The Search for a Non-addicting Analgesic

Abstract

Since potent analgesics are indispensable in clinical practice and at the same time constitute a danger because of their addiction-producing properties, a drug has long been sought which would be non-addicting and at the same time combine the following properties: analgesic potency equal to that of morphine; toxicity no greater and, if possible, less than that of morphine; no undesirable side effects; and at the same time no tolerance to the pain-relieving effect.

Details

Author: Harris Isbell, M.D.
Pages: 5 to 5
Creation Date: 1956/01/01

The Search for a Non-addicting Analgesic

Harris Isbell, M.D. From the Addiction Research Center, Public Health Service Hospital, Lexington, Kentucky*

Since potent analgesics are indispensable in clinical practice and at the same time constitute a danger because of their addiction-producing properties, a drug has long been sought which would be non-addicting and at the same time combine the following properties: analgesic potency equal to that of morphine; toxicity no greater and, if possible, less than that of morphine; no undesirable side effects; and at the same time no tolerance to the pain-relieving effect.

Such a substance has been sought since 1929 under the aegis of the Committee on Drug Addiction and Narcotics of the National Research Council. The first approach was to modify the molecule of morphine. This effort shifted to the synthetics with the discovery of pethidine and methadone. In the last few years emphasis has shifted to the analgesic properties of nalorphine and mixtures of opiates and nalorphine. Although nalorphine is itself a modification of morphine, it is an opiate antagonist and has quite different properties. For the time being, the object of this search has not been attained; analgesic potency and addiction liability seem to equal each other.

Six groups of analgesics are known: the morphine, morphinan, pethidine, hexamethyleneimine, methadone, and dithienylbutenylamine families. It is possible, with some imagination, to make out in all six families a central phenyl-piperidine nucleus, and it may be that such a structure is

The present note summarizes, by permission of the author, a paper he published in the Journal of the American Medical Association, 161: (13) 1254 (July 28) 1956. necessary for analgesia but is always associated with physical dependence. Such a gloomy view is not necessarily justified. The synthetic analgesics have been discovered, either by preparing a new compound with a structure similar to a drug already known, or by a synthesis made for some purpose other than analgesia. In the latter case, routine testing disclosed that the drug in question induced morphine-like effects in mice and in other animals. Thus new drugs were discovered by their pharmacological resemblance to morphine. Therefore it seems that a new approach could be found: drugs with the phenylpiperidine structure and drugs giving morphine-like effects in lower animals should be avoided and an agent should be looked for which would be analgesic without being otherwise morphine-like; one difficulty in this approach is that it is not easy to deduce the effect on subjective reaction to pain in patients from the analgesic effect in lower animals. It may be that a number of promising drugs have already been discarded because of only weak analgesia in animals; an example of what is meant is nalorphine, which is a very weak analgesic in animal tests but is as effective as morphine in relieving post-operative pain.

Nalorphine does not create physical dependence, but it has undesirable side effects (disturbed mental reactions). Furthermore, it is not known whether tolerance to its analgesic effects would develop with continued use. Investigations are currently under way on possible modifications of the nalorphine structure, which might reduce the side effects while retaining the analgesic effects and the lack of addiction liability.