Tilidine

File:12-08-18-tilidin-retard.jpg

Tilidine is used in the form of hydrochloride or phosphate salt. In Germany, tilidine is available in a fixed combination with naloxone for oral administration (Valoron N and generics); the mixture of naloxone is claimed to lower the abuse 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.{{cite book | isbn = 978-0-07-162442-8 | title = Goodman and Gilman's The Pharmacological Basis of Therapeutics | edition = 12th | vauthors = Brunton L, Chabner B, Knollman B | year = 2010 | publisher = McGraw-Hill Professional | location = New York }} 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.{{cite journal | vauthors = Tings T, Trenkwalder C | title = [When L-Dopa preparations, dopamine agonists or opioids? Therapy of restless legs syndrome] | language = de | journal = MMW Fortschritte der Medizin | volume = 145 | issue = 10 | pages = 48–9 | date = March 2003 | pmid = 12688028 }} The reverse ester{{cite patent | country = US | number = 4291059 | status = issued | invent1 = Reynolds DP | title = Cycloaliphatic Compounds Thereof as analgesics | gdate = 22 September 1981 }}{{not in reference|reason=Not reversed ester of tilidine|date=May 2023}} is also known and is also a prodrug.

Tilidine explicitly without Naloxone is a controlled substance in most countries, listed in the German BtMG, Austrian SMG, and in the USA under the Controlled Substances Act 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).{{cite web | title = Conversion Factors for Controlled Substances | url = http://www.deadiversion.usdoj.gov/quotas/conv_factor/index.html | publisher = U.S. Department of Justice | work = Drug Enforcement Administration | access-date = 2016-02-26 | archive-date = 2016-03-02 | archive-url = https://web.archive.org/web/20160302162948/http://deadiversion.usdoj.gov/quotas/conv_factor/index.html | url-status = dead }}

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.

It usually comes in its hydrochloride hemihydrate salt form; in this form it is highly soluble in water, ethanol and dichloromethane 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.

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 sulfate orally. It is administered orally (by mouth), rectally (by a suppository), or by injection (SC, IM, or slowly IV).{{cite book | vauthors = Waldvogel HH | title = Analgetika, Antinozizeptiva, Adjuvanzien: Handbuch für die Schmerzpraxis | language = de | year = 2001 | publisher = Springer | isbn = 978-3-540-65796-5 }}

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.{{cite book | author = Buschmann, H | title = Analgesics: From Chemistry and Pharmacology to Clinical Application | publisher = Wiley-VCH | year = 2002 | isbn = 978-3-527-30403-5 | url-access = registration | url = https://archive.org/details/analgesicsfromch0000unse }}{{cite journal | vauthors = Schulz R, Bläsig J, Wüster M, Herz A | title = The opiate-like action of tilidine is mediated by metabolites | journal = Naunyn-Schmiedeberg's Archives of Pharmacology | volume = 304 | issue = 2 | pages = 89–93 | date = September 1978 | pmid = 212687 | doi = 10.1007/bf00495543 | s2cid = 499783 }} It is the (1S,2R)-isomer (dextilidine){{cite web|url=http://www.chemspider.com/Chemical-Structure.27988.html?rid=61b9b5fa-0630-4dcb-8f35-ba86b3ba7000|title=dextilidine - C17H23NO2 - ChemSpider|website=www.chemspider.com}} that is responsible for its analgesic activity.{{cite journal | vauthors = Satzinger G | title = Drug discovery and commercial exploitation | journal = Drug News & Perspectives | volume = 14 | issue = 4 | pages = 197–207 | date = May 2001 | pmid = 12819791 | doi = 10.1358/dnp.2001.14.4.858403 }} 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 naloxone. 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.{{Cite web |last=RealWookie |date=2021-12-21 |title=Tilidin und das Naloxon Thema |url=http://www.reddit.com/r/drogen/comments/rllxnh/tilidin_und_das_naloxon_thema/ |access-date=2023-12-03 |website=r/drogen}}

==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.{{cite web | title = Tilidin | url = https://www.gelbe-liste.de/wirkstoffe/Tilidin_18896 | work = Gelbe Liste Online }}

File:Tilidine synthesis.svg

The condensation between Crotonaldehyde (1) and dimethylamine (2) give dimethylaminobutadiene [139943-10-5] (3). The Diels-Alder reaction with ethyl atropate [22286-82-4] (4) yields a mixture of isomers, of which only the (E)-(trans)-isomers are active.

The separation from the mixture by precipitation of the inactive (Z)-(cis)-isomers as zinc complex. The inactive (Z)-(cis)-isomers may be epimerized to the more thermodynamically favored (E)-(trans)-isomers via reflux in diluted phosphoric acid.

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