Tilidine, or tilidate (brand names: Tilidin, Valoron, Tetova and Valtran) is a synthetic

opioid Opioids are substances that act on opioid receptors to produce morphine-like effects. Medically they are primarily used for pain relief, including anesthesia. Other medical uses include suppression of diarrhea, replacement therapy for opioid use ...

painkiller An analgesic drug, also called simply an analgesic (American English), analgaesic (British English), pain reliever, or painkiller, is any member of the group of drugs used to achieve relief from pain (that is, analgesia or pain management). It i ...

, used mainly in

Belgium Belgium, ; french: Belgique ; german: Belgien officially the Kingdom of Belgium, is a country in Northwestern Europe. The country is bordered by the Netherlands to the north, Germany to the east, Luxembourg to the southeast, France to th ...

Bulgaria Bulgaria (; bg, България, Bǎlgariya), officially the Republic of Bulgaria,, ) is a country in Southeast Europe. It is situated on the eastern flank of the Balkans, and is bordered by Romania to the north, Serbia and North Macedon ...

Germany Germany,, officially the Federal Republic of Germany, is a country in Central Europe. It is the second most populous country in Europe after Russia, and the most populous member state of the European Union. Germany is situated betwe ...

Luxembourg Luxembourg ( ; lb, Lëtzebuerg ; french: link=no, Luxembourg; german: link=no, Luxemburg), officially the Grand Duchy of Luxembourg, ; french: link=no, Grand-Duché de Luxembourg ; german: link=no, Großherzogtum Luxemburg is a small lan ...

South Africa South Africa, officially the Republic of South Africa (RSA), is the southernmost country in Africa. It is bounded to the south by of coastline that stretch along the South Atlantic and Indian Oceans; to the north by the neighbouring countri ...

and

Switzerland ). Swiss law does not designate a ''capital'' as such, but the federal parliament and government are installed in Bern, while other federal institutions, such as the federal courts, are in other cities (Bellinzona, Lausanne, Luzern, Neuchâtel ...

for the treatment of moderate to severe pain, both acute and chronic. Its onset of pain relief after oral administration is about 10–15 minutes and peak relief from pain occurs about 25–50 minutes after oral 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 alternative na ...

phosphate 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 orthophosphoric acid . The phosphate or orthophosphate ion is derived from phospho ...

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

naloxone Naloxone, sold under the brand names Narcan (4 mg) and Kloxxado (8 mg) among others, is a medication used to reverse or reduce the effects of opioids. It is commonly used to counter decreased breathing in opioid overdose. Effects begin within ...

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

abuse Abuse is the improper usage or treatment of a 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, crimes, or other t ...

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 generally a long-term disorder that causes a strong urge to move one's legs. There is often an unpleasant feeling in the legs that improves somewhat by moving them. This ...

. The reversed ester is also known and is also a

prodrug A prodrug is a 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 used to improve how the drug ...

. Tilidine is a controlled substance in most countries, listed in the German BtMG, Austrian SMG, and in the USA under the Controlled Substances Act 1970 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 hydrochloride (free base conversion ratio 0.882) and HCl hemihydrate (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

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 cell In geometry, biology, mineralogy and solid state physics, a unit cell is ...

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

dichloromethane Dichloromethane (DCM or methylene chloride, methylene bichloride) is an organochlorine compound with the formula . This colorless, volatile liquid with a chloroform-like, sweet odour 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 is a strong opiate that is found naturally in opium, a dark brown resin in poppies (''Papaver somniferum''). It is mainly used as a analgesic, pain medication, and is also commonly used recreational drug, recreationally, or to make ...

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

suppository A suppository is a dosage form used to deliver medications by insertion into a body orifice where it dissolves or melts to exert local or systemic effects. There are three types of suppositories, each to insert into a different sections: rectal su ...

), 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 metabolised in the liver and gut to its active metabolite

nortilidine Nortilidine is the major active metabolite of 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. The (1R,2S) isomer has NMDA antagonist ...

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 counteract the abuse potential, tilidine is used in combination with the opioid receptor antagonist

. Naloxone abolishes the central depressant and peripheral effects of tilidine. The mixing ratio with naloxone is chosen so that the analgesic effect of tilidine is not impaired.

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 metabolised to 90% and eliminated renally. The rest appears in the faeces. 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 antagonisation of the nortilidine 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 ...

(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 aroun ...

(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 formulae – that is, same number of atoms of each element – but distinct arrangements of atoms in space. Isomerism is existence or possibility of isomers. Iso ...

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 under gravitational pull from clouds. The main forms of precipitation include drizzle, rain, sleet, snow, ice pellets, graupel and hail. ...

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

zinc Zinc is a chemical element with the symbol Zn and atomic number 30. Zinc 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 periodi ...

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 epimerised to the more thermodynamically favoured (''E'')-(''trans'')-isomers via reflux in diluted phosphoric acid.

References

External links

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