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Codeine-7,8-oxide (codeine epoxide) (Fig. 1) was recently identified as a new metabolite of codeine (1). Findings of Takayanagi et al. (2) using electrically stimulated guinea-pig ileum suggested that codeine-7,8-oxide had a potent narcotic analgesic activity as described in the preliminary report of Miyata et al. (3), and epoxidation of 7,8-double bond of codeine resulted in a trend for a decrease in the dependence liability. Furthermore, Yoshimura and his co-workers (4-6) found that the antinociceptive actions of morphine-6 glucuronide and morphine-6-sulfate were 2 to 3 times as potent as morphine, while morphine-3-glucuronide, a major metabolite, had no biological activity. In this paper we studied the antinociceptive activity, development of tolerance and the inhibitory activity of abstinence syndrome to clarify pharmacological properties of this new metabolite of codeine. Antinociceptive activity was measured after subcutaneous injection in the conscious male Wistar rats (80 to 100 g in body weight) with a Randal-Sellito apparatus (Ugo Vasile). Pressure was given to a hind paw and the maximal pressure measured was 250 g. In order to test development of tolerance in antinociceptive activity, 10 mg/kg of codeine-7,8-oxide or 20 mg/kg of codeine were given subcutaneously every 4 hr for 3 days to male Wistar strain rats (60 to 100 g in body weight). Antinociceptive activities of both the drugs were measured after every injection. The rats (80 to 100 g) were made dependent on morphine by a daily sub cutaneous injection of morphine. The dose of morphine was increased during a period of 4 weeks until a daily dose of 80 mg/kg (40 mg/kg twice a day at 10 a.m. and 6 p.m.) : the first week, 20 mg/day, the second week, 40 mg/day, the third week, 60 mg/day and the fourth week, 80 mg/day (7, 8). The body weight of the treated animals rapidly decreased upon withdrawal, the mean decrease being 24.5±1.5 g (mean±S.E.). After the confirmation of the decrease in body weight upon withdrawal, the animals were further treated with 20 mg/kg of morphine at 10 a.m. and 6 p.m. Next week, the animals were divided into 6 groups of 7 rats. A control was administered saline and the others were used as test groups which were subcutaneously injected with morphine, codeine or codeine-7,8-oxide. Decrease in the body weight was measured 24 hr after the injection. Statistical significance was evaluated by the Student's t-test. Drugs used: codeine

Pharmacological properties of codeine-7,8-oxide (codeine epoxide), a new metabolite of codeine.