment for trigeminal neuralgia and this medication, and even more so selective sodium channel blockers, may prove helpful in
other conditions of spontaneous neuropathic pain due
to sodium channel-dependent hyperexcitability.
Spinal Mechanisms: Sensitization and
Disinhibition
Chronic neuropathic pain often extends spatially
beyond the area of the initially involved root or nerve,
resulting in a zone of secondary hyperalgesia, which
commonly becomes independent of the initial noxious
event.156 These symptoms cannot be explained by
changes in the peripheral nervous system, but rather
reflect changes in spinal and supraspinal networks that
result in a functional shift of the sensory system from
physiological high-threshold nociception to pathological low-threshold pain hypersensitivity.
One major mechanism responsible for this shift is central sensitization.93,156 The International Association for
the Study of Pain defines ‘‘central sensitization’’
broadly as the ‘‘increased responsiveness of nociceptive
neurons in the CNS to their normal or subthreshold
afferent input.’’ Activity-dependent mechanisms of central sensitization include homosynaptic long-term
potentiation—with exaggeration of nociceptor responsiveness—and heterosynaptic potentiation—recruiting
low threshold Ab fiber inputs into the pain pathway,
and these mechanisms may be driven and sustained by
ectopic activity in the injured nerve.93 Other longlasting consequences of nerve injury include central neuroinflammation (driven by alterations in microglia, astrocytes, and invading T lymphocytes),81 neuronal
phenotypic changes due to altered gene transcription
and post-translational modification of membrane proteins,156 and degeneration of inhibitory neurons resulting in the facilitation of pain pathways.38,47,128
Homosynaptic facilitation occurs at the synapse between the nociceptor and dorsal horn neuron, and clinically can present as temporal summation, a progressive
increase in pain intensity during repetition of identical
Vardeh, Mannion, and Woolf
noxious stimuli. Heterosynaptic facilitation in the spinal
cord differs fundamentally from homosynaptic changes
in that it takes place at synapses not restricted to the initiating nociceptor input.150 For example, in healthy
human volunteers, subcutaneous injection of capsaicin
produces several minutes of severe pain restricted to
the site of injection (the noxious conditioning stimulus)
and this is followed by tactile allodynia in the areas
around the site of injection, and pinprick hyperalgesia
in an even larger area.156 These symptoms result from
the novel functional recruitment of Ab and Ad fibers
into the nociceptive pathway by strengthening synapses
between the fibers and nociceptive neurons in the spinal
cord dorsal horn, by heterosynaptic facilitation. They are
clinically referred to as secondary hyperalgesia, and
contribute to the spread of pain sensitivity in inflammatory conditions (eg, osteoarthritis99,114,140) and many
neuropathic pain conditions.44 Principal molecular
mechanisms of this form of central sensitization are the
activation of several protein kinases by the neurotransmitter glutamate and various neuropeptide transmitters,
which lead to post-translational and transcriptional
changes in postsynaptic receptors (eg, the NMDA receptor). The specific circuitry underlying central sensitization is beginning to emerge.38,100,119 That central
sensitization is a major driver of neuropathic pain is
supported by the action of drugs that reduce central
excitability, including gabapentanoids (eg, gabapentin
and
pregabalin),
tricyclic
antidepressants
(eg,
amitriptyline), SNRIs (eg, duloxetine), and NMDA
antagonists (eg, ketamine).161 The extent to which a
persistent and autonomous central sensitization type of
phenomenon can be set up in patients with cLBP but
without damage to the peripheral nervous system or
CNS is uncertain, as are the circuits involved and the
mechanism responsible.
Temporal summation as a surrogate for central sensitization can be measured clinically by applying repetitive
heat or mechanical stimuli.136 There might be a correlation between the intensity of the initial conditioning
injury and the degree of secondary hyperalgesia as well
as time to recovery, as shown in patients with cervical
whiplash injury who develop a higher degree of sensory
disturbance, lowered pain thresholds, and prolonged
symptoms if the initial whiplash injury pain was severe
as opposed to mild or moderate.137,138 This raises the
question whether there might be an advantage in
treating more severe patients early and aggressively.
Disinhibition
In addition to the strengthening excitatory synapses in
the spinal cord, loss of inhibition by decreasing GABAergic and glycinergic tone also contributes to central hyperexcitability, and can be produced by peripheral
nerve lesions.76,128 Increasing spinal inhibition with
intrathecal gamma aminobutryic acid (GABA) or by
activation of inhibitory interneurons results in an
antinociceptive effect, while blocking inhibitory
transmission (eg, by selective ablation of glycinergic
dorsal horn interneurons), leads to lowered pain
The Journal of Pain
T57
thresholds and the development of hyperalgesia and
tactile allodynia.47,66 Mechanisms of disinhibition
include reduced descending inhibitory control, loss of
GABAergic or glycinergic interneurons through cell
death, reduced GABA or GABA-synthesizing enzyme
(eg, glutamate decarboxylase), and altered properties
of GABAA receptors, glycinergic receptors, and cationchloride cotransporters.66,90 Restoring spinal cord
inhibition by, for example, subtype-specific GABA receptor agonists, may offer the opportunity to reduce pain
without limiting side effects like sedation.163
Contribution of the Immune System
Reciprocal signaling between neurons and immune
cells in the CNS has been identified as a possible key
contributory mechanism to some chronic pain conditions. After peripheral nerve injury, a cocktail of
neuronally-derived mediators activate spinal microglia,
which transition to a state of reactive gliosis and release
molecules causing astrogliosis and invasion of T cells into
the spinal cord.62,109 Subsequent release of immune
mediators from microglia can enhance synaptic
neurotransmission, presynaptically by for example,
increasing glutamate release or postsynaptically by
AMPA and NMDA receptor modulation.62 Astrocytes
contribute indirectly to increased synaptic glutamate
levels and nociceptive hypersensitivity by downregulation of the spinal astrocyte glutamate transporters after
peripheral nerve injury.159
Other cytokines (eg, TNF-a, IL-1b, and IL-6) contribute
to a disinhibition of spinal pain networks by reducing
the release of GABA and glycine from interneurons and
inhibitory descending projections.19,62,71 In cLBP
patients, activation of microglia can be detected in the
thalamus, pre- and postcentral gyri, and paracentral
lobule using functional imaging (positron emission
tomography/MRI) and the radioligand 11C-PBR28, a
marker for activated microglia and reactive
astrocytes.97 This biomarker might prove useful as a diagnostic tool, identifying subsets of patients whose pain is
driven by non-neuronal cells in the CNS, and who may
benefit therefore, from treatment targeting central
immune cells.
Supraspinal Mechanisms
In chronic pain patients, structural changes such as a
decrease in neocortex gray matter have been
detected,8,53 as well as changes in excitatory and
inhibitory transmitters67 and in functional connectivity.21,58 How these changes relate to the cognitive,
sensory, and emotional pain experience, and if these
changes are dependent on the original peripheral or
central insult is uncertain, although some of these
changes (eg, gray matter volume loss) seem to be
reversible after pain treatment.68
The end result of increased excitability and reduced inhibition in the CNS is an increase in the gain of incoming
sensory information, resulting in exaggerated pain, secondary hyperalgesia, allodynia, and temporal summation. In cLBP patients, this increased gain can be
T58
Toward a Mechanism-Based Approach to Pain Diagnosis
The Journal of Pain
observed by applying mechanical pressure, which evokes
muscle pain at a significantly higher intensity, in a wider
distribution and for significantly longer time than in control subjects.118 This corroborates with functional brain
MRI imaging, where cLBP patients show widespread
activity in response to mechanical pressures at levels
that in control subjects only evoke focal somatosensory
cortex activation.58
The Challenge of Applying an
Understanding of Pain Mechanisms Into
Clinical Practice
Can the traditional clinical methods (Table 4) of history, examination, and investigation inform the clinician
about probable pain mechanism(s) and their locus, in the
absence of information about a patient’s genotype, transcriptional, cellular, and neurophysiological status? Can
clinicians appreciate anatomically the predominant
pain generator, pain state, and the underlying mechanism(s)?
Efforts to ascertain information about mechanisms using a symptom-oriented approach have resulted in several
patient questionnaires, most of them with the stated
focus only of identifying a neuropathic component within
a given pain syndrome, such as cLBP.49,50 The Neuropathic
Pain Special Interest Group of the International
Association for the Study of Pain has recommended 5
questionnaires to screen for neuropathic pain: ID Pain,
Table 4.
Leeds Assessment of Neuropathic Symptoms and Signs,
PainDETECT questionnaire, Douleur Neuropathique 4,
and Neuropathic Pain Questionnaire, with the latter 2
having the largest evidence base.102 The validity of questionnaires is hampered by lack of any diagnostic gold
standard for neuropathic pain in a patient, such that the
questionnaires define the syndrome, rather than the syndrome being revealed by the questionnaire. Other problems arise from the coexistence of neuropathic pain
with other pain states in many patients and the poor
cross-cultural validity of translated questionnaires.102
Some questionnaires rely entirely on patient-reported
symptoms, which are convenient but may distort the
signal to noise ratio, whereas others require a detailed
sensory examination done by a clinician—a challenge in
a busy clinical practice. In the end, the most important
question will be whether such approaches are sensitive
and specific enough for diagnosis and can help with
informed treatment choices.
On the basis of the 5 questionnaires mentioned, the
most common signs and symptoms of neuropathic pain
are considered mechanical and temperature-evoked
allodynia, numbness to all modalities, burning/tingling/
electric shock-like paresthesias, absence of persistent
pain, and presence of intermittent pain attacks. An
assumption is that these symptoms reflect the neuropathic pain mechanisms discussed previously, but their
specificity is poor. For example, tactile allodynia could
be caused by recruitment of low-threshold A-b
Common Diagnostic Testing for Patients With Chronic Low Back Pain
DIAGNOSTIC TEST
History
Quality and severity of pain
Physical examination
SLR test
Dermatomal sensory
loss/myotomal deficit
Musculoskeletal maneuvers
(eg, facet loading, sacroiliac joint
and hip maneuvers,
low back palpation)
Investigations
NCS/EMG
QST
MRI imaging
INTERPRETATION
LIMITATIONS
Burning/tingling/electric shock like
paresthesias = neuropathic pain
Dull, aching = nociceptive pain
Poor specificity
Coexistence of more than 1 pain state
Different mechanisms can produce same symptoms
No gold standard
Lumbar radiculopathy/sciatic
nerve irritation
Low specificity (eg, many patients have hamstring and gluteal
tightness eliciting pain upon SLR)
Unable to distinguish between L4, L5, S1, root, or sciatic nerve
Inconsistent finding
Significant dermatomal/myotomal overlap
Poor specificity
Multiple structures are simultaneously stimulated
Root compression/damage
Anatomic localization of pain driver
Presence/absence of neuropathy
or radiculopathy
‘‘Sensory fingerprint’’ indicative
of pain mechanism
Degenerative changes judged as
causative of pain syndrome
Only evaluates large-diameter fibers (not A-d and C fibers)
Lesions proximal to DRG are not routinely captured
Time-consuming and resource-heavy
No gold standard
Same disease with multiple sensory clusters
Poor specificity
Degree of degenerative changes does not correlate
with symptoms
Only anatomical changes considered (but not functional,
eg, inflammation, etc)
Abbreviations: SLR, straight leg raise; NCS, nerve conduction study; EMG, electromyogram.
NOTE. Examples of commonly used diagnostic tools including patient’s symptoms, examination findings, and ancillary testing with clinical interpretations and shortcomings.
Vardeh, Mannion, and Woolf
mechanoreceptive fibers due to central sensitization in
the spinal cord or spinal disinhibition. Similarly, burning
pain may reflect activity somewhere in the pathway
dedicated to heat sensation, but where? Is it due to activation of heat nociceptors by body temperature after peripheral sensitization, ectopic activity in injured heat
nociceptors, or disinhibition of heat pain projection neurons in the spinal cord? It is clearly difficult to infer mechanism from positive symptoms, although negative
symptoms such as numbness generally reflect disruption
of the nervous system in a way that respects anatomy.129
For certain pain conditions, a distinctive ‘‘sensory
fingerprint’’ may give useful insight into pathogenesis.
For example, distinct symptom patterns or ‘clusters’
have been identified in patients with painful radiculopathy versus axial low back pain (see the section on Quantitative Sensory Testing [QST]), although clinical signs
seem to be more reliable than symptoms. Decreased
pinprick sensation was found to be the best discriminator
between axial low back pain and radicular pain
(compared with a clinical ‘gold standard’) and 3 parameters (response to pinprick, straight leg-raising test, vibration sense) could reliably discriminate between painful
diabetic neuropathy, postherpetic neuralgia, and radicular lower back pain.129 Therefore, questionnaires,
although convenient to administer, probably cannot
substitute for a focused physical examination, and
should be used with caution for making clinical diagnoses by themselves.
Clinical Examination
Experimentally, the presence of secondary hyperalgesia, temporal summation, and tactile allodynia are all
considered signs reflective of central sensitization.118,134
In the clinical setting however, mechanistic identification
is challenging. Typically, a clinical examination tries to
localize a pathology to a distinct anatomical structure.
The straight leg- and crossed straight leg-raising test is
a reliable test for painful radiculopathy or sciatica, and
shows relatively high sensitivity and specificity, respectively,125,129 but other physical tests (motor deficit,
muscle wasting, impaired reflexes, sensory deficits) are
rather unreliable.147 Similarly, physical examination for
other components of cLBP, including musculoskeletal
palpation and manipulation, or provocative tests for facetogenic and sacroiliac pain, show poor diagnostic validity and interobserver reliability.70,126 In summary,
standard clinical examination techniques, although
helpful to screen for serious pathology such as spinal
cord compression or cauda equina compression,
perform poorly in identifying the anatomic source of
cLBP and even more so, the mechanistic nature of low
back pain and radiculopathy.
QST
QST is currently used as a research tool but is impractical for standard clinical practice. Standardized sensory
testing algorithms and a modality-specific evaluation
of stimulus-evoked pain may add value to nerve conduc-
The Journal of Pain
T59
tion studies, which only examine large nerve fibers, and
assist in conclusions as to underlying mechanisms.10 For
example, secondary hyperalgesia can be systematically
assessed in patients with knee osteoarthritis, where
lower pressure pain thresholds at remote sites from the
diseased joint correlate with poorer outcome for total
knee replacement.99 Hyperalgesia to cold and heat stimuli in oxaliplatin- but not cisplatin-induced neuropathy,
points to distinct mechanisms of nerve damage of the 2
drugs, which might drive treatment choice in the individual patient.9 For axial low back pain, several sensory clusters with potentially distinct underlying mechanisms
have been identified.46 For example, one cluster characterized by pressure tenderness of paraspinal muscles and
a dull and aching pain quality, was interpreted as reflecting nociceptive pain of musculoskeletal structures,
possibly driven by muscle spasm and mechanical degenerative change in the facet joint and disc. Another cluster
of patients had pain in a similar distribution, but characterized by severe pain attacks precipitated by routine
movements, which may be due to inflammation in facet
joints or discs resulting in sensitization of the nerve
fibers. Yet another cluster was defined by burning and
prickling sensations, possibly reflecting a neuropathic
etiology.46,48 Such symptom clusters present an
interesting research opportunity to see whether they
may be indicative of distinct underlying pain states
(nociceptive,
inflammatory,
neuropathic)
or
mechanisms (eg, peripheral or central sensitization),
although even within a seemingly homogenous group
of patients with cLBP multiple different mechanisms
are likely to be at play, creating complex and
overlapping phenotypic symptom clusters. Biological
biomarkers may be required to tease them out.
Correlations have been sought between QST parameters and analgesic response to improve therapy choice
for the individual patient. As an example, baseline heat
pain thresholds predicted response to opioid treatment
but not to amitriptyline in patients with postherpetic
neuralgia.41 However, because of the heterogeneity of
conditions and outcomes, no robust QST parameter for
reliable analgesic response prediction has been identified so far.65 Similarly, because of the large variability
in the pain phenotype of patients with cLBP, identifying
a sensitive/specific and time-efficient diagnostic QST test
in a clinical setting may not be feasible.
Imaging
Imaging cLBP patients is considered a key component
for establishing diagnosis. Yet, as discussed earlier, the
ubiquitous nature of degenerative changes in the spine
makes any correlation between symptoms and imaging
poor.79,103,129 Although imaging can rule out serious
pathology (eg, tumors, spinal infection, fractures,
cauda
equina
syndrome),
routine
computed
tomography and MRI imaging of cLBP patients
increased 300% between 1994 and 2005 without
improved clinical outcomes.103 Nevertheless, as our understanding of cLBP mechanisms progresses, the role of
imaging is likely to evolve. An annular tear might be,
T60
The Journal of Pain
for example, the trigger for an immunogenic response,
ingrowth of nociceptors into the inner area and hence
the source of discogenic, nociceptive pain; Modic
changes in vertebral endplates are associated with
cLBP and in some cases possibly represent infection;
discs with adjacent Modic type I changes show higher
levels of inflammatory markers (eg, TNF-a) and
increased nerve fiber density.12,144,164 Recent studies
using T2* sequences to quantify features of disc
health have shown a better correlation between disc
degeneration and functional spinal mechanics than
traditional MRI techniques.42 Single-photon emission
computed tomography is being used more widely to
identify activity (assumed to be a marker of inflammation/possible nociceptor sensitization) in facet and
sacroiliac joints and several studies have found that patients
with
single-photon
emission
computed
tomography-positive facet arthropathy had better outcomes with intra-articular lumbar facet joint injections
than patients who underwent medial branch blocks
(the nerve supplying the facet joint).1,121
Targeting Mechanisms With Interventions
Pharmacological
Pharmacological pain relief in clinical practice often
represents an empirical journey up an analgesic ladder
(nonsteroidal anti-inflammatory drugs, ‘‘neuropathic’’
agents, other adjunct medications including antiepileptic drugs, and finally opioid medications), and is
more often dictated by patient-centered factors
(including medical history, tolerance of side-effects,
compatibility with other medications), rather than targeting a pain mechanism. Because of the recognized difficulties in identifying mechanisms clinically, one
strategy is to postulate the mechanism on the basis of
pharmacological response (ex juvantibus)—give a
drug, assess its efficacy, and for the successes, postulate
a likely mechanism. For example, if a patient improves
after being prescribed gabapentin or an antiinflammatory agent, does this reflect a neuropathic or
inflammatory pain state, respectively? As indicated in
Table 2, most of the currently used medications have
broad and complex mechanisms of action, often acting
at several sites and molecular targets, and hence clinical
response rarely allows postulation of a specific pain
mechanism.
Physical and Psychological Treatment
Physical back pain management strategies can be
divided into passive therapies (eg, manipulation and
massage) and active therapies such as patient-directed
exercise, stretching, and core-stability techniques. There
is some evidence for such therapies working in the shortto medium-term.86,133 Clearly, they do not work for every
patient and there are a host of factors that influence
their efficacy above and beyond the pain mechanism
(eg, placebo-responder status, premorbid condition
and fitness level, age, motivation, and compliance).
There is debate about how these techniques influence
Toward a Mechanism-Based Approach to Pain Diagnosis
cLBP and the evidence for or against the use of physical
therapy at least as a stand-alone treatment is weak.88
As part of a multimodal approach to pain treatment,
psychological interventions like cognitive behavioral
therapy and treatment of negative affect appear useful
for patients suffering from depression and pain catastrophizing,39 and are explored in dedicated reviews in
this issue of The Journal of Pain.40,146
Spinal Injection
Spinal injections (local anesthetics with or without
steroids) have increased many fold over the past 10 to
15 years.152 Although some of these injections appear
to have clinical benefit for select patients for weeks to
a few months, their clinical use remains controversial,28,72,131,132 and cynics might argue that it has
become an industry driven more by financial than
health-outcome factors. What do injections teach us
of mechanisms? There are some observations that are
difficult to explain. For example, the clinical response
to an injection with local anesthetic often far outlasts
the pharmacological action of the injected agent;
cLBP patients have lowered pain thresholds to mechanical, heat, chemical, and electrical stimulation, in the
lower back and at more distal sites, and functional
brain imaging and magnetic encephalography reveals
an increase in the gain of central processing after peripheral stimuli in lower back pain patients.58,61 How
then can the temporary numbing of a localized
peripheral site, with or without the addition of
steroids, result in long-lasting and profound changes
in pain perception? One possibility is that a stable
‘‘pathological pain network’’ is established in the CNS
of chronic pain patients and this is dependent on
continuous input from peripheral sites to maintain it;
when this generator is temporarily removed, the system
reverts to lower amplification levels.63 Alternatively,
locally administered anesthetics could have systemic effects. Lidocaine infusions are routinely used in pain
clinics for widespread pain syndromes, and again pain
relief outlasts the pharmacological activity of lidocaine
on sodium channels by weeks. This might be related to
off-target effects of lidocaine, like its anti-inflammatory
properties,20 including its ability to decrease cytokine
production of activated microglia in the CNS.80 Another
important explanation is the placebo, which pain medicine is particularly prone to,74 and interventional procedures result in higher placebo responses than
pharmacological therapies.105
A further question is how to interpret an analgesic
response (or a failure to respond) after a local injection.
What does this inform us about the location of the primary pain generator or the underlying pain state? A positive response to a facet joint medial branch block might
be, for example, due to decreased afferent information
from a primarily osteoarthritic/inflamed facet joint,
decreased neuropathic pain from a mechanically compressed medial branch nerve or neither—the pain driver
may be more proximal in the dorsal root, the dorsal root
ganglion, or even the CNS, and normal input from the
Vardeh, Mannion, and Woolf
medial nerve is perceived as pain. Also, in analogy to surgical rhizotomy, which can cause chronic denervation
pain, could radiofrequency lesioning of medial nerve
branches contribute to chronic neuropathic pain in susceptible patients?
Surgical
Perhaps the most controversial topic in the management of chronic back pain is the role of surgery, best
exemplified by the ‘failed back surgery syndrome’
(FBSS).24 This is a real problem for a condition in which
the natural history, even without surgery, is typically of
improvement over time. If there is earlier resolution of
pain symptoms with surgery versus nonsurgical treatment, but long-term clinical outcome is no different,
does this constitute success or failure? FBSS can result
as a consequence of poorly executed surgery, but it is
much more commonly the result of poor surgical
decision-making, inadequate management of patient
expectations, or a failure to improve despite a technically
sound procedure. A predisposition to develop neuropathic pain may be present in FBSS patients because of
genetic or epigenetic factors, independent of surgical
technique or patient management, but at present we
cannot identify these factors preoperatively, although
genetic polymorphisms may eventually help. Patients
with more and wider-spread secondary hyperalgesia as
well as with psychological dysfunction have a higher
risk of poor surgical outcome.11,14,22 Whether this
reflects higher susceptibility to establishment of an
autonomous centralized state is intriguing to consider,
but requires evidence to support it.
Despite some caution about the role of surgery for
cLBP, the transformative benefits of surgery in certain
clinical scenarios, for example, unrelenting radicular
leg pain in patients with concordant nerve root compression on imaging must be recognized. A patient receiving
maximum doses of narcotic and neuropathic agents,
with significant side effects yet still suffering agonizing
pain for many weeks, can be pain-free within hours of
surgery. But clearly, this is not always the case, and there
are certainly unknown factors that lie beyond sound patient selection.
In summary, the clinical diagnostic and management
problem for any individual cLBP patient requires identification of one or several pain states (nociceptive, inflammatory, neuropathic) as well as general pain mechanisms
at play. These factors are modified by the individual’s genotype, sex, and psychosocial characteristics,40,146 which
may individually and collectively influence susceptibility
to elevated pain intensity and chronification, as well as
therapeutic response and drug metabolism. Current
diagnostic tools are too blunt to decipher this
complexity, especially under the current pressures
(time, financial, documentation, liability) of a busy pain
practice. The pain history with self-reported symptoms,
even when carefully recorded in detail, is often unreliable.102,129 Many aspects of the physical examination
suffer from poor validity and reliability70,126,129,147 or
demand extensive time for minute sensory testing with
The Journal of Pain
T61
questionable benefit to the patient. Imaging, although
important for exclusion of dangerous disease, more
often than not does not correlate with the patient’s
symptoms and is heavily overutilized without any
proven clinical benefit.79,103 Diagnostic/therapeutic
interventions, like nerve blocks with local anesthetics,
remain difficult to interpret and are of controversial
clinical benefit,28,72,131,132 and surgery such as
discectomy for radiculopathy, has no proven long-term
benefit over medical therapy alone.78 Although acute
pain syndromes have rather defined treatment algorithms (eg, nerve blocks and short course of opioids for
postsurgical pain, and nonsteroidal anti-inflammatory
drugs, muscle relaxants, and light physical activity for
acute low back strain), treatment choices on the basis
of the length of a chronic pain condition are purely
empirical with few data to guide us. Naturally, treatment
invasiveness increases as chronic pain condition persist,
including spinal cord/peripheral nerve stimulation implants and as intrathecal pumps, although the pathophysiological changes in the nervous system being
targeted with such therapies and their change over
time, remain unclear as does their efficacy in many cases.
Having Recognized the Current Limitations
in Chronic Back Pain Diagnosis and
Management, How Do We Move Forward?
Emerging New Molecular Targets
Several lines of evidence are providing important new
clues about the molecular mechanisms of chronic pain,
including human genetic studies that are starting to
identify some potentially clinically relevant pain genes.
Some of these genes we will briefly highlight, emphasizing therapeutic opportunities.
Pain Genetics
A recent twin studies review estimated a heritability of
35% for back and neck pain,115 highlighting the huge
potential for unraveling underlying mechanisms using
genetic analysis and for identifying novel targets for
pharmacological therapy. Although no adequately powered genome wide study in a large, well-phenotyped
cLBP cohort has been carried out so far, several human
‘‘pain genes’’ have been shown to be important in
some acquired and familial pain syndromes.34
Human genes with a link to dramatic, familial pain
phenotypes include SCN9A coding for the voltage-gated
sodium channel Nav1.7, SCN11A (Nav1.9), and
TRPA1. Loss-of-function of Nav1.7 leads to congenital
inability to experience pain without affecting other sensory modalities32 whereas gain-of-function mutations
result in paroxysmal extreme pain disorder and primary
erythromelalgia.37,45 Less dramatic, but probably more
clinically relevant, is the haplotype of a single
nucleotide
polymorphism
which
modifies
Nav1.7 activity and correlates with increased pain
scores in several human cohorts suffering from sciatica,
osteoarthritis,
pancreatitis,
lumbar
discectomy,
T62
Toward a Mechanism-Based Approach to Pain Diagnosis
The Journal of Pain
123
phantom limb pain, and experimental pain.
Gain of
function mutations of SCN11A, coding the nociceptive
sodium channel Nav1.9, interestingly result in a congenital inability to sense pain in humans95 likely by producing sustained sodium channel inactivation, as can
homozygous mutations in PRDM12, an epigenetic regulator that plays a key role in sensory neurogenesis.26
Because of the dramatic phenotype of Nav1.7 mutations,
with gain and loss of function, as well as the absence of
serious cognitive or cardiac effects in individuals with
complete loss of function, the channel has spurred
huge interest as a drug target. Specific Nav1.7 channels
are currently under investigation111 and targeting
Nav1.7 with an antibody in mouse models of inflammatory and neuropathic pain resulted in significant analgesic effects.94 Clinical trials using selective Nav1.7
channel blockers have been successful in conditions
like inherited erythromelalgia,60 but so far the limited
early trial data have been surprisingly disappointing in
other chronic human pain conditions. A gain-offunction mutation in TRPA1, a membrane-associated
sensor of environmental irritants, has been identified
in a rare disorder called familial episodic pain syndrome,
causing upper body pain,89 and several TRPA1 antagonists are currently under investigation in phase I and II
clinical trials.
Various haplotypes of other human genes cause less
dramatic clinical effects, but might be more clinically
relevant because they apply to a much larger population.
Examples include: voltage-gated calcium channels
CACNG2 (reduced postmastectomy pain116) and CACNA2D3 (reduced postsurgical pain 1 year after discectomy113); voltage-gated potassium channel KCNS1
(increased pain in axial low back pain, amputation,
sciatica, phantom limb, and experimental pain in healthy
adults30); Nav1.8 in patients with painful peripheral neuropathy43; and the cation channel P2X7 (decreased postmastectomy and osteoarthritic pain130). Exploiting these
molecular targets remains a challenge because of potentially serious side effects because of their function in
many systems.
Besides pain genes altering ion channel properties,
genes altering the metabolism of neurotransmitters
also seem to account for pain phenotype differences. Examples include genetic variations in catecholamine
biosynthesis and transmission (eg, the serotonin transporter gene [SLC6A4] and serotonin and epinephrine receptors162), in the enzymatic breakdown of the
neurotransmitters dopamine, epinephrine, and norepinephrine by variations in catecholamine-O-methyltransferase7 and in guanosine triphosphate cyclohydrolase
(GCH1), the rate-limiting enzyme for tetrahydrobiopterin (BH4) synthesis, an essential cofactor for phenylalanine, tyrosine, and tryptophan hydroxylases.142
Increased levels of GCH1 and BH4 are implicated in inflammatory and neuropathic pain, whereas blockade
of this pathway results in analgesia.92,141 Variants in
the human GCH1 haplotype reduce radicular leg pain
after discectomy, experimental pain, and improve
outcomes after surgically treated degenerative disc
disease.141 Although the anti-inflammatory drug sulfasa-
STATE
MECHANSIM
TARGET
•
•
•
•
NocicepƟve
Inflammatory
Neuropathic
DysfuncƟonal
•
•
•
•
•
NocicepƟve transmission
Peripheral sensiƟzaƟon
Ectopic acƟvity
Central sensiƟzaƟon
Central disinhibiƟon
•
•
•
•
•
•
NGF
TrkA
TRPV1
Nav1.7
NMDAR
etc
Figure 2. Pain diagnostic ladder. Proposed clinical conceptual
framework for approaching and managing a pain patient in
the future when specific biomarkers and more targeted treatments become available. Identifying the pain state, general
pain mechanism, and molecular target will result in precise, individualized pain medicine. Note that more than 1 pain state can
coexist and multiple mechanisms can be at play.
lazine, which decreases BH4 levels, has not shown
benefit in patients with lumbar spondylarthritis,15 pharmacological blockade of sepiapterin reductase,32 which
decreases neuronal and macrophage BH4 production, is
effective in rodent chronic inflammatory and neuropathic pain and constitutes a possible pharmacological
target for humans.92
Other New Therapeutic Possibilities
An interesting target for pharmaceutical intervention
is neuroinflammation in the peripheral and CNS, which
drives chronic pain via neuron-glial and neuronimmune cell interactions.81 Pharmacological targeting
of some of the key molecular players include chemokines (CXCL1, CCL2, and CX3CL1), proteases (MMP9,
Vardeh, Mannion, and Woolf
cathepsin S, and caspase 6) and the WNT signaling
pathway, which have yielded some promising preclinical results, but are compromised by immune suppression and inhibition of synaptic plasticity.81 One
emerging target is leukocyte elastase, released by
T cells invading the dorsal root ganglion after peripheral nerve injury, and contributing to neuropathic
pain. Sivelestat, a drug currently awaiting U.S. Food
and Drug Administration approval and already in clinical use in some countries for treating airway inflammation, inhibits leukocyte elastase and might represent a
novel treatment to interrupt immune cell-driven sensitization of DRG neurons.149
Other novel drug targets currently undergoing phase II
clinical trials on lower back pain are VVZ-149, an antagonist of glycine transporter type 2 and serotonin receptor 2A, for lumbar radiculopathy and epidermal
growth factor receptor inhibitors such as cetuximab
and panitumumab for various neuropathic pain conditions including complex regional pain syndrome and
‘‘failed back syndrome,’’ as well as ethosuximide, an antiepileptic agent, tenazemub, an anti-NGF antibody,
V116517, a TRPV1 inhibitor, cebranopadol, an opioid,
and angiotensin type II receptor antagonists (https://
clinicaltrials.gov/).
Restoring spinal cord inhibition using GABA receptor
agonists represents another pharmacological strategy,
which is mainly challenged by the limited analgesic effect and serious side effects of nonselective GABA receptor agonists like benzodiazepines. However, recent work
on different GABA-A receptor subunits has revealed the
a2 subunit as a pharmacological target which produces
strong antihyperalgesia with reduced sedation, encouraging development of subunit-specific GABA-A receptor
benzodiazepines.163
Stem cell therapy is another interesting strategy to
restore spinal inhibition and thus treat chronic pain conditions, at least experimentally. Delivery of precursors of
cortical inhibitory (GABAergic) interneurons results in
restoration of GABA-driven inhibition in relevant spinal
cord segments to improve neuropathic pain in
mice.16,17 Intrathecal delivery of bone marrow stromal
cells similarly has a therapeutic effect in neuropathic
mice models by paracrine secretion of the
neuromodulator transforming growth factor-b1 at the
site of injured DRG neurons.25
Finally, personalized human nociceptor profiling by reprogramming fibroblasts into nociceptors151 will enable
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