REVIEW The Role of Descending Inhibitory Pathways on Chronic Pain Modulation and Clinical Implications Mikwang Kwon, MD*; Murat Altin, MD † ; Hector Duenas, MD ‡ ; Levent Alev, MD § *Eli Lilly Medical, Quality and Regulatory Affairs Department, Eli Lilly Korea Ltd., Seoul, Korea; † Eli Lilly Neuroscience, Eli Lilly & Company Turkey, _ Istanbul, Turkey; ‡ Eli Lilly Mexico, Mexico City, Mexico; § Lilly Research Laboratories Japan, Eli Lilly Japan K.K, Kobe, Japan & Abstract: The treatment and management of chronic pain is a major challenge for clinicians. Chronic pain is often underdiagnosed and undertreated, and there is a lack of awareness of the pathophysiologic mechanisms that contrib- ute to chronic pain. Chronic pain involves peripheral and central sensitization, as well as the alteration of the pain modulatory pathways. Imbalance between the descending facilitatory systems and the descending inhibitory systems is believed to be involved in chronic pain in pathological conditions. A pharmacological treatment that could restore the balance between these 2 pathways by diminishing the descending facilitatory pain pathways and enhancing the descending inhibitory pain pathways would be a valuable therapeutic option for patients with chronic pain. Due to the lack of evidence for pharmacological options that act on descending facilitation pathways, in this review we summa- rize the role of the descending inhibitory pain pathways in pain perception. This review will focus primarily on mono- aminergic descending inhibitory pain pathways and their contribution to the mechanism of chronic pain and several pharmacological treatment options that enhance these pathways to reduce chronic pain. We describe anatomical structures and neurotransmitters of the descending inhibi- tory pain pathways that are activated in response to nociceptive pain and altered in response to sustained and persistent pain which leads to chronic pain in various pathological conditions. & Key Words: review, descending inhibition, central nervous system, chronic pain, pain modulation, inhibitory pathways INTRODUCTION Pain has been defined as the “unpleasant sensory and emotional experience associated with actual or potential tissue damage or described in terms of such damage”. 1 Pain can be classified in temporal terms as either acute or chronic, depending on the onset and duration of pain. 2 Acute pain usually has a sudden onset after strong external stimuli, trauma, or surgery, and it normally results from damage or injury to tissues or inflammation as a protective mechanism of our bodies. The cause of acute pain can usually be determined and treated and, therefore, its duration is limited. On the other hand, chronic pain persists for a longer period of time and in many cases, the causes of chronic pain can be hard to determine, because chronic pain is thought to result not only from physical injury, but also from a combination of psychological, social, and physical abnormalities. 3 Address correspondence and reprints requests to: Mikwang Kwon, MD, Eli Lilly Korea Ltd. 4th floor STX Namsan Tower, 631 Namdaemunro- 5Ga, Jung-Gu, Seoul 100-958, Korea. E-mail: mikwang74@hanmail.net. Submitted: March 24, 2013; Revision accepted: October 03, 2013 DOI. 10.1111/papr.12145 © 2013 World Institute of Pain, 1530-7085/13/$15.00 Pain Practice, Volume 14, Issue 7, 2014 656–667