Novel Therapies of chronic pain: peripherally Acting 14-Alkoxymorphinan Derivatives

The main objective of the project proposal is the development of new-generation peripherally acting pharmaceuticals for the treatment of chronic pain. Present treatment of moderate to severe pain has mostly relied on the use of non-steroidal anti-inflammatory drugs (NSAIDs) and centrally acting opioid analgesics (i. e. morphine). Both classes of drugs produce serious side effects: NSAIDs cause gastrointestinal disturbances, ulceration, renal damage, and hypersensitivity reactions. A significant drawback to the use of centrally acting opioids is a variety of adverse side effects mediated predominantly via the central nervous system (CNS) such as sedation, nausea, constipation, confusion, respiratory depression, tolerance and possibly dependence. So far, these problems have not been overcome. More effective pharmacotherapy with significant reduced side effects for chronic pain conditions is highly demanded. Due to the fact that the newly developed opioid compounds would not cross the blood-brain barrier and thus not enter into the CNS, they will not produce the usual adverse side-effects (physical dependence, tolerance, respiratory depression, sedation, nausea, confusion) of centrally acting opioid analgesics, such as morphine. It is further expected that the novel therapeutics would show their analgesic action upon systemic and oral administration. Moreover, the peripherally acting analgesics are expected to be very potent in chronic nociceptive and neuropathic pain, but could be used to treat acute pain as well. Systemic administration of morphine was shown to attenuate adjuvant arthritis in animals. Immune mechanisms are likely to be involved in the anti-inflammatory effect of morphine and other opioids. Thus, it is expected that the novel peripherally acting analgesics proposed would exhibit synergistic effects (analgesia and anti-inflammatory action) in the treatment of rheumatoid arthritis, which affects ca. 1% of the world population (ca. sixty million people).

The main objective of the project was the development of a new generation of opioid drugs with an improved side- effect profile for the treatment of severe acute and chronic pain. Current therapy of moderate to severe and chronic pain mostly relies on the use of non-steroidal anti-inflammatory drugs (NSAIDs) and centrally acting opioid analgesics such as morphine. Both classes of drugs produce serious side effects, e.g. NSAIDs cause gastrointestinal disturbances, ulceration, renal damage and hypersensitivity reactions. The advent of the selective cyclooxygenase-2 (COX-2) inhibitors such as rofecoxib (Vioxx) and celecoxib (Celebrex) has been viewed as a major advance in NSAID pharmacology. Yet, they offer no clear improvement in efficacy over conventional NSAIDs. Adverse effects such as dyspepsia, renal impairment and mainly the increased risk of myocardial infarction in COX-2-treated patients have considerably limited their clinical use. A significant drawback to the use of centrally acting opioids is a variety of adverse effects mediated predominantly via the central nervous system (CNS) such as sedation, nausea, confusion, respiratory depression, tolerance and dependence. So far, these problems have not been overcome. More effective pharmacotherapy with significant reduced side effects for chronic pain conditions is highly demanded. We were successful in the design and synthesis of new highly potent opioid analgesics with an improved side- effect profile. Due to the fact that the novel opioids do not cross the blood-brain barrier, they do not produce the usual adverse side-effects of centrally acting opioid analgesics like morphine. Considering the demographic changes worldwide with a continuous increase in the proportion of elderly people, a tremendous increase in the number of patients with chronic pain can be anticipated. This will impose a considerable burden on the medical and social welfare systems. Until now, pharmacotherapy of chronic pain has only been useful for patients with slight to moderate symptoms, partly because of the side effects at higher doses. Thus, the patients in the greatest need, constituting a major proportion, are left without a viable alternative. Our new opioid drugs for the treatment of chronic pain could be an important contribution in order to improve the quality of life of pain sufferers. The social aspect of the project is evident from a variety of perspectives. It is expected to reduce the need of hospitalization, rehabilitation, work training and individual adjustment of working conditions. The social deliverable is 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. For those not capable of pursuing a professional career, it may enhance independent life at home without the support of social services. The economical component of the project involves the market exploitation of the new opioid compounds generated in the project, given that they prove to represent new and better treatment alternatives in further preclinical and clinical studies.