Topical analgesics for neuropathic pain: Preclinical exploration, clinical validation, future development

Abstract

Topical analgesics applied locally to skin or to specialized compartments modify pain by actions on sensory nerve endings and/or adjacent cellular elements. With this approach, there are low systemic drug levels, good tolerability and few drug interactions, and combination with oral formulations is feasible. The goal of this review is to provide an overview of the potential for topical analgesics to contribute to improved management of neuropathic pain. Mechanistic and preclinical studies indicate much potential for development of novel topical analgesics for neuropathic pain. In humans, two topical analgesics are approved for use in postherpetic neuralgia (lidocaine 5% medicated plaster, capsaicin 8% patch), and there is evidence for efficacy in other neuropathic pain conditions. Comparative trials indicate similar efficacy between topical and oral analgesics. Not all individuals respond to topical analgesics, and there is interest in determining factors (patient factors, sensory characteristics) which might predict responsiveness to topical analgesics. There is a growing number of controlled trials and case reports of investigational agents (vasodilators, glutamate receptor antagonists, α2-adrenoreceptor agonists, antidepressants, centrally acting drugs), including combinations of several agents, indicating these produce pain relief in neuropathic pain. There is interest in compounding topical analgesics for neuropathic pain, but several challenges remain for this approach. Topical analgesics have the potential to be a valuable additional approach for the management of neuropathic pain.

Evaluation of the Percutaneous Absorption of Ketamine HCl, Gabapentin, Clonidine HCl, and Baclofen, in Compounded Transdermal Pain Formulations, Using the Franz Finite Dose Model

“…The a2-adrenergic agonist clonidine is a centrally acting antinociceptive agent with the added benefit of prolonging the analgesic effect of other drugs [28,33]. Topical clonidine HCl has also been shown to be effective in the treatment of painful diabetic neuropathy [34] and inflammatory nerve injury (reviewed in [18]). …”

“…Within the epidermis, the stratum corneum is the outermost layer of the skin that serves as the main barrier to drug entry [17]. Formulation of a medicine that is adequately absorbed through the skin depends on the careful determination of optimal drug combinations, effective concentrations of each drug, and suitable vehicles for delivery [18]. Consequently, solubility characteristics, skin barrier modifications, and stability are among the key determinants of effective compounding bases [19].…”

Topical and Peripheral Ketamine as an Analgesic

“…While controlled trials do not provide consistent data for efficacy, there may be a concentrationresponse relationship, 78,79 and placebo-controlled trials generally have examined lower concentrations. 95 For example, post hoc analysis indicates catastrophizing can contribute to outcomes in topical analgesic trials, including formulations containing ketamine. 93,94 Future controlled trials of topical analgesics will need to attend to factors that might predict responses to topical analgesics, such as pain or sensory characteristics, patient characteristics, and disease duration and severity.…”

The molecular structure and vibrational, 1H and 13C NMR spectra of lidocaine hydrochloride monohydrate

“…Lidocaine is a commonly used drug with many applications due to its antiarrhythmic and local anesthetic effects [1][2][3][4][5][6][7][8]. It mainly acts by blocking the pore-forming region of neuronal voltage-gated sodium (Na + ) channels [9].…”