Modification and delivery of enkephalins for pain modulation.

Chronic pain negatively affects patient's quality of life and poses a significant economic burden. First line pharmaceutical treatment of chronic pain, including NSAIDs or antidepressants, is often inefficient to reduce pain, or produces intolerable adverse effects. In such cases, opioids are frequently prescribed for their potent analgesia, but chronic opioid use is also frequently associated with debilitating side effects that may offset analgesic benefits. Nonetheless, opioids continue to be widely utilized due to the lack of effective alternative analgesics. Since their discovery in 1975, a class of endogenous opioids called enkephalins (ENKs) have been investigated for their ability to relieve pain with significantly reduced adverse effects compared to conventional opioids. Their low metabolic stability and inability to cross biological membranes, however, make ENKs ineffective analgesics. Over past decades, much effort has been invested to overcome these limitations and develop ENK-based pain therapies. This review summarizes and describes chemical modifications and ENK delivery technologies utilizing ENK conjugates, nanoparticles and ENK gene delivery approaches and discusses valid lessons, challenges, and future directions of this evolving field.