Clinical trial of the p38 MAP kinase inhibitor dilmapimod in neuropathic pain following nerve injury

Abstract

Current treatments of neuropathic pain arising from conditions such as nerve injury/compression are only partially effective, and limited in their use by side-effects. p38 mitogen-activated protein kinase (MAPK) is involved in the regulation and synthesis of inflammatory mediators, and is the target for a novel class of cytokine-suppressive anti-inflammatory drugs. p38 inhibitors may reduce neuronal sensitisation in preclinical models of neuropathic pain, particularly where there is a substantial inflammatory component. An exploratory, multicentre, double-blind, placebo-controlled, two-period, cross-over trial was undertaken to evaluate the effect of dilmapimod (SB-681323), a selective p38 MAPK inhibitor, on neuropathic pain symptoms and signs. Fifty patients with nerve trauma, radiculopathy or carpal tunnel syndrome were randomised; 43 patients completed the study. Eligible patients received oral dilmapimod and placebo twice daily for 2 weeks, with an intervening washout period of 2-4 weeks. Subjects attended weekly for efficacy and safety assessments, which included evaluation of daily and current pain intensity using an 11-point numerical rating scale (NRS), quantitative sensory testing, allodynia and global impression of change. There was a statistically significant reduction in the primary endpoint of average daily pain score during the second week of treatment among patients treated with dilmapimod (15 mg/day) compared to placebo using NRS [0.80; 95% CI (0.28, 1.33); p=0.0034]. A similar trend for effect was seen in some secondary endpoints. Dilmapimod was well tolerated, with no clinically relevant safety findings. p38 MAPK inhibitors merit further evaluation for neuropathic pain in larger clinical trials, particularly for clinically meaningful analgesic effect size.

Ubiquitin-conjugating enzyme Ubc13 controls breast cancer metastasis through a TAK1-p38 MAP kinase cascade

“…The p38 MAPK also participates in different steps of metastasis, including ECM invasion by primary cancer cells, migration across the surrounding tissue, entry into the circulation, and colonization of distant sites (20). p38 inhibitors are not toxic and were found effective in prevention and attenuation of inflammatory pain in humans (21,22). Here we show that a Ubc13-controled TAK1-p38 cascade controls BCa metastatic dissemination and that a p38 inhibitor can cause regression of established metastases.…”

“…Given that a number of small molecule p38 inhibitors were found to be effective and safe for the treatment of inflammatory pain in humans (21,22), these findings suggest that p38 inhibitors should be evaluated as antimetastatic drugs in human BCa. Because bone metastasis is frequently associated with inflammatory and neuropathic pain, such inhibitors can be first evaluated for their ability to alleviate pain in bone metastatic BCa, an application that will facilitate the testing of their antimetastatic potential (63).…”

Wnt/beta-Catenin Signaling and Small Molecule Inhibitors

“…Interestingly, both compounds affect only GSK3 , but not GSK3 , making the intervention isoform-specific. Several p38 MAPK inhibitors are in clinical trials including the anti-inflammatory drug PH-797804 and dilmapimod [138,139].…”

Protein Kinases and Pain

“…p38 MAPK phosphorylates targets that transduce cellular signals to molecules and transcription factors that are involved in regulating the biosynthesis of inflammatory cytokines such as IL-1 and TNF-. The inhibitor dilmapimod was associated with a significant reduction in pain intensity in patients with neuropathic pain following nerve injury (Anand et al, 2011). The clinical efficacy of p38 MAPK inhibitors in acute pain was also demonstrated in an assay of acute postsurgical dental pain; these inhibitors increased the time to rescue medication and decreased pain intensity when compared with the placebo group (Tong et al 2011).…”