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.

Insights into the Promising Prospect of G Protein and GPCR-Mediated Signaling in Neuropathophysiology and Its Therapeutic Regulation

“…Antidepressant drug therapy does not appear to alter G protein expression levels in the central nervous system (CNS) consistently in preclinical trials. Chronic treatment with the tricyclic antidepressant imipramine results in relatively stable mRNA expression of G α s, G α o, and G α i in the rat hippocampus, according to one study [ 127 ]. However, the measurement of G protein mRNA levels does not necessarily provide insight into its protein expression [ 128 ].…”

Peripheral Voltage-Gated Cation Channels in Neuropathic Pain and Their Potential as Therapeutic Targets

“…Effects of clonidine may be mediated by α 2 -adrenergic inhibition of neurotransmitter release leading to modulation of pain processing at the spinal level (5) and/or by attenuation of aberrant interactions between sympathetic and sensory nerves in the periphery (156,157,373). Its effectiveness is however limited to subsets of patients within the diabetic neuropathy, complex regional pain syndrome or postherpetic neuralgia cohorts (88)(89)(90)(91)(92). In view of the restricted effectiveness of clonidine, it does not meet the criteria for first line treatment of neuropathic pain (1) (Table 1).…”

A Systematic Review on Cannabinoids for Neuropathic Pain Administered by Routes Other than Oral or Inhalation

“…There is no evidence to support the use of conventional analgesics such as paracetamol or non-steroidal anti-inflammatory drugs (NSAIDs) in the treatment of chronic neuropathic pain [ 16 ]. Some studies have addressed topical management with local anesthetics and capsaicin patches with results not always optimal [ 17 , 18 , 19 , 20 , 21 ]. The most widely accepted treatment is with neuromodulators, such as antidepressants (duloxetine and amitriptyline) [ 22 ] or anticonvulsants (gabapentin or pregabalin) [ 23 ].…”