Tilidine or tilidate (BAN

British Approved Name

A British Approved Name is the official non-proprietary or generic name given to a pharmaceutical substance, as defined in the British Pharmacopoeia...

) (Valoron, Valtran, Tilidin) is a synthetic opioid

Opioid

An opioid is a psychoactive chemical that works by binding to opioid receptors, which are found principally in the central and peripheral nervous system and the gastrointestinal tract...

 analgesic, used mainly in Germany, Switzerland and Belgium for treatment of moderate to severe pain, both acute and chronic.

Pharmacology

Considered a low- to medium-potency opioid, tilidine has the oral potency of about 0.2, i.e., a dose of 100 mg p.o. is equianalgesic to approximately 20 mg morphine

Morphine

Morphine is a potent opiate analgesic medication and is considered to be the prototypical opioid. It was first isolated in 1804 by Friedrich Sertürner, first distributed by same in 1817, and first commercially sold by Merck in 1827, which at the time was a single small chemists' shop. It was more...

 sulfate orally. It is administered orally (by mouth), rectally (by a suppository

Suppository

A suppository is a drug delivery system that is inserted into the rectum , vagina or urethra , where it dissolves.They are used to deliver both systemically-acting and locally-acting medications....

), or by injection

Injection (medicine)

An injection is an infusion method of putting fluid into the body, usually with a hollow needle and a syringe which is pierced through the skin to a sufficient depth for the material to be forced into the body...

 (s.c., i.m. or slowly i.v.) with single doses of 50 to 100 mg, the maximal daily dose being up to 600 mg.

Tilidine itself is only a weak opioid, but is rapidly metabolised in the liver and gut to its active metabolite nortilidine

Nortilidine

Nortilidine is the active metabolite of the drug Tilidine. It is formed from Tilidine by demethylation in the liver. The racemate has opioid analgesic effects roughly equivalent in potency to that of morphine but virtually all of the activity resides in the isomer....

 and then to bisnortilidine.

Indications

Tilidine is used in the form of hydrochloride

Hydrochloride

In chemistry, hydrochlorides are salts resulting, or regarded as resulting, from the reaction of hydrochloric acid with an organic base . This is also known as muriate, derived from hydrochloric acid's other name: muriatic acid....

 or phosphate

Phosphate

A phosphate, an inorganic chemical, is a salt of phosphoric acid. In organic chemistry, a phosphate, or organophosphate, is an ester of phosphoric acid. Organic phosphates are important in biochemistry and biogeochemistry or ecology. Inorganic phosphates are mined to obtain phosphorus for use in...

 salt. In Germany, tilidine is available in a fixed combination with naloxone

Naloxone

Naloxone is an opioid antagonist drug developed by Sankyo in the 1960s. Naloxone is a drug used to counter the effects of opiate overdose, for example heroin or morphine overdose. Naloxone is specifically used to counteract life-threatening depression of the central nervous system and respiratory...

 for oral administration (Valoron N and generics); the admixture of naloxone is claimed to lower the abuse

Drug abuse

Substance abuse, also known as drug abuse, refers to a maladaptive pattern of use of a substance that is not considered dependent. The term "drug abuse" does not exclude dependency, but is otherwise used in a similar manner in nonmedical contexts...

 liability of the opioid analgesic. In Switzerland the original Valoron brand with only tilidine and no naloxone is also available.

As well as its use as an analgesic, tilidine is also commonly used in Germany for treatment of restless legs syndrome

Restless legs syndrome

Restless legs syndrome or Willis-Ekbom disease is a neurological disorder characterized by an irresistible urge to move one's body to stop uncomfortable or odd sensations. It most commonly affects the legs, but can affect the arms, torso, and even phantom limbs...

.

Synthesis

It is manufactured by a Diels-Alder reaction

Diels-Alder reaction

The Diels–Alder reaction is an organic chemical reaction between a conjugated diene and a substituted alkene, commonly termed the dienophile, to form a substituted cyclohexene system. The reaction can proceed even if some of the atoms in the newly formed ring are not carbon...

 of 1-N,N-dimethylaminobuta-1,3-diene with ethyl atropate, yielding a mixture of isomer

Isomer

In chemistry, isomers are compounds with the same molecular formula but different structural formulas. Isomers do not necessarily share similar properties, unless they also have the same functional groups. There are many different classes of isomers, like stereoisomers, enantiomers, geometrical...

s, of which only the (E)-(trans)-isomers are active and is separated subsequently from the mixture by precipitation

Precipitation (chemistry)

Precipitation is the formation of a solid in a solution or inside anothersolid during a chemical reaction or by diffusion in a solid. When the reaction occurs in a liquid, the solid formed is called the precipitate, or when compacted by a centrifuge, a pellet. The liquid remaining above the solid...

 of the inactive (Z)-(cis)-isomers as zinc

Zinc

Zinc , or spelter , is a metallic chemical element; it has the symbol Zn and atomic number 30. It is the first element in group 12 of the periodic table. Zinc is, in some respects, chemically similar to magnesium, because its ion is of similar size and its only common oxidation state is +2...

 complex

Complex (chemistry)

In chemistry, a coordination complex or metal complex, is an atom or ion , bonded to a surrounding array of molecules or anions, that are in turn known as ligands or complexing agents...

.