Interpretation of Urine Drug Testing in Pain Patients | Pain Medicine | Oxford Academic
morphine and codeine were monitored following the ingestion help characterize codeine/morphine excretion patterns fol- .. One of the major goals of this study is to .. tromethorphan: Relationship to the presence of immunoidentified. Morphine, heroin, codeine and related drugs are among the opioids. . The ultimate goal of treatment is lasting abstinence, but the immediate goals are. Codeine is an opiate used to treat pain, as a cough medicine, and for diarrhea. It is typically Codeine works following being broken down by the liver into morphine. .. Drugs bearing resemblance to codeine in effects due to close structural relationship are variations on the methyl groups at the 3 position including.
CYP2D6 converts codeine into morphine, which then undergoes glucuronidation. Life-threatening intoxication, including respiratory depression requiring intubation, can develop over a matter of days in patients who have multiple functional alleles of CYP2D6, resulting in ultra-rapid metabolism of opioids such as codeine into morphine.
Evidence supporting the hypothesis that ultrarapid metabolizers may get greater analgesia from codeine due to increased morphine formation is limited to case reports. Guidelines released by the Clinical Pharmacogenomics Implementation Consortium CPIC advise against administering codeine to ultrarapid metabolizers, where this genetic information is available. The CPIC also suggests that codeine use be avoided in poor metabolizers, due to its lack of efficacy in this group.
Codeine and its metabolites are excreted almost entirely by the kidney, mainly as conjugates with glucuronic acid. Chemistry[ edit ] Relation to other opioids[ edit ] Codeine has been used in the past as the starting material and prototype of a large class of mainly mild to moderately strong opioids; such as hydrocodone in Germanyoxycodone in Germanydihydrocodeine in Germanyand its derivatives such as nicocodeine in Austria.
In general, the various classes of morphine derivatives such as ketones, semisynthetics like dihydromorphinehalogeno-morphides, esters, ethers, and others have codeine, dihydrocodeine, and isocodeine analogues. As an analgesic, codeine compares weakly to other opiates. Related to codeine in other ways are codoximethebaconcodeine-N-oxide genocodeinerelated to the nitrogen morphine derivatives as is codeine methobromide, and heterocodeinewhich is a drug six times stronger than morphine and 72 times stronger than codeine due to a small re-arrangement of the molecule, viz.
Drugs bearing resemblance to codeine in effects due to close structural relationship are variations on the methyl groups at the 3 position including ethylmorphine a.
While having no narcotic effects of its own, the important opioid precursor thebaine differs from codeine only slightly in structure. Pseudocodeine and some other similar alkaloids not currently used in medicine are found in trace amounts in opium as well.
History[ edit ] Codeine, or 3-methylmorphine, is an alkaloid found in the opium poppyPapaver somniferum var. Opium poppy has been cultivated and utilized throughout human history for a variety of medicinal analgesic, anti-tussive and anti-diarrheal and hypnotic properties linked to the diversity of its active components, which include morphine, codeine and papaverine. Until the beginning of the 19th century, raw opium was used in diverse preparations known as laudanum see Thomas de Quincey 's Confessions of an English Opium-Eaterand paregoric elixirsa number of which were popular in England since the beginning of the 18th century; the original preparation seems to have been elaborated in Leidenthe Netherlands around by a chemist named Lemort; in the London Pharmacopoeia mentions an Elixir Asthmaticum, replaced by the term Elixir Paregoricum "pain soother" in The progressive isolation of opium's several active components opened the path to improved selectivity and safety of the opiates-based pharmacopeia.
Codeine is the most widely used opiate in the world,   and is one of the most commonly used drugs overall according to numerous reports by organizations including the World Health Organization and its League of Nations predecessor agency.
It is one of the most effective orally administered opioid analgesics and has a wide safety margin. While codeine can be directly extracted from opium, its original source, most codeine is synthesized from the much more abundant morphine through the process of O- methylation  through a process first completed in the late 20th century by Robert C.
Corcoran and Junning Ma.
Facts About Opioids — Hydrocodone, Oxycodone, Codeine & Others
They quickly succeeded using petroleum or coal tar and a process developed at the United States' National Institutes of Health. Numerous codeine salts have been prepared since the drug was discovered. The most commonly used are the hydrochloride freebase conversion ratio 0.
The latter was introduced as Codeonal inindicated for pain with nervousness. Codeine hydrochloride is more common worldwide and the citrate, hydroiodide, hydrobromide, tartrate, and other salts are also seen. Brand named as Phenergan with Codeine or in generic form as promethazine with codeine. In the s it started to be mixed with soft drinks to be used as a recreational drug and was called 'syrup', 'lean', or ' purple drank '.
Drug abuse screening programs generally test urinehairsweat or saliva.
Many commercial opiate screening tests directed at morphine cross-react appreciably with codeine and its metabolites, but chromatographic techniques can easily distinguish codeine from other opiates and opioids. It is important to note that codeine usage results in significant amounts of morphine as an excretion product. Furthermore, heroin contains codeine or acetyl codeine as an impurity and its use will result in excretion of small amounts of codeine.
The principal reason for this is to be found partly in governmental restrictions cf. The classical method of extracting opium incising the capsule and gathering the dried latex utilizes only a fraction of the plant's total alkaloidal content. The rest remains in the straw and the capsules which are mostly burnt or left to rot away.
The method is based on almost two thousand years of tradition and is gradually being replaced by methods which require less human labour.
Opium poppy grown in Norway. A large proportion of all the opium produced is used for the extraction of opium alkaloids. 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.
Facts About Opioids — Hydrocodone, Oxycodone, Codeine & Others
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.
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. 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.
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 ].
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.
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.