Peripheral neuropathic damage by mechanical, chemical, or inflammatory insults causes injury to small myelinated Aδ and unmyelinated C-fibers. These are responsible for transmitting noxious sensory potentials. Peripheral sensitization of the nociceptive system is characterized by an increased responsiveness and reduced activating threshold of these afferent C-fibers and Aδ fibers to stimulation. ^, Chemical mediators of inflammation including histamine, bradykinin, prostaglandins, and Substance P, are released following tissue damage, resulting in further stimulation of the nociceptive receptors. ^,

In response to receptor activation, there is increased expression and activity of voltage-gated sodium channels throughout the somatosensory system and downregulation of voltage-gated potassium channels within nociceptive pathways. These molecular changes, which occur on injured and noninjured nociceptive fibers, result in a lower threshold for nerve fiber action potential generation and propagation. ^, This occurs at all levels of the peripheral nervous system, including the peripheral nerves, dorsal root ganglion, and central terminal synapse at the dorsal horn.

Nerve injury also results in upregulation of various receptor proteins, including transient receptor proteins (TRPs, such as TRPA1, TRPV1, and TRPV4). This leads to increased spontaneous nerve activity on peripheral nociceptive endings and sensation of heat hyperalgesia and burning pain.

Axons may undergo collateral sprouting and contribute to referred pain patterns by activating neighboring sensory and nociceptive circuits.

With repeated or sufficiently intense nociceptive input, spinal and supraspinal nociceptive pathways can become sensitized to subsequent stimuli. The IASP defines this process of central sensitization as increased responsiveness of nociceptive neurons in the central nervous system to their normal or subthreshold afferent input .

Increased peripheral nociceptor fiber activity induces higher levels of excitatory neuropeptides in the dorsal horn region. This activates second-order neurons via increased activity and presence of N-methyl- d -aspartate (NMDA) and α-amino-3-hydroxy-5-methyl-4-isoxazolepropionicacid receptors in postsynaptic membranes. ^, This results in microglial activation and collateral sprouting within the dorsal horn, causing greater hypersensitivity of the nociceptive afferent pathways. ^,

Toll-like receptors (TLRs), especially TLR-2 and TLR-4, also play a significant role in the development and maintenance of neuropathic pain. They are expressed widely within the central nervous system on neurons, microglia, and astrocytes. TLRs detect both external (pathogen-associated molecular patterns) and internal (damage-associated molecular patterns) signals of inflammation. These signals induce the activation of microglia or astrocytes and the production of proinflammatory cytokines in the spinal cord, resulting in the development and maintenance of inflammatory pain and neuropathic pain. ^,

Within the ascending and descending fibers of the spinal cord, there is an imbalance of inhibitory and facilitatory pathways via downregulation of the gamma-aminobutyric acid (GABA) interneurons. Decreased level of GABA results in a curtailed disinhibition of excitatory pathways within the spinothalamic and spinobrachial tracts. ^, An imbalance between activating and inhibitory serotonergic pathways also facilitates nociceptive activity.

Cortical and subcortical brain regions undergo maladaptive changes after nerve damage, further contributing to the imbalance between facilitatory and inhibitory pathways. Maladaptive neuroplasticity contributes to the dysregulated interpretation of incoming painful inputs, ultimately promoting a chronic pain state ^, ( Fig. 3 ).

Neuroanatomy with its functional role in pain transmission and modulation ( yellow boxes ). Ascending pathways generate sensory and affective signaling ( left ). Descending pathways originate in higher centers and modulate spinal function ( right ). Pathologic changes are listed next to neuroanatomical regions. Possible pharmacologic agents and their targets are highlighted ( red boxes ). (−) α2R, inhibition of neuronal activity. (+) 5-HT3R, stimulation of neuronal activity. A5 and A7, brain stem nuclei containing noradrenergic neurons; Am, amygdala; 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.

(Reprinted with permission from Elsevier The Lancet Neurology, November 2013, 12 (11), 1084-1095.)

Central neuropathic pain occurs after direct injury to the spinal cord or brain. Injury to the ascending sensory pathways within the spinal cord can result in decreased sensation. In addition, injury to the inhibitory centers and circuits leads to further dysregulation and imbalance of electrical activity propagation. Spinal cord injury models have shown increased collateral sprouting of C fiber nociceptors, affecting pain perception at the dorsal horn region. Direct brain injury may lead to maladaptive neuroplasticity within the cortex, resulting in abnormal interpretation of incoming nociceptive signals.

Multiple genetic risk factors from distinct pathways have been found to influence neuropathic pain susceptibility. Variations in HLA-DRB1∗13, HLA-DRB1∗04, HLA-DQB1∗03, HLA-A∗33, and HLA-B∗44 have been linked to an increased risk of developing neuropathic pain, while variants in HLA-A∗02 decrease the risk of developing neuropathic pain.

A standardized bedside sensory examination should include testing of light touch, deep touch, vibration, proprioception, cold, and heat. These sensory domains are chosen to specifically evaluate different pathways within the peripheral and central somatosensory system. Light touch, deep touch, vibration, and proprioception evaluate somatic sensory pathways, while temperature and pinprick stimuli assess nociceptive pathways.

Changes within sensory testing are divided into negative and positive signs. Negative signs, such as hypoesthesia or hypoalgesia, are defined as sensory loss. This occurs due to dysfunction or loss of function of nerve fibers and/or central ascending pathways. Positive signs, including paresthesia, hyperesthesia, hyperalgesia, allodynia, or hypersensitivity, indicate overactive somatic pathways. These occur due to spontaneous and stimulus-evoked pain transmission secondary to gain-of-function and maladaptive neuroplasticity after injury. ^,

Screening tools can help distinguish neuropathic pain from nociceptive pain. Most screening tools, such as the Neuropathic Pain Questionnaire, painDETECT, and the Neuropathic Pain Symptom Inventory, are based on questions about characteristic pain descriptors, including burning pain, paresthesia, pain attacks, mechanical and thermal hypersensitivity, and numbness. They have a sensitivity of approximately 80% to 90%. Linking this tool with a proper clinical assessment can be extremely helpful in guiding further diagnostic testing and treatment. Their ease of use by professionals and patients alike, in clinic, via telephone, or internet, makes them attractive because they provide immediately available information. It is important to note that there is limited utility in patients with widespread pain or those who are unable to self-report.

Neuropsychological testing includes standard nerve conduction studies and somatosensory-evoked potentials. These are useful in confirming, localizing, and quantifying the severity of lesions along peripheral and central sensory pathways. These electrodiagnostic studies have variable sensitivities, specificities, and validation based on the location and type of lesion. ^,

Skin biopsies measure the intraepidermal nerve fiber density and should be performed in patients with clinical signs of small fiber dysfunction. C-fiber morphology and pathology can be investigated by immunostaining for nerve fibers in 3-mm punch skin biopsies (including nerve fibers, sweat glands, blood vessels, and resident or infiltrating cells in the epidermis and superficial dermis) from the affected area. Nerve fibers can be visualized with antibodies against PGP 9.5, a panaxonal marker. Bright field immunohistochemistry or immunofluorescence may also be used. The density of nerve fibers crossing into the epidermis is quantified using strict published criteria. Structural changes such as axonal swelling, fragmentation, and sweat gland innervation are also evaluated. Skin biopsy testing has a reported sensitivity of 84% and specificity of 86% for the diagnosis of small fiber neuropathy. Skin biopsies can be repeated to evaluate disease progression or response to treatment.

Imaging may be useful in identifying structural and functional changes of the somatosensory nervous system. PET and functional MR imaging (fMRI) evaluate brain activity during noxious stimulus delivery. PET and fMRI testing are currently limited to the research setting without clear clinical utilization. ^,

When many of these medications are used as monotherapies, they fail to provide adequate relief, with an efficacy rate of approximately 40%. Therefore, combination pharmacotherapy remains a valuable strategy, but large-scale studies are lacking.

Based on the most recent evidence-based international recommendations, gabapentinoids (gabapentin, pregabalin, mirogabalin), tricyclic antidepressants (amitriptyline and nortriptyline), serotonin-norepinephrine reuptake inhibitor antidepressants (Duloxetine), are recommended as the first-line therapy for peripheral and central neuropathic pain ( Table 1 ).

Tramadol, lidocaine patches, and high-concentration capsaicin patches have weaker evidence supporting their use and lower tolerability. Therefore, they are considered second-line treatments.

Particular topical treatments, such as lidocaine 5% patch, are recommended for peripheral neuropathic pain with presumed local pain generator (post-traumatic painful neuropathies, postherpetic neuralgia, and painful polyneuropathies) or when there are side-effects or safety concerns related to first-line treatments, particularly in frail and elderly patients.

Stronger opioids (oxycodone and morphine) and botulinum toxin A have weak recommendations for use. They are recommended as third line treatments because of safety concerns (opioids) or weak quality of evidence (botulinum toxin A).

Although widely used, there is currently insufficient evidence for the use of cannabinoids and cannabinoid agonists, including delta-9-tetrahydrocannabinol and cannabidiol in the treatment of neuropathic pain.

Intravenous drugs, including Lidocaine and Ketamine, an NMDA receptor antagonist, and intrathecal Ziconotide, a neuronal calcium channel blocker, have insufficient evidence to be used in the early stages of symptoms but may be considered in refractory cases. Ziconotide administration requires the surgical implantation of an intrathecal catheter and pump system, and the decision to proceed should involve a careful discussion of the potential risks and benefits for the individual patient.