Morphine

Morphine is a molecule that can lay claim to being the original alkaloid and the first true drug, according to assistant professor Paul R. Blakemore and professor emeritus James D. White at Oregon State University, Corvallis (Chem. Commun. 2002, 1159).

Alkaloids are natural organic nitrogen-containing bases found mainly in plants. Morphine, a bitter white crystalline compound, is the principal alkaloid in the opium poppy Papaver somniferum. Traces of the compound, possibly from dietary sources, also occur in animal tissues and fluids, including human heart tissue and urine.

"The morphine story is one of the most enthralling in all of science," Blakemore and White note. "Early attempts to unlock the mysteries of opium provided a major stimulus to the development of organic chemistry and, it may be argued, spawned the entire field of medicinal chemistry."

THE POTENT analgesic and euphoric properties of opium poppy pods have been known for thousands of years. Opium was used, for example, as a narcotic in Sumerian cultures in Asia Minor as early as 4000 B.C. Its use and addiction were widespread in Roman times. In the 16th century, the Swiss physician and alchemist Paracelsus (1493-1541) popularized its use in Europe with the introduction of laudanum--a tincture, or alcoholic solution, of opium.

Morphine was first isolated in pure form from dried poppy resin by German apothecary Friedrich W. Sertrner (1783-1841) in the early 1800s. He named the compound "morphium" after Morpheus--the Greek god of dreams.

In 1925, University of Oxford chemistry professor Sir Robert Robinson (1886-1975) proposed the correct structure of the alkaloid following degradation studies of the compound. The molecule has a pentacyclic structure with a benzylisoquinoline nucleus supporting ether, hydroxyl, and olefinic functions.

The 70 or so poppy species that belong to the genus Papaver biosynthesize around 2,500 different benzylisoquinoline alkaloids. The opium poppy contains more than 80 alkaloids including morphine and codeine (morphine monomethyl ether). The poppy also contains the alkaloid thebaine, which is not an analgesic but is used to produce semisynthetic opioid morphine analogs such as oxycodone.

Morphine is produced commercially from either opium or concentrated poppy straw. Opium is a sticky brown resin obtained by collecting and drying the latex that exudes from the lanced poppy pods, whereas concentrated poppy straw is extracted from the pods after the plants have been harvested.

"Over the last 20 years, India has supplied a relatively stable amount of about 600 tons of opium per annum for the extraction of alkaloids," says Peter J. Facchini, professor of plant biotechnology at the University of Calgary, Alberta. "Global production of poppy straw containing morphine as the main alkaloid has fluctuated between 30,000 and 52,000 tons per annum. The main producers of the straw are Australia, France, Spain, and Turkey."

Morphine is extracted from opium resin or poppy straw in a series of extraction and purification steps involving water, organic solvents, and pH adjustment. Morphine free base in its anionic (morphinate) form is soluble in basic aqueous solutions at pH 11 or above, whereas other opium alkaloids are relatively insoluble and generally precipitate out of basic aqueous solutions.

"Codeine and thebaine are only present as trace amounts in poppy cultivated for the purpose of morphine extraction," Facchini notes. "Approximately 95% of the morphine extracted from licit opium is chemically converted to codeine, a more versatile pharmaceutical. The large quantities of morphine produced by the plant are the basis for illicit cultivation of opium poppy in many regions of the world for the synthesis of O,O-diacetylmorphine--heroin or diamorphine. Illicit production of opium exceeds licit usage by almost 10-fold."

Morphine is commercially available in a variety of products as the free base monohydrate and as hydrochloride, sulfate, tartrate, and other salts. The drug, which is administered by mouth or injection, is particularly effective in relieving severe, continuous pain--for example, the pain experienced by patients with terminal cancer--without loss of consciousness where other analgesics fail. It also has a euphoric effect. On the downside, it causes severe constipation, respiratory depression, drowsiness, vomiting, loss of appetite, confusion, blurred vision, dry mouth, and other adverse reactions. Morphine is also highly addictive and induces tolerance, which means that higher and higher doses are required to maintain the same effect.

The drug is a central nervous system depressant that binds to and activates opioid receptors in the brain, spinal cord, and gut. It competes with endorphins--the endogenous opioids in the body that attenuate pain--for the receptors.

Morphine occurs naturally as the (-) form. It was first synthesized in 1952 by chemists at the University of Rochester, in New York (J. Amer. Chem. Soc. 1952, 74, 1109). There have been a number of other syntheses since, but it is highly unlikely that a practical synthesis that can compete commercially with biosynthesis in the opium poppy will ever be achieved.

Morphine

Name
◾ (5α,6α)-7,8-Didehydro-4,5 -epoxy-17-methylmorphinan-3,6-diol

CAS Registry
◾ 57-27-2

Introduced
Poppy pods used as early as 4000 B.C.

Regulated
◾ In 1914, the Harrison Narcotics Act was passed; it called for control of each phase of the preparation and distribution of medicinal opium, morphine, heroin, cocaine, and any new derivative that could be shown to have similar properties. It made illegal the possession of these controlled substances.

Did you know that in 1898, Bayer registered diacetylmorphine (diamorphine) under the proprietary name Heroin in Germany as a cough medicine for children?