“Specific” Drug Antagonists to Barbiturates, Morphine and Hallucinogens
We studied morphine side effects and the fact that it had a marked effect on histamine release. (Gershon and Shaw, 1958 a). Previously we mentioned in our studies that IV succinic acid exerted a rapid and dramatic antagonistic effect on morphine effects in animals (especially dogs) and humans, but we did not discover the mode of action.
It seemed obvious to try the effects of anti-histaminic compounds on morphinised animals; given IV to dogs these produced sedation but in the morphinised dog the opposite effect occurred with alerting effects.
As a result of this preliminary work we felt what would be of clinical value was a partial morphine antagonist. This would permit the use of doses of morphine to produce maximum pain control while the antagonist would preserve vital functions, such as respiration. There was considerable interest in this possibility following the emergency experiences with major wounds during World War II WW 11 when Australia had troops posted all over the world in conditions of extremes of weather, isolated from specialized medical resources.
Our department had developed an excellent working relationship with the Army Medical section. My Chairman, Dr. Frank Shaw, had been working in this area for some time and the laboratory had selected a candidate partial morphine antagonist. This compound was amiphenazole, (Daptazole) and animal work had been carried out with members of our department. Our first paper on this topic was entitled “Morphine Antagonism” (Shaw FH. Gershon S. and Bentley GA, 1957). The first clinical effort was to obtain a normative profile of morphine effects. In the absence of pain it had a much higher incidence of side effects such as nausea and vomiting.
As mentioned with succinic acid, we could antagonize the CNS depressant effects of morphine in animals and man and improve vital functions with some loss of analgesia. So, with amiphenazole, we were looking to achieve full retention of pain control, but with antagonism of depressed vital functions.
These studies were pursued on one of the cancer units of a University affiliated hospital and published in the British Medical Journal. (Christie G., Shaw FH., McCance I., Bruce DW. and Gershon S, 1958 b) followed by “Amiphenazole and Morphine in the production of Analgesia.” (Gershon S,. Bruce, D.W. Orchard, N. and Shaw FH, 1958 c). As in prior work with barbiturates, we considered the development of a one pill mixture of two compounds to provide efficacy and safety which would ensure against over dosage with less risk of lethality. We again negotiated with a small pharmaceutical company and this combination was effective in achieving the goal of increased safety with adequate dosing of morphine and without causing decreased pain control. The product went on the market and was used fairly widely in Australia and England producing published results that were all positive. However, after a year or so, the sales diminished and it was taken off the market. Our efforts established efficacy, however the market determined the outcome and so we returned to the laboratory.
Christie 0G, Shaw FH, McCance I, .Bruce DW, Gershon S. Treatment of certain side effects of
morphine. Brit. Med. J. 1958 b; 1: 675-80.
Gershon S., Bruce DW. Orchard N, Shaw FH. Amiphenazole and morphine in the
production of analgesia. Brit. Med. J. 1958 c; 2: 366-8.
Gershon S, Shaw FH. Morphine and histamine release. J.Pharm. 1958 a; 10: 22-9.
Shaw FH, Gershon S., Bentley GA. Morphine antagonism. J. Pharm. 1957; 9: 666-671.
July 30, 2015