Azidomorphine and rymazolium an approach to the ideal analgesic

Abstract

Summary From a series of newly synthetized morphine derivatives 6-deoxy-6-azido-dihydroisomorphine /azido-morphine/ and 6-deoxy-6-azido-dihydroisocodeine /azido-codeine/ were selected for detailed pharmacological study. In the hot plate test in rats, azidomorphine proved to be about 300 times, azidocodeine about 13 times more potent than morphine. Administration of azidomorphine over a period of ten weeks proved it to be significantly less toxic in the rat than morphine. In the jumping test severe withdrawal symptoms could be precipitated in mice who received 40 times the analgesic ED50 dose /200 mg/kg/ of morphine. In contrast, only moderate dependence could be demonstrated with this test in mice who received 2800 times the analgesic ED50 dose of azidomorphine /70 mg/kg/. Treatment with increasing doses of morphine led to the development of high grade tolerance and physical dependence in rats and monkeys /Rhesus macacus/. Severe abstinence syndrome was precipitated following the administration of nalorphine in rats pretreated for 24 days with rapidly increasing doses of morphine. Severe abstinence symptoms were elicited in addicted monkeys on abrupt withdrawal of morphine on the 55th, 176th and 300th days of treatment. In parallel experiments no tolerance or physical dependence developed in rats or monkeys pretreated with increasing, equianalgesic doses of azidomorphine. Rymazolium /1,6-dimethyl1-3-carbethoxy-4-oxo-6,7,8,9, tetra-hydrohomopyrimidazole methylsulphate, Probon, MZ-144/ a new non-narcotic analgesic strongly potentiated the analgesic effect of azidomorphine and azidocodeine. On the basis of the reported animal experiments and preliminary clinical trials it is reasonable to expect that with the combined administration of azidomorphine or azidocodeine with Rymazolium it will be possible to obtain relief of severe, acute or chronic pain without significant risk of the development of addiction and/or tolerance.