Natural and Synthetic Drugs with Morphine-like Effects Considered from a Pharmacognostic Point of View




Author: Arnold Nordal
Pages: 18 to 27
Creation Date: 1956/01/01

Natural and Synthetic Drugs with Morphine-like Effects Considered from a Pharmacognostic1 Point of View

Ph.D. Arnold Nordal Professor of Pharmacognosy. Director of the Pharmaceutical Institute, University of Oslo, Norway


In the present article reference is made to the all-important part which the study of drugs and natural substances has played in the development of synthetic substances, including synthetic drugs with morphine-like effects. Advantages and disadvantages in the use of natural and synthetic drugs are discussed from the point of view of therapeutics, economics, and production technique. The subsequent section refers to the predominant role of the poppy plant in the world's production of morphine and morphine derivatives. Then follows a critical examination of the various drugs.

Definitions and Terminology

Morphine belongs to a large group of drugs designated in pharmacology as narcotics. In therapy a distinction is usually made between four principal types of narcotic - ([1] ) analgesics(pain-killing drugs), ([2] ) hypnotics(sleep-inducing drugs), ([3] ) sedatives(soothing drugs) and ([4] ) anaesthetics(drugs inducing unconsciousness). The lines of demarcation between these groups are not clearly drawn, and depend usually in part on the size of the dose.

Administered in proper doses and at the appropriate time, morphine can act either as a sedative, as a hypnotic, or-particularly in combination with other drugs-as an anaesthetic (for example, morphine-scopolamine in basal narcosis).


Pharmacognosy is the study of crude medicinal drugs-i.e., the raw materials of vegetable and animal origin which are used directly for medicinal purposes or in the manufacture of pharmaceutical preparations.

Nevertheless, its most striking feature is its analgesic action-Therefore the present article is restricted to a discussion of the analgesic properties of morphine and morphine-like substances.


  1. Natural drugs with morphine-like effects

    Opium and medicinal preparations of opium, poppy straw (or poppy capsules), morphine and the principal secondary opium alkaloids.

  2. Semi-synthetic drugs with morphine-like effects (derivatives of opium alkaloids)

    For example: Benzylmorphine (peronine), ethylmorphine (dionine), diacetylmorphine (heroin), dihydrodesoxymorphine-D (desomorphine), ethyldihydromorphinone, methyldihydromorphinone, (metopon), monoacetylmorphine, α-isomorphine, β-isomorphine, γ-isomorphine, tetrahydroxydesoxymorphine, dihydromorphinone (dilaudid), allopseudocodeine, heterocodeine, isocodeine, pseudocodeine, dihydrocodeinone (dicodid), dihydrohydroxycodeinone (eucodal), morpholinylethylmorphine (pholcodin).

  3. Synthetic drugs with morphine-like effects ([4] )

    For example, representatives from the pethidine group, the methadone group, the morphinan group and the dithienylbutenylamine group.

    The substances from these groups are prepared exclusively by synthesis from common chemicals not related to the poppy plant.



Our modern science of drug therapy is built upon centuries of empirical knowledge and scientific research.

Through experience and tradition a large number of the substances used in modern medicine have been used in much the same way for centuries by primitive people throughout the world. This is true of important substances such as opium, digitalis, quinine bark, coca leaf, ergot, curare and rauwolfia, to mention but a few.

One of the first scientists who devoted his attention to a closer study of the active principles of the crude drugs was Paracelsus (1493-1541). He attempted through distillation, pyroanalysis and other alchemical processes to isolate the "quintessence "-the active principle--of opium. His crude methods failed to produce results; but he had shown the way, and other men of science in turn tackled the same problems more successfully. The introduction by the pharmacist C. W. Scheele of crystallization as a method for the purification of natural substances was of fundamental importance in this development.

The isolation of the active components of drugs in pure crystalline form paved the way for accurate analyses of their chemical structure and pharmacodynamic effect, and thereby also directly influenced the development of the synthesis of new drugs.

The chemical transformation and gradual breaking down and re-synthesis of the natural substances of medicinal value, combined with pharmacological research, provided valuable information about the relationship between chemical structure and pharmacological effects. As will be seen later, similar studies of the structure of morphine were also of great importance for the development of a series of synthetic morphine substitutes.


(a) The Therapeutic Aspect

In the case of drugs with morphine-like effects the choice between the natural substances and synthetics goes back only a couple of decades. Although morphine and some of the secondary alkaloids of opium can now be synthesized by organic chemical methods, the poppy plant is still the source of commercially manufactured morphine and also the basic material for the semi-synthetic drugs with morphine-like effects (cf. group 2). With the morphine substitutes of synthetic origin (cf. group 3) it is quite different, as they are totally artificial substances.

Generally speaking, the new morphine substitutes are very similar to morphine, both in their analgesic effect and in their addictive properties. The method of their manufacture, however, is widely different from that of the corresponding natural substances. As a result of the synthesis of new substances, the range of preparations with morphine-like effects is now wider and more varied than it was in former years, as none of the morphine substitutes produces exactly the same effects or, more accurately speaking the same side-effects. The physician's choice of an analgesic for the treatment of various cases is often determined by the nature of these side-effects. For example, although pethidine has weaker analgesic properties than morphine, this drug is generally preferred to morphine for biliary or renal colic because of its pronounced spasmolytic properties.

From the standpoint of practical therapy, the new synthetic drugs offer wider therapeutic possibilities than the natural drugs, and therefore call for further development. On the other hand, it cannot be denied that a steadily growing number of physicians, healers and the general public view with concern the increasing use, both in therapy and in our daily diet, of synthetic substances alien to human cells ([23] ).

One of the determining factors in the physician's choice of an analgesic is the centuries-old body of tradition underlying the use of opium therapy throughout the world. Opium and opium preparations are still officinal medicaments in the pharmacopoeias of all countries, and in many instances physicians, guided by clinical experience, choose opium extracts or compounds of pure alkaloids in preference to morphine itself or synthetic morphine substitutes.

(b) The Economic Aspect, the National Economy and Production Technique

The great advantage of synthetic chemistry is its almost limitless capacity for producing chemical and therefore pharmacodynamic variants. On the other hand, the synthesis of medicinal preparations requires a certain degree of technical skill which is not yet available in all parts of the world.

A minimum of technical apparatus is required to manufacture analgesics from the poppy plant. In many countries with a rudimentary chemical industry the opium poppy is now and has been for hundreds of years a well-established crop. It is often an important element in the economy of a country, not merely as the raw material for the manufacture of opium and opium alkaloids, but frequently, and to a far greater extent, as the source of poppy seeds and poppy-seed oil. There is little likelihood that the cultivation of the poppy for these latter purposes will decline or disappear in thenear future. If these countries were to turn to imported synthetic analgesics instead of using their own available sources of supply, they would be following an unsound economic policy.

(c) The Social Aspect

It is well known that the production of opium and the accompanying smuggling and abuse of the drug give rise to a series of social problems with serious and far-reaching implications. Various countries have attempted to cope with the evil by prohibiting the cultivation of the poppy plant, and to find an alternative solution to the analgesic problem partly through the import of opium and opium alkaloids and partly through the synthesis of morphine-like substances under strict national control. Obviously a policy of this kind may to some extent solve the problem as it affects a particular country, but not the international problem. As stated above, the cultivation of the poppy plant and the production of opium are so closely connected with the needs of national economies that a total prohibition of the cultivation of the opium poppy throughout the world at the present time would have serious economic consequences.

If there were a sudden change-over from the use of natural drugs to the use of synthetics, the normal outlets for opium would be suddenly reduced. Quantities of opium which could not be disposed of would sooner or later in all probability find their way into the illicit traffic, and the opium-producing countries would consequently be faced with a grave problem.



Today there are a great many known varieties and subspecies of the opium poppy, Papaver somniferum L. Papaveraceae. History shows that it is one of the world's oldest cultivated plants. This is also obvious from the fact that the plant is no longer found in a wild state. Most of the world's utility plants are more or less confined to a definite climate and within relatively narrow geographical limits. This is not the case with the opium poppy, which can be successfully grown in relatively large areas of the world with a high yield of opium alkaloids ([11] ). (cf. Fig. 1 and 2). It does not require any particular type of soil and reacts well to fertilizers. This is one of the main advantages in terms of agronomics, national economy and the available supply. As will be seen from the following diagram (Table I) several important industries all over the world are dependent on the opium poppy.

The world production of opium reported to the Permanent Central Opium Board amounted to 1,291 tons in 1953 ([26] ). The annual world production of poppy seeds amounts to several thousand tons.

Today only a small fraction of the opium poppy grown throughout the world is used for production of opium and opium alkaloids.

The opium poppy each year provides employment and a livelihood for a very large number of people in all its related industries and trades. Moreover, the world economy does not yet by any means exploit its potentialities to the full. The principal reason for this is to be found partly in governmental restrictions (cf. the Opium Poppy Control Act, 1942, which prohibits cultivation of the opium poppy in the United States without a licence), and partly in irrational operating methods dictated by tradition. The classical method of extracting opium (incising the capsule and gathering the dried latex) utilizes only a fraction of the plant's total alkaloidal content. The rest remains in the straw and the capsules which are mostly burnt or left to rot away. The method is based on almost two thousand years of tradition and is gradually being replaced by methods which require less human labour.

Opium poppy grown in Norway.

Full size image: 122 kB, Opium poppy grown in Norway.

A large proportion of all the opium produced is used for the extraction of opium alkaloids. It immediately becomes obvious that when alkaloids are the end product, the intermediate stage of producing opium is an unnecessary expense.

Recognition of this fact is now becoming general, and the manufacture of opium alkaloids from poppy capsules and poppy straw is growing in certain countries, especially in eastern Europe. For example, 8 tons of morphine were manufactured from poppy straw in 1946, 17 tons in 1952, and 19 tons in 1953. In other words, in 1953 approximately one-quarter, in 1952 one-fifth and in 1946 one-sixth of all morphine manufactured was extracted from poppy straw ([20] ).

The extraction of morphine according to this principle has long been dependent upon the development of practicable, economical methods. Today this problem has been solved in principle ([3] ), and new and improved methods are constantly being developed.

The future prospects of the poppy plant seem to be closely linked to the following conditions, to mention but a few : ([1] ) an expanded manufacture of opium alkaloids from the poppy plant itself (cf. above); ([2] ) the development of new varieties of the opium poppy; ([3] ) a steady and preferably increasing use of opium alkaloids. The last condition depends in part on the continued development of synthetic morphine substitutes and on whether science will succeed in manufacturing drugs free from the undesirable side-effects of morphine-primarily that of addiction. Research along this line is now in progress ([29] ).

The development of new varieties of the opium poppy should probably be planned with a dual purpose - (a) to develop varieties with a higher alkaloidal content than is found today in plants grown for both alkaloids and seeds;2(b) to develop plants with a low alkaloidal content or none at all, exclusively for seed production (cf. C. C. Fulton, p. 82).


This type of poppy would probably have to be grown under supervision.

Table I

Full size image: 32 kB, Table I

The results obtained with the quinine tree Cinchona species demonstrated clearly that it is now possible to double the alkaloidal content of a plant. It would therefore not be unreasonable to assume that the alkaloidal content of the opium poppy can also be altered in one way or another. The methods formerly used by Dutch scientists in developing the quinine tree were primarily selection and crossing. In addition to these classical methods, there are today a number of new ones which have already produced noteworthy results in the cultivation of drug-producing plants. I refer particularly to polyploidys and the modern mutation methods using various rays (neutron rays in uranium piles, X-rays, ultra-violet rays and the like). The former method has been used particularly on higher types of plants, the latter on lower organisms, for example in the development of new strains of moulds and actinomycetes, etc., in the production of penicillin and other antibiotics.

The poppy plant contains the same alkaloids as opium (cf. below) but in much smaller quantities.

According to Wiest and Frey ([11] ), the morphine content of poppy capsules varies between 0.18 and 0.89 per cent, with an average of 0.37 to 0.53 per cent. The results of analyses of the morphine content of the stalks differ greatly, some reports showing between 0.01 and 0.05 per cent and others from 0.10 to 0.15 per cent ([11] ).


Opium, the air-dried milky exudation obtained by incising the unripe capsules of Papaver somniferum L., is produced in many temperate and subtropical regions. It has been found to contain approximately twenty alkaloids, which together make up about twenty per cent of its weight.

Henry ([14] ) divides the alkaloids of opium into the following five categories:

  1. Tetrahydroisoquinoline derivatives, comprising Hydrocotarnine, C 12H 15O 8N;

  2. Benzylisoquinolinederivatives--e.g.,Papaverine, C 20H 21O 4N, Narcotine, C 22C 23O 7N, Narceine, C 23H 27O 8N;

  3. Cryptopine type--e.g., Cryptopine, C 21H 23O 5N;

  4. Morphine type--e.g., Morphine, C 17H 19O 3N, Codeine, C 18H 21O 3N, Thebaine, C 19H 21O 3N, Porphyroxine, C 19H 23O 4N;

  5. Alkaloids of unknown constitution

The approximate percentage contents of the six alkaloids found in the largest quantities are, according to Fulton ([11] ), the following:

Morphine, 3 to 23 per cent;

Narcotine, 1 to 11 per cent;

Codeine, from several tenths of 1 per cent up to 4 per cent;

Thebaine, from several tenths of l per cent up to 4 per cent;

Papaverine, from a few tenths of 1 per cent up to 2 per cent at least;

Narceine, from 0.1 per cent or so, probably up to 1 per cent.

Although intensive research has been carried out for centuries to ascertain the chemical composition of opium, much remains to be done before that goal is achieved. This point was also emphasized strongly in a recent article in the Bulletin on Narcotics ([5] ).

The pharmacopoeias require medicinal opium to be prepared with a fixed morphine content, usually approximately 10 percent. It should here be kept in mind that the various assay methods can give widely differing results ([1] , [14] ).

It is particularly important in this connexion to make clear the great significance of opium in modern therapy and the existing possibilities of replacing it with synthetic drugs. A study of the components of opium clearly shows it to be a product with a complex structure. Besides the active principle, morphine, a characteristic pharmacodynamic effect has also been observed in a number of the secondary alkaloids ([18] , [22] ). A synergistic or antagonistic relationship has also been found to exist between the various alkaloids ([18] ), and it has been possible to demonstrate that even the nitrogen free ballast components influence absorption from the intestine and thus the effectiveness of the drug. Accordingly, opium cannot yet be replaced by any single synthetic substance.

The other problem which still remains to be discussed is the role which opium plays in modern therapy and as a raw material for pharmaceutical preparations. Opium is included in all modem pharmacopoeias, and a large proportion of all the medicinal opium produced is used in the manufacture of galenical preparations such as Pulvis antasthmaticus, Pulvis Cynoglossi compositus, Pulvis Ipecacuanhae opiatus, Extractum Opii siccum, Tinctura Opii, Tinctura Opii Camphorata, Tinctura Opii Crocata, and the like. In this connexion also, the mixture of opium alkaloids should be mentioned.

In 1909 Sahliintroduced into medicine under the name of pantopon ([15] ), a preparation containing all the alkaloids of opium in the form of hydrochlorides. Preparations of this type (often simplified to include morphine salts and some of the most important secondary alkaloids of opium in a fixed proportion) are used today all over the world. As compared with aqueous or alcoholic extracts from opium, preparations of the pantopon type have the great advantage that they can be used for injection. Many years of clinical experience have also shown that these compounds have a different effect on the central nervous system from that of morphine itself. Thus they are not so likely as pure morphine ([18] , [22] ) to produce unpleasant side-effects such as nausea and vomiting. This illustrates the advantages often found in natural mixtures of compounds over simple chemical individuals. In this connexion it should be remembered that many of the pantoponlike preparations are merely mixtures of isolated pure opium alkaloids in the proportion in which they occur in Turkish opium (cf. Pharm. Helv. 1933, Pharm. Suec. 1946, Pharm. Dan. 1948).

It may therefore be concluded that opium and opium preparations still play an important role in modem therapy.

As has already been stated, the chemistry and pharmacology of the opium alkaloids are stillto a certain extent unknown, and they thus offer a rich field for future chemical and medical research.


The unripe capsules of the opium poppy were formerly included in a number of pharmacopoeias under the designation Fructus Papaveris immaturus. The drug was used largely in the manufacture of poppy syrup (Syrupus Papaveris), a preparation which was well known for its effectiveness in keeping young children-even infants-quiet at night. (Bearing in mind the unhealthy effects of morphine on young children, this may be cited as an example of the dubious therapy of the past.) Since the alkaloidal content of poppy capsules is consi derably higher than that of the other parts of the plant, this drug is popular today as a raw material for the manufacture of opium alkaloids by extraction ([3] ).

Table II


Full size image: 45 kB, Table II

4. MORPHINE (cf. table II-l)

The isolation of morphine by Derosne ([15] ) in 1804 and the discovery of its basic character by Sertürner ([15] ) in 1817 were of epoch-making importance not only for the development of the chemistry of alkaloids, but also for extensive studies of the active principle of opium.

These studies, which have been in progress for 150 years and are in fact still going on, made possible the improvement of morphine through the manufacture of derivatives, the determination of the chemical structure of morphine, the manufacture of synthetic substances with morphine-like effects, and culminating in the total synthesis of morphine, which was accomplished by Gates and his co-workers ([12] ) in 1950-1952 on the basis of preparatory studies by Grewe and his co-workers ([13] ).

Although morphine is a natural substance and also the most important representative of the natural analgesics, its total chemical synthesis is of great interest in this connexion. The question naturally arises: what effect will the chemical synthesis of morphine have on the present world supremacy of the opium plant as a source of morphine? This question is difficult to answer at present, as it is too early to form a reliable opinion. That will depend not only on the ability of the synthetic products to compete in the morphine market, but also - and in at least equal measure - on such factors as the needs of national economy as reflected in trade agreements, customs barriers and the like. At the present time, however, there seems to be no indication that the synthesis of morphine can have any practical value in morphine production.

The main part of all morphine manufactured is used for conversion into codeine and other morphine derivatives.


The five secondary alkaloids which are of medical and economical importance in opium are codeine (II-2), thebaine (II-3), narcotine (II-4), papaverine (II-5) and narceine (II-6).

Papaverine was synthesized as early as 1909 by Pictet & Gams (15). In the following year narcotine was synthesized by Perkin & Robinson (15). Narceine can be prepared from narcotine. The complete synthesis of morphine and codeine by Gates ([12] ) and his co-workers has also made the total synthesis of thebaine possible. Except for the partial synthesis of codeine from morphine, the aforesaid syntheses have little or no practical significance nowadays, for the other substances are obtained as by-products of the manufacture of morphine from opium or opium derivates.

As mentioned above, the secondary alkaloids in medicinal opium seem to intensify the analgesic effect of the morphine ([18] ), and, as will be shown below, some of them have greatly influenced the development of the semi-synthetic morphine substitutes in the next group. Papaverine is one of the most potent coronary vasodilator agents, and narcotine has recently been found to possess marked cough depressing properties.


Although morphine in appropriate doses relieves any pain, it is not by any means the ideal analgesic. Among the most conspicuous undesirable side-effects ([6] ) are a depressive effect on the respiratory centre, nausea and vomiting, constipation and serious addiction liability. It is also rather toxic.

Table III


Full size image: 45 kB, Table III

There has therefore been no lack of attempts to "improve" morphine and other opium alkaloids by producing derivatives from them ([18] ). When the chemical and pharmacological relationship between morphine and its methyl ether (codeine) became known (codeine has a lower addiction liability than morphine), attempts were made to exploit this discovery by producing its ethyl ether (dionine, III-1) and its benzyl ether (peronine III-2).

In addition, a number of isomers of codeine, such as pseudo-codeine, isocodeine and allopseudocodeine, were prepared and tested. These substances produce an effect similar in kind to that of morphine, but are less powerful analgesics. On the other hand, some of the primary alkaloid's characteristic effects are intensified.

Acetylation of both the hydroxyl groups in morphine yielded a substance (diacetylmorphine, III-3) which was introduced into therapy as early as 1898 under the name of heroin. While heroin has a considerably stronger analgesic action than morphine, its addiction liability is also much greater.

By a rather simple chemical process thebaine is converted into dihydrohydroxycodeinone (eucodal, III-4), a substance that has approximately the same analgesic effect as morphine, but is less likely than morphine to provoke nausea and vomiting.

Great therapeutic interest was centred on certain morphine derivates prepared by Skita and his co-workers in the German firm of Knoll, Ludwigshafen, in the period 1910-1918 ([18] ). By a special process of hydration and isomerization, dihydromorphinone (dilaudid, III-5) was obtained, the methylation of which yields dihydrocodeinone (dicodide, III-6): Müller ([22] ) says of these substances: "As a rule, laudacon (dilaudid) has no therapeutic advantages over morphine. It is indicatedin cases in which a powerful analgesic effect is desired but in which morphine would be particularly stupefying or cause undesirable side-effects. It must be used with the same caution as morphine." According to the same author, dicodide is intermediate between codeine and morphine both in its action and in its addiction liability.

A large-scale systematic study of morphine substitutes was carried out between 1930 and 1940 by the Committee on Drug Addiction of the United States National Research. Council ([27] ). The primary purpose of the study, which was directed by Small & Eddy, was to find morphine substi tutes lacking the addiction liability of morphine. About 125 morphine derivatives were prepared and tested for analgesic and other pharmacological properties. Among the new substances developed during the course of this study, dihydrodesoxymorphine D (desomorphine, III-7) and methyldihydro-morphinone (metopon, III-8) are of special interest.

Table IV


Alkaloidal base

Formula No. (cf. tables II-III)

Toxicity LD 5o (mg./kg.)

Convulsant action (mg./kg.)

Analgesia (mg./kg.)

Exciting effect (mg./kg.)

Emetic action (mg./kg.)

General depression (mg./kg.)

Respiratory effects (mg. /kg.)

531 531 0.75 0.57 0.22 6.75 0.15
241 161 8.04 8.04
16.0 +
Ethylmorphine (Dionine)
136 122 7.66 17.0
42.6 0.48
- 890 - 0.80 0.89 0.13 22.2 0.15
- 589 589 13.0 13.0 - 58.9
- 324 324 10.1 9.26 4.63 74.0 2.14
- 267 178 13.3 26.7
13.3 +
80.1 -
2,000 +
- 7.09 7.09 1.77
133 +
- 1,780 - 17.8 22.2 4.45 89.1 48.0
- 293 180 0.18 0.18
0.18 +
0.9 -
- 72 65 0.48 0.32
2.40 +
1.40 0.016
Dihydromorphinone (Dilaudid)
84 67 0.17 0.17 0.08 0.88 0.011
Dihydrocodeinone (Dicodid)
86 47 1.28 0.86
4.20 0.08
Dihydrodesoxymorphine-D (Desomorphine)
104 104 0.08 0.16 - 0.32 0.012
Tetrahydrodesoxymorphine ...
- 221 - 0.62 1.86
6.20 +
14.0 -
25 25 0.07 0.10 0.07 3.0 0.011
- 27 22 0.17 0.09 0.17 2.01 0.021
426 426 1.34 0.89
0.89 +
1.34 0.10

According to Eddy (cf. Burger, p. 161) ([6] ), "Pharmacological and clinical studies of metopon have revealed that it is relatively free from nauseating effects and does not produce mental dullness. It affords adequate relief of chronic deep-seated pain by oral administration and has been introduced for analgesia in inoperable terminal neoplastic disease. Tolerance to metopon and addiction develop slowly. Its main disadvantage is the difficulty of its preparation." Desomorphine has an analgesic action approximately nine times as great as that of morphine. It has the further advantage of being almost entirely free from the emetic and other effects of morphine on the gastrointestinal tract.3

Table IV sets forth the result of a comparative study of morphine and codeine and some of its principal semi-synthetic substitutes.

The survey is taken from" Studies on Drug Addiction" ([27] ) and tabulated in the same way as that of Burger ([6] ).

The following notes explain the column headings in the table:


See the study entitled "The therapeutic value and the addiction-producing properties of dihydrodesoxymorphine-D (desomorphine)" prepared on request of the World Health Organization by Dr. P. O. Wolff, formerly Chief, Addiction-producing Drugs Section, WHO (Document WHO/APD/54, 14 March 1955--E/CN.7/L.90, 30 March 1955).

Toxicity (LD50): Average fatal dose, amount killing 50 per cent or more of animals used, administered subcutaneously to mice.

Convulsant action: The smallest amount with which convulsions were observed during the determination of the average fatal dose in mice.

Analgesia:Amount of substance administered intramuscularly which caused in at least four of the five cats receiving the dose an increase in the pressure required to evoke a response when applied to the terminal portion of the tail.

Exciting effect: Smallest dose with which definite signs of exciting action were seen in at least two of a group of five cats.

Emetic action: Smallest dose with which a cat vomited, or in many instances, when no dose used caused vomiting, the smallest close with which nausea, or licking, with or without salivation, occurred.

General depression: Smallest dose preventing immediate righting of at least 75 per cent of a group of twenty rats, thirty minutes after intraperitoneal injection.

Respiratory effect: Minimal effective depressant dose as defined by Wright & Barbour: J. Pharmacol. Exptl. Therap., 1937, 61, p. 422.

The work of "improving" morphine and the secondary opium alkaloids on the general lines described above is proceeding constantly. For example the drug "pholcodine" (III-9), was recently developed by French investigators ([8] ). Mention must also be made in this connexion of the efforts which have been made to prepare glycosidic derivatives from morphine and codeine ([17] ), although the results have not so far been very satisfactory.

Table V

Full size image: 27 kB, Table V


The morphine substitutes in group 2 possess the fundamental structure of morphine. Investigators have sought to attain their objective - i.e., substances having a morphine-like effect but not the addiction liability of morphine - by varying the peripheralstructure of the morphine molecule. The same is to some extent true with respect to the morphinan group of synthetic morphine substitutes (group 3 d). The situation of the morphine-like drugs of the pethidine-, methadone-and diethienylbutenylamine groups is quite different. These substances may be regarded as the result of radicalchanges in the central part of the morphine molecule - about the pharmacophorous nucleus itself : the quaternary carbon atom in position 4 of the piperidine ring (cf. the C atom at the point marked " x" in figures V-1 and V-2).4

In contrast to the morphine substitutes of group 2, which are produced with the aid of the opium alkaloids, the corresponding representatives of group 3 are purely artificial products obtained by organic chemical synthesis from generally available chemicals. This also applies to the substances of the morphinan group.

As will be shown, the substances of group 3 are based on the same basic pharmacophorous principle as morphine. They can be prepared by pure organic chemical synthesis, and they are in direct competition with the corresponding natural substances. Only the future will reveal the outcome of this competition, which is dependent on a number of factors.


On the relationship between chemical structure and analgesic action see Braenden, O. J., Eddy, N. B. & Halbach, H. (1955), Bull. Wld. Hlth. Org. 13, 937, where features common to the structural formulae of substances with morphine - like analgesic effect are pointed out.

(a) The Pethidine Group

If the formula of pethidine (V-l) is compared with that of morphine (V-2) certain points of structural similarity are readily demonstrable. It was, moreover, a comparison of this kind that first led Eisleb & Schaumann and their coworkers in 1937 to suspect that the quaternary carbon atom in the piperidine ring of morphine constituted the molecule's analgiphorous group ([6] ).

The primary purpose of Eisleb & Schaumann's synthesis of pethidine was to produce, not a substitute for morphine, but an antispasmodic of the atropine type. Pharmacological tests showed, however, that the new substance had a pronounced morphine - like effect in addition to its spasmolytic action.

The synthesis of pethidine and the discovery of its analgesic effect opened up a very important new field in synthetic drug manufacture. The new methods of synthesis did not, however, constitute a corresponding advance from the point of view of pharmacology and therapeutics, as the new synthetic morphine substitutes are marred by most of the undesirable side-effects of morphine - especially by its addiction liability. This feature is reported to be especially prominent in ketobemidone ([20] ). On the other hand, some of the new substances exhibit certain desirableside-effects which give them specific advantages over morphine and therefore make them clinically superior in special cases. Pethidine itself is the best example of this kind: even though, in a general way, its action is less powerful than that of morphine5 pethidine is, on account of its marked spasmolytic effect, preferred to morphine in such conditions as biliary and renal colic.

(b) The Methadone Group

The laevogyric natural substances usually have a much stronger physiological action than the corresponding dextrogyric compounds. This is true of methadone (V-3) also. It is stated ([6] ) that, while the laevogyric compound is about 2.2 times as potent as morphine, the action of the corresponding dextro-isomer is only one-tenth of that of morphine. However, the general pharmacodynamic action of the two substances is so similar that no practical purpose is served by separating them. In its main features, the mode of action of methadone is the same as that of morphine. It also has about the same addiction liability as morphine. The abstinence symptoms on withdrawal are milder and fewer with methadone than with morphine. This feature has been utilized in the treatment of morphine addicts: they are first transferred to an adequate dose of methadone, and then, after about a week, when the morphine in the system has been replaced by methadone, the methadone is withdrawn. Morphinism can be treated in this way with less distress than otherwise. This does not mean, however, that addiction to methadone is less serious than morphinism ([22] ).


According to Troxil (1948) ([22] ), the same analgesic effect is achieved with 1 cg methadone, 1.5 cg morphine or 15 cg pethidine.

Methadone is used as an analgesic in the same way as morphine. It seems to be less apt to cause constipation, nausea, vomiting and pruritus than morphine, and is especially indicated in cases where morphine causes distressing side-effects. As methadone is the most important representative of the methadone group, it does not seem necessary to discuss the others here.

(c) The Morphinan Group

The representative of the new synthetic morphine substitutes that is closest to morphine in chemical structure is N-methyl-morphinan (V-4) and its derivatives. The pioneering synthesis in this series was carried out in 1946 by Grewe & Mondon ([4] ). In these compounds there has been a much closer approximation to the structural features of morphine itself than in the two previous groups. Morphinan consists of the fundamental structure of morphine without the ether linkage. It really bears the same chemical relationship to morphine as tropan bears to cocaine and atropine. The synthesis of morphinan was a remarkable advance in several respects: in addition to being the forerunner of the actual synthesis of morphine, it provided the starting-point for a new series of synthetic drugs.

One of these drugs, 3-hydroxy-N-methyl-morphinan, acts about three times as powerfully as morphine on man, and it is three to six times as toxic. It resembles morphine in its action, but its addiction liability is said to be less than that of morphine: It has been used especially in postoperative practice and in incurable cancer ([6] ).

(d) The Dithienylbutenylamine Group

The discussion of this group will also be limited to a single representative, viz.,3-dimethylamino-1, 1-di(2'thienyl)-l-butene (cf. V-5), "dimethylthiambutene"

This substance was synthesized by D. W. Adamson ([4] ) in 1950. As its formula shows, C 1represents the quaternarily linked carbon atom of the piperidine ring of morphine, marked x in figure V-2. Thus the connexion with the morphine molecule may be anticipated in this case also. The substances of this group likewise have an action strongly resembling that of morphine, but clinicalexperience with them is as yet relatively scanty.


A survey of the 1953 world trade in opium, morphine and several substances having morphine-like effects is given in table VI ([20] ). As this survey shows, the synthetic morphine substitutes at present account for only a modest proportion of world trade.

Table VI


1. Raw opium
2. Morphine
3. Codeine
4. Ethylmorphine (dionine)
5. Diacetylmorphine
6. Pethidine
7. Methadone


  1. The therapeutic use of natural drugs is in many cases based on a thousand years' experience of both their effects and their side-effects. In this respect the natural substances have a great advantage over the new synthetic drugs. This rule is valid also in the case of analgesics.

  2. By virtue of its traditions and its high reputation with both the medical profession and the public, the poppy is still the most important source of analgetic remedies in the world.

  3. Large poppy fields are at present needed for seed production. The by-products of this production (the alkaloid-containing capsules and straw, by application of suitable methods) yield opium alkaloids which at least for the present can compete favourably with synthetic analgesics as far as the cost of manufacture is concerned.

  4. The prospects of improving the opium plant in order to obtain varieties with a higher alkaloidal content are greater today than formerly, owing to the development of new methods for effecting mutations.

  5. The results obtained by comparative chemical and pharmacological studies of morphine and its derivatives often serve as patterns in the synthesis of the new synthetic morphine substitutes.

  6. One of the greatest advantages of the synthetic drug industry lies in its almost unlimited potentialities for making variations of the natural substances and for producing new substances which are not produced by nature.

  7. The synthetic drugs industry is not dependent on climatic conditions. It is also affected very little by trade barriers. If the basic raw materials are available, it is the method and the technical equipment that determine the production capacity. Obviously this fact is of great significance in the national economy. It is also clearly a factor which states must take into account in planning for their long-term needs.

  8. As far as their margin of therapeutic safety is concerned, the natural drugs are by no means inferior to the synthetic ones. In fact morphine is in this respect superior to all known analgetics. In therapeutic value the natural and synthetic drugs are almost on a par with one another. The extent to which each is used therefore depends largely on such factors as therapeutic traditions, production costs, national interests, trade restrictions, etc.

  9. Many of the synthetic morphine substitutes are still so new that their undesirable side-effects are not fully assessable. In addition, many people are somewhat averse to and distrustful of synthetic drugs, and therefore prefer well-tested natural products.

  10. The natural drugs with a morphine-like action which are produced from the poppy plant can readily be manufactured even in countries with an under-developed chemical industry. The corresponding synthetic substances require a relatively highly developed chemical industry equipped with the necessary analytical and biological laboratories.

  11. The present study shows that the synthetic drugs at present account for a relatively modest proportion of the annual consumption of the drugs here classified as "drugs with morphine-like effects".



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