Opioid analgesics for improved pain control

Pain is one of the most common experiences of mankind ever since its existence. Few sensations are as disturbing to the individual as that of pain. It is the most common reason that patients seek help from their physicians. Being a disabling symptom of many medical conditions, pain control is one of the most important therapeutic priorities. Within the research program, it is planned to acquire new insights and knowledge in the field of opioid pain treatment aiming to identify and to develop scientifically proven novel opioid drugs with reliable target-oriented pharmacological profile, established efficacy, with minimal side effects and a favourable safety profile for the treatment of severe and chronic pain.

Pain is a complex multidimensional phenomenon, and a major health problem with an enormous impact on the individual and the society. Worldwide, ca. 20-30% people suffer from chronic pain. Pain is not only a disabling symptom of various medical conditions, but a disease state in its own right, with pain control as a key therapeutic priority. Opioids such as morphine are the most potent and effective analgesics for the treatment of pain. However, their clinical use is largely limited by numerous and serious side effects, including respiratory depression, sedation, constipation, tolerance and abuse potential. The current pharmacotherapy of severe and chronic pain conditions has proven to offer unsatisfactory long-term solutions, stressing the need of research for new and superior therapeutic strategies. The perspectives of this project are of high relevance due to the increasing number of patients suffering from chronic pain. The rationale of the project is based on the knowledge that the mu opioid receptor is the primary target for all clinically used opioid analgesics, being responsible for beneficial (analgesia), but also unwanted side effects. Theoretical and experimental investigations were performed to attain new insights and knowledge in the field of opioid morphinans targeting the mu opioid receptor, aiming to identify and develop scientifically proven novel mu opioid receptor agonists with reliable target-oriented pharmacological profile, established efficacy and favorable safety profile for pain therapy. Combining modern computational strategies with chemical synthetic methods and pharmacological studies resulted in the development and identification of novel active mu opioid receptor agonists with improved benefit/risk ratio as new potential pain therapeutics. The developed compounds represent new morphinan derivatives which bind with high affinity and show agonist activity at the mu receptor. Efficacy in experimental models of nociceptive, visceral, inflammatory, neuropathic and cancer pain was demonstrated for this class of molecules paralleled by reduced propensity for adverse effects. Detailed studies on the structural, molecular and functional mechanisms that can form the basis for such an improvement of the benefit/risk index were performed. The new mu opioid agonists developed during this project have the potential to considerably improve the quality of life of patients suffering of severe and chronic pain. Besides the scientific aspect, this project entails medical, social and economic perspectives in a long-term basis. One is to offer patient relief from incapacitating severe and chronic pain conditions, by introducing more efficient analgesic drugs with reduced side effects. The social aspect can be a decrease in sick-listing and early retirement because of chronic pain, which will reduce the social costs. Thus, more effective and well-tolerated pharmacotherapy may facilitate return to professional life and improve work performance. The economic aspect is to open up a new market within the pharmaceutical sector.