Analgesic efficacy and safety of the novel p38 MAP kinase inhibitor, losmapimod, in patients with neuropathic pain following peripheral nerve injury: a double‐blind, placebo‐controlled study

Abstract

Losmapimod could not be differentiated from placebo in terms of a primary analgesia response in patients with pain following peripheral nerve injury. The lack of response could reflect inadequate exposure at central sites of action or differences between rodent and human with respect to the target or neuropathic pain mechanisms.

Intrathecal administration of antisense oligonucleotide against p38α but not p38β MAP kinase isoform reduces neuropathic and postoperative pain and TLR4-induced pain in male mice

“…However, our knowledge about p38 isoforms in pain regulation is still limited, in part because commercial antibodies for phosphorylated p38 (p-p38) MAPK and inhibitors of p38 MAPK are not isoform-specific (Ji and Suter, 2007). Of note, the oral administration of p38 inhibitor (losmapimod), targeting p38α and p38β MAPK, failed to produce analgesic effects in patients suffering neuropathic pain (Ostenfeld et al, 2013). In another trial, p38α inhibitor dilmapimod alleviated pain via oral route in patients with neuropathic pain (Anand et al, 2011).…”

“…In one trial, p38α MAPK inhibitor dilmapimod, administered via oral route, alleviated pain in patients with neuropathic pain (Anand et al, 2011). In another trial, oral administration of p38 MAPK inhibitor losmapimod that targets both p38α and p38β MAPK did not produce significant analgesic effects in patients suffering neuropathic pain (Ostenfeld et al, 2013). The lack of response could reflect insufficient losmapimod levels in the spinal cord (Ostenfeld et al, 2013).…”

“…In another trial, oral administration of p38 MAPK inhibitor losmapimod that targets both p38α and p38β MAPK did not produce significant analgesic effects in patients suffering neuropathic pain (Ostenfeld et al, 2013). The lack of response could reflect insufficient losmapimod levels in the spinal cord (Ostenfeld et al, 2013). It may also result from different pain models/conditions between lumbosacral radiculopathy in patients and animal models of neuropathic pain (Ostenfeld et al, 2013), as we showed in this study.…”

A Randomized, Placebo-controlled Trial of the Analgesic Efficacy and Safety of the p38 MAP Kinase Inhibitor, Losmapimod, in Patients With Neuropathic Pain From Lumbosacral Radiculopathy

“…Timing of the intervention and insufficient drug levels in the spinal cord may explain why losmapimod did not relieve pain in this trial, and an earlier study in chronic pain (duration of Z3 mo) after peripheral nerve injury caused by trauma or surgery. 43 Clinical studies in patients with radicular back pain are recognized to present significant challenges in terms of the identification of a neuropathic pain population, choice of optimal trial design, and endpoints for revealing clinically important effects while minimizing high placebo response rates. 39,44,45 The majority of our patients (> 90% in each group) had concomitant back pain and at least half in each treatment group received the study medication as adjunctive therapy.…”

The role of slow and persistent TTX-resistant sodium currents in acute tumor necrosis factor-α-mediated increase in nociceptors excitability

“…Administration of a p38 MAPK blocker prevented hyperexcitable effects of TNF-␣ in vitro and the acute effect of TNF-␣ in vivo, without interfering with the late onset TNF-␣-mediated pain hypersensitivity. Blockade of p38 MAPK leads to a decrease in sodium current density (Hudmon et al 2008;Ostenfeld et al 2013) and to a leftward shift in slow inactivation (Fig. 9A).…”