Codeine

White crystalline or amorphous powder obtained as short orthorhombic needles or prisms from alcohols melts at 197°C (386.6°F) decomposes at 254°C (489.2°F) darkens on exposure to light almost insoluble in water [0.02 g/100 g at 20°C (68°F], shghtly soluble in ethanol, chloroform, ether, and benzene dissolves in alkali solutions. 

Severe morphine poisoning may result in respiratory failure after fainting fits, accompanied by coma and acute miosis. It exerts effects on the gastrointestinal tract, decreasing the spasmotic reflexes in the intestinal tract, thus resulting in constipation. 

LD50 value, oral (mice) 524 mg/kg LD50 value, subcutaneous (mice) 220 mg/kg 

Girardot and Holloway (1985) have investigated the effect of cold-water immersion on analgesic responsiveness to morphine in mature rats of different ages. This study indicates that chronic stress affects the reactivity to morphine in young mature rats but not in old rats. 

Studies show that when coadministered with morphine, certain substances potentiated morphine s toxicity or mortality in rats. These substances include gentamicin [1403- 

Heroin can sometimes be very pure and can then be smoked, a practice that is increasingly replacing injection. Many young people are meanwhile switching to other substances such as amphetamine and its derivatives or to cocaine, whose consumption is said to produce a more intense high . 

The epidemiological data for DHC is analogous to that for codeine, although this substance is more favored than codeine by drug users. In the frequently practiced DHC substitution therapy, a 2.5% solution is used, but patients in a few cases have increased the usual daily dose from the 300-500 mg range to as 

---

Morphine is the principal alkaloid of opium. It acts both as a base and as a phenol and reacts to form methylmorphine (codeine ) and diacetylmorphine (diamorphine or heroin). 

Partial synthesis is relatively unimportant in the field of alkaloid synthesis, since only a few compounds are available at low price (see table 23). An exception is the derivatization of the morphine base, which leads to codeine, heroin, and other important compounds. These trivial reactions, however, are covered in elementary text books. 

Marquis reagent (gives a purple-red coloration, then violet, then blue with morphine, codeine, dionine, and heroine) mix 3 mL of concentrated H2SO4 with 3 drops of a 35% formaldehyde solution. 

Barnett and colleagues developed a new method for determining the concentration of codeine during its extraction from poppy plants. As part of their study they determined the method s response to codeine relative to that for several potential interferents. For example, the authors found that the method s signal for 6-methoxycodeine was 6 (arbitrary units) when that for an equimolar solution of codeine was 40. 

Therefore, the concentration of 6-methoxycodeine cannot exceed 3.3% of codeine s concentration. 

There are four broad classes of alkaloids whose general economic aspects are important (/) the opiates such as morphine and codeine (2, R = H and R = CH3, respectively) (2) cocaine (11) (both Hcit and iUicit) (2) caffeine (16) and related bases in coffee and tea, and (4) the tobacco alkaloids such as nicotine (21). 

The Opiates. The International Narcotics Control Board—Vienna, tracks the tick production of narcotic dmgs and annually estimates world requkements for the United Nations. Thek most recent pubHcation (100) points out that more than 95% of the opium for Hcit medical and scientific purposes is produced by India and, in a declining trend, only about 600 t was utilized in 1988. This trend appears to be due to the fact that the United States, the largest user of opium for alkaloid extraction, reduced the amount of opium being imported from about 440 t in 1986 to 249 t in 1987 and 224 t in 1988. The United States used about 48 t of morphine (2, R = H) in 1988, most (about 90%) being converted to codeine (2, R = CH3) and the remainder being used for oral adrninistration to the terminally ill (about 2 t) and for conversion to other materials of minor commercial import which, while clearly alkaloid-derived, are not naturally occurring. 

Opium is the dried, powdered sap of the unripe seed pod of Papaver somniferum, a poppy plant indigenous to Asia minor. Theophrastus described its medical properties in the third century BC, but the Sumerians, ca BC 4000, probably perceived its utility. Arab physicians knew of the dmg, and Arab traders carried it to the Orient where it was used as a treatment for dysentery. Paracelsus is credited with repopularizing the dmg in western Europe in the early sixteenth century by formulating opium into "laudanum", which is still in use. More than 20 different alkaloids (qv) of two different classes comprise 25% of the weight of dry opium. The benzylisoquinolines, characterized by papaverine [58-74-2] (1.0%), a smooth muscle relaxant, and noscapine [128-62-1] (6.0%), an antitussive agent, do not have any analgesic effects. The phenanthrenes, the second group, are the more common and include 10% morphine (1, = R = H), 0.5% codeine [76-57-3], C gH2 N03, (1, R = H, R = CH3), and 0.2 thebaine [115-37-7], C 2H2 N03, (2). 

Codeine, mol wt 299.3, is a significantly less potent analgesic than morphine, requiring 60 mg (0.20 mmol) to equal the effectiveness of 10 mg (0.04 mmol) of morphine. However, codeine is orally effective, and it is less addictive and associated with less nausea than morphine. Codeine is used as an antitussive agent, although newer, nonaddictive agents are preferred (see Expectorants, antitussives, and related agents). 

Narcotic Antitussives. Since its isolation in 1832, codeine [76-57-3] (27) has been one of the most widely used and effective compounds for the treatment of cough. Though less potent than morphine [57-27-2] (28), it has become the reference against which most antitussives are measured. 

Codeine, like morphine, is isolated from the opium poppy. However, the low yield of 0.7—2.5% does not provide sufficient material to meet commercial demands. The majority of marketed codeine is prepared by methylating the phenolic hydroxyl group of morphine. Morphine yields from opium poppy are 4—21%. When prescribed for cough, the usual oral dose is 10—20 mg, three to four times daily. At these doses, adverse side effects are very few. Although the abuse potential for codeine is relatively low, the compound can substitute for morphine in addicts (47). 

Molecular modifications of the morphine skeleton have produced numerous derivatives with antitussive properties, some of which have become commercially significant. Ethyknorphine [76-58-4] (29), a simple homologue of codeine, is prepared by ethylating morphine. It is pharmacologically similar to codeine but is seldom used clinically. Pholcodine [509-67-1] (30), the morpholinoethyl derivative of morphine, is used as an antitussive in a number of European countries. It is about one and a half times as potent as codeine, has Htde or no analgesic activity, and produces minimal physical dependence. The compound is prepared by the amino alkylation of morphine (48). 

Hydromorphone [466-99-9] (31) and hydrocodone [125-29-1] (32) are isomers of morphine and codeine, respectively. Hydromorphone can be prepared by catalytic rearrangement of morphine (49) or by oxidation of the aliphatic hydroxyl group of dihydromorphine (50). Hydrocodone can be similarly prepared. As an antitussive, hydromorphone is several times more active than morphine and hydrocodone is slightly more active than codeine. Hydromorphone has a much higher addiction potential than hydrocodone. 

Dihydrocodeine [125-28-0] (33), introduced in Germany before 1930, and dihydrocodeinone enol acetate [466-90-0] (34) both have clinical activity and addiction potential comparable to codeine. 

Modifications of the morphine skeleton have produced butorphanol [42408-82-2] (35) and drotebanol [3176-03-2] (36), which in animal models have demonstrated antitussive activity much greater than that of codeine (51,52). Butorphanol is also a potent analgetic of the narcotic antagonist type (51). Both compounds possess a unique 14-hydroxyl group. 

Nonnarcotic Antitussives. The most centrally active, noimarcotic antitussive is dextromethorphan [125-71-3] (39). It is similar to codeine in terms of potency and mechanism of action, ie, it is a direct depressant of the cough center. It is unique in that even though it is stmcturaHy related to codeine, it is not addictive. 

Levopropoxyphene [2338-37-6] (42), the optical antipode of the dextrorotatory analgetic propoxyphene, is an antitussive without analgetic activity. The 2-naphthalenesulfonate salt has a less unpleasant taste than the hydrochloride salt, and is widely used. Clinical effectiveness has been demonstrated against pathological and artificially induced cough, but the potency is somewhat less than codeine. The compound is reported not to cause addiction. Levopropoxyphene can be prepared (62) by first resolving [ -dimethylamino-CX-methylpropiophenone with dibenzoyl-(+)-tartaric acid. The resolved... 

The citrate salt of isoaminile [77-51-0] (50) is a nitrile used as an antitussive in numerous European countries. In clinical trials it was shown to be as effective as codeine or chlophedianol, with few mild side effects. Isoaminile citrate is longer acting than chlophedianol and does not cause the respiratory depression of codeine (68). 

Diphenhydramine [58-73-1] (55) was originally developed as an antihistamine and was first used clinically for this purpose in 1946 (see HiSTAMlNE AND HISTAMINE antagonists). In addition to this primary effect, however, central antitussive activity has also been demonstrated in animals (75,76) and in humans (77). Its antitussive activity is about half that of codeine. Drowsiness is the most frequent side effect. Diphenhydramine can be prepared as follows (78) ... 

Another antitussive with weak antihistaminic activity is the Japanese compound picoperine [21755-66-8] (56). This compound is a stmctural isomer of the weU-known antihistamine tripelennamine and is more potent than codeine. The chemistry (79) and pharmacology (80) of picoperine have been reported. 

Oxolamine [959-14-8] (57) is sold in Europe. It is an oxadiazole, and its general pharmacological profile is described (81). The compound possesses analgesic, antiinflammatory, local anesthetic, and antispasmodic properties, in addition to its antitussive activity. Although a central mechanism may account for some of the activity, peripheral inhibition of the cough reflex may be the dominant effect. The compound has been shown to be clinically effective, although it is less active than codeine (82,83). The synthesis of oxolamine is described (84). 

Dia2epam [439-14-5] (60) and clona2epam [1622-61 -3] (61) suppress cough induced by electrical stimulation of the lower brainstem of cats (90). Clona2epam and dia2epam adrninistered intravenously are about thirty-five times and six times more potent than codeine, respectively. Nevertheless, the compounds have not been widely used as antitussives in humans. Dia2epam is used in the treatment of anxiety, and clona2epam as an anticonvulsant. 

N. B. Eddy and co-workers. Codeine andits Alternatives For Pain and Cough Relief, World Health Organization, Geneva, Switzerland, 1970, p. 127. 

---