title: 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.
authors.affiliation: Peripheral Neuropathy Unit, Hammersmith Hospital, Imperial College, London, UK. p.anand@imperial.ac.uk
authors.forename: Praveen
authors.initials: P
authors.lastname: Anand
authors.forename: Ravikiran
authors.initials: R
authors.lastname: Shenoy
authors.forename: Joanne E
authors.initials: JE
authors.lastname: Palmer
authors.forename: Amanda J
authors.initials: AJ
authors.lastname: Baines
authors.forename: Robert Y K
authors.initials: RY
authors.lastname: Lai
authors.forename: Jonathan
authors.initials: J
authors.lastname: Robertson
authors.forename: Nick
authors.initials: N
authors.lastname: Bird
authors.forename: Thor
authors.initials: T
authors.lastname: Ostenfeld
authors.forename: Boris A
authors.initials: BA
authors.lastname: Chizh
mesh_terms: D000328:Adult; D000368:Aged; D000700:Analgesics / Q000008:administration & dosage* / Q000009:adverse effects; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000008:administration & dosage* / Q000009:adverse effects; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D009437:Neuralgia / Q000188:drug therapy* / Q000201:enzymology; D047428:Protein Kinase Inhibitors / Q000008:administration & dosage* / Q000009:adverse effects; D011728:Pyridones / Q000008:administration & dosage* / Q000009:adverse effects; D011743:Pyrimidines / Q000008:administration & dosage* / Q000009:adverse effects; D055815:Young Adult; D048051:p38 Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors*
chemical_list: D000700:Analgesics; D000894:Anti-Inflammatory Agents, Non-Steroidal; D047428:Protein Kinase Inhibitors; D011728:Pyridones; D011743:Pyrimidines; D048051:p38 Mitogen-Activated Protein Kinases; C574213:dilmapimod