In nociceptors present in the skin (or deep tissues), under pathological conditions, such as peripheral nerve or nerve root lesion, changes may occur in ion channels and receptor expression [32]. Changes have been demonstrated in transient receptor potential vanilloid 1 (TRPV1) channels on the terminal surface, leading to hyperexcitability to heat but also participating in mechanical and cold-induced neuropathic pain [33]. The role of transient receptor potential melastatin 8 (TRPM8) is more ambiguous, as its activation promotes cold hypersensitivity, but decreases mechanical hypersensitivity [33]. In diabetes-related neuropathic pain, TRPV1 channels are stimulated by hyperglycemic and hypoxic conditions, inducing heat and mechanical hypersensitivity. Transient receptor potential ankyrin 1 (TRPA1) receptors are also directly stimulated by a diabetes by-product, methylglyoxal (MG), which leads to mechanical hyperalgesia. Recent in vitro evidence suggests a similar role for TRPM8 [33]. In chemotherapy-induced neuropathic pain, protease-activated receptor 2 (PAR2)-mediated TRPV1 sensitization has been implicated in heat and mechanical hypersensitivity mediated by chemotherapeutic drugs. TRPA1 activation participates in both mechanical and cold hypersensitivity, whereas TRPM8 has a major role in cold hypersensitivity [33].

Na⁺ channels are located at the coding site [34] (where the action potential is generated), along nerve fibres and on the DRG; their overexpression leads to hyperexcitability to various stimuli [35]. The voltage-gated sodium channel Na_v1.7 is expressed selectively in sensory and autonomic neurons; inactivating mutations in sodium voltage-gated channel alpha subunit 9 (SCN9A), which encodes Na_v1.7, result in congenital insensitivity to pain, whereas gain-of-function mutations in this gene produce pain syndromes such as erythromelalgia, paroxysmal extreme pain disorder, and small-fibre neuropathy [36]. Na_v1.8 is involved in peripheral sensitization due to inflammatory conditions, and it has been demonstrated that an injury-induced redistribution of Na_v1.8 to uninjured axons leads to hyperexcitability in animal models [37]. There is evidence of a role for Na_v1.9 in inflammatory, diabetic neuropathy, and orofacial neuropathic pain [37].

In case of peripheral nerve lesion, an immune response is activated in order to repair the damage; the inflammatory mediator cytokines such as IL-1b, TNF-α, together with peptides released from the nerve terminals, substance P (SP) and calcitonin gene related peptide (CGRP), sensitize and stimulate nociceptors generating hypersensitivity to stimuli (allodynia) or spontaneous pain [38]. The inflammatory response is functional to nerve repair; therefore, the treatment should modulate and not suppress inflammation [38]. Histamine, released by mast cells, has been shown to contribute to hypersensitivity in peripheral nerve injury models [39].

Clinically, alterations of TRPV and Na⁺ channels and peripheral neurogenic inflammation present with the “irritable nociceptors” [32] or “thermal hyperalgesia” [12] phenotype, characterized by the prevalence of positive signs of all sensory modalities. This clinical presentation is often present in polyneuropathies and ganglionopathies (e.g., postherpetic neuralgia).

When a peripheral sensitization due to overexpression or overactivity of TRPV1 receptors is hypothesized, topical capsaicin is a treatment option. It can be applied in cream from 0.025% to 0.1% more times a day or in 8% plasters every three months [40]. High-concentration capsaicin induces a long-term defunctionalisation of TRPV1 receptors, through the ablation of TRPV1-expressing axon terminals induced by a calcium-dependent protease, which is followed by regeneration [41]. Capsaicin demonstrated a disease-modifying effect in some forms of neuropathic pain [42].

In order to target Na⁺ channels, lidocaine 5% patches can be used and have been demonstrated to be effective for pain paroxysms and deep aching pain [43]. Systemic oxcarbazepine, an antiepileptic drug acting on Na⁺ channels has been demonstrated to be more efficacious for relief of peripheral neuropathic pain in patients with the irritable vs. the non-irritable nociceptor phenotype [44]. Another Na⁺ channel blocker, lacosamide, failed to demonstrate efficacy in a population of peripheral neuropathic pain patients [45]. An old drug, ambroxol, used for its antitussive or anti-secretory effects, has been demonstrated to block Na_v1.7 and Na_v1.8 channels and a subtype of Ca channels with anti-inflammatory benefits and some effect on neuropathic pain symptoms in animal models of neuropathic pain and some case reports as a topical formulation [46]. Given the involvement of Na⁺ channels in pain perception, several blockers are being studied; recently, a new drug, suzetrigine, a potent and selective Na_v1.8 inhibitor, has been approved by the FDA for acute pain. Suzetrigine binds to a specific site on the voltage-sensing domain 2 (VSD2) of Na_v1.8, stabilizing the channel in the closed state [47]. Clinical studies in models of acute pain demonstrated efficacy compared to placebo, similar to opioids; interestingly, central nervous system or cardiovascular side effects were not observed at effective dosage [47]. The actual indication is acute pain, but the characteristics of the drug induce to considering it promising for neuropathic pain.

The possible role of histamine receptor antagonism in the treatment of neuropathic pain has been assessed in a recent review [39]: the authors present a possible role of different histamine antagonists on the symptoms of neuropathic pain; particularly interesting is the analgesic effectiveness of H3 receptor antagonists/inverse agonists, mainly on mechanical and cold allodynia.

Botulinum toxin (BTX), usually used to reduce spasticity, has been studied for the relief of pain, not only related to muscle hyperactivity, in particular for neuropathic pain. BTX acts by inhibiting the release of Ach at the neuromuscular junction, and also SP, CGRP, and glutamate, which are involved in neurogenic inflammation at the nerve endings [48].

Various forms of electrical stimulation applied to the skin or just beneath the skin have been proposed and are used to reduce pain and improve function [49]. Different electrical parameters can be delivered to the painful anatomical target through the skin, transcutaneous electrical nerve stimulation (TENS), through percutaneous temporary leads, percutaneous electrical nerve stimulation (PENS), or through implantable leads, peripheral nerve field stimulation (PNFS); unfortunately, the evidence for effectiveness is poor mainly due to the lack of standardization for each treatment [49].

Neuromodulation treatments applied to the nerve trunk or on the DRG can also modify the functionality of peripheral nerve endings.

A lesion along the axon can be caused by compression in entrapment syndromes, by trauma, or by surgery. According to the type and quantity of fibers involved, clinical presentation can be grouped in the “thermal hyperalgesia”, “mechanical hyperalgesia” or “sensory loss” phenotypes [13]; it is important to understand that in case of sensory loss we should consider denervation and not deafferentation since an activity in the peripheral axon and DRG is still transmitted to the second order neuron.

Ectopic sites can develop in the areas of axonal lesion, in regenerating sprouts and neuromas (terminal or in continuity), in the site of demyelination, and in DRG cell bodies [50]. An altered distribution of voltage-dependent Na⁺ channels has been demonstrated in the demyelinated segments of the membrane. The newly expressed channels include Na_v1.7, Na_v1.3, a channel normally expressed only in sensory neurons during embryonic development, and Na_v1.8 [51]. Combined with a decrease in K⁺ channels and an increase in nonselective hyperpolarization-activated cyclic nucleotide-gated (HCN) channels, these changes can result in lowered depolarization threshold with the possibility of ectopic discharge, spontaneous or evoked by mechanical and chemical stimuli, and enhancement of action potential transmission through the demyelinated segment [52].

Pain is always radiated in the peripheral innervation territory, and it is not perceived at the site of injury. The frequency and type of discharge can be different from case to case: they vary from very slow (< 1 pulse/second) to very high (> 100 pulses/second). Some afferents discharge single pulses (spikes) at a low frequency with an irregular rhythm, others discharge trains of pulses at a regular rhythm in sequences (bursts) [53].

Ectopic sites can be generated on any fiber type, and the sensation varies from fiber to fiber, such as burning or constriction for unmyelinated C-fibers, electric discharge for myelinated Aδ fibers, and paresthesias for myelinated Aβ fibers. In physiological and pathological nociceptive pain, only C fibers and Aδ are involved in the generation of action potentials from tissue terminals, but in neuropathic pain, tactile and proprioceptive Aβ fibers are also involved. In neuropathic pain, the encoding of the message at the site of nociceptive terminals that characterizes nociceptive pain does not occur, therefore, the perceived sensation does not correlate with the type of stimulus but with the type of fibers involved [28]. Ectopic impulses can generate spontaneously and/or be evoked by stimuli of various kinds (e.g., Tinel’s sign).

The spontaneous origin of the potential is a function of the degree of subthreshold high-frequency oscillation of the membrane potential of the ectopic site [52]. Ectopic spikes can also originate from healthy fibers close to those involved by the injury, especially from C-fibers [54].

In some conditions of neuropathic pain, the involved nerve fibers present a rest period after the discharge; this feature has been shown in animals, and is typical in patients with trigeminal neuralgia, where the ectopic site is proximal to the ganglion [55].

In addition to ion channels and receptors, altered expression, accumulation of infiltrating immune cells such as neutrophils, macrophages, and mast cells at the site of nerve injury contribute to axonal hyperexcitability and sustained electrical discharge in the majority of neuropathic conditions [56].

Axonal sensitivity to various types of inflammatory mediators, such as bradykinin (BK), E2 prostaglandins, acid pH, and capsaicin, has been demonstrated [57, 58]. Neuroma sprouts present mechano-sensitivity and thermo-sensitivity [57, 59].

As inflammation and mechanical stimuli contribute to the genesis of pain in peripheral nerve lesions, it is important to diagnose the presence of entrapment and/or inflammatory processes in order to resolve the hyperexcitability phenomenon due to hypoxia and inflammatory mediators.

If we consider carpal tunnel syndrome, a typical entrapment syndrome, the literature on the use of Na⁺ channel blockers is poor; symptoms may be improved by corticosteroid injections [60], which act on inflammatory mediators and oedema contributing to compression. Symptoms of carpal tunnel syndrome may be relieved by splinting, which limits range of motion and thus mechanical stimulation [61]. Surgery is often curative [23]. Reconstructive surgery has been proposed for neuromas with significant results [62].

If surgery is not an option, the first step is pharmacological therapy targeting altered Na⁺ channel activity. In addition to the antiepileptic drugs that act on Na⁺ channels, such as carbamazepine, oxacarbazepine, lacosamide, topiramate, and lamotrigine, some antidepressants have shown inhibitory activity on Na⁺ channels expressed on nerve fibres, particularly on the DRG, with amitriptyline being the most potent inhibitor [63]. Carbamazepine is the drug of choice for trigeminal neuralgia [10].

TENS has been shown to modulate action potential propagation when applied to a peripheral nerve [64] and may therefore be an option in the treatment of peripheral neuropathic pain [11]. Peripheral nerve stimulation (PNS) with implanted leads and temporary leads (PENS) has shown positive results for postoperative neuropathic pain [65] and may share the same mechanism of action as TENS. Other neuromodulation techniques, such as cryoneurolysis or pulsed radiofrequency, are commonly used for peripheral neuropathic pain, but evidence of their efficacy is currently lacking. Cryoneurolysis, through the application of intense cold to a specific nerve (approximately −70°C), creates a reversible injury to the nerve fibers: the duration and degree of tissue injury depend on the time of application and probe dimension [66]. Pulsed radiofrequency applied proximal to a nerve lesion has been demonstrated to reverse hypersensitivity through an epigenetic mechanism [67].

Dorsal root neurons show altered activity both in diseases directly affecting the ganglion (e.g., radiculopathy due to disc herniation, herpes zoster) and in diseases affecting the axons. Ganglion cells have many important roles in the physiology of nociception: they nourish the axons and are involved in metabolic diseases causing polyneuropathy; they produce ion channels, receptors, and chemical mediators involved in pain transduction, transmission, and inflammatory processes; they regulate action potential propagation [68].

Clinically, DRG dysfunction can present with signs and symptoms of all three phenotypes. In the case of sensory loss due to disease affecting the ganglion, the pathophysiological mechanism is deafferentation [26]. Mechanosensitivity of ganglion cells is well known in herniated disc compression injuries and is characterized by prolonged discharges along all afferent sensory axons [69]. Ganglion cells become hyperexcitable following nerve injury and generate spontaneous and evoked action potentials. After peripheral nerve injury, there is a reorganization of ion channel expression in DRG neurons. Regarding Na⁺ channels, some are reduced, some are newly expressed, and some are redistributed to different parts of the neuron [70]. Indeed, an increase in tetrodotoxin-sensitive (TTX-s) Na_v1.3 (not normally expressed by ganglion cells) and Na_v1.7 channels was observed, together with a reduction in TTX-r (resistant) Na_v1.8 and Na_v1.9 channels [71]. The increase in Na_v1.3 leads to hyperexcitability of the cell and the onset of ectopic discharges. A redistribution of Na_v1.8 channels from the cell body to the axon may explain the increased sensitivity of neuromas [72].

Peripheral nerve injury also causes increased expression of the Ca²⁺ channel subunits Cav α₂-δ1 in DRGs, BK B1 and capsaicin (TRPV1) receptors, and a reduction in B2 receptors, SP, and opioid receptors [73]. A reduction in K⁺ channels contributes to neuronal hyperexcitability.

Sprouting of sympathetic neurons contributes to the development of ectopic activity. Under normal conditions, ganglion neurons are insensitive to norepinephrine, but after nerve fiber injury, there is an increase in α-adrenergic receptors and the formation of clusters of sympathetic axons around ganglion neurons [74].

In a recent article, Hanani [75] highlights the importance of satellite glial cells (SGCs) that surround DRGs; a lesion to peripheral sensory neurons increases their firing rate, inducing increased production of nitric oxide in the neurons; nitric oxide diffuses from the injured neurons and activates SGCs that surround them and probably adjacent neurons. SGC activation causes increased gap junctional coupling, increased sensitivity to ATP, upregulation of ERK, and increased release of pro-inflammatory cytokines (IL-1β, TNF, IL-6, fractalkine, and others). The increased gap junctions and sensitivity to ATP will enhance Ca²⁺ waves, leading to neuronal excitation. Cytokines released from SGCs will also contribute to neuronal sensitization and excitation. The overall effect will be increased firing (spontaneous and/or evoked) of sensory neurons and pain.

Using the spinal nerve ligation (SNL) model in rats, it has been shown that cell bodies in the DRG contribute 3 times more to ectopic nerve activity than the site of nerve injury. The DRG is therefore a fundamental target for pain control [73]. Functional changes involve large, medium, and small neurons in both injured and uninjured afferents [76]. Targeted administration of lidocaine to the DRG at sub-anesthetic concentrations is able to temporarily suppress allodynia [77]. Neurons with axotomized peripheral processes present a diminished filtering of action potential (AP) trains at the T-junction of C-type neurons, enhancing the transmission of impulses originating ectopically in a neuroma, possibly contributing to pain generation [78].

The DRG is a fundamental site to determine pain characteristics: a neural lesion distal to the ganglion can cause peripheral neuropathic pain, while a lesion involving the ganglion or proximal to it, if sufficiently extensive, can cause deafferentation pain, a form of central pain [27].

Direct involvement of the DRG by an inflammatory process, such as radiculopathy secondary to disc herniation, can be treated with local anesthetic and steroid injections [79, 80]. Surgery can release the nerve root in cases of compression due to disc herniation.

There are no selective drugs targeting plastic changes at the DRG level in chronic pain, but many different approaches have been hypothesized and are under investigation, such as compounds acting on transient receptor potential (TRP) channels, monoclonal antibodies targeting CGRP, NGF, TNF already available for other diseases, bacterial products, gene therapy, stem cells, systemically or topically administered [81].

The DRG is also the target of neuromodulation techniques, in particular DRG pulsed radiofrequency and DRG stimulation. DRG pulsed radiofrequency is widely used for radicular pain due to disc herniation and other painful ganglionopathies, such as post-herpetic neuralgia [82, 83]. The quality of evidence is currently low [82]. DRG stimulation has been shown to be effective for lower extremity complex regional pain syndrome (CRPS), but the evidence is considered to be of low quality. Observational studies and case series show promising results for DRG-S in painful diabetic neuropathy (PDN), focal neuropathy, and polyneuropathy [84].

The spinal nociceptive synapse in the dorsal horn is rarely directly involved in diseases that cause neuropathic pain. Dorsal horn cells can be damaged by infectious (e.g., herpes zoster) or inflammatory diseases, by trauma or ischemia; the central terminal of the first-order neuron can be damaged by avulsion, preganglionic or ganglionic radiculopathy. In all these cases, the most likely phenotype is “sensory loss” with deafferentation pain. The perisynaptic area is an important site of plasticity in all cases of subacute or chronic pain. A synaptic dysfunction clinically presents the characteristics of “mechanical hyperalgesia” but also of “thermal hyperalgesia”.

The state of hyperexcitability of spinal neurons has been widely discussed and attributed to functional changes in the mechanisms involved in transmission and inhibition, but also to truly plastic and therefore persistent changes [85]. Many events can cause changes that alter spinal transmission and create a state of altered processing of afferent impulses or produce pain in the absence of afferent impulses. In neuropathic pain, the excitability of the presynaptic element is influenced by the increased synthesis of neurotransmitters and neuromodulators, the density of Ca²⁺ and voltage-gated Na⁺ channels expressed on the membrane [85]. HCN channels contribute to the increased excitability and ectopic firing of peripheral sensory neurons, which is further enhanced by the downregulation of K⁺ channels [85]. At the same time, processing of afferent messages can be altered or spontaneous activity can be generated at the level of the postsynaptic element.

Aβ fibers, which physiologically transmit harmless sensations and have an inhibitory function, can generate pain either by the establishment of postsynaptic sensitization through release of excitatory mediators [SP, brain-derived neurotrophic factor (BDNF), and cofactor for nitric oxide synthase (NOS)] and creating new spinal cord connections through sprouts from deep to superficial laminae [86].

The term “deafferentation pain” is generally used to define pain that results from the interruption of afferent impulses between one neuron and the next in the nerve pathway. Peripheral deafferentation occurs when the lesion affects the root or sensory ganglion but not the peripheral nerve. Central deafferentation pain (or simply central pain), which would theoretically include all forms of deafferentation pain, refers to that which occurs after injury to the central nervous system, spinal and supraspinal pain pathways (e.g., post-stroke pain, syringomyelia, spinal lesions) [94]. In patients with brachial plexus avulsion, the incidence of deafferentation pain is reported to be as high as 90% [95].

The majority of analgesic drugs recommended for neuropathic pain [10] act at the first synapse level.

Antidepressants, acting on the bioavailability of inhibitory mediators, noradrenaline and serotonin, represent one of the first classes of drugs used for neuropathic pain. Tricyclic antidepressants (amitriptyline, nortriptyline, imipramine), serotonin-norepinephrine reuptake inhibitor (SNRI) antidepressants (particularly duloxetine and venlafaxine) are recommended as first line for peripheral and central neuropathic pain [10]. Although the amount of literature favors the use of SNRI, they present an NNT of 6.4 compared to 3.6 for tricyclic antidepressants (TCAs). The number needed to harm (NNH) of TCAs for major adverse effects leading to discontinuation of the drug is 28, and 6 for minor adverse effects (sedation, dizziness, dry mouth, constipation, urinary retention, and headache) [96]. SNRIs have an NNH (sedation or insomnia, headache, and/or decreased appetite or libido) of 11.8 [10]. It is important to emphasize that the analgesic action in patients with neuropathic pain is independent of the antidepressant action.

Gabapentin and pregabalin represent a relatively recent class of anti-epileptics [10]. These drugs, which have become the gold standard for neuropathic pain, have inaugurated a new class of antiepileptics, called the α₂-δ ligands. Newer α₂-δ ligands, such as mirogabalin, available in Japan, or newer gabapentin formulations (gabapentin extended release) have been subsequently developed [97]. Gabapentin has a strong recommendation for use in neuropathic pain (high quality based on new evidence and trials) [10]. In the French revised recommendations, Moisset et al. [11] downgraded pregabalin as a second-line choice because of modest results from recent double-blind trials and reporting of abuse and misuse (higher than gabapentin).

There is no evidence on clonazepam, a benzodiazepine acting on GABA-B receptors that has been reported effective on pain paroxysms and in cases of night awakening due to pain [11].

Tramadol, a weak opioid acting also on noradrenaline and serotonin reuptake, is recommended as a second-line drug [10]. Because of the opioid crisis, particularly in North America, strong opioids are only used as third-line treatment when first and second-line treatments are ineffective for neuropathic pain [97]. The effective dose of these different opioids is generally higher than the doses used in acute or non-neuropathic chronic pain [97]. The main reason for the limitation of long-term use of opioids is the number of side effects they can induce, mainly dizziness, confusion, nausea, constipation, but also respiratory depression, and more importantly, tolerance and a high risk of substance abuse [98].

Other pharmacologic options considered for neuropathic pain are cannabinoids and oral ketamine, for which there is no clear evidence [11].

The main non-pharmacological option for neuropathic pain acting at the spinal cord level is spinal cord stimulation (SCS); it acts with different demonstrated mechanisms that change the balance of nociceptive and antinociceptive inputs through the activation of segmental and supraspinal pathways [99]. SCS has been used for more than 40 years to treat localized chronic medically refractory neuropathic pain involving limb(s) and trunk. The most frequent indications remain CRPS, failed back surgery syndrome (FBSS), and peripheral neuropathy. The risk/benefit ratio is favorable to SCS, considering that chronic pain patients undergoing this procedure are usually resistant to all the other therapies [100]. A recent review demonstrated a weak GRADE recommendation for the use of conventional SCS in neuropathic pain associated with FBSS and diabetic painful neuropathies (moderate final quality of evidence) [11].

Intrathecal delivery of drugs acting at the synaptic level, mainly morphine and ziconotide, can be considered for neuropathic pain patients not responsive to other therapies, but there is no literature evidence [11].

In addition to the peripheral and spinal mechanisms discussed, supraspinal mechanisms have been shown to play an important role in neuropathic pain.

Descending neuronal pathways from midbrain and brainstem nuclei physiologically modulate pain perception at the level of the spinal cord with a predominant inhibitory effect. In chronic pain, both inflammatory and neuropathic, serotonergic-mediated facilitation may prevail over descending noradrenergic and serotonergic inhibition [85].

Functional plasticity of many components of the so-called “pain matrix”, the network of brain regions activated by painful stimuli, has been demonstrated in chronic pain patients in general. Specific cortical areas are involved in nociception and pain localization (mainly posterior operculo-insular areas), whereas conscious pain is elaborated in a second-order network involving posterior parietal, prefrontal, and anterior insular areas [101]. These regions are responsible for conscious perception, attentional modulation, and control of vegetative responses. The experience of pain is influenced by a third network that takes into account past experiences, beliefs, and emotional state. Neuropathic pain is associated with alterations at all levels of integration [101].

Pain can originate directly from the central nervous system in lesions or diseases of the central somatosensory pathways: spinal cord injury, stroke, multiple sclerosis, and other diseases of the central nervous system are often associated with pain [102]. In these cases, sensory and motor deficits can be observed in typical distributions according to the site of the lesion. Pain can result from the spontaneous activity of deafferented neurons in the central nervous system and/or the altered activity of spared neurons in the spinothalamic tract [102].

Unfortunately, there is a paucity of literature on the treatment of central pain, and a number of drugs that have been studied have been shown to have an effect on signal transmission at the first synapses (opioids, gabapentinoids), whereas in these cases, the pain originates more rostrally [103].

The impairment of endogenous analgesia following nerve injury may be the rationale for the use of SNRIs in neuropathic pain [104]. Dopaminergic neurotransmission has been shown to play a central role in the modulation of pain perception and analgesia in supraspinal regions, including the basal ganglia, insula, anterior cingulate cortex, thalamus, and periaqueductal grey, and in descending inhibition [105]. Fluphenazine, a dopaminergic antipsychotic, has been shown to be effective in controlling neuropathic pain symptoms [106]. Second-generation antipsychotics have fewer extrapyramidal side effects and may be useful in the treatment of neuropathic pain; in addition to blocking dopamine (D2) receptors, they also act on adrenergic, acetylcholine, catecholamine, histamine, and serotonin receptors in the central nervous system [107].

Non-invasive neuromodulation techniques [repetitive transcranial magnetic stimulation (rTMS), and transcranial direct current stimulation (tDCS)] targeting cortical areas involved in the affective component of pain (prefrontal cortex, motor cortex) have shown some analgesic effects, but with low-quality evidence [11].

Invasive MCS has been used in cases of resistant central pain, but the number of patients enrolled is very small [11].

As the affective component is one of the main aspects of chronic pain, psychological interventions such as cognitive-behavioral therapy or mindfulness therapy may be recommended along with other treatment modalities [108].