Topical Treatments and Their Molecular/Cellular Mechanisms in Patients with Peripheral Neuropathic Pain-Narrative Review

Abstract

Neuropathic pain in humans results from an injury or disease of the somatosensory nervous system at the peripheral or central level. Despite the considerable progress in pain management methods made to date, peripheral neuropathic pain significantly impacts patients' quality of life, as pharmacological and non-pharmacological methods often fail or induce side effects. Topical treatments are gaining popularity in the management of peripheral neuropathic pain, due to excellent safety profiles and preferences. Moreover, topical treatments applied locally may target the underlying mechanisms of peripheral sensitization and pain. Recent studies showed that peripheral sensitization results from interactions between neuronal and non-neuronal cells, with numerous signaling molecules and molecular/cellular targets involved. This narrative review discusses the molecular/cellular mechanisms of drugs available in topical formulations utilized in clinical practice and their effectiveness in clinical studies in patients with peripheral neuropathic pain. We searched PubMed for papers published from 1 January 1995 to 30 November 2020. The key search phrases for identifying potentially relevant articles were "topical AND pain", "topical AND neuropathic", "topical AND treatment", "topical AND mechanism", "peripheral neuropathic", and "mechanism". The result of our search was 23 randomized controlled trials (RCT), 9 open-label studies, 16 retrospective studies, 20 case (series) reports, 8 systematic reviews, 66 narrative reviews, and 140 experimental studies. The data from preclinical studies revealed that active compounds of topical treatments exert multiple mechanisms of action, directly or indirectly modulating ion channels, receptors, proteins, and enzymes expressed by neuronal and non-neuronal cells, and thus contributing to antinociception. However, which mechanisms and the extent to which the mechanisms contribute to pain relief observed in humans remain unclear. The evidence from RCTs and reviews supports 5% lidocaine patches, 8% capsaicin patches, and botulinum toxin A injections as effective treatments in patients with peripheral neuropathic pain. In turn, single RCTs support evidence of doxepin, funapide, diclofenac, baclofen, clonidine, loperamide, and cannabidiol in neuropathic pain states. Topical administration of phenytoin, ambroxol, and prazosin is supported by observational clinical studies. For topical amitriptyline, menthol, and gabapentin, evidence comes from case reports and case series. For topical ketamine and baclofen, data supporting their effectiveness are provided by both single RCTs and case series. The discussed data from clinical studies and observations support the usefulness of topical treatments in neuropathic pain management. This review may help clinicians in making decisions regarding whether and which topical treatment may be a beneficial option, particularly in frail patients not tolerating systemic pharmacotherapy.

Keywords: BTX-A; capsaicin; ion channels; lidocaine; localized neuropathic pain; peripheral mechanisms; peripheral neuropathic pain; peripheral sensitization; polyneuropathy; receptors; topical treatment.

Figure 1

Peripheral nerve endings, keratinocytes, and immune cells express ion channels and receptors and release numerous signaling molecules to create a complex interaction, involved in physiological nociception and neuropathic pain (NP) generation. Abbreviations: Nav—voltage-gated sodium channels, TRP—transient receptor potential channels, VGCCs—voltage-gated calcium channels, NMDAR—N-methyl-D-aspartate receptors, ASIC—acid-sensing ion channels, TLR—Toll-like receptors, α1-AR—α1 adreno receptors, α2-AR—α2 adreno receptors, EP—prostaglandin E2 receptors, GABAAR—gamma-aminobutyric acid receptors A, GABABR—gamma-aminobutyric acid receptors B, Kv—voltage-gated potassium channels, OR—opioid receptors, CB1, CB2—cannabinoid receptors type 1 or 2, CCL-R—chemokine receptors, IL-R—interleukin receptors, TrkA—tropomyosin receptor kinase A, HCN—hyperpolarization-activated cyclic nucleotide-gated channels, P2X3—P2X purinoceptors 3, GPCR—G protein-coupled receptors, TLR—Toll-like receptors. Created with BioRender.com.

Figure 2

Topical treatments utilized in clinical practice and their molecular/cellular mechanisms in patients suffering from localized NP (LNP). Active molecules from topically applied drug formulations modulate the corresponding ion channels, receptors, enzymes, or proteins on neuronal and non-neuronal cells. Abbreviations: Nav—voltage-gated sodium channels, TRPV1—transient receptor potential vanilloid 1, VGCCs—voltage-gated calcium channels, NMDAR—N-methyl-D-aspartate receptors, α1-AR—α1 adreno receptors, α2-AR—α2 adreno receptors, GABAR—gamma-aminobutyric acid receptors, CB—cannabinoid receptors, COX-2—cyclooxygenase 2, SNAP-25—synaptosome associated protein 25, OR—opioid receptors, TRPM8—transient receptor potential melastatin 8.