Topical Medication for Neuropathic Pain

In 1994, the International Association for the Study of Pain (IASP) established a clear taxonomy of nociceptive and neuropathic pain as two different types of pain (1). Nociceptive pain originates from activation of nociceptive receptors, while neuropathic pain is directly linked to a lesion or disease of either the central or peripheral nervous systems (2). A variety of topical medications are used to treat neuropathic pain with varying degrees of efficacy, such as anaesthetic agents, muscle relaxants, anti-inflammatory agents, NSAIDs, etc.

Currently, lidocaine in the form of 5% medicated plaster is the most widely studied local anaesthetic agent for the treatment of neuropathic pain (3). The application of 5% lidocaine medicated plaster has shown effectiveness for the treatment of post-herpetic neuralgia (PHN) and diabetic polyneuropathy (DPN). Roughly 51% of the patients in the study of PHN reported at least moderate pain relief after lidocaine treatment (1). On another note, ketamine is an example of a general anesthetic that may also relieve neuropathic pain. Ketamine’s topical application for neuropathic pain relies on an NMDA receptor blockade in a non-competitive fashion, and pain modulation occurs via the blocking of glutamate production (1). Only a few studies have described the results after the topical application of ketamine alone, as the agent is more commonly used in combination with other drugs. For instance, the isolated use of 1% ketamine ointment in patients with PHN showed no significant difference between the active group and the placebo in a double-blinded RCT crossover study in patients (1). On the contrary, promising results were obtained from an open label study of patients with PHN treated with a topical application of 0.5% ketamine, as well as patients with complex regional pain syndrome (CRPS), lumbar radiculopathy, and PHN (1).

Baclofen is a muscle relaxant traditionally used for the systemic treatment of spasticity. The topical application of baclofen offers the potential of neuropathic pain relief, due to its GABAB receptor agonist features (1). GABAB receptor activation entails slow and prolonged inhibitory transmission, mediated by changes in membrane permeability due to an intracellular increase in K+ and a decrease in Ca2+ ions (4). In 2008, the effectiveness of single subcutaneous Baclofen in reducing thermal hyperalgesia was investigated in mice with advanced skin cancer and mixed nociceptive and neuropathic pain, with mild to moderate success (1). Since then, in only two studies involving humans, baclofen was used as a single topical agent for the treatment of neuropathic pain, and as an add-on therapy in a case with lumbar hernia-derived neuropathic pain. In both studies, topical baclofen application was shown to be effective in pain relief.

Capsaicin is a natural vanilloid derived from the capsicum plant, and is primarily responsible for the burning sensation felt during the consumption of ‘spicy’ foods (1). Interestingly, it has very significant analgesic effects. In 2013, a systematic review of six studies and a total of 2000 patients by Derry et al. reported that the topical use of an 8% capsaicin patch was more effective than a ‘placebo’ by rendering 30–50% significant post-treatment pain relief in patients with PHN and HIV-distal sensory polyneuropathy (HIV-DSP) (5). In the case of DPN, a 2012 prospective observational study of 91 cases treated with a single high-dose capsaicin patch showed a significant reduction in pain that persisted by week 12 in 34% of the patients (6). Unfortunately, among all topical agents used for the treatment of neuropathic pain, a high-dose 8% capsaicin patch was more likely to produce topical side effects, which included mild to moderate transient burning in the area of application, pain, papules, swelling, and dryness (1).

Peripheral nerve injury induces an inflammatory response with increased prostaglandin production, which leads to the depolarization of second-order nociceptive neurons. The topical application of non-steroidal anti-inflammatory drugs (NSAIDs) plays a crucial role, as they interrupt the progression of the inflammatory pathway (1). Diclofenac, an example of an NSAID, has great cyclooxygenase-2 (COX-2) inhibition. Its efficacy has been described experimentally for the treatment of neuropathic orofacial pain, with promising results after 5% topical diclofenac administration (1). In 2015, a study conducted by Ahmed et al. also found satisfying results in pain relief for patients with PHN and CRPS after the topical application of 1.5% diclofenac (1). As of 2017, no other NSAID drug has been used topically as a single agent for the treatment of neuropathic pain (1).

References

1. Casale, R., Symeonidou, Z., & Bartolo, M. (2017). Topical Treatments for Localized Neuropathic Pain. Current pain and headache reports, 21(3), 15. doi:10.1007/s11916-017-0615-y
2. Treede, R, Jensen, T. S., Campbell, J. N., Cruccu, G., Dostrovsky, J. O., Griffin, J. W., Hansson, P., Hughes, R., Nurmikko, T., Serra, J. (2008). Neuropathic pain. Neurology, 70(18), 1630-1635; doi: 10.1212/01.wnl.0000282763.29778.59
3. de León-Casasola, O. A., & Mayoral, V. (2016). The topical 5% lidocaine medicated plaster in localized neuropathic pain: a reappraisal of the clinical evidence. Journal of pain research, 9, 67–79. doi:10.2147/JPR.S99231
4. Reis, G. M., & Duarte, I. D. (2006). Baclofen, an agonist at peripheral GABAB receptors, induces antinociception via activation of TEA-sensitive potassium channels. British journal of pharmacology, 149(6), 733–739. doi:10.1038/sj.bjp.0706898
5. Derry S, Sven-Rice A, Cole P, Tan T, Moore RA. Topical capsaicin (high concentration) for chronic neuropathic pain in adults. Cochrane Database Syst Rev. 2013;2:CD007393.
6. Martini, C., Yassen, A., Olofsen, E., Passier, P., Stoker, M., & Dahan, A. (2012). Pharmacodynamic analysis of the analgesic effect of capsaicin 8% patch (Qutenza™) in diabetic neuropathic pain patients: detection of distinct response groups. Journal of pain research, 5, 51–59. doi:10.2147/JPR.S30406