Dextromoramide

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Dextromoramide
Dextromoramide2DACS.svg
Systematic (IUPAC) name
(3S)-3-methyl-4-morpholin-4-yl-2,2-diphenyl-1-pyrrolidin-1-yl-butan-1-one
Clinical data
Trade names Palfium
AHFS/Drugs.com International Drug Names
Pregnancy cat. C (AU)
Legal status Controlled (S8) (AU) Schedule I (US)
Routes Oral, Rectal, Intravenous, Insufflation[1]
Pharmacokinetic data
Bioavailability >75%[2]
Metabolism Liver, partly mediated by CYP3A4[2]
Half-life 3.5 hours[2]
Excretion Urine, faeces[2]
Identifiers
CAS number 357-56-2 N
ATC code N02AC01
PubChem CID 92943
DrugBank DB01529
ChemSpider 83901 YesY
UNII 9S4S6CIY83 YesY
KEGG D07287 YesY
ChEBI CHEBI:74274 N
ChEMBL CHEMBL431928 N
Chemical data
Formula C25H32N2O2 
Mol. mass 392.534
 N (what is this?)  (verify)

Dextromoramide (Palfium, Palphium, Jetrium, Dimorlin)[3] is a powerful opioid analgesic approximately three times more potent than morphine but shorter acting.[4] It is subject to drug prohibition regimes, both internationally through UN treaties and by the criminal law of individual states. It is still marketed solely in the Netherlands.[1]

History[edit]

Dextromoramide was discovered and patented in 1956 by Dr Paul Janssen at Janssen Pharmaceutica, who also discovered fentanyl, another important synthetic opioid, widely used to treat pain and in combination with other drugs as an anaesthetic. Other discoveries include piritramide, diphenoxylate and family and others (q.q.v.)

Dextromoramide was singled out along with ketobemidone and several other synthetics by the United Nations and European Union as being "extra-dangerous" in the early 1960s, with dextromoramide being alleged to have treble the activity of heroin as a euphoriant,[5] though this did little to stem production in the first half of the decade. The development of the moramides and the coming to fruition of work on piritramide were two of the events that precipitated the 1961 update to the Single Convention On Narcotic drugs, as cited by Dr Shulgin in Controlled Substances and various monographs.

Dextromoramide was much favoured by drug users in Australia in the 1970s and the United Kingdom.[6] 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. 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 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.

Medical use[edit]

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.[7]

Chemistry[edit]

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).[8]

References[edit]

  1. ^ a b Brayfield, A, ed. (13 December 2013). "Dextromoramide". Martindale: The Complete Drug Reference. Pharmaceutical Press. Retrieved 23 April 2014. 
  2. ^ a b c d "SAMENVATTING VAN DE PRODUCTKENMERKEN" (PDF). ACE Pharmaceuticals website (in Dutch). ACE Pharmaceuticals. January 2002. Retrieved 23 April 2014. 
  3. ^ GB Patent 822055
  4. ^ Twycross and Lack, (1989) Oral morphine in advanced cancer. (2nd) Beaconsfield.
  5. ^ Escohotado, pp 94
  6. ^ Australian Journal of Pharmacy 1980;61:641-644.
  7. ^ Addictive Behaviours. 1999 Sep-Oct;24(5):707-13. PMID 10574310
  8. ^ Paul A J Janssen. Synthetic Analgesics Part 1: Diphenylpropylamines. Pergamon Press 1960. p141-145.
  • Den Otter G, Pain control with dextromoramide (pyrrolamidolum, R 875, palfium), Ned Tijdschr Geneeskd. 1958 Aug 23;102(34):1637-41.
  • Lasagna L, De Kornfeld T, Safar P, A clinical trial of dextromoramide, (R 875, SKF D-5137), J Chronic Dis. 1958 Dec;8(6):689-93.