NEUROPATHIC PAIN (NP) HAS A COMPLEX, severe, and persistent character with varying intensity and duration. It may accompany many diseases but can also be related to an injury. This chapter provides an overview of NP, including the definition, history, epidemiology, and pathophysiology. Also, clinical manifestations, assessment methods, screening tests, and diagnostic tools are reviewed. The classification of NP syndromes with respect to their anatomic localization (peripheral nervous system, central nervous system, and mixed) will be investigated in detail, in addition to pharmacologic and onpharmacologic treatment options. First-line medication choice in the management of NP includes tricyclic antidepressants (TCAs), serotonin-norepinephrine reuptake inhibitors (SNRIs), anticonvulsants, opioids, cannabinoids, and topical agents.¹ Physical therapy modalities such as superficial and deep heat applications, traction, laser, transcutaneous electrical nerve stimulation (TENS), and diadynamic and interferential electrical currents are more helpful when combined with therapeutic exercises. Psychotherapy, cognitive-behavioral therapy (CBT), and relaxation therapy are recommended in the management of NP. Noninvasive (repetitive transcranial magnetic stimulation [rTMS] and transcranial direct current stimulation [tDCS]) and invasive neuromodulation techniques (deep brain stimulation [DBS], motor cortex stimulation [MCS], and spinal cord stimulation [SCS]) are also focused on the treatment of NP.

The history of pain originates from the beginning of humanity. Pain has evolutionary importance and can be experienced by anyone in their lifetime because it is the most primitive warning sign of external and internal threats. Its presentation and expression can vary among different cultures, ethnics, ages, and genders. NP has been identified since 3000 BC, and was initially formally defined and characterized in the nineteenth century. In 1773, John Fothergill described trigeminal neuralgia, which is the first definition of a subtype of NP in the literature.² Silas Weir Mitchell observed that the soldiers who had gunshot wounds during the American Civil War had permanent burning pain and defined “causalgia” in 1864.³ Paget described local paralysis and peripheral NP during the same period. The term “central pain” was first used by Edinger in 1891.⁴ Déjerine and Roussy described “Le syndrome thalamiqué” as severe, persistent, paroxysmal, often intolerable pain on the hemiplegic side unresponsive to all analgesic treatments for stroke patients in Paris in 1906.⁵ Several medications and methods emerged for the treatment of NP in the early 1900s. Bonica, the father of modern pain medicine, emphasized the importance of an multimodality and multidisciplinary approach in pain management.⁶

Previously, the definition of NP was “pain initiated or caused by a primary lesion, dysfunction, or transitory perturbation of the peripheral or central nervous system,” which has several missing points in order to address pathological findings.⁷ The definition for NP has been updated recently by the International Association for Study of Pain (IASP) as “pain arising as a direct consequence of a lesion or disease affecting the somatosensory system.”⁸ The two major advantages of the new definition are (1) it specifies the general term “dysfunction” as “lesion” or “disease” and (2) it addresses the anatomic location of the pathology to the somatosensory system. In the future, this definition may need to be revised when we better understand the nature of NP.

Accurate information about the incidence and prevalence of NP helps clinicians to estimate the burden of NP in the general population. It is not easy to design population-based epidemiological studies according to the definition of NP because the “lesion” or “disease” concept cannot clearly cover the different clinical pictures of NP. According to recent literature, the best estimate of the prevalence of NP ranges between 6.9% and 10%.⁹ Some authors have found a prevalence of “pain of predominantly neuropathic origin” of 8.2% in the United Kingdom,¹⁰ and the others have reported a prevalence of “chronic pain with neuropathic features” of 6.9% in France,¹¹ and another group reported 9.8% prevalence of NP in the United States.¹² In a recent study conducted with chronic NP patients, 17% of the patients described their pain as “worse than death” in health-related quality-of-life scores.¹³ Also, the prevalence of chronic widespread pain has been found to be 14.7%; of those afflicted with chronic widespread pain, 15.9% of them have demonstrated the typical features of NP.¹⁴ In a similar study, the diagnosis of fibromyalgia syndrome (FMS) has been established in 27.3% of patients with chronic low back pain.¹⁵ It has also been suggested that neuropathic features are more prevalent in patients with chronic pain,¹⁶ diabetes,^17,18 and herpes zoster¹⁸ when compared with the general population.

Current knowledge regarding the pathophysiology of NP mostly depends on preclinical studies. The animal models include transection of the sciatic nerve,¹⁹ chronic constriction of the sciatic nerve, (CCI)²⁰ partial sciatic nerve ligation (PSNL),²¹ spinal nerve ligation (SNL),²² spared nerve injury (SNI),²³ and chronic compression of the dorsal root ganglia (DRG).²⁴ NP is also induced by infection, inflammation, or demyelination of the sciatic nerve,²⁵ as well as by chemotherapy agents (e.g., paclitaxel)²⁶ and toxins (e.g., 2′-3′-dideoxycytidine).²⁷ However, translation from animal behavior to human pain sensation has several difficulties. The genetic component of NP should also be taken into consideration. Based on a twin study, it has been suggested that heritability has an important role in the pathophysiology of NP.¹⁴ Also, it has been shown in inbred mouse models that NP can be accompanied by 50% genetic involvement.²⁸ In recent years, pain research in humans with quantitative sensory testing, questionnaires, skin biopsies, functional imaging methods, and even experimental human pain models has provided further insights into clinically important pain mechanisms (Fig. 40–1).

When a tissue is injured, the painful stimulus activates Aδ mechanothermal and C polymodal nociceptors.²⁹ The painful stimulus is carried to the substantia gelatinosa via Aδ and unmyelinated C fibers. Tissue injury and neurogenic inflammation triggered by nociceptive stimulus cause secretion of some substances. Macrophages as well as other types of immune cells (i.e., neutrophils, T cells) infiltrate to the damaged area,^30,31 and proinflammatory cytokines (i.e., interleukins, tumor necrosis factor-α), inflammatory substances (i.e., bradykinin, prostaglandins, and other derivatives of arachidonic acid), neurotransmitters (i.e., excitatory amino acids, neurokinins, serotonin, noradrenalin, histamine), growth factors (i.e., nerve growth factor),³² and lipid metabolites like lysophosphatidic acid (LPA)³³ play a role in the development of NP.³⁴ The secretion of these molecules in primary afferent neurons are activated due to spontaneous ectopic discharges and hyperexcitability of primary afferent nociceptors. This process results in “peripheral sensitization.” Another factor of peripheral sensitization of nociceptive fibers includes transient receptor potential vanilloid 1 (TRPV1), which is a pivotal member of the TRP family of nonspecific cation channels.³⁵ It is activated by heat, strong acids,³⁶ and capsaicin (TRPV1 agonist), and its activation evokes a burning pain that is highly expressed in Aδ and C fibers. Recently, there has been emerging evidence for the possible ameliorative effect of TRPV1 antagonist on chronic NP states.³⁷ However, further clinical trials are needed to implement these compounds as potential therapies. Pain messages are modulated via intermediate neurons in the dorsal horn with the secretion of the peptides, and the signals cross to the other side and travel to the brain via the spinothalamic tract. When pain impulses reach the thalamic nuclei, pain perception is influenced by signals from the somatosensory cortex, limbic system, and prefrontal cortex. In higher centers of the brain, pain is interpreted and a behavioral response is developed (Fig. 40–1).

When the healing process does not get completed, central plasticity develops over time.³⁸ Low-threshold mechanoreceptors (Aβ fibers) are also activated. This activation of Aβ fibers leads to “central sensitization,” which is characterized by prolonged but reversible increase in the excitability and synaptic efficacy of neurons in the spinal cord, brainstem, and brain. The hyperexcitability of dorsal horn neurons is also controlled by spinal microglias.³⁹ Microglias and astrocytes also release proinflammatory cytokines and growth factors, and increase glutamate concentrations and chemokines (i.e., fractalkine [CX3CL1] and monocyte chemotactic protein 1 [MCP-1]), which modulate the pain process.⁴⁰ CX3CL1 is the main modulator of neural-microglial signaling, and MCP-1 plays a crucial role in central sensitization via increased activity of N-methyl-D-aspartate receptor (NMDA) receptors and spinal cord glial cells. Besides microglial pathology, glutamate receptors also play an essential role in the central sensitization process. Disinhibition caused by the loss of inhibitory GABAergic interneurons of the spinal cord also contributes to hyperalgesia.^41,42 The activity of the dorsal horn neurons projecting into central structures plays a pivotal role in pain perception. Descending inhibitory serotonergic, noradrenergic, and dopaminergic pathways originate from the periaqueductal gray matter, locus coeruleus, raphe nuclei, and rostral ventral medulla. At the spinal dorsal horn GABAergic and glycinergic synapses exert inhibitory effects. Inhibitory synaptic transmission by gamma-aminobutyric acid (GABA and glycine has been shown to drop in chronic NP.⁴³ Consequently, these changes account for a disinhibition of nociceptive input and increase in pain sensitivity. Several mechanisms are responsible for NP in the same patient, and these mechanisms can also lead to the same symptoms in different patients due to the complexity of pain. In response to tissue damage, chemical mediators are released and can sensitize or directly affect nociceptors (Fig. 40–2). The understanding of NP mechanisms has led us to develop new pain treatment approaches such as neuromodulation techniques.

An evaluation of clinical and family history and environmental and personal risk factors is critical in the diagnosis of NP.⁴⁴ Whereas increasing age, increased body mass index (BMI), female gender, and smoking are identified risk factors for NP, high socioeconomic status correlates negatively.¹⁴

Characteristics of Pain and Abnormal Sensations

Neuropathic pain usually presents with allodynia, hyperalgesia, and burning and/or shooting pain with unusual tingling, crawling, or electrical sensations (dysesthesia). Location, intensity, character of pain, and exacerbating and alleviating factors should all be addressed. Touch, pinprick, pressure, cold, heat, vibration, and temporal summation are the standardized assessment components of NP and should be evaluated bilaterally.^44–46 The outcome is graded as decreased, normal, or increased. Aβ fibers are assessed for touch with fingers, a piece of cotton wool, or soft brush and for vibration with a tuning fork. Aδ fibers are also evaluated for pinprick, for sharp pain with wooden cocktail sticks, and for cold with cold objects (20°C). The warm objects (40°C) are used in the assessment of unmyelinated C fibers.⁴⁷

Positive Symptoms and Signs

Stimulus-Independent Pain and Abnormal Sensations (Spontaneous Sensations or Pain)

Stimulus-independent pain can be superficial or deep. Superficial pain is defined as a painful ongoing sensation, often a burning pain in the skin.⁴⁸ Deep pain presents with lancinating pain in articular/muscular nociceptors. This type of pain can also be paroxysmal, which manifests with shooting electrical attacks for seconds. Sometimes dysesthesia could also be an accompanying unpleasant abnormal sensation. Paresthesia is another nonpainful ongoing sensation (skin crawling sensation, tingling) that is seen in NP. (See Table 40–1.)

Stimulus-Evoked Pain and Abnormal Sensations

Allodynia: Allodynia is elicited by non-noxious stimulus (clothing, air movement, touch), and it presents with sharp, burning superficial pain in the primary affected zone. It can spread beyond into unaffected skin areas (secondary zone). In particular, tactile allodynia is a pivotal symptom of NP.⁴⁹ Touch assessment can be performed by gently applying cotton wool, a painter’s brush, or gauze to the skin; deep pain assessment is made by applying gentle pressure on muscles and joints. In mechanical dynamic allodynia, pain arises from normally nonpainful slight moving stimuli on the skin, and in mechanical static allodynia, slight pressure stimuli can evoke a painful response.⁵⁰ Cold and heat allodynia can be assessed by measuring the response to a nonpainful thermal stimulus (e.g., metal objects kept at 20°C and 40°C).

Hyperalgesia: Hyperalgesia is the exaggerated pain response to a mildly noxious stimulus. Mechanical hyperalgesia can be examined with sharp pinprick stimuli. Mechanical static hyperalgesia (pain caused by normally nonpainful gentle static pressure stimuli on skin) presents with dull pain in the area of the sensitized primary zone when manual gentle mechanical pressure is applied to the skin. Mechanical punctate, pinprick hyperalgesia (pain caused by normally stinging but nonpainful stimuli) is typical with sharp superficial pain in the primary zone but spreads beyond into the secondary zone when the skin is pricked with a safety pin, sharp stick, or monofilaments. Cold hyperalgesia (pain caused by normally nonpainful cold stimuli) manifests with painful, often burning, temperature sensation in the area of the primary zone when the skin is touched with objects at 20°C (metal roller, glass with water, coolants such as acetone) and objects at skin temperature as a control. Heat hyperalgesia (pain caused by normally nonpainful heat stimuli) presents as a painful burning temperature sensation in the primary zone when the skin is touched with objects at 40°C (metal roller, glass with water) for the examination and with objects at skin temperature for control. Mechanical deep somatic hyperalgesia (pain caused by normally nonpainful pressure on deep somatic tissues) presents with deep pain when manual light pressure is applied at the joints or muscles.

Temporal summation: This type of pain presents with an increasing pain sensation (wind-up–like pain) from repetitive application of a single noxious stimuli. For example, when the skin is pricked with a safety pin at intervals of <3 seconds for 30 seconds, it manifests as sharp superficial pain of increasing intensity.

Hyperesthesia: Hyperesthesia is characterized by increased sensitivity to any kind of stimulation without pain. There is decreased threshold to all kinds of stimuli and exaggerated response to non-noxious stimuli. Therefore, it could be suggested that hyperesthesia includes both allodynia and hyperalgesia.

Negative Symptoms and Signs

Hypoalgesia: Hypoalgesia is defined as diminished pain sensation to a normally painful stimuli. When the skin is pricked with a single pin stimulus, it presents as reduced perception and numbness.

Hypoesthesia: Hypoesthesia is reduced sensation to nonpainful stimuli. Mechanical hypoesthesia presents with decreased perception and numbness when the skin is touched with a painter’s brush, cotton swab, or gauze. Pall hypoesthesia is characterized by reduced sensation to vibration. It is demonstrated by a lower perception threshold when a tuning fork is applied to a bone or joint. Thermal hypoesthesia is elucidated as diminished sensation to cold or warm stimuli. When skin is touched with objects at 20°C or 40°C, it presents with reduced perception.

Autonomic Changes

NP may be accompanied by autonomic changes such as swelling, vasomotor instability, color changes, temperature changes, and trophic changes (i.e., hypertrichosis, dystrophic changes of skin, atrophy of subcuticular tissue and nails). Autonomic features, including cyanosis, mottling, abnormal growth of hair, diffuse swelling in periarticular tissue, and coldness, may occur in the later stages. Sympathetically maintained pain is often linked to the complex regional pain syndrome (CRPS), acute herpes zoster, phantom limb pain, traumatic neuropathies, and plexus lesions. Increased sympathetically mediated vasomotor activity leads to altered microcirculation and impaired nutrition and oxygenation.⁵¹ Also inflammation is in part regulated by the sympathetic nervous system. For instance bradykinin-induced plasma extravasation has been shown to depend on intact peripheral sympathetic structures.⁵²

The Other Effects of Neuropathic Pain

Psychological problems and sleep disturbances affect the quality of life in patients with NP due to chronicity and persistency. The most common psychiatric problems related to NP are depression, anxiety, panic attack, and post-traumatic stress disorder (PTSD). It has been reported that patients with anxiety disorder present with lower pain threshold, decreased tolerance to pain, and worse scores in pain scales.⁵³ The most prevalent sleep problems are insomnia and increased daytime sleepiness.⁵⁴ These patients experience difficulties in falling asleep, initiating, and sustaining sleep. When any sleep disturbances exist, pain threshold decreases and muscle pain and stiffness occur.^54,55 All of these factors limit physical functioning, and increase morbidity and mortality. Besides, these comorbidities can negatively affect social life (i.e., disturbed family relations, decreased libido, lack of social interactions), and it has a socioeconomic burden (health care costs, disability, lost workdays) for patients, their families, and society.

Detailed patient history and physical examination are crucial steps in the diagnosis of NP. Better management of NP and comorbidities necessitates appropriate diagnosis. Certain reliable and valid tests can aid the physician during clinical evaluation. General pain assessment tools are also convenient for NP. These tests include the visual analogue scale (VAS), faces pain scale (FPS), numerical rating scale (NRS), verbal rating scale (VRS), McGill pain questionnaire, and brief pain inventory (BPI). In addition to specific screening tools, electrodiagnostic tests, evoked potentials, autonomic testing, microneurography, imaging/functional neuroimaging techniques, and skin biopsy aid the clinician in making a diagnosis. The Hamilton Depression Scale,⁵⁶ Beck Depression Inventory,⁵⁷ and Hamilton Anxiety Scale⁵⁸ are helpful as generic tools to evaluate depression and anxiety. (See Table 40–2.)

Standardized Screening Tools

The subjective nature of pain perception and individual description make the standardized screening tools a necessity in the clinical encounter. Leeds Assessment of Neuropathic Symptoms and Signs (LANSS), Neuropathic Pain Questionnaire (NPQ), the Douleur Neuropathique en 4 questions (DN4), Identification Pain (ID-Pain), PainDETECT Questionnaire (PD-Q), and the Standardized Evaluation of Pain (StEP) are some of the screening tests that are available to help in the evaluation of NP.^59,60 Pricking, tingling, pin and/or needle sensations, electric shocks or shooting, burning pain, paresthesia, pain attacks, mechanical and thermal hypersensitivity, and numbness are the typical symptoms and signs that could be assessed by these questionnaires.^44,60–62 LANSS is a clinician-administered questionnaire (CAQ) with five symptom items and two clinical examination items with yes/no answers. It is validated for peripheral neuropathy (PNP) with 83% to 85% sensitivity and 80% to 87% specificity.⁶³ The short version of the LANSS (S-LANSS) is a self-administered questionnaire (SAQ) without clinical examination items.⁶⁴ The NPQ is also SAQ with 12 items scored between 0 and 100. It is validated for PNP and does not include any clinical examination items. It has 66.6% sensitivity and 74.4% specificity.⁶⁵ The DN4 is CAQ with seven items with yes/no answers and three clinical examination items. It is validated for PNP and central neuropathic pain (CNP) with 82.9% sensitivity and 89.9% specificity.⁶⁶ The DN4-Interview is an SAQ with seven items with yes/no answers, and there is no clinical examination item. The ID-Pain is also an SAQ with six items with yes/no answers without clinical examination items. Although it is validated for PNP, its sensitivity and specificity have not been assessed.⁶⁷ Pain DETECT is another SAQ with seven items scored between 0 and 5, and there is no clinical examination item. It is validated for PNP with 85% sensitivity and 80% specificity.⁶⁸ The StEP is a CAQ with six items with yes/no answers, and there are ten clinical examination items. It is validated for nonspecific low back pain with 92% sensitivity and 97% specificity.⁶⁹ Standardized screening tools help clinicians with the initial assessment of the patients with NP. However, 10% to 20% of patients with clinician-diagnosed NP remain unidentified with these screening tools.⁴⁴ Recent studies suggest that DN4 and NPQ are the most suitable screening tools for clinical use.⁷⁰ Furthermore, these questionnaires could be a standardized tool to assess and follow up the outcomes of clinical trials. This situation addresses the importance of good clinical practice, which is irreplaceable with any test or questionnaire in the therapeutic decision-making process.⁴⁴

Quantitative Sensory Testing

Negative and positive symptoms could be assessed with Quantitative Sensory Testing (QST).^71,72 This psychophysical method evaluates nociceptive fibers, and it is useful for studying the whole somatosensory system.⁷³ There is an available standardized protocol with age-matched reference values.⁷⁴ QST helps clinicians compare the threshold differences between normal and pathological areas and measures the perception of various thermal, mechanical, and painful cutaneous stimuli.⁴⁶ Monofilaments are used to evaluate small-fiber functions (Aδ and C fibers). Abnormal light touch sensation should be assessed with stimuli-dependent pain threshold.^75,76 However, it requires patient collaboration, is available in just a few centers, uses different protocols among certain countries, and cannot define the level of the lesion.^73,77

Electrodiagnostic Tests

Electrodiagnostic tests, including electromyography (EMG), electroneurography (ENG), and the study of reflex responses (i.e., trigeminal reflexes), evaluate large non-nociceptive afferent fibers. They provide information about etiology, level of pathology (i.e., motor neuron, root, plexus, peripheral nerve, muscle), localization of the involved structure (myelin or axon), severity of injury (mild, moderate, severe), phase of injury (acute, chronic), the extent of damage (sensory or sensorimotor involvement, even at subclinical stage), and the prognosis.^75,77 However, they do not evaluate nociceptive fibers. Because of this, it is preferred in severe NP cases for the investigation of large myelinated fiber involvement and exclusion of other painful conditions.

Evoked Potentials

Somatosensory evoked potentials (SEPs) are electrical potentials that are recorded from peripheral, spinal, subcortical, and cortical levels after the stimulation of peripheral or cutaneous nerves. Abnormal SEP recordings usually accompany a loss of proprioception because of the involvement of Aβ fibers. When there is damage in dorsal column pathways, the amplitudes of SEP potentials could be very low or the potentials may not be obtained.⁷⁸ If the segmental dorsal column is intact, SEPs are not affected. They are valuable to show the axonal integrity after peripheral nerve lesions. However, SEP studies are not beneficial in addressing the localization of the lesion because the neuroanatomic origin of all SEP potentials is not completely documented.^79,80 Laser evoked potentials (LEPs) measure brain signals evoked by cutaneous heat stimuli and evaluate the function of Aδ and C fibers.⁴⁶ During laser stimulation, high temperature at the superficial layers of the skin creates a burning and/or needling sensation. The potentials are recorded from scalp electrodes. LEPs are considered the most reliable neurophysiological technique for assessing nociceptive fibers and pathway functions. Suppression of LEPs aids the diagnosis of NP.⁸¹ However it is painful, requires patient collaboration, and is not available in many clinics.⁷⁷ The role of LEPs is not clear for the assessment of pain symptoms such as allodynia and hyperalgesia. Further randomized controlled trials that investigate the role of LEPs in painful nerve lesions are needed.

Autonomic Tests

Autonomic tests are used to assess sudomotor activity, sweating, and skin temperature at rest. The quantitative sudomotor axon reflex test (QSART) evaluates acetylcholine at the skin via iontophoresis at the postganglionic sudomotor axon and provides objective information about the function of the sudomotor reflex arc.⁷⁸ The Thermoregulatory Sweat Test (TST) evaluates the center of sympathetic sudomotor function and peripheral structures, and gives information about the distribution of the pathological involvement. The sympathetic skin response (SSR) is a useful method to evaluate the function of spontaneous or evoked electrical activity and sudomotor function, and to screen the early phase of various neuropathies. However, recordings among patients—and even within the same patient—vary dramatically and decrease the reliability of this test.^82–84 These are less costly and less sensitive. Laser Doppler fluxometry and computerized venous impedance plethysmography can also be used to rule out vascular etiology.^85,86

Microneurography

Individual action potentials from single fibers can be recorded with microneurography, which shows and quantifies spontaneous activity from nociceptive fibers.⁸⁷ It allows direct recordings from peripheral axons and identifies positive sensory changes. However, it is not practical to use this method because it is time consuming, needs patient collaboration, is available in very few centers, requires an expert investigator, and has no standard normative published data. It is only preferred in select cases and for research purposes.

Imaging

Imaging techniques identify a pathological process in the peripheral and central nervous systems; however, they do not explore nociceptive fibers and pathways.⁸⁸ Radiography is helpful to identify bone-related pain etiologies (i.e., acute skeletal trauma, fracture, arthritis, suspected bone and joint infection, bone tumors). Computerized tomography (CT) uses ionizing x-radiation to generate images and produces high-resolution two- or three-dimensional images. It provides a 3D assessment of bone in the setting of trauma, and it is helpful to assess fractures with metallic fixation. Ultrasonography (USG) uses high-frequency sound pulses for the evaluation of the musculoskeletal system. Musculoskeletal USG can be used for the diagnosis of PNP. The main sonographic findings in nerve pathologies are an increase in nerve diameter and a change in the echotexture of the nerve. Despite the literature supporting the use of musculoskeletal USG in entrapment neuropathies, some studies suggest cautious use in patients with NP due to metabolic and rheumatic diseases.⁸⁹ The application of Doppler USG also allows accurate assessment of superficial vessels. Magnetic resonance imaging (MRI) uses the movement of protons within a magnetic field to generate an image. It provides a desired level of contrast between soft tissues, such as articular cartilage, bone marrow, muscle, and ligaments. MRI is particularly limited by patient motion, which produces image artifacts. It is helpful to verify soft tissue pathologies but has a limited role in the diagnosis of NP.

Functional Neuroimaging

In functional neuroimaging, brain responses to spontaneous or evoked pain (i.e., the pain matrix) and functional status of Aδ and C fibers can be explored.⁸⁸ Positron emission tomography (PET) uses radioisotopes and evaluates energy consumption at the tissue level. Nuclear medicine examinations are highly sensitive but have a significant number of false-positive results and lower specificity for painful conditions. The radiation dose that the patient is exposed to must also be taken into consideration. Functional neuroimaging techniques are good research tools; however, they are not suitable for routine clinical use in the assessment of NP. It is expensive, available in few centers, and requires expert opinion.

Skin Biopsy

Skin biopsy provides information about the intradermal nerve fiber intensity (Aδ and C fibers) in the epidermis and dermis.^46,75,90 This technique is preferred for small-fiber neuropathy because it requires special staining techniques.⁹¹ However, there are contradictory data among nerve fiber density and the nature of NP.^92,93 It has been suggested that the underlying mechanisms are related to pain intensity rather than axonal loss.^94,95 It is time consuming, expensive, and available only in a few centers.

Grading System for Neuropathic Pain

The diagnosis of NP is easier with the aid of a grading system. The four criteria used in the grading system of NeuPSIG are (1) pain distribution is reasonable neuroanatomically, (2) patient history is relevant to lesion or disease, (3) negative or positive sensory symptoms are present in the damaged area, and (4) one of the diagnostic tools confirms lesion or disease.⁸ The first two criteria must be satisfied in order to be considered as having “possible” NP. In that case, confirmatory testing is necessary to make the diagnosis. If the criteria 3 or 4 is fulfilled, the diagnosis is “probable” NP, and if all four criteria are met, the diagnosis is “definite” NP.

There are various classifications of NP, but the most common ones are according to pathological and/or anatomic localizations. The involvement of central nervous system (CNS), peripheral nervous system (PNS), and mixed types has been summarized in Table 40–3. The involvement of PNS is divided into two groups: focal and systemic. Some examples of focal PNS disorders are entrapment neuropathies, radiculopathies, and postherpetic neuralgia; examples of systemic PNS disorders are metabolic, nutritional, drug, and toxin-related generalized polyneuropathies. Central pain has been defined by the IASP as pain elicited due to a lesion or a dysfunction in the CNS.⁷ The main etiologies of central pain are stroke, spinal cord lesions, and multiple sclerosis. The diagnosis of central NP in this context is extremely difficult and resistant to conventional treatment approaches. In the mixed type of neuropathies (i.e., complex regional pain syndrome and phantom limb pain), different levels and areas of the nervous system are involved and the pathology becomes more complicated.

Diabetic Neuropathy

Neuropathic pain affects 16% to 26% of patients with diabetes mellitus.^96,97 It includes different syndromes (i.e., symmetric polyneuropathies, distal sensorimotor, autonomic, small-fiber polyneuropathy, cranial neuropathy, radiculopathy, plexopathy). Diabetic neuropathy (DN) correlates with age, body mass index, waist circumference, physical activity level, disease duration and severity, presence of nephropathy, and peripheral artery disease. The symptoms of DN are numbness, tingling, or pain in the feet and hands; muscle weakness; gastrointestinal problems (i.e., gastroparesis, indigestion, nausea, vomiting, diarrhea, or constipation); autonomic nervous system dysfunction–related disorders (i.e., dizziness or faintness due to orthostatic hypotension, vasomotor changes, problems with urination, erectile dysfunction in men, and vaginal dryness in women); and balance and coordination problems. Better glycemic control, improving other metabolic markers, and reducing cardiovascular risk factors are recommended for prevention of DN. TCAs, anticonvulsants, and SNRIs are the first-line drugs, while tramadol and opioids are the second-line drugs for the treatment of DN.

Postherpetic Neuralgia

Postherpetic neuralgia (PHN) is defined as severe pain in the area of dermatomal distribution of herpes zoster virus eruption. There is an 8% incidence of PHN in patients with herpes zoster.⁹⁸ Inflammatory components and nociceptor sensitization play a major role in the pathophysiology.⁵⁰ In a recent study, it has been reported that there are certain predictive factors for PHN (i.e., older age, male gender, immunodeficiency, smoking, previous trauma at the site of lesion, lack of antiviral therapy, lower general health status).⁴⁸ The pain usually presents as continuous deep aching, burning, stabbing, and shooting pain; allodynia can also be present. The condition is self-limiting, resolving within 2 months in half of the patients, but may persist longer. PHN is usually difficult to treat, and first-line medications include antidepressants, anticonvulsants, opioids, or their combinations. Topical application of capsaicin or lidocaine patches may bring temporary relief.

Postsurgical Pain

Postsurgical pain is common in the postmastectomy patient. The incidence is predicted to be 30% to 40% after breast cancer surgery (i.e., mastectomy, lumpectomy, lymph node dissection, reconstruction, augmentation).⁹⁹ It is described as burning, stabbing, tightness, or aching pain in the incision site. It occurs shortly after surgery or months later and can persist for years. There are certain predictors for postsurgical pain (i.e., psychological distress, high body mass index, pain at first 2 days [VAS >3], and the presence of secondary hyperalgesia, hypoesthesia, and/or hyperesthesia).⁴⁸ In the acute stage, nonsteroidal anti-inflammatory drugs (NSAIDs), anticonvulsants, systemic opioids, or their combinations and topical application of capsaicin or lidocaine patches can be preferred. It is important to control pain because it can easily become chronic.

Trigeminal Neuropathic Pain

Trigeminal NP is a syndrome of severe, steady facial pain related to injury to the trigeminal nerve or ganglion or their diseases. Maxillofacial surgery, skull and/or facial trauma, deafferentation, or intrinsic pathological conditions in any part of the trigeminal system can cause this type of pain.¹⁰⁰ Trigeminal neuralgia (TN), which is a typical example of trigeminal NP, is also characterized by unilateral, sudden, shocklike, and brief (fractions of a second to minutes) painful attacks. Trigeminal NP follows the distribution of trigeminal nerve branches without presentation of other sensorimotor or autonomic signs and symptoms. The incidence of TN is estimated at 27/100,000 person-years.¹⁰¹ Simple activities and the stimulation of trigger zones may aggravate the attacks, and bilateral symptoms suggest other secondary causes (i.e., multiple sclerosis). MRI and neurophysiological investigations may exclude secondary causes of TN. Carbamazepine and oxcarbazepine are first choices for the treatment of TN. Pregabalin, gabapentin, and baclofen are second-line drugs. Invasive treatments (e.g., microvascular decompression, Gasserian ganglion radiofrequency) may help in the treatment of refractory TN. MCS is a new method with promising effects in the treatment of trigeminal NP.¹⁰⁰

Low Back Pain

Low back pain (LBP) has a lifetime prevalence of 70%. Various spinal skeletal structures are responsible for nociceptive LBP. Frequent causes of neuropathic LBP include herniated disc with root compression, lumbar spinal stenosis, and scar tissue from previous spinal surgery. The pain characteristics are burning or aching referred pain in a unilateral lower extremity, numbness, and/or dysesthesia. Spinal MRI and CT, electrodiagnostic tests, and SEPs are often inconclusive in patients with LBP. Reduced exercise capacity, increased nonproductive hours of work, depression, and feeling useless are associated with poor prognosis.¹⁰² The treatment of LBP involves appropriate medication in combination with physical therapy modalities and exercises. Rapid weight loss, fever, pain at rest and during the night, no relief after 6 to 8 weeks of treatment, distal numbness and weakness, saddle anesthesia, and loss of bowel and bladder control suggest a potential serious cause and should always be investigated further.

Cancer Pain

Cancer is a chronic debilitating disease, and patients suffering from cancer need comprehensive and interdisciplinary approaches designed to relieve symptoms of pain, fatigue, and muscle weakness in addition to treating the underlying pathology.¹⁰³ Cancer pain is a mixed type of pain that includes both nociceptive and neuropathic components, and presents in 51% of cancer patients (74% in the advanced stage). It has psychological, cognitive, and behavioral components and affects quality of life and functionality negatively. Different types of pain can be seen in cancer patients: (1) pain related to direct tumoral involvement (i.e., bone invasion, compression, or invasion of peripheral nerves); (2) pain related to cancer treatment (e.g., postoperative, post-chemotherapy, or post-radiation pain); and (3) pain related to cancer complications or comorbidities (e.g., paraneoplastic syndrome, bed sores, constipation, rectal or bladder spasm). With mild cancer pain, simple analgesics (acetaminophen, paracetamol) and NSAIDs could be given.¹⁰⁴ In this stage, physical therapy modalities (i.e., TENS, diadynamic electrical currents), therapeutic massage, biofeedback, and relaxation exercises are very helpful. In moderate painful situations, opioids (i.e., codeine, tramadol, oxycodone, hydrocodone) should be recommended. When it is necessary for functionality, therapeutic exercises such as range of motion (ROM), muscle stretching, strengthening, balance, and coordination exercises are added to the treatment program. In severe pain, opioids (i.e., morphine, hydromorphone, and methadone) are used and additionally adjuvant drugs (TCAs, anticonvulsants) are given.¹⁰⁴ In situations unresponsive to treatment spinal opioid administration and invasive techniques (nerve blockages, stellate and lumbar ganglion blocks), other interventions (dorsal root rhizotomy, tractotomy, cordotomy, myelotomy) are recommended. Although pain is a symptom that should be overcome, sometimes therapy can get hard and it can delay return to normal activities of daily life.

Central Post-Stroke Pain

Central post-stroke pain (CPSP) is a central NP condition caused by a vascular lesion of the somatosensory nervous system.¹⁰⁵ Symptoms almost always develop within the primary sensory dysfunction area, and CPSP is most commonly seen on the hemiplegic side after stroke. It is observed in 8% of patients with stroke.¹⁰⁶ Most patients with CPSP have allodynia elicited by movement, cold, or touch. It is suggested that decrease of inhibition in the thermal system of the nociceptive neurons causes the burning pain and cold allodynia. The severity is usually variable, increases with external stimuli such as stress and cold, and decreases with rest and distraction. Pain severity does not correlate with the degree of spinothalamic deafferentation, but it occurs in the affected side of the body when there is a loss of pain sensation. In the pharmacotherapy of CPSP, amitriptyline is currently the first-line drug.¹⁰⁷ However, it is generally ineffective and a high dose is commonly not tolerated in these patients. Lamotrigine is also used as a first-line therapy. Anticonvulsants such as gabapentin or pregabalin are effective in various NP syndromes, but their effect on CPSP is still unclear.¹⁰⁸ Pregabalin may improve pain-related anxiety and sleep disturbances in addition to NP. Nonpharmacologic treatments such as MCS or DBS have promising effect on the treatment of CPSP. However, they require further investigation.

Multiple Sclerosis

Multiple sclerosis (MS)–associated NP is a common and disabling symptom. Twenty-eight percent of patients with MS present with NP.¹⁰⁹ NP secondary to demyelination, neuroinflammation, and axonal damage in the CNS is one of the most irritating pain types. Dysesthetic extremity pain, Lhermitte’s sign, and trigeminal neuralgia are the most common NP-related conditions in patients with MS.¹¹⁰ MRI may show the localization of demyelinating lesions. QST and LEPs may document sensory deficits but are not largely used in clinical practice. TCAs, α2-δ ligands, and lamotrigine might help because they are useful in other types of central NP.

Complex Regional Pain Syndrome

CRPS is a multifactorial pain disorder that has sensory, motor, autonomic, and trophic abnormalities and affects the somatomotor, somatosensory, and sympathetic nervous system.¹¹¹ It is characterized by regional burning pain, increased sensitivity to tactile stimuli and sensations of pain in response to normally non-painful stimuli.¹¹² The exact cause of CRPS is still unknown. Three-phase bone scintigraphy, infrared thermography, and QST are helpful for the diagnosis of CRPS.^113,114 SSR and QSART have also been used to assess sudomotor activity.⁸⁶ There is no single protocol for the treatment of CRPS; physicians prescribe some medications such as NSAIDs, antidepressants, anticonvulsants, or opioids. Medications should be combined with a rehabilitation program that aims to help the patient get back to a normal life; increase ROM, muscle strength, and endurance; and provide desensitization and functional restoration. If all else fails, the next step is sympathetic blockade. It is very important to address the potential psychological problems, psychiatric disturbances, and personality disorders in individual patients as part of a multidisciplinary program of treatment.

Radiculopathy

The diagnosis of radiculopathies with or without LBP mostly depends on clinical assessment. The frequently used diagnosing tool is imaging; however, imaging modalities have not been well correlated to pain severity and disability. The electrophysiological studies help to prevent false-positive results of the imaging modalities.^115,116 Some studies have suggested that there are three predictors for persistence of radicular pain: negative outcome expectancies, pain-related fear of movement, and passive pain coping.⁴⁸ Physical therapy modalities and therapeutic exercises should be combined with medical treatment such as NSAIDs, myorelaxants, analgesics, α2-δ ligands, and antidepressants when need. Surgical indication should be reserved for unresponsive cases to conventional treatment and patients with progressive neurologic deficit.

Phantom Limb Pain

Phantom limb pain (PLP) refers to mild to extreme pain sensation in the area where a limb has been amputated. The characteristics of PLP are sharp or shooting, aching, burning, and cramping pain. Pruritus and twitch may also be accompanying symptoms.¹¹⁷ PLP usually disappears or decreases over time; however, the improvement is poor when it continues for more than 6 months.¹¹⁸ Psychogenic theory shifted to peripheral and central neural changes involving cortical reorganization. In addition, the mirror neurons in the brain have been suggested to play a role in the generation of phantom limb pain. Stump-associated problems and spinal and cortical changes can also contribute to the pathology. Some treatments such as physical therapy modalities, relaxation techniques, massage of the amputation area, injections with local anesthetics and/or steroids, nerve blocks, surgery to remove scar tissue entangling a nerve, and neuromodulation techniques such as SCS or DBS are helpful in clinical practice. Additionally, medications such as analgesics, anticonvulsants, antidepressants, beta-blockers, and sodium channel blockers can be recommended. Mirror therapy has mixed results in randomized controlled trials.¹¹⁹ Further investigations are necessary to understand the underlying mechanisms and offer better treatment options.¹²⁰

Spinal Cord Lesions

Spinal cord lesions (SCLs) lead to varying degrees of motor and/or sensory deficits and paralysis.¹²¹ Pain is common in patients with SCLs, and it may be related to injury, infarction, inflammation, spinal stenosis, or iatrogenic causes. NP due to SCLs is mostly below the lesion level with a burning or aching character.¹²² Amitriptyline, gabapentin, and pregabalin are the primary choices in clinical practice. Topical applications of capsaicin or lidocaine as well as intradermal injections of botulinum toxin-A (BTX-A) are new treatment modalities in patients with painful SCLs. Nonpharmacologic approaches may also be effective. Further clinical studies are needed to assess the effect of different management options.

The management of NP mainly necessitates a multidisciplinary approach with pharmacologic and nonpharmacologic therapeutic modalities.¹²³ Although recent advances in the understanding of pathophysiology are useful to clinicians in order to address the clear etiology of NP, insufficient pain management is still an important problem in the clinical setting. Management approaches consist of empowering patients through counseling, education, self-management strategies, and psychosocial support, as well as curative medical treatment. The only clinically proven method in the prevention of NP is vaccination against varicella zoster virus, which is effective in preventing postherpetic neuralgia.¹²⁴ The primary goals of treatment are to reduce pain, eliminate risk factors, improve quality of life, and decrease negative side effects of treatment. Once NP appears, it becomes more difficult to successfully manage, and aggressive treatments may be required.¹²⁵ For the pharmacologic therapy of NP, recent guidelines and recommendations have been reviewed, and the key points have been mentioned (See Table 40–4).^126–131

Medications

Tricyclic Antidepressants

TCAs such as amitriptyline, nortriptyline, and desipramine are currently the preferred treatment options for NP. TCAs inhibit reuptake of serotonin and/or norepinephrine and block sodium channels. Analgesic effects of TCAs can be explained by their neuroadrenergic descendent inhibitor way stimulation and partial sodium channel blockage. These mechanisms are independent from the antidepressant effect. TCAs provide an advantage in the treatment of depressive symptoms as a comorbidity of NP.¹²³ They should be used cautiously for patients with cardiac disease, glaucoma, liver disorders, seizure disorder, prostatic hypertrophy, and certain medication use (i.e., tramadol). The major side effects are sedation, anticholinergic actions (i.e., dry mouth, urinary retention, weight gain), heart block, and hypomania. Side effects are reduced with a lower starting dosage and slow titration, which are especially suggested for elderly.

Serotonin-Norepinephrine Reuptake Inhibitors

SNRIs such as duloxetine and venlafaxine have been extensively investigated in the treatment of PNP. They inhibit both serotonin and norepinephrine reuptake and reduce NP, depression, and anxiety. Efficacy levels of SNRIs are level A for diabetic neuropathy. Smaller doses are started at first; however, a gradual increase would be preferred in order to reach the optimal treatment dose. Their major side effects are nausea, dizziness, sedation, agitation, and withdrawal syndrome after sudden discontinuation. It is important to evaluate hepatic dysfunction, renal insufficiency, alcohol abuse, use of certain medications other medications with duloxetine, and cardiac disease for with venlafaxine. Their efficacy is better than selective serotonin reuptake inhibitors (SSRIs; fluoxetine, sertraline, citalopram) which resulted in disappointment in the treatment of NP.

Anticonvulsants

Gabapentin and Pregabalin

The pharmacologic mechanisms of gabapentin and pregabalin are still unclear. They bind to the voltage-gated calcium channels at the α2-δ subunit and inhibit neurotransmitter release and decrease neuronal excitability.¹²⁸ They increase the level of GABA, which plays an important role in pain modulation, and also suppress release of glutamate, norepinephrine, and substance P. There are no clinically significant drug interactions. They also improve sleep disturbances and anxiety. Their efficacy levels are level A for diabetic neuropathy, PHN, and cancer-related NP. The starting dose is low and increased gradually. The major side effects are sedation, dizziness, peripheral edema, and weight gain. They should be used with caution in patients with renal insufficiency, and the dose should be adapted to creatinine clearance.

Carbamazepine, Lamotrigine, Oxcarbazepine, and Topiramate

Membrane stabilizing anticonvulsants (sodium channel blockers) such as carbamazepine can also be used in the treatment of NP. Carbamazepine is the first-line drug of choice for trigeminal NP. Complete blood count should be monitored. Besides drowsiness, aplastic anemia and syndrome of inappropriate antidiuretic hormone can also be seen. There is also a small risk for the development of Stevens-Johnson syndrome and toxic epidermal necrolysis.⁷⁷ Lamotrigine is the first-line drug option for the treatment of CPSP.¹³² It has been shown to be efficacious in NP due to HIV infection¹³³ and diabetic neuropathy.¹³⁴ Adverse reactions, which are similar with carbamazepine, could be reduced with slow titration. It may take many weeks to reach an effective dosage. However, significant supporting evidence is lacking for its widespread use for the treatment of NP.¹³⁵ Oxcarbazepine is the first-line drug of choice in the treatment of trigeminal NP. It is better tolerated than carbamazepine. It should be used with a lower starting dosage and slower titration in the elderly. Topiramate might reduce NP (i.e., diabetic neuropathy), but it has limited usage in clinical practice.^136,137