The opium analgesics

We are now going to look in detail at one of the oldest fields in medicinal chemistry, yet one where true success has proved illusive—the search for a safe, orally active, and non-addictive analgesic based on the opiate structure. 

It is important to appreciate that the opiates are not the only compounds which are of use in the relief of pain and that there are several other classes of compounds, including aspirin, which combat pain. These compounds, however, operate by different mechanisms from those employed by the opiates, and therefore relieve a different, sharper kind of pain. The opiates have proved ideal for the treatment of deep chronic pain and work in the central nervous system (CNS). 

The term opium alkaloids has been used rather loosely to cover all narcotic analgesics, whether they be synthetic compounds, partially synthetic, or extracted from plant material. To be precise, we should really only use the term for those natural compounds which have been extracted from opium—the sticky exudate obtained from the poppy (Papaver somniferum). The term alkaloid refers to a natural product which contains a nitrogen atom and is therefore basic in character. There are, in fact, several thousand alkaloids which have been extracted and identified from various plant sources and examples of some of the better known alkaloids are shown in Fig. 12.1. These compounds provide a vast library of biologically active compounds which can be used as lead compounds into many possible fields of medicinal chemistry. However, we are only interested at present in the alkaloids derived from opium. 

The opiates are perhaps the oldest drugs known to man. The use of opium was recorded in China over two thousand years ago and was known in Mesopotamia before that. Over the centuries the crude extract derived from poppies has been widely used as a sedative. A tincture of opium called laudanum was introduced to England and was considered indispensable to medicine. It is ironic that a compound renowned for its sedative effects should have led to at least one war. In the nineteenth century, the Chinese authorities became so alarmed about the addictive properties of opium that they tried to ban all production of it. This was contrary to the interests of the British traders dealing in opium and as a result the British sent in the gunboats to reverse the 

Chinese decision—one of the least savoury aspects of an otherwise relatively benevolent British Empire. 

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Patrick, G. L. The opium analgesics. In An Introduction to Medicinal Chemistry, 1st Edition. Oxford University Press Oxford, 1995, pp. 250-254. 

Many alkaloids have pronounced biological properties, and a substantial number of the pharmaceutical agents used today are derived from naturally occurring amines. As a few examples, morphine, an analgesic agent, is obtained from the opium poppy Papaver somnifemm. Cocaine, both an anesthetic and a central nervous system stimulant, is obtained front the coca bush Erythroxylon coca, endemic to upland rain forest areas of Colombia, Ecuador, Peru, Bolivia, and western Brazil. Reserpine, a tranquilizer and antihypertensive, comes from powdered roots of the semitropical plant Rauwolfia serpentina. Ephedrine, a bronchodilator and decongestant, is obtained front the Chinese plant Ephedra sinica. 

Opioid analgesics are the narcotic analgesics obtained from the opium plant. More than 20 different alkaloids are obtained from the unripe seed of the opium poppy... 

The development of the first effective analgesic drug, opium, was almost certainly adventitious, and occurred in prehistoric times. The use of the dried exudate from slitting the immature capsule of the opium poppy, Papaver somniferum, as an analgesic, sedative and euphoriant, has a long folkloric history. Isolation of the principal active component morphine (1) as a pure crystalline compound represented one of the early landmarks in organic chemistry. 

Narcotic analgesics Morphine and many of its homologues, when administered in medicinal doses, relieve pain and produce sleep. In poisonous doses, these produce stupor, coma, convulsions and ultimately death. Morphine narcotics are sometimes referred to as opiates, since they are obtained from the opium poppy. 

Morphine is the major alkaloid in opium, the dried latex obtained from the opium poppy, Papaver somniferum. About 25% of the mass of opium is composed of alkaloids, with morphine constituting about 12-15%. Morphine is a powerful analgesic, and remains one of the most valuable for relief of severe pain. However, most of the morphine extracted from opium is processed further to give a range of semi-synthetic drugs, with enhanced or improved properties. A means of extracting morphine from the other alkaloids in opium is thus desirable. 

Opium is a cmde exudate obtained from the opium poppy Papaver somniferum, and it provides several medicinally useful alkaloids. One of these is codeine, which is widely used as a moderate analgesic. Opium contains only relatively small amounts of codeine (1-2%), however, and most of the codeine for dmg use is obtained by semi-synthesis from morphine, which is the major component (12-20%) in opium. Conversion of morphine into... 

Both morphine and codeine are valuable analgesics. Morphine is extracted from opium, the dried latex of the opium poppy, and codeine is usually obtained from morphine by semi-synthesis (see Box 6.2), since the amounts in opium are rather small. Thebaine is a valuable raw material for semi-synthesis of a wide range of morphine-like drugs. 

Catalytic reduction of codeine gives dihydrocodeine and Oppenauer oxidation (a ketone such as acetone and an aluminum alkoxide, the ketone being reduced to an alcohol) gives hydrocodone. Hydrocodone can also be prepared directly from codeine with a metal catalyst, which isomerizes the allylic alcohol to a ketone. Codeine is prepared by methylation of morphine, which is isolated from the opium poppy. Hydrocodone is more potent than codeine. Acetaminophen is a mild analgesic and is discussed in Section 8. 

The discovery of morphine s analgesic activity by Sertumer in 1806 started a long series of studies of the alkaloids from the opium poppy, including morphine s first correctly postulated structure in 1925 and its total... 

Morphine and cocaine Morphine is medically the most important alkaloid present in opium. Opium itself consists of the dried milky exudate extracted from unripe capsules of the opium poppy (Papaver somniferum), which is grown mainly in Asia, but also in some parts of India and China. Morphine is a powerful analgesic and has been used to treat severe pain. However, its addictive properties complicate its long-term medical use and it is also a drug of abuse. In addition to morphine, opium also contains codeine, which has similar, but weaker, actions. 

The opium alkaloid morphine is representative for this group of opiates and also for other opioid analgesics. Morphine is a full agonist for both the jx and the k receptors. It is used to relieve severe acute pain, or chronic pain in terminally ill patients. Its oral bioavailability varies from 15% to 35% and its... 

Noscapine is a naturally occurring product of the opium poppy. It is a benzylisoquinoline with no analgesic or other CNS effects. Its antitussive effects are weak, but it is used in combination with other agents in mixtures for cough relief. 

Diphenoxylate (marketed in combination with atropine as Lomotil in the United States) is chemically related to both analgesic and anticholinergic compounds. It is as effective in the treatment of diarrhea as the opium derivatives, and at the doses usually employed, it has a low incidence of central opioid actions. Diphenoxylate is rapidly metabolized by ester hydrolysis to the biologically active metabolite difenoxylic acid. Lomotil is recommended as adjunctive therapy in the management of diarrhea. It is contraindicated in children under 2 years old and in patients with obstructive jaundice. Adverse reactions often caused by the atropine in the preparation include anorexia, nausea, pruritus, dizziness, and numbness of the extremities. 

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