Chapter XXX: Part VI: Alkaloids and Poisonous Vegetable Principles Separated for the (4)

In a Swedish case quoted by Maschka,[392] a girl, nine years old, in weak health and suffering from slight bronchitis, had been given a non-officinal acetate of morphia lozenge, which was supposed to contain 5 mgrms. (·075 grain) of morphine acetate. She took the lozenge at eight in the evening; soon slept, woke at ten, got out of bed, laughed, talked, and joked with the nurse, again got into bed, and very quickly fell asleep. At four A.M. the nurse came and found her breathing with a rattling sound, and the physician, who arrived an hour later, found the girl in a state of coma, with contracted pupils, breathing stertorously, and the pulse scarcely to be felt. Despite all attempts to rouse the patient, she died at eight in the morning, twelve hours after taking the lozenge.

[392] Maschka’s _Handbuch_, Band ii. p. 438; also Svenska, _Läk-Sällsk. Förhandl._, Apr. 1, p. 90; Apr. 8, p. 160, 1873. For other cases see Nasmyth, _Edin. Med. Journ._, Dec. 1878; Kirby, _Dub. Med. Press_, Dec. 24, 1845; W. Boyd Muschet, _Med. Times and Gaz._, March 20, 1858.

The _post-mortem_ examination showed some hyperæmia of the brain and serous effusion in the ventricles, and there was also tubercle in the pleura. Three lozenges similar to the one taken by the patient were chemically investigated by Hamberg, who found that the amount of acetate was very small, and that the lozenges, instead of morphine acetate, might be considered as prepared with almost pure morphine; the content in the three of morphine being respectively 35, 37, and 42 mgrms. (that is, from half a grain to three-fifths of a grain). There was a difference of opinion among the experts as to whether in this case the child died from morphine poisoning or not--a difference solely to be attributed to the waking up of the child two hours after taking the poison. Now, considering the great probability that a large dose for a weakly child of that age had been taken, and that this is not the only case in which a relapse has occurred, it seems just to infer that it was really a case of poisoning.

As unusual symptoms (or rather sequelæ) may be noted in a few cases, hemiplegia, which soon passes off; a weakness of the lower extremities may also be left, and inability to empty the bladder thoroughly; but usually on recovery from a large dose of opium, there is simply heaviness of the head, a dry tongue, constipation, and loss of appetite. All these symptoms in healthy people vanish in a day or two. There have also been noticed slight albuminuria, eruptions on the skin, loss of taste, and numbness of parts of the body.

Opium, whether taken in substance, or still more by subcutaneous injection, in some individuals constantly causes faintness. In my own case, I have several times taken a single grain of opium to relieve either pain or a catarrh; almost invariably within an hour afterwards there has been great coldness of the hands and feet, lividity of the face, a feeling of deadly faintness followed by vomiting; this stage (which has seldom lasted more than half an hour) passed, the usual narcotic effects have been produced.

Some years ago I injected one-sixth of a grain of morphine hydrochlorate subcutaneously into an old gentleman, who was suffering from acute lumbago, but was otherwise healthy, and had no heart disease which could be detected; the malady was instantly relieved, and he called out, “I am well; it is most extraordinary.” He went out of the front door, and walked some fifty yards, and then was observed to reel about like a drunken man. He was supported back and laid in the horizontal posture; the face was livid, the pulse could scarcely be felt, and there was complete loss of consciousness. This state lasted about an hour, and without a doubt the man nearly died. Medical men in practice, who have been in the habit of using hypodermic injections of morphine, have had experiences very similar to this and other cases, and although I know of no actual death, yet it is evident that morphine, when injected hypodermically even in a moderate dose, may kill by syncope, and within a few minutes.[393] Absorption by hypodermic administration is so rapid that by the time, or even before the needle of the syringe is withdrawn, a contraction of the pupil may be observed.

[393] See a case of morphia poisoning by hypodermic injection, and recovery, by Philip E. Hill, M.R.C.S., _Lancet_, Sept. 30, 1882. In this instance a third of a grain introduced subcutaneously caused most dangerous symptoms in a gardener, aged 48.

Opium or morphine is poisonous by whatever channel it gains access to the system, the intestinal mucous membrane absorbs it readily, and narcotic effects may be produced by external applications, whether a wound is present or not. A case of absorption of opium by a wound is related in Chevers’s _Jurisprudence_.[394] A Burman boy, about nine or ten years of age, was struck on the forehead by a brick-bat, causing a gaping wound about an inch long; his parents stuffed the wound with opium. On the third day after the accident, and the opium still remaining in the wound, he became semi-comatose, and, in short, had all the symptoms of opium narcosis; with treatment he recovered. The unbroken skin also readily absorbs the drug. Tardieu states that he had seen 30 grms. of laudanum, applied on a poultice to the abdomen, produce death. Christison has also cited a case in which a soldier suffered from erysipelas, and died in a narcotic state, apparently produced from the too free application of laudanum to the inflamed part.

[394] Third ed., p. 228.

To these cases may be added the one cited by Taylor, in which a druggist applied 30 grains of morphine to the surface of an ulcerated breast, and the woman died with all the symptoms of narcotic poisoning ten hours after the application--an event scarcely surprising. It is a curious question whether sufficient of the poison enters into the secretions--_e.g._, the milk--to render it poisonous. An inquest was held in Manchester, Nov. 1875, on the body of a male child two days old, in which it seemed probable that death had occurred through the mother’s milk. She was a confirmed opium-eater, taking a solid ounce per week.

§ 360. =Diagnosis of Opium Poisoning.=--The diagnosis is at times between poisoning by opium or other narcotic substances, at others, between opium and disease. Insensibility from chloral, from alcohol, from belladonna or atropine, and from carbon oxide gas, are all more or less like opium poisoning. With regard to chloral, it may be that only chemical analysis and surrounding circumstances can clear up the matter. In alcohol poisoning, the breath commonly smells very strongly of alcohol, and there is no difficulty in separating it from the contents of the stomach, &c., besides which the stomach is usually red and inflamed. Atropine and belladonna invariably dilate the pupil, and although just before death opium has the same effect, yet we must hold that mostly opium contracts, and that a widely-dilated pupil during life would, _per se_, lead us to suspect that opium had not been used, although, as before mentioned, too much stress must not be laid upon the state of the pupils. In carbon oxide, the peculiar rose-red condition of the body affords a striking contrast to the pallor which, for the most part, accompanies opium poisoning. In the rare cases in which convulsions are a prominent symptom, it may be doubtful whether opium or strychnine has been taken, but the convulsions hitherto noticed in opium poisoning seem to me to have been rather of an epileptiform character, and very different from the effects of strychnine. No rules can be laid down for cases which do not run a normal course; in medicine such are being constantly met with, and require all the care and acumen of the trained observer. Cases of disease render a diagnosis often extremely difficult, and the more so in those instances in which a dose of laudanum or other opiate has been administered. In a case under my own observation, a woman, suffering from emphysema and bronchitis, sent to a chemist for a sleeping draught, which she took directly it arrived. A short time afterwards she fell into a profound slumber, and died within six hours. The draught had been contained in an ounce-and-a-half bottle; the bottle was empty, and the druggist stated in evidence that it only contained 20 minims of laudanum, 10 grains of potassic bromide, and water. On, however, diluting the single drop remaining in the bottle, and imitating its colour with several samples of laudanum diluted in the same way, I came to the conclusion that the quantity of laudanum which the bottle originally contained was far in excess of that which had been stated, and that it was over 1 drachm and under 2 drachms. The body was pallid, the pupils strongly contracted, the vessels of the brain membranes were filled with fluid blood, and there was about an ounce of serous fluid in each ventricle. The lungs were excessively emphysematous, and there was much secretion in the bronchi; the liver was slightly cirrhotic. The blood, the liver, and the contents of the stomach were exhaustively analysed with the greatest care, but no trace of morphine, narcotine, or meconic acid could be separated, although the woman did not live more than six hours after taking the draught. I gave the opinion that it was, in the woman’s state, improper to prescribe a sedative of that kind, and that probably death had been accelerated, if not directly caused, by opium.

Deaths by apoplexy will only simulate opium-poisoning during life; a _post-mortem_ examination will at once reveal the true nature of the malady. In epilepsy, however, it is different, and more than once an epileptic fit has occurred and been followed by coma--a coma which certainly cannot be distinguished from that produced by a narcotic poison. Death in this stage may follow, and on examining the body no lesion may be found.

§ 361. =Opium-eating.=--The consumption of opium is a very ancient practice among Eastern nations, and the picture, drawn by novelist and traveller, of poor, dried-up, yellow mortals addicted to this vice, with their faculties torpid, their skin hanging in wrinkles on their wasted bodies, the conjunctivæ tinged with bile, the bowels so inactive that there is scarcely an excretion in the course of a week, the mental faculties verging on idiocy and imbecility, is only true of a percentage of those who are addicted to the habit. In the _British Medical Journal_ for 1894, Jan. 13 and 20, will be found a careful digest of the evidence collated from 100 Indian medical officers, from which it appears that opium is taken habitually by a very large number of the population throughout India, those who are accustomed to the drug taking it in quantities of from 10 to 20 grains in the twenty-four hours; so long as this amount is not exceeded they do not appear to suffer ill-health or any injurious effect. The native wrestlers even use it whilst training. The habitual consumption of opium by individuals has a direct medico-legal bearing. Thus in India, among the Rajpoots, from time immemorial, infused opium has been the drink both of reconciliation and of ordinary greeting, and it is no evidence of death by poison if even a considerable quantity of opium be found in the stomach after death, for this circumstance taken alone would, unless the history of the case was further known, be considered insufficient proof. So, again, in all climates, and among all races, it is entirely unknown what quantity of an opiate should be considered a poisonous dose for an opium-eater. Almost incredible quantities have, indeed, been consumed by such persons, and the commonly-received explanation, that the drug, in these cases, passes out unabsorbed, can scarcely be correct, for Hermann mentions the case of a lady of Zurich who daily injected subcutaneously 1 to 2 grms. (15-31 grains) of a morphine salt. In a case of uterine cancer, recorded by Dr. W. C. Cass,[395] 20 grains of morphine in the twelve hours were frequently used subcutaneously; during thirteen months the hypodermic syringe was used 1350 times, the dose each time being 5 grains. It is not credible that an alkaloid introduced into the body hypodermically should not be absorbed.

[395] _Lancet_, March 25, 1882. See also Dr. Boulton’s case, _Lancet_, March 18, 1882.

Opium-smoking is another form in which the drug is used, but it is an open question as to what poisonous alkaloids are in opium smoke. It is scarcely probable that morphine should be a constituent, for its subliming point is high, and it will rather be deposited in the cooler portion of the pipe. Opium, specially prepared for smoking, is called “Chandoo”; it is dried at a temperature not exceeding 240°. H. Moissan[396] has investigated the products of smoking chandoo, but only found a small quantity of morphine. N. Gréhant and E. Martin[397] have also experimented with opium smoke; they found it to have no appreciable effect on a dog; one of the writers smoked twenty pipes in succession, containing altogether 4 grms. of chandoo. After the fourth pipe there was some headache, at the tenth pipe and onwards giddiness. Half an hour after the last pipe the giddiness and headache rapidly went off. In any case, opium-smoking seems to injure the health of Asiatics but little. Mr. Vice-Consul King, of Kew-Kiang, in a tour through Upper Yangtse and Stechnan, was thrown much into the company of junk sailors and others, “almost every adult of whom smoked more or less.” He says:--“Their work was of the hardest and rudest, rising at four and working with hardly any intermission till dark, having constantly to strip and plunge into the stream in all seasons, and this often in the most dangerous parts. The quantity of food they eat was simply prodigious, and from this and their work it seems fairly to be inferred that their constitution was robust. The two most addicted to the habit were the pilot and the ship’s cook. On the incessant watchfulness and steady nerve of the former the safety of the junk and all on board depended, while the second worked so hard from 3 A.M. to 10 P.M., and often longer, and seemed so independent of sleep or rest, that to catch him seated or idle was sufficient cause for good-humoured banter. This latter had a conserve of opium and sugar which he chewed during the day, as he was only able to smoke at night.”

[396] _Compt. Rend._, cxv. 988-992.

[397] _Compt. Rend._, 1012-1014.

§ 362. =Treatment of Opium or Morphine Poisoning.=--The first thing to be done is doubtless to empty the stomach by means of the flexible stomach tube; the end of a sufficiently long piece of indiarubber tubing is passed down into the pharynx and allowed to be carried into the stomach by means of the natural involuntary movements of the muscles of the pharynx and gullet; suction is then applied to the free end and the contents syphoned out; the stomach is, by means of a funnel attached to the tube, washed out with warm water, and then some coffee administered in the same way.

Should morphine have been taken, and permanganate of potash be at hand, it has been shown that under such circumstances potassic permanganate is a perfect antidote, decomposing at once any morphine remaining in the stomach, but it, of course, will have no effect upon any morphine which has already been absorbed. In a case of opium poisoning, reported in the _Lancet_ of June 2, 1894, by W. J. C. Merry, M.B., inhalations of oxygen, preceded by emptying the stomach and other means, appeared to save a man, who, three hours before the treatment, had drank 2 ozs. of chlorodyne. It is also the received treatment to ward off the fatal sleep by stimulation; the patient is walked about, flicked with a towel, made to smell strong ammonia, and so forth. This stimulation must, however, be an addition, but must never replace the measures first detailed.

§ 363. =Post-mortem Appearances.=--There are no characteristic appearances after death save hyperæmia of the brain and blood-vessels of the membranes, with generally serous effusion into the ventricles. The pupils are sometimes contracted, sometimes dilated, the dilatation occurring, as before mentioned, in the act of dying. The external surface of the body is either livid or pale. The lungs are commonly hyperæmic, the bladder full of urine; still, in not a few cases, there is nothing abnormal, and in no single case could a pathologist, from the appearance of the organs only, declare the cause of death with confidence.

§ 364. =Separation of Morphine from Animal Tissues and Fluids.=--Formerly a large proportion of the opium and morphine cases submitted to chemical experts led to no results; but owing to the improved processes now adopted, failure, though still common, is less frequent. The constituents of opium taken into the blood undergo partial destruction in the animal body, but a portion may be found in the secretions, more especially in the urine and fæces. First Bouchardat[398] and then Lefort[399] ascertained the excretion of morphine by the urine after medicinal doses; Dragendorff and Kauzmann showed that the appearance of morphine in the urine was constant, and that it could be easily ascertained and separated from the urine of men and animals; and Levinstein[400] has also shown that the elimination from a single dose may extend over five or six days. The method used by Dragendorff to extract morphine from either urine or blood is to shake the liquid (acidified with a mineral acid) several times with amyl alcohol, which, on removal, separates urea and any bile acids. The liquid thus purified is then alkalised, and shaken up with amyl alcohol, and this amyl alcohol should contain any morphine that was present. On evaporation it may be pure enough to admit of identification, but if not, it may be redissolved and purified on the usual principles. Considerable variety of results seems to be obtained by different experimenters. Landsberg[401] injected hypodermically doses of ·2 to ·4 grm. of morphine hydrochlorate into dogs, making four experiments in all, but failed to detect morphine in the urine. A large dose with 2·4 mgrms. of the salt gave the same result. On the other hand, ·8 grm. of morphine hydrochlorate injected direct into the jugular vein, was partly excreted by the kidneys, for 90 c.c. of the urine yielded a small quantity of morphine. Voit, again, examined the urine and fæces of a man who had taken morphine for years; he could detect none in the urine, but separated morphine from the fæces.[402] Morphine may occasionally be recognised in the blood. Dragendorff[403] found it in the blood of a cat twenty-five minutes after a subcutaneous dose, and he also separated it from the blood of a man who died of morphine poisoning in six hours. Haidlen[404] recognised morphine in the blood of a suicide who had taken opium extract.

[398] _Bull. Gén. de Thérap._, Dec. 1861.

[399] _Journ. de Chim._, xi. 93, 1861.

[400] _Berl. klin. Wochenschr._, 1876, 27.

[401] _Pflüger’s Archiv._, 23, 433, 413-433. _Chem. Soc. Journ._, May 1882, 543.

[402] _Arch. Pharm._, pp. [3], vii. pp. 23-26.

[403] Kauzmann, _Beiträge für den gerichtlich-chemischen Nachweis des Morphia u. Narcotins_, Dissert., Dorpat, 1868. Dragendorff, _Pharm. Zeitschr. f. Russland_, 1868, Hft. 4.

[404] _Würtbg. Correspondenzbl._, xxxiv. 16, 1863.

On the other hand, in a case recorded at p. 304, where a woman died in six hours from a moderate dose, probably of laudanum, although the quantity of blood operated upon was over a pound in weight, and every care was taken, the results were entirely negative. In poisoning by laudanum there may be some remaining in the stomach, and also if large doses of morphine have been taken by the mouth; but when morphine has been administered hypodermically, and in all cases in which several hours have elapsed, one may almost say that the organ in which there is the least probability of finding the poison is the stomach. It may, in some cases, be necessary to operate on a very large scale;--to examine the fæces, mince up the whole liver, the kidney, spleen, and lungs, and treat them with acid alcohol. The urine will also have to be examined, and as much blood as can be obtained. In cases where all the evidence points to a minute quantity (under a grain) of morphine, it is decidedly best to add these various extracts together, to distil off the alcohol at a very gentle heat, to dry the residue in a vacuum, to dissolve again in absolute alcohol, filter, evaporate again to dryness, dissolve in water, and then use the following process:--

§ 365. =Extraction of Morphine.=--To specially search for morphine in such a fluid as the urine, it is, according to the author’s experience, best to proceed strictly as follows:--The urine is precipitated with acetate of lead, the powdered lead salt being added to the warm urine contained in a beaker on the water-bath, until a further addition no longer produces a precipitate; the urine is then filtered, the lead precipitate washed, and the excess of lead thrown down by SH₂; the lead having been filtered off, and the precipitate washed, the urine is concentrated down to a syrup in a vacuum. The syrup is now placed in a separating tube (if not acid, it is acidified with hydrochloric acid), and shaken up successively with petroleum ether, chloroform, ether, and, lastly, with amylic alcohol (the latter should be warm); finally, the small amount of amylic alcohol left dissolved in the liquid is got rid of by shaking it up with petroleum ether. To get rid of the last traces of petroleum ether, it may be necessary to turn the liquid into an evaporating dish, and gently heat for a little time over the water-bath. The acid liquid is now again transferred to the separating tube, and shaken up with ether, after being made alkaline with ammonia; this will remove nearly all alkaloids save morphine,--under the circumstances, a very small quantity of morphine may indeed be taken up by the ether, but not the main bulk. After separating the ether, the liquid is again made slightly acid, so as to be able to precipitate morphine in the presence of the solvent; the tube is warmed on the water-bath, at least its own bulk of hot amylic alcohol added and the liquid made alkaline, and the whole well shaken. The amylic alcohol is removed in the usual way, and shaken with a small quantity of decinormal sulphuric acid; this washes out the alkaloid from the amyl alcohol, and the same amyl alcohol can be used again and again. It is best to extract the liquid for morphine at least thrice, and to operate with both the solution and the amyl hot. The decinormal acid liquid is made slightly alkaline with ammonia, and allowed to stand for at least twelve hours; any precipitate is collected and washed with ether, and then with water; the alkaline liquid from which the morphine has been separated is concentrated to the bulk of 5 c.c. on the water bath, and again allowed to stand for twelve hours; a little more morphine may often in this way be obtained.

The author in some test experiments, in which weighed small quantities of morphine (60-80 mgrms.) were dissolved in a little decinormal sulphuric acid, and added to large quantities of urine, found the process given to yield from 80 to 85 per cent. of the alkaloid added, and it was always recovered in fine crystals of a slight brown tint, which responded well to tests.

Various other methods were tried, but the best was the one given; the method not only separates the alkaloid with but little loss, but also in a sufficiently pure state to admit of identification.

From the tissues the alkaloid may be dissolved out by the general method given at p. 239, and the ultimate aqueous solution, reduced to a bulk of not more than 25 c.c., treated by the ethereal solvents in the way just described.

§ 366. =Narcotine= (C₂₂H₂₃NO₇) crystallises out of alcohol or ether in colourless, transparent, glittering needles, or groups of needles, belonging to the orthorhombic system.

It is only slightly soluble in boiling, and almost insoluble in cold water. One part requires 100 parts of cold, and 20 of boiling 84 per cent. alcohol; 126 parts of cold, 48 of boiling ether (specific gravity 0·735); 2·69 parts of chloroform; 400 of olive oil; 60 of acetic ether; 300 of amyl alcohol; and 22 parts of benzene, for solution. The neutral solution of narcotine turns the plane of polarisation to the left [α]_r_ = 130·6; the acid solution to the right. Narcotine has no effect on red litmus paper.

Narcotine gives no crystalline sublimate; its behaviour in the subliming cell is described at p. 259. Its melting-point, taken in a tube, is about 176°.

=Behaviour of Narcotine with Reagents.=--Narcotine, dissolved in dilute hydrochloric acid, and then treated with a little bromine, gives a yellow precipitate, which on boiling is dissolved; by gradually adding solution of bromine and boiling, a fine rose colour is produced, readily destroyed by excess of bromine. This is perhaps the best test for the presence of narcotine. Concentrated sulphuric acid dissolves narcotine; the solution in the cold is at first colourless, after a few minutes yellow, and in the course of a day or longer the tints gradually deepen. If the solution is warmed, it first becomes orange-red, then at the margin violet-blue; and if heated until hydric sulphate begins to volatilise, the colour is an intense red-violet. If the heating is not carried so far, but the solution allowed to cool, a delicate cherry-red hue slowly develops. If the sulphuric acid solution contains 1 : 2000 of the alkaloid, this test is very evident; with 1 : 40,000, the colour is only a faint carmine.--_A. Husemann._

A solution of narcotine in pure sulphuric acid, to which a drop of nitric acid has been added, becomes of a red colour; if the solution is warmed to 150°, hypochlorite of soda develops a carmine-red; and chloride of iron, first a violet, then a cherry-red. The precipitants of narcotine are--phosphomolybdic acid, picric acid, sulphocyanide of potash, potassio cadmic iodide, mercuric chloride, platinic chloride, auric chloride, and several other reagents.

From the brown mass left after heating narcotine above 200°, hydrochloric acid extracts a small portion of a base but little studied. The residue consists of humopic acid (C₄₀H₁₉O₁₄), which can be obtained by dissolving in caustic potash, precipitating with HCl, dissolving the precipitate in boiling alcohol, and finally throwing it down by water.

§ 367. =Effects.=--Narcotine in itself has toxic action only in rather large doses; from 1 to 2 grms. have been given to man, and slight hypnotic effects have followed. It is poisonous in very large doses; an ordinary-sized cat is killed by 3 grms. The symptoms are mainly convulsions.

§ 368. =Codeine= (=Codomethylene=), C₁₇H₁₇OCH₃(OH)NO + H₂O, is the methyl of morphine; it is an alkaloid contained in opium in small quantity only. Mulder, indeed, quotes ·66 to ·77 per cent. as present in Smyrna opium, but Merck and Schindler give ·25 per cent. Schindler found in Constantinople, ·5 per cent.; and Merck, in Bengal, ·5 per cent. also.

Codeine crystallises out of dry ether in small, colourless, anhydrous, crystals; but crystallised slowly from an aqueous solution, the crystals are either in well-defined octahedra, or in prisms, containing one atom of water, and melting in boiling-water to an oily fluid. The anhydrous crystals have a melting-point of 150°, and solidify again on cooling. Its watery solution is alkaline to litmus paper.

It requires 80 parts of cold, 17 of boiling water, 10 parts of benzole, and 7 parts of amyl alcohol respectively, for solution. Alcohol, benzene, ether, carbon disulphide, and chloroform freely dissolve it, but in petroleum ether it is almost insoluble. Further, it is also soluble in aqueous ammonia, and in dilute acids, but insoluble in excess of caustic potash or soda, and may thus be thrown out of an aqueous solution. A solution of codeine turns the plane of polarisation to the left, [α]_r_ = 118·2°.

Concentrated sulphuric acid dissolves codeine without colour, but after eight days the solution becomes blue; this reaction is quicker if the acid contains a trace of nitric acid. If the sulphuric acid solution be warmed to 150°, and a drop of nitric acid be added after cooling, a blood-red colour is produced. Fröhde’s reagent produces a dirty green colour, soon becoming Prussian blue, and terminating after twenty-four hours in a pale yellow.

Cyanogen gas, led into an alcoholic solution of codeine, gives first a yellow and then a brown colour; lastly, a crystalline precipitate falls. On warming with a little sulphuric acid and ferric chloride, a blue colour is produced. This blue colour is apparently common to all ethers of the codeine class.

Of the group reagents, the following precipitate solutions of codeine:--Mercuric potassium iodide, mercuric chloride, mercuric bromide, picric acid, and tannin solutions. The following do not precipitate:--Mercuric cyanide and potassium ferrocyanide solutions. Potassium dichromate gives no immediate precipitate, but crystals form on long standing. It does not give the reaction with iodic acid like morphine; it is distinguished from narceine by dropping a small particle of iodine into the aqueous solution, the iodine particle does not become surrounded with fine crystals.

§ 369. =Effects.=--The physiological action of codeine on animals has been investigated by Claude Bernard, Magendie, Crum Brown and Fraser, Falck, and a large number of others.[405] It has also been administered to man, and has taken in some degree the place of morphine. Claude Bernard showed that, when given to dogs in sufficient quantity to produce sleep, the sleep was different in some respects to that of morphine sleep, especially in its after-effects. Thus, in his usual graphic way, he describes the following experiment:--“Two young dogs, accustomed to play together, and both a little beyond the average size, received in the cellular tissue of the axillæ, by the aid of a subcutaneous syringe, the one 5 centigrammes of morphine hydrochloride, the other 5 centigrammes of codeine hydrochloride. At the end of a quarter of an hour both dogs showed signs of narcosis. They were placed on their backs in the experimental trough, and slept tranquilly for three or four hours. When the animals woke, they presented the most striking contrast. The morphine dog ran with a hyena-like gait (_démarche hyénoid_), the eye wild, recognising no one, not even his codeine comrade, who vainly bit him playfully, and jumped sportively on his back. It was not until the next day that the morphine dog regained his spirits and usual humour. A couple of days after, the two dogs being in good health, I repeated the same experiment, but in an inverse order--that is to say, I gave the codeine to that which previously had the morphine, and _vice versâ_. Both dogs slept about as long as the first time; but on waking the attitudes were completely reversed, just as the administration of the two substances had been. The dog which, two days before, after having been codeinised, woke lively and gay, was now bewildered and half paralysed at the end of his morphine sleep; whilst the other was wide awake and in the best spirits.”

[405] _Ann. Chem. Phys._ [5], 27, pp. 273-288; also, _Journ. Chem. Soc._, No. ccxliv., 1883, p. 358.

Subsequent experimenters found what Bernard does not mention--viz., that codeine produced epileptiform convulsions. Falck made some very careful experiments on pigeons, frogs, and rabbits. To all these in high enough doses it was fatal. Falk puts the minimum lethal dose for a rabbit at 51·2 mgrms. per kilo. Given to man, it produces a sleep very similar to that described by Claude Bernard--that is, a sleep which is very natural, and does not leave any after-effect. Therefore it is declared to be the best alkaloid of a narcotic nature to give when lengthened slumber is desired, more especially since it does not confine the bowels, nor has it been found to produce any eruption on the skin. Before it has a full narcotic effect, vomiting has often been excited, and in a few cases purging. The maximum dose for an adult is about ·1 grm. (1·5 grain); three times this quantity, ·3 grms. (4-5 grains), would probably produce unpleasant, if not dangerous, symptoms.[406]

[406] For further details as to the action of codeine, the reader is referred to L. O. Wach’s monograph, _Das Codein_ (1868), which contains reference to the earlier literature. See also Harley, _The Old Vegetable Neurotics_, London.

§ 370. =Narceine=, C₂₃H₂₇NO₈ + 3H₂O.--Two of the three molecules of
water are expelled at 100°, the other molecule requires a higher
temperature; anhydrous narceine is hygroscopic, and melts in a tube
at about 140°; when exposed to air it unites with one molecule of
water, and then melts at about 160°.

The constitution of narceine is probably that of a substituted
phenylbenzylketone, and the following structural formula has been
attributed to it:[407]--

[407] M. Freund and G. B. Frankforter, _Annalen_, 277, pp. 20-58.

3 I:2 4 1’ 2’
COOH,C₆H₂-(OMe)₂CO-CH₂-C₆H(CH₂-CH₂NMe₂)
O
3 or 6/ \
OMe CH₂
\ /
O

It therefore contains three methoxyl groups.

Narceine forms good crystals, the form being that of long,
four-sided rhombic prisms or fine bushy united needles.

Narceine hydrochloride crystallises with 5½H₂O and with 3H₂O; the
anhydrous salt melts at 190°-192°. The platinochloride is a definite
salt, m.p. 190°-191°; it decomposes at 195°-196°. The nitrate forms
good crystals, which decompose at 97°. Narceine also forms
crystalline salts with potassium and sodium; these may be obtained
by heating the base at 60°-70° with a 33 per cent. of NaHO or KHO.

The potassium compound melts at 90°, the sodium at 159°-160°. The
alkaloid is regenerated when the alkali salts are treated with acids
or with CO₂. Crude narceine may be purified by means of the sodium
salt; the latter is dissolved in alcohol and precipitated with
ether.

It is soluble in alcohol, but almost insoluble in alcohol and ether,
or benzene and ether; it is slightly soluble in ether, carbon
disulphide, and chloroform. It has no reaction on moist litmus
paper.

Benzole and petroleum ether extract narceine neither from acid nor
alkaline solutions; chloroform extracts narceine both from acid and
from alkaline solutions, the latter in small proportion only.
Narceine turns the plane of polarisation to the left, [α]_r_ =
66·7°. Narceine may be separated from narcotine by the addition of
ammonia to the acid aqueous solution; narcotine is fully
precipitated by ammonia, but narceine is left in solution.

In the subliming cell it melts at 134°, but gives no crystalline
sublimate. The tube melting-point of the trihydrate is 170°. The
melted substance is at first colourless; but on raising the
temperature, the usual transitions of colour through different
shades of brown to black are observed. If melted, and kept a few
degrees above its melting-point, and then cooled slowly, the residue
is straw-coloured, divided into lobes, most of which contain
feathery crystals.

At high temperatures narceine develops a herring-like odour; the
residue becomes darkish blue with iron chloride. Concentrated nitric
acid dissolves it with a yellow colour; on heating, red vapours are
produced; the fluid contains crystals of oxalic acid, and develops
with potash a volatile base. Concentrated sulphuric acid colours
pure narceine brown; but if impure, a blood-red or blue colour may
be produced. It does not reduce iron salts.

Fröhde’s reagent colours it first brown-green, then red, passing
into blue. Narceine forms precipitates with bichromate of potash,
chloride of gold, bichloride of platinum, and several other
reagents. The one formed by the addition of potassio zinc iodide is
in hair-like crystals, which after twenty-four hours become blue.

Weak iodine solution colours narceine crystals a black-blue; they
dissolve in water at 100° without colour, but on cooling again
separate with a violet or blue colour. If on a saturated solution of
narceine a particle of iodine is strewn, fine needle-like grey
crystals form around the iodine. A drop of “Nessler” solution, added
to solid narceine, at once strikes a brown colour; on diluting the
drop with a little water, beautiful little bundles of crystals
appear.--_Flückiger._

The following group reagents precipitate narceine:--picric acid,
tannin solution, and potassium dichromate on long standing. The
following give no precipitate:--mercuric cyanide, mercuric potas.
iodide, mercuric chloride, mercuric bromide, and potas. ferrocyanide
solutions.

§ 371. =Effects.=--The physiological action of narceine has been
variously interpreted by different observers. Claude Bernard[408]
thought it the most somniferous of the opium alkaloids. He said that
“the narceinic sleep was characterised by a profound calm and
absence of the excitability of morphine, the animals narcotised by
narceine on awaking returning to their natural state without
enfeeblement of the hind limbs or other sequelæ.” It has been amply
confirmed that narceine possesses somniferous properties, but
certainly not to the extent that Bernard’s observations led
physiologists to expect. In large doses there is some irritation of
the stomach and intestines, and vomiting occurs, and even diarrhœa;
moderate doses induce constipation. The maximum medicinal dose may
be put at ·14 grm. (or 2·26 grains), and a probably dangerous dose
would be three times that quantity.[409]

[408] _Compt. Rend._, lix. p. 406, 1864.

[409] See J. Bouchardat, _La Narcéine_, Thèse, Paris, 1865; Harley, _The Old Vegetable Neurotics_, Lond.; Ch. Liné, _Études sur la Narcéine et son Emploi Thérapeutique_, Thèse, Paris, 1865; also, Husemann’s _Planzenstoffe_, in which these and other researches are summarised.

§ 372. =Papaverine= (C₂₁H₂₁NO₄) crystallises from alcohol in white
needles or scales. It possesses scarcely any alkaline reaction, but
its salts have an acid reaction; it has but little effect on a ray
of polarised light. It is almost insoluble in water; it is easily
soluble in acetone, amyl alcohol, alcohol, and chloroform. One part
of the alkaloid is dissolved in 36·6 of benzene, and in 76 parts of
amyl alcohol. Petroleum ether dissolves it by the aid of heat, but
the alkaloid separates in crystals on cooling. Chloroform extracts
it from either acid or alkaline solutions. Papaverine gives no
crystalline sublimate. The melting-point of pure samples in a tube
is 147°, with scarcely any colour; it solidifies again to crystals
on cooling; in the subliming cell it melts at 130°, and decomposes
about 149°; the vapours are alkaline; the residue is amorphous,
light brown, and is not characteristic. Concentrated sulphuric acid
colours it a deep violet-blue, and dissolves it to a violet, slowly
fading. This solution, by permanganate of potash, is first green and
then grey. Fröhde’s reagent gives a beautiful violet colour, which
becomes blue, and vanishes after twenty-four hours. Diluted
solutions of salts of papaverine are not precipitated by
phosphomolybdic acid. It is precipitated by ammonia, by the caustic
and carbonated alkalies, by potassic-cadmic iodide, iodine in
hydriodic acid, and by alkaloidal reagents generally--save by the
important exception mentioned above. A solution in amyl alcohol is
also precipitated by bromine; the precipitate is crystalline. An
alcoholic solution of platinic chloride also separates papaverine
platin chloride in crystals. An alcoholic solution of iodine, added
to an alcoholic solution of papaverine, separates in a little time
crystals of the composition C₂₁H₂₁NO₄I₃. From the mother-liquor, by
concentration, can be obtained needles of another iodine
combination, C₂₁H₂₁NO₄I₅; the latter heated above 100° parts with
free iodine. These compounds with iodine are decomposed by ammonia
and potash, papaverine separating. The decomposition may be watched
under the microscope. Nitric acid precipitates from a solution of
the sulphate a white nitrate soluble in excess; the precipitate does
not appear at once, but forms in the course of an hour; it is at
first amorphous, but subsequently crystalline; this, with its
physical properties, is a great assistance to identification.

§ 373. =Effects.=--Claude Bernard ranked papaverine with the
convulsants; probably the papaverine he had was impure. In any case,
subsequent observations have shown that it is to be classed rather
with the hypnotic principles of opium. Leidesdorf[410] administered
it to the insane, and noted slowness of the pulse, muscular
weakness, and drowsiness to follow. The doses were given
subcutaneously (·42 grm. of the hydrochloride). Baxt,[411]
experimenting with the frog, found that a milligramme caused deep
sleep and slowing of the heart’s action. This action on the heart is
witnessed also on the recently-removed frog’s heart. Guinea-pigs,
and other small animals poisoned by strychnine or thebaine, and then
given papaverine, did not seem to be so soon affected with tetanus
as when no such remedy was administered. The fatal dose of
papaverine for a man is unknown. I should conjecture that the least
quantity that would cause dangerous symptoms would be 1 grm. (15·4
grains).

[410] _Ztschr. d. Wien. Aerzte_, pp. 13, 115, 1868.

[411] _Arch. Anat. Phys._, p. 70, 1869.

§ 374. =Thebaine=, C₁₇H₁₅NO(OCH₃)₂.--Opium seldom contains much more
than 1 per cent. of this alkaloid. It usually forms needles or short
crystals. It is alkaline, and by rubbing becomes negatively
electric. It is almost insoluble in water, aqueous ammonia, and
solutions of the alkalies. It requires 10 parts of cold alcohol for
solution, and dissolves readily in hot. Ether, hot or cold, is also
a good solvent. 100 parts of benzene are required for 5·27 parts of
thebaine, and 100 of amyl alcohol for 1·67 parts. Chloroform
dissolves thebaine with difficulty out of both acid and alkaline
solutions; petroleum ether extracts it from neither. Thebaine melts
in a tube at 193°, sublimes at 135°. The sublimate is in minute
crystals, similar to theine; at higher temperatures (160° to 200°)
needles, cubes, and prisms are obtained. The residue is fawn
coloured. Fröhde’s reagent (as well as concentrated sulphuric acid)
dissolves it, with the production of a blood-red colour, passing
gradually into yellow. The precipitate with picric acid is yellow
and amorphous; with tannic acid yellow; with gold chloride,
red-yellow; and with platinic chloride, citron-yellow, gradually
becoming crystalline. A concentrated alcoholic solution of thebaine,
just neutralised with HCl, deposits well-formed rhombic crystals of
the composition C₁₉H₂₁NO₃HCl + H₂O.

If 200 mgrms. of thebaine are heated to boiling with 1·4 c.c. of HCl
and 2·8 c.c. of water, and the solution diluted, after boiling, with
4 c.c. of water, crystals of thebaine hydrochloride form in the
yellow fluid in the course of a few hours.--_Flückiger._

§ 375. =Effects.=--There is no disagreement of opinion as to the
action of thebaine. By the united testimony of all who have
experimented with it, the alkaloid belongs to those poisons which
produce tetanus, and the symptoms can scarcely be differentiated
from strychnia. In Baxt’s experiments on frogs he showed that there
was some considerable difference in details in the general course of
the symptoms, according to the dose of the poison. A small dose
(such, for example, as ·75 mgrm.) injected into a frog
subcutaneously produces immediate excitement, the animal jumping
about, and this stage lasting for about a minute; it then becomes
quieter, and has from three to six minutes’ sleep; in a little time
this comatose state is followed by reflex tetanic spasms and then
spontaneous tetanic spasms. With three times the dose, the tetanic
convulsions commence early, and death takes place in from two to six
hours. Baxt[412] found 6 to 7 mgrms. kill rabbits with tetanic
convulsions in from fifteen to twenty-five minutes. Crum Brown and
Fraser also found that 12 mgrms. injected into rabbits were fatal;
it may then be presumed that the lethal dose for a rabbit is about 5
mgrms. per kilo. A frog’s heart under the action of thebaine, and
removed from the body, beats quicker and ceases earlier than one in
distilled water. Thebaine has been administered to the insane
subcutaneously in doses of from 12 to 40 mgrms., when a rise of
temperature and an increase in the respiratory movements and in the
circulation were noticed.[413]

[412] _Sitzungsber. d. Wien. Akadem._, lvi. pp. 2, 89, 1867; _Arch. f. Anat. u. Physiol._, Hft. 1, p. 112, 1869.

[413] F. W. Müller, _Das Thebaine, eine Monographie_, Diss., Marburg 1868.

The fatal dose for a man is not known; ·5 grm., or about 8 grains,
would probably be a poisonous quantity.

§ 376. =Cryptopine= (C₂₁H₂₃NO₅) was discovered by T. & H. Smith in
1867.[414] It is only contained in very minute traces in
opium--something like ·003 per cent. It is a crystalline substance,
the crystals being colourless, six-sided prisms, without odour, but
with a bitter taste, causing an after-sensation like peppermint. The
crystals melt at 217°, and congeal in a crystalline form again at
171°; at high temperatures they are decomposed with evolution of
ammoniacal vapour. Cryptopine is insoluble, or almost so, in ether,
water, and oil of turpentine; it is soluble in acetone, benzene, and
chloroform; the latter is the best solvent, or hot alcohol; it is
insoluble in aqueous ammonia and in solutions of the caustic
alkaloids. Cryptopine is strongly basic, neutralising fully mineral
acids. Concentrated sulphuric acid colours cryptopine pure blue, the
tint gradually fading from absorption of water from the atmosphere.
On a crystal of potassic nitrate being added, the colour changes
into a permanent green. With ferric chloride cryptopine gives no
colour--thus distinguishing it from morphine. The physiological
properties of cryptopine have been investigated by Dr. Harley;[415]
it has a narcotic action, about double as strong as narceine, and
four times weaker than morphine. Munk and Sippell[416] found that it
gave rise in animals to paralysis of the limbs, and occasionally
asphyxic convulsions before death.

[414] _Pharm. Journ. Trans._ [2], viii. pp. 495 and 716.

[415] _The Old Vegetable Neurotics._

[416] Munk, _Versuche über die Wirkung des Cryptopins_, Berlin, 1873. Sippell, _Beiträge zur Kentniss des Cryptopins_, Marburg, 1874.

§ 377. =Rhœadine= (C₂₁H₂₁NO₆).--Rhœadine was separated from _Papaver
rhœas_ by Hesse, and has also been found in _Papaver somniferum_ and
in opium. Rhœadine is in the form of small anhydrous tasteless
prisms, melting at 230° and partly subliming. In a vacuum
sublimation is almost complete, and at a much lower temperature. It
is a very insoluble substance, and is scarcely dissolved, when
crystalline, by water, alcohol, ether, chloroform, benzene, and
solutions of the fixed or volatile alkalies. When in an amorphous
state it is rather soluble in ether, and may be dissolved out of any
substance by treating with dilute acetic acid, and neutralising by
ammonia, and shaking up with ether before the precipitate becomes
crystalline. Rhœadine is easily recognised by its striking a red
colour with hydrochloric acid. Either spontaneously or on gentle
warming, the colour is produced--one part of rhœadine will colour in
this way 10,000 parts of acid water blue or purple-red, 200,000
rose-red, and 800,000 pale red. The reaction depends on a splitting
up of the rhœadine into a colourless substance, _rhœadin_, and a red
colouring-matter. Rhœadine is not poisonous.

§ 378. =Pseudomorphine= (C₁₇H₁₉NO₄).--Pseudomorphine was discovered
by Pelletier and Thiboumery in 1835. As precipitated by ammonia out
of the hot solution, pseudomorphine falls as a white crystalline
precipitate; but if the solution is cold, the precipitate is
gelatinous. It possesses no taste, and has no action on vegetable
colours. On heating, it decomposes and then melts. It dissolves
easily in caustic alkalies and in milk of lime, but is insoluble in
all the ordinary alcoholic and ethereal solvents, as well as in
diluted sulphuric acid. The most soluble salt is the hydrochlorate
(C₁₇H₁₉NO₄HCl + H₂O), and that requires 70 parts of water at 20° for
solution. Various salts, such as the sulphate, oxalate, &c., may be
prepared from the hydrochlorate by double decomposition.
Concentrated sulphuric acid dissolves pseudomorphine gradually, with
the production of an olive-green colour.

§ 379. =Opianine= (C₆₆H₇₂N₄O₂₁).--Opianine crystallises in
colourless, glittering ortho-rhombic needles. Ammonia precipitates
it from its solution in hydrochloric acid as a fine white powder. It
is without odour, and has a bitter taste. It is a strong base, and
is soluble in cold, but slightly soluble in boiling water. It is
also but little soluble in boiling alcohol.

An alcoholic solution of the alkaloid gives a voluminous precipitate
with mercuric chloride; after standing a little time, the
precipitate becomes crystalline, the crystals being in the shape of
fine needles. They have the following composition--C₆₆H₇₂N₄O₂₁,
2HCl, 2HgCl--and are with difficulty soluble in water or alcohol.

Opianine, administered to cats in doses of ·145 grm., produces
complex symptoms--_e.g._, dilated pupils, foaming at the mouth,
uncertain gait, paralysis of the hinder extremities, and stupor--but
the alkaloid is rare, and few experiments have been made with it.

§ 380. =Apomorphine= (C₁₇H₁₉NO₃).--Apomorphine is a derivative of
morphine, and is readily prepared by saponifying morphine by heating
it with dilute hydrochloric acid in sealed tubes. The result is
apomorphine hydrochloride, the morphine losing one molecule of
water, according to the equation C₁₇H₁₉NO₃ = C₁₇H₁₇NO₂ + H₂O.

To extract apomorphine, the bases are precipitated by sodic
bicarbonate, and the precipitate extracted by ether or chloroform,
either of which solvents leaves morphine undissolved. The
apomorphine is again converted into hydrochloride, and once more
precipitated by sodic bicarbonate, and is lastly obtained as a
snow-white substance, rapidly becoming green on exposure to the air.
The mass dissolves with a beautiful green colour in water, and also
in alcohol, whilst it colours ether purple-red, and chloroform
violet.

A test for apomorphine is the following:--The chloride is dissolved
in a little acetic acid and shaken with a crystal of potassic iodate
(KIO₃); this immediately turns red from liberated iodine on shaking
it up with a little chloroform; on standing, the chloroform sinks to
the bottom, and is coloured by the alkaloid a beautiful blue colour;
on now carefully pouring a little CS₂ on the surface of the liquid
at the point of junction it is coloured amethyst owing to dissolved
iodine, and apocodeine gives a similar reaction.

Apomorphine is the purest and most active emetic known: whether
injected beneath the skin or taken by the mouth, the effect is the
same--there is considerable depression, faintness, and then
vomiting. The dose for an adult is about 6 mgrms. (·092 grain)
subcutaneously administered.

§ 381. The reactions of some of the rarer alkaloids of opium with
sulphuric acid and ferric chloride are as follows: none of them have
at present any toxicological importance:--

TABLE SHOWING SOME OF THE REACTIONS OF THE RARER ALKALOIDS OF OPIUM.

+---------------+---------+----------------------+----------------+
| Alkaloid. |Formula. | Reaction with Warm | Reaction with |
| | | Sulphuric Acid. |Ferric Chloride.|
+---------------+---------+----------------------+----------------+
|Codamine, |C₂₀H₂₅NO₄ {|Dirty red-violet |} |
| | {|colour, turning dark |} Dark green. |
|Landamine, |C₂₀H₂₅NO₄ {|violet on the |} |
| | {|addition of HNO₃. |} |
| | | | |
|Landanosine, |C₂₀H₂₇NO₄ }|Dirty green to |} |
| | }|brownish-green. |} No colour. |
|Protapine, |C₂₀H₁₉NO₅ }| |} |
| | | | |
|Lanthopine, |C₂₃H₂₅NO₄ |Dark brown or black. | No colour. |
| | | | |
|Hydrocotarnine,|C₁₂H₁₅NO₃ {|Dirty red-violet; |} |
| | {|not changed by |} No colour. |
| | {|trace of HNO₃. |} |
+---------------+---------+----------------------+----------------+

§ 382. =Tritopine= (C₄₂H₅₄N₂O₇).--This is a rare alkaloid that has
been found in small quantities in opium. It is crystalline,
separating in transparent prisms. Melting-point 182°. It is soluble
in alcohol and chloroform, and slightly soluble in ether.[417]

[417] E. Kander, _Arch. Pharm._, 228, pp. 419-431.

§ 383. =Meconin (Opianyl)= (C₁₀H₁₀O₄) is in the form of white
glittering needles, which melt under water at 77° and in air at 90°,
again coagulating at 75°. It may be sublimed in beautiful crystals.
It is soluble in 22 parts of boiling, and 700 of cold water;
dissolves easily in alcohol, ether, acetic acid, and ethereal oil,
and is not precipitated by acetate of lead. Its solution in
concentrated sulphuric acid becomes, on warming, purple, and gives,
on the addition of water, a brown precipitate. Meconin may be
prepared by treating narcotine with nitric acid. Meconin, in large
doses, is a feeble narcotic; 1·25 grm. (20 grains) has been given to
man without result.