Editorial [Hot Topic:New Approaches for the Treatment of Pain and Inflammation (Guest Editor: Kaustav Biswas)]

Pain is defined as an unpleasant sensory and emotional experience associated with actual or potential tissue damage. It is a frequent reason for physician consultation, and a major symptom in many medical conditions, significantly interfering with a person's quality of life and general functioning. Inflammation is the sequence of events that characterizes the biological response of vascular tissues to harmful stimuli. It is a protective attempt by the body to remove the injurious stimuli as well as initiate the healing process for the tissue. Malfunctions in the processes associated with inflammation comprise a number of disorders which underlie a variety of human diseases There are a number of commonly used drugs available for treatment various conditions of severe pain and inflammation. Opioids, the most powerful of analgesics, are the mainstay for treatment of severe acute and chronic pain. However, opioids have many well-known side effects. Since the isolation of salicylic acid from willow bark almost two hundred years ago, NSAIDs (non-steroidal anti-inflammatory drugs) have become an important part of the pharmaceutical treatment of pain (at low doses) and inflammation (at higher doses). Unlike opioids, NSAIDs do not produce sedation or respiratory depression and have a very low addiction rate. They are, however, not without adverse effects; for example, irritation of the stomach lining. Other anti-inflammatory therapies include steroids, such as glucocorticoids, and new biologics such as TNF-alpha blockers which have had a dramatic effect on many inflammatory conditions. While there is a spectrum of medicinal agents currently available that are indicated as pain and inflammation treatments, they suffer from many limitations. There is a need for the development of better, more efficacious new drugs for these conditions. Researchers are actively working on newer targets that have the potential to selectively interfere with the processes of nociception and inflammation. This special issue of Current Topics in Medicinal Chemistry highlights the some of the state of the art in research aimed at discovering new avenues for treating pain and inflammation. In the first review by Kuduk and Bock, the authors present a case study of the structure-activity relationship and lead optimization efforts made at Merck in targeting the bradykinin B1 receptor with antagonists for treatment of pain. This research has resulted in the identification of a clinical candidate. Reviewing another much-studied target for pain therapy, Broad, Keding and Blanco present an overview of the progress made in development of antagonists of the transient receptor potential vanilloid sub-type 1 (TRPV1), previously vanilloid receptor 1 (VR1). A number of compounds have been evaluated in the clinic for different indications of pain, and this review catalogs the state of the art, along with related pre-clinical data. Fioravanti and Vanderah discuss the pros and cons of antagonizing the opioid receptor like-1 (ORL-1) system in pain therapy. The authors present a systematic review of the published literature that examines the validity of this G-protein coupled receptor of the opioid family as a suitable target for drug candidates. The next review by Pettus and Wurz provides an update on the decade-long effort to develop inhibitors of the p38 mitogenactivated protein (MAP) kinase as anti-inflammatory agents. This review discusses the latest generation of selective p38 inhibitors from different organizations, and the progress towards identifying a small molecule counterpart of current biological anti-inflammatory agents that block TNF-α. Finally, Davis and Xu review the recent progress in developing antagonists of the calcitonin gene-related peptide (CGRP) receptor for treatment of migraine. They present exciting new results that have emerged from clinical evaluation of smallmolecule therapies that validate this target for migraine therapy. Furthermore, large-molecule approaches are also discussed. Pain and inflammation have been the targets of extensive research for the development of new molecular therapeutics. There is a definite unmet medical need for new drugs despite the current availability of multiple treatment approaches in the clinic. This special issue of Current Topics in Medicinal Chemistry presents the progress made in identifying new targets for drugs that address these indications. Some of these targets have now been validated in the clinic; others are being interrogated with new tools in human clinical trials. They represent exciting opportunities afforded by widespread and diligent research by scientists involved in drug discovery that have been documented in these excellent reviews. I would like to thank the authors for taking the time in submitting these highly informative reviews of the current literature. I would also like to thank the chief editor for giving me the opportunity of organizing this effort describing the latest research in this important area. I hope the information presented here is useful in stimulating new ideas and areas of scientific discovery.