The Opiates

History

Excavations of the remains of neolithic settlements in Switzerland (the Cortaillod culture, 32002600 B.C.), have shown that Papaver was already being cultivated then; perhaps for the food value in the seeds (45% oil), which we know as poppy seeds. The slightly narcotic property of this plant was undoubtedly already known then. NOTE 11

The milky fluid extracted from the plant's ovary is highly narcotic after drying. This is then opium. The writings of Theophrastus (3rd century B.C.) are the first known written source mentioning opium. The word opium derives from the Greek word for juice of a plant, after all, opium is prepared from the juice of Papaver somniferum.

The Arabic doctors were well aware of the beneficial effects of opium and Arabic traders introduced it to the Far East. In Europe it was reintroduced by Paracelsus (14931541) and in 1680 the English doctor Sydenham could write:

'Among the remedies which it has pleased Almighty God to give to man to relieve his sufferings, none is so universal and so efficacious as opium.'

In the eighteenth century opium smoking was popular in the Far East and the opium trade was a very important source of income for the colonial rulers the English, the Dutch, with even the Spanish getting their share in the Philippines. Although opium was readily available in Europe at that time, its use was not problematical.

Opium contains a considerable number of different substances, and in the nineteenth century these were isolated. In 1806 Friedrich Serturner was the first to extract one of these substances in its pure form. He called morphine after Morpheus, the Greek god of sleep. Codeine (Robiquet, 1832) and papaverine (Merck, 1848) followed. These pure substances supplanted the use of raw opium for medical purposes. Like opium they were frequently used as painkillers and against diarrhea. The invention of the hypodermic in the midnineteenth century lead to widespread use of morphine intravenously as a painkiller.

In the United States opiate use rose greatly in the last century, partly because of the opiumsmoking Chinese immigrants, and partly because many of those wounded in the Civil War were given it intravenously. In addition many 'patent medicines' contained opium extract: laudanum, paregoric, etc. It was partly due to this that morphine also became fashionable as a 'remedy' for opium addiction; for if the doctor gave an opium addict morphine, he was no longer interested in opium so he was cured.

This was also the case in Europe and although its use was at that time much more widespread than is now regarded as acceptable for medical purposes, it led to few problems. NOTE 12

At the end of the last century, the United States started to try to curb the nonmedical use of opium, especially in China, and later tried to prohibit it. American interest here was twofold: they wanted an economically strong China as a market for their own products, and the moral element played a major role. As a result of the SpanishAmerican War, the Philippines became American and the new rulers were confronted with a widespread problem.The American bishop of the Philippines, Charles Henry Brent, carried on a moral crusade in the US against the opium trade and opium addiction, and found widespread support. And not only because he was riding on the waves of Prohibition, for as we have already seen, unlike the European countries, the US also had a domestic opium problem.

China, with its economy weakening, also saw the rise of a strong antiopium movement. England and the Netherlands, however, looked upon this development with disfavor as the cultivation of the papaver was a very important source of income for Britain and Dutch East India.

In 1909, under American pressure, representatives from countries with colonial possessions in the Far East and Persia met at Shanghai to hold the International Opium Conference, chaired by Bishop Brent. This conference laid the foundation for the International Opium Conference in The Hague in 1911. The English proposed that for participation in this second conference and the treaty that would result from it the condition be set that the effects of the treaty should extend to the preparation and trade in cocaine and morphine. The Germans had considerable difficulty with this condition as their pharmaceutical industry substantial interests in this area.

The conference lead to the first international convention, the Opium Convention of 23 January 1912, although it went no further than obliging the affiliated countries to take measures to control the trade in opium within their own national legal systems. The Germans were eventually successful in having the wording changed in all articles to do with morphine and cocaine from 'undertake to' to 'try to'. The ratification of the convention was ultimately made dependent on countries not present at the conference, in short it was as leaky as a sieve.

A second conference, held in The Hague in 1913, was equally unsuccessful in effectuating the convention and it was only at the third conference in The Hague in 1914 that a protocol was signed allowing the convention to take effect without the signatures of all the participating countries.

The United States immediately gave substance to this convention with the Harrison Narcotics Act of 17 December 1914 which not only controled the trade, but went much further by making illegal possession of substances named in the convention by unauthorised persons. A maximum fine of $2000 and/or five years imprisonment was the penalty set. The basis for the criminalization of the use of drugs had now been formalized!

World War I brought all efforts to a standstill, and the matter only came up again after the Treaty of Versailles was signed. In this convention the US introduced the provision that all countries which had not signed and/or ratified the convention of 1912 should still do this. The convention was handed over to the League of Nations in 1920 for enforcement.

In England the Dangerous Drugs Act came into force in 1920. Of interest here is that while the Americans also outlawed the use of heroin for medical purposes, the English upheld this usage and even found the provision of opiates, in this case heroin, to addicts to be acceptable medical practice.

As stated earlier, the treaty of 1912 was 'as leaky as a sieve' because it allowed the states to determine for themselves when and how they would fulfil their obligations with regard to opium, which of course kept the use of opium legal until that time. The chemical derivatives did, however, fall under this· commitment: their use was illegal, making these substances more than opium the object of the battle. To make this battle more effective the League of Nations held two conferences which led to two Geneva Conventions: one of 11 February and one on 19 February 1925.

The first convention concerned limiting the domestic production of and trade in opium in the colonies in the Far East. The second extended the number of substances covered under the Convention to include the coca leaf, raw cocaine, ecgonine and Indian hennep. Also, the states were to step up monitoring of the preparation, trade and possession of the 'numbing' substances involved.

Use as such was not made a punishable offence. After all, opium was still being legally cultivated and consumed in the East. An opium monopoly was seen as an effective way of combatting misuse.

In 1931 there was an international change of course and efforts were also made to forbid the legal production and consumption of opium for nonmedical purposes. New conventions were signed for this purpose: the conventions of Geneva (13 July 1931), of Bangkok (27 November 1931) and Geneva (26 June 1936) a more and more complicated network of conventions. The last convention especially for the suppression of the illicit traffic in narcotics went further towards criminalizing the use of drugs by requiring the convention partners to lay down harsher punishment, in this case with imprisonment for all offenders of the provision from the relevant conventions.

Ironically enough the Americans did not sign this one because it did not go far enough.

After World War II the United Nations took over the matter. The Economic and Social Council of this organization set up the U.N. Commission of Narcotic Drugs. This Commission, made up then of 40 member states, started preparations for a worldwide drugs policy.

This resulted in the Single Convention (New York, 30 March 1961) which replaced all previous conventions with one.

Under this convention all parties are required to take the necessary legal and administrative measures to restrict the trade, production and possession of narcotics to scientific and medical purposes. All activities which are not directed towards these scientific and medical purposes must be considered as punishable offenses.

The convention has four lists of substances with regard of which a different regime of supervision applies, and on recommendation of the World Health Organization (WHO) the UN can add certain new substances to these lists. However it must be shown that these substances present a serious threat for public health or are involved in illicit traffic. The first is a clear criterium, the second clearly not. As long as a substance is not forbidden, production, trade and use can, of course, not be illegal!

Depending on the degree of misuse, substances from one list can be put on another. National legislation would then have to be adapted to these changes.

It is of interest with this to note when the European ratified all these conventions drug abuse was not a social problem. Unlike all other laws, the opium laws in Europe were not introduced as a reaction to a social problem, but were more or less imposed by foreign countries, namely the United States, the '...barbarians of the West' for their 'extraordinary savage idea of stamping out all people who happen to disagree ... with their social theories' against narcotics, against alcohol and in 'their recent treatment of Socialists'. NOTE 13

And, the world was a victim of American puritanism, for in Europe it was really only still in a few Chinese communities that nonmedical opium was used. It was no longer a problem in Asia either now that the aggressive sales tactics by the colonial rulers had ended. That is also disputed in most European countries, but in the Netherlands, in Amsterdam and in Rotterdam, it was tolerated as long as its use remained limited to the Chinese.

For a more comprehensive survey of the history of the opiates please refer to Musto, NOTE 14 Taylor NOTE 15 and McCoy. NOTE 16

The pharmacology of opiates.

The pharmacological effects of opiates result from the fact that these substances have a bit (like a key) just like the endorphins and thus directly stimulate the endorphinreceptors (fig. 9). Because the opiates were known earlier than the endorphins, these are usually called opiatereceptors. We can trace these receptors in the brain by injecting radioactive opiates and then by monitoring where the radioactivity collects in the brain. This appears to be in very specific areas in the brain. Figure 10 shows these areas in diagram.


The first concentration of opiatereceptors is formed by a nerve cell system which plays an important role in transmitting pain stimuli. A brief digression regarding pain is required here.

If someone unexpectedly pricks herself, for instance on an improperly stored needle in the sewing box, she will already retract the injured finger (and bleeding or not, put it in her mouth) before any pain is felt. This is due to an emergency telegraph from the finger to the spinal cord from whence another message is immediately transmitted back to the arm muscles (comparable to the kneejerk reflex). At the same time, a message from the spinal cord is transmitted to the cortex of the cerebrum, which results in the first experience of pain. Until then, there are only signals aimed at a direct reaction to end the painful stimuli. If that were to be the end of it, there is every chance that the person would put her hand into the sewing box just as carelessly on a second occasion. In order to prevent this, and to introduce a moment of learning, stimuli are sent (slowly) from the spinal cord to the part of the brainstem where the opiate receptors are located.

This area is responsible for the alarming or threatening aspect of pain and it is exactly this effect which is remedied so effectively by the administration of opiates. The feeling itself does not disappear so much as lose its threatening character. It is this which lends the opiates their painkilling (analgesic) effect.

The most striking quality of this painkilling effect of opiates is that it has virtually no effect whatever on the other sensory perceptions, consciousness or the motor functions. All other substances with a painkilling effect, such as laughing gas, alcohol, ether and barbiturates also have, in an effective dose, a definate effect on consciousness, motor coordination, the intellect and emotional control. The drowsiness which can be caused by opiates is experienced only at high dosage.

A concentration of opiate receptors are also located in the respiratory center. These cells serve as a kind of metronome, that apparatus countless people have standing on their pianos to keep the beat. This metronome regulates the breath in a similar way, with fast or slow settings according to requirements, but allowing in and out breaths to take place regularly. Opiates also have an inhibiting effect on these cells: both the frequency and the depth of breathing is reduced under the influence of opiates. In the case of an overdose, respiration can come to a complete halt. Through shortage of oxygen, the heart muscles can no longer beat and as a result, brain cells die, and death occurs. Besides this, opiates inhibit sensitivity to the impulse to cough. Codeine in particular is used in many cough remedies, but even heroin is used for this purpose in England.

The third concentration is in the vomitting center, which, stimulated by the stomach (contaminated food etc.), normally causes the stomach muscles to contract, resulting in vomitting. These cells are stimulated into activity by opiates: opiate use causes nausea nd vomitting. However, tolerance for this effect is built up very quickly, although some users continue to vomit after each 'shot' for years. This effect is strongest with the opiate apomorphine, which is used medically specifically for this purpose.

The effect of opiates on the digestive system, which also contains large numbers of opiate receptors, has been known about for the longest period of time. Long before opiates were used as painkillers, opium was used for diarrea: opiates inhibit intestinal peristalsis. For this reason, most heroin addicts are constipated.

Opiates also affect the endocrinal system. By influencing the hypothalmus, the part of the brain linked to the hypophysis, the conductor of the hormonal orchestra, body temperature is slightly lowered, although it goes up with chronic use of high doses. Via the hypophysis, opiates lower the amounts of cortisol and testosterone in the blood, although these effects disappear again with chronic use as a result of tolerance.

Opiates influence the pupils: they contract (miosis). This is an extremely reliable signal of opiate use. Besides this, when suffocation occurs (as a result of respiratory inhibition) in the case of an overdose, the pupils dilate (mydriasis).

In the usual therapeutic dosage, morphine widens the veins in the skin, often giving the face, throat and upper part of the chest a flushed appearance and a warm sensation. This is due to the fact that morphine releases histamine. This is also the reason for the itching and perspiration often seen in opiate users.

The effects mentioned so far do not explain the mood changes which occur with opiateuse, and even less, the phenomenon of 'addiction'. These are dependent on the influence of opiates on the largest cell complex which is strewn with opiate receptors, the limbic system and the nucleus accumbens. In this way,opiates cause euphoria, but lessen negative stimuli such as pain and distress, leading to emotional indifference often combined with inhibition of the sexual functions. The effect is comparable to that on pain: the signal is not removed, but the emotions linked to it are.

Chronic use of all opiates leads to a definate tolerance and a strong physical dependence. The relative severity of the abstinence syndrome is in general related to the duration of efficacy, leading to the paradoxical situation in which the abstinence syndrome of heroin, although occurring extremely quickly, is nonetheless less extreme than that of methadone.

The various opiates.

Opium is smoked, eaten and injected. The duration of efficacy is long (at least 36 hours) and the abstinence sydrome, although slow to occur because of the long period of effectiveness, is severe and longlasting compared to for instance, heroin.

Another means of preparation is that of the 'compote', a boiled down extract of the whole poppy plant, which is very popular in Poland and other former East Block countries, where poppy cultivation takes place on a large scale for the seeds.

Morphine is, as we have seen, the most important opiate derivative of opium. The morphine content of opium is between 5 and 15 %. The period of effectiveness of morphine is 4 - 6 hours. The usual therapeutic dose is 5 - 15 mg.

, In 1832 another opiate was isolated in opium: codeine, which is used mostly as a cough remedy.

When morphine is heated in waterfree conditions with acetic acid anhydrides, two acetic acid molecules combine with the morphine molecule and make diacetylmorphine. This substance was synthesized for the first time in 1898 by Dresser and was put on the market commercially by the firm, Bayer under the name by which the substance is still known: heroin, together with another new product, 'aspirin'.

Heroin is more fat soluble than morphine and thus passes the bloodbrain barrier more quickly. It therefore works more quickly, but for a shorter time: 34 hours. The usual therapeutic dose is 4 mg. With an equal analgesic effect, it has even less influence on the consciousness than morphine.

Heroin was used in the first place for patients with the then incurable tuberculosis. The patient died anyway, but without coughing and pain, and with a hefty dose, in euphoria. The second indication was....'to combat' morphine addiction. Just as morphine was originally used 'to combat' opium addiction, heroin was now used to combat morphine addiction. The result speaks for itself.

Nonmedical use of heroin was primarily an American problem. After the lifting of the alcohol prohibition, both the mafia which had in the meantime come into being and the exopponents of alcohol threw themselves upon 'drugs'. Particularly after World War II, morphine was extracted from Turkish opium in small southern European (Marseilles!) laboratories, and was then turned into heroin. This was then smuggled into the US: the 'French connection'. It was only late in the sixties that some of this production leaked away to the European population (Note 16). At the same time, opium began to leak away from the Chinese communities to the indiginous Europeans. They also went over to injecting the opium.

In 1972, the opium supply suddenly dried up. To begin with, it was thought that this had to do with effective police action, but it soon became clear that it had more to do with developments in SouthEast Asia. With active support from the CIA, heroin production was heavily increased and then dumped on the West European market. Within no time, all the former opium users had become heroin users.

With equal speed, heroin became the vogue amongst the socalled 'speed freaks', users of amphetamines and metamphetamines (Pervitine), who combatted the overstimulation caused by these substances with heroin, often taken in a 'shot'.

Heroin use then spread steadily to newer groups, particularly the various immigrant groups which had begun to populate Europe in the mean time.

After the end of the Vietnam war, the flow of SouthEast Asian heroin, the socalled 'brown sugar' dwindled quite quickly, although it was compensated for by a growing supply of SouthWest Asian heroin, originating in Pakistan and Afghanistan. A connection with the war in Afghanistan seems clear. In any case, the fierce competition between these two heroin sources led to a sharp fall in heroin prices. The provision of methadone has, in Holland, also certainly had an influence on prices.

Heroin is the first example of a semisynthetic opiate: changes in the morphine molecule are brought about chemically. Many other semisynthetic opiates followed, such as Methadone, a synthetic opiate, which was synthesized by German chemists at I.G. Farben at the end of World War II while researching spasmolytica. The narcoticanalgesic effect was discovered only after the war, this not being expected as the chemical structure differed so much from the known opiates.

The story about methadone being produced to take the place of morphine, which was said to be in short supply as a result of the obstruction of opium imports in favor of war activities, is untrue. The name Methadone was given by the Council on Drugs of the American Medical Association in 1947.

It differs from morphine and heroin in that it is broken down in another way, works well taken orally, and works for longer. It is said to be effective for 24 hours, although there are many indications that 20 hours may be nearer to the truth. In any case, efficacy varies considerably in duration from individual to individual. continued at Opiates II

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