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Neuropathic Pain: Principles of Diagnosis and Treatment

      Abstract

      Neuropathic pain is caused by disease or injury of the nervous system and includes various chronic conditions that, together, affect up to 8% of the population. A substantial body of neuropathic pain research points to several important contributory mechanisms including aberrant ectopic activity in nociceptive nerves, peripheral and central sensitization, impaired inhibitory modulation, and pathological activation of microglia. Clinical evaluation of neuropathic pain requires a thorough history and physical examination to identify characteristic signs and symptoms. In many cases, other laboratory investigations and clinical neurophysiological testing may help identify the underlying etiology and guide treatment selection. Available treatments essentially provide only symptomatic relief and may include nonpharmacological, pharmacological, and interventional therapies. Most extensive evidence is available for pharmacological treatment, and currently recommended first-line treatments include antidepressants (tricyclic agents and serotonin-norepinephrine reuptake inhibitors) and anticonvulsants (gabapentin and pregabalin). Individualized multidisciplinary patient care is facilitated by careful consideration of pain-related disability (eg, depression and occupational dysfunction) as well as patient education; repeat follow-up and strategic referral to appropriate medical/surgical subspecialties; and physical and psychological therapies. In the near future, continued preclinical and clinical research and development are expected to lead to further advancements in the diagnosis and treatment of neuropathic pain.

      Abbreviations and Acronyms:

      CHEP (contact heat–evoked potential), CNS (central nervous system), CPRS (complex regional pain syndrome), LEP (laser-evoked potential), NMDA (N-methyl-d-aspartate), NNT (number needed to treat), QSART (quantitative sudomotor axon reflex test), RCT (randomized controlled trial), SNRI (serotonin-norepinephrine reuptake inhibitor), TCA (tricyclic antidepressant)
      CME Activity
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      Learning Objectives: On completion of this article, you should be able to (1) identify the key pathophysiologic mechanisms implicated in the development of neuropathic pain, (2) apply the necessary clinical tools to appropriately assess patients with neuropathic pain, and (3) formulate an evidence-based approach for the pharmacologic treatment of neuropathic pain.
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      In their editorial and administrative roles, William L. Lanier, Jr, MD, Terry L. Jopke, Kimberly D. Sankey, and Nicki M. Smith, MPA, have control of the content of this program but have no relevant financial relationship(s) with industry.
      Dr Jensen has received financial support from Pfizer, Grunenthal, Orion and Astellas as compensation for participating as consultant.
      Grant Support: This work was supported in part by grant # MSH-55041 from the Canadian Institutes of Health Research (CIHR grant number MSH-55041) award to IG.
      This review discusses a wide variety of treatment modalities, several of which are not necessarily labeled for use in the treatment of neuropathic pain in all countries. Therefore, readers are expected to determine the labeled indications in their country of clinical practice for any of the discussed treatments.
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      Questions? Contact [email protected] .
      Neuropathic pain has most recently been redefined by the International Association for the Study of Pain as “pain caused by a lesion or disease of the somatosensory system.”
      • Jensen T.S.
      • Baron R.
      • Haanpää M.
      • et al.
      A new definition of neuropathic pain.
      Nociceptive pain (eg, arthritis) involves peripheral sources of noxious stimulation (eg, inflammatory mediators) that are processed by an otherwise normal somatosensory system, whereas the primary cause of neuropathic pain is the lesion or disease that leads to an abnormal and dysfunctional somatosensory system.
      • Woolf C.J.
      American College of Physicians; American Physiological Society
      Pain: moving from symptom control toward mechanism-specific pharmacologic management.
      Keeping this definition in mind, neuropathic pain refers to a broad range of clinical conditions (Table 1)
      • Gilron I.
      • Jensen T.S.
      • Dickenson A.H.
      Combination pharmacotherapy for management of chronic pain: from bench to bedside.
      that can be categorized anatomically (eg, peripheral vs central) and etiologically (eg, degenerative, traumatic, infectious, metabolic, and toxic).
      Table 1Classification of Neuropathic Pain According to Site of Major Pathology
      From Lancet Neurol,
      • Gilron I.
      • Jensen T.S.
      • Dickenson A.H.
      Combination pharmacotherapy for management of chronic pain: from bench to bedside.
      with permission.
      PathologyPeripheralSpinalBrain
      GeneticFabry neuropathySyringomyeliaSyringobulbia
      MetabolicPainful diabetic neuropathyB12 myelopathy
      TraumaticNerve injurySpinal cord injuryMultiple sclerosis
      VascularVasculitic neuropathySpinal cord strokeBrain stroke
      NeoplasticTumor compression neuropathyTumor compressionTumor compression
      ImmunologicalGuillain-Barré syndromeMultiple sclerosisMultiple sclerosis
      InfectiousHIV, BorreliosisInfectious myelitisEncephalitis
      ToxicChemotherapy neuropathy
      The “positive” symptoms of neuropathic pain conditions include both stimulus-independent (“spontaneous”) and stimulus-dependent (“evoked”) pain and other symptoms such as tingling (ie, paresthesias).
      • Gilron I.
      • Watson C.P.
      • Cahill C.M.
      • Moulin D.E.
      Neuropathic pain: a practical guide for the clinician.
      The “negative” signs and symptoms that may be observed include numbness, weakness, and loss of deep tendon reflexes in the involved nerve territory. Neuropathic pain can follow different temporal profiles (eg, continuous vs intermittent) and may be described with different pain quality descriptors.
      • Gilron I.
      • Attal N.
      • Bouhassira D.
      • Dworkin R.
      Neuropathic pain assessment.
      • Bouhassira D.
      • Attal N.
      Diagnosis and assessment of neuropathic pain: the saga of clinical tools.
      • Haanpää M.
      • Attal N.
      • Backonja M.
      • et al.
      NeuPSIG guidelines on neuropathic pain assessment.
      Stimulus-evoked pain includes allodynia, defined as pain in response to a normally nonpainful stimulus (eg, contact of clothing on skin), and hyperalgesia, defined as increased pain in response to a normally painful stimulus. These sensory abnormalities are often observed to extend beyond dermatomal or nerve territory distributions, leading to the inappropriate diagnosis of a functional or psychosomatic disorder.
      Describing the epidemiology of neuropathic pain is particularly challenging given this diversity of related clinical entities. However, the validation of a number of assessment tools for the identification of pain with neuropathic characteristics
      • Gilron I.
      • Attal N.
      • Bouhassira D.
      • Dworkin R.
      Neuropathic pain assessment.
      • Bouhassira D.
      • Attal N.
      Diagnosis and assessment of neuropathic pain: the saga of clinical tools.
      • Bennett M.I.
      • Attal N.
      • Backonja M.M.
      • et al.
      Using screening tools to identify neuropathic pain.
      has facilitated epidemiological studies that estimate the prevalence of neuropathic pain to be as high as 7% to 8% of the general population.
      • Bouhassira D.
      • Lantéri-Minet M.
      • Attal N.
      • Laurent B.
      • Touboul C.
      Prevalence of chronic pain with neuropathic characteristics in the general population.
      • Torrance N.
      • Smith B.H.
      • Bennett M.I.
      • Lee A.J.
      The epidemiology of chronic pain of predominantly neuropathic origin: results from a general population survey.
      Furthermore, quality-of-life studies indicate that in addition to the obvious pain-related suffering experienced by patients, neuropathic pain is associated with depression, disordered sleep, and impairments in physical function.
      • Atlas S.J.
      • Deyo R.A.
      • Patrick D.L.
      • Convery K.
      • Keller R.B.
      • Singer D.E.
      The Quebec Task Force classification for Spinal Disorders and the severity, treatment, and outcomes of sciatica and lumbar spinal stenosis.
      • Coplan P.M.
      • Schmader K.
      • Nikas A.
      • et al.
      Development of a measure of the burden of pain due to herpes zoster and postherpetic neuralgia for prevention trials: adaptation of the brief pain inventory.
      • Schmader K.E.
      Epidemiology and impact on quality of life of postherpetic neuralgia and painful diabetic neuropathy.
      The purpose of this article was to review and describe current principles of neuropathic pain diagnosis and neuropathic pain treatment with a focus on pharmacological therapy.

      Neuropathic Pain Mechanisms Relevant to Diagnosis and Treatment

      As illustrated in the Figure, an understanding of the diverse mechanisms of pain transmission and pain modulation is crucial for appropriate clinical assessment as well as the development and application of analgesic therapies. Development of several preclinical pain models involving injury (eg, surgical), or disease induction (eg, streptozocin-induced diabetic neuropathy), of peripheral or central neurons has facilitated many sophisticated investigations, providing a wealth of information about cellular and molecular mechanisms of neuropathic pain.
      • Campbell J.N.
      • Meyer R.A.
      Mechanisms of neuropathic pain.
      • von Hehn C.A.
      • Baron R.
      • Woolf C.J.
      Deconstructing the neuropathic pain phenotype to reveal neural mechanisms.
      • Wang L.X.
      • Wang Z.J.
      Animal and cellular models of chronic pain.
      • Mogil J.S.
      Animal models of pain: progress and challenges.
      Also, clinical manifestations of underlying neuropathic pain mechanisms (eg, sensitization and impaired descending inhibition) have emerged from human neuropathic pain studies involving quantitative sensory testing, electrophysiology, nerve and skin biopsy, and functional brain imaging studies.
      • Gilron I.
      • Attal N.
      • Bouhassira D.
      • Dworkin R.
      Neuropathic pain assessment.
      • Haanpää M.
      • Attal N.
      • Backonja M.
      • et al.
      NeuPSIG guidelines on neuropathic pain assessment.
      Prominent and well-characterized mechanisms observed to be important in neuropathic pain conditions include (1) ectopic activity, (2) peripheral sensitization, (3) central sensitization, (4) impaired inhibitory modulation, and (5) activation of microglia.
      • Campbell J.N.
      • Meyer R.A.
      Mechanisms of neuropathic pain.
      • von Hehn C.A.
      • Baron R.
      • Woolf C.J.
      Deconstructing the neuropathic pain phenotype to reveal neural mechanisms.
      Figure thumbnail gr1
      FigureMain pathways and mechanisms by which pain is transmitted and modulated. The ascending pathways, by which sensory and affective components are generated, are shown on the left. Top-down modulation, by which higher centers can alter spinal function through changes in descending controls, is shown on the right. The major functional roles of different neural components in these pathways are summarized in yellow boxes. Changes that occur after tissue or nerve damage are listed, and pharmacological agents that modulate pain are shown at their sites of action in red boxes. Peripheral inputs are indicated by the horizontal purple arrow. The peripheral mechanisms of inflammatory and neuropathic pain are very different, and this difference is reflected in their different treatments. However, central mechanisms might be more common than peripheral mechanisms. (–) α2R = inhibition of neuronal activity. (+) 5-HT3R = stimulation of neuronal activity; Am = amygdala; A5 and A7 = brain stem nuclei containing noradrenergic neurons; CC = cerebral cortex; CN = cuneate nucleus; Hyp = hypothalamus; LC = locus coeruleus; NG = nucleus gracilis; NMDA = N-methyl-d-aspartate; NSAID = nonsteroidal anti-inflammatory drug; PAG = periaqueductal gray matter; PB = parabrachial nucleus; Po = posterior nuclei of the thalamus; RVM = rostroventral medial medulla; SNRI = serotonin-norepinephrine reuptake inhibitor; TCA = tricyclic antidepressant; VPM and VPL = ventrobasal thalamus, medial and lateral components.
      From Lancet Neurol,
      • Gilron I.
      • Jensen T.S.
      • Dickenson A.H.
      Combination pharmacotherapy for management of chronic pain: from bench to bedside.
      with permission from Elsevier, Inc.

      Ectopic Activity

      Following nerve injury, hyperexcitability leading to ectopic action potentials in primary afferent neurons, and sometimes their central projections,
      • Amir R.
      • Kocsis J.D.
      • Devor M.
      Multiple interacting sites of ectopic spike electrogenesis in primary sensory neurons.
      is likely an important mechanism of spontaneous (stimulus-independent) paresthesias, dysesthesias, and pain,
      • von Hehn C.A.
      • Baron R.
      • Woolf C.J.
      Deconstructing the neuropathic pain phenotype to reveal neural mechanisms.
      which may demonstrate different temporal patterns (eg, brief paroxysmal, continuous intermittent, or continuous constant).
      Evidence points to various molecular changes that likely contribute to ectopic activity including postinjury alterations in voltage-gated sodium (eg, Nav1.3, Nav1.6, and Nav1.9) channels, voltage-gated potassium (eg, KCNQ Kv7) channels, and hyperpolarization-activated cyclic nucleotide-gated (eg, HCN2) channels.
      • Chaplan S.R.
      • Guo H.Q.
      • Lee D.H.
      • et al.
      Neuronal hyperpolarization-activated pacemaker channels drive neuropathic pain.

      Peripheral Sensitization

      Although thought to be one of the most important mechanisms of inflammatory pain, peripheral sensitization—exhibited as hyperexcitability and reduced activation threshold of primary afferent neurons—is also an important mechanism of peripherally mediated hyperalgesia and allodynia after nerve injury.
      • von Hehn C.A.
      • Baron R.
      • Woolf C.J.
      Deconstructing the neuropathic pain phenotype to reveal neural mechanisms.
      Postinjury changes in the transient receptor potential TRPV1 ion channel
      • Kim H.Y.
      • Park C.K.
      • Cho I.H.
      • Jung S.J.
      • Kim J.S.
      • Oh S.B.
      Differential changes in TRPV1 expression after trigeminal sensory nerve injury.
      and possibly other members of this ion channel family are thought to contribute to peripheral sensitization in neuropathic conditions, which has led to the clinical evaluation of the TRPV1 agonist capsaicin.
      • Simpson D.M.
      • Brown S.
      • Tobias J.
      NGX-4010 C107 Study Group. Controlled trial of high-concentration capsaicin patch for treatment of painful HIV neuropathy.

      Central Sensitization

      A body of animal investigations has demonstrated that nerve disease or injury—as well as other peripheral nociceptive stimulation—can trigger central (ie, spinal and supraspinal) neuroplastic changes referred to as central sensitization.
      • Woolf C.J.
      Central sensitization: implications for the diagnosis and treatment of pain.
      Central sensitization has been defined as “a prolonged but reversible increase in the excitability and synaptic efficacy of neurons in central nociceptive pathways” that manifests as allodynia (touch-evoked pain), hyperalgesia (pain experience that is exaggerated with respect to a standardized noxious stimulus), enhanced temporal summation (escalating pain in response to repeated application of a constant stimulus), and secondary hyperalgesia (pain and hypersensitivity beyond the dermatome of the nerve injury).
      • Woolf C.J.
      Central sensitization: implications for the diagnosis and treatment of pain.
      Proposed mechanisms by which nerve injury results in central sensitization include phenotypic changes in A-beta touch fibers, which subsequently expressed increased levels of neuropeptides such as calcitonin gene-related peptide and substance P
      • Nitzan-Luques A.
      • Devor M.
      • Tal M.
      Genotype-selective phenotypic switch in primary afferent neurons contributes to neuropathic pain.
      and increased activity of excitatory amino acid transmission (eg, via N-methyl-d-aspartate [NMDA] receptors).
      • Kohno T.
      • Moore K.A.
      • Baba H.
      • Woolf C.J.
      Peripheral nerve injury alters excitatory synaptic transmission in lamina II of the rat dorsal horn.
      The latter mechanism has provided the therapeutic rationale for studying excitatory amino acid antagonists to treat neuropathic pain, although agents with an optimal therapeutic profile are yet to be identified.
      • Gilron I.
      • Dickenson A.H.
      Emerging drugs for neuropathic pain.
      • Chizh B.A.
      • Headley P.M.
      NMDA antagonists and neuropathic pain–multiple drug targets and multiple uses.

      Impaired Inhibitory Modulation

      In addition to changes that enhance nociception, evidence has emerged to indicate that nerve injury can lead to the impairment of endogenous inhibitory mechanisms of nociception in some situations.
      • Campbell J.N.
      • Meyer R.A.
      Mechanisms of neuropathic pain.
      • von Hehn C.A.
      • Baron R.
      • Woolf C.J.
      Deconstructing the neuropathic pain phenotype to reveal neural mechanisms.
      For example, post–nerve injury excitatory transmission has been shown to cause apoptosis (cell death) of GABAergic spinal inhibitory interneurons contributing further to postinjury pain sensitivity.
      • Scholz J.
      • Broom D.C.
      • Youn D.H.
      • et al.
      Blocking caspase activity prevents transsynaptic neuronal apoptosis and the loss of inhibition in lamina II of the dorsal horn after peripheral nerve injury.

      Activation of Microglia

      Evidence has been mounting over the past 15 years to demonstrate that neuropathic conditions (and other pain states) are associated with activation of glia, and other nonneuronal cells in the central nervous system (CNS), and furthermore that changes in these activated glia may be important contributors to the phenomenon of central sensitization.
      • Tsuda M.
      • Inoue K.
      • Salter M.W.
      Neuropathic pain and spinal microglia: a big problem from molecules in “small” glia.
      Several molecular changes resulting from postinjury glial activation have been identified to contribute to pain hypersensitivity and include phosphorylation of mitogen-activated protein kinase, upregulation of chemokine receptors, and release of glial cytokines and growth factors.
      • Ji R.R.
      • Berta T.
      • Nedergaard M.
      Glia and pain: is chronic pain a gliopathy?.
      It is important to recognize that in patients with neuropathic pain, more than one mechanism, or pain phenotype, may be apparent and, furthermore, a seemingly singular condition (eg, postherpetic neuralgia) often includes a heterogeneous population, with patient subgroups exhibiting different mechanisms.
      • Fields H.L.
      • Rowbotham M.
      • Baron R.
      Postherpetic neuralgia: irritable nociceptors and deafferentation.
      • Maier C.
      • Baron R.
      • Tölle T.R.
      • et al.
      Quantitative sensory testing in the German Research Network on Neuropathic Pain (DFNS): somatosensory abnormalities in 1236 patients with different neuropathic pain syndromes.
      For example, some patients with postherpetic neuralgia have been reported to exhibit hyperalgesia and/or allodynia thought to be due to peripheral sensitization (“irritable nociceptors”) but with minimal sensory loss. Another subgroup of patients exhibits deafferentation of small nociceptive fibers, resulting in impaired temperature sensation but profound allodynia thought to be due to central sensitization. Yet another subgroup exhibits sensory loss without hyperalgesia or allodynia but severe spontaneous pain thought be related to ectopic activity in deafferented central neurons and/or central neuronal reorganization.
      • Fields H.L.
      • Rowbotham M.
      • Baron R.
      Postherpetic neuralgia: irritable nociceptors and deafferentation.
      Perhaps even more relevant to individualizing therapy, it is also notable that multiple pain mechanisms may be involved in the same patient in some cases.
      • Maier C.
      • Baron R.
      • Tölle T.R.
      • et al.
      Quantitative sensory testing in the German Research Network on Neuropathic Pain (DFNS): somatosensory abnormalities in 1236 patients with different neuropathic pain syndromes.

      Primary Care Approach to Neuropathic Pain Assessment

      In the setting of clinical care for a patient suspected of having neuropathic pain, careful history and physical examination and special laboratory tests serve to (1) aid in formulating a differential diagnosis of the presenting problem, (2) guide appropriate treatment selection, and (3) follow-up individual responses to treatment.
      • Backonja M.M.
      • Galer B.S.
      Pain assessment and evaluation of patients who have neuropathic pain.
      • Hansson P.
      • Haanpää M.
      Diagnostic work-up of neuropathic pain: computing, using questionnaires or examining the patient?.
      • Baron R.
      • Tölle T.R.
      Assessment and diagnosis of neuropathic pain.
      Diagnosis of neuropathic pain is primarily based on history and physical examination although other special investigations are often useful.
      • Bouhassira D.
      • Attal N.
      Diagnosis and assessment of neuropathic pain: the saga of clinical tools.
      • Backonja M.M.
      • Galer B.S.
      Pain assessment and evaluation of patients who have neuropathic pain.
      Clinical assessment should focus on ruling out treatable conditions (eg, spinal cord compression and neoplasm), confirming the diagnosis of neuropathic pain, and identifying clinical features (eg, insomnia and autonomic neuropathy) that might help individualize treatment. As with other chronic pain conditions, evaluation of a suspected neuropathic condition should always include an assessment of pain location, quality, intensity and temporal variation, functional impact on mood, sleep, and other activities of daily living, responses to previously attempted treatments, and coexisting or previous alcohol or substance abuse.
      • Gilron I.
      • Jensen T.S.
      • Dickenson A.H.
      Combination pharmacotherapy for management of chronic pain: from bench to bedside.

      Signs and Symptoms Characteristic of Neuropathic Pain

      Although no single sign or symptom is pathognomonic of neuropathic pain, research over the past 15 years or so has implicated a set of sensory signs and symptoms that are much more likely to be associated with a neuropathic pain condition versus other nonneuropathic conditions.
      • Gilron I.
      • Watson C.P.
      • Cahill C.M.
      • Moulin D.E.
      Neuropathic pain: a practical guide for the clinician.
      • Gilron I.
      • Attal N.
      • Bouhassira D.
      • Dworkin R.
      Neuropathic pain assessment.
      • Bennett M.I.
      • Attal N.
      • Backonja M.M.
      • et al.
      Using screening tools to identify neuropathic pain.
      Much of this information has emerged from the development and publication of several neuropathic pain (or neuropathy) screening tools including the Michigan Neuropathy Screening Instrument,
      • Feldman E.L.
      • Stevens M.J.
      • Thomas P.K.
      • Brown M.B.
      • Canal N.
      • Greene D.A.
      A practical two-step quantitative clinical and electrophysiological assessment for the diagnosis and staging of diabetic neuropathy.
      Neuropathic Pain Scale,
      • Galer B.S.
      • Jensen M.P.
      Development and preliminary validation of a pain measure specific to neuropathic pain: the Neuropathic Pain Scale.
      Leeds Assessment of Neuropathic Symptoms and Signs,
      • Bennett M.
      The LANSS Pain Scale: the Leeds assessment of neuropathic symptoms and signs.
      Neuropathic Pain Questionnaire,
      • Krause S.J.
      • Backonja M.M.
      Development of a neuropathic pain questionnaire.
      Neuropathic Pain Symptom Inventory,
      • Bouhassira D.
      • Attal N.
      • Fermanian J.
      • et al.
      Development and validation of the Neuropathic Pain Symptom Inventory.
      “Douleur Neuropathique en 4 questions,”
      • Bouhassira D.
      • Attal N.
      • Alchaar H.
      • et al.
      Comparison of pain syndromes associated with nervous or somatic lesions and development of a new neuropathic pain diagnostic questionnaire (DN4).
      pain DETECT,
      • Freynhagen R.
      • Baron R.
      • Gockel U.
      • Tölle T.R.
      painDETECT: a new screening questionnaire to identify neuropathic components in patients with back pain.
      Pain Quality Assessment Scale,
      • Jensen M.P.
      • Gammaitoni A.R.
      • Olaleye D.O.
      • Oleka N.
      • Nalamachu S.R.
      • Galer B.S.
      The pain quality assessment scale: assessment of pain quality in carpal tunnel syndrome.
      and the Short-Form McGill Pain Questionnaire-2.
      • Dworkin R.H.
      • Turk D.C.
      • Revicki D.A.
      • et al.
      Development and initial validation of an expanded and revised version of the Short-form McGill Pain Questionnaire (SF-MPQ-2).
      Although several differences exist, the sensory quality descriptors “tingling” (or “pins and needles” or “prickling), “burning” (or “hot”), and “shooting” (or “electrical shocks”) are included in nearly all these various tools, and these 3 descriptors are perhaps the most characteristic of neuropathic pain.
      • Gilron I.
      • Watson C.P.
      • Cahill C.M.
      • Moulin D.E.
      Neuropathic pain: a practical guide for the clinician.
      • Bouhassira D.
      • Attal N.
      Diagnosis and assessment of neuropathic pain: the saga of clinical tools.
      The above, self-report, neuropathic pain assessment tools (some of which include a physical examination component) may be useful for the diagnostic characterization of neuropathic pain. However, some of these tools have also been used to describe subgroups of patients with neuropathic pain in whom unique underlying mechanisms are operant. For example, Baron et al
      • Baron R.
      • Tölle T.R.
      • Gockel U.
      • Brosz M.
      • Freynhagen R.
      A cross-sectional cohort survey in 2100 patients with painful diabetic neuropathy and postherpetic neuralgia: differences in demographic data and sensory symptoms.
      found 5 distinct subgroups of sensory symptoms assessed using the pain DETECT instrument in 1623 patients with painful diabetic neuropathy and 498 patients with postherpetic neuralgia. Furthermore, pain quality descriptors can provide more detail in characterizing treatment effect beyond just global measures of pain intensity.
      • Attal N.
      • Bouhassira D.
      • Baron R.
      • et al.
      Assessing symptom profiles in neuropathic pain clinical trials: can it improve outcome?.
      For example, secondary analyses of neuropathic pain clinical trials have demonstrated that drug therapy can preferentially reduce certain pain quality descriptors and have little effect on others.
      • Jensen M.P.
      • Chiang Y.K.
      • Wu J.
      Assessment of pain quality in a clinical trial of gabapentin extended release for postherpetic neuralgia.
      • Gilron I.
      • Tu D.
      • Holden R.R.
      Sensory and affective pain descriptors respond differentially to pharmacological interventions in neuropathic conditions.
      • Bouhassira D.
      • Wilhelm S.
      • Schacht A.
      • et al.
      Neuropathic pain phenotyping as a predictor of treatment response in painful diabetic neuropathy: data from the randomized, double-blind, COMBO-DN study.

      Basic Sensory Examination

      Relatively simple bedside methods can be used to assess sensory abnormalities such as hypoesthesia (abnormally reduced sensation of a tactile stimulus) to touch or cold; hypoalgesia (abnormally reduced pain sensation to a noxious stimulus); hyperalgesia (abnormally increased pain sensation to a noxious stimulus) to pinprick, blunt pressure, heat, or cold; and, finally, allodynia (pain sensation to a nonnoxious stimulus).
      • Bouhassira D.
      • Attal N.
      Diagnosis and assessment of neuropathic pain: the saga of clinical tools.
      Sensory nerve fibers assessed by clinical examination include A-beta touch fibers (eg, with fingers, wisp of cotton, or soft brush), A-delta “fast” pain fibers (eg, with a metal straight pin or sharp wooden stick), and C “slow” pain fibers (eg, with a warm 40°C object).
      • Hansson P.
      • Backonja M.
      • Bouhassira D.
      Usefulness and limitations of quantitative sensory testing: clinical and research application in neuropathic pain states.
      Detection of abnormal sensory findings can often be validated by comparison with normal contralateral and/or other unaffected body sites. Efforts should be made to explain how observed sensory abnormalities relate to a suspected neurological lesion. For example, polyneuropathies such as diabetic neuropathy are often associated with distal and symmetrical sensory abnormalities,
      • Tesfaye S.
      • Boulton A.J.
      • Dickenson A.H.
      Mechanisms and management of diabetic painful distal symmetrical polyneuropathy.
      whereas more focal neural conditions such as postherpetic neuralgia or lumbar radiculopathy are often associated with abnormalities along the affected dermatome.
      • Baron R.
      • Binder A.
      • Wasner G.
      Neuropathic pain: diagnosis, pathophysiological mechanisms, and treatment.

      Quantitative Sensory Testing

      Patients with neuropathic pain suffer from various sensory abnormalities that can occur in different combinations. It is thought that sensory signs and symptoms are closely linked to underlying mechanisms of pain generation, and it is therefore likely that precise analysis of the individual somatosensory pattern might facilitate a mechanism-based treatment strategy. Thus, it is important to assess the individual sensory phenotype as precisely as possible. In addition to the self-report instruments discussed above, quantitative sensory testing to assess sensory signs has shown promising results in characterizing underlying “mechanistic clusters” in neuropathic pain as well as in predicting response to analgesic treatment with certain drugs. A standardized quantitative sensory testing protocol for routine use and clinical trials was introduced by the German Research Network on Neuropathic Pain (Deutscher Forschungsverbund Neuropathischer Schmerz [DFNS]) in 2006 because standardization is crucial to compare study results.
      • Rolke R.
      • Baron R.
      • Maier C.
      • et al.
      Quantitative sensory testing in the German Research Network on Neuropathic Pain (DFNS): standardized protocol and reference values.
      Sensory stimuli are applied to the skin or deep somatic structures to elicit a painful or nonpainful sensation that can be quantified on a rating scale. Quantitative sensory testing uses a battery of mechanical and thermal stimuli (graded von Frey hairs, several pinprick stimuli, pressure algometry, quantitative thermal testing, etc) and assesses both minus signs (loss of function) and positive signs (gain of function) in the nociceptive and nonnociceptive afferent nervous systems. On the basis of quantitative sensory testing, a novel classification and subgroupings of neuropathic pain syndromes have been proposed. Similar to the way tumors are graded, patients are classified (LoGa classification) according to their function of small and large afferent fibers.
      • Maier C.
      • Richter H.
      • Baron R.
      A new classification of neuropathic pain (LoGa).
      In the setting of neuropathic pain treatment, Demant et al

      Demant DT, Lund K, Vollert J, et al. The effect of oxcarbazepine in peripheral neuropathic pain depends on pain phenotype: a randomised, double-blind, placebo-controlled phenotype-stratified study [published online ahead of print August 17, 2014]. Pain. http://dx.doi.org/10.1016/j.pain.2014.08.014.

      examined in a randomized, double-blind, placebo controlled trial the pain-relieving effect of oxcarbazepine in 72 patients with postherpetic neuralgia, surgical or traumatic nerve injury, or polyneuropathy. They performed quantitative sensory testing according to the LoGa classification in the beginning of the trial and stratified the patients according to their sensory profile into the following 2 groups: (1) “irritable nociceptor” with predominantly a “gain of function” and a preserved small-fiber nerve function and (2) “deafferentation type” dominated by sensory loss. This stratification is based on the assumption that ectopic activity from upregulated sodium channels is mainly responsible for hyperalgesia (“irritable nociceptor”), and therefore oxcarbazepine as a sodium channel blocker should have an effect in these patients.

      Demant DT, Lund K, Vollert J, et al. The effect of oxcarbazepine in peripheral neuropathic pain depends on pain phenotype: a randomised, double-blind, placebo-controlled phenotype-stratified study [published online ahead of print August 17, 2014]. Pain. http://dx.doi.org/10.1016/j.pain.2014.08.014.

      Although oxcarbazepine is recommended as first-line therapy for trigeminal neuralgia, it plays a minor role in the treatment of other neuropathic pain syndromes because of equivocal study results. This study showed positive results and a treatment response depending on the sensory phenotype. For all patients, the number needed to treat (NNT) for 50% pain relief was 6.9. The NNT in the group with the “irritable nociceptor phenotype” was only 3.9, whereas the NNT was 13 for the “nonirritable nociceptor” phenotype.

      Demant DT, Lund K, Vollert J, et al. The effect of oxcarbazepine in peripheral neuropathic pain depends on pain phenotype: a randomised, double-blind, placebo-controlled phenotype-stratified study [published online ahead of print August 17, 2014]. Pain. http://dx.doi.org/10.1016/j.pain.2014.08.014.

      Other Special Tests

      Clinical neurophysiological examinations are vital assessment tools in establishing a diagnosis of neuropathic pain with peripheral nerve involvement.
      • Truini A.
      • Garcia-Larrea L.
      • Cruccu G.
      Reappraising neuropathic pain in humans—how symptoms help disclose mechanisms.
      However, clinical neurophysiology examines large fibers but is generally not useful in determining the possible involvement of small nerve fibers in neuropathic pain conditions. A number of other tests can be performed in patients with suspected small-fiber neuropathy. Apart from clinical and electrophysiological examination, other assessments include both structural tests such as various skin biopsy analyses, sural nerve biopsy, and structural imaging tests of, for example, larger nerves. The functional tests include, apart from quantitative sensory testing, sudomotor function test, heart rate variability, contact heat–evoked potentials (CHEPs), laser-evoked potentials (LEPs), and quantitative axon reflex measures. Dysfunction of the sudomotor nerves with changed sweat is an early neurophysiologic abnormality in neuropathies. There are different methods to determine sudomotor functionality. A commonly used one is the quantitative sudomotor axon reflex test (QSART).
      • Thaisetthawatkul P.
      • Fernandes Filho J.A.
      • Herrmann D.N.
      Contribution of QSART to the diagnosis of small fiber neuropathy.
      The test measures resting skin temperature, resting sweat output, and iontophoretic-stimulated sweat output. The QSART can be used as a diagnostic tool for small-fiber neuropathy, and it has been shown that increased diagnostic yield can be obtained by incorporating the QSART into the diagnostic criteria for small-fiber neuropathy.
      • Thaisetthawatkul P.
      • Fernandes Filho J.A.
      • Herrmann D.N.
      Contribution of QSART to the diagnosis of small fiber neuropathy.
      A recently devised objective “sweat test” has demonstrated the ability to detect and quantify early changes in sudomotor nerves by quantifying reduced water produced by partial denervation of individual sweat glands.
      • Provitera V.
      • Nolano M.
      • Caporaso G.
      • Stancanelli A.
      • Santoro L.
      • Kennedy W.R.
      Evaluation of sudomotor function in diabetes using the dynamic sweat test.
      Contact heat–evoked potentials and LEPs assess noxious information of thermal nature that is mediated via C- and A-delta fibers.
      • Truini A.
      • Garcia-Larrea L.
      • Cruccu G.
      Reappraising neuropathic pain in humans—how symptoms help disclose mechanisms.
      • Madsen C.S.
      • Johnsen B.
      • Fuglsang-Frederiksen A.
      • Jensen T.S.
      • Finnerup N.B.
      Increased contact heat pain and shortened latencies of contact heat evoked potentials following capsaicin-induced heat hyperalgesia.
      Contact heat–evoked potentials use contact heat stimulation and thereby stimulates a larger number of nociceptors in the skin, whereas LEPs use high-energy lasers to selectively activate single nociceptors.
      • Valeriani M.
      • Pazzaglia C.
      • Cruccu G.
      • Truini A.
      Clinical usefulness of laser evoked potentials.
      Laser-evoked potentials have the advantage of requiring no skin contact, but they do not activate the nerve fibers naturally. Despite these considerations, both CHEPs and LEPs are considered reliable methods to study nociceptive pathways.
      • Bouhassira D.
      • Attal N.
      Diagnosis and assessment of neuropathic pain: the saga of clinical tools.
      However, there is no clear correlation between LEPs and structural changes such as the intraepidermal nerve fiber density,
      • Truini A.
      • Biasiotta A.
      • Di Stefano G.
      • et al.
      Does the epidermal nerve fibre density measured by skin biopsy in patients with peripheral neuropathies correlate with neuropathic pain?.
      • Devigili G.
      • Tugnoli V.
      • Penza P.
      • et al.
      The diagnostic criteria for small fibre neuropathy: from symptoms to neuropathology.
      indicating that loss of nerve fibers is not necessarily associated with loss of function of remaining nerve fibers. Casanova-Molla et al
      • Casanova-Molla J.
      • Grau-Junyent J.M.
      • Morales M.
      • Valls-Solé J.
      On the relationship between nociceptive evoked potentials and intraepidermal nerve fiber density in painful sensory polyneuropathies.
      reported that in subgroups of 52 patients with small-fiber neuropathy and 40 patients with mixed (small-fiber and large-fiber) neuropathy, both showed in general reasonable correlation between intraepidermal nerve fiber density and the latency and amplitude of LEPs and CHEPs. Punch skin biopsy with a diameter of 2 or 3 mm is a fast and minimally invasive technique with a high diagnostic yield and is today a commonly used procedure in patients suspected of having small-fiber neuropathy.
      • Devigili G.
      • Tugnoli V.
      • Penza P.
      • et al.
      The diagnostic criteria for small fibre neuropathy: from symptoms to neuropathology.
      • Cruccu G.
      • Sommer C.
      • Anand P.
      • et al.
      EFNS guidelines on neuropathic pain assessment: revised 2009.
      • Karlsson P.
      • Porretta-Serapiglia C.
      • Lombardi R.
      • Jensen T.S.
      • Lauria G.
      Dermal innervation in healthy subjects and small fiber neuropathy patients: a stereological reappraisal.
      • Lauria G.
      • Hsieh S.T.
      • Johansson O.
      • et al.
      European Federation of Neurological Societies; Peripheral Nerve Society
      European Federation of Neurological Societies/Peripheral Nerve Society Guideline on the use of skin biopsy in the diagnosis of small fiber neuropathy: report of a joint task force of the European Federation of Neurological Societies and the Peripheral Nerve Society.
      • Lauria G.
      • Merkies I.S.
      • Faber C.G.
      Small fibre neuropathy.
      • Malik R.A.
      Which test for diagnosing early human diabetic neuropathy?.
      Following fixation and cutting, slices are immunostained with protein gene product 9.5 for visualization of the density of nerve fibers crossing from the dermis into the epidermis. Over the past decade, there has been some progress in extracting further quantitative measurements from the skin biopsies, including axonal swellings, nerve fiber length densities, and sweat gland innervation (Karlsson et al, unpublished data, 2014). An advantage of skin biopsies is that they can be repeated over time and allow the clinician to follow the disease course quantitatively, and they may disclose changes in the small nerve fibers, which a normal neurological examination is not capable of. A similar and completely noninvasive technique is confocal microscopy of the cornea in which corneal small nerve fibers are quantified.
      • Malik R.A.
      Which test for diagnosing early human diabetic neuropathy?.
      • Petropoulos I.N.
      • Alam U.
      • Fadavi H.
      • et al.
      Rapid automated diagnosis of diabetic peripheral neuropathy with in vivo corneal confocal microscopy.
      This technique developed by Malik
      • Malik R.A.
      Which test for diagnosing early human diabetic neuropathy?.
      has been shown to be reproducible and sensitive and with a high degree of specificity not only in patients with signs of nerve damage but also in patients without neurophysiological signs of nerve abnormality.
      • Petropoulos I.N.
      • Alam U.
      • Fadavi H.
      • et al.
      Rapid automated diagnosis of diabetic peripheral neuropathy with in vivo corneal confocal microscopy.
      The limitation of these structural nerve fiber measures is that they only demonstrate loss of nerve fibers, not the functionality of the remaining nerve fibers that can be intact, damaged, or overactive.

      Overview of Treatment Goals and Strategies in Neuropathic Pain

      In addition to symptom control, management of patients with neuropathic pain requires periodic reevaluation to rule out other treatable underlying medical conditions, patient education, and reassurance. Education about the natural history of the patient’s underlying neuropathic condition as well as the limitations of currently available pain treatments helps generate appropriate treatment expectations; that is, current therapies are often not curative, and residual pain, even during treatment, is common. Because some patients may respond well to safer, less expensive, and less invasive treatments, a stepwise treatment approach is prudent.
      • Chen H.
      • Lamer T.J.
      • Rho R.H.
      • et al.
      Contemporary management of neuropathic pain for the primary care physician.
      However, in many cases, various challenges and complexities of individual cases may indicate the need for more intensive treatments as well as a multimodal, multidisciplinary pain management strategy. For example, referral to, and concurrent treatment by, an occupational, rehabilitation, or physical therapist may be helpful in cases in which pain interferes substantially with work and other daily activities. Furthermore, early assessment for coexisting depression, anxiety, and/or substance abuse disorders may facilitate early referral to a psychologist, psychiatrist, and/or tertiary care pain management clinic. Responses to initial patient trials of first-line pain treatments (discussed below) should be carefully evaluated and documented to help guide next management steps.

      Drug Therapy for Neuropathic Pain

      Various drug classes with analgesic effects have been compared to placebo in clinical trials involving patients with various neuropathic pain conditions including antidepressants, anticonvulsants, local anesthetic drugs, NMDA receptor antagonists, opioids, cannabinoids, botulinum toxin, topical capsaicin, and other agents.
      • Finnerup N.B.
      • Sindrup S.H.
      • Jensen T.S.
      The evidence for pharmacological treatment of neuropathic pain.
      Several of these drugs were first developed for other indications (eg, depression and epilepsy) and subsequently evaluated in neuropathic pain. Systematic review and meta-analysis of neuropathic pain trials—with careful consideration of both analgesic efficacy and treatment-related adverse effects—and development of recommendations by several societies and associations have led to the current strong recommendations (based on the Grading of Recommendations Assessment, Development, and Evaluation system) for tricyclic antidepressants, gabapentin, pregabalin, and serotonin-norepinephrine reuptake inhibitor (SNRI) antidepressants (first-line therapies); weak recommendations for lidocaine patches, high-concentration capsaicin patches, opioids, botulinum toxin A, and combinations of selected first-line agents; strong recommendation against the use of levetiracetam and mexiletine; and weak recommendations against the use of cannabinoids and valproate.

      Finnerup NB, Attal N, Haroutounian S, et al. Pharmacotherapy for neuropathic pain in adults: a systematic review and meta-analysis [published online ahead of print January 6, 2015]. Lancet Neurol. http://dx.doi.org/10.1016/S1474-4422(14)70251-0.

      Table 2 describes recently recommended prescribing information, and Table 3 describes common adverse effects, precautions, and contraindications for first-line neuropathic pain drugs.
      • Haanpaa M.L.
      • Gourlay G.K.
      • Kent J.L.
      • et al.
      Treatment considerations for patients with neuropathic pain and other medical cornorbidities.
      Given the focus of this review, currently recommended first-line therapies, and also opioids, are reviewed below in further detail.
      Table 2Currently Recommended Neuropathic Pain Drugs
      GRADE = Grading of Recommendations Assessment, Development, and Evaluation.
      From Lancet Neurol,

      Finnerup NB, Attal N, Haroutounian S, et al. Pharmacotherapy for neuropathic pain in adults: a systematic review and meta-analysis [published online ahead of print January 6, 2015]. Lancet Neurol. http://dx.doi.org/10.1016/S1474-4422(14)70251-0.

      with permission.
      DrugTotal daily dose and dose regimenRecommendations
      Strong recommendations for use
       Gapabentin1200-3600 mg, in 3 divided dosesFirst line
       Gabapentin extended release or enacarbil1200-3600 mg, in 2 divided dosesFirst line
       Pregabalin300-600 mg, in 2 divided dosesFirst line
       Serotonin-norepinephrine reuptake inhibitors duloxetine or venlafaxine
      Duloxetine is the most studied, and therefore recommended, of the serotonin-norepinephrine reuptake inhibitors.
      60-120 mg, once a day (duloxetine); 150-225 mg, once a day (venlafaxine extended release)First line
       Tricyclic antidepressants25-150 mg, once a day or in 2 divided dosesFirst line
      Tricyclic antidepressants generally have similar efficacy; tertiary amine tricyclic antidepressants (amitriptyline, imipramine, and clomipramine) are not recommended at doses >75 mg/d in adults aged 65 y and older because of major anticholinergic and sedative adverse effects and potential risk of falls32; an increased risk of sudden cardiac death has been reported with tricyclic antidepressants at doses >100 mg/d.33
      Weak recommendations for use
       Capsaicin 8% patchesOne to 4 patches to the painful area for 30-60 min every 3 moSecond line (peripheral neuropathic pain)
      The long-term safety of repeated applications of high-concentration capsaicin patches in patients has not been clearly established, particularly with respect to the degeneration of epidermal nerve fibers, which might be a cause for concern in progressive neuropathy.
       Lidocaine patchesOne to 3 patches to the region of pain once a day for up to 12 hSecond line (peripheral neuropathic pain)
       Tramadol200-400 mg, in 2 (tramadol extended release) or 3 divided dosesSecond line
       Botulinum toxin A (subcutaneously)50-200 units to the painful area every 3 moThird line; specialist use (peripheral neuropathic pain)
       Strong opioidsIndividual titrationThird line
      Sustained-release oxycodone and morphine have been the most studied opioids (maximum doses of 120 and 240 mg/d, respectively, in clinical trials); long-term opioid use might be associated with abuse, particularly at high doses, cognitive impairment, and endocrine and immunological changes.34,35
      a GRADE = Grading of Recommendations Assessment, Development, and Evaluation.
      b Duloxetine is the most studied, and therefore recommended, of the serotonin-norepinephrine reuptake inhibitors.
      c Tricyclic antidepressants generally have similar efficacy; tertiary amine tricyclic antidepressants (amitriptyline, imipramine, and clomipramine) are not recommended at doses >75 mg/d in adults aged 65 y and older because of major anticholinergic and sedative adverse effects and potential risk of falls
      • Backonja M.M.
      • Galer B.S.
      Pain assessment and evaluation of patients who have neuropathic pain.
      ; an increased risk of sudden cardiac death has been reported with tricyclic antidepressants at doses >100 mg/d.
      • Hansson P.
      • Haanpää M.
      Diagnostic work-up of neuropathic pain: computing, using questionnaires or examining the patient?.
      d The long-term safety of repeated applications of high-concentration capsaicin patches in patients has not been clearly established, particularly with respect to the degeneration of epidermal nerve fibers, which might be a cause for concern in progressive neuropathy.
      e Sustained-release oxycodone and morphine have been the most studied opioids (maximum doses of 120 and 240 mg/d, respectively, in clinical trials); long-term opioid use might be associated with abuse, particularly at high doses, cognitive impairment, and endocrine and immunological changes.
      • Baron R.
      • Tölle T.R.
      Assessment and diagnosis of neuropathic pain.
      • Feldman E.L.
      • Stevens M.J.
      • Thomas P.K.
      • Brown M.B.
      • Canal N.
      • Greene D.A.
      A practical two-step quantitative clinical and electrophysiological assessment for the diagnosis and staging of diabetic neuropathy.
      Table 3Common Adverse Effects, Precautions, and Contraindications for First-Line Neuropathic Pain Drugs
      ECG = electrocardiogram; MAO = monoamine oxidase inhibitor; SNRI = serotonin-norepinephrine reuptake inhibitor; SSRI = selective serotonin reuptake inhibitor; TCA = tricyclic antidepressant.
      ,
      Adapted from Mayo Clin Proc72 with permission.
      MedicationMajor adverse effectsPrecautionsContraindicationsComments and recommendations
      TCAs
       Nortriptyline and desipramine (amitriptyline, imipramine)Cardiac conduction block, sedation, confusion, anticholinergic effects (dry mouth, constipation, urinary retention, blurred vision), orthotratic hypotension, weight gainUse with caution in patients with history of seizures, prostatic hypertrophy, urinary retention, chronic constipation, narrow-angle glaucoma, increased intraocular pressure, or suicidal ideation; use with caution in patients receiving concomitant SSRI, SNRI, or tramadol treatmentRecovery phase after myocardial infarction, arrhythmias (particularly heart block of any degree), concomitant use of MAO inhibitors, porphyriaECG screening recommended in adults older than 40 y; heart rate and blood pressure follow-up (both supine and standing measurements) recommended with dose escalation; ECG and blood concentration follow-up recommended at doses of >150 mg/d: follow-up of weight recommended, especially in diabetic patients
      SNRIs
       DuloxetineNausea, loss of appetite, constipation, sedation, dry mouth, hyperhidrosis, anxietyUse with caution in patients with history of mania, seizures, or bleeding tendency or those taking anticoagulants; use with caution in patients taking concomitant SSRI or tramadol treatmentConcomitant use of MAO inhibitors: uncontrolled hypertensionBlood pressure follow-up recommended in patients with known hypertension and/or other cardiac disease, especially during the first month of treatment. Smokers have almost 50% lower plasma concentrations of duloxetine than do nonsmokers
       VenlafaxineNausea, loss of appetite, hypertension, sedation, insomnia, anxiety, dry mouth, hyperhidrosis, constipationUse with caution in patients with hypertension; use with caution in patients taking concomitant SSRI or tramadol treatmentConcomitant use of MAO inhibitorsBlood pressure follow-up recommended
      Gabapentinoids
       GabapentinSedation, dizziness, weight gain, edema, blurred visionSimple antacids reduce bioavailabilityFollow-up of weight recommended, especially in diabetic patients
       PregabalinSedation, dizziness, weight gain, edema, blurred visionFollow-up of weight recommended, especially in diabetic patients
      a ECG = electrocardiogram; MAO = monoamine oxidase inhibitor; SNRI = serotonin-norepinephrine reuptake inhibitor; SSRI = selective serotonin reuptake inhibitor; TCA = tricyclic antidepressant.
      b Adapted from Mayo Clin Proc
      • Haanpaa M.L.
      • Gourlay G.K.
      • Kent J.L.
      • et al.
      Treatment considerations for patients with neuropathic pain and other medical cornorbidities.
      with permission.

      Antidepressants

      Various pharmaceutical agents evaluated for the treatment of depression, and thus referred to as antidepressant drugs, have been classified according to their chemical structure and/or pharmacological mechanisms and include the older tricyclic antidepressants (TCAs; eg, amitriptyline, nortriptyline, and imipramine), selective serotonin reuptake inhibitors (eg, fluoxetine), SNRIs (eg, venlafaxine and duloxetine), monoamine oxidase inhibitors (eg, moclobemide), and others.
      • Baldessarini R.J.
      Drugs and the treatment of psychiatric disorders: depression and anxiety disorders.
      Antidepressants reduce chronic pain in both depressed and nondepressed patients, suggesting independent analgesic mechanisms; however, additional benefits of these drugs may include treatment of comorbid depression and pain-related sleep interference.
      • Watson C.P.N.
      • Gilron I.
      • Pollock B.
      • Lipman A.G.
      • Smith M.
      Antidepressant analgesics.
      Putative analgesic mechanisms of antidepressant drugs include increased supraspinal availability of norepinephrine (and enhancement of descending inhibitory bulbospinal control), activation of endogenous μ- and δ-opioid receptors, sodium channel blockade, and NMDA receptor inhibition.
      • Micó J.A.
      • Ardid D.
      • Berrocoso E.
      • Eschalier A.
      Antidepressants and pain.
      More than a dozen randomized controlled trials (RCTs) of TCAs demonstrate efficacy in painful diabetic neuropathy,
      • Max M.B.
      • Lynch S.A.
      • Muir J.
      • Shoaf S.E.
      • Smoller B.
      • Dubner R.
      Effects of desipramine, amitriptyline, and fluoxetine on pain in diabetic neuropathy.
      • Sindrup S.H.
      • Ejlertsen B.
      • Frøland A.
      • Sindrup E.H.
      • Brøsen K.
      • Gram L.F.
      Imipramine treatment in diabetic neuropathy: relief of subjective symptoms without changes in peripheral and autonomic nerve function.
      postherpetic neuralgia,
      • Watson C.P.
      • Evans R.J.
      • Reed K.
      • Merskey H.
      • Goldsmith L.
      • Warsh J.
      Amitriptyline versus placebo in postherpetic neuralgia.
      • Raja S.N.
      • Haythornthwaite J.A.
      • Pappagallo M.
      • et al.
      Opioids versus antidepressants in postherpetic neuralgia: a randomized, placebo-controlled trial.
      and central poststroke pain.
      • Leijon G.
      • Boivie J.
      Central post-stroke pain: a controlled trial of amitriptyline and carbamazepine.
      • Vranken J.H.
      • Hollmann M.W.
      • van der Vegt M.H.
      • et al.
      Duloxetine in patients with central neuropathic pain caused by spinal cord injury or stroke: a randomized, double-blind, placebo-controlled trial.
      Meta-analyses of these trials resulted in estimated NNTs of 1.7 to 3.2 for imipramine, 1.9 to 4.5 for desipramine, and 2.5 to 4.2 for amitriptyline.

      Finnerup NB, Attal N, Haroutounian S, et al. Pharmacotherapy for neuropathic pain in adults: a systematic review and meta-analysis [published online ahead of print January 6, 2015]. Lancet Neurol. http://dx.doi.org/10.1016/S1474-4422(14)70251-0.

      • Saarto T.
      • Wiffen P.J.
      Antidepressants for neuropathic pain.
      • Lunn M.P.
      • Hughes R.A.
      • Wiffen P.J.
      Duloxetine for treating painful neuropathy or chronic pain.
      Although efficacy in more than 1 peripheral neuropathic pain condition (eg, diabetic neuropathy and postherpetic neuralgia) may provide evidence to consider a drug efficacious in all peripheral neuropathic pain conditions,
      • Dworkin R.H.
      • Turk D.C.
      • Basch E.
      • et al.
      Considerations for extrapolating evidence of acute and chronic pain analgesic efficacy.
      it should be noted that several high-quality RCTs failed to demonstrate the efficacy of TCAs in HIV-related neuropathy
      • Kieburtz K.
      • Simpson D.
      • Yiannoutsos C.
      • et al.
      A randomized trial of amitriptyline and mexiletine for painful neuropathy in HIV infection. AIDS Clinical Trial Group 242 Protocol Team.
      • Shlay J.C.
      • Chaloner K.
      • Max M.B.
      • et al.
      Acupuncture and amitriptyline for pain due to HIV-related peripheral neuropathy: a randomized controlled trial. Terry Beirn Community Programs for Clinical Research on AIDS.
      or in lumbar radiculopathy.
      • Khoromi S.
      • Cui L.
      • Nackers L.
      • Max M.B.
      Morphine, nortriptyline and their combination vs. placebo in patients with chronic lumbar root pain.
      There are fewer trials of selective serotonin reuptake inhibitors in neuropathic pain; however, an estimated NNT
      • Finnerup N.B.
      • Sindrup S.H.
      • Jensen T.S.
      The evidence for pharmacological treatment of neuropathic pain.
      of 6.8 and at least 1 head-to-head comparative trial suggest inferior efficacy compared with that of TCAs.
      • Sindrup S.H.
      • Gram L.F.
      • Brøsen K.
      • Eshøj O.
      • Mogensen E.F.
      The selective serotonin reuptake inhibitor paroxetine is effective in the treatment of diabetic neuropathy symptoms.
      The SNRIs venlafaxine and duloxetine have been studied more recently, with NNTs estimated in the range of 3.4 to 14.
      • Finnerup N.B.
      • Sindrup S.H.
      • Jensen T.S.
      The evidence for pharmacological treatment of neuropathic pain.
      • Lunn M.P.
      • Hughes R.A.
      • Wiffen P.J.
      Duloxetine for treating painful neuropathy or chronic pain.

      Anticonvulsants

      Although several anticonvulsants have been studied in neuropathic pain, only the α-2-δ ligand calcium channel antagonists, gabapentin and pregabalin, are currently recommended as first-line treatments.

      Finnerup NB, Attal N, Haroutounian S, et al. Pharmacotherapy for neuropathic pain in adults: a systematic review and meta-analysis [published online ahead of print January 6, 2015]. Lancet Neurol. http://dx.doi.org/10.1016/S1474-4422(14)70251-0.

      Other anticonvulsants (eg, carbamazepine and oxcarbazepine) are often used as first-line therapy for trigeminal neuralgia, which is discussed below. Several RCTs of gabapentin have been conducted in patients with diabetic neuropathy, postherpetic neuralgia, and other neuropathic conditions. Older meta-analyses estimated the efficacy of gabapentin with NNTs of 4.3 to 6.4
      • Finnerup N.B.
      • Sindrup S.H.
      • Jensen T.S.
      The evidence for pharmacological treatment of neuropathic pain.
      • Wiffen P.
      • Collins S.
      • McQuay H.
      • Carroll D.
      • Jadad A.
      • Moore A.
      Anticonvulsant drugs for acute and chronic pain.
      ; however, a recently updated Cochrane meta-analysis of gabapentin (for daily doses of 1200 mg or more) involving neuropathic pain as well as fibromyalgia provided NNTs of 9.6 for the patient global impression of change outcome of “very much improved” and 6.1 for “much or very much improved.”
      • Moore R.A.
      • Wiffen P.J.
      • Derry S.
      • McQuay H.J.
      Gabapentin for chronic neuropathic pain and fibromyalgia in adults.
      The newer α-2-δ ligand anticonvulsant pregabalin was studied in many large trials in diabetic neuropathy, postherpetic neuralgia, and central neuropathic pain. A broad-ranging systematic review of most of these trials
      • Moore R.A.
      • Straube S.
      • Wiffen P.J.
      • Derry S.
      • McQuay H.J.
      Pregabalin for acute and chronic pain in adults.
      reported varying NNTs depending on daily doses ranging from 300 to 600 mg/d such that higher doses were associated with lower NNTs (ie, greater efficacy). The NNTs for pregabalin varied from 3.9 to 5.3 for postherpetic neuralgia, from 5 to 11 for diabetic neuropathy, and 5.6 for central neuropathic pain from 2 RCTs involving doses of 600 mg/d.
      • Moore R.A.
      • Straube S.
      • Wiffen P.J.
      • Derry S.
      • McQuay H.J.
      Pregabalin for acute and chronic pain in adults.

      Opioids

      Opioids including morphine, oxycodone, tramadol, and several other agents have been evaluated in more than 30 RCTs of patients with neuropathic pain including peripheral conditions such as postherpetic neuralgia and diabetic neuropathy and central conditions such as poststroke pain.
      • McNicol E.D.
      • Midbari A.
      • Eisenberg E.
      Opioids for neuropathic pain.
      Depending on different trial inclusion criteria and outcomes of interest (eg, 30% vs 50% pain reduction), recent meta-analyses have estimated the analgesic efficacy of opioids in neuropathic pain (expressed as NNTs) as ranging between 4.0 NNTs
      • McNicol E.D.
      • Midbari A.
      • Eisenberg E.
      Opioids for neuropathic pain.
      and 4.7.

      Finnerup NB, Attal N, Haroutounian S, et al. Pharmacotherapy for neuropathic pain in adults: a systematic review and meta-analysis [published online ahead of print January 6, 2015]. Lancet Neurol. http://dx.doi.org/10.1016/S1474-4422(14)70251-0.

      The degree of certainty of these efficacy estimates has come into question given potential risks of bias from included trials related to small trial size, short treatment duration, and study dropouts.
      • McNicol E.D.
      • Midbari A.
      • Eisenberg E.
      Opioids for neuropathic pain.
      Common, but not life-threatening, opioid-related adverse effects reported in these trials included constipation, sedation, nausea, and vomiting, and these were frequent causes of trial discontinuation.
      • McNicol E.D.
      • Midbari A.
      • Eisenberg E.
      Opioids for neuropathic pain.
      Recent consensus reports have recommended opioids as either second-line
      • Moulin D.
      • Boulanger A.
      • Clark A.J.
      • et al.
      Pharmacological management of chronic neuropathic pain: revised consensus statement from the Canadian Pain Society.
      or third-line

      Finnerup NB, Attal N, Haroutounian S, et al. Pharmacotherapy for neuropathic pain in adults: a systematic review and meta-analysis [published online ahead of print January 6, 2015]. Lancet Neurol. http://dx.doi.org/10.1016/S1474-4422(14)70251-0.

      therapy for neuropathic pain not only because of the above efficacy and tolerability results but also because of well-recognized concerns regarding opioid abuse/misuse, diversion, and addiction potential.
      • Furlan A.D.
      • Reardon R.
      • Weppler C.
      Opioids for chronic noncancer pain: a new Canadian practice guideline.
      • Nuckols T.K.
      • Anderson L.
      • Popescu I.
      • et al.
      Opioid prescribing: a systematic review and critical appraisal of guidelines for chronic pain.

      Interventional Management of Neuropathic Pain

      Given that our treatment-related focus is on pharmacological therapy, an in-depth review of interventional management is beyond the scope of this review. However, we provide some brief comments here in context of other treatment modalities. Patients with neuropathic pain often do not respond adequately to pharmacologic treatments used alone or in combination with nonpharmacologic treatments and their pain is therefore called refractory.
      • Hansson P.T.
      • Attal N.
      • Baron R.
      • Cruccu G.
      Toward a definition of pharmacoresistant neuropathic pain.
      Before patients continue endless pharmacological rotation that does not produce the desired pain relief or induces intolerable adverse effects, interventional strategies should be considered. Techniques of interventional pain management include neural blockade, spinal cord stimulation, intrathecal medication, and neurosurgical interventions. A recent systematic review assessed the effect of interventional treatments in many neuropathic pain syndromes, that is, herpes zoster and postherpetic neuralgia, painful diabetic and other peripheral neuropathies, spinal cord injury neuropathic pain and central poststroke pain, radiculopathy and failed back surgery syndrome, complex regional pain syndrome (CRPS), and trigeminal neuralgia and trigeminal neuropathy.
      • Dworkin R.H.
      • O’Connor A.B.
      • Kent J.
      • et al.
      International Association for the Study of Pain Neuropathic Pain Special Interest Group
      Interventional management of neuropathic pain: NeuPSIG recommendations.
      It was concluded that evidence for the effectiveness of interventional management of neuropathic pain is limited. No more than 40% to 60% of the patients obtain lasting, even though partial, pain relief. In summary, weak recommendations for chronic neuropathic pain were formulated—spinal cord stimulation for chronic radiculopathy (failed back surgery syndrome) and spinal cord stimulation for CRPS type 1. It is important to emphasize that rigorous evaluation of interventional, as well as surgical (see Trigeminal Neuralgia section below), pain treatments is fraught with several risks of bias related to ethical and practical challenges to treatment blinding and the use of optimal sham, or other, control interventions; study patient dropouts due to severity and intractability of treated patients; and cost/logistics of follow-up and study duration. Furthermore, it should be recognized that relative lack of evidence of efficacy does not necessarily suggest evidence of lack of efficacy and so, rational interventional management of patients with chronic neuropathic pain should be considered an integral component of a more comprehensive approach that also includes pharmacologic and nonpharmacologic, noninterventional treatments.
      • Dworkin R.H.
      • O’Connor A.B.
      • Kent J.
      • et al.
      International Association for the Study of Pain Neuropathic Pain Special Interest Group
      Interventional management of neuropathic pain: NeuPSIG recommendations.

      Special Conditions

      Central Pain

      Central pains are conditions caused by a lesion or disease affecting the somatosensory system within the CNS.
      • Jensen T.S.
      • Baron R.
      • Haanpää M.
      • et al.
      A new definition of neuropathic pain.
      The diseases or lesions giving rise to central neuropathic pain are multiple and include stroke, multiple sclerosis, a syrinx within the cord or the brain stem, and an injury to the spinal cord. Even pains experienced by patients with Parkinson disease have been suggested to represent a central neuropathic pain state. Central pains are not rare. For example, central poststroke pain, formerly known as thalamic pain, occurs in 7% to 8% of the patients with stroke.
      • Andersen G.
      • Vestergaard K.
      • Ingeman-Nielsen M.
      • Jensen T.S.
      Incidence of central post-stroke pain.
      • Klit H.
      • Finnerup N.B.
      • Andersen G.
      • Jensen T.S.
      Central poststroke pain: a population-based study.
      In spinal cord injury, nociceptive and neuropathic pain is common. A recent prospective study found that 60% of the patients with spinal cord injury neuropathic pain have pain because of the CNS lesion.
      • Finnerup N.B.
      • Norrbrink C.
      • Trok K.
      • et al.
      Phenotypes and predictors of pain following traumatic spinal cord injury: a prospective study.
      Despite their etiological differences, these conditions share certain clinical characteristics: (1) partial or complete loss of spinothalamic functions (temperatures and pinprick sensation) and (2) the development of hypersensitivity in those body parts that have lost their normal somatosensory information because of a CNS lesion.
      • Jensen T.S.
      • Baron R.
      Translation of symptoms and signs into mechanisms in neuropathic pain.
      Corresponding to these cardinal phenomena, patients have positive and negative signs and symptoms. The negative signs and symptoms reflect the damage to the CNS, resulting in partial or complete sensory loss and numbness in the distribution of the nervous structure that has been damaged. The positive phenomena such as allodynia, hyperalgesia, and hyperpathia are all manifestations of hyperexcitability in the nervous system.
      • Jensen T.S.
      • Finnerup N.B.
      Allodynia and hyperalgesia in neuropathic pain: clinical manifestations and mechanisms.
      Central neuropathic pain is characterized by spontaneous ongoing pain and various types of evoked pain, often occurring in different combinations. Burning, pricking, lancinating, icy, tearing, cutting, and squeezing types of pain are often described, but there is no pathognomonic set of descriptors that permit a diagnosis of central pain. Importantly, in pain associated with central lesions, there is often a combination of factors that can contribute to the pain. For example, in pain after stroke, there may, in addition to the classical central poststroke pain with its characteristic sensory manifestations, be headache, shoulder pain, musculoskeletal pain, and painful spasticity, which adds to the complexity of the clinical picture of central pain conditions.
      • Klit H.
      • Finnerup N.B.
      • Jensen T.S.
      Central post-stroke pain: clinical characteristics, pathophysiology, and management.

      Complex regional pain syndrome

      Complex regional pain syndrome is a condition that usually develops after minor trauma or injury to a limb.
      • Marinus J.
      • Moseley G.L.
      • Birklein F.
      • et al.
      Clinical features and pathophysiology of complex regional pain syndrome.
      It is per tradition divided into 2 types: CRPS type 1, with no signs of nerve damage, and CRPS type 2, with evidence of nerve lesion. Per definition, CRPS type 1 does not fulfill the existing criteria for neuropathic pain.
      • Jensen T.S.
      • Baron R.
      • Haanpää M.
      • et al.
      A new definition of neuropathic pain.
      The key element in CRPS is the presence of sensory, autonomic, and motor abnormalities.
      • Marinus J.
      • Moseley G.L.
      • Birklein F.
      • et al.
      Clinical features and pathophysiology of complex regional pain syndrome.
      • Gierthmühlen J.
      • Binder A.
      • Baron R.
      Mechanism-based treatment in complex regional pain syndromes.
      Less-specific symptoms of CRPS include abnormal posture, sometimes even contractures, neglect-like phenomena, and cognitive problems.
      • Marinus J.
      • Moseley G.L.
      • Birklein F.
      • et al.
      Clinical features and pathophysiology of complex regional pain syndrome.
      • Gierthmühlen J.
      • Binder A.
      • Baron R.
      Mechanism-based treatment in complex regional pain syndromes.
      The presence of these signs and symptoms varies between patients, and can change over time in a given individual patient. The distribution of pain and signs is important and is characterized by a distal distribution of symptoms and signs that can spread proximally in a glove stocking-like fashion, somewhat similar to what is seen in distal length-dependent neuropathies. In the acute phase, the injured limb is usually very painful, warm red, and edematous. In later stages, the affected limb continues to be painful, but is now colder with pale atrophic skin and often also has motor phenomena such as dystonia and tremor.

      Trigeminal Neuralgia

      Trigeminal neuralgia, a condition that is clinically distinct from other neuropathic pain conditions, responds differently to pharmacological therapy.
      • Zakrzewska J.M.
      • Linskey M.E.
      Trigeminal neuralgia.
      Meta-analysis of multiple positive RCTs of carbamazepine in trigeminal neuralgia, and the better-tolerated oxcarbazepine, resulted in estimated NNTs of 1.4 to 2.8.
      • Finnerup N.B.
      • Sindrup S.H.
      • Jensen T.S.
      The evidence for pharmacological treatment of neuropathic pain.
      • Wiffen P.
      • Collins S.
      • McQuay H.
      • Carroll D.
      • Jadad A.
      • Moore A.
      Anticonvulsant drugs for acute and chronic pain.
      In drug-resistant cases, interventions such as gamma-knife nerve root destruction and surgical treatments such as microvascular decompression are often used, with a limited evidence base and variable results.
      • Zakrzewska J.M.
      • Linskey M.E.
      Trigeminal neuralgia.

      Conclusion

      A diverse array of clinical conditions cause neuropathic pain in both the peripheral and central nervous systems. Several features of clinical presentation (eg, development of pain after nervous system injury/disease, certain pain quality descriptors, allodynia, and sensory loss) and treatment response (eg, to anticonvulsant drugs) indicate that neuropathic pain is fundamentally different from inflammatory or nociceptive conditions such as osteoarthritis. Given the association between neuropathic pain and other clinical conditions, patients with suspected neuropathic pain require a thorough history and physical examination and, in many cases, special investigations to make a diagnosis and identify etiology as well as important comorbidities requiring intervention. A stepwise, multidisciplinary approach to neuropathic pain evaluation and treatment helps to promote comprehensive care and effective treatment with minimal risks, adverse effects, and costs. Currently, the best evidence of treatment safety and efficacy suggests first-line therapy with antidepressant and anticonvulsant drugs. However, even with these agents, efficacy is modest, with many patients failing to enjoy meaningful benefit. With the continued expansion of knowledge about the underlying causes and mechanisms of neuropathic pain, development of new and improved treatment is expected.

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