Morphine

History

Morphine was simultaneously discovered in 1804 by Séguin and Courtois, like by Charles Derosne, but it is with F.W. Sertürner, Pharmacien of Hanover, which returns the merit (in its work published in 1805 - 1806 and 1817) to have seen that the isolated crystallized substance was an alkaloid “alkali vegetable”. It is the first known alkaloid and Sertürner names at once it morphium because its effects point out the god of the dreams of ancient Greece, Morphée.

Morphine (Codex 1818) and its salts (Codex 1866) is the Sédatif par excellence painful, acute or chronic syndromes. It will meet the invention of the hypodermic syringe with switches digs developed in 1850 by the Lyons doctor Charles Pravaz. The intravenous injection of an active ingredient of a plant is carried out for the first time in the history of sciences. Morphine was thus the first really powerful Médicament and inaugurated the modern era of the Pharmacologie and the Médecine. Starting from this date, a massive use of morphine against the pain becomes possible as well at the hospital as on the battle fields.

It is this use in its injectable form on the battle fields (American Civil War to the the United States, Crimean War in Russia, Guerre austro-Prussian, Franco-German Guerre of 1870 in Europe…) in particular for the Amputation S which it makes bearable which will be at the origin of what one then called the “disease of the soldier” then morphinism and finally morphine addiction. The first descriptions of morphine addiction appear as of 1871 the more so as it is then on sale free in many artisanal pharmaceutical preparations to look after the most various evils. In 1877, Dr. Levinstein and the pharmacologist Louis Lewin introduce the concept of Manie resulting from the Psychiatrie, then being born, and describe for the first time what one will call Toxicomanie stigmatizing for the general public morphine in this pejorative image. Its price less accessible than alcohol makes a product of it sails about it in the aristocracy until the beginning of the 20th century and many known characters are famous for their morphine addiction (John Pemberton, Bela Lugosi, Hermann Göring, Otto von Bismarck, Alphonse Daudet, the general Boulanger…).

In addition to its use as Antidouleur (Analgesic), it was used with the the United States of America to look after a whole range of mental affections (Alcoolisme, depression, maniaco-depressive Psychose, Hystérie, etc) until the measurements taken by the Opium Act in 1906 (which prohibit the production, the trade, the detention and the use of the Drogue S of opium and its derivatives in the United States). And it is on the initiative of the United States that the first international conventions will be held on the Stupéfiant S whose International convention of the Opium which regulates morphine specifically and on which were moulded the world majority of the laws anti-drug until our days.

It is only in 1925 that its complex molecular structure is established by the British chemist Robert Robinson (1886 - 1975).

At the beginning of the Years 1950, one redécouvre benefits of morphine thanks to the cocktail of Brompton, but by reserving it to alleviate the sufferings at the end of the lifetime.

Starting from 1952, it is possible to chemically synthesize morphine or its derivatives. The extraction of opium will remain used despite everything because of its cost weaker than the industrial method. Nevertheless, the chemical synthesis will give rise to chemical compounds of close structure but of different effects like the Lévorphanol (powerful analgesic) or the Dextrorphane.

In France, Henri Laborit works out an injectable cocktail associating opiated and Neuroleptique S which was used during the Guerre of Indo-China to facilitate the transfer of wounded to the back where one could operate them. This mixture was precursory neuroleptanalgesy.

Starting from the Years 1970, the use of morphine developed because of the nurses, who more with listening of the pain of the patients, claimed the best dealt with of the pain. In parallel, the basic research made great progress in the comprehension of the operation of morphine.

In 1973, researchers Swedish and American S highlight, In vitro, the existence of receivers specific to the Opioïde S on the level of the central Nervous system.

In 1975, in Scotland, Hughes and Kosterlitz leave the assumption that morphine " vegetable " must take the place on the endogenous receivers of molecules. They will thus discover the endomorphines, " morphines" naturally produced by the human body, which they will name This discovery Enképhaline S. will open the way with a multitude of others which will make it possible in years 1980 to better include/understand the operation of the pain and the action of morphine.

In the Years 1980, one continued progress in the adaptation of the amounts to the needs for the patients and one discovered new routes of administration (medullary way, cérébro-ventricular way, intravenous or subcutaneous way continuous). One also sees appearing the first compressed ones or gélules with prolonged action which make it possible to the patient to take only one amount every 12 hours and to thus find a share of its autonomy. Versions with only one catch per day will appear in the Années 1990.

Mode of action

The exact mode of action of the Opiacé S remains unknown. One considers that morphine acts on the central Nervous system (limbic Système and Hypothalamus) by saturation of the receivers with the opiates (named receiving Mu), implied in the phenomenon of perception of the pain. The action of morphine on the Récepteurs opiates in the remainder of the body is at the origin of the side effects: Constipation, respiratory Depression, etc

Dosage forms

Morphine exists in various forms according to the targeted use:

parenteral Way:

intravenous Injection
injection under cutaneous
intravenous injection in perfusion: in general this use is reserved to the patients under respiratory assistance.
injection péridurale
injection intrathécale
the pumps with morphine are used more and more in post-operative care or palliative care (PCA)

oral Way:

Compressed or Gélule
compressed or gélule with prolonged release (LP): used in the treatment of the chronic pains. There exist versions in gélule with two catches per day (BID) and more recently of the versions to a catch per day (OAD, of English " Ounce has day"). In both cases, the tablet or the gélule or its contents underwent a treatment in order to obtain a release spread out in time.
drinkable Syrup
Solution

other ways:

Suppositoire (nonavailable in France, available in Swiss and to the Canada)
Patch has release continues

The necessary amount depends on the route of administration, morphine by oral way undergoing a first hepatic passage, only 30% of the introduced amount is used by the body. There thus exist tables of equivalence (for the adult):

Mode of use

The startup of a treatment by morphine depends on the indication.

In the case of the treatment of an acute pain, (open fracture during an evacuation towards the health care centres, reduction of very painful luxation like the hip or the shoulder) one carries out a titration of the morphine amount. One starts by diluting the bulb of 10 Mg in a syringe of 10 ml of physiological salt solution then one carries out a first injection whose amount is precisely 0,1 mg/kg (either 7 Mg for a person of 70 kg) then one renews the injection with half proportions (or 0,05 mg/kg) every five minutes until obtaining sufficient an analgesic effect. The level of the pain is evaluated at the beginning and thereafter thanks to " échelles" visual or numerical. Any morphine injection by intravenous way must be realized under strict monitoring of the patient including/understanding his state of consciousness, its ventilatory frequency and if possible under monitoring of the tension, the heart rate and saturation artériolaire out of oxygen being given the respiratory risk of depression.
In the case of chronic pains, the startup of the treatment by morphine comes to replace an other antalgic treatment. One estimates that the starting amount corresponds to approximately 1 Mg/kg /jour, i.e. for an adult of sixty kilograms, the initial amount day laborer will begin to 60 Mg per day in oral form, 30 Mg per day in injection under cutaneous… etc titration is carried out gradually according to the antalgic answer felt by the patient. The amounts are increased regularly by stage by 60 daily Mg. After 3 days with an amount (for example 60mg/j PO), if the antalgic answer is insufficient, the amount is increased by 60 Mg per day (cad 120mg/jour PO) and so on until the satisfaction of the patient.

Undesirable effects

Morphine has many side effects due to its operating process of which most frequent are the digestive disorders (the Constipation, the nausea S and Vomissement S). In the event of administration over one long period, of the disorders of the central nervous system (somnolence, giddinesses) appear. Nauseas and the vomiting will disappear from themselves but the constipation must be treated. There exist also cardiorespiratory disorders (hypotension, bradycardia, bradypnée, dyspnea, pauses respiratory), behavioral problems (euphoria, aggressiveness) rarer.

Morphine and dependence

Like all Opiated, morphine is likely to cause a dependence in certain precise contexts out of the medical context. Its regulation engages the responsibility for the Médecin S since it is a product which can generate a Toxicomanie or be the subject of an illicit traffic. Under medical control, the regulation stipulates catches at hour fixes and controlled which allow the catch before the reappearance of the Douleur in order to avoid any association between medication and immediate relief as well as a progressive stop making it possible to avoid the syndrome of weaning. The tolerance which develops is a normal phenomenon and does not have to be lived by the patient like a sign of a possible drug-addiction, within a medical framework, the morphine regulation involves drug-addiction only in 4 cases for 10.000. If morphine is a product which posed many problems of drug-addiction at the beginning of the 20th century, in particular owing to the fact that it was primarily managed in injectable form. Its diverted use is, nowadays, relatively anecdotic; it is hardly any more used by the drug addicts than in empirical substitution of heroin. It can exceptionally be used as substitution therapy after the failure of the Subutex and the Méthadone in the treatment of the héroïn omanie, even if this use does not correspond, in France, with its AMM.

Overdose (Overdose) and toxicity

The overdose of morphine is a serious event of which the Symptôme S are the appearance of a state of somnolence, Hypothermie and Hypotension, and quickly a respiratory Dépression (difficulty of breathing). The most severe cases can lead to the Coma and the death.

The treatment begins in priority by a ventilation assisted to mitigate the respiratory depression then a gastric Lavage or absorption of Activated carbon to eliminate the drug not absorptive, when a formulation with modified release was swallowed.

The medicamentous treatment passes then by the use of a Antagoniste of the receivers of opiates, in general of the Naloxone, specific Antidote of the respiratory depression by opiates. The treatment begins to 0,2 Mg from naloxone by intravenous way followed by additional administrations from 0,1 Mg every two minutes.

At the time of a massive overdose, one manages of the naloxone to the amount of 0,4-0,8 Mg per intravenous way. The effects of the naloxone are one relatively short duration, a perfusion of naloxone can be installed until a spontaneous Respiration returns. Morphine can persist in the Sang up to 12 midnight after the administration, and the treatment of the morphine overdose is adapted consequently.

The naloxone is managed with precaution at the people having a physical dependence with morphine, a brutal or complete inversion of the effects of the Opiacé S which can precipitate a syndrome of acute weaning.

The amount necessary to reach a toxicity by overdose depends on the presence of a painful state or not and its intensity. Thus, of the cases of patients treated for chronic pains, with morphine sulfate by oral way, are known to have taken more than 3000 mg/jour without feeling toxic effects. Nevertheless, the available data suggest that the lethal amount can be reached dice 60 morphine sulfate Mg by oral way for a normal person, without painful state and not receiving already morphine.

lethal Amount morphine at various species

Chemistry

Morphine is described in the Pharmacopée S, inter alia the European Pharmacopée which gives of them the techniques of characterization as well as the standards and the methods of analysis for its use as a Médicament.

Synthesis

Chemical methods of Synthèse exist but the production starting from the poppy remains most profitable. The semi-synthetic derivatives are prepared starting from the morphine extracted the poppy. The synthetic derivatives like the Methadone or the Péthidine are prepared completely by chemical synthesis.

Industrially morphine can be obtained in two ways: ; starting from Poppy Oil poppy: One uses the shelled capsule and the end of the stem of the poppy oil poppy (Papaver somniferum nigrum) collected " green " during the summer. In France, the plant is cultivated primarily in Champagne-Ardenne. The parts of the plant are dried, then morphine is extracted in medium hydroalcoolic with other Opiacé S. It will be separated by a selective precipitation before being purified. ; starting from the Opium: Opium is resulting from poppies (Papaver somniferum), cultivated in India, by evaporation of the latex which runs out of incisions made on the capsule. Morphine (and other alkaloids) is obtained by acid aqueous extraction since the opium which contains about 10% of them. It is then obtained only by a selective precipitation.

Sulfate and morphine hydrochlorate

Morphine is often used in the form of salt in order to facilitate its use and its absorption by the organization in the noninjectable forms.

There exist two salts, sulfate and morphine hydrochlorate which once in the body will be in the form of morphine bases.

The morphine sulfate is obtained by reaction of morphine in hydroalcoolic solution (Eau + ethanol) with sulphuric Acid diluted. A similar reaction in the Hydrochloric acid is used for obtaining the morphine hydrochlorate.

Sulfate with the characteristic to be a pentahydrate including two morphine molecules

source: European Pharmacopeia 5.5 , EDQM, 12/2005; The Merck index', 13th édition

Impurities

From the complexity of the composition of the Opium and resemblance of the products which composes it, one finds some systematically others Alcaloïde S in the morphine which one regards as impurities. Their content in morphine is limited to 1% (0.2% for each impurity and 0.4% for the pseudomorphine):

Codeine (impurity has European pharmacopeia)
Pseudomorphine (impurity B of the European pharmacopeia)
Oripavine (impurity C of the European pharmacopeia)
10R- hydroxymorphine (impurity D of the European pharmacopeia)
morphinone (impurity E of the European pharmacopeia)
Thébaïne
Morphine N-oxide
Apomorphine

Legislation

Morphine is registered in Table I of the single Convention on the narcotics of 1961 and its use is regulated in many countries. In Belgium and France, morphine and its salts are Stupéfiant S. So morphine is subjected to a particular regulation for the regulation (particular ordinance limited in time - 4 weeks in France), the delivery (the pharmacist must note it on a special book), the use (only for the patient) and detention (regarded as a drug).

Like all Narcotic, morphine is a doping substance and, in certain countries, it is interdict with the sportsmen taking part in the competitions to use some.

Related terms

Morphine addiction: term made up of morphine and mania, of the Greek handled for “Folie, passion”. It indicates a regular and not controlled Consommation morphine, bringing a state of dependence.
Morphine addict: nominate the person reached of morphine addiction.

References

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