Dextromoramide

Dextromoramide

Clinical data
Trade names	Palfium
AHFS/Drugs.com	International Drug Names
Pregnancy category	AU:C
Routes of administration	Oral, Rectal, Intravenous, Insufflation [1]
ATC code	N02AC01 ( WHO )
Legal status
Legal status	AU: S8 (Controlled drug) BR: Class A1 (Narcotic drugs) [2] CA: Schedule I DE: Anlage II (Authorized trade only, not prescriptible) US: Schedule I
Pharmacokinetic data
Bioavailability	>75% [3]
Protein binding	High [3]
Metabolism	Liver, partly mediated by CYP3A4 [3]
Elimination half-life	3.5 hours [3]
Excretion	Urine, faeces [3]
Identifiers
IUPAC name (3S)-3-methyl-4-morpholin-4-yl-2,2-diphenyl-1-pyrrolidin-1-yl-butan-1-one
CAS Number	357-56-2  N
PubChem CID	92943
DrugBank	DB01529  Y
ChemSpider	83901  Y
UNII	9S4S6CIY83
KEGG	D07287  Y
ChEBI	CHEBI:74274  N
ChEMBL	ChEMBL431928  N
CompTox Dashboard (EPA)	DTXSID8022909
ECHA InfoCard	100.006.013
Chemical and physical data
Formula	C25H32N2O2
Molar mass	392.543 g·mol−1
3D model (JSmol)	Interactive image
SMILES C[C@H](CN1CCOCC1)C(C(=O)N1CCCC1)(c1ccccc1)c1ccccc1
InChI InChI=1S/C25H32N2O2/c1-21(20-26-16-18-29-19-17-26)25(22-10-4-2-5-11-22,23-12-6-3-7-13-23)24(28)27-14-8-9-15-27/h2-7,10-13,21H,8-9,14-20H2,1H3/t21-/m1/s1 Y Key:INUNXTSAACVKJS-OAQYLSRUSA-N Y
NY  (what is this?)    (verify)

Dextromoramide ^[4] (Palfium, Palphium, Jetrium, Dimorlin) ^[5] is a powerful opioid analgesic approximately three times more potent than morphine but shorter acting. ^[6] It is subject to drug prohibition regimes, both internationally through UN treaties and by the criminal law of individual nations, and is usually prescribed only in the Netherlands.

History

Dextromoramide was discovered and patented in 1956 by Paul Janssen at Janssen Pharmaceuticals, who also discovered fentanyl, another important synthetic opioid, widely used to treat pain and in combination with other drugs as an anaesthetic, as well as haloperidol, piritramide, the loperamide-diphenoxylate series and other important drugs. ^[7]

Dextromoramide was much favoured by drug users in Australia in the 1970s and the United Kingdom. ^[8] It has the main proprietary name of Palfium amongst others, though as of mid-2004 the drug was discontinued in the UK due to limited supplies of precursor chemicals. Although this is true, it is believed there was an approximate one year shortage of Dextromoramide and the real reason that Palfium was not put back into production for the UK market is because of how addictive and potent it is as an oral painkiller.^{[ citation needed ]} Dependence liability is similar to morphine, but with a less severe withdrawal syndrome.

The only European countries that now use the brand Palfium are the Netherlands, Ireland and Luxembourg. It is presumably able to be imported into other Schengen zone countries under Title 76 of said treaty coming into force in 2002.^{[ citation needed ]} It is a Schedule I Narcotic controlled substance in the United States, with a DEA ACSCN of 9613 and an annual aggregate manufacturing quota of zero as of 2013, and had been out of use in the United States for around a decade when the new Controlled Substances Act 1970 was promulgated. The salts of dextromoramide in use are the hydrochloride (free base conversion ratio 0.915) and tartrate (0.724). ^[9] Racemoramide and moramide intermediate are also controlled.

Medical use

The main advantage of this drug is that it has a fast onset of action when taken orally, and has a high bioavailability which means that oral dosing produces almost as much effect as injection. It also has a relatively low tendency to cause constipation which is a common problem with opioid analgesics used for cancer pain relief, and tolerance to the analgesic effects develops relatively slowly compared to most other short-acting opioids. ^[10]

Pharmacokinetics

Dextromoramide has a mean elimination half life of 215.3 ± 78.4 minutes and volume of distribution of 0.58 ± 0.20 L/kg. ^[11] Peak plasma levels are reached within 0.5–4.0 h after dosing, decline of plasma concentrations after the peak follow a biphasic pattern, with half-lives of 0.4–1.6 h for the first phase and 6.3–21.8 h for the terminal phase. While in about 40% of patients, half-lives range from 1.5 to 4.7 h, in a monophasic manner. Less than 0.06% of the dose is excreted unchanged in urine within 8 h of administration. ^[12]

Chemistry

Dextromoramide is the right-handed isomer of the moramide molecule. The left-handed molecule is called levomoramide, and a mixture of the two is called racemoramide. Its full chemical name is (+)-1-(3-Methyl-4-morpholino-2,2-diphenylbutyryl)pyrrolidine, and its molecular formula: C₂₅H₃₂N₂O₂, with an atomic weight of ~392.5.

Dextromoramide was discovered during the course of research into a related family of compounds, the α,α-Diphenyl-γ-Dialkyamino-Butyramides, which show no analgesic activity, but are extremely active physiologically as inhibitors of gastric secretions in man. Other drugs from this series show antispasmodic and antihistamine effects, but most research was put into researching analgesics.

The structure-activity relationships of this family of drugs was investigated extensively, with dextromoramide representing the optimisation of several different structural features;

(i) at the 1-amide group only the pyrrolidine and dimethylamide substituents were active, with pyrrolidine being more potent

(ii) the alkyl chain was more potent when methylated, 3-methylation was more potent than 4-methylation, and in the 3-methyl analogues the dextro isomer was more active

(iii) while morpholine, dimethylamine, pyrrolidine and piperidine were all active at the 4-amine group, morpholine was the most active

(iv) any substitution on the phenyl rings reduces activity.

So dextromoramide, with a pyrrolidine ring on the 1-amide position, a dextro methyl group on the 3-position of the alkyl chain, a morpholine ring around the 4-amine group, and both phenyl rings unsubstituted, was by far the most potent out of all the compounds in this series and was the only one that became widely used in medicine (although the racemic mix racemoramide saw some limited use). ^[13]

References

1. Brayfield A, ed. (13 December 2013). "Dextromoramide". Martindale: The Complete Drug Reference. Pharmaceutical Press. Retrieved 23 April 2014.
2. Anvisa (2023-03-31). "RDC Nº 784 - Listas de Substâncias Entorpecentes, Psicotrópicas, Precursoras e Outras sob Controle Especial" [Collegiate Board Resolution No. 784 - Lists of Narcotic, Psychotropic, Precursor, and Other Substances under Special Control] (in Brazilian Portuguese). Diário Oficial da União (published 2023-04-04). Archived from the original on 2023-08-03. Retrieved 2023-08-16.
3. "SAMENVATTING VAN DE PRODUCTKENMERKEN" (PDF). ACE Pharmaceuticals website (in Dutch). ACE Pharmaceuticals. January 2002. Retrieved 23 April 2014.^{[ permanent dead link ]}
4. GB Patent 822055 Improvements in or relating to new analgesically active substituted alpha, alpha-diphenyl--y-amino-butyramides and the manufacture thereof
5. GB Patent 822055
6. Twycross RG, Lack SA (1989). Oral morphine in advanced cancer (2nd ed.). Beaconsfield. ISBN   978-0-906584-27-9.
7. López-Muñoz F, Alamo C (April 2009). "The consolidation of neuroleptic therapy: Janssen, the discovery of haloperidol and its introduction into clinical practice". Brain Research Bulletin. 79 (2): 130–41. doi:10.1016/j.brainresbull.2009.01.005. PMID   19186209. S2CID   7720401.
8. Newgreen DB (1980). "Dextromoramide: Review and Case Report". Australian Journal of Pharmacy. 61: 641–44.
9. "Conversion Factors for Controlled Substances". Drug Enforcement Administration. U.S. Department of Justice. Archived from the original on 2016-03-02. Retrieved 2016-02-27.
10. de Vos JW, Ufkes JG, van den Brink W, van Brussel GH, de Wolff FA (1999). "Craving patterns in methadone maintenance treatment with dextromoramide as adjuvant". Addictive Behaviors. 24 (5): 707–13. doi:10.1016/s0306-4603(98)00081-1. PMID   10574310.
11. Lançon JP, Pechinot A, Athis PD, Pechinot M, Pointaire P, Obadia JF, Caillard B (1989). "[Pharmacokinetics of dextromoramide in the surgical patient]". Annales Françaises d'Anesthésie et de Réanimation. 8 (5): 488–92. doi:10.1016/s0750-7658(89)80015-2. PMID   2576345.
12. Pagani I, Barzaghi N, Crema F, Perucca E, Ego D, Rovei V (1989). "Pharmacokinetics of dextromoramide in surgical patients". Fundamental & Clinical Pharmacology. 3 (1): 27–35. doi:10.1111/j.1472-8206.1989.tb00027.x. PMID   2714730. S2CID   39837195.
13. Janssen PA (1960). Synthetic Analgesics Part 1: Diphenylpropylamines. Pergamon Press. pp. 141–145.

Further reading

• Den Otter G (August 1958). "[Pain control with dextromoramide (pyrrolamidolum, R 875, palfium)]". Nederlands Tijdschrift voor Geneeskunde (in Flemish). 102 (34): 1637–41. PMID   13590312.
• Lasagna L, De Kornfeld T, Safar P (December 1958). "A clinical trial of dextromoramide, (R 875, SKF D-5137)". Journal of Chronic Diseases. 8 (6): 689–93. doi:10.1016/0021-9681(58)90124-3. PMID   13598780.