Dextromoramide
Encyclopedia
Dextromoramide is a powerful opioid
analgesic
approximately three times more potent than morphine but shorter acting. It is subject to drug prohibition regimes, both internationally through UN treaties, and by the criminal law of individual states. It is still rarely used in Australia and some European countries, but prescription is avoided due to its abuse potential and so use of dextromoramide is now mainly limited to terminal care.
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. Dextromoramide was much favoured by drug abusers in Australia
in the 1970s. It has the proprietary name Palfium, though as of mid 2004 the drug was discontinued in the UK due to limited supplies of precursor chemicals.
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.
However dextromoramide has several disadvantages, firstly that it has a high potential for development of dependence and addiction, even in patients who are taking it as directed for pain relief and have no previous history of drug abuse, and secondly it has a particularly strong tendency to induce respiratory depression, especially in patients who have low opioid tolerance, and so can be dangerous when used outside of a hospital setting. Another disadvantage is that the bioavailability of oral or sublingual formulations can be variable, and so the medicine may work well for one patient, but poorly for another, or even produce different plasma levels of the drug following the same dose taken on different days. This can be especially dangerous as it may encourage patients to deviate from the prescribed dosage. Suppository
dosage formulations may therefore be preferable due to more consistent bioavailability.
The typical dose is 5mg every four hours for cancer pain - the drug has a short half life comparable with pethidine
. Because of its short duration of action it is unsuitable for maintenance treatment, but can be very useful for acute breakthrough pain. Another advantage is that its high affinity for the opioid receptor allows it to still be effective even when the patient is maintained on relatively high doses of strong analgesics such as methadone
. Dextromoramide thus fills the role which is more commonly played by hydromorphone
in pain treatment in the USA.
Dextromoramide is sometimes also used as a short-acting analgesic for minor surgical procedures. In this case it is administered sublingual
ly and reaches a therapeutic concentration after around 12 minutes. Another application that has been trialled in the Netherlands
is prescription of oral dextromoramide as a way to try to reduce injecting drug use in recidivist opioid addicts who continued to abuse heroin despite being maintained on methadone. This saw modest success in reducing illicit drug use among addicts who wished to regain control over their drug use but were unable to cope being maintained on methadone alone.
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).
Opioid
An opioid is a psychoactive chemical that works by binding to opioid receptors, which are found principally in the central and peripheral nervous system and the gastrointestinal tract...
analgesic
Analgesic
An analgesic is any member of the group of drugs used to relieve pain . The word analgesic derives from Greek an- and algos ....
approximately three times more potent than morphine but shorter acting. It is subject to drug prohibition regimes, both internationally through UN treaties, and by the criminal law of individual states. It is still rarely used in Australia and some European countries, but prescription is avoided due to its abuse potential and so use of dextromoramide is now mainly limited to terminal care.
History
Dextromoramide was discovered and patented in 1956 by Dr Paul JanssenPaul Janssen
Paul Adriaan Jan, Baron Janssen was the founder of Janssen Pharmaceutica, a pharmaceutical company with over 20,000 employees. In 2005 he finished as runner up, after Father Damien, in the poll for The Greatest Belgian organized by the regional Flemish television...
at Janssen Pharmaceutica
Janssen Pharmaceutica
Janssen Pharmaceutica is pharmaceutical company, established in Belgium in 1953 by Paul Janssen. Its headquarters are located in Beerse, in the Campine region of the province of Antwerp, Belgium. It was created not as a subsidiary of a chemical factory but solely with the aim of conducting...
, who also discovered fentanyl, another important synthetic opioid, widely used to treat pain and in combination with other drugs as an anaesthetic. Dextromoramide was much favoured by drug abusers in Australia
Australia
Australia , officially the Commonwealth of Australia, is a country in the Southern Hemisphere comprising the mainland of the Australian continent, the island of Tasmania, and numerous smaller islands in the Indian and Pacific Oceans. It is the world's sixth-largest country by total area...
in the 1970s. It has the proprietary name Palfium, though as of mid 2004 the drug was discontinued in the UK due to limited supplies of precursor chemicals.
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 constipationConstipation
Constipation refers to bowel movements that are infrequent or hard to pass. Constipation is a common cause of painful defecation...
which is a common problem with opioid analgesics used for cancer pain
Cancer pain
Pain is a symptom frequently associated with cancer. Cancer can cause pain by irritating or damaging nerves, by stimulating nociceptors , or by releasing chemicals that make nociceptors respond to normally non-painful stimuli. Cancer pain may be caused by the tumor itself or by medical...
relief, and tolerance to the analgesic effects develops relatively slowly compared to most other short-acting opioids.
However dextromoramide has several disadvantages, firstly that it has a high potential for development of dependence and addiction, even in patients who are taking it as directed for pain relief and have no previous history of drug abuse, and secondly it has a particularly strong tendency to induce respiratory depression, especially in patients who have low opioid tolerance, and so can be dangerous when used outside of a hospital setting. Another disadvantage is that the bioavailability of oral or sublingual formulations can be variable, and so the medicine may work well for one patient, but poorly for another, or even produce different plasma levels of the drug following the same dose taken on different days. This can be especially dangerous as it may encourage patients to deviate from the prescribed dosage. Suppository
Suppository
A suppository is a drug delivery system that is inserted into the rectum , vagina or urethra , where it dissolves.They are used to deliver both systemically-acting and locally-acting medications....
dosage formulations may therefore be preferable due to more consistent bioavailability.
The typical dose is 5mg every four hours for cancer pain - the drug has a short half life comparable with pethidine
Pethidine
Pethidine or meperidine Pethidine (INN) or meperidine (USAN) Pethidine (INN) or meperidine (USAN) (commonly referred to as Demerol but also referred to as: isonipecaine; lidol; pethanol; piridosal; Algil; Alodan; Centralgin; Dispadol; Dolantin; Mialgin (in Indonesia); Petidin Dolargan (in Poland);...
. Because of its short duration of action it is unsuitable for maintenance treatment, but can be very useful for acute breakthrough pain. Another advantage is that its high affinity for the opioid receptor allows it to still be effective even when the patient is maintained on relatively high doses of strong analgesics such as methadone
Methadone
Methadone is a synthetic opioid, used medically as an analgesic and a maintenance anti-addictive for use in patients with opioid dependency. It was developed in Germany in 1937...
. Dextromoramide thus fills the role which is more commonly played by hydromorphone
Hydromorphone
Hydromorphone, a more common synonym for dihydromorphinone, commonly a hydrochloride is a very potent centrally-acting analgesic drug of the opioid class. It is a derivative of morphine, to be specific, a hydrogenated ketone thereof and, therefore, a semi-synthetic drug...
in pain treatment in the USA.
Dextromoramide is sometimes also used as a short-acting analgesic for minor surgical procedures. In this case it is administered sublingual
Sublingual
Sublingual, literally 'under the tongue', from Latin, refers to the pharmacological route of administration by which drugs diffuse into the blood through tissues under the tongue...
ly and reaches a therapeutic concentration after around 12 minutes. Another application that has been trialled in the Netherlands
Netherlands
The Netherlands is a constituent country of the Kingdom of the Netherlands, located mainly in North-West Europe and with several islands in the Caribbean. Mainland Netherlands borders the North Sea to the north and west, Belgium to the south, and Germany to the east, and shares maritime borders...
is prescription of oral dextromoramide as a way to try to reduce injecting drug use in recidivist opioid addicts who continued to abuse heroin despite being maintained on methadone. This saw modest success in reducing illicit drug use among addicts who wished to regain control over their drug use but were unable to cope being maintained on methadone alone.
Chemistry
Dextromoramide is the right-handed isomerIsomer
In chemistry, isomers are compounds with the same molecular formula but different structural formulas. Isomers do not necessarily share similar properties, unless they also have the same functional groups. There are many different classes of isomers, like stereoisomers, enantiomers, geometrical...
of the moramide molecule. The left-handed molecule is called levomoramide
Levomoramide
Levomoramide is the inactive isomer of the opioid analgesic dextromoramide, invented by the chemist Paul Janssen in 1956. Unlike dextromoramide, which is a potent analgesic with high abuse potential, levomoramide is virtually without activity....
, and a mixture of the two is called racemoramide
Racemoramide
Racemoramide , or simply moramide, is a opioid analgesic and a racemic mixture of the substances dextromoramide and levomoramide , two enantiomers of a chiral molecule....
. 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).