STUDIES ON HEPTAZONE (6-MORPHOLINO-4, 4-DIPHENYL-3-HEPTANONE HYDROCHLORIDE) IN COMPARISON WITH OTHER ANALGESIC DRUGS

¹ Merck Institute for Therapeutic Research, Rahway, N. J.

1. The acute toxicity of Heptazone in mice and rats is significantly lower than that of methadone or isomethadone.

2. A method was devised for expressing analgesic effect in rats by means of a single figure which takes into account both intensity and duration of analgesia.

3. Heptazone, in comparable subcutaneous doses by weight, gives a higher peak of analgesia in rats than does methadone, isomethadone, or morphine, but the duration of analgesia is shorter. Therefore, the total analgesic effect of subcutaneously administered Heptazone in this species does not differ significantly from that of methadone. Heptazone is more effective orally in rats than is methadone. In dogs, Heptazone is only about half as potent an analgesic as is methadone, either orally or subcutaneously.

4. In rats or dogs chronically injected, tolerance to the analgesic effect developed at nearly the same rate for Heptazone, methadone, isomethadone, or morphine, when these drugs were administered in doses that were of approximately equal analgesic effect at the beginning.

5. In chronic experiments in dogs, the side effects of sedation and general depression were much less marked with Heptazone and isomethadone than with methadone or morphine. Tolerance to this effect developed much more slowly with methadone than with the other drugs.

6. Salivation, miosis, and hypothermia were less pronounced with Heptazone and isomethadone than with methadone. Some degree of tolerance developed to the two latter side effects, but the salivation became established as a conditioned reflex.

7. All the drugs produced about an equal degree of bradycardia, and no tolerance developed to this effect. Acute effects on the electrocardiogram were seen after injection of the drugs, and chronic administration produced reduction in voltages of P and R waves.

8. Withdrawal signs were observed in all the dogs, but were minimal in those addicted to Heptazone and isomethadone, and most severe in the morphinetreated animals.

9. Cross-tolerance studies showed that methadone was able to break through a tolerance to morphine or Heptazone, and dogs rendered only moderately tolerant to methadone were more tolerant to the other drugs used than to methadone itself.