PART VI.—ALKALOIDS AND POISONOUS VEGETABLE PRINCIPLES SEPARATED FOR THE MOST PART BY ALCOHOLIC SOLVENTS. (continued 2)

§ 341. Symptoms and Effects.—Aniline, like picric acid, coagulates albumin. Aniline is a blood poison; it produces, even during life, in some obscure way, methæmoglobin, and it disintegrates the red blood corpuscles; both these effects lessen the power of the blood corpuscles to convey oxygen to the tissues, hence the cyanosis observed so frequently in aniline poisoning is explained. Engelhardt[367] has found that aniline black is produced; in every drop of blood there are fine black granules, the total effect of which produce a pale blue or grey-blue colour of the skin. Aniline has also an action on the central nervous system, at first stimulating, and then paralysing. Schmiedeberg finds that para-amido-phenol-ether-sulphuric acid is produced, and appears in the urine as an alkali salt; a small quantity of fuchsine is also produced, and has been found in the urine. Some aniline may be excreted unchanged.

The symptoms are giddiness, weakness, cyanosis, blueness of the skin, sinking of the temperature, and dilatation of the pupil. The pulse is small and frequent, the skin moist and cold. The patient smells of aniline. Towards the end coma and convulsions set in. The urine may be brown to brown-black, and may contain hyaline cylinders. The blood shows the spectrum of methæmoglobin, and has the peculiarities already mentioned. Should the patient recover, jaundice often follows. The outward application of aniline produces eczema.

Chronic poisoning by aniline is occasionally seen among workers in the manufacture of aniline. Headache, loss of muscular power, diminished sensibility of the skin, vomiting, loss of appetite, pallor, eruptions on the skin, and general malaise are the chief symptoms. The perspiration has been noticed to have a reddish colour.

Cases of aniline poisoning are not common; Dr. Fred. J. Smith has recorded one in the Lancet of January 13, 1894.[368] The patient, a woman, 42 years of age, of alcoholic tendencies, swallowed, 13th December 1893, at 1.40 P.M., about 3 ounces of marking ink, the greatest part of which consisted of aniline; in a very little while she became unconscious, and remained so until death. At 3 P.M. her lips were of a dark purple, the general surface of the skin was deadly white, with a slight bluish tinge; the pupils were small and sluggish, the breathing stertorous, and the pulse full and slow—60 per minute. The stomach was washed out, ether injected, and oxygen administered, but the patient died comatose almost exactly twelve hours after the poison had been taken.

The post-mortem examination showed slight congestion of the lungs; the heart was relaxed in all its chambers, and empty of blood; it had a peculiar green-blue appearance. All the organs were healthy. The blood was not spectroscopically examined.

§ 342. Fatal Dose.—This is not known, but an adult would probably be killed by a single dose of anything over 6 grms. Recovery under treatment has been known after 10 grms.; the fatal dose for rabbits is 1-1·5 grms., for dogs 3-5 grms.

§ 343. Detection of Aniline.—Aniline is easily separated and detected. Organic fluids are alkalised by a solution of potash, and distilled. The organs, finely divided, are extracted with water acidulated with sulphuric acid, the fluid filtered, and then alkalised and distilled. The distillate is shaken up with ether, the ether separated and allowed to evaporate spontaneously. Any aniline will be in the residue left after evaporation of the ether, and may be identified by the following tests:—An aqueous solution of aniline or its salts is coloured blue by a little chloride of lime or hypochlorite of soda; later on the mixture becomes red. The blue colour has an absorption band, when examined spectroscopically, extending from W.L. 656 to 560, and therefore in the red and yellow from Fraunhofer’s line C, and overlapping D. Another test for aniline is the addition of kairine, hydrochloric acid, and sodium nitrite, which strikes a blue colour.

III.—The Opium Group of Alkaloids.

§ 344. General Composition.—Opium contains a larger number of basic substances than any plant known. The list reaches at present to 18 or 19 nitrogenised bases, and almost each year there have been additions. Some of these alkaloids exist in very small proportion, and have been little studied. Morphine and narcotine are those which, alone, are toxicologically important. Opium is a gummy mass, consisting of the juice of the incised unripe fruit of the Papaver somniferum hardened in the air. The following is a nearly complete list of the constituents which have been found in opium:—

Morphine, C₁₇H₁₉NO₃.

Narcotine, C₂₂H₂₃NO₇.

Narceine, C₂₃H₂₉NO₉.

Apomorphine, C₁₇H₁₀NO₂ - By dehydration of morphine and codeine respectively.

Apocodeine, C₁₈H₁₉NO₂

Pseudomorphine, C₁₇H₁₉NO₄.

Codamine, C₂₀H₂₅NO₄.

Ladanine, C₂₀H₂₅NO₄.

Ladanosine, C₂₁H₂₇NO₄.

Protapine, C₂₀H₁₉NO₅.

Cryptopine, C₂₁H₂₃NO₅.

Lanthopine, C₂₃H₂₅NO₄.

Hydrocotarnine, C₁₂H₁₅NO₃.

Opianine, C₂₁H₂₁NO₇.

Cnoscopine, C₃₄H₃₆N₂O₁₁.

Rhœadine, C₂₀H₂₁NO₇.

Codeine, C₁₈H₂₁NO₃.

Thebaine, C₁₉H₂₁NO₃.

Papaverine, C₂₀H₂₁NO₄.

Meconidine, C₂₁H₂₃NO₄.

Meconin, C₁₀H₁₀O₄.

Meconic acid, C₇H₄O₇.

Thebolactic acid.

Fat.

Resin.

Caoutchouc.

Gummy matters—Vegetable mucus.

Ash, containing the usual constituents.

The various opiums differ, the one from the other, in the percentages of alkaloids, so that only a very general statement of the mean composition of opium can be made. The following statement may, however, be accepted as fairly representative of these differences:—

Per cent.

Morphine, 6 to 15

Narcotine, 4 to 8

Other alkaloids, 5 to 2

Meconin, Under 1

Meconic acid, 3 to 8

Peculiar resin and caoutchouc, 5 to 10

Fat, 1 to 4

Gum and soluble humoid acid matters, 40 to 50

Insoluble matters and mucus, 18 to 20

Ash, 4 to 8

Water, 8 to 30

The general results of the analysis of 12 samples of Turkey opium, purchased by Mr. Bott,[369] from leading druggists in London, Dublin, and Edinburgh, are as follows:—

Water.—Highest, 31·2; lowest, 18·4; mean, 22·4 per cent.

Insoluble Residue.—Highest, 47·9; lowest, 25·45; mean, 32·48 per cent.

Aqueous Extract.—Highest, 56·15; lowest, 20·90; mean, 45·90 per cent.

Crude Morphine (containing about ⁷⁄₁₀ of pure morphine).—Highest, 12·30; lowest, 6·76; mean, 9·92 per cent., which equals 12·3 per cent. of the dried drug.

Persian Opium, examined in the same way, varied in crude morphine from 2·1 to 8·5 per cent.; Malwa, from 5·88 to 7·30. In 18 samples of different kinds of opium, the mean percentage of crude morphine was 8·88 per cent. (11 per cent. of the dried opium). According to Guibourt, Smyrna opium, dried at 100°, yields 11·7 to 21·46 per cent., the mean being 12 to 14 per cent.; Egyptian, from 5·8 to 12 per cent.; Persian, 11·37 per cent. In East Indian Patna opium, for medical use, he found 7·72; in a sample used for smoking, 5·27 per cent.; in Algerian opium, 12·1 per cent.; in French opium, 14·8 to 22·9 per cent.

§ 345. Action of Solvents on Opium.—The action of various solvents on opium has been more especially studied by several scientists who are engaged in the extraction of the alkaloids.

Water dissolves nearly everything except resin, caoutchouc, and woody fibre. Free morphine would be left insoluble; but it seems always to be combined with meconic and acetic acids. The solubility of free narcotine in water is extremely small.

Alcohol dissolves resin and caoutchouc, and all the alkaloids and their combinations, with meconic acid, &c.

Amylic Alcohol dissolves all the alkaloids, if they are in a free state, and it also takes up a little of the resin.

Ether, Benzene, and Carbon Sulphide do not dissolve the resin, and only slightly morphine, if free; but they dissolve the other free alkaloids as well as caoutchouc.

Acids dissolve all the alkaloids and the resin.

Fixed Alkalies, in excess, dissolve in part resin; they also dissolve morphine freely; narcotine remains insoluble.

Lime Water dissolves morphine, but is a solvent for narcotine only in presence of morphine.

Ammonia dissolves only traces of morphine; but narceine and codeine readily. It does not dissolve the other alkaloids, nor does it dissolve the resin.

§ 346. Assay of Opium.—The following processes may be described:—

Process of Teschemacher and Smith.—This process, with a few modifications, is as follows:—10 grms. of opium are as completely exhausted with proof spirit at a boiling temperature as possible. The resulting alcoholic extract is treated with a few drops of ammonium oxalate solution, and the solution is almost neutralised with ammonia. The solution is concentrated to one-third, cooled, and filtered. The filtrate is farther concentrated to 5 c.c., and transferred to a small flask, it is washed into this flask by 4 c.c. of water, and 3 c.c. of 90 per cent. alcohol; next 2 c.c. solution of ammonia (sp. gr. 0·960) and 25 c.c. of dry ether are added. The flask is corked, shaken, and then allowed to rest over-night.

The ether is decanted as completely as possible. Two filter papers are taken and counterpoised—that is to say, they are made precisely the same weight. The filters are placed one inside the other, and the precipitate collected on the inner one; the precipitate is washed with morphinated water—that is to say, water in which morphine has been digested for some days. The filter papers with their contents are washed with benzene and dried, the outer paper put on the pan of the balance carrying the weights, and the inner filter with the precipitate weighed. The precipitate is now digested with a known volume of decinormal acid, and then the excess of acid ascertained by titration with decinormal alkali, using either litmus or methyl orange; each c.c. of decinormal acid is equal to 30·3 mgrms. of morphine.[370]

Dott’s Process.—Dott has recently proposed a new process, which he states has given good results. The process is as follows:—10 grammes of powdered opium are digested with 25 c.c. water; 1·8 gramme barium chloride dissolved in about 12 c.c. water is then added, the solution made up to 50 c.c., well mixed, and after a short time filtered. 22 c.c. (representing 5 grammes opium) are mixed with dilute sulphuric acid in quantity just sufficient to precipitate the barium. About 1 c.c. is required, and the solution should be warmed to cause the precipitate to subside, and the solution to filter clear. To this filtered solution a little dilute ammonia, about 0·5 c.c. is added to neutralise the free acid, and the solution concentrated to 6 or 7 c.c., and allowed to cool. 1 c.c. spirit and 1 c.c. ether are then added, and next ammonia in slight excess. The ammonia should be added gradually until there is no further precipitation, and a perceptible odour of ammonia remains after well stirring and breaking down any lumps with the stirring rod. After three hours the precipitate is collected on counterpoised filters and washed. Before filtering, it should be noted that the solution has a faint odour of ammonia: if not, one or two drops of ammonia solution should be added. The dried precipitate is washed with benzene or chloroform, dried, and weighed. It is then titrated with ⁿ⁄₁₀ acid, until the morphine is neutralised, as indicated by the solution reddening litmus paper.[371]

§ 347. Medicinal and other Preparations of Opium.—The chief mixtures, pills, and other forms, officinal and non-officinal, in which opium may be met with, are as follows:—

(1.) Officinal.

Compound Tincture of Camphor, P. B. (Paregoric).—Opium, camphor, benzoic acid, oil of anise, and proof spirit: the opium is in the proportion of about 0·4 per cent., or 1 grain of opium in 240 minims.

Ammoniated Tincture of Opium (Scotch paregoric).—Strong solution of ammonia, rectified spirit, opium, oil of anise, saffron, and benzoic acid. Nearly 1 per cent. or 1 grain of opium in every 96 minims.

The Compound Powder of Kino, P. B.

Opium, 5 per cent.

Cinnamon, 20 „

Kino, 75 „

The Compound Powder of Opium, P. B.

Opium, 10·00 per cent.

Black Pepper, 13·33 „

Ginger, 33·33 „

Caraway Fruit, 40·00 „

Tragacanth, 3·33 „

Pill of Lead and Opium, P. B.

Acetate of Lead, 75·0 per cent.

Opium, 12·5 „

Confection of Roses, 12·5 „

Tincture of Opium (Laudanum).—Opium and proof spirit. One grain of opium in 14·8 min.—that is, about 6·7 parts by weight in 100 by measure.

The amount of opium actually contained in laudanum has been investigated by Mr. Woodland,[372] from fourteen samples purchased from London and provincial chemists. The highest percentage of extract was 5·01, the lowest 3·21, the mean being 4·24; the highest percentage of morphine was ·70 per cent., the lowest ·32, the mean being ·51 per cent. It is, therefore, clear that laudanum is a liquid of very uncertain strength.

Aromatic Powder of Chalk and Opium.—Opium 2·5 per cent., the rest of the constituents being cinnamon, nutmeg, saffron, cloves, cardamoms, and sugar.

Compound Powder of Ipecacuanha (Dover’s Powder).

Opium, 10 per cent.

Ipecacuanha, 10 „

Sulphate of Potash, 80 „

Confection of Opium (Confectio opii) is composed of syrup and compound powder of opium; according to its formula, it contains 2·4 per cent. of opium by weight.

Extract of Opium contains the solid constituents capable of extraction by water; it should contain 20 per cent. of morphine, and is therefore about double the strength of dry powdered opium.

Liquid Extract of Opium has been also examined by Mr. Woodland:[373] ten samples yielded as a mean 3·95 per cent. of dry extract, the highest number being 4·92 per cent., the lowest 3·02. The mean percentage of morphine was ·28 per cent., the highest amount being ·37, and the lowest ·19 per cent.

Liniment of Opium is composed of equal parts of laudanum and soap liniment; it should contain about 0·0375 per cent. morphine.

The Compound Soap-pill is made of soap and opium, one part of opium in every 5·5 of the mass—i.e., about 18 per cent.

Ipecacuanha and Morphine Lozenges, as the last, with the addition of ipecacuanha; each lozenge contains ¹⁄₃₆ grain (1·8 mgrms.) morphine hydrochlorate, ¹⁄₁₂ grain (5·4 mgrms.) ipecacuanha.

Morphia Suppositories are made with hydrochlorate of morphine, benzoated lard, white wax, and oil of theobroma; each suppository contains ¹⁄₂ grain (32·4 mgrms.) of morphine salt.

Opium Lozenges are composed of opium extract, tincture of tolu, sugar, gum, extract of liquorice, and water. Each lozenge contains ¹⁄₁₀ grain (6·4 mgrms.) of extract of opium, or about ¹⁄₅₀ grain (1·3 mgrm.) morphine.

The Ointment of Galls and Opium contains one part of opium in 14·75 parts of the ointment—i.e., opium 6·7 per cent.

Opium Wine, P. B.—Sherry, opium extract, cinnamon, and cloves. About 5 of opium extract by weight in 100 parts by measure (22 grains to the ounce).

Solutions of Morphine, both of the acetate and hydrochlorate, P. B., are made with a little free acid, and with rectified spirit. The strength of each is half a grain in each fluid drachm (·0324 grm. in 3·549), or ·91 part by weight in 100 by measure.

Solution of Bimeconate of Morphine.—One fluid oz. contains 5¹⁄₂ grains of bimeconate of morphine.

Morphia Lozenges are made with the same accessories as opium lozenges, substituting morphine for opium; each lozenge contains ¹⁄₃₆ grain of hydrochlorate of morphia (1·8 mgrm.).

Syrup of Poppies.—The ordinary syrup of poppies is sweetened laudanum. It should, however, be what it is described—viz., a syrup of poppy-heads. As such, it is said to contain one grain of extract of opium to the ounce.

(2.) Patent and other Non-Officinal Preparations of Opium.

Godfrey’s Cordial is made on rather a large scale, and is variable in strength and composition. It usually contains about 1¹⁄₂ grains of opium in each fluid ounce,[374] and, as other constituents: sassafras, molasses or treacle, rectified spirit, and various flavouring ingredients, especially ginger, cloves, and coriander; aniseed and caraways may also be detected.

Grinrod’s Remedy for Spasms consists of hydrochlorate of morphine, spirit of sal-volatile, ether, and camphor julep; strength, 1 grain of the hydrochlorate in every 6 ounces.

Lemaurier’s Odontalgic Essence is acetate of morphine dissolved in cherry-laurel water; strength, 1 grain to the ounce.

Nepenthe is a preparation very similar to Liq. Opii sedativ., and is of about the same strength as laudanum.[375]

Black Drop (known also by various names, such as Armstrong’s Black Drop) is essentially an acetic acid solution of the constituents of opium. It is usually considered to be of four times the strength of laudanum. The wholesale receipt for it is: Laudanum, 1 oz., and distilled vinegar 1 quart, digested for a fortnight. The original formula proposed by the Quaker doctor of Durham, Edward Tunstall, is—Opium, sliced, ¹⁄₂ lb.; good verjuice,[376] 3 pints; and nutmeg, 1¹⁄₂ oz.; boiled down to a syrup thickness; ¹⁄₄ lb. of sugar and 2 teaspoonfuls of yeast are then added. The whole is set in a warm place for six or eight weeks, after which it is evaporated in the open air until it becomes of the consistence of a syrup. It is lastly decanted and filtered, a little sugar is added, and the liquid made up to 2 pints.

“Nurse’s Drops” seem to be composed of oil of caraway and laudanum.

Powell’s Balsam of Aniseed, according to evidence in the case of Pharmaceutical Society v. Armson (Pharm. Journ., 1894), contains in every oz. ¹⁄₁₀ grain of morphine.

Dalby’s Carminative—

Carbonate of magnesia, 40 grains.

Tincture of castor, and compound tincture of cardamoms, of each 15 drops.

Laudanum, 5 dr„

Oil of aniseed, 3 dr„

Oil of nutmeg, 2 dr„

Oil of peppermint, 1 dr„

Peppermint water, 2 fl. ounces

Dose, from a half to one teaspoonful. Another recipe has no laudanum, but instead syrup of poppies.

Chlorodyne—Brown’s Chlorodyne is composed of—

Chloroform, 6 drachms.

Chloric ether, 1 dra„

Tincture of capsicum, ¹⁄₂ dra„

Hydrochlorate of morphine, 8 grains.

Scheele’s prussic acid, 12 drops

Tincture of Indian hemp, 1 drachm.

Treacle, 1 dra„

Atkinson’s Infant Preserver—

Carbonate of magnesia, 6 drachms.

White sugar, 2 ounces

Oil of aniseed, 20 drops.

Spirit of sal-volatile, 2 ¹⁄₂ drachms.

Laudanum, 1 dra„

Syrup of saffron, 1 ounce.

Caraway water, to make up, 1 pint.

Boerhave’s Odontalgic Essence—

Opium, ¹⁄₂ drachm.

Oil of cloves, 2 dra„

Powdered camphor, 5 dra„

Rectified spirit, 1 ¹⁄₂ fl. ounce.

§ 348. Statistics.—During the ten years 1883-1892 no less than 1424 deaths in England and Wales were attributed to some form or other of opium or its active constituents; 45 of these deaths were ascribed to various forms of soothing syrup or to patent medicines containing opium or morphine; 876 were due to accident or negligence; 497 were suicidal and 6 were homicidal deaths. The age and sex distribution of the deaths ascribed to accident and those ascribed to suicide are detailed in the following tabular statement:—

DEATHS IN ENGLAND AND WALES DURING THE TEN YEARS 1883-1892 FROM OPIUM, LAUDANUM, MORPHINE, &c.

Accident.

Ages, 0-1 1-5 5-15 15-25 25-65 65 and above Total

Males, 72 27 1 16 302 85 503

Females, 50 23 4 21 189 86 373

Total, 122 50 5 37 491 171 876

Suicide.

Ages, 5-15 15-25 25-65 65 and above Total

Males, 1 26 269 34 330

Females, ... 24 126 17 167

Total, 1 50 395 51 497

Of European countries, England has the greatest proportional number of opium poisonings. In France, opium or morphine poisoning accounts for about 1 per cent. of the whole; and Denmark, Sweden, Switzerland, Germany, all give very small proportional numbers; arsenic, phosphorus, and the acids taking the place of opiates. The more considerable mortality arises, in great measure, from the pernicious practice—both of the hard-working English mother and of the baby-farmer—of giving infants various forms of opium sold under the name of “soothing syrups,” “infants’ friends,” “infants’ preservatives,” “nurses’ drops” and the like, to allay restlessness, and to keep them during the greater part of their existence asleep. Another fertile cause of accidental poisoning is mistakes in dispensing; but these mistakes seem to happen more frequently on the Continent than in England. This is in some degree due to the decimal system, which has its dangers as well as its advantages, e.g.:—A physician ordered ·5 decigrm. of morphine acetate in a mixture for a child, but omitted the decimal point, and the apothecary, therefore, gave ten times the dose desired, with fatal effect. Again, morphine hydrochlorate, acetate, and similar soluble salts are liable to be mistaken for other white powders, and in this way unfortunate accidents have occurred—accidents that, with proper dispensing arrangements, should be impossible.

§ 349. Poisoning of Children by Opium.—The drugging of children by opium—sometimes with a view to destroy life, sometimes merely for the sake of the continual narcotism of the infant—is especially rife in India.[377] A little solid opium is applied to the roof of the mouth, or smeared on the tongue, and some Indian mothers have been known to plaster the nipples with opium, so that the child imbibes it with the milk. Europeans, again and again, have discovered the native nurses administering opiates to the infants under their care, and it is feared that in many cases detection is avoided.

The ignorant use of poppy-tea has frequently caused the death of young children; thus in 1875 an inquest was held at Chelsea on the body of a little boy two years and a half old. He had been suffering from whooping-cough and enlargement of the bowels, and poppy-tea was by the advice of a neighbour given to him. Two poppy-heads were used in making a quart of tea, and the boy, after drinking a great portion of it, fell into a deep sleep, and died with all the symptoms of narcotic poisoning.

§ 350. Doses of Opium and Morphia.—Opium in the solid state is prescribed for adults in quantities not exceeding 3 grains, the usual dose being from 16·2 mgrms. to 64·8 mgrms. (¹⁄₄ to 1 grain). The extract of opium is given in exactly the same proportions (special circumstances, such as the habitual use of opium, excepted); the dose of all the compounds of opium is mainly regulated by the proportion of opium contained in them.

The dose for children (who bear opium ill) is usually very small; single drops of laudanum are given to infants at the breast, and the dose cautiously increased according to age. Most practitioners would consider half a grain a very full dose, and, in cases requiring it, would seldom prescribe at first more than ¹⁄₁₆ to ¹⁄₄ grain.

The dose of solid opium for a horse is from 1·77 grm. to 7·08 grms. (¹⁄₂ drachm to 2 drachms); in extreme cases, however, 4 drachms (14·16 grms.) have been given.

The dose for large cattle is from ·648 grm. to 3·88 grms. (10 to 60 grains); for calves, ·648 grm. (10 grains); for dogs it is greatly regulated by the size of the animal, 16·2 to 129·6 mgrms. (¹⁄₄ grain to 2 grains).

Fatal Dose.—Cases are recorded of infants dying from extremely small doses of opium, e.g., ·7, 4·3, and 8·1 mgrms. (¹⁄₉₀, ¹⁄₁₅, and ¹⁄₈ of a grain); but in such instances one cannot help suspecting some mistake. It may, however, be freely conceded that a very small quantity might be fatal to infants, and that 3 mgrms. given to a child under one year would probably develop serious symptoms.

The smallest dose of solid opium known to have proved fatal to adults was equal to 259 mgrms. (4 grains) of crude opium (Taylor), and the smallest dose of the tincture (laudanum), 7·0 c.c. (2 drachms), (Taylor); the latter is, however, as already shown, uncertain in its composition.

A dangerous dose (save under special circumstances) is:—For a horse, 14·17 grms. (4 drachms); for cattle, 7·04 grms. (2 drachms); for a dog of the size and strength of a foxhound, 204 mgrms. (3 grains).

Enormous and otherwise fatal doses may be taken under certain conditions by persons who are not opium-eaters. I have seen 13 cgrms. (2 grains) of morphine acetate injected hypodermically in a strong man suffering from rabies with but little effect. Tetanus, strychnine, convulsions, and excessive pain all decrease the sensibility of the nervous system to opium.

§ 351. General Method for the Detection of Opium.—It is usually laid down in forensic works that, where poisoning by opium is suspected, it is sufficient to detect the presence of meconic acid in order to establish that of opium. In a case of adult poisoning there is generally substance enough available to obtain one or more alkaloids, and the presence of opium may, without a reasonable doubt, be proved, if meconic acid (as well as either morphine, narcotine, thebaine, or other opium alkaloid) has been detected. Pills containing either solid opium or the tincture usually betray the presence of the drug by the odour, and in such a case there can be no possible difficulty in isolating morphine and meconic acid, with probably one or two other alkaloids. The method of extraction from organic fluids is the same as before described, but it may, of course, be modified for any special purpose. If opium, or a preparation of opium, be submitted to Dragendorff’s process (see p. 242), the following is a sketch of the chief points to be noticed.

If the solution is acid—

(1.) Benzene mainly extracts meconin, which dissolves in sulphuric acid very gradually (in twenty-four to forty-eight hours), with a green colour passing into red. Meconin has no alkaloidal reaction.

(2.) Amyl alcohol dissolves small quantities of meconic acid, identified by striking a blood-red colour with ferric chloride.

If now the amyl alcohol is removed with the aid of petroleum ether, and the fluid made alkaline by ammonia—

(1.) Benzene extracts narcotine, codeine, and thebaine. On evaporation of the benzene the alkaloidal residue may be dissolved in water, acidified with sulphuric acid, and after filtration, on adding ammonia in excess, thebaine and narcotine are precipitated, codeine remaining in solution. The dried precipitate, if it contain thebaine, becomes blood-red when treated with cold concentrated sulphuric acid, while narcotine is shown by a violet colour developing gradually when the substance is dissolved in dilute sulphuric acid 1 : 5, and gently warmed. The codeine in the ammoniacal solution can be recovered by shaking up with benzene, and recognised by the red colour which the solid substance gives when treated with a little sugar and sulphuric acid.

(2.) Chloroform especially dissolves the narceine, which, on evaporation of the chloroform, may be identified by its general characters, and by its solution in Fröhde’s reagent becoming a beautiful blue colour. Small quantities of morphine may be extracted with codeine.

(3.) Amyl alcohol extracts from the alkaline solution morphine, identified by its physical characters, by its forming a crystalline precipitate with iodine and hydriodic acid, and the reaction with iodic acid to be described.

§ 352. Morphine (C₁₇H₁₇NO(OH)₂ + H₂O).—Morphine occurs in commerce as a white powder, sp. gr. 1·205, usually in the form of more or less perfect six-sided prisms, but sometimes in that of white silky needles. When heated in the subliming cell (described at pp. 257-8), faint nebulæ, resolved by high microscopic powers into minute dots, appear on the upper disc at 150°. As the temperature is raised the spots become coarser, and at 188° distinct crystals may be obtained, the best being formed at nearly 200°, at which temperature morphine begins distinctly to brown, melt, and carbonise. At temperatures below 188°, instead of minute dots, the sublimate may consist of white circular spots or foliated patterns. One part of morphine, according to P. Chastaing, is soluble at a temperature of 3° in 33,333 parts of water; at 22°, in 4545 parts; at 42°, 4280; and at 100°, 4562. It is scarcely soluble in ether or benzene. Absolute alcohol, according to Pettenkofer, dissolves in the cold one-fortieth of its weight; boiling, one-thirtieth. Amyl alcohol, in the cold, dissolves one-fourth per cent., and still more if the alkaloid be thrown out of an aqueous acid solution by ammonia in the presence of amyl alcohol; for under such circumstances the morphine has no time to become crystalline. According to Schlimpert, 1 part of morphine requires 60 of chloroform for solution; according to Pettenkofer, 175.

Morphine is easily soluble in dilute acids, as well as in solutions of the caustic alkalies and alkaline earths; carbonated alkalies and chloride of ammonium also dissolve small quantities. The acid watery, and the alcoholic solutions, turn the plane of polarisation to the left; for sulphuric, nitric, and hydrochloric acids [α]r = 89·8°; in alkaline solution the polarisation is less, [α]r = 45·22°. It is alkaline in reaction, neutralising acids fully; and, in fact, a convenient method of titrating morphine is by the use of a centinormal sulphuric acid—each c.c. equals 2·85 mgrms. of anhydrous morphine.

§ 353. The salts of morphine are for the most part crystalline, and are all bitter, neutral, and poisonous. They are insoluble in amylic alcohol, ether, chloroform, benzene, or petroleum ether.

Morphine meconate is one of the most soluble of the morphine salts; it is freely soluble in water. Of all salts this is most suitable for subcutaneous injection; it is the form in which the alkaloid exists in opium.

Morphine hydrochlorate (C₁₇H₁₉NO₃HCl) crystallises in silky fibres; it is readily soluble in alcohol, and is soluble in cold, more freely in boiling water. The purest morphine hydrochlorate is colourless, but that which is most frequently met with in commerce is fawn or buff-coloured.

Morphine acetate is a crystallisable salt, soluble in water or alcohol; it is in part decomposed by boiling the aqueous solution, some of the acetic acid escaping.

Morphine Tartrates.—These are readily soluble salts, and it is important to note that the morphine might escape detection, if the expert trusted alone to the usual test of an alkaloidal salt giving a precipitate when the solution is alkalised by the fixed or volatile alkalies; for the tartrates of morphine do not give this reaction, nor do they give any precipitate with calcic chloride. By adding a solution of potassium acetate in spirit, and also alcohol and a little acetic acid to the concentrated solution, the tartrate is decomposed, and acid tartrate of potassium is precipitated in the insoluble form; the morphine in the form of acetate remains in solution, and then gives the usual reactions.

The solubility of morphine salts in water and alcohol has been investigated by Mr. J. U. Lloyd. His results are as follows:—

Morphine Acetate.

11 ·70 parts of water by weight at 15·0° dissolve 1 part of morphine acetate.

61 ·5 parts of water by weight at 100° dissolve 1 part of morphine acetate.

68 ·30 parts of alcohol by weight (·820 specific gravity) at 15·0° dissolve 1 part of morphine acetate.

13 ·30 parts of alcohol by weight (·820 specific gravity) at 100° dissolve 1 part of morphine acetate.

Morphine Hydrochlorate.

23 ·40 parts of water dissolve at 15° 1 morphine hydrochlorate.

·51 part of water dissolves at 100° 1 morphine hydrochlorate.

62 ·70 parts of alcohol (·820 specific gravity) dissolve at 15° 1 morphine hydrochlorate.

30 ·80 parts of alcohol (·820 specific gravity) dissolve at 100° 1 morphine hydrochlorate.

Morphine Sulphate.

21 ·60 parts of water at 15° dissolve 1 morphine sulphate.

·75 part of water at 100° dissolves 1 morphine sulphate.

701 ·5 parts of alcohol (·820) at 15° dissolve 1 morphine sulphate.

144 ·00 parts of alcohol (·820) at 100° dissolve 1 morphine sulphate.

§ 354. Constitution of Morphine.—The chief facts bearing on the constitution of morphine are as follows:—

It certainly contains two hydroxyl groups, because by the action of acetic anhydride, acetyl morphine and diacetyl morphine, C₁₇H₁₈(CH₃CO)NO₃ and C₁₇H₁₇(CH₃CO)₂NO₃ are produced. The formation of the monomethyl ether of morphine (codeine), C₁₇H₁₇(OH)(OCH₃)NO, is also a testimony to the existence of hydroxyl groups. One of the hydroxyl groups has phenolic functions, the other alcoholic functions. By suitable oxidation morphine yields trinitrophenol (picric acid), and by fusion with an alkali, protocatechuic acid; both of these reactions suggest a benzene ring. On distilling with zinc dust phenanthrene, pyridine, pyrrol, trimethylamine, and ammonia are formed; evidence of a pyridine nucleus. If morphine is mixed with 10 to 15 times its weight of a 20 per cent. solution of potash, and heated at 180° for from four to six hours, air being excluded, a phenol-like compound is formed, and a volatile amine, ethylmethylamine (the amine boils at 34° to 35°, and its hydrochloride melts at 133°). This reaction is interpreted by Z. H. Skrauk[378] and L. Wiegmann to indicate that the nitrogen is directly connected with two alkyl groups—that is, ethyl and methyl.

G. N. Vis,[379] after a careful review of the whole of the reactions of morphine, has proposed the following constitutional formula as the one that agrees best with the facts:—

§ 355. Tests for Morphine.—(1.) One hundredth of a milligrm. of pure morphine gives a blue colour to a paste of ammonium molybdate in sulphuric acid; 20 mgrms. of ammonium molybdate are rubbed with a glass rod in a porcelain dish, and well mixed with 5 drops of pure strong sulphuric acid and the morphine in a solid form applied; titanic acid and tungstates give similar reactions.

(2.) Morphine possesses strong reducing properties; a little solid morphine dissolved in a solution of ferric chloride gives a Prussian blue precipitate when ferridcyanide solution is added. A number of ptomaines and other substances also respond to this test, so that in itself it is not conclusive.

(3.) Iodic Acid Test.—The substance supposed to be morphine is converted into a soluble salt by adding to acid reaction a few drops of hydrochloric acid, and then evaporating to dryness. The salt thus obtained is dissolved in as little water as possible—this, as in toxicological researches only small quantities are recovered, will probably be but a few drops. A little of the solution is now mixed with a very small quantity of starch paste, and evaporated to dryness at a gentle heat in a porcelain dish. After cooling, a drop of a solution of 1 part of iodic acid in 15 of water is added to the dry residue; and if even the ¹⁄₂₀₀₀₀ of a grain of morphine be present, a blue colour will be developed.

Another way of working the iodic acid test is to add the iodic acid solution to the liquid in which morphine is supposed to be dissolved, and then shake the liquid up with a few drops of carbon disulphide. If morphine be present, the carbon disulphide floats to the top distinctly coloured pink. Other substances, however, also set free iodine from iodic acid, and it has, therefore, been proposed to distinguish morphine from these by the after addition of ammonia. If ammonia is added to the solution, which has been shaken up with carbon disulphide, the pink or red colour of the carbon disulphide is deepened, if morphine was present; on the contrary, if morphine was not present, it is either discharged or much weakened.

Other Reactions.—There are some very interesting reactions besides the two characteristic tests just mentioned. If a saturated solution of chloride of zinc be added to a little solid morphine, and heated over the water-bath for from fifteen minutes to half-an-hour, the liquid develops a beautiful and persistent green colour. This would be an excellent test for morphine were it not for the fact that the colour is produced with only pure morphine. For example, I was unable to get the reaction from morphine in very well-formed crystals precipitated from ordinary laudanum by ammonia, the least trace of resinous or colouring-matter seriously interfering. By the action of nitric acid on morphine, the liquid becomes orange-red, and an acid product of the formula C₁₀H₉NO₉ is produced, which, when heated in a closed tube with water at 100°, yields trinitrophenol or picric acid. This interesting reaction points very decidedly to the phenolic character of morphine. On adding a drop of sulphuric acid to solid morphine in the cold, the morphine solution becomes of a faint pink; on gently warming and continuing the heat until the acid begins to volatilise, the colour changes through a series of brownish and indefinite hues up to black. On cooling and treating the black spot with water, a green solution is obtained, agreeing in hue with the same green produced by chloride of zinc. Vidali[380] has proposed the following test:—Morphine is dissolved in strong sulphuric acid, and a little arsenate of sodium is added; on gently warming, a passing blue colour develops; on raising the temperature higher, the liquid changes into green, then into blue, and finally again into green. Codeine acts very similarly. The following test originated with Siebold (American Journal of Pharmacy, 1873, p. 544):—The supposed morphine is heated gently with a few drops of concentrated sulphuric acid and a little pure potassic perchlorate. If morphine be present the liquid immediately takes a pronounced brown colour—a reaction said to be peculiar to morphine, and to succeed with ¹⁄₁₀ of a mgrm. In order to obtain absolutely pure perchlorate, potassic perchlorate is heated with hydrochloric acid so long as it disengages chlorine; it is then washed with distilled water, dried, and preserved for use. There is also a test known as “Pellagri’s”; it depends on the production of apomorphine. The suspected alkaloid is dissolved in a little strong hydrochloric acid, and then a drop of concentrated sulphuric acid is added, and the mixture heated for a little time from 100° to 120°, until it assumes a purple-black colour. It is now cooled, some hydrochloric acid again added, and the mixture neutralised with sodic carbonate. If morphine be present, on the addition of iodine in hydriodic acid, a cherry-red colour is produced, passing into green. Morphine and codeine are believed alone to give this reaction.

The acetate of morphine, and morphine itself, when added to ferric chloride solution, develop a blue colour. When 1 molecule of morphine is dissolved in alcohol, containing 1 molecule of sodium hydroxide, and 2 vols. of methyl iodide are added, and the mixture gently heated, a violent reaction sets in and the main product is codeine methiodide (C₁₇H₁₈NO₂OCH,MeI). If only half the quantity of methyl iodide is added, then free codeine is in small quantity produced; if ethyl iodide be substituted for methyl, a new base is formed homologous with codeine—codeine is therefore the methyl ether of morphine. If morphine is heated with iodide of methyl and absolute alcohol in a closed tube for half an hour at 100°, methyl iodide of morphine is obtained in colourless, glittering, quadratic crystals, easily soluble in water (C₁₇H₁₉NO₃MeI + H₂O); similarly the ethyl iodide compound can be produced.

If morphine is heated for from two to three hours in a closed tube with dilute hydrochloric acid, water is eliminated—

(C₁₇H₁₉NO₃ = C₁₇H₁₇NO₂ + H₂O),

and the hydrochlorate of apomorphine is produced. This succeeds when even ¹⁄₂ mgrm. is heated with ¹⁄₁₀ c.c. of strong HCl, and the tests for apomorphine applied.

If concentrated sulphuric acid be digested on morphine for twelve to fifteen hours (or heated for half an hour at 100°), on adding to the cooled violet-coloured solution either a crystal of nitrate of potash or of chlorate of potash, or a drop of dilute nitric acid, a beautiful violet-blue colour is produced, which passes gradually into a dark blood-red. ¹⁄₁₀₀ of a mgrm. will respond distinctly to this test. Fröhde’s reagent strikes with morphine a beautiful violet colour, passing from blue into dirty green, and finally almost vanishing. ¹⁄₂₀₀ of a mgrm. will respond to the test, but it is not itself conclusive, since papaverine and certain glucosides give an identical reaction.

§ 356. Symptoms of Opium and Morphine Poisoning.—The symptoms of opium and morphine poisoning are so much alike, that clinically it is impossible to distinguish them; therefore they may be considered together.

Action on Animals—Frogs.—The action of morphine or opium on frogs is peculiar: the animal at first springs restlessly about, and then falls into a condition extremely analogous to that seen in strychnine poisoning, every motion or external irritation producing a tetanic convulsion. This condition is, however, sometimes not observed. The tetanic stage is followed by paralysis of reflex movements and cessation of breathing, the heart continuing to beat.

Dogs.—0·2 to 0·5 grm. of morphine meconate, or acetate, injected directly into the circulation of a dog, shows its effects almost immediately. The dog becomes uneasy, and moves its jaws and tongue as if some peculiar taste were experienced; it may bark or utter a whine, and then in a minute or two falls into a profound sleep, which is often so deep that while it lasts—usually several hours—an operation may be performed. In whatever attitude the limbs are placed, they remain. The respiration is rapid and stertorous, and most reflex actions are extinguished. Towards the end of the sleep, any sudden noise may startle the animal, and when he wakes his faculties are evidently confused. A partial paralysis of the hind legs has often been noticed, and then the dog, with his tail and pelvis low, has something the attitude of the hyena. Hence this condition (first, I believe, noticed by Bernard) has been called the “hyenoid” state. If the dose is larger than 2 to 3 grms. (31 to 46 grains), the symptoms are not dissimilar, save that they terminate in death, which is generally preceded by convulsions.[381]

Goats.—According to Guinard, goats are proof against the narcotic influence of morphine. Large doses kill goats, but death is caused by interference with the respiratory function. A young goat weighing 30 kilos, showed little effect beyond a slightly increased cerebral excitability after two doses of 8 and 8·5 grms. respectively of morphine hydrochlorate had been administered by intravenous injection, the second being given an hour and a half after the first. To the same animal two days afterwards 195 grms. were administered in the same way, yet the goat recovered. The lethal dose for a goat seems to be no less than 1000 times that which will produce narcotism in man, and lies somewhere between 0·25 to 0·30 per kilo. of the body weight.[382]

Cats and the Felidæ.—According to Guinard,[383] morphine injected subcutaneously or intravenously into cats, in doses varying from 0·4 mgrm. to 90 mgrms. per kilo., never produces sleep or narcotic prostration. On the contrary, it causes a remarkable degree of excitement, increasing in intensity with the dose given. This excitement is evidently accompanied by disorder in the functions of the brain, and if the dose is large convulsions set in, ending in death. According to Milne-Edwards, the same symptoms are produced in lions and tigers.

Birds, especially pigeons, are able to eat almost incredible quantities of opium. A pigeon is said[384] to have consumed 801 grains of opium, mixed with its food, in fourteen days. The explanation of this is that the poison is not absorbed; for subcutaneous injections of salts of morphine act rapidly on all birds hitherto experimented upon.

§ 357. Physiological Action.—From experiments on animals, the essential action of morphine on the nervous and arterial systems has in some measure been examined. There is no very considerable action on the heart. The beats are first accelerated, then diminished in frequency; but very large doses introduced directly into the circulation at once diminish the pulsations, and no acceleration is noticed. The slowing may go on to heart-paralysis. The slowing is central in its origin, for on the vagi being cut, morphine always quickens. With regard to the peripheric ends of the vagi, small doses excite, large paralyse. If all the nerves going to the heart are divided, there is first a considerable acceleration, and then a slowing and weakening of the pulsations. The arterial blood-pressure, at first increased, is afterwards diminished. This increase of blood-pressure is noticed during the acceleration of the pulse, and also during some portion of the time during which the pulse is slowed. Stockman and D. B. Dott,[385] experimenting on rabbits and frogs, consider that a medium dose of morphine first of all depresses the spinal cord and then excites it, for tetanus follows. If morphine is in sufficient quantity thrown into the circulation then tetanus at once occurs. It would thus appear that depression and stimulation is entirely a matter of dosage. Gescheidlen, in his researches on the frog, found the motor nerves at first excited, and then depressed. When the doses were large, there was scarcely any excitement, but the reverse effect, in the neighbourhood of the place of application. According to other observers, the function of the motor nerves may be annihilated.[386] According to Meihuizen, reflex action, at first much diminished, is later, after several hours, normal, and later still again increased. The intestinal movements are transitorily increased. In the dog there has been noticed a greater flow of saliva than usual, and the flow of bile from the gall-bladder is diminished. The pupils in animals are mostly contracted, but, if convulsions occur towards death, they are dilated.

§ 358. Physiological Effect of Morphine Derivatives.—By introducing methyl, or amyl, or ethyl, into the morphine molecule, the narcotic action is diminished, while the tetanic effects are increased. Acetyl, diacetyl, benzoyl, and dibenzoyl morphine, morphine sulphuric ether, and nitrosomorphine are all weaker narcotics than morphine, but, on the other hand, they depress the functions of the spinal cord and bring on, in large doses, tetanus.

The introduction of two methyl groups into morphine, as in metho-codeine, C₁₇H₁₇MeNO(OH)-Me, entirely alters the physiological effect. This compound has an action on voluntary muscle causing gradual paralysis.

The chlorine derivatives, trichlormorphine and chlorcodeine, have the characteristic action of the morphine group on the central nervous system and, in addition, act energetically as muscle poisons, soon destroying the contractile power of the voluntary muscles with which they first come into contact at the place of injection, and more gradually affecting the other muscles of the body.[387]

§ 359. Action on Man.—There are at least three forms of opium poisoning:—(1) The common form, as seen in about 99 per cent. of cases; (2) A very sudden form, in which death takes place with fearful rapidity (the foudroyante variety of the French);[388] and (3) a very rare entirely abnormal form, in which there is no coma, but convulsions.

In the common form there are three stages, viz.:—(1) Excitement; (2) Narcosis; (3) Coma. In from half an hour to an hour[389] the first symptoms commence, the pulse is quickened, the pupils are contracted, the face flushes, and the hands and feet reddened,—in other words, the capillary circulation is active. This stage has some analogy to the action of alcohol; the ideas mostly flow with great rapidity, and instead of a feeling of sleepiness, the reverse is the case. It, however, insensibly, and more or less rapidly, passes into the next stage of heaviness and stupor. There is an irresistible tendency to sleep; the pulse and the respiration become slower; the conjunctivæ are reddened; the face and head often flushed. In some cases there is great irritability of the skin, and an eruption of nettle-rash. If the poison has been taken by the mouth, vomiting may be present. The bowels are usually—in fact almost invariably—constipated. There is also some loss of power over the bladder.

In the next stage, the narcosis deepens into dangerous coma; the patient can no longer be roused by noises, shaking, or external stimuli; the breathing is loud and stertorous; the face often pale; the body covered with a clammy sweat. The pupils are still contracted, but they may in the last hours of life dilate: and it is generally agreed that, if a corpse is found with the pupils dilated, this circumstance, taken in itself, does not contra-indicate opium or morphine poisoning. Death occasionally terminates by convulsion.

The sudden form is that in which the individual sinks into a deep sleep almost immediately—that is, within five or ten minutes—and dies in a few hours. In these rapid cases the pupils are said to be constantly dilated.

Examples of the convulsive form are to be sought among opium-eaters, or persons under otherwise abnormal conditions.

A man, forty years old, who had taken opiates daily since his twenty-second year—his dose being 6 grms. (92·4 grains) of solid opium—when out hunting, of which sport he was passionately fond, took cold, and, as a remedy, administered to himself three times his accustomed dose. Very shortly there was contraction of the left arm, disturbance of vision, pain in the stomach, faintness, inability to speak, and unconsciousness which lasted half an hour. Intermittent convulsions now set in, and pains in the limbs. There was neither somnolence nor delirium, but great agitation; repeated vomiting and diarrhœa followed. After five hours these symptoms ceased; but he was excessively prostrate.[390] There was complete recovery.

One may hazard a surmise that, in such a case, tolerance has been established for morphine, but not for other morphine alkaloids in the same degree, and that the marked nervous symptoms were in no small degree the effect of some of the homologous alkaloids, which, in such an enormous dose, would be taken in sufficient quantity to have a physiological action.

There are several instances of a relapsing or remittent form of poisoning—a form in which the patient more or less completely recovers consciousness, and then sinks back into a fatal slumber. One of the best known is the case of the Hon. Mrs Anson (January 1859), who swallowed an ounce and a half of laudanum by mistake. After remaining in a comatose condition for more than nine hours, she revived. The face became natural, the pulse steady. She was able to recognise her daughter, and in a thick voice to give an account of the mistake. But this lasted only ten minutes, when she again became comatose, and died in fourteen hours.[391]

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.

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.

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.

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.

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.

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.”

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]

§ 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]—

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]

§ 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]

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.

§ 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.