Morphine and codeine relationship problems

Opioid Metabolism

morphine and codeine relationship problems

CYP2D6 converts codeine in to its active metabolite, morphine, which provides its analgesic effect. However, pain relief may be inadequate in. Prescription opioids, which include morphine, fall into this category of drugs relationships between smoking marijuana and health problems. would be treated like opioids like morphine and codeine,” McCormick said. They are both used to treat pain, and share the same molecular backbone Codeine and morphine are the two natural painkillers made by the opium poppy.

It immediately becomes obvious that when alkaloids are the end product, the intermediate stage of producing opium is an unnecessary expense. Recognition of this fact is now becoming general, and the manufacture of opium alkaloids from poppy capsules and poppy straw is growing in certain countries, especially in eastern Europe.

For example, 8 tons of morphine were manufactured from poppy straw in17 tons inand 19 tons in In other words, in approximately one-quarter, in one-fifth and in one-sixth of all morphine manufactured was extracted from poppy straw [ 20 ]. The extraction of morphine according to this principle has long been dependent upon the development of practicable, economical methods. Today this problem has been solved in principle [ 3 ]and new and improved methods are constantly being developed.

The future prospects of the poppy plant seem to be closely linked to the following conditions, to mention but a few: The last condition depends in part on the continued development of synthetic morphine substitutes and on whether science will succeed in manufacturing drugs free from the undesirable side-effects of morphine-primarily that of addiction.

Research along this line is now in progress [ 29 ]. The development of new varieties of the opium poppy should probably be planned with a dual purpose - a to develop varieties with a higher alkaloidal content than is found today in plants grown for both alkaloids and seeds; 2 b to develop plants with a low alkaloidal content or none at all, exclusively for seed production cf.

This type of poppy would probably have to be grown under supervision. Table I The results obtained with the quinine tree Cinchona species demonstrated clearly that it is now possible to double the alkaloidal content of a plant.

morphine and codeine relationship problems

It would therefore not be unreasonable to assume that the alkaloidal content of the opium poppy can also be altered in one way or another. The methods formerly used by Dutch scientists in developing the quinine tree were primarily selection and crossing.

In addition to these classical methods, there are today a number of new ones which have already produced noteworthy results in the cultivation of drug-producing plants. I refer particularly to polyploidys and the modern mutation methods using various rays neutron rays in uranium piles, X-rays, ultra-violet rays and the like.

The former method has been used particularly on higher types of plants, the latter on lower organisms, for example in the development of new strains of moulds and actinomycetes, etc. The poppy plant contains the same alkaloids as opium cf. According to Wiest and Frey [ 11 ]the morphine content of poppy capsules varies between 0. The results of analyses of the morphine content of the stalks differ greatly, some reports showing between 0.

Opioid Metabolism

It has been found to contain approximately twenty alkaloids, which together make up about twenty per cent of its weight. Henry [ 14 ] divides the alkaloids of opium into the following five categories: Morphine, 3 to 23 per cent; Narcotine, 1 to 11 per cent; Codeine, from several tenths of 1 per cent up to 4 per cent; Thebaine, from several tenths of l per cent up to 4 per cent; Papaverine, from a few tenths of 1 per cent up to 2 per cent at least; Narceine, from 0. Although intensive research has been carried out for centuries to ascertain the chemical composition of opium, much remains to be done before that goal is achieved.

This point was also emphasized strongly in a recent article in the Bulletin on Narcotics [ 5 ]. The pharmacopoeias require medicinal opium to be prepared with a fixed morphine content, usually approximately 10 percent. It should here be kept in mind that the various assay methods can give widely differing results [ 1 ][ 14 ].

It is particularly important in this connexion to make clear the great significance of opium in modern therapy and the existing possibilities of replacing it with synthetic drugs. A study of the components of opium clearly shows it to be a product with a complex structure. Besides the active principle, morphine, a characteristic pharmacodynamic effect has also been observed in a number of the secondary alkaloids [ 18 ][ 22 ].

A synergistic or antagonistic relationship has also been found to exist between the various alkaloids [ 18 ]and it has been possible to demonstrate that even the nitrogen free ballast components influence absorption from the intestine and thus the effectiveness of the drug.

Accordingly, opium cannot yet be replaced by any single synthetic substance. The other problem which still remains to be discussed is the role which opium plays in modern therapy and as a raw material for pharmaceutical preparations.

Opium is included in all modem pharmacopoeias, and a large proportion of all the medicinal opium produced is used in the manufacture of galenical preparations such as Pulvis antasthmaticus, Pulvis Cynoglossi compositus, Pulvis Ipecacuanhae opiatus, Extractum Opii siccum, Tinctura Opii, Tinctura Opii Camphorata, Tinctura Opii Crocata, and the like.

morphine and codeine relationship problems

In this connexion also, the mixture of opium alkaloids should be mentioned. In Sahliintroduced into medicine under the name of pantopon [ 15 ]a preparation containing all the alkaloids of opium in the form of hydrochlorides. Preparations of this type often simplified to include morphine salts and some of the most important secondary alkaloids of opium in a fixed proportion are used today all over the world.

As compared with aqueous or alcoholic extracts from opium, preparations of the pantopon type have the great advantage that they can be used for injection. Many years of clinical experience have also shown that these compounds have a different effect on the central nervous system from that of morphine itself.

Thus they are not so likely as pure morphine [ 18 ][ 22 ] to produce unpleasant side-effects such as nausea and vomiting. This illustrates the advantages often found in natural mixtures of compounds over simple chemical individuals. In this connexion it should be remembered that many of the pantoponlike preparations are merely mixtures of isolated pure opium alkaloids in the proportion in which they occur in Turkish opium cf.

It may therefore be concluded that opium and opium preparations still play an important role in modem therapy. As has already been stated, the chemistry and pharmacology of the opium alkaloids are stillto a certain extent unknown, and they thus offer a rich field for future chemical and medical research. The drug was used largely in the manufacture of poppy syrup Syrupus Papaverisa preparation which was well known for its effectiveness in keeping young children-even infants-quiet at night.

Bearing in mind the unhealthy effects of morphine on young children, this may be cited as an example of the dubious therapy of the past. Since the alkaloidal content of poppy capsules is consi derably higher than that of the other parts of the plant, this drug is popular today as a raw material for the manufacture of opium alkaloids by extraction [ 3 ]. These studies, which have been in progress for years and are in fact still going on, made possible the improvement of morphine through the manufacture of derivatives, the determination of the chemical structure of morphine, the manufacture of synthetic substances with morphine-like effects, and culminating in the total synthesis of morphine, which was accomplished by Gates and his co-workers [ 12 ] in on the basis of preparatory studies by Grewe and his co-workers [ 13 ].

morphine and codeine relationship problems

Although morphine is a natural substance and also the most important representative of the natural analgesics, its total chemical synthesis is of great interest in this connexion. The question naturally arises: This question is difficult to answer at present, as it is too early to form a reliable opinion. That will depend not only on the ability of the synthetic products to compete in the morphine market, but also - and in at least equal measure - on such factors as the needs of national economy as reflected in trade agreements, customs barriers and the like.

At the present time, however, there seems to be no indication that the synthesis of morphine can have any practical value in morphine production.

morphine and codeine relationship problems

The main part of all morphine manufactured is used for conversion into codeine and other morphine derivatives. Narceine can be prepared from narcotine. The complete synthesis of morphine and codeine by Gates [ 12 ] and his co-workers has also made the total synthesis of thebaine possible. Except for the partial synthesis of codeine from morphine, the aforesaid syntheses have little or no practical significance nowadays, for the other substances are obtained as by-products of the manufacture of morphine from opium or opium derivates.

As mentioned above, the secondary alkaloids in medicinal opium seem to intensify the analgesic effect of the morphine [ 18 ]and, as will be shown below, some of them have greatly influenced the development of the semi-synthetic morphine substitutes in the next group. Papaverine is one of the most potent coronary vasodilator agents, and narcotine has recently been found to possess marked cough depressing properties.

Among the most conspicuous undesirable side-effects [ 6 ] are a depressive effect on the respiratory centre, nausea and vomiting, constipation and serious addiction liability. It is also rather toxic. When the chemical and pharmacological relationship between morphine and its methyl ether codeine became known codeine has a lower addiction liability than morphineattempts were made to exploit this discovery by producing its ethyl ether dionine, III-1 and its benzyl ether peronine III In addition, a number of isomers of codeine, such as pseudo-codeine, isocodeine and allopseudocodeine, were prepared and tested.

These substances produce an effect similar in kind to that of morphine, but are less powerful analgesics. On the other hand, some of the primary alkaloid's characteristic effects are intensified. Acetylation of both the hydroxyl groups in morphine yielded a substance diacetylmorphine, III-3 which was introduced into therapy as early as under the name of heroin.

While heroin has a considerably stronger analgesic action than morphine, its addiction liability is also much greater. By a rather simple chemical process thebaine is converted into dihydrohydroxycodeinone eucodal, III-4a substance that has approximately the same analgesic effect as morphine, but is less likely than morphine to provoke nausea and vomiting. Great therapeutic interest was centred on certain morphine derivates prepared by Skita and his co-workers in the German firm of Knoll, Ludwigshafen, in the period [ 18 ].

It exerts its effects via the opioid receptors found throughout the body including the central nervous system and the gastrointestinal system. Codeine is a prodrug that only weakly binds the mu opioid receptor.

morphine and codeine relationship problems

Its analgesic properties depend upon its conversion to morphine that binds to the mu opioid receptor with fold greater affinity than codeine. Codeine is indicated for the relief of mild to moderately severe pain, where the use of an opioid analgesic is appropriate.

Codeine is a Schedule II controlled substance, and there is a risk of misuse and abuse.

D.3 Structures of codeine, morphine and diamorphine (SL)

As with any opioid drug, the dosing regimen should be adjusted for each individual patient. When the patient no longer requires codeine, the doses should be tapered gradually to prevent withdrawal symptoms in patients who have become physically dependent 1.

For codeine to exert its opioid activity, it must first undergo o-demethylation by CYP2D6 to morphine. Morphine is further metabolized to morphineglucuronide, which also has analgesic properties. To avoid treatment complications in patients who are either ultrarapid or poor metabolizers, opioids that are not metabolized by CYP2D6 may be used e. The most common adverse reactions to codeine include drowsiness, lightheadedness, dizziness, sedation, shortness of breath, nausea, vomiting, and sweating.

One of the main serious adverse reactions associated with codeine is respiratory depression. Death related to ultra-rapid metabolism of codeine to morphine. CYP2D6 The cytochrome P superfamily CYP is a large and diverse group of enzymes that form the major system for metabolizing lipids, hormones, toxins, and drugs in the liver. The CYP genes are very polymorphic and can result in decreased, absent, or increased enzyme activity. CYP2D6 is responsible for the metabolism of many commonly prescribed drugs, including antidepressants, antipsychotics, analgesics, and beta-blockers.

UNODC - Bulletin on Narcotics - Issue 1 -

However, there is a large amount of variability in codeine response within patients genotyped as normal metabolizers, and the causes of this variation, among individuals with the same diplotype, are unknown 2. Other CYP2D6 alleles include variants that produce a non-functioning enzyme e.

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These individuals may not respond as well to codeine because the metabolism of codeine to morphine is reduced. In these individuals, codeine will provide little or no pain relief.

Poor metabolizers are more commonly found in European Caucasians and their descendants. Patients who are ultrarapid metabolizers carry at least 3 copies of the CYP2D6 gene. Each normal function CYP2D6 allele increases the rate of codeine metabolism, increasing the risk of an initial morphine "overdose", with more side effects and a shorter duration of pain control Even low codeine doses can result in toxic levels of morphine in patients with more than 2 normal function alleles 2.

Several case reports have recorded the severe or life-threatening adverse effects that have occurred in patients who were ultrarapid metabolizers and were treated with standard doses of codeine 25, Each allele is assigned an activity value: The total CYP2D6 activity score is the sum of the values assigned to each allele—patients with a score of 1. Poor metabolizers have an activity score of 0, patients with a score of 0.

However, evidence is lacking on whether genetic testing for these variants will aid optimum codeine dosing 7,