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Ethylmorphine (also known as codethyline, dionine, and ethyl morphine) is an opiate narcotic analgesic.

Ethylmorphine was invented in Germany at Merck in 1884 and was used as a weaker alternative to heroin for all indications. Chemically, ethylmorphine is a morphine molecule with a -OC₂H₅ group substituted for the aromatic 3-OH group. Therefore, the closest chemical relative of ethylmorphine is codeine, also known as methylmorphine. Ethylmorphine also has a hydromorphone analogue (ethyldihydromorphinone or 3-ethoxy-7,8-dihydro-morphin-6-one), and a dihydromorphine analogue known as ethyldihydromorphine (CID:5492914), although none of them appears to be commercially distributed at the current time.

As is the case with all narcotic analgesics, ethylmorphine is potentially habit-forming and can generate drug dependence of the codeine type. In most countries and internationally ethylmorphine and codeine are regulated much the same way. Like codeine, dihydrocodeine and similar weak opioid drugs, ethylmorphine is listed under the international Single Convention on Narcotic Drugs in Schedule III, which leads to some ethylmorphine preparations being available over the counter in some countries. In the US, ethylmorphine, like its methyl analog codeine, is controlled under the Controlled Substances Act, Schedule II as a pure compound and Schedule III when combined with non-opioid analgesics such as paracetamol (akin to US Schedule III paracetamol/codeine combinations sold under the brand name Tylenol 3/4). In theory, cough syrup containing ethylmorphine is listed in US Schedule V, meaning that it can be bought without prescription in certain states if the patient presents ID and/or the chemist knows the person and the patient signs a dispensary log that is monitored by the DEA. However, there are currently no ethylmorphine-based pharmaceuticals marketed in the US, making this a moot point; codeine-based products, on the other hand, are still relatively common.

Metabolism

After ingestion, ethylmorphine is converted to morphine in the human liver by the CYP450-isozyme CYP2D6, similarly to codeine. Morphine is a powerful analgesic and the main active compound found in naturally occurring opium. Ethylmorphine's metabolism is hindered by ethanol,^[1] which, being a central nervous system depressant, also boosts the drug's sedative effect—creating a potentially dangerous combination as both drugs cause depression of the respiratory system that can be mutually amplified.

Medical uses

Ethylmorphine is used as an antitussive to treat dry cough. It is also a moderately strong analgesic. It is most widely used in ophthalmology for removing inflammation products from the eyes, inducing miosis and relief of various symptoms. Ethylmorphine was once used, as was heroin, to attempt to cure morphine addiction, including being present in patent medicines sold for this purpose. Ethylmorphine is being investigated as a possible substitution agent for maintenance treatment of opioid dependence as it can quell withdrawal symptoms and also has a ceiling effect, i.e. additional doses beyond a certain level produce no extra euphoria. In France, tablets are available without prescription (under the name Tussipax, also contains codeine and sold as antitussive), they are commonly used by heroin-addicts to avoid withdrawal symptoms and by not dependent at héroin, for recreative opiate sensations.

Dionine is an ingredient of Schlesinger's Analgesic Solution, invented in the first decade of the previous century for use as a general-purpose analgesic as well as drops for painful eye conditions and an antitussive. The combination, as given in the 1913 US Pharmacopoeia and other national formularies, is 15 mg dionine hydrochloride, 10 mg morphine sulphate, and 125 µg scopolamine hydrobromide per cc. Some sources give the recipe as ¹/₄ grain dionine, ¹/₆ grain morphine, and ~²⁹/₈₁₀ grain of scopolamine; in some cases the salts of morphine and dionine may differ.

Dionine eye drops are used to cleanse the eye of inflammation products, and is generally seen to be somewhat more effective than codeine and benzylmorphine for this purpose.

Dosage

Ethylmorphine is "less potent than morphine" but "more potent than codeine" by a small percentage. Medical oral dosages vary from 5 to 30, even 50 mg. Like codeine and close chemical relatives, ethylmorphine should not be injected directly into the veins as the sudden histamine release can have dangerous impacts, Naturally, all doses are much lower in parenteral use. Ethylmorphine shares codeine's good oral bioavailability and is the fifth- or sixth-most-commonly used drug of the codeine-based semi-synthetic group of moderate to strong narcotic analgesics. This series includes codeine, dihydrocodeine, ethylmorphine, dihydroethylmorphine, benzylmorphine (Peronine), acetyldihydrocodeine, nicocodeine, nicodicodeine, hydrocodone, thebacon, oxycodone, acetylcodone, methyldihydromorphine and others.

The lethal dose is unknown. One source (in Finnish),^[2] however, suggests it to be as low as 500 mg. (Google-translation in english)

Problems

Tolerance to the drug's effects develops fast. That is why ethylmorphine is normally used only as a temporary medicine to treat e.g. cough. Patients may develop addiction. Side effects, which are rare for medical doses but normal for recreational doses, include the classical opiate side-effects: nausea, vomiting, urinary retention, miosis and constipation. Also, some people are hypersensitive or allergic to ethylmorphine and should never take it. Additionally, the same dose of ethylmorphine can have completely different effects on two different people because of large individual differences in metabolism.

Opioids are known for causing severe physical dependence, in addition to psychological addiction. This type of addiction is hard to treat.

Taking ethylmorphine in combination with alcohol or other drugs that have a suppressive effect on the central nervous system boosts both drugs' effects, creating a dangerous combination. Possible outcome is death through respiratory arrest.

In recreational use the most common problem, however, is liver damage and other effects caused by other compounds besides ethylmorphine. Some analgesics with ethylmorphine also contain indometacin (e.g. Indalgin), which is toxic in high doses.

Antidepressants such as fluoxetine (Prozac) inhibit the enzyme that metabolizes ethylmorphine. Taking ethylmorphine while using such an antidepressant may therefore lead to major changes in ethylmorphine's effects. Conversely, barbiturate compounds such as phenobarbitone induce the same enzyme, which rapidly increases the metabolism of ethylmorpine. Other current medications therefore always have to be taken into account when using this compound.

Brand names

Analgesics

Indalgin (with indometacin)

Antitussives

Cocillana
Cosylan
Feco Syrup
Solvipect Comp.
Tussipax (with Codeine)
CLARIX 0,1% Syrup
SIROP PETER'S 0,049% Syrup

 cophedrin-E

References

^ Xu, BQ; Aasmundstad, TA; Lillekjendlie, B; Bjørneboe, A; Christophersen, AS; Mørland, J (1997). "Effects of ethanol on ethylmorphine metabolism in isolated rat hepatocytes: characterization by means of a multicompartmental model". Pharmacology & toxicology 80 (4): 171–81. doi:10.1111/j.1600-0773.1997.tb00392.x. PMID 9140136.
^ Etyylimorfiini (Finnish). Accessed (via the Internet Archive) on February 27, 2010.

External links

Journal of Analytical Toxicology article on ethylmorphine metabolism

English Journal

Development of a new multi-analyte assay for the simultaneous detection of opioids in serum and other body fluids using liquid chromatography-tandem mass spectrometry.

Eckart K1, Röhrich J2, Breitmeier D2, Ferner M3, Laufenberg-Feldmann R3, Urban R2.
Journal of chromatography. B, Analytical technologies in the biomedical and life sciences.J Chromatogr B Analyt Technol Biomed Life Sci.2015 Sep 15;1001:1-8. doi: 10.1016/j.jchromb.2015.06.028. Epub 2015 Jul 19.
A liquid chromatography-tandem mass spectrometry method using electrospray ionization in positive ionization mode was developed for the simultaneous detection of multiple opioid-type drugs in plasma. The presented assay allows the quantitative determination of alfentanil, buprenorphine, codeine, des
PMID 26241181

Insights into hydrate formation and stability of morphinanes from a combination of experimental and computational approaches.

Braun DE1, Gelbrich T, Kahlenberg V, Griesser UJ.
Molecular pharmaceutics.Mol Pharm.2014 Sep 2;11(9):3145-63. doi: 10.1021/mp500334z. Epub 2014 Aug 1.
Morphine, codeine, and ethylmorphine are important drug compounds whose free bases and hydrochloride salts form stable hydrates. These compounds were used to systematically investigate the influence of the type of functional groups, the role of water molecules, and the Cl(-) counterion on molecular
PMID 25036525

Validation of an automated solid-phase extraction method for the analysis of 23 opioids, cocaine, and metabolites in urine with ultra-performance liquid chromatography-tandem mass spectrometry.

Ramírez Fernández Mdel M1, Van Durme F, Wille SM, di Fazio V, Kummer N, Samyn N.
Journal of analytical toxicology.J Anal Toxicol.2014 Jun;38(5):280-8. doi: 10.1093/jat/bku024. Epub 2014 Apr 30.
The aim of this work was to automate a sample preparation procedure extracting morphine, hydromorphone, oxymorphone, norcodeine, codeine, dihydrocodeine, oxycodone, 6-monoacetyl-morphine, hydrocodone, ethylmorphine, benzoylecgonine, cocaine, cocaethylene, tramadol, meperidine, pentazocine, fentanyl,
PMID 24790061

Japanese Journal

無水硫酸ナトリウムを用いる血液及び尿からのモルヒネの脱水抽出法

佐藤元泰
衛生化学 42(2), 167-171, 1996-04-30
… Ethylmorphine was used as an internal standard. …
NAID 110003642207

Extraction of Morphine in Blood and Urine by Dehydrating with Anhydrous Sodium Sulfate.

佐藤元泰
衛生化学 42(2), 167-171, 1996
… Ethylmorphine was used as an internal standard. …
NAID 130003912032

Effect of Systemic Anaphylaxis on the Hepatic Drug-Metabolizing System in Rats.

Ishikawa Masaaki,Ozaki Masayasu,Takayanagi Yoshio,Sasaki Ken-ichi
The Japanese Journal of Pharmacology 62(4), 407-410, 1993
… The cytochrome P-450 content and ethylmorphine N-demethylase, benzphetamine N-demethylase, arylhydrocarbon hydroxylase and 7-ethoxycoumarin O-deethylase activities significantly decreased in rats treated with ovalbumin compared with control groups treated with saline, whereas there was no significant reduction in cytochrome b5, NADPH-cytochrome c reductase and NADH-cytochrome c reductase. …
NAID 130000840376

Related Pictures

★リンクテーブル★

リンク元	「麻薬」「エチルモルヒネ」
拡張検索	「methylmorphine」「ethylmorphine hydrochloride」「ethylmorphine-N-demethylase」

「麻薬」

Ethylmorphine
Systematic (IUPAC) name
	7,8-didehydro-4,5-α-epoxy- 3-ethoxy-17-methylmorphinan-6-α-ol
Clinical data
AHFS/Drugs.com	International Drug Names
Legal status	DE: Anlage II; US: Schedule II (Single-Entity), Schedule III (In Combination Products);
Identifiers
CAS Number	76-58-4
ATC code	R05DA01 S01XA06
PubChem	CID 5359271
DrugBank	DB01466
ChemSpider	4514250
UNII	RWO67D87EU
Chemical data
Formula	C19H23NO3
Molar mass	313.391 g/mol
	SMILES O[C@H]2\C=C/[C@H]5[C@@H]4N(CC[C@@]51c3c(O[C@H]12)c(OCC)ccc3C4)C ;
	InChI InChI=1S/C19H23NO3/c1-3-22-15-7-4-11-10-13-12-5-6-14(21)18-19(12,8-9-20(13)2)16(11)17(15)23-18/h4-7,12-14,18,21H,3,8-10H2,1-2H3/t12-,13+,14-,18-,19-/m0/s1 ; Key:OGDVEMNWJVYAJL-LEPYJNQMSA-N ;
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