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.
Highlights
Neuropathic pain (NP) in humans arises as a consequence of a lesion or disease of the somatosensory nervous system [1] and affects 7–10% of the world population [2].Patients suffering from chronic NP are characterized by higher health care utilization, higher risk of comorbidities such as depression, anxiety, and sleep disturbances, and lower quality of life compared to patients with chronic non-neuropathic pain [3]
Looking at molecular mechanisms, topical drugs act locally at peripheral mechanisms involved in NP generation, which is in line with current principles creams or gels, local side effects such as skin irritation, itch, or reddening, special requirements for 8% capsaicin patches and botulinum toxin A (BTX-A) application, and clinical usefulness limited to patients with localized neuropathic pain” (LNP) only [17,18,19,20,21]
In the subsequent molecular/cellular mechanisms presented, a short analgesics, description of it theispathological changes occurring upon NP conditions, followed by topically administered worth learning which receptors, ion channels, preclinical and clinical data on topical treatments modulating a given ion channel, recepand/or enzymes involved in peripheral sensitization topical treatments may modulate tor, enzyme, or protein
Summary
Neuropathic pain (NP) in humans arises as a consequence of a lesion or disease of the somatosensory nervous system [1] and affects 7–10% of the world population [2]. Patients suffering from chronic NP are characterized by higher health care utilization, higher risk of comorbidities such as depression, anxiety, and sleep disturbances, and lower quality of life compared to patients with chronic non-neuropathic pain [3]. The negative impact of NP on patients’ functioning and quality of life results, among others, from an unsatisfactory analgesic effect of neuropathic pain treatments. Topical routes of analgesics administration are gaining popularity in pain medicine since topical treatments have an excellent safety profile and preference compared to systemic drugs in patients with peripheral NP [5,6]. The current knowledge on topical treatments, possible molecular mechanisms, and their effectiveness in clinical practice is crucial for health care professionals dealing with patients suffering from peripheral NP. Our review did not include studies indexed in databases other than PubMed
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