The somatosensory nervous system may become injured at the peripheral or central level, which can result in peripheral or central NP, respectively. Common conditions associated with peripheral NP in humans include postherpetic neuralgia (PHN), painful diabetic neuropathy (PDN), trigeminal neuralgia, painful radiculopathy, HIV-associated neuropathy (human immunodeficiency virus), post-amputation pain, chemotherapy-induced peripheral neuropathy (CIPN), and peripheral nerve injury pain such as carpal tunnel syndrome or postsurgical NP. Stroke, spinal cord injury, and multiple sclerosis may, in turn, result in central NP syndromes [8].

The peripheral somatosensory nervous system may be damaged at several levels—peripheral nerve endings, axons, or cell bodies in the dorsal root ganglions (DRG)—in multiple ways, such as mechanically, thermally, chemically, and through infectious factors. In humans, the exact mechanisms of NP generation are not fully elucidated. However, preclinical studies with NP animal models gave some insight into the peripheral mechanisms involved [9]. The injury of peripheral neurons, independently of the cause and level of the damage, induces complex functional and structural changes not only in neurons (sensory and motor) and glial cells but also in non-neuronal cells such as keratinocytes and immunocompetent cells (e.g., macrophages, mast cells, neutrophils). The complex neuro–immune–cutaneous interactions, their changes observed after peripheral nerve injury, and their role in generation and maintenance of NP were reviewed in our paper published recently [10].

Although only a few molecular/cellular mechanisms of NP in humans are directly elucidated [10], the following preclinical and clinical findings justify the utilization of topical analgesics in clinical practice.

• Input from hyperexcitable peripheral neurons is crucial for development, modulation, and maintenance of NP [11].
• Upon physiological nociception, peripheral neurons exert complex interactions with immunocompetent cells and keratinocytes via neuropeptides, neurotransmitters, cytokines, and other signaling molecules acting on corresponding ion channels or receptors (Figure 1) [12]. Once pathological conditions (i.e., nerve injury, inflammation) occur, these interactions result in overactivation and disturbed functioning of neuronal and non-neuronal cells, finally contributing to neuronal hyperexcitability, peripheral sensitization, and pain [11].
• Inhibition of peripheral sensitization can diminish and/or abolish the signs and symptoms of central sensitization in humans with peripheral and central NP [13,14].

A peripheral lesion of the nervous system induces more localized signs and symptoms of NP (e.g., allodynia, hyperalgesia) compared to a central lesion, which might be targeted by analgesics applied topically [15]. To improve daily clinical practice and to identify patients for whom a topical treatment should be considered, the definition of “localized neuropathic pain” (LNP) has been proposed [16]. LNP is a type of NP that is characterized by a consistent and circumscribed area(s) of maximum pain, associated with negative or positive sensory signs and/or spontaneous symptoms characteristic of neuropathic pain [16] and is felt superficially [15]. The circumscribed area of LNP is not larger than a letter-size piece of paper and may be diagnosed in 60% of NP patients, and up to more than 80% of PHN patients [16]. However, epidemiological data are scarce and estimation of LNP prevalence is broad [2]. Nevertheless, the proposed definition of LNP may help clinicians to optimally select the patients being best candidates for topical treatments.

Clinical data reviewed by Finnerup et al. [5] and Moisset et al. [6] show relatively good evidence supporting the use of topical analgesics in patients with LNP, especially in view of the low risk of side effects associated with this route of administration. Based on the current literature, the best evidence coming from randomized clinical trials (RCTs) to treat LNP with topical analgesics is for 5% lidocaine patches, 8% capsaicin patches, and botulinum toxin A (BTX-A) intradermal injections [5,6]. A recent review and clinical recommendations on NP management determined 5% lidocaine patches (local anesthetic drug) as first-line treatment and 8% capsaicin patches (local anesthetic drug) and BTX-A (peripherally acting muscle relaxant) as second-line treatments in patients with LNP [6].

The recommendation for the use of 5% lidocaine patches in LNP is weak with a moderate quality of evidence, according to the Grading of Recommendations Assessment, Development, and Evaluation (GRADE) system. However, topical lidocaine has an excellent safety profile and is commonly used in patients with several LNP syndromes [6]. Topically applied 8% capsaicin patches and BTX-A injections have a weak recommendation for use in patients with LNP with a high quality of evidence [6]. The clinical use of 8% capsaicin patches is limited by the special requirements of the application, i.e., application in specialized pain clinics by a well-trained team. Similar concerns are related to subcutaneous injections of BTX-A, whose availability is limited to specialized pain centers only [6].

Despite lacking robust evidence, several other topical treatments are currently used in clinical practice in patients with LNP, such as anesthetic drugs (capsaicin at low concentrations, ketamine), antiepileptics (gabapentin, phenytoin, cannabidiol), muscle relaxants (baclofen), antidepressants (amitriptyline, doxepin), mucolytics (ambroxol), antihypertensives (clonidine, prazosin), anti-inflammatory and antirheumatic drugs (diclofenac), antipruritics (menthol), antipropulsives (loperamide), and other analgesics (funapide) [17,18,19,20,21]. The scientific evidence for their use is inconclusive and comes mainly from case reports, case series, observational studies, or single RCTs. However, the low level of evidence does not exclude the possible effectiveness and beneficial analgesic effect in a given subject, particularly when other treatments fail, are contraindicated, or induce unacceptable side effects.

Topical analgesics utilized in clinical practice have undoubted advantages, including reduction in or absence of systemic side effects and reduced risk of overdose due to low or no systemic absorption from topical formulations, relatively few drug–drug interactions, ease of use and dose determination, avoidance of first-pass metabolism, improved patients’ compliance, and direct access to the target site and underlying pain mechanism. The disadvantages include the need for repeated applications per day for creams or gels, local side effects such as skin irritation, itch, or reddening, special requirements for 8% capsaicin patches and BTX-A application, and clinical usefulness limited to patients with LNP only [17,18,19,20,21]. Nevertheless, looking at molecular mechanisms, topical drugs act locally at peripheral mechanisms involved in NP generation, which is in line with current principles in pain medicine pointing out the need for personalized and mechanism-based approaches to pain management [22].

Molecules smaller than 500 dalton can easily penetrate the stratum corneum [23]. Nearly all active molecules are smaller than 500 dalton, and thus topically applied active molecules diffuse across the stratum corneum and influence structures in the epidermis (e.g., nociceptors, keratinocytes). Some active molecules penetrate deeper layers depending on the active molecule and the topical formulation. Active molecules of topical formulations may act on several distinct ion channels, receptors, proteins, or enzymes expressed by either neuronal or non-neuronal cells (Figure 1). The result of this process is the interruption of mutually intensifying stimulation loops, reduction in peripheral sensitization, and peripheral input, resulting in a reduction in NP, e.g., hyperalgesia and allodynia, in patients with LNP (Figure 2).

Since peripheral hyperexcitable cells of different types may become a target for topically administered analgesics, it is worth learning which receptors, ion channels, and/or enzymes involved in peripheral sensitization topical treatments may modulate directly or indirectly. In the subsequent sections, molecular/cellular mechanisms are presented, with a short description of the pathological changes occurring upon NP conditions, followed by preclinical and clinical data on topical treatments modulating a given ion channel, receptor, enzyme, or protein. Topical drugs utilized in subjects with LNP often exert multiple mechanisms of action, but to what extent each of these contributes to the analgesic effect observed in humans is not elucidated. This paper focuses mainly on topical treatments utilized in clinical practice. However, there are numerous preclinical trials pointing at the antinociceptive effect of substances administered topically in NP animal models, though they have not yet been introduced in clinical practice and are thus not included in this review [24,25].