I. THE TIME-ACTION CURVES OF MORPHINE, CODEINE, DILAUDID AND DEMEROL BY VARIOUS METHODS OF ADMINISTRATION II. ANALGESIC ACTIVITY OF ACETYLSALICYLIC ACID AND AMINOPYRINE
1. An adaptation of the Hardy-Wolff-Goodell method for measuring analgesia is described which makes the method suitable for pharmacological investigations on small laboratory animals. With the aid of this technique, it was possible to make some new observations and determinations, viz.:
2. Rats exhibit two reaction patterns. Both patterns are constant in untreated animals.
This observation proved useful for determining the pain threshold under varying conditions. Different doses of analgesics influenced the two reaction patterns in different degrees.
3. For purposes of exact comparison, the time-action curves of analgesia for four opiates were determined on the same species (rat) by subcutaneous, intravenous, intraperitoneal, or oral administration.—Subcutaneous administration of any of the four produced the most uniform pattern of action and an effect of longest duration. Medium size doses necessary to produce comparable intensities of analgesia show also comparable parabolic time action curves.—Intravenous injection produced analgesia of significantly shorter duration. Oral administration produced analgesia of variable duration and with high doses only.—Intraperitoneal injection of morphine, dilaudid, or demerol gave a smaller effect than subcutaneous. For codeine, the figures were approximately the same.
4. In a significant number of cases, there followed after intravenous administration a type of analgesia which showed an irregular and intermittent course.
5. For morphine, given by subcutaneous administration, the existence of a maximum analgesic dose has been ascertained. It stands at 20 mgm./kgm. rat.—With doses lower than 20 mgm., the total duration of analgesia was proportionate in general to the individual peak intensity reached, while the duration of the peak itself was proportionate to the dose.
6. With each of the opiates used, onset, intensity, and duration of analgesia on the one hand and depression on the other showed different time-sequences.
7. The ratios between the effectiveness of codeine, dilaudid, and demerol on the one hand and that of morphine on the other vary with the degree of pain stimulation. These ratios were established for different pain relief levels by giving the drugs subcutaneously.
8. The activity ratios between several opiates vary with the different routes of administration.
9. Aminopyrine does exert some analgesic action. This, however, is qualitatively different from that of the opiates.
10. The observation previously reported in the literature that acetylsalicylic acid has no analgesic activity was confirmed by our observations.