[4][better source needed] Because it is characterized by a strong dependency potential and a tendency to produce profound respiratory depression, it is not used in humans.

[citation needed] Etonitazene and its related opioid agonist benzimidazoles were discovered in the late 1950s,[5][6][7][8][9][10] by a team of Swiss researchers working at the pharmaceutical firm CIBA (now Novartis).

One of the first compounds investigated by the Swiss team was 1-(β-diethylaminoethyl)-2-benzylbenzimidazole, which was found to possess 10% of the analgesic activity of morphine when tested in rodent bioassays.

The most versatile synthesis[6] developed by the Swiss team first involved alkylation of 2,4-dinitrochlorobenzene with 1-amino-2-diethylaminoethane to form N-(β-Diethylaminoethyl)-2,4-dinitroaniline [aka: N'-(2,4-Dinitrophenyl)-N,N-diethyl-ethane-1,2-diamine].

The intermediate formed by the selective reduction of the 2-nitro substituent, 2-(β-Diethylaminoethylamino)-5-nitroaniline, is then reacted with the hydrochloride salt of the imino ethyl ether of 4-ethoxyphenylacetonitrile (aka: p-ethoxybenzyl cyanide).

The imino ether, 2-(4-Ethoxyphenyl)-acetimidic acid ethyl ester hydrochloride, is prepared by dissolving the 4-substituted benzyl cyanide in a mixture of anhydrous ethanol and chloroform and then saturating this solution with dry hydrogen chloride gas.

Varying the choice of the substituted phenylacetic acid imino ether affords compounds with a diversity of substituents on the benzene ring at the 2- position.

The problem with the conventional synthesis was the lability of the imino ether reactant, 2-(4-Ethoxyphenyl)-acetimidic acid ethyl ester (prepared by reacting 4-ethoxyphenylacetonitrile with ethanolic HCl).

The authors discovered that when this condensation was performed in the presence of 2 or more molar equivalents of EEDQ (added portionwise in 3 steps) in THF at 50 °C for 192 hours (8 days), a near quantitative yield (100%) of etonitazene was obtained.

In the United States Etonitazene is a Schedule I narcotic controlled substance with a DEA ACSCN of 9624 and a 25 gram (7⁄8 oz) manufacturing quota as of 2022.