morphine, codeine and heroin

Morphine, first isolated circa. 1803, and first "experienced" in a near-fatal overdose by F.W Serturner in 1805 (1), is the most abundant and important alkaloid in Papaver somniferum. The morphine content of opium latex -- the milky exudate of the "fruit" which appears after flowering -- averages 10-20%. Other parts of the plant contain significantly less of the alkaloid.

Morphine base is extracted from opium by treating the raw product with alkali and crystallising the precipitate in an appropriate solvent (e.g., ethyl alchohol). A procedure for the extraction of morphine from opium is given by Beckett and Stenlake (2):

"Triturate the sample (8 g) with water (30 ml) and calcium hydroxide (2 g) in a mortar. This liberates the alkaloids from their salts, and converts morphine and narcotine into their water soluble calcium salts. Transfer the mixture (grease the lip of the mortar) to a tared flask and make up to exactly 90 g with water. Shake occasionally during half an hour and filter through a dry Buchner funnel into a dry Buchner flask. Transfer exactly 52 ml of the filtrate to a clean dry conical flask, and add ammonium chloride (2 g), ether (25 ml) and 90% ethanol (5 ml). The function of the ammonium chloride is to decompose the calcium salts of the alkaloids.

(RO)₂Ca + 2NH₄Cl --> 2ROH + 2NH₃ + CaCl₂

Ether acts as a solvent for narcotine and the ethanol facilitates the crystallization of the morphine which separates from the solution. Cork the flask, shake for 5 minutes and occasionally during half an hour, so that total shaking time is about 15 minutes. Allow to stand overnight. Decant the ethereal solution as completely as possible with a tight plug of cotton wool retaining the crystals in the flask as far as possible. Wash the contents of the flask with a further quantity of ether (10 ml) and decant through the filter. Wash the filter with solvent ether (5 ml) added slowly and in small quantities. Displace the air in the flask gently with air from a bellows to ensure removal of ammonia fumes. Transfer the contents of the funnel back to the flask with water from a wash bottle. Add N/10 [0.1 M] HCl (25 ml), boil gently to remove CO₂, and back titrate the excess acid with N/10 [0.1 M] NaOH using methyl red as indicator."

Investigations into the chemical properties and physiological effects of morphine expanded throughout the 19th century. The molecular formula would eventually be determined to be C₁₇H₁₉NO₃. The molecular structure, pictured above, was not determined until 1925 (3). Despite their ignorance regarding the exact chemical composition of morphine, 19th- and early 20th-century chemists successfully manipulated the molecule, synthesizing many compounds that are still in use today, including codeine, heroin, dihydromorphinone (Dilaudid®), and apomorphine (3).

Codeine was first isolated from opium in 1832 by Robiquet (1). It is present in the latex only in small amounts -- around 0.5% to 1.5%. Codeine on the pharmaceutical market is not extracted from opium but prepared via the methylation of morphine. Codeine is the most widely consumed (licit) opiate. The International Narcotics Board estimated that some 180 metric tons of codeine were consumed worldwide in 1995, against a total morphine-derivative consumption level of 236 metric tons for the same year (4).

While codeine is present only in small amounts in opium latex as a whole, since it comprises some 5% to 15% of the narcotic alkaloid content of the gum, it may be present as a contaminant in illicit opiate products. The narcotic content of street heroin typically includes about 10% acetylcodeine, and Soine (6) has suggested that this may account for some toxic reactions to street heroin: "[acetylcodeine is] two times more toxic and three times more active as a convulsant than diacetylmorphine [heroin]". He speculates that, "based on the common occurence of acetylcodeine in heroin at relatively high concentrations it could contribute to its toxicity."

First synthesized from morphine in 1874 by C.R.A. Wright, 3,6-diacetylmorphine (left), was marketed under the trade-name "Heroin" by Bayer Co. in 1898, as an analgesic, a cough medicine, and in some instances as a "cure" for morphine addiction.

Heroin is a "pro-drug." It has little nervous-system activity itself, but is rapidly metablized to the active drugs morphine and 6-monoacetylmorphine. The advantage of heroin over morphine, both as an analgesic and as a euphoriant, lies in its high lipid solubility. Compared to morphine, heroin achieves about three times more blood-brain barrier penetration (7). Thus it may be delivered at one third the volume for the same effect, which may spare the user/patient much histamine-related discomfort and other side-effects characteristic of large doses of opiate drugs.

Heroin is used licitly in only a few countries, including the United Kingdom and Canada. Illicitly, an estimated 4000 metric tons of opium were produced in 1995 (8), destined for conversion to 300 to 400 metric tons of heroin. The majority of this opium grown and processed in Burma (2000 to 2500 metric tons) and Afghanistan (1000 to 2000 metric tons). Other major growers include Thailand, Laos, Pakistan, Colombia and Mexico. Generally speaking, Southeast Asian heroin is marketed worldwide, Southwest Asian product is found in Europe, and Latin American heroin comes solely to the U.S. (4).

Heroin comes in many varieties, from Mexican "black tar" to "China White," a fine, white powder of Southeast Asian origin. Although pure heroin is white, it does not follow that white heroin is pure. Other white powders may easily be added to dilute the product. On the other side of the coin, the "dirty" appearance of brown heroin or tar may belie its purity. As one researcher quipped, "cutting a piece of black tar heroin is somewhat analogous to attempting dilution of a piece of semihardened chewing gum" (9). Also, unlike cocaine, it is not only heroin base that is smoked. Far-Eastern "smoking heroin" ("Heroin No. 3") is a 1:1 mixture of diacetylmorphine HCl and caffeine, often flavored with quinine or strychnine (10). Caffeine is used because it vaporizes at a low temperature, maximizing the amount of heroin vaporized without decomposition (11). On the rare occasion that strychnine-flavored heroin is encountered, evidently it is present in such small proportions that it is unlikely to poison the user (10). (That's what the heroin is there for, silly!)

assorted derivative compounds

recommended online readings

references

1. Macht, D.I. "The history of opium and some of its preparations and alkaloids", The Journal of the American Medical Association, 1915, 64:6, pp477-81.

2. Beckett, A,H & Stenlake, J.B. Practical pharmaceutical chemistry: 2nd Ed, 1968, (Atholone Press: London).

3. Small, L.F. & Lutz, R.E. Chemistry of the Opium Alkaloids, 1932, Public Health Reports Suppl. No. 103.

4. International Narcotics Control Board Report, 1996.

5. O'Neil, P.J. & Pitts, J.E. "Illicitly imported heroin products (1984-1989): Some physical and chemical features indicative of their origin", Journal of Pharmacy and Phamacology,1992, 44, pp1-6.

6. Soine, W.J. "Clandestine drug synthesis", Medicinal Research Reviews, 1986, 6:1, pp41-74.

7. Julien, R.M. A Primer of Drug Action, 7th ed., 1995, (Freeman: New York).

8. The Supply of Illicit Drugs to the United States in 1995, 1996, National Narcotics Intelligence Consumers Committee (NNICC).

9. Sperry, K. "An epidemic of intravenous narcotism deaths associated with the resurgence of black tar heroin", Journal of Forensic Sciences, 1988, 33:5, pp1156-62.

10. Eskes, D. & Brown, J.K. "Heroin-caffeine-strychnine mixtures -- where and why?" Bulletin on Narcotics, 1975, 27:1, pp67-69.

11. Kools, J-P. From 0 to 600 centigrade in 2 seconds: Chasing the dragon. (From Mainline, special edition VIIIth International Conference on AIDS Amsterdam, July 1992)