Tilidine, sold under the brand name Valoron among others, is a synthetic

opioid Opioids are a class of Drug, drugs that derive from, or mimic, natural substances found in the Papaver somniferum, opium poppy plant. Opioids work on opioid receptors in the brain and other organs to produce a variety of morphine-like effects, ...

analgesic An analgesic drug, also called simply an analgesic, antalgic, pain reliever, or painkiller, is any member of the group of drugs used for pain management. Analgesics are conceptually distinct from anesthetics, which temporarily reduce, and in s ...

, used mainly in

Belgium Belgium, officially the Kingdom of Belgium, is a country in Northwestern Europe. Situated in a coastal lowland region known as the Low Countries, it is bordered by the Netherlands to the north, Germany to the east, Luxembourg to the southeas ...

Bulgaria Bulgaria, officially the Republic of Bulgaria, is a country in Southeast Europe. It is situated on the eastern portion of the Balkans directly south of the Danube river and west of the Black Sea. Bulgaria is bordered by Greece and Turkey t ...

Germany Germany, officially the Federal Republic of Germany, is a country in Central Europe. It lies between the Baltic Sea and the North Sea to the north and the Alps to the south. Its sixteen States of Germany, constituent states have a total popu ...

Albania Albania ( ; or ), officially the Republic of Albania (), is a country in Southeast Europe. It is located in the Balkans, on the Adriatic Sea, Adriatic and Ionian Seas within the Mediterranean Sea, and shares land borders with Montenegro to ...

Luxembourg Luxembourg, officially the Grand Duchy of Luxembourg, is a landlocked country in Western Europe. It is bordered by Belgium to the west and north, Germany to the east, and France on the south. Its capital and most populous city, Luxembour ...

South Africa South Africa, officially the Republic of South Africa (RSA), is the Southern Africa, southernmost country in Africa. Its Provinces of South Africa, nine provinces are bounded to the south by of coastline that stretches along the Atlantic O ...

, and

Switzerland Switzerland, officially the Swiss Confederation, is a landlocked country located in west-central Europe. It is bordered by Italy to the south, France to the west, Germany to the north, and Austria and Liechtenstein to the east. Switzerland ...

for the treatment of moderate to severe

pain Pain is a distressing feeling often caused by intense or damaging Stimulus (physiology), stimuli. The International Association for the Study of Pain defines pain as "an unpleasant sense, sensory and emotional experience associated with, or res ...

, both acute and chronic. Its onset of pain relief after

oral administration Oral administration is a route of administration whereby a substance is taken through the Human mouth, mouth, swallowed, and then processed via the digestive system. This is a common route of administration for many medications. Oral administ ...

is about 10–15 minutes and peak relief from pain occurs about 25–50 minutes after administration.

Medical uses

Tilidine is used in the form of

hydrochloride In chemistry, a hydrochloride is an acid salt resulting, or regarded as resulting, from the reaction of hydrochloric acid with an organic base (e.g. an amine). An alternative name is chlorhydrate, which comes from French. An archaic alternati ...

phosphate Phosphates are the naturally occurring form of the element phosphorus. In chemistry, a phosphate is an anion, salt, functional group or ester derived from a phosphoric acid. It most commonly means orthophosphate, a derivative of orthop ...

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

naloxone Naloxone, sold under the brand name Narcan among others, is an opioid antagonist, a medication used to reverse or reduce the effects of opioids. For example, it is used to restore breathing after an opioid overdose. Effects begin within two ...

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

abuse Abuse is the act of improper usage or treatment of a person or thing, often to unfairly or improperly gain benefit. Abuse can come in many forms, such as: physical or verbal maltreatment, injury, assault, violation, rape, unjust practices, ...

liability of the opioid analgesic. This is so that if people take the medication orally (which is the way they are meant to) the opioid blocker, naloxone, has minimal effects on them but if they inject it the naloxone becomes bioavailable and hence antagonises the effects of the tilidine producing withdrawal effects. 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 (RLS), also known as Willis–Ekbom disease (WED), is a neurological disorder, usually chronic, that causes an overwhelming urge to move one's legs. There is often an unpleasant feeling in the legs that improves temporaril ...

. The reverse

ester In chemistry, an ester is a compound derived from an acid (either organic or inorganic) in which the hydrogen atom (H) of at least one acidic hydroxyl group () of that acid is replaced by an organyl group (R). These compounds contain a distin ...

is also known and is also a

prodrug A prodrug is a pharmacologically inactive medication or compound that, after intake, is metabolized (i.e., converted within the body) into a pharmacologically active drug. Instead of administering a drug directly, a corresponding prodrug can be ...

. Tilidine explicitly without Naloxone is a controlled substance in most countries, listed in the German

BtMG The Narcotic Drugs Act (, or BtMG) is the controlled substances law of Germany. In common with the Misuse of Drugs Act of 1971 of the United Kingdom and Controlled Substances Acts of the US and Canada, it is a consolidation of prior regulati ...

, Austrian SMG, and in the USA under the

Controlled Substances Act The Controlled Substances Act (CSA) is the statute establishing federal government of the United States, federal drug policy of the United States, U.S. drug policy under which the manufacture, importation, possession, use, and distribution of ...

as ACSCN 9750 as a Narcotic under Schedule I, with an annual aggregate manufacturing quota of 10 grams in 2014. It is used as the

(

free base In chemistry, a free base (freebase, free-base) is a term for the neutral form of an amine or other Lewis base. The term is used in the pharmaceutical industry in contrast to salt-based formulations like hydrochlorides. The amine is often an ...

conversion ratio 0.882) and HCl

hemihydrate In chemistry, a hemihydrate (or semihydrate) is a hydrate whose solid contains one molecule of water of crystallization per two other molecules, or per two unit cells. This is sometimes characterized as a solid that has one "half molecule" of water ...

(0.858).

Adverse effects

Its most common adverse effects are transient nausea and vomiting, dizziness, drowsiness, fatigue, headache and nervousness; less commonly, nausea and vomiting (after repeated dosing), hallucinations, confusion, euphoria, tremor, hyperreflexia, clonus and increased sweating. Uncommonly, somnolence; rarely, diarrhoea and abdominal pain.

Physicochemistry

It usually comes in its

salt form; in this form it is highly soluble in water, ethanol and

dichloromethane Dichloromethane (DCM, methylene chloride, or methylene bichloride) is an organochlorine compound with the formula . This colorless, volatile liquid with a chloroform-like, sweet odor is widely used as a solvent. Although it is not miscible with ...

and appears as a white/almost white crystalline powder. Its storage is restricted by its sensitivity to degradation by light and oxygen, hence necessitating its storage in amber bottles and at temperatures below 30 degrees Celsius, respectively.

Pharmacology

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

morphine Morphine, formerly also called morphia, is an opiate that is found naturally in opium, a dark brown resin produced by drying the latex of opium poppies (''Papaver somniferum''). It is mainly used as an analgesic (pain medication). There are ...

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

suppository A suppository is a dosage form used to deliver pharmaceutical drug, medications by insertion into a body orifice (any opening in the body), where it dissolves or melts to exert local or systemic effects. There are three types of suppositories, eac ...

), or by

injection Injection or injected may refer to: Science and technology * Injective function, a mathematical function mapping distinct arguments to distinct values * Injection (medicine), insertion of liquid into the body with a syringe * Injection, in broadca ...

(SC, IM, or slowly IV). Tilidine itself is only a weak opioid, but is rapidly metabolized in the liver and gut to its active metabolite nortilidine and then to bisnortilidine. It is the (1''S'',2''R'')-isomer (dextilidine) that is responsible for its analgesic activity. Nortilidine binds to opiate receptors in the central and peripheral nervous systems and suppresses pain perception and transmission. To purportedly counteract the abuse potential, tilidine is used in combination with the opioid receptor antagonist

. The mixing ratio with naloxone is chosen so that the analgesic effect of tilidine is not impaired. The effectiveness of this has been called into question and users largely report no reduction of peripheral effects.

Pharmacokinetics

Tilidine is rapidly absorbed after oral administration and is subject to a pronounced first-pass effect. The conversion of tilidine into the more active metabolite nortilidine occurs with the participation of CYP3A4 and CYP2C19. The inhibition of these enzymes can thus alter the efficacy and tolerability profile of tilidine. The analgesic effect occurs after 10–15 minutes. After oral administration of 100 mg tilidine plus 8 mg naloxone, the maximum effect is reached in about 25–50 minutes. The duration of action is given as 4-6 hours. The elimination half-life for nortilidine is 3–5 hours. Tilidine is metabolized to 90% and eliminated renally. The rest appears in the feces. Depending on the extent of the impairment, the maximum concentration of nortilidine in plasma is lower in insufficient liver function than in healthy individuals and the half-life is prolonged. In case of severe hepatic insufficiency the therapy is questionable. In these cases, it is possible that the formation of active nortilidine may be so low that the analgesic effect is insufficient. In addition, in the combination preparations with naloxone, the inactivation of the same can only be insufficient. The consequent antagonism of nortilidine’s effect can lead to a further loss of activity.

Synthesis

The condensation between

Crotonaldehyde Crotonaldehyde is a chemical compound with the formula CH3CH=CHCHO. The compound is usually sold as a mixture of the ''E''- and ''Z''-isomers, which differ with respect to the relative position of the methyl and formyl groups. The ''E''-isomer i ...

(1) and

dimethylamine Dimethylamine is an organic compound with the formula (CH3)2NH. This secondary amine is a colorless, flammable gas with an ammonia-like odor. Dimethylamine is commonly encountered commercially as a solution in water at concentrations up to around ...

(2) give dimethylaminobutadiene 39943-10-5(3). The Diels-Alder reaction with ethyl atropate 2286-82-4(4) yields a mixture of

isomer In chemistry, isomers are molecules or polyatomic ions with identical molecular formula – that is, the same number of atoms of each element (chemistry), element – but distinct arrangements of atoms in space. ''Isomerism'' refers to the exi ...

s, of which only the (''E'')-(''trans'')-isomers are active. The separation from the mixture by

precipitation In meteorology, precipitation is any product of the condensation of atmospheric water vapor that falls from clouds due to gravitational pull. The main forms of precipitation include drizzle, rain, rain and snow mixed ("sleet" in Commonwe ...

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

zinc Zinc is a chemical element; it has symbol Zn and atomic number 30. It is a slightly brittle metal at room temperature and has a shiny-greyish appearance when oxidation is removed. It is the first element in group 12 (IIB) of the periodic tabl ...

complex Complex commonly refers to: * Complexity, the behaviour of a system whose components interact in multiple ways so possible interactions are difficult to describe ** Complex system, a system composed of many components which may interact with each ...

. The inactive (''Z'')-(''cis'')-isomers may be epimerized to the more thermodynamically favored (''E'')-(''trans'')-isomers via reflux in diluted phosphoric acid.

References

External links

* {{Opioidergics Opioids Ethyl esters Mu-opioid receptor agonists Cyclohexenes Dimethylamino compounds