title: Inhibiting the breakdown of endogenous opioids and cannabinoids to alleviate pain.
abstract: Chronic pain remains unsatisfactorily treated, and few novel painkillers have reached the market in the past century. Increasing the levels of the main endogenous opioid peptides - enkephalins - by inhibiting their two inactivating ectopeptidases, neprilysin and aminopeptidase N, has analgesic effects in various models of inflammatory and neuropathic pain. Stemming from the same pharmacological concept, fatty acid amide hydrolase (FAAH) inhibitors have also been found to have analgesic effects in pain models by preventing the breakdown of endogenous cannabinoids. Dual enkephalinase inhibitors and FAAH inhibitors are now in early-stage clinical trials. In this Review, we compare the effects of these two potential classes of novel analgesics and describe the progress in their rational design. We also consider the challenges in their clinical development and opportunities for combination therapies.
authors.affiliation: Pharmaleads SAS, 11 Rue Watt, 75013 Paris, France. bernard.roques@pharmaleads.com
authors.forename: Bernard P
authors.initials: BP
authors.lastname: Roques
authors.forename: Marie-Claude
authors.initials: MC
authors.lastname: Fournié-Zaluski
authors.forename: Michel
authors.initials: M
authors.lastname: Wurm
mesh_terms: D000581:Amidohydrolases / Q000037:antagonists & inhibitors; D000700:Analgesics / Q000493:pharmacokinetics* / Q000494:pharmacology*; D000818:Animals; D063385:Cannabinoid Receptor Modulators / Q000037:antagonists & inhibitors* / Q000493:pharmacokinetics* / Q000494:pharmacology; D059350:Chronic Pain / Q000188:drug therapy* / Q000378:metabolism; D004745:Enkephalins / Q000037:antagonists & inhibitors*; D006801:Humans; D000099252:Fatty Acid Amide Hydrolases
chemical_list: D000581:Amidohydrolases; D000700:Analgesics; D063385:Cannabinoid Receptor Modulators; D004745:Enkephalins; D000099252:Fatty Acid Amide Hydrolases