Full text: Controlling Fentanyl-Related Substances – China's Contribution

I. Defining Fentanyl-Related Substances Based on Science

Fentanyl is a substance that acts on opioid receptors in organisms and thus has narcotic and analgesic effects. As a potent new narcotic analgesic with 100 times the potency of morphine, it is often used for the treatment of moderate to severe pain and is a narcotic on the United Nations control list. 

Fentanyl was first synthesized in 1960 by Belgian pharmacologist Paul Janssen. It was then produced by Janssen Pharmaceutica, Belgium, and has been widely used in Europe since the mid-1960s. It was approved for medical use in the United States in 1968. Later, sufentanil, remifentanil, and alfentanil were developed and came onto the market. These four fentanyl-related medications are now used globally for medical purposes. Their usual dosage form includes injection, transdermal patch, sublingual tablet, and nasal spray.

By slightly modifying the chemical structure of fentanyl, fentanyl-related derivatives with similar structures and effects – and even stronger effects – can be obtained. Most of them have either been illegally produced based on formulae retrieved from academic articles published by pharmaceutical companies, or designed to circumvent legal controls. At present, nearly 100 fentanyl-related substances are being abused around the world, and potentially they may number in the tens of thousands. Unlike the four fentanyl-related medications, the remaining fentanyl-related substances have not been found to have any medical value, and are often abused together with heroin, cocaine, or other controlled drugs to cause euphoria, an effect of taking opioids. In addition, their anesthetic and sedative effects affect the central nervous system of abusers, and an overdose can lead to coma, respiratory depression, or even death.

On April 1, 2019, China issued a statement to implement full control of fentanyl-related substances, in which these are clarified as substances with a chemical structure that meets one or more of the following conditions as compared to fentanyl (N-phenyl-N-[1-(2-phenylethyl)piperidin-4-yl]propanamide): 

• Replacement of the N-propionyl group by another acyl group;

• Replacement of the N-phenyl group with any aromatic monocycle whether or not further substituted in or on the aromatic monocycle;

• Substitution in or on the piperidine ring with alkyl, alkenyl, alkoxyl, ester, ether, hydroxyl, halo, haloalkyl, amino, or nitro groups;

• Replacement of the phenethyl group with another group, excluding hydrogen atom.

China introduced the concept of "related substances" and provided an accurate and scientific legal definition of fentanyl-related substances. This definition covers all types that require scheduling in the list of controlled substances, provides a strong legal basis for striking against drug crimes involving fentanyl-related substances, and minimizes the impact on legitimate needs in fields such as medicine, industry, and scientific research.

Fentanyl-related substances are obtained through chemosynthesis, and the chemical raw materials used to manufacture fentanyl-related substances are collectively known as their precursors. The synthetic routes to chemicals are diverse and the many alternatives make easy substitutions. In recent years, the precursors of fentanyl-related substances have constantly changed, and the number of variations soared. 4-anilino-N-phenethylpiperidine (4-ANPP) and N-phenethyl-4-piperidone (NPP) are two most immediate precursors of fentanyl-related substances. They were listed as controlled substances in Table I annexed to the United Nations Convention Against Illicit Traffic in Narcotic Drugs and Psychotropic Substances, 1988 (the "1988 Convention") at the 60th session of the UN's Commission on Narcotic Drugs in March 2017, and included in the Catalog of Classification and Types of Scheduled Precursor Chemicals annexed to the Regulations on the Administration of Scheduled Precursor Chemicals by China in the same year. 

As the two precursors were brought under control, lawbreakers upgraded synthetic processes in order to evade legal sanctions by using multiple precursors to synthesize fentanyl-related substances. These include: N-phenyl-4-piperidinamine (4-AP), tert-butyl 4-(phenylamino)piperidine-1-carboxylate (1-boc-4-AP), N-phenyl-N-(piperidin-4-yl)propionamide (norfentanyl), 4-piperidone, and tert-butyl 4-oxopiperidine-1-carboxylate (1-boc-4-piperidone). This creates new challenges in the battle against the smuggling, manufacturing, and trafficking of precursors of fentanyl-related substances.