THE ANALGESIC EFFECT OF OPIATE-OPIATE ANTAGONIST COMBINATIONS IN THE RAT

¹ Department of Pharmacology, Sterling-Winthrop Research Institute, Rensselaer, New York

The analgesic effect of 10 different opiates, alone and in combination with various doses of nalorphine and levallorphan, was measured in the rat by the original D'Amour-Smith method.

The dose of nalorphine required to reduce the analgesic effect from the 80 to the 40% level was found to be constant (about 95 µg/kg, s.c.) regardless of the relative potency (range = 1 to 1350) or chemical nature of the opiate (morphine, phenazocine, methadone, ketobemidone, meperidine, and 5 derivatives of meperidine). The same result was obtained with levallorphan against 4 opiates except that the constant dose was about 40 µg/kg, s.c.

Gaddum Drug-Ratios (molar ratio of opiate and antagonist doses producing a 50% analgesic effect) were determined for 2 potent opiates against nalorphine and levallorphan at analgesic doses up to 64 ED80's. The ratios for each pair of the 4 pairs studied were constant over this range, and, when corrected for the relative potencies of the opiates and antagonists studied, equal to each other. The Gaddum Drug-Ratio so corrected is 0.85.

The results obtained in the Drug-Ratio studies support the view that analgesic antagonism is a "surmountable" one with the opiate and antagonist interacting competitively at a common receptor site. The hypothesis which most simply explains the facts that the Drug-Ratios for individual pairs are not only constant but identical and that the AD50's also are, is that, in the rat at least, all opiates regardless of their chemical nature have the same mode of action and are equally potent at the site of activity. Differences in analgesic potency are therefore due to differences in affinity for the receptor site.