Precipitation of Withdrawal Phenomena by N-Allylnormorphine

Abstinence syndromes could be induced after the subcutaneous injection of 15 mg. of N-allylnormorphine as early as 1 week after experimental addiction to morphine 15 mg. or methadone 10 mg. four times daily. The syndrome was recognized by the subjects themselves, who nicknamed the 

Later in the addiction period, the same dose of A -allylnormorphine evoked more intense syndromes, although the morphine dose schedule remained unchanged. As the daily dose level of morphine and the duration of addiction increased, smaller amounts of iV-allylnormorphine precipitated abstinence phenomena. After stabilization on 360 mg. of morphine per day or 140 mg. of methadone per day, severe abstinence syndromes were precipitated by 5 mg. of A -allylnormorphine. The most intense abstinence syndrome ever observed at the U.S. Public Health Service Hospital in Lexington occurred when 30 mg. of iV-allylnormorphine were administered subcutaneously to a subject who had been stabilized on 300 mg. of morphine per day. 

Abstinence phenomena were not precipitated by 15 mg. of Al-allylnor-morphine when administered 3 days after all clinical evidence of physical dependence had disappeared following rapid withdrawal of morphine. At this time, iV-allylnormorphine exerted effects identical with those observed before addiction had begun. 

Three of the four subjects on the methadone study refused to continue with the experiments, an event which rarely happens at the U.S. Public Health Service laboratory in Lexmgton, Kentucky, after they had experienced the abstinence syndrome precipitated by iV-allylnormorphine. The acute syndrome precipitated by IV-allylnormorphine in methadone addicts contrasts strikingly with the mild changes which are observed after abrupt withdrawal of methadone. The subjects who refused to continue with the methadone study exhibited only lethargy, anorexia, and irritability during the first week after abrupt termination of methadone administration. N-Allylnormorphine failed to precipitate abstinence phenomena 3 days after completion of withdrawal of methadone by rapid reduction in the subject who continued with the study. 

Following a 2-day period on 15 mg. of heroin four times daily, 15 mg. of iV-allyInormorphine 2 hr. after the regular dose of heroin evoked yawming, perspiration, lacrimation, rhinorrhea, mydriasis, increase in cardiac and respiratory rates, elevation of systolic and diastolic blood pressures, restlessness, generalized discomfort, and irritability. After 25 days of addiction at the level of 60 mg. of heroin daily, 2 mg. of Al-allylnormorphine sufficed to precipitate an abstinence syndrome comparable in intensity to that produced by 15 mg. of nalline after 2 days of addiction. 

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