[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.”
§ 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.
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 51⁄2H2O 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).
§ 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]