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Toward a Mechanism-Based Approach to Pain Diagnosis

      Highlights

      • Chronic pain can be classified on anatomical, pathological and mechanistic bases.
      • Pain includes nociceptive, inflammatory, neuropathic and central hypersensitivity states.
      • The multiple mechanisms driving pain involve different drug targets.
      • Identifying pain mechanisms enables rational individualized treatment choices.
      • Precision pain medicine is possible through a pain diagnostic ladder.

      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 mechanism-based 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.

      Key words

      A mechanistic approach to address chronic pain has been actively promoted over the past few decades in an attempt to exploit the growing understanding of underlying pathological processes as a means to improve patient management.
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      Management of neuropathic pain: Translating mechanistic advances and evidence-based research into clinical practice.
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      Towards a mechanism-based classification of pain?.
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      Neuropathic pain: Aetiology, symptoms, mechanisms, and management.
      Medicine is obviously most impactful when defined 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 morbidity-related health care costs are unacceptably high, per data from the Global Health Data Exchange.

      Institute of Health Metrics and Evaluation (IHME). Available at: http://ghdx.healthdata.org. Accessed January 19, 2016

      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 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,

      Merskey H, Bogduk N, eds. Classification of Chronic Pain Descriptions, of Chronic Pain Syndromes and Definition of Pain Terms, 2nd ed., Seattle, International Association for the Study of Pain Press, 1994

      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.
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      • Kallmes D.F.
      • Jarvik J.G.
      Systematic literature review of imaging features of spinal degeneration in asymptomatic populations.
      However, only a minority of people develop cLBP, and there is no strong correlation between cLBP and age or activity,
      • Hildebrandt V.H.
      • Bongers P.M.
      • Dul J.
      • van Dijk F.J.
      • Kemper H.C.
      The relationship between leisure time, physical activities and musculoskeletal symptoms and disability in worker populations.

      Institute of Health Metrics and Evaluation (IHME). Available at: http://ghdx.healthdata.org. Accessed January 19, 2016

      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 arthritis, spondyloarthritis, or ongoing nerve compression, which might be amenable to specific disease-modifying 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.
      • Dib-Hajj S.D.
      • Waxman S.G.
      Translational pain research: Lessons from genetics and genomics.
      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 disability
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      Pain, catastrophizing, and depression in the rheumatic diseases.
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      • Haythornthwaite J.A.
      • Edwards R.R.
      Rethinking the fear avoidance model: Toward a multidimensional framework of pain-related disability.
      and are explored in other review articles in this issue of The Journal of Pain.
      • Edwards R.R.
      • Dworkin R.H.
      • Sullivan M.D.
      • Turk D.C.
      • Wasan A.D.
      The role of psychosocial processes in the development and maintenance of chronic pain.
      • Turk D.C.
      • Fillingim R.B.
      • Ohrbach R.
      • Patel K.V.
      Assessment of psychosocial and functional impact of chronic pain.
      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 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,
      • Hancock M.J.
      • Maher C.G.
      • Latimer J.
      • Spindler M.F.
      • McAuley J.H.
      • Laslett M.
      • Bogduk N.
      Systematic review of tests to identify the disc, SIJ or facet joint as the source of low back pain.
      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.
      • Manchikanti L.
      • Benyamin R.M.
      • Singh V.
      • Falco F.J.
      • Hameed H.
      • Derby R.
      • Wolfer L.R.
      • Helm 2nd, S.
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      • Datta S.
      • Snook L.T.
      • Caraway D.L.
      • Hirsch J.A.
      • Cohen S.P.
      An update of the systematic appraisal of the accuracy and utility of lumbar discography in chronic low back pain.
      • Tibrewal S.
      • Khan O.H.
      • Tibrewal S.B.
      Facet joint injection in lower back pain–is its continued use justified?.
      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.
      • Jensen M.C.
      • Brant-Zawadzki M.N.
      • Obuchowski N.
      • Modic M.T.
      • Malkasian D.
      • Ross J.S.
      Magnetic resonance imaging of the lumbar spine in people without back pain.
      • Maus T.
      Imaging the back pain patient.
      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.
      • Giesecke T.
      • Gracely R.H.
      • Grant M.A.
      • Nachemson A.
      • Petzke F.
      • Williams D.A.
      • Clauw D.J.
      Evidence of augmented central pain processing in idiopathic chronic low back pain.
      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.
      Figure thumbnail gr1
      Figure 1Chronic 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.

       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 hypersensitivity in the presence of either sterile or pathogen-driven inflammation, and neuropathic pain results from damage to the nervous system.
      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.
      Table 1Pain States
      Pain StateClinical Diagnostic Criteria
      NociceptiveEvidence 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
      InflammatoryEvidence 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
      NeuropathicEvidence of sensory nerve damage

      Symptoms: burning, tingling or shock-like, spontaneous pain; paresthesias or dysthesias

      Signs: decreased pinprick
      Most specific
      or vibration sense, and straight leg raise,
      Most specific
      mechanical and cold allodynia
      Dysfunctional/centralizedPain 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

       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 (Table 2, Table 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 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.
      Table 2General Pain Mechanisms
      General Pain MechanismClinical Diagnostic CriteriaSpecific Treatment ExamplesNonspecific Treatment Examples
      Gaba-PentinoidAEDADOpioid
      Nociceptive transductionProportionate pain in response to identifiable noxious stimulusRemoving mechanical stimulus (eg, decompression of nerve)X
      Peripheral SensitizationPrimary hyperalgesia due to decreased transduction threshold of nociceptor terminalAnti-inflammatory (eg, NSAID, coxibs); immunosuppressantXPossiblyX
      Ectopic activitySpontaneous pain in the absence of obvious trigger; relieved by local nerve blockNav channel blockersXXX
      Central sensitizationSecondary hyperalgesia; temporal summation; allodyniaNMDA antagonists (eg, ketamine)XSome (eg, VA, TPM)XX
      Central disinhibitionSecondary hyperalgesia; allodyniaGABA-A subunit agonists; dual amine uptake inhibitorsXSee aboveXX
      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 3Specific Pain Targets
      Selected Specific Pain MechanismsPreclinical ManifestationSpecific Clinical ManifestationMolecular TargetGenetic ValidationSpecific Treatment
      Increased NGF synthesisNociceptor activation at lowered heat thresholdPeripheral sensitization

      No specific diagnostic criteria
      TrkA (NGF receptor); TRPV1HSAN IV

      HSAN V
      anti-NGF AB (phase 3); TrkA R antagonist (phase 2)
      NMDA receptor phosphorylationIncreased postsynaptic activityPain amplification

      No specific diagnostic criteria
      NMDA receptorNoNMDA receptor antagonist (eg, ketamine)
      Excitatory transmitter releaseIncreased postsynaptic activityPain amplification No specific diagnostic criteriaCa(v)α2δ-1NoGabapentinoids
      Nav1.7 hyperexcitabilityIncreased nociceptor firingParoxysmal extreme pain disorder; primary erythromelalgiaNav1.7Paroxysmal extreme pain disorder; primary erythromelalgiaNav1.7 antagonist (phase 2)
      Spinal interneuron degenerationDecreased inhibitory transmissionPain amplification

      No specific diagnostic criteria
      Gaba A receptorNoGaba A receptor subtype selective agonist
      TRPA1 sensitizationIncreased nociceptor firingFamilial episodic pain syndromeTRPA1Familial episodic pain syndromeTRPA1 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.

      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-δ 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.
      • Costigan M.
      • Scholz J.
      • Woolf C.J.
      Neuropathic pain: A maladaptive response of the nervous system to damage.
      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.
      • Gangadharan V.
      • Kuner R.
      Pain hypersensitivity mechanisms at a glance.
      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.
      • Kuner R.
      Central mechanisms of pathological pain.
      The following sections, and Table 1, Table 2, Table 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.
      • Gellhorn A.C.
      • Katz J.N.
      • Suri P.
      Osteoarthritis of the spine: The facet joints.
      In an experimental setting, injecting saline into a healthy lumbar facet joint—thus increasing pressure—causes pain,
      • Kaplan M.
      • Dreyfuss P.
      • Halbrook B.
      • Bogduk N.
      The ability of lumbar medial branch blocks to anesthetize the zygapophysial joint. A physiologic challenge.
      and neurophysiologic recordings from facet joints confirm activation of high-threshold fibers upon joint extension.
      • Lu Y.
      • Chen C.
      • Kallakuri S.
      • Patwardhan A.
      • Cavanaugh J.M.
      Neural response of cervical facet joint capsule to stretch: A study of whiplash pain mechanism.
      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.

       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.
      • Goode A.P.
      • Carey T.S.
      • Jordan J.M.
      Low back pain and lumbar spine osteoarthritis: How are they related?.
      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.
      • Igarashi A.
      • Kikuchi S.
      • Konno S.
      Correlation between inflammatory cytokines released from the lumbar facet joint tissue and symptoms in degenerative lumbar spinal disorders.
      • Lewin T.
      Osteoarthritis in lumbar synovial joints. A morphologic study.
      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.
      • Amaya F.
      • Samad T.A.
      • Barrett L.
      • Broom D.C.
      • Woolf C.J.
      Periganglionic inflammation elicits a distally radiating pain hypersensitivity by promoting COX-2 induction in the dorsal root ganglion.
      For example, patients with lumbar canal stenosis show higher pain scores and disability if IL-1β levels are elevated in the facet joints.
      • Igarashi A.
      • Kikuchi S.
      • Konno S.
      Correlation between inflammatory cytokines released from the lumbar facet joint tissue and symptoms in degenerative lumbar spinal disorders.
      IL-1β can induce cyclooxygenase (COX)-2 in neurons and the production of matrix metalloproteinases in synovial fibroblasts, the enzymes responsible for cartilage degradation,
      • Burrage P.S.
      • Mix K.S.
      • Brinckerhoff C.E.
      Matrix metalloproteinases: Role in arthritis.
      • Xu D.
      • Sun Y.
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      • Liu W.
      • Zhu X.
      • Cui S.
      • Fan J.
      • Cui Z.
      MMP-1 overexpression induced by IL-1beta: Possible mechanism for inflammation in degenerative lumbar facet joint.
      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.
      • Kato T.
      • Haro H.
      • Komori H.
      • Shinomiya K.
      Sequential dynamics of inflammatory cytokine, angiogenesis inducing factor and matrix degrading enzymes during spontaneous resorption of the herniated disc.
      • Mulleman D.
      • Mammou S.
      • Griffoul I.
      • Watier H.
      • Goupille P.
      Pathophysiology of disk-related sciatica. I.–Evidence supporting a chemical component.
      • Olmarker K.
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      • Thomsen P.
      • Rydevik B.
      Inflammatogenic properties of nucleus pulposus.
      Several inflammatory markers (eg, IL-1α, tumor necrosis factor [TNF]-α, transforming growth factor-β) have been found in herniated discs, and increased levels of discogenic cytokines correlate with increased pain levels.
      • Ahn S.H.
      • Cho Y.W.
      • Ahn M.W.
      • Jang S.H.
      • Sohn Y.K.
      • Kim H.S.
      mRNA expression of cytokines and chemokines in herniated lumbar intervertebral discs.
      • Weiler C.
      • Nerlich A.G.
      • Bachmeier B.E.
      • Boos N.
      Expression and distribution of tumor necrosis factor alpha in human lumbar intervertebral discs: A study in surgical specimen and autopsy controls.
      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.
      • Freemont A.J.
      • Peacock T.E.
      • Goupille P.
      • Hoyland J.A.
      • O'Brien J.
      • Jayson M.I.
      Nerve ingrowth into diseased intervertebral disc in chronic back pain.
      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-1β, TNF-α).
      • Gold M.S.
      • Gebhart G.F.
      Nociceptor sensitization in pain pathogenesis.
      • Julius D.
      • Basbaum A.I.
      Molecular mechanisms of nociception.
      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).
      • Costigan M.
      • Scholz J.
      • Woolf C.J.
      Neuropathic pain: A maladaptive response of the nervous system to damage.
      • Gangadharan V.
      • Kuner R.
      Pain hypersensitivity mechanisms at a glance.
      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.
      • Chahine M.
      • O'Leary M.E.
      Regulation/modulation of sensory neuron sodium channels.
      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-β
      • Samad T.A.
      • Moore K.A.
      • Sapirstein A.
      • Billet S.
      • Allchorne A.
      • Poole S.
      • Bonventre J.V.
      • Woolf C.J.
      Interleukin-1beta-mediated induction of Cox-2 in the CNS contributes to inflammatory pain hypersensitivity.
      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.
      • Vardeh D.
      • Wang D.
      • Costigan M.
      • Lazarus M.
      • Saper C.B.
      • Woolf C.J.
      • Fitzgerald G.A.
      • Samad T.A.
      COX2 in CNS neural cells mediates mechanical inflammatory pain hypersensitivity in mice.
      COX-2 inhibitors with well documented blood-brain barrier penetration (eg, celecoxib)
      • Dembo G.
      • Park S.B.
      • Kharasch E.D.
      Central nervous system concentrations of cyclooxygenase-2 inhibitors in humans.
      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-α, interleukin IL-1β, and IL-6 can directly activate and sensitize nociceptors in a fashion similar to that which occurs in tissue damage-associated inflammatory conditions.
      • Ren K.
      • Dubner R.
      Interactions between the immune and nervous systems in pain.
      However, only recently has it been shown that gram-negative and gram-positive bacteria directly activate nociceptors, independent of the immune response.
      • Chiu I.M.
      • Heesters B.A.
      • Ghasemlou N.
      • Von Hehn C.A.
      • Zhao F.
      • Tran J.
      • Wainger B.
      • Strominger A.
      • Muralidharan S.
      • Horswill A.R.
      • Bubeck Wardenburg J.
      • Hwang S.W.
      • Carroll M.C.
      • Woolf C.J.
      Bacteria activate sensory neurons that modulate pain and inflammation.
      • Diogenes A.
      • Ferraz C.C.
      • Akopian A.N.
      • Henry M.A.
      • Hargreaves K.M.
      LPS sensitizes TRPV1 via activation of TLR4 in trigeminal sensory neurons.
      • Meseguer V.
      • Alpizar Y.A.
      • Luis E.
      • Tajada S.
      • Denlinger B.
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      • Talavera A.
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      • Navia B.
      • Sanchez A.
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      • Voets T.
      • Belmonte C.
      • Talavera K.
      • Viana F.
      TRPA1 channels mediate acute neurogenic inflammation and pain produced by bacterial endotoxins.
      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.
      • Stirling A.
      • Worthington T.
      • Rafiq M.
      • Lambert P.A.
      • Elliott T.S.
      Association between sciatica and Propionibacterium acnes.
      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.
      • Albert H.B.
      • Lambert P.
      • Rollason J.
      • Sorensen J.S.
      • Worthington T.
      • Pedersen M.B.
      • Norgaard H.S.
      • Vernallis A.
      • Busch F.
      • Manniche C.
      • Elliott T.
      Does nuclear tissue infected with bacteria following disc herniations lead to Modic changes in the adjacent vertebrae?.
      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.
      • Albert H.B.
      • Sorensen J.S.
      • Christensen B.S.
      • Manniche C.
      Antibiotic treatment in patients with chronic low back pain and vertebral bone edema (Modic type 1 changes): A double-blind randomized clinical controlled trial of efficacy.
      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 compression (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 relief
      • Peul W.C.
      • van Houwelingen H.C.
      • van den Hout W.B.
      • Brand R.
      • Eekhof J.A.
      • Tans J.T.
      • Thomeer R.T.
      • Koes B.W.
      Surgery versus prolonged conservative treatment for sciatica.
      ; the degree of mechanical compression does not correlate well with the severity of clinical symptoms
      • Jensen M.C.
      • Brant-Zawadzki M.N.
      • Obuchowski N.
      • Modic M.T.
      • Malkasian D.
      • Ross J.S.
      Magnetic resonance imaging of the lumbar spine in people without back pain.
      • Maus T.
      Imaging the back pain patient.
      ; conservative therapies targeted at reducing inflammation and musculoskeletal remodeling can be successful even when radiological compression persists
      • Mulleman D.
      • Mammou S.
      • Griffoul I.
      • Watier H.
      • Goupille P.
      Pathophysiology of disk-related sciatica. I.–Evidence supporting a chemical component.
      ; direct nerve root stimulation can cause dysesthesia, numbness, and motor loss, but not pronounced pain
      • Kuslich S.D.
      • Ulstrom C.L.
      • Michael C.J.
      The tissue origin of low back pain and sciatica: A report of pain response to tissue stimulation during operations on the lumbar spine using local anesthesia.
      ; and nucleus pulposus material, introduced into the epidural space at a distance from the nerve root, can induce nerve fiber degeneration without any compression.
      • Cornefjord M.
      • Olmarker K.
      • Rydevik R.
      • Nordborg C.
      Mechanical and biochemical injury of spinal nerve roots: A morphological and neurophysiological study.
      • Olmarker K.
      • Blomquist J.
      • Stromberg J.
      • Nannmark U.
      • Thomsen P.
      • Rydevik B.
      Inflammatogenic properties of nucleus pulposus.
      In recognition of the prominent inflammatory component in neuropathic pain, several inflammatory markers have been identified as potential therapeutic targets. As an example, TNF-α is elevated in the periradicular epidural fat in patients with radiculopathy from herniated disc disease
      • Genevay S.
      • Finckh A.
      • Payer M.
      • Mezin F.
      • Tessitore E.
      • Gabay C.
      • Guerne P.A.
      Elevated levels of tumor necrosis factor-alpha in periradicular fat tissue in patients with radiculopathy from herniated disc.
      and infusion with a TNF-α neutralizing antibody is reported to result in pain reduction for up to 3 months in patients with severe sciatic pain due to disc herniation.
      • Karppinen J.
      • Korhonen T.
      • Malmivaara A.
      • Paimela L.
      • Kyllonen E.
      • Lindgren K.A.
      • Rantanen P.
      • Tervonen O.
      • Niinimaki J.
      • Seitsalo S.
      • Hurri H.
      Tumor necrosis factor-alpha monoclonal antibody, infliximab, used to manage severe sciatica.
      In a randomized trial of patients with acute radicular leg pain due to disc herniation, 2 subcutaneous treatments with the anti-TNF-α antibody showed a small but significant improvement in leg pain over 6 months, favorable outcomes regarding back pain and disability,
      • Genevay S.
      • Viatte S.
      • Finckh A.
      • Zufferey P.
      • Balague F.
      • Gabay C.
      Adalimumab in severe and acute sciatica: A multicenter, randomized, double-blind, placebo-controlled trial.
      and a decreased rate of surgery at a 3-year follow-up.
      • Genevay S.
      • Finckh A.
      • Zufferey P.
      • Viatte S.
      • Balague F.
      • Gabay C.
      Adalimumab in acute sciatica reduces the long-term need for surgery: A 3-year follow-up of a randomised double-blind placebo-controlled trial.
      Although the long-term benefit of TNF-α antibodies remains controversial
      • Korhonen T.
      • Karppinen J.
      • Paimela L.
      • Malmivaara A.
      • Lindgren K.A.
      • Bowman C.
      • Hammond A.
      • Kirkham B.
      • Jarvinen S.
      • Niinimaki J.
      • Veeger N.
      • Haapea M.
      • Torkki M.
      • Tervonen O.
      • Seitsalo S.
      • Hurri H.
      The treatment of disc-herniation-induced sciatica with infliximab: One-year follow-up results of FIRST II, a randomized controlled trial.
      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.
      • Mulleman D.
      • Mammou S.
      • Griffoul I.
      • Watier H.
      • Goupille P.
      Pathophysiology of disk-related sciatica. I.–Evidence supporting a chemical component.
      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.
      • Kreiner D.S.
      • Hwang S.W.
      • Easa J.E.
      • Resnick D.K.
      • Baisden J.L.
      • Bess S.
      • Cho C.H.
      • DePalma M.J.
      • Dougherty 2nd, P.
      • Fernand R.
      • Ghiselli G.
      • Hanna A.S.
      • Lamer T.
      • Lisi A.J.
      • Mazanec D.J.
      • Meagher R.J.
      • Nucci R.C.
      • Patel R.D.
      • Sembrano J.N.
      • Sharma A.K.
      • Summers J.T.
      • Taleghani C.K.
      • Tontz Jr., W.L.
      • Toton J.F.
      An evidence-based clinical guideline for the diagnosis and treatment of lumbar disc herniation with radiculopathy.

       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 irritable bowel syndrome, and possibly cognitive impairments such as chronic fatigue syndrome.
      • Mayer T.G.
      • Neblett R.
      • Cohen H.
      • Howard K.J.
      • Choi Y.H.
      • Williams M.J.
      • Perez Y.
      • Gatchel R.J.
      The development and psychometric validation of the central sensitization inventory.
      Attempts to diagnose these disorders on the basis of their “central” component include self-reported symptom questionnaires such as the Central Sensitization Inventory
      • Mayer T.G.
      • Neblett R.
      • Cohen H.
      • Howard K.J.
      • Choi Y.H.
      • Williams M.J.
      • Perez Y.
      • Gatchel R.J.
      The development and psychometric validation of the central sensitization inventory.
      • Neblett R.
      • Cohen H.
      • Choi Y.
      • Hartzell M.M.
      • Williams M.
      • Mayer T.G.
      • Gatchel R.J.
      The Central Sensitization Inventory (CSI): Establishing clinically significant values for identifying central sensitivity syndromes in an outpatient chronic pain sample.
      and Fibromyalgia Criteria and Severity Scales,
      • Wolfe F.
      • Clauw D.J.
      • Fitzcharles M.A.
      • Goldenberg D.L.
      • Hauser W.
      • Katz R.S.
      • Mease P.
      • Russell A.S.
      • Russell I.J.
      • Winfield J.B.
      Fibromyalgia criteria and severity scales for clinical and epidemiological studies: A modification of the ACR Preliminary Diagnostic Criteria for Fibromyalgia.
      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 activity-dependent 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,
      • Staud R.
      • Nagel S.
      • Robinson M.E.
      • Price D.D.
      Enhanced central pain processing of fibromyalgia patients is maintained by muscle afferent input: A randomized, double-blind, placebo-controlled study.
      as well as visceral and cutaneous hypersensitivity in irritable bowel syndrome patients.
      • Price D.D.
      • Craggs J.G.
      • Zhou Q.
      • Verne G.N.
      • Perlstein W.M.
      • Robinson M.E.
      Widespread hyperalgesia in irritable bowel syndrome is dynamically maintained by tonic visceral impulse input and placebo/nocebo factors: Evidence from human psychophysics, animal models, and neuroimaging.
      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.
      • Graven-Nielsen T.
      • Arendt-Nielsen L.
      Assessment of mechanisms in localized and widespread musculoskeletal pain.
      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,
      • Gwilym S.E.
      • Oag H.C.
      • Tracey I.
      • Carr A.J.
      Evidence that central sensitisation is present in patients with shoulder impingement syndrome and influences the outcome after surgery.
      • Lundblad H.
      • Kreicbergs A.
      • Jansson K.A.
      Prediction of persistent pain after total knee replacement for osteoarthritis.
      • Sterling M.
      • Jull G.
      • Vicenzino B.
      • Kenardy J.
      Sensory hypersensitivity occurs soon after whiplash injury and is associated with poor recovery.
      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.
      • Binshtok A.M.
      Mechanisms of nociceptive transduction and transmission: A machinery for pain sensation and tools for selective analgesia.
      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 hypersensitivity symptoms confined to the site of the inflamed tissue (zone of primary hyperalgesia).
      • Costigan M.
      • Scholz J.
      • Woolf C.J.
      Neuropathic pain: A maladaptive response of the nervous system to damage.
      • Woolf C.J.
      Central sensitization: Implications for the diagnosis and treatment of pain.

       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,
      • Djouhri L.
      • Koutsikou S.
      • Fang X.
      • McMullan S.
      • Lawson S.N.
      Spontaneous pain, both neuropathic and inflammatory, is related to frequency of spontaneous firing in intact C-fiber nociceptors.
      and from the DRG itself.
      • Amir R.
      • Kocsis J.D.
      • Devor M.
      Multiple interacting sites of ectopic spike electrogenesis in primary sensory neurons.
      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 channels
      • Costigan M.
      • Belfer I.
      • Griffin R.S.
      • Dai F.
      • Barrett L.B.
      • Coppola G.
      • Wu T.
      • Kiselycznyk C.
      • Poddar M.
      • Lu Y.
      • Diatchenko L.
      • Smith S.
      • Cobos E.J.
      • Zaykin D.
      • Allchorne A.
      • Gershon E.
      • Livneh J.
      • Shen P.H.
      • Nikolajsen L.
      • Karppinen J.
      • Mannikko M.
      • Kelempisioti A.
      • Goldman D.
      • Maixner W.
      • Geschwind D.H.
      • Max M.B.
      • Seltzer Z.
      • Woolf C.J.
      Multiple chronic pain states are associated with a common amino acid-changing allele in KCNS1.
      • Tulleuda A.
      • Cokic B.
      • Callejo G.
      • Saiani B.
      • Serra J.
      • Gasull X.
      TRESK channel contribution to nociceptive sensory neurons excitability: modulation by nerve injury.
      membrane depolarization, and modulation of sodium channels like Nav1.7, Nav1.8, and Nav1.9, resulting in hyperexcitability
      • Costigan M.
      • Scholz J.
      • Woolf C.J.
      Neuropathic pain: A maladaptive response of the nervous system to damage.
      • von Hehn C.A.
      • Baron R.
      • Woolf C.J.
      Deconstructing the neuropathic pain phenotype to reveal neural mechanisms.
      ). 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.
      • Woolf C.J.
      Central sensitization: Implications for the diagnosis and treatment of pain.
      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.
      • Latremoliere A.
      • Woolf C.J.
      Central sensitization: A generator of pain hypersensitivity by central neural plasticity.
      • Woolf C.J.
      Central sensitization: Implications for the diagnosis and treatment of pain.
      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 Aβ fiber inputs into the pain pathway, and these mechanisms may be driven and sustained by ectopic activity in the injured nerve.
      • Latremoliere A.
      • Woolf C.J.
      Central sensitization: A generator of pain hypersensitivity by central neural plasticity.
      Other long-lasting consequences of nerve injury include central neuroinflammation (driven by alterations in microglia, astrocytes, and invading T lymphocytes),
      • Ji R.R.
      • Xu Z.Z.
      • Gao Y.J.
      Emerging targets in neuroinflammation-driven chronic pain.
      neuronal phenotypic changes due to altered gene transcription and post-translational modification of membrane proteins,
      • Woolf C.J.
      Central sensitization: Implications for the diagnosis and treatment of pain.
      and degeneration of inhibitory neurons resulting in the facilitation of pain pathways.
      • Duan B.
      • Cheng L.
      • Bourane S.
      • Britz O.
      • Padilla C.
      • Garcia-Campmany L.
      • Krashes M.
      • Knowlton W.
      • Velasquez T.
      • Ren X.
      • Ross S.E.
      • Lowell B.B.
      • Wang Y.
      • Goulding M.
      • Ma Q.
      Identification of spinal circuits transmitting and gating mechanical pain.
      • Foster E.
      • Wildner H.
      • Tudeau L.
      • Haueter S.
      • Ralvenius W.T.
      • Jegen M.
      • Johannssen H.
      • Hosli L.
      • Haenraets K.
      • Ghanem A.
      • Conzelmann K.K.
      • Bosl M.
      • Zeilhofer H.U.
      Targeted ablation, silencing, and activation establish glycinergic dorsal horn neurons as key components of a spinal gate for pain and itch.
      • Scholz J.
      • Broom D.C.
      • Youn D.H.
      • Mills C.D.
      • Kohno T.
      • Suter M.R.
      • Moore K.A.
      • Decosterd I.
      • Coggeshall R.E.
      • Woolf C.J.
      Blocking caspase activity prevents transsynaptic neuronal apoptosis and the loss of inhibition in lamina II of the dorsal horn after peripheral nerve injury.
      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 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.
      • von Hehn C.A.
      • Baron R.
      • Woolf C.J.
      Deconstructing the neuropathic pain phenotype to reveal neural mechanisms.
      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.
      • Woolf C.J.
      Central sensitization: Implications for the diagnosis and treatment of pain.
      These symptoms result from the novel functional recruitment of Aβ and Aδ 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, osteoarthritis
      • Lundblad H.
      • Kreicbergs A.
      • Jansson K.A.
      Prediction of persistent pain after total knee replacement for osteoarthritis.
      • Neogi T.
      • Frey-Law L.
      • Scholz J.
      • Niu J.
      • Arendt-Nielsen L.
      • Woolf C.
      • Nevitt M.
      • Bradley L.
      • Felson D.T.
      Sensitivity and sensitisation in relation to pain severity in knee osteoarthritis: Trait or state?.
      • Suokas A.K.
      • Walsh D.A.
      • McWilliams D.F.
      • Condon L.
      • Moreton B.
      • Wylde V.
      • Arendt-Nielsen L.
      • Zhang W.
      Quantitative sensory testing in painful osteoarthritis: A systematic review and meta-analysis.
      ) and many neuropathic pain conditions.
      • Fernandez-de-las-Penas C.
      • de la Llave-Rincon A.I.
      • Fernandez-Carnero J.
      • Cuadrado M.L.
      • Arendt-Nielsen L.
      • Pareja J.A.
      Bilateral widespread mechanical pain sensitivity in carpal tunnel syndrome: Evidence of central processing in unilateral neuropathy.
      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.
      • Duan B.
      • Cheng L.
      • Bourane S.
      • Britz O.
      • Padilla C.
      • Garcia-Campmany L.
      • Krashes M.
      • Knowlton W.
      • Velasquez T.
      • Ren X.
      • Ross S.E.
      • Lowell B.B.
      • Wang Y.
      • Goulding M.
      • Ma Q.
      Identification of spinal circuits transmitting and gating mechanical pain.
      • Maier C.
      • Baron R.
      • Tolle T.R.
      • Binder A.
      • Birbaumer N.
      • Birklein F.
      • Gierthmuhlen J.
      • Flor H.
      • Geber C.
      • Huge V.
      • Krumova E.K.
      • Landwehrmeyer G.B.
      • Magerl W.
      • Maihofner C.
      • Richter H.
      • Rolke R.
      • Scherens A.
      • Schwarz A.
      • Sommer C.
      • Tronnier V.
      • Uceyler N.
      • Valet M.
      • Wasner G.
      • Treede R.D.
      Quantitative sensory testing in the German Research Network on Neuropathic Pain (DFNS): Somatosensory abnormalities in 1236 patients with different neuropathic pain syndromes.
      • Peirs C.
      • Williams S.P.
      • Zhao X.
      • Walsh C.E.
      • Gedeon J.Y.
      • Cagle N.E.
      • Goldring A.C.
      • Hioki H.
      • Liu Z.
      • Marell P.S.
      • Seal R.P.
      Dorsal horn circuits for persistent mechanical pain.
      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).
      • Yaksh T.L.
      • Woller S.A.
      • Ramachandran R.
      • Sorkin L.S.
      The search for novel analgesics: Targets and mechanisms.
      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.
      • Staud R.
      • Weyl E.E.
      • Riley 3rd, J.L.
      • Fillingim R.B.
      Slow temporal summation of pain for assessment of central pain sensitivity and clinical pain of fibromyalgia patients.
      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.
      • Sterling M.
      • Jull G.
      • Vicenzino B.
      • Kenardy J.
      Characterization of acute whiplash-associated disorders.
      • Sterling M.
      • Jull G.
      • Vicenzino B.
      • Kenardy J.
      Sensory hypersensitivity occurs soon after whiplash injury and is associated with poor recovery.
      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.
      • Inquimbert P.
      • Bartels K.
      • Babaniyi O.B.
      • Barrett L.B.
      • Tegeder I.
      • Scholz J.
      Peripheral nerve injury produces a sustained shift in the balance between glutamate release and uptake in the dorsal horn of the spinal cord.
      • Scholz J.
      • Broom D.C.
      • Youn D.H.
      • Mills C.D.
      • Kohno T.
      • Suter M.R.
      • Moore K.A.
      • Decosterd I.
      • Coggeshall R.E.
      • Woolf C.J.
      Blocking caspase activity prevents transsynaptic neuronal apoptosis and the loss of inhibition in lamina II of the dorsal horn after peripheral nerve injury.
      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 thresholds and the development of hyperalgesia and tactile allodynia.
      • Foster E.
      • Wildner H.
      • Tudeau L.
      • Haueter S.
      • Ralvenius W.T.
      • Jegen M.
      • Johannssen H.
      • Hosli L.
      • Haenraets K.
      • Ghanem A.
      • Conzelmann K.K.
      • Bosl M.
      • Zeilhofer H.U.
      Targeted ablation, silencing, and activation establish glycinergic dorsal horn neurons as key components of a spinal gate for pain and itch.
      • Guo D.
      • Hu J.
      Spinal presynaptic inhibition in pain control.
      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 cation-chloride cotransporters.
      • Guo D.
      • Hu J.
      Spinal presynaptic inhibition in pain control.
      • Kuner R.
      Central mechanisms of pathological pain.
      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.
      • Zeilhofer H.U.
      • Ralvenius W.T.
      • Acuna M.A.
      Restoring the spinal pain gate: GABA(A) receptors as targets for novel analgesics.

       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.
      • Grace P.M.
      • Hutchinson M.R.
      • Maier S.F.
      • Watkins L.R.
      Pathological pain and the neuroimmune interface.
      • Milligan E.D.
      • Watkins L.R.
      Pathological and protective roles of glia in chronic pain.
      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.
      • Grace P.M.
      • Hutchinson M.R.
      • Maier S.F.
      • Watkins L.R.
      Pathological pain and the neuroimmune interface.
      Astrocytes contribute indirectly to increased synaptic glutamate levels and nociceptive hypersensitivity by downregulation of the spinal astrocyte glutamate transporters after peripheral nerve injury.
      • Xin W.J.
      • Weng H.R.
      • Dougherty P.M.
      Plasticity in expression of the glutamate transporters GLT-1 and GLAST in spinal dorsal horn glial cells following partial sciatic nerve ligation.
      Other cytokines (eg, TNF-α, IL-1β, 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.
      • Burrage P.S.
      • Mix K.S.
      • Brinckerhoff C.E.
      Matrix metalloproteinases: Role in arthritis.
      • Grace P.M.
      • Hutchinson M.R.
      • Maier S.F.
      • Watkins L.R.
      Pathological pain and the neuroimmune interface.
      • Harvey R.J.
      • Depner U.B.
      • Wassle H.
      • Ahmadi S.
      • Heindl C.
      • Reinold H.
      • Smart T.G.
      • Harvey K.
      • Schutz B.
      • Abo-Salem O.M.
      • Zimmer A.
      • Poisbeau P.
      • Welzl H.
      • Wolfer D.P.
      • Betz H.
      • Zeilhofer H.U.
      • Muller U.
      GlyR alpha3: An essential target for spinal PGE2-mediated inflammatory pain sensitization.
      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.
      • Loggia M.L.
      • Chonde D.B.
      • Akeju O.
      • Arabasz G.
      • Catana C.
      • Edwards R.R.
      • Hill E.
      • Hsu S.
      • Izquierdo-Garcia D.
      • Ji R.R.
      • Riley M.
      • Wasan A.D.
      • Zurcher N.R.
      • Albrecht D.S.
      • Vangel M.G.
      • Rosen B.R.
      • Napadow V.
      • Hooker J.M.
      Evidence for brain glial activation in chronic pain patients.
      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,
      • Apkarian A.V.
      • Hashmi J.A.
      • Baliki M.N.
      Pain and the brain: Specificity and plasticity of the brain in clinical chronic pain.
      • Geha P.Y.
      • Baliki M.N.
      • Harden R.N.
      • Bauer W.R.
      • Parrish T.B.
      • Apkarian A.V.
      The brain in chronic CRPS pain: Abnormal gray-white matter interactions in emotional and autonomic regions.
      as well as changes in excitatory and inhibitory transmitters
      • Gussew A.
      • Rzanny R.
      • Gullmar D.
      • Scholle H.C.
      • Reichenbach J.R.
      1H-MR spectroscopic detection of metabolic changes in pain processing brain regions in the presence of non-specific chronic low back pain.
      and in functional connectivity.
      • Cauda F.
      • Sacco K.
      • Duca S.
      • Cocito D.
      • D'Agata F.
      • Geminiani G.C.
      • Canavero S.
      Altered resting state in diabetic neuropathic pain.
      • Giesecke T.
      • Gracely R.H.
      • Grant M.A.
      • Nachemson A.
      • Petzke F.
      • Williams D.A.
      • Clauw D.J.
      Evidence of augmented central pain processing in idiopathic chronic low back pain.
      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.
      • Gwilym S.E.
      • Filippini N.
      • Douaud G.
      • Carr A.J.
      • Tracey I.
      Thalamic atrophy associated with painful osteoarthritis of the hip is reversible after arthroplasty: A longitudinal voxel-based morphometric study.
      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 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.
      • O'Neill S.
      • Manniche C.
      • Graven-Nielsen T.
      • Arendt-Nielsen L.
      Generalized deep-tissue hyperalgesia in patients with chronic low-back pain.
      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.
      • Giesecke T.
      • Gracely R.H.
      • Grant M.A.
      • Nachemson A.
      • Petzke F.
      • Williams D.A.
      • Clauw D.J.
      Evidence of augmented central pain processing in idiopathic chronic low back pain.

       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)?
      Table 4Common Diagnostic Testing for Patients With Chronic Low Back Pain
      Diagnostic TestInterpretationLimitations
      History
       Quality and severity of painBurning/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
      Physical examination
       SLR testLumbar radiculopathy/sciatic nerve irritationLow specificity (eg, many patients have hamstring and gluteal tightness eliciting pain upon SLR)

      Unable to distinguish between L4, L5, S1, root, or sciatic nerve
       Dermatomal sensory loss/myotomal deficitRoot compression/damageInconsistent finding

      Significant dermatomal/myotomal overlap
       Musculoskeletal maneuvers (eg, facet loading, sacroiliac joint and hip maneuvers, low back palpation)Anatomic localization of pain driverPoor specificity

      Multiple structures are simultaneously stimulated
      Investigations
       NCS/EMGPresence/absence of neuropathy or radiculopathyOnly evaluates large-diameter fibers (not A-δ and C fibers)

      Lesions proximal to DRG are not routinely captured
       QST“Sensory fingerprint” indicative of pain mechanismTime-consuming and resource-heavy

      No gold standard

      Same disease with multiple sensory clusters
       MRI imagingDegenerative changes judged as causative of pain syndromePoor 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.
      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.
      • Freynhagen R.
      • Baron R.
      The evaluation of neuropathic components in low back pain.
      • Freynhagen R.
      • Baron R.
      • Gockel U.
      • Tolle T.R.
      PainDETECT: A new screening questionnaire to identify neuropathic components in patients with back pain.
      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, 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.
      • Mathieson S.
      • Maher C.G.
      • Terwee C.B.
      • Folly de Campos T.
      • Lin C.W.
      Neuropathic pain screening questionnaires have limited measurement properties. A systematic review.
      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.
      • Mathieson S.
      • Maher C.G.
      • Terwee C.B.
      • Folly de Campos T.
      • Lin C.W.
      Neuropathic pain screening questionnaires have limited measurement properties. A systematic review.
      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-β 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.
      • Scholz J.
      • Mannion R.J.
      • Hord D.E.
      • Griffin R.S.
      • Rawal B.
      • Zheng H.
      • Scoffings D.
      • Phillips A.
      • Guo J.
      • Laing R.J.
      • Abdi S.
      • Decosterd I.
      • Woolf C.J.
      A novel tool for the assessment of pain: Validation in low back pain.
      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.
      • Scholz J.
      • Mannion R.J.
      • Hord D.E.
      • Griffin R.S.
      • Rawal B.
      • Zheng H.
      • Scoffings D.
      • Phillips A.
      • Guo J.
      • Laing R.J.
      • Abdi S.
      • Decosterd I.
      • Woolf C.J.
      A novel tool for the assessment of pain: Validation in low back pain.
      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.
      • O'Neill S.
      • Manniche C.
      • Graven-Nielsen T.
      • Arendt-Nielsen L.
      Generalized deep-tissue hyperalgesia in patients with chronic low-back pain.
      • Staud R.
      Evidence for shared pain mechanisms in osteoarthritis, low back pain, and fibromyalgia.
      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,
      • Ropper A.H.
      • Zafonte R.D.
      Sciatica.
      • Scholz J.
      • Mannion R.J.
      • Hord D.E.
      • Griffin R.S.
      • Rawal B.
      • Zheng H.
      • Scoffings D.
      • Phillips A.
      • Guo J.
      • Laing R.J.
      • Abdi S.
      • Decosterd I.
      • Woolf C.J.
      A novel tool for the assessment of pain: Validation in low back pain.
      but other physical tests (motor deficit, muscle wasting, impaired reflexes, sensory deficits) are rather unreliable.
      • van der Windt D.A.
      • Simons E.
      • Riphagen I.I.
      • Ammendolia C.
      • Verhagen A.P.
      • Laslett M.
      • Deville W.
      • Deyo R.A.
      • Bouter L.M.
      • de Vet H.C.
      • Aertgeerts B.
      Physical examination for lumbar radiculopathy due to disc herniation in patients with low-back pain.
      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.
      • Hancock M.J.
      • Maher C.G.
      • Latimer J.
      • Spindler M.F.
      • McAuley J.H.
      • Laslett M.
      • Bogduk N.
      Systematic review of tests to identify the disc, SIJ or facet joint as the source of low back pain.
      • Rubinstein S.M.
      • van Tulder M.
      A best-evidence review of diagnostic procedures for neck and low-back pain.
      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 conduction studies, which only examine large nerve fibers, and assist in conclusions as to underlying mechanisms.
      • Backonja M.M.
      • Attal N.
      • Baron R.
      • Bouhassira D.
      • Drangholt M.
      • Dyck P.J.
      • Edwards R.R.
      • Freeman R.
      • Gracely R.
      • Haanpaa M.H.
      • Hansson P.
      • Hatem S.M.
      • Krumova E.K.
      • Jensen T.S.
      • Maier C.
      • Mick G.
      • Rice A.S.
      • Rolke R.
      • Treede R.D.
      • Serra J.
      • Toelle T.
      • Tugnoli V.
      • Walk D.
      • Walalce M.S.
      • Ware M.
      • Yarnitsky D.
      • Ziegler D.
      Value of quantitative sensory testing in neurological and pain disorders: NeuPSIG consensus.
      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.
      • Lundblad H.
      • Kreicbergs A.
      • Jansson K.A.
      Prediction of persistent pain after total knee replacement for osteoarthritis.
      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.
      • Attal N.
      • Bouhassira D.
      • Gautron M.
      • Vaillant J.N.
      • Mitry E.
      • Lepere C.
      • Rougier P.
      • Guirimand F.
      Thermal hyperalgesia as a marker of oxaliplatin neurotoxicity: A prospective quantified sensory assessment study.
      For axial low back pain, several sensory clusters with potentially distinct underlying mechanisms have been identified.
      • Forster M.
      • Mahn F.
      • Gockel U.
      • Brosz M.
      • Freynhagen R.
      • Tolle T.R.
      • Baron R.
      Axial low back pain: One painful area–many perceptions and mechanisms.
      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.
      • Forster M.
      • Mahn F.
      • Gockel U.
      • Brosz M.
      • Freynhagen R.
      • Tolle T.R.
      • Baron R.
      Axial low back pain: One painful area–many perceptions and mechanisms.
      • Freemont A.J.
      • Peacock T.E.
      • Goupille P.
      • Hoyland J.A.
      • O'Brien J.
      • Jayson M.I.
      Nerve ingrowth into diseased intervertebral disc in chronic back pain.
      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.
      • Edwards R.R.
      • Haythornthwaite J.A.
      • Tella P.
      • Max M.B.
      • Raja S.
      Basal heat pain thresholds predict opioid analgesia in patients with postherpetic neuralgia.
      However, because of the heterogeneity of conditions and outcomes, no robust QST parameter for reliable analgesic response prediction has been identified so far.
      • Grosen K.
      • Fischer I.W.
      • Olesen A.E.
      • Drewes A.M.
      Can quantitative sensory testing predict responses to analgesic treatment?.
      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.
      • Jensen M.C.
      • Brant-Zawadzki M.N.
      • Obuchowski N.
      • Modic M.T.
      • Malkasian D.
      • Ross J.S.
      Magnetic resonance imaging of the lumbar spine in people without back pain.
      • Maus T.
      Imaging the back pain patient.
      • Scholz J.
      • Mannion R.J.
      • Hord D.E.
      • Griffin R.S.
      • Rawal B.
      • Zheng H.
      • Scoffings D.
      • Phillips A.
      • Guo J.
      • Laing R.J.
      • Abdi S.
      • Decosterd I.
      • Woolf C.J.
      A novel tool for the assessment of pain: Validation in low back pain.
      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.
      • Maus T.
      Imaging the back pain patient.
      Nevertheless, as our understanding of cLBP mechanisms progresses, the role of imaging is likely to evolve. An annular tear might be, 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-α) and increased nerve fiber density.
      • Bailey J.F.
      • Liebenberg E.
      • Degmetich S.
      • Lotz J.C.
      Innervation patterns of PGP 9.5-positive nerve fibers within the human lumbar vertebra.
      • Toyone T.
      • Takahashi K.
      • Kitahara H.
      • Yamagata M.
      • Murakami M.
      • Moriya H.
      Vertebral bone-marrow changes in degenerative lumbar disc disease. An MRI study of 74 patients with low back pain.
      • Zhang Y.H.
      • Zhao C.Q.
      • Jiang L.S.
      • Chen X.D.
      • Dai L.Y.
      Modic changes: A systematic review of the literature.
      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.
      • Ellingson A.M.
      • Mehta H.
      • Polly D.W.
      • Ellermann J.
      • Nuckley D.J.
      Disc degeneration assessed by quantitative T2* (T2 star) correlated with functional lumbar mechanics.
      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).
      • Ackerman 3rd, W.E.
      • Ahmad M.
      Pain relief with intraarticular or medial branch nerve blocks in patients with positive lumbar facet joint SPECT imaging: A 12-week outcome study.
      • Pneumaticos S.G.
      • Chatziioannou S.N.
      • Hipp J.A.
      • Moore W.H.
      • Esses S.I.
      Low back pain: Prediction of short-term outcome of facet joint injection with bone scintigraphy.

      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 anti-inflammatory 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 short- to medium-term.
      • Kizhakkeveettil A.
      • Rose K.
      • Kadar G.E.
      Integrative therapies for low back pain that include complementary and alternative medicine care: A systematic review.
      • Standaert C.J.
      • Friedly J.
      • Erwin M.W.
      • Lee M.J.
      • Rechtine G.
      • Henrikson N.B.
      • Norvell D.C.
      Comparative effectiveness of exercise, acupuncture, and spinal manipulation for low back pain.
      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 cLBP and the evidence for or against the use of physical therapy at least as a stand-alone treatment is weak.
      • Kreiner D.S.
      • Hwang S.W.
      • Easa J.E.
      • Resnick D.K.
      • Baisden J.L.
      • Bess S.
      • Cho C.H.
      • DePalma M.J.
      • Dougherty 2nd, P.
      • Fernand R.
      • Ghiselli G.
      • Hanna A.S.
      • Lamer T.
      • Lisi A.J.
      • Mazanec D.J.
      • Meagher R.J.
      • Nucci R.C.
      • Patel R.D.
      • Sembrano J.N.
      • Sharma A.K.
      • Summers J.T.
      • Taleghani C.K.
      • Tontz Jr., W.L.
      • Toton J.F.
      An evidence-based clinical guideline for the diagnosis and treatment of lumbar disc herniation with radiculopathy.
      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,
      • Edwards R.R.
      • Cahalan C.
      • Mensing G.
      • Smith M.
      • Haythornthwaite J.A.
      Pain, catastrophizing, and depression in the rheumatic diseases.
      and are explored in dedicated reviews in this issue of The Journal of Pain.
      • Edwards R.R.
      • Dworkin R.H.
      • Sullivan M.D.
      • Turk D.C.
      • Wasan A.D.
      The role of psychosocial processes in the development and maintenance of chronic pain.
      • Turk D.C.
      • Fillingim R.B.
      • Ohrbach R.
      • Patel K.V.
      Assessment of psychosocial and functional impact of chronic pain.

       Spinal Injection

      Spinal injections (local anesthetics with or without steroids) have increased many fold over the past 10 to 15 years.
      • Wanderer J.P.
      • Rathmell J.P.
      Epidural injections and the new subspeciality of pain medicine.
      Although some of these injections appear to have clinical benefit for select patients for weeks to a few months, their clinical use remains controversial,
      • Cohen S.P.
      • Bicket M.C.
      • Jamison D.
      • Wilkinson I.
      • Rathmell J.P.
      Epidural steroids: A comprehensive, evidence-based review.
      • Henschke N.
      • Kuijpers T.
      • Rubinstein S.M.
      • van Middelkoop M.
      • Ostelo R.
      • Verhagen A.
      • Koes B.W.
      • van Tulder M.W.
      Injection therapy and denervation procedures for chronic low-back pain: A systematic review.
      • Staal J.B.
      • Nelemans P.J.
      • de Bie R.A.
      Spinal injection therapy for low back pain.
      • Staal J.B.
      • Nelemans P.J.
      • De Bie R.A.
      Use of spinal injections for low back pain–reply.
      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.
      • Giesecke T.
      • Gracely R.H.
      • Grant M.A.
      • Nachemson A.
      • Petzke F.
      • Williams D.A.
      • Clauw D.J.
      Evidence of augmented central pain processing in idiopathic chronic low back pain.
      • Goode A.P.
      • Carey T.S.
      • Jordan J.M.
      Low back pain and lumbar spine osteoarthritis: How are they related?.
      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.
      • Gracely R.H.
      • Lynch S.A.
      • Bennett G.J.
      Painful neuropathy: Altered central processing maintained dynamically by peripheral input.
      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,
      • Caracas H.C.
      • Maciel J.V.
      • Martins P.M.
      • de Souza M.M.
      • Maia L.C.
      The use of lidocaine as an anti-inflammatory substance: A systematic review.
      including its ability to decrease cytokine production of activated microglia in the CNS.
      • Jeong H.J.
      • Lin D.
      • Li L.
      • Zuo Z.
      Delayed treatment with lidocaine reduces mouse microglial cell injury and cytokine production after stimulation with lipopolysaccharide and interferon gamma.
      Another important explanation is the placebo, which pain medicine is particularly prone to,
      • Hrobjartsson A.
      • Gotzsche P.C.
      Placebo interventions for all clinical conditions.
      and interventional procedures result in higher placebo responses than pharmacological therapies.
      • Meissner K.
      • Fassler M.
      • Rucker G.
      • Kleijnen J.
      • Hrobjartsson A.
      • Schneider A.
      • Antes G.
      • Linde K.
      Differential effectiveness of placebo treatments: A systematic review of migraine prophylaxis.
      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 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).
      • Chan C.W.
      • Peng P.
      Failed back surgery syndrome.
      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.
      • Baert I.A.
      • Lluch E.
      • Mulder T.
      • Nijs J.
      • Noten S.
      • Meeus M.
      Does pre-surgical central modulation of pain influence outcome after total knee replacement? A systematic review.
      • Block A.R.
      • Ben-Porath Y.S.
      • Marek R.J.
      Psychological risk factors for poor outcome of spine surgery and spinal cord stimulator implant: A review of the literature and their assessment with the MMPI-2-RF.
      • Celestin J.
      • Edwards R.R.
      • Jamison R.N.
      Pretreatment psychosocial variables as predictors of outcomes following lumbar surgery and spinal cord stimulation: A systematic review and literature synthesis.
      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,
      • Edwards R.R.
      • Dworkin R.H.
      • Sullivan M.D.
      • Turk D.C.
      • Wasan A.D.
      The role of psychosocial processes in the development and maintenance of chronic pain.
      • Turk D.C.
      • Fillingim R.B.
      • Ohrbach R.
      • Patel K.V.
      Assessment of psychosocial and functional impact of chronic pain.
      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.
      • Mathieson S.
      • Maher C.G.
      • Terwee C.B.
      • Folly de Campos T.
      • Lin C.W.
      Neuropathic pain screening questionnaires have limited measurement properties. A systematic review.
      • Scholz J.
      • Mannion R.J.
      • Hord D.E.
      • Griffin R.S.
      • Rawal B.
      • Zheng H.
      • Scoffings D.
      • Phillips A.
      • Guo J.
      • Laing R.J.
      • Abdi S.
      • Decosterd I.
      • Woolf C.J.
      A novel tool for the assessment of pain: Validation in low back pain.
      Many aspects of the physical examination suffer from poor validity and reliability
      • Hancock M.J.
      • Maher C.G.
      • Latimer J.
      • Spindler M.F.
      • McAuley J.H.
      • Laslett M.
      • Bogduk N.
      Systematic review of tests to identify the disc, SIJ or facet joint as the source of low back pain.
      • Rubinstein S.M.
      • van Tulder M.
      A best-evidence review of diagnostic procedures for neck and low-back pain.
      • Scholz J.
      • Mannion R.J.
      • Hord D.E.
      • Griffin R.S.
      • Rawal B.
      • Zheng H.
      • Scoffings D.
      • Phillips A.
      • Guo J.
      • Laing R.J.
      • Abdi S.
      • Decosterd I.
      • Woolf C.J.
      A novel tool for the assessment of pain: Validation in low back pain.
      • van der Windt D.A.
      • Simons E.
      • Riphagen I.I.
      • Ammendolia C.
      • Verhagen A.P.
      • Laslett M.
      • Deville W.
      • Deyo R.A.
      • Bouter L.M.
      • de Vet H.C.
      • Aertgeerts B.
      Physical examination for lumbar radiculopathy due to disc herniation in patients with low-back pain.
      or demand extensive time for minute sensory testing with 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.
      • Jensen M.C.
      • Brant-Zawadzki M.N.
      • Obuchowski N.
      • Modic M.T.
      • Malkasian D.
      • Ross J.S.
      Magnetic resonance imaging of the lumbar spine in people without back pain.
      • Maus T.
      Imaging the back pain patient.
      Diagnostic/therapeutic interventions, like nerve blocks with local anesthetics, remain difficult to interpret and are of controversial clinical benefit,
      • Cohen S.P.
      • Bicket M.C.
      • Jamison D.
      • Wilkinson I.
      • Rathmell J.P.
      Epidural steroids: A comprehensive, evidence-based review.
      • Henschke N.
      • Kuijpers T.
      • Rubinstein S.M.
      • van Middelkoop M.
      • Ostelo R.
      • Verhagen A.
      • Koes B.W.
      • van Tulder M.W.
      Injection therapy and denervation procedures for chronic low-back pain: A systematic review.
      • Staal J.B.
      • Nelemans P.J.
      • de Bie R.A.
      Spinal injection therapy for low back pain.
      • Staal J.B.
      • Nelemans P.J.
      • De Bie R.A.
      Use of spinal injections for low back pain–reply.
      and surgery such as discectomy for radiculopathy, has no proven long-term benefit over medical therapy alone.
      • Jacobs W.C.
      • van Tulder M.
      • Arts M.
      • Rubinstein S.M.
      • van Middelkoop M.
      • Ostelo R.
      • Verhagen A.
      • Koes B.
      • Peul W.C.
      Surgery versus conservative management of sciatica due to a lumbar herniated disc: A systematic review.
      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,
      • Nielsen C.S.
      • Knudsen G.P.
      • Steingrimsdottir O.A.
      Twin studies of pain.
      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.
      • Dib-Hajj S.D.
      • Waxman S.G.
      Translational pain research: Lessons from genetics and genomics.
      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 modalities
      • Cox J.J.
      • Reimann F.
      • Nicholas A.K.
      • Thornton G.
      • Roberts E.
      • Springell K.
      • Karbani G.
      • Jafri H.
      • Mannan J.
      • Raashid Y.
      • Al-Gazali L.
      • Hamamy H.
      • Valente E.M.
      • Gorman S.
      • Williams R.
      • McHale D.P.
      • Wood J.N.
      • Gribble F.M.
      • Woods C.G.
      An SCN9A channelopathy causes congenital inability to experience pain.
      whereas gain-of-function mutations result in paroxysmal extreme pain disorder and primary erythromelalgia.
      • Drenth J.P.
      • Finley W.H.
      • Breedveld G.J.
      • Testers L.
      • Michiels J.J.
      • Guillet G.
      • Taieb A.
      • Kirby R.L.
      • Heutink P.
      The primary erythermalgia-susceptibility gene is located on chromosome 2q31-32.
      • Fertleman C.R.
      • Baker M.D.
      • Parker K.A.
      • Moffatt S.
      • Elmslie F.V.
      • Abrahamsen B.
      • Ostman J.
      • Klugbauer N.
      • Wood J.N.
      • Gardiner R.M.
      • Rees M.
      SCN9A mutations in paroxysmal extreme pain disorder: Allelic variants underlie distinct channel defects and phenotypes.
      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, phantom limb pain, and experimental pain.
      • Reimann F.
      • Cox J.J.
      • Belfer I.
      • Diatchenko L.
      • Zaykin D.V.
      • McHale D.P.
      • Drenth J.P.
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      • Wheeler J.
      • Sanders F.
      • Wood L.
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      • Nikolajsen L.
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      • Max M.B.
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      • Poddar M.
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      • Smith S.
      • Gibson D.
      • Kelempisioti A.
      • Maixner W.
      • Gribble F.M.
      • Woods C.G.
      Pain perception is altered by a nucleotide polymorphism in SCN9A.
      Gain of function mutations of SCN11A, coding the nociceptive sodium channel Nav1.9, interestingly result in a congenital inability to sense pain in humans
      • Leipold E.
      • Liebmann L.
      • Korenke G.C.
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      • Weis J.
      • Heinemann S.H.
      • Hubner C.A.
      • Kurth I.
      A de novo gain-of-function mutation in SCN11A causes loss of pain perception.
      likely by producing sustained sodium channel inactivation, as can homozygous mutations in PRDM12, an epigenetic regulator that plays a key role in sensory neurogenesis.
      • Chen Y.C.
      • Auer-Grumbach M.
      • Matsukawa S.
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      • Moore A.W.
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      • Moog U.
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      • Pereira D.
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      • Katona I.
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      • Stafford F.
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      • Nicholas A.K.
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      • Michiue T.
      • Bennett D.L.
      • Woods C.G.
      • Senderek J.
      Transcriptional regulator PRDM12 is essential for human pain perception.
      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 investigation
      • Nardi A.
      • Damann N.
      • Hertrampf T.
      • Kless A.
      Advances in targeting voltage-gated sodium channels with small molecules.
      and targeting Nav1.7 with an antibody in mouse models of inflammatory and neuropathic pain resulted in significant analgesic effects.
      • Lee J.H.
      • Park C.K.
      • Chen G.
      • Han Q.
      • Xie R.G.
      • Liu T.
      • Ji R.R.
      • Lee S.Y.
      A monoclonal antibody that targets a NaV1.7 channel voltage sensor for pain and itch relief.
      Clinical trials using selective Nav1.7 channel blockers have been successful in conditions like inherited erythromelalgia,
      • Goldberg Y.P.
      • Price N.
      • Namdari R.
      • Cohen C.J.
      • Lamers M.H.
      • Winters C.
      • Price J.
      • Young C.E.
      • Verschoof H.
      • Sherrington R.
      • Pimstone S.N.
      • Hayden M.R.
      Treatment of Na(v)1.7-mediated pain in inherited erythromelalgia using a novel sodium channel blocker.
      but so far the limited early trial data have been surprisingly disappointing in other chronic human pain conditions. A gain-of-function 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,
      • Kremeyer B.
      • Lopera F.
      • Cox J.J.
      • Momin A.
      • Rugiero F.
      • Marsh S.
      • Woods C.G.
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      • Fricker F.R.
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      • Bedoya G.
      • Bennett D.L.
      • Wood J.N.
      • Ruiz-Linares A.
      A gain-of-function mutation in TRPA1 causes familial episodic pain syndrome.
      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 pain
      • Nissenbaum J.
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      • Darvasi A.
      Susceptibility to chronic pain following nerve injury is genetically affected by CACNG2.
      ) and CACNA2D3 (reduced postsurgical pain 1 year after discectomy
      • Neely G.G.
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      • Bellen H.J.
      • Woolf C.J.
      • Penninger J.M.
      A genome-wide Drosophila screen for heat nociception identifies alpha2delta3 as an evolutionarily conserved pain gene.
      ); voltage-gated potassium channel KCNS1 (increased pain in axial low back pain, amputation, sciatica, phantom limb, and experimental pain in healthy adults
      • Costigan M.
      • Belfer I.
      • Griffin R.S.
      • Dai F.
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      • Poddar M.
      • Lu Y.
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      • Zaykin D.
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      • Goldman D.
      • Maixner W.
      • Geschwind D.H.
      • Max M.B.
      • Seltzer Z.
      • Woolf C.J.
      Multiple chronic pain states are associated with a common amino acid-changing allele in KCNS1.
      ); Nav1.8 in patients with painful peripheral neuropathy
      • Faber C.G.
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      • Han C.
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      • Pierro T.
      • Lombardi R.
      • Kapetis D.
      • Dib-Hajj S.D.
      • Waxman S.G.
      Gain-of-function Nav1.8 mutations in painful neuropathy.
      ; and the cation channel P2X7 (decreased postmastectomy and osteoarthritic pain
      • Sorge R.E.
      • Trang T.
      • Dorfman R.
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      • Tichauer D.
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      • Mogil J.S.
      Genetically determined P2X7 receptor pore formation regulates variability in chronic pain sensitivity.
      ). 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 receptors
      • Young E.E.
      • Lariviere W.R.
      • Belfer I.
      Genetic basis of pain variability: Recent advances.
      ), in the enzymatic breakdown of the neurotransmitters dopamine, epinephrine, and norepinephrine by variations in catecholamine-O-methyltransferase
      • Andersen S.
      • Skorpen F.
      Variation in the COMT gene: Implications for pain perception and pain treatment.
      and in guanosine triphosphate cyclohydrolase (GCH1), the rate-limiting enzyme for tetrahydrobiopterin (BH4) synthesis, an essential cofactor for phenylalanine, tyrosine, and tryptophan hydroxylases.
      • Thony B.
      • Auerbach G.
      • Blau N.
      Tetrahydrobiopterin biosynthesis, regeneration and functions.
      Increased levels of GCH1 and BH4 are implicated in inflammatory and neuropathic pain, whereas blockade of this pathway results in analgesia.
      • Latremoliere A.
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      Reduction of neuropathic and inflammatory pain through inhibition of the tetrahydrobiopterin pathway.
      • Tegeder I.
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      • Woolf C.J.
      GTP cyclohydrolase and tetrahydrobiopterin regulate pain sensitivity and persistence.
      Variants in the human GCH1 haplotype reduce radicular leg pain after discectomy, experimental pain, and improve outcomes after surgically treated degenerative disc disease.
      • Tegeder I.
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      GTP cyclohydrolase and tetrahydrobiopterin regulate pain sensitivity and persistence.
      Although the anti-inflammatory drug sulfasalazine, which decreases BH4 levels, has not shown benefit in patients with lumbar spondylarthritis,
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      • Sieper J.
      Efficacy of sulfasalazine in patients with inflammatory back pain due to undifferentiated spondyloarthritis and early ankylosing spondylitis: A multicentre randomised controlled trial.
      pharmacological blockade of sepiapterin reductase,
      • Cox J.J.
      • Reimann F.
      • Nicholas A.K.
      • Thornton G.
      • Roberts E.
      • Springell K.
      • Karbani G.
      • Jafri H.
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      • Woods C.G.
      An SCN9A channelopathy causes congenital inability to experience pain.
      which decreases neuronal and macrophage BH4 production, is effective in rodent chronic inflammatory and neuropathic pain and constitutes a possible pharmacological target for humans.
      • Latremoliere A.
      • Latini A.
      • Andrews N.
      • Cronin S.J.
      • Fujita M.
      • Gorska K.
      • Hovius R.
      • Romero C.
      • Chuaiphichai S.
      • Painter M.
      • Miracca G.
      • Babaniyi O.
      • Remor A.P.
      • Duong K.
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      • Barrett L.B.
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      • Woolf C.J.
      Reduction of neuropathic and inflammatory pain through inhibition of the tetrahydrobiopterin pathway.

       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 neuron-immune cell interactions.
      • Ji R.R.
      • Xu Z.Z.
      • Gao Y.J.
      Emerging targets in neuroinflammation-driven chronic pain.
      Pharmacological targeting of some of the key molecular players include chemokines (CXCL1, CCL2, and CX3CL1), proteases (MMP9, 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.
      • Ji R.R.
      • Xu Z.Z.
      • Gao Y.J.
      Emerging targets in neuroinflammation-driven chronic pain.
      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.
      • Vicuna L.
      • Strochlic D.E.
      • Latremoliere A.
      • Bali K.K.
      • Simonetti M.
      • Husainie D.
      • Prokosch S.
      • Riva P.
      • Griffin R.S.
      • Njoo C.
      • Gehrig S.
      • Mall M.A.
      • Arnold B.
      • Devor M.
      • Woolf C.J.
      • Liberles S.D.
      • Costigan M.
      • Kuner R.
      The serine protease inhibitor SerpinA3N attenuates neuropathic pain by inhibiting T cell-derived leukocyte elastase.
      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 α2 subunit as a pharmacological target which produces strong antihyperalgesia with reduced sedation, encouraging development of subunit-specific GABA-A receptor benzodiazepines.
      • Zeilhofer H.U.
      • Ralvenius W.T.
      • Acuna M.A.
      Restoring the spinal pain gate: GABA(A) receptors as targets for novel analgesics.
      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.
      • Braz J.M.
      • Juarez-Salinas D.
      • Ross S.E.
      • Basbaum A.I.
      Transplant restoration of spinal cord inhibitory controls ameliorates neuropathic itch.
      • Braz J.M.
      • Wang X.
      • Guan Z.
      • Rubenstein J.L.
      • Basbaum A.I.
      Transplant-mediated enhancement of spinal cord GABAergic inhibition reverses paclitaxel-induced mechanical and heat hypersensitivity.
      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-β1 at the site of injured DRG neurons.
      • Chen G.
      • Park C.K.
      • Xie R.G.
      • Ji R.R.
      Intrathecal bone marrow stromal cells inhibit neuropathic pain via TGF-beta secretion.
      Finally, personalized human nociceptor profiling by reprogramming fibroblasts into nociceptors
      • Wainger B.J.
      • Buttermore E.D.
      • Oliveira J.T.
      • Mellin C.
      • Lee S.
      • Saber W.A.
      • Wang A.J.
      • Ichida J.K.
      • Chiu I.M.
      • Barrett L.
      • Huebner E.A.
      • Bilgin C.
      • Tsujimoto N.
      • Brenneis C.
      • Kapur K.
      • Rubin L.L.
      • Eggan K.
      • Woolf C.J.
      Modeling pain in vitro using nociceptor neurons reprogrammed from fibroblasts.
      will enable detailed electrophysiological characterization of an individual's nociceptive phenotype, and could be used to study risk of developing chronic or neuropathic pain and the response profile to particular treatments in a patient. This approach could offer the tantalizing opportunity of one day being able to screen individual patients for pain risk and efficacy in a dish, before initiating treatment.

      Conclusions

      We have attempted to capture the opportunities and problems facing identification of pain mechanisms in patients, especially those with cLBP. We highlight the limitations of contemporary clinical practice, with an oversimplistic mostly anatomical approach and almost no mechanistic considerations, but recognize that the exciting potential of a more scientific and precision-based strategy will be difficult to achieve. This will require basic scientists and clinicians working together. To do so we need more human-focused efforts by neurobiologists, weeding out, for example, models that are not true surrogates of chronic human pain conditions, and a more scientific focus by clinicians, such that they make a greater attempt to identify where and how their patient's pain is being generated and use this information to guide treatment choice. We therefore propose the introduction of a pain diagnostic ladder (Fig 2)—analogous to but quite different from the World Health Organization therapeutic ladder—where at each step, one or several mechanisms can be identified that progressively increases the specificity of treatment choice, starting with the broadest category, pain states, and then narrowing down to pain mechanisms, and eventually to molecular targets. Putting such a diagnostic and therapeutic strategy into practice will clearly not be easy, and currently may seem almost impossible, not least because sensitive and precise biomarkers/diagnostic tools of mechanisms are largely absent and because analgesic treatments are generally either not specific for a particular mechanism or there are no treatments available for a definable mechanism. Therefore, until this mechanistic diagnostic approach can evolve and be fully justified scientifically and rigorously validated clinically, chronic pain diagnoses must rely on clinical diagnostic criteria like those described in the AAPT, despite their limitations. Nevertheless, we have a roadmap of what could be possible, and therefore should work together to make it happen.
      Figure thumbnail gr2
      Figure 2Pain 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.

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