1 A brief history of the development of narcotic antagonists is outlined. 2 The clinical and pharmacological observations leading to the discovery of dualism of opiate receptors are reviewed. 3 An extension of this theory to a three‐receptor model (mu, kappa and sigma) is required to rationalize the pharmacology of the antagonists analgesics cyclazocine, pentazocine and nalorphine. 4 The methodologies available for the study of compounds with dual agonist‐antagonist activity are discussed in the light of the above receptor multiplicity, and data appertaining to the kappa‐partial agonist, nalorphine and the mu‐partial agonist buprenorphine are outlined.

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The potent narcotic antagonist, cyclazocine, has a long duration of action and is effective when administered orally. Although tolerance develops to many of the effects of cyclazocine, including dysphoria and sedation, tolerance does not develop to the drug's ability to antagonize the toxic, euphoric properties of morphine. Subjects who had received cyclazocine orally twice daily on a continuing basis experienced only a very mild degree of euphoria when given very large doses of morphine, and developed only a very mild degree of physical dependence after continued administration of large doses of morphine. Cyclazocine antagonizes pharmacological actions of importance in the addiction to narcotic analgesics, and it could be useful in the ambulatory treatment of the abstinent addict.

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