Bocarmé actually studied chemistry in order to prepare the alkaloid

himself, and, after having succeeded in enticing his victim to the

chateau of Bitremont, administered the poison forcibly. It acted

immediately, and death took place in five minutes. Bocarmé now attempted

to hide all traces of the nicotine by pouring strong acetic acid into

the mouth and over the body of the deceased. The wickedness and cruelty

of the crime were only equalled by the clumsy and unskilful manner of

its perpetration. The quantity of nicotine actually used in this case

must have been enormous, for Stas separated no less than ·4 grm. from

the stomach of the victim.

The second known case of nicotine-poisoning was that of a man who took

it for the purpose of suicide. The case is related by Taylor. It

occurred in June 1863. The gentleman drank an unknown quantity from a

bottle; he stared wildly, fell to the floor, heaving a deep sigh, and

died quietly without convulsion. The third case happened at

Cherbourg,[355] where an officer committed suicide by taking nicotine,

but how much had been swallowed, and what were the symptoms, are equally

unknown, for no one saw him during life.

[355] _Ann. d’Hygiène_, 1861, x. p. 404.

Poisoning by nicotine, pure and simple, then is rare. Tobacco-poisoning

is very common, and has probably been experienced in a mild degree by

every smoker in first acquiring the habit. Nearly all the fatal cases

are to be ascribed to accident; but criminal cases are not unknown.

Christison relates an instance in which tobacco in the form of snuff was

put into whisky for the purpose of robbery. In 1854, a man was accused

of attempting to poison his wife by putting snuff into her ale, but

acquitted. In another case, the father of a child, ten weeks old, killed

the infant by putting tobacco into its mouth. He defended himself by

saying that it was applied to make the child sleep.

In October 1855,[356] a drunken sailor swallowed (perhaps for the

purpose of suicide) his quid of tobacco, containing from about half an

ounce to an ounce. He had it some time in his mouth, and in half an hour

suffered from frightful tetanic convulsions. There was also diarrhœa;

the pupils were dilated widely; the heart’s action became irregular; and

towards the end the pupils again contracted. He died in a sort of

syncope, seven hours after swallowing the tobacco.

[356] _Edin. Med. Journ._, 1855.

§ 333. In 1829 a curious instance of poisoning occurred in the case of

two girls, eighteen years of age, who suffered from severe symptoms of

tobacco-poisoning after drinking some coffee. They recovered; and it was

found that tobacco had been mixed with the coffee-berries, and both

ground up together.[357]

[357] Barkhausen, _Pr. Ver. Ztg._, v. 17, p. 83, 1838.

Accidents have occurred from children playing with old pipes. In

1877[358] a child, aged three, used for an hour an old tobacco-pipe, and

blew soap bubbles with it. Symptoms of poisoning soon showed themselves,

and the child died in three days.

[358] _Pharm. Journ._ [3], 377, 1877.

Tobacco-juice, as expressed or distilled by the heat developed in the

usual method of smoking, is very poisonous. Sonnenschein relates the

case of a drunken student, who was given a dram to drink, into which his

fellows had poured the juice from their pipes. The result was fatal.

Death from smoking is not unknown.[359] Helwig saw death follow in the

case of two brothers, who smoked seventeen and eighteen German pipefuls

of tobacco. Marshall Hall[360] records the case of a young man, nineteen

years of age, who, after learning to smoke for two days, attempted two

consecutive pipes. He suffered from very serious symptoms, and did not

completely recover for several days. Gordon has also recorded severe

poisoning from the consecutive smoking of nine cigars. The external

application of the leaf may, as already shown in the case of the horse,

produce all the effects of the internal administration of nicotine. The

old instance, related by Hildebrand, of the illness of a whole squadron

of hussars who attempted to smuggle tobacco by concealing the leaf next

to their skin, is well known, and is supported by several recent and

similar cases. The common practice of the peasantry, in many parts of

England, of applying tobacco to stop the bleeding of wounds, and also as

a sort of poultice to local swellings, has certainly its dangers. The

symptoms--whether nicotine has been taken by absorption through the

broken or unbroken skin, by the bowel, by absorption through smoking, or

by the expressed juice, or the consumption of the leaf itself--show no

very great difference, save in the question of time. Pure nicotine acts

with as great a rapidity as prussic acid; while if, so to speak, it is

entangled in tobacco, it takes more time to be separated and absorbed;

besides which, nicotine, taken in the concentrated condition, is a

strong enough base to have slight caustic effects, and thus leaves some

local evidences of its presence. In order to investigate the effects of

pure nicotine, Dworzak and Heinrich made auto-experiments, beginning

with 1 mgrm. This small dose produced unpleasant sensations in the mouth

and throat, salivation, and a peculiar feeling spreading from the region

of the stomach to the fingers and toes. With 2 mgrms. there was

headache, giddiness, numbness, disturbances of vision, torpor, dulness

of hearing, and quickened respirations. With 3 to 4 mgrms., in about

forty minutes there was a great feeling of faintness, intense

depression, weakness, with pallid face and cold extremities, sickness,

and purging. One experimenter had shivering of the extremities and

cramps of the muscles of the back, with difficult breathing. The second

suffered from muscular weakness, fainting, fits of shivering, and

creeping sensations about the arms. In two or three hours the severer

effects passed away, but recovery was not complete for two or three

days. It is therefore evident, from these experiments and from other

cases, that excessive muscular prostration, difficult breathing, tetanic

cramps, diarrhœa, and vomiting, with irregular pulse, represent both

tobacco and nicotine poisoning. The rapidly-fatal result of pure

nicotine has been already mentioned; but with tobacco-poisoning the case

may terminate lethally in eighteen minutes. This rapid termination is

unusual, with children it is commonly about an hour and a half, although

in the case previously mentioned, death did not take place for two days.

[359] The question as to whether there is much nicotine in tobacco-smoke

cannot be considered settled; but it is probable that most of the

poisonous symptoms produced are referable to the pyridene bases of the

general formula (C_{n}H_{2n-5}N). Vohl and Eulenberg (_Arch. Pharmac._,

2, cxlvi. p. 130) made some very careful experiments on the smoke of

strong tobacco, burnt both in pipes and also in cigars. The method

adopted was to draw the smoke first through potash, and then through

dilute sulphuric acid. The potash absorbed prussic acid, hydric

sulphide, formic, acetic, propionic, butyric, valeric, and carbolic

acids; while in the acid the bases were fixed, and these were found to

consist of the whole series of pyridene bases, from pyridene (C₅H₅N),

boil. point 117°, picoline (C₆H₇N), boil. point 133°, lutidine (C₇H₉N),

boil. point 154°, upwards. When smoked in pipes, the chief yield was

pyridene; when in cigars, collidine (C₈H₁₁N); and in general,

pipe-smoking was found to produce a greater number of volatile bases.

The action of these bases has been investigated by several observers.

They all have a special action on the organism, and all show an increase

in physiological activity as the series is ascended. The lowest produce

merely excitement from irritation of the encephalic nervous centres, and

the highest, paralysis of those centres. Death proceeds from gradual

failure of the respiratory movements, leading to asphyxia--(Kendrick and

Dewar, _Proc. Roy. Soc._, xxii. 442; xxiii. 290). The most recent

experimental work is that of A. Gautier; he found that tobacco smoked in

a pipe produced basic compounds, a large quantity of nicotine, and a

higher homologue of nicotine, C₁₁H₁₆N₂, which pre-exists in tobacco

leaves, and a base C₆H₉NO, which seems to be a hydrate of

picoline--(_Compt. Rend._, t. cxv. p. 992, 993). The derivatives of the

pyridene series are also active. The methiodides strongly excite the

brain and paralyse the extremities. A similar but more energetic action

is exerted by the ethyl and allyl derivatives; the iodyallyl derivatives

are strong poisons. Methylic pyridene carboxylate is almost inactive,

but the corresponding ammonium salt gives rise to symptoms resembling

epilepsy--(Ramsay, _Phil. Mag._, v. 4, 241). One member of the pyridene

series β-lutidine has been elaborately investigated by C. Greville

Williams and W. H. Waters--(_Proc. Roy. Soc._, vol. xxxii. p. 162,

1881). They conclude that it affects the heart profoundly, causing an

increase in its tonicity, but the action is almost confined to the

ventricles. The auricles are but little affected, and continue to beat

after the ventricles have stopped. The rate of the heart’s beat is

slowed, and the inhibitory power of the vagus arrested. By its action on

the nervous cells of the spinal cord, it in the first place lengthens

the time of reflex action, and then arrests that function. Finally, they

point out that it is antagonistic to strychnine, and may be successfully

employed to arrest the action of strychnine on the spinal cord.

[360] _Edin. Med. and Surg. Jour._, xii., 1816.

§ 334. =Physiological Action.=--Nicotine is absorbed into the blood and

excreted unchanged, in part by the kidneys and in part by the saliva

(_Dragendorff_). According to the researches of Rosenthal and

Krocker,[361] nicotine acts energetically on the brain, at first

exciting it, and then lessening its activity; the spinal marrow is

similarly affected. The convulsions appear to have a cerebral origin;

paralysis of the peripheral nerves follows later than that of the nerve

centres, whilst muscular irritability is unaffected. The convulsions are

not influenced by artificial respiration, and are therefore to be

considered as due to the direct influence of the alkaloid on the nervous

system. Nicotine has a striking influence on the respiration, first

quickening, then slowing, and lastly arresting the respiratory

movements: section of the vagus is without influence on this action.

The cause of death is evidently due to the rapid benumbing and paralysis

of the respiratory centre. Death never follows from heart-paralysis,

although nicotine powerfully influences the heart’s action, small doses

exciting the terminations of the vagus in the heart, and causing a

slowing of the beats. Large doses paralyse both the controlling and

exciting nerve-centres of the heart; the heart then beats fast,

irregularly, and weakly. The blood-vessels are first narrowed, then

dilated, and, as a consequence, the blood-pressure first rises, then

falls. Nicotine has a special action on the intestines. As O. Nasse[362]

has shown, there is a strong contraction of the whole tract, especially

of the small intestine, the lumen of which may be, through a continuous

tetanus, rendered very small. This is ascribed to the peripheral

excitation of the intestinal nerves and the ganglia. The uterus is also

excited to strong contraction by nicotine; the secretions of the bile

and saliva are increased.

[361] _Ueber die Wirkung des Nicotines auf den thierischen Organismus_,

Berlin, 1868.

[362] _Beiträge zur Physiologie der Darmbewegung, Leipsic_, 1866.

§ 335. =Fatal Dose.=--The fatal dose for dogs is from ½ to 2 drops; for

rabbits, a quarter of a drop; for an adult not accustomed to tobacco the

lethal dose is probably 6 mgrms.

§ 336. =Post-mortem Appearances.=--There seem to be no appearances so

distinctive as to be justly ascribed to nicotine or tobacco-poisoning

and no other.

A more or less fluid condition of the blood, and, generally, the signs

of death by the lungs, are those most frequently found. In

tobacco-poisoning, when the leaves themselves have been swallowed, there

may be some inflammatory redness of the stomach and intestine.

§ 337. =Separation of Nicotine from Organic Matters, &c.=--The process

for the isolation of nicotine is precisely that used for coniine (see p.

269). It appears that it is unaltered by putrefaction, and may be

separated and recognised by appropriate means a long time after death.

Orfila detected it in an animal two or three months after death; Melsens

discovered the alkaloid unmistakably in the tongues of two dogs, which

had been buried in a vessel filled with earth for seven years; and it

has been found, by several experiments, in animals buried for shorter

periods. Nicotine should always be looked for in the tongue and mucous

membrane of the mouth, as well as in the usual viscera. The case may be

much complicated if the person supposed to be poisoned should have been

a smoker; for the defence would naturally be that there had been either

excessive smoking or chewing, or even swallowing accidentally a quid of

tobacco.[363] A ptomaine has been discovered similar to nicotine.

Wolckenhaar separated also an alkaloid not unlike nicotine from the

corpse of a woman addicted to intemperate habits; but this base was not

poisonous, nor did it give any crystals when an ethereal solution was

added to an ether solution of iodine. It will be well always to support

the chemical evidence by tests on animal life, since the intensely

poisonous action of nicotine seems not to be shared by the nicotine-like

ptomaines.

[363] In an experiment of Dragendorff’s, nicotine is said to have been

detected in 35 grms. of the saliva of a person who had half an hour

previously smoked a cigar.

3. PITURIE.[364]

[364] See “The Alkaloid from Piturie,” by Prof. Leversidge, _Chem.

News_, March 18 and 25, 1881.

§ 338. Piturie (C₆H₈N) is a liquid, nicotine-like alkaloid, obtained

from the _Duboisia hopwoodii_, a small shrub or tree belonging to

the natural order _Solanaceæ_, indigenous in Australia. The natives

mix piturie leaves with ashes from some other plant, and chew them.

Piturie is obtained by extracting the plant with boiling water

acidified with sulphuric acid, concentrating the liquid by

evaporation, and then alkalising and distilling with caustic soda,

and receiving the distillate in hydrochloric acid. The solution of

the hydrochlorate is afterwards alkalised and shaken up with ether,

which readily dissolves out the piturie. The ether solution of

piturie is evaporated to dryness in a current of hydrogen, and the

crude piturie purified by distillation in hydrogen, or by changing

it into its salts, and again recovering, &c. It is clear and

colourless when pure and fresh, but becomes yellow or brown when

exposed to air and light. It boils and distils at 243° to 244°. It

is soluble in all proportions in alcohol, water, and ether; its

taste is acrid and pungent; it is volatile at ordinary temperatures,

causing white fumes with hydrochloric acid; it is very irritating to

the mucous membranes, having a smell like nicotine at first, and

then, when it becomes browner, like pyridine. It forms salts with

acids, but the acetate, sulphate, and hydrochlorate are varnish-like

films having no trace of crystallisation; the oxalate is a

crystalline salt. Piturie gives precipitates with mercuric chloride,

cupric sulphate, gold chloride, mercur-potassic iodide, tannin, and

an alcoholic solution of iodine. If an ethereal solution of iodine

is added to an ethereal solution of piturie, a precipitate of

yellowish-red needles, readily soluble in alcohol, is deposited. The

iodine compound melts at 110°, while the iodine compound of nicotine

melts at 100°. Piturie is distinguished from coniine by its aqueous

solution not becoming turbid either on heating or on the addition of

chlorine water; it differs from picoline in specific gravity,

picoline being ·9613 specific gravity at 0°, and piturie sinking in

water; it differs from aniline by not being coloured by chlorinated

lime. From nicotine it has several distinguishing marks, one of the

best being that it does not change colour on warming with

hydrochloric acid and the addition to the mixture afterwards of a

little nitric acid. The physiological action seems to be but little

different from that of nicotine. It is, of course, poisonous, but as

yet has no forensic importance.

4. SPARTEINE.

§ 339. In 1851 Stenhouse[365] separated a poisonous volatile

alkaloid from _Spartium scoparium_, the common broom, to which he

gave the name of sparteine. At the same time a crystalline

non-poisonous substance, _scoparin_, was discovered.

[365] _Phil. Trans._, 1851.

Sparteine is separated from the plant by extraction with sulphuric

acid holding water, and then alkalising the acid solution and

distilling: it has the formula (C₁₅H₂₆N₂), and belongs to the class

of tertiary diamines. It is a clear, thick, oily substance, scarcely

soluble in water, to which it imparts a strong, alkaline reaction;

it is soluble in alcohol, in ether, and chloroform; insoluble in

benzene and in petroleum; it boils at 288°. Sparteine neutralises

acids fully, but the oxalate is the only one which can be readily

obtained in crystals. It forms crystalline salts with platinic

chloride, with gold chloride, with mercuric chloride, and with zinc

chloride. The picrate is an especially beautiful salt, crystallising

in long needles, which, when dried and heated, explode. On sealing

sparteine up in a tube with ethyl iodide and alcohol, and heating to

100° for an hour, ethyl sparteine iodide separates in long,

needle-like crystals, which are somewhat insoluble in cold alcohol.

=Effect on Animals.=--A single drop kills a rabbit; the symptoms are

similar to those produced by nicotine, but the pupils are

dilated.[366]

[366] To the nicotine group, gelsemine (C₂₄H₂₈N₂O₄) and oxalathylin

(C₆H₁₀N₂) also belong, in a physiological sense, but gelsemine, like

sparteine, dilates the pupil.

5. ANILINE.

§ 340. =Properties.=--Aniline or amido-benzol (C₆H₅NH₂) is made by

the reduction of nitro-benzol. It is an oily fluid, colourless when

quite pure, but gradually assuming a yellow tinge on exposure to the

air. It has a peculiar and distinctive smell. It boils at 182·5°,

and can be congealed by a cold of 8°. It is slightly soluble in

water, 100 parts of water at 16° retaining about 3 of aniline, and

easily soluble in alcohol, ether, and chloroform. It does not blue

red-litmus paper, but nevertheless acts as a weak alkali, for it

precipitates iron from its salts. It forms a large number of

crystalline salts. The hydrochloride crystallises in white plates,

and has a melting-point of 192°. The platinum compound has the

formula of (C₆H₅NH₂HCl)₂PtCl₄, and crystallises in yellow needles.

§ 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.

[367] _Beiträge zur Tox. des Anilins. Inaug.-Diss._, Dorpat, 1888.

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.

[368] See also a case reported by K. Dehio, in which a person drank 10

grms. and recovered, _Ber. klinis. Wochen._, 1888, Nr. 1.

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, C₁₇H₁₇NO₂ } By dehydration of morphine and codeine

Apocodeine, C₁₈H₁₉NO₂ } respectively.

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:--

[369] _Year Book of Pharmacy_, 1876.

=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]

[370] _Pharm. Journal_, xix. 45, 82; xxii. 746. Wright and Farr,

_Chemist and Druggist_, 1893, i. 78.

=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]

[371] Other methods of opium assay have been published: see Mr. A. B.

Prescott’s method (_Proceedings of Amer. Pharm. Assoc._, 1878); Allen

(_Commercial Org. Analysis_, vol. ii. p. 473); E. R. Squibb’s

modification of Flückiger’s method (_Pharm. Journ._ (3), xii. p. 724); a

rapid mode of opium assay, MM. Portes and Lanjlois (_Journ. de Pharm. et

de Chim._, Nov. 1881); _Year Book of Pharmacy_, 1882.

To the above may be added--(1.) _Schacht’s Method._--5 to 10 grms. of

dry, finely-powdered opium are digested with sufficient distilled water

to make a thin pulp. After twenty-four hours the whole is thrown on a

weighed filter, and washed until the washings are almost colourless and

tasteless. The portion insoluble in water is dried at 100° and weighed;

in good opium this should not exceed 40 per cent. The filtrate is

evaporated until it is about one-fifth of the weight of the opium taken

originally; cooled, filtered, and treated with pure animal charcoal,

until the dark brown colour is changed into a brownish-yellow. The

liquid is then refiltered, precipitated with a slight excess of ammonia,

allowed to stand in an open vessel until all odour of ammonia

disappears, and at the same time frequently stirred, in order that the

precipitate may not become crystalline--a form which is always more

difficult to purify. The precipitate is now collected on a tared filter,

washed, dried, and weighed. With an opium containing 10 per cent. of

morphine, its weight is usually 14 per cent. A portion of the

precipitate is then detached from the filter, weighed, and exhausted,

first with ether, and afterwards with boiling alcohol (0·81 specific

gravity). Being thus purified from narcotine, and containing a little

colouring-matter only, it may now be dried and weighed, and the amount

of morphine calculated, on the whole, from the data obtained.

(2.) _Fleury_ has proposed a titration by oxalic acid as follows:--2

grms. of the powdered opium are macerated a few hours with 8 c.c. of

aqueous oxalate of ammonia, brought on a filter, and washed with 5 c.c.

of water. To the filtrate an equal volume of 80 per cent. alcohol and

ammonia to alkaline reaction is added; and, after standing twenty-four

hours in a closed flask, it is filtered, and the flask rinsed out with

some c.c. of 40 per cent. alcohol. The filter, with its contents, after

drying, is placed in the same flask (which should not be cleansed), a

few drops of alcoholic logwood solution are added, with an excess of

oxalic acid solution of known strength, the whole being made up to 100

c.c. This is divided into two parts, and the excess of acid titrated

back with diluted soda-lye. If the oxalic acid solution is of the

strength of 4·42 grms. to the litre, every c.c. of the oxalic acid

solution which has become bound up with morphine, corresponds to 0·02

grm. of morphine.

§ 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.

[372] _Year Book of Pharmacy_, 1882.

=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.

[373] _Op. cit._

=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 ½ 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 5½ 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 1½ 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.

[374] If made according to Dr. Paris’ formula, 1⅙ grains in an ounce.

=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]

[375] It may be regarded as a purified alcoholic solution of meconate of

morphia, with a little excess of acid, and of about the same strength as

laudanum.--_Taylor._

=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, ½ lb.; good verjuice,[376] 3 pints; and nutmeg,

1½ oz.; boiled down to a syrup thickness; ¼ 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.

[376] Verjuice is the juice of the wild crab.

=“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 „

Oil of aniseed, 3 „

Oil of nutmeg, 2 „

Oil of peppermint, 1 „

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 „

Tincture of capsicum, ½ „

Hydrochlorate of morphine, 8 grains.

Scheele’s prussic acid, 12 drops

Tincture of Indian hemp, 1 drachm.

Treacle, 1 „

=Atkinson’s Infant Preserver=--

Carbonate of magnesia, 6 drachms.

White sugar, 2 ounces

Oil of aniseed, 20 drops.

Spirit of sal-volatile, 2½ drachms.

Laudanum, 1 „

Syrup of saffron, 1 ounce.

Caraway water, to make up, 1 pint.

=Boerhave’s Odontalgic Essence=--

Opium, ½ drachm.

Oil of cloves, 2 „

Powdered camphor, 5 „

Rectified spirit, 1½ 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 Total

above

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 Total

above

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.

[377] See Dr. Chevers’s _Jurisprudence_, 3rd ed., 232 _et seq._

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. (¼ 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 ¼ grain.

The dose of solid opium for a horse is from 1·77 grm. to 7·08 grms. (½

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. (¼ 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 ⅛ 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.

[378] _Monatsb._, x. 110-114.

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:--

CH--CH--CH--CH--CH----------------C--CH--CH

| | | | | |

CH--CH--CH--O NMe--CH₂--CH(OH)--C--CH--CH

[379] _J. pr. Chemie_ (2), xlvii. 584. Knorr’s formula is--

CHOH--CHO--CH₂

/ | \

OH.C₁₀H₅ | >

\ | /

CH₂---CH.NMeCH₂

_Ber._, xxii. 1113-1119.

§ 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.

[380] D. Vidali, _Bull. Farmaceut._, Milano, 1881, p. 197; D. E. Dott,

_Year Book of Pharmacy_, 1882.

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 ½ 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]

[381] MM. Grasset and Amblard have studied the action of morphine in

causing convulsions in the mammalia. They found that if small doses of

hydrochlorate of morphine (from 1 to 15 centigrammes) are administered

to dogs, the brief sleep which is produced may be accompanied by partial

muscular contractions (in one paw, for instance), which are renewed at

variable intervals. Then occur true convulsive shocks in the whole body

or in the hind limbs. After an interval, the phenomena recur in more

intense degree, and are followed by true convulsions. Regularly, ten or

sixteen times a minute, at each inspiration, the hind limbs present a

series of convulsive movements, which may become general. Sometimes they

are excited by external stimulation, but they are usually spontaneous.

The sleep may continue profound during this convulsive period, or it may

become distinctly lighter. These convulsive phenomena may continue, with

intervals, for an hour. Differences are observed with different animals;

but the chief characters of the phenomena are as described. In certain

animals, and with small doses, there may be a brief convulsive phase at

the commencement of the sleep, but it is much less constant than the

later period of spasm. These convulsions, the authors believe, have not

previously been described, except as a consequence of very large doses,

amounting to grammes. The period of cerebral excitement, described by

Claude Bernard as occurring at the commencement of the sleep from

morphine, is a phenomenon of a different order. The conclusions drawn

from the experiments are--(1) That morphia is not diametrically opposed

to thebaine, as is often stated, since it has, to a certain degree, the

convulsive properties of the latter alkaloid. (2) That the excitomotor

action of opium cannot be exclusively attributed to the convulsive

alkaloids, but is, in fact, due to those which are soporific. According

to the ordinary composition of opium, 5 centigrammes of morphine

represent about a milligramme of thebaine. But these experiments show

that the quantity of morphine has a much more powerful convulsive action

than a milligramme of thebaine. (3) There is not the supposed antagonism

between the action of morphine on the frog and on the mammalia. (4) The

researches hitherto undertaken on the antagonism between morphine and

other agents need to be repeated, and a separate study made of the

substances which antagonise the convulsive and soporific action.

=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]

[382] _Compt. Rend._, t. cxvi. pp. 520-522.

=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.

[383] _Compt. Rend._, t. cxi. pp. 981-983. The _bovine_ animals also get

excited, and no narcotic effect is produced by dosing them with

morphine.--_Compt. Rend. Soc. de Biologie_, t. iv., v.

=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.

[384] Hermann’s _Lehrbuch der exper. Toxicologie_, p. 374.

§ 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.

[385] _Brit. Med. Journ._ (2), 1890, 189-192.

[386] _Arch. f. d. Ges. Physiol._, vii. p. 201.

§ 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]

[387] R. Stockman and Dott, _Brit. Med. Journ._ (2), 1890, 189-192.

§ 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.

[388] Tardieu, _Étude Méd. Légale sur l’Empoisonnement._

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.

[389] In a remarkable case related by Taylor, a lady took a large dose

(supposed to be 1½ oz.) of laudanum, and there were no symptoms for four

and a half hours. She died in twenty-two hours.

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.

[390] Demontporcellet, _De l’Usage Quotidien de l’Opium_, Paris, 1874.

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]

[391] Taylor, _op. cit._

In a Swedish case quoted by Maschka,[392] a girl, nine years old, in

weak health and suffering from slight bronchitis, had been given a

non-officinal acetate of morphia lozenge, which was supposed to contain

5 mgrms. (·075 grain) of morphine acetate. She took the lozenge at eight

in the evening; soon slept, woke at ten, got out of bed, laughed,

talked, and joked with the nurse, again got into bed, and very quickly

fell asleep. At four A.M. the nurse came and found her breathing with a

rattling sound, and the physician, who arrived an hour later, found the

girl in a state of coma, with contracted pupils, breathing stertorously,

and the pulse scarcely to be felt. Despite all attempts to rouse the

patient, she died at eight in the morning, twelve hours after taking the

lozenge.

[392] Maschka’s _Handbuch_, Band ii. p. 438; also Svenska, _Läk-Sällsk.

Förhandl._, Apr. 1, p. 90; Apr. 8, p. 160, 1873. For other cases see

Nasmyth, _Edin. Med. Journ._, Dec. 1878; Kirby, _Dub. Med. Press_, Dec.

24, 1845; W. Boyd Muschet, _Med. Times and Gaz._, March 20, 1858.

The _post-mortem_ examination showed some hyperæmia of the brain and

serous effusion in the ventricles, and there was also tubercle in the

pleura. Three lozenges similar to the one taken by the patient were

chemically investigated by Hamberg, who found that the amount of acetate

was very small, and that the lozenges, instead of morphine acetate,

might be considered as prepared with almost pure morphine; the content

in the three of morphine being respectively 35, 37, and 42 mgrms. (that

is, from half a grain to three-fifths of a grain). There was a

difference of opinion among the experts as to whether in this case the

child died from morphine poisoning or not--a difference solely to be

attributed to the waking up of the child two hours after taking the

poison. Now, considering the great probability that a large dose for a

weakly child of that age had been taken, and that this is not the only

case in which a relapse has occurred, it seems just to infer that it was

really a case of poisoning.

As unusual symptoms (or rather sequelæ) may be noted in a few cases,

hemiplegia, which soon passes off; a weakness of the lower extremities

may also be left, and inability to empty the bladder thoroughly; but

usually on recovery from a large dose of opium, there is simply

heaviness of the head, a dry tongue, constipation, and loss of appetite.

All these symptoms in healthy people vanish in a day or two. There have

also been noticed slight albuminuria, eruptions on the skin, loss of

taste, and numbness of parts of the body.

Opium, whether taken in substance, or still more by subcutaneous

injection, in some individuals constantly causes faintness. In my own

case, I have several times taken a single grain of opium to relieve

either pain or a catarrh; almost invariably within an hour afterwards

there has been great coldness of the hands and feet, lividity of the

face, a feeling of deadly faintness followed by vomiting; this stage

(which has seldom lasted more than half an hour) passed, the usual

narcotic effects have been produced.

Some years ago I injected one-sixth of a grain of morphine hydrochlorate

subcutaneously into an old gentleman, who was suffering from acute

lumbago, but was otherwise healthy, and had no heart disease which could

be detected; the malady was instantly relieved, and he called out, “I am

well; it is most extraordinary.” He went out of the front door, and

walked some fifty yards, and then was observed to reel about like a

drunken man. He was supported back and laid in the horizontal posture;

the face was livid, the pulse could scarcely be felt, and there was

complete loss of consciousness. This state lasted about an hour, and

without a doubt the man nearly died. Medical men in practice, who have

been in the habit of using hypodermic injections of morphine, have had

experiences very similar to this and other cases, and although I know of

no actual death, yet it is evident that morphine, when injected

hypodermically even in a moderate dose, may kill by syncope, and within

a few minutes.[393] Absorption by hypodermic administration is so rapid

that by the time, or even before the needle of the syringe is withdrawn,

a contraction of the pupil may be observed.

[393] See a case of morphia poisoning by hypodermic injection, and

recovery, by Philip E. Hill, M.R.C.S., _Lancet_, Sept. 30, 1882. In this

instance a third of a grain introduced subcutaneously caused most

dangerous symptoms in a gardener, aged 48.

Opium or morphine is poisonous by whatever channel it gains access to

the system, the intestinal mucous membrane absorbs it readily, and

narcotic effects may be produced by external applications, whether a

wound is present or not. A case of absorption of opium by a wound is

related in Chevers’s _Jurisprudence_.[394] A Burman boy, about nine or

ten years of age, was struck on the forehead by a brick-bat, causing a

gaping wound about an inch long; his parents stuffed the wound with

opium. On the third day after the accident, and the opium still

remaining in the wound, he became semi-comatose, and, in short, had all

the symptoms of opium narcosis; with treatment he recovered. The

unbroken skin also readily absorbs the drug. Tardieu states that he had

seen 30 grms. of laudanum, applied on a poultice to the abdomen, produce

death. Christison has also cited a case in which a soldier suffered from

erysipelas, and died in a narcotic state, apparently produced from the

too free application of laudanum to the inflamed part.

[394] Third ed., p. 228.

To these cases may be added the one cited by Taylor, in which a druggist

applied 30 grains of morphine to the surface of an ulcerated breast, and

the woman died with all the symptoms of narcotic poisoning ten hours

after the application--an event scarcely surprising. It is a curious

question whether sufficient of the poison enters into the

secretions--_e.g._, the milk--to render it poisonous. An inquest was

held in Manchester, Nov. 1875, on the body of a male child two days old,

in which it seemed probable that death had occurred through the mother’s

milk. She was a confirmed opium-eater, taking a solid ounce per week.

§ 360. =Diagnosis of Opium Poisoning.=--The diagnosis is at times

between poisoning by opium or other narcotic substances, at others,

between opium and disease. Insensibility from chloral, from alcohol,

from belladonna or atropine, and from carbon oxide gas, are all more or

less like opium poisoning. With regard to chloral, it may be that only

chemical analysis and surrounding circumstances can clear up the matter.

In alcohol poisoning, the breath commonly smells very strongly of

alcohol, and there is no difficulty in separating it from the contents

of the stomach, &c., besides which the stomach is usually red and

inflamed. Atropine and belladonna invariably dilate the pupil, and

although just before death opium has the same effect, yet we must hold

that mostly opium contracts, and that a widely-dilated pupil during life

would, _per se_, lead us to suspect that opium had not been used,

although, as before mentioned, too much stress must not be laid upon the

state of the pupils. In carbon oxide, the peculiar rose-red condition of

the body affords a striking contrast to the pallor which, for the most

part, accompanies opium poisoning. In the rare cases in which

convulsions are a prominent symptom, it may be doubtful whether opium or

strychnine has been taken, but the convulsions hitherto noticed in opium

poisoning seem to me to have been rather of an epileptiform character,

and very different from the effects of strychnine. No rules can be laid

down for cases which do not run a normal course; in medicine such are

being constantly met with, and require all the care and acumen of the

trained observer. Cases of disease render a diagnosis often extremely

difficult, and the more so in those instances in which a dose of

laudanum or other opiate has been administered. In a case under my own

observation, a woman, suffering from emphysema and bronchitis, sent to a

chemist for a sleeping draught, which she took directly it arrived. A

short time afterwards she fell into a profound slumber, and died within

six hours. The draught had been contained in an ounce-and-a-half bottle;

the bottle was empty, and the druggist stated in evidence that it only

contained 20 minims of laudanum, 10 grains of potassic bromide, and

water. On, however, diluting the single drop remaining in the bottle,

and imitating its colour with several samples of laudanum diluted in the

same way, I came to the conclusion that the quantity of laudanum which

the bottle originally contained was far in excess of that which had been

stated, and that it was over 1 drachm and under 2 drachms. The body was

pallid, the pupils strongly contracted, the vessels of the brain

membranes were filled with fluid blood, and there was about an ounce of

serous fluid in each ventricle. The lungs were excessively

emphysematous, and there was much secretion in the bronchi; the liver

was slightly cirrhotic. The blood, the liver, and the contents of the

stomach were exhaustively analysed with the greatest care, but no trace

of morphine, narcotine, or meconic acid could be separated, although the

woman did not live more than six hours after taking the draught. I gave

the opinion that it was, in the woman’s state, improper to prescribe a

sedative of that kind, and that probably death had been accelerated, if

not directly caused, by opium.

Deaths by apoplexy will only simulate opium-poisoning during life; a

_post-mortem_ examination will at once reveal the true nature of the

malady. In epilepsy, however, it is different, and more than once an

epileptic fit has occurred and been followed by coma--a coma which

certainly cannot be distinguished from that produced by a narcotic

poison. Death in this stage may follow, and on examining the body no

lesion may be found.

§ 361. =Opium-eating.=--The consumption of opium is a very ancient

practice among Eastern nations, and the picture, drawn by novelist and

traveller, of poor, dried-up, yellow mortals addicted to this vice, with

their faculties torpid, their skin hanging in wrinkles on their wasted

bodies, the conjunctivæ tinged with bile, the bowels so inactive that

there is scarcely an excretion in the course of a week, the mental

faculties verging on idiocy and imbecility, is only true of a percentage

of those who are addicted to the habit. In the _British Medical Journal_

for 1894, Jan. 13 and 20, will be found a careful digest of the

evidence collated from 100 Indian medical officers, from which it

appears that opium is taken habitually by a very large number of the

population throughout India, those who are accustomed to the drug taking

it in quantities of from 10 to 20 grains in the twenty-four hours; so

long as this amount is not exceeded they do not appear to suffer

ill-health or any injurious effect. The native wrestlers even use it

whilst training. The habitual consumption of opium by individuals has a

direct medico-legal bearing. Thus in India, among the Rajpoots, from

time immemorial, infused opium has been the drink both of reconciliation

and of ordinary greeting, and it is no evidence of death by poison if

even a considerable quantity of opium be found in the stomach after

death, for this circumstance taken alone would, unless the history of

the case was further known, be considered insufficient proof. So, again,

in all climates, and among all races, it is entirely unknown what

quantity of an opiate should be considered a poisonous dose for an

opium-eater. Almost incredible quantities have, indeed, been consumed by

such persons, and the commonly-received explanation, that the drug, in

these cases, passes out unabsorbed, can scarcely be correct, for Hermann

mentions the case of a lady of Zurich who daily injected subcutaneously

1 to 2 grms. (15-31 grains) of a morphine salt. In a case of uterine

cancer, recorded by Dr. W. C. Cass,[395] 20 grains of morphine in the

twelve hours were frequently used subcutaneously; during thirteen months

the hypodermic syringe was used 1350 times, the dose each time being 5

grains. It is not credible that an alkaloid introduced into the body

hypodermically should not be absorbed.

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

March 18, 1882.

Opium-smoking is another form in which the drug is used, but it is an

open question as to what poisonous alkaloids are in opium smoke. It is

scarcely probable that morphine should be a constituent, for its

subliming point is high, and it will rather be deposited in the cooler

portion of the pipe. Opium, specially prepared for smoking, is called

“Chandoo”; it is dried at a temperature not exceeding 240°. H.

Moissan[396] has investigated the products of smoking chandoo, but only

found a small quantity of morphine. N. Gréhant and E. Martin[397] have

also experimented with opium smoke; they found it to have no appreciable

effect on a dog; one of the writers smoked twenty pipes in succession,

containing altogether 4 grms. of chandoo. After the fourth pipe there

was some headache, at the tenth pipe and onwards giddiness. Half an hour

after the last pipe the giddiness and headache rapidly went off. In any

case, opium-smoking seems to injure the health of Asiatics but little.

Mr. Vice-Consul King, of Kew-Kiang, in a tour through Upper Yangtse and

Stechnan, was thrown much into the company of junk sailors and others,

“almost every adult of whom smoked more or less.” He says:--“Their work

was of the hardest and rudest, rising at four and working with hardly

any intermission till dark, having constantly to strip and plunge into

the stream in all seasons, and this often in the most dangerous parts.

The quantity of food they eat was simply prodigious, and from this and

their work it seems fairly to be inferred that their constitution was

robust. The two most addicted to the habit were the pilot and the ship’s

cook. On the incessant watchfulness and steady nerve of the former the

safety of the junk and all on board depended, while the second worked so

hard from 3 A.M. to 10 P.M., and often longer, and seemed so independent

of sleep or rest, that to catch him seated or idle was sufficient cause

for good-humoured banter. This latter had a conserve of opium and sugar

which he chewed during the day, as he was only able to smoke at night.”

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

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

§ 362. =Treatment of Opium or Morphine Poisoning.=--The first thing to

be done is doubtless to empty the stomach by means of the flexible

stomach tube; the end of a sufficiently long piece of indiarubber tubing

is passed down into the pharynx and allowed to be carried into the

stomach by means of the natural involuntary movements of the muscles of

the pharynx and gullet; suction is then applied to the free end and the

contents syphoned out; the stomach is, by means of a funnel attached to

the tube, washed out with warm water, and then some coffee administered

in the same way.

Should morphine have been taken, and permanganate of potash be at hand,

it has been shown that under such circumstances potassic permanganate is

a perfect antidote, decomposing at once any morphine remaining in the

stomach, but it, of course, will have no effect upon any morphine which

has already been absorbed. In a case of opium poisoning, reported in the

_Lancet_ of June 2, 1894, by W. J. C. Merry, M.B., inhalations of

oxygen, preceded by emptying the stomach and other means, appeared to

save a man, who, three hours before the treatment, had drank 2 ozs. of

chlorodyne. It is also the received treatment to ward off the fatal

sleep by stimulation; the patient is walked about, flicked with a towel,

made to smell strong ammonia, and so forth. This stimulation must,

however, be an addition, but must never replace the measures first

detailed.

§ 363. =Post-mortem Appearances.=--There are no characteristic

appearances after death save hyperæmia of the brain and blood-vessels of

the membranes, with generally serous effusion into the ventricles. The

pupils are sometimes contracted, sometimes dilated, the dilatation

occurring, as before mentioned, in the act of dying. The external

surface of the body is either livid or pale. The lungs are commonly

hyperæmic, the bladder full of urine; still, in not a few cases, there

is nothing abnormal, and in no single case could a pathologist, from the

appearance of the organs only, declare the cause of death with

confidence.

§ 364. =Separation of Morphine from Animal Tissues and

Fluids.=--Formerly a large proportion of the opium and morphine cases

submitted to chemical experts led to no results; but owing to the

improved processes now adopted, failure, though still common, is less

frequent. The constituents of opium taken into the blood undergo partial

destruction in the animal body, but a portion may be found in the

secretions, more especially in the urine and fæces. First

Bouchardat[398] and then Lefort[399] ascertained the excretion of

morphine by the urine after medicinal doses; Dragendorff and Kauzmann

showed that the appearance of morphine in the urine was constant, and

that it could be easily ascertained and separated from the urine of men

and animals; and Levinstein[400] has also shown that the elimination

from a single dose may extend over five or six days. The method used by

Dragendorff to extract morphine from either urine or blood is to shake

the liquid (acidified with a mineral acid) several times with amyl

alcohol, which, on removal, separates urea and any bile acids. The

liquid thus purified is then alkalised, and shaken up with amyl alcohol,

and this amyl alcohol should contain any morphine that was present. On

evaporation it may be pure enough to admit of identification, but if

not, it may be redissolved and purified on the usual principles.

Considerable variety of results seems to be obtained by different

experimenters. Landsberg[401] injected hypodermically doses of ·2 to ·4

grm. of morphine hydrochlorate into dogs, making four experiments in

all, but failed to detect morphine in the urine. A large dose with 2·4

mgrms. of the salt gave the same result. On the other hand, ·8 grm. of

morphine hydrochlorate injected direct into the jugular vein, was partly

excreted by the kidneys, for 90 c.c. of the urine yielded a small

quantity of morphine. Voit, again, examined the urine and fæces of a man

who had taken morphine for years; he could detect none in the urine, but

separated morphine from the fæces.[402] Morphine may occasionally be

recognised in the blood. Dragendorff[403] found it in the blood of a cat

twenty-five minutes after a subcutaneous dose, and he also separated it

from the blood of a man who died of morphine poisoning in six hours.

Haidlen[404] recognised morphine in the blood of a suicide who had taken

opium extract.

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

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

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

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

1882, 543.

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

[403] Kauzmann, _Beiträge für den gerichtlich-chemischen Nachweis des

Morphia u. Narcotins_, Dissert., Dorpat, 1868. Dragendorff, _Pharm.

Zeitschr. f. Russland_, 1868, Hft. 4.

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

On the other hand, in a case recorded at p. 304, where a woman died in

six hours from a moderate dose, probably of laudanum, although the

quantity of blood operated upon was over a pound in weight, and every

care was taken, the results were entirely negative. In poisoning by

laudanum there may be some remaining in the stomach, and also if large

doses of morphine have been taken by the mouth; but when morphine has

been administered hypodermically, and in all cases in which several

hours have elapsed, one may almost say that the organ in which there is

the least probability of finding the poison is the stomach. It may, in

some cases, be necessary to operate on a very large scale;--to examine

the fæces, mince up the whole liver, the kidney, spleen, and lungs, and

treat them with acid alcohol. The urine will also have to be examined,

and as much blood as can be obtained. In cases where all the evidence

points to a minute quantity (under a grain) of morphine, it is decidedly

best to add these various extracts together, to distil off the alcohol

at a very gentle heat, to dry the residue in a vacuum, to dissolve again

in absolute alcohol, filter, evaporate again to dryness, dissolve in

water, and then use the following process:--

§ 365. =Extraction of Morphine.=--To specially search for morphine in

such a fluid as the urine, it is, according to the author’s experience,

best to proceed strictly as follows:--The urine is precipitated with

acetate of lead, the powdered lead salt being added to the warm urine

contained in a beaker on the water-bath, until a further addition no

longer produces a precipitate; the urine is then filtered, the lead

precipitate washed, and the excess of lead thrown down by SH₂; the lead

having been filtered off, and the precipitate washed, the urine is

concentrated down to a syrup in a vacuum. The syrup is now placed in a

separating tube (if not acid, it is acidified with hydrochloric acid),

and shaken up successively with petroleum ether, chloroform, ether, and,

lastly, with amylic alcohol (the latter should be warm); finally, the

small amount of amylic alcohol left dissolved in the liquid is got rid

of by shaking it up with petroleum ether. To get rid of the last traces

of petroleum ether, it may be necessary to turn the liquid into an

evaporating dish, and gently heat for a little time over the water-bath.

The acid liquid is now again transferred to the separating tube, and

shaken up with ether, after being made alkaline with ammonia; this will

remove nearly all alkaloids save morphine,--under the circumstances, a

very small quantity of morphine may indeed be taken up by the ether, but

not the main bulk. After separating the ether, the liquid is again made

slightly acid, so as to be able to precipitate morphine in the presence

of the solvent; the tube is warmed on the water-bath, at least its own

bulk of hot amylic alcohol added and the liquid made alkaline, and the

whole well shaken. The amylic alcohol is removed in the usual way, and

shaken with a small quantity of decinormal sulphuric acid; this washes

out the alkaloid from the amyl alcohol, and the same amyl alcohol can be

used again and again. It is best to extract the liquid for morphine at

least thrice, and to operate with both the solution and the amyl hot.

The decinormal acid liquid is made slightly alkaline with ammonia, and

allowed to stand for at least twelve hours; any precipitate is collected

and washed with ether, and then with water; the alkaline liquid from

which the morphine has been separated is concentrated to the bulk of 5

c.c. on the water bath, and again allowed to stand for twelve hours; a

little more morphine may often in this way be obtained.

The author in some test experiments, in which weighed small quantities

of morphine (60-80 mgrms.) were dissolved in a little decinormal

sulphuric acid, and added to large quantities of urine, found the

process given to yield from 80 to 85 per cent. of the alkaloid added,

and it was always recovered in fine crystals of a slight brown tint,

which responded well to tests.

Various other methods were tried, but the best was the one given; the

method not only separates the alkaloid with but little loss, but also in

a sufficiently pure state to admit of identification.

From the tissues the alkaloid may be dissolved out by the general method

given at p. 239, and the ultimate aqueous solution, reduced to a bulk of

not more than 25 c.c., treated by the ethereal solvents in the way just

described.

§ 366. =Narcotine= (C₂₂H₂₃NO₇) crystallises out of alcohol or ether in

colourless, transparent, glittering needles, or groups of needles,

belonging to the orthorhombic system.

It is only slightly soluble in boiling, and almost insoluble in cold

water. One part requires 100 parts of cold, and 20 of boiling 84 per

cent. alcohol; 126 parts of cold, 48 of boiling ether (specific gravity

0·735); 2·69 parts of chloroform; 400 of olive oil; 60 of acetic ether;

300 of amyl alcohol; and 22 parts of benzene, for solution. The neutral

solution of narcotine turns the plane of polarisation to the left [α]_r_

= 130·6; the acid solution to the right. Narcotine has no effect on red

litmus paper.

Narcotine gives no crystalline sublimate; its behaviour in the subliming

cell is described at p. 259. Its melting-point, taken in a tube, is

about 176°.

=Behaviour of Narcotine with Reagents.=--Narcotine, dissolved in dilute

hydrochloric acid, and then treated with a little bromine, gives a

yellow precipitate, which on boiling is dissolved; by gradually adding

solution of bromine and boiling, a fine rose colour is produced,

readily destroyed by excess of bromine. This is perhaps the best test

for the presence of narcotine. Concentrated sulphuric acid dissolves

narcotine; the solution in the cold is at first colourless, after a few

minutes yellow, and in the course of a day or longer the tints gradually

deepen. If the solution is warmed, it first becomes orange-red, then at

the margin violet-blue; and if heated until hydric sulphate begins to

volatilise, the colour is an intense red-violet. If the heating is not

carried so far, but the solution allowed to cool, a delicate cherry-red

hue slowly develops. If the sulphuric acid solution contains 1 : 2000 of

the alkaloid, this test is very evident; with 1 : 40,000, the colour is

only a faint carmine.--_A. Husemann._

A solution of narcotine in pure sulphuric acid, to which a drop of

nitric acid has been added, becomes of a red colour; if the solution is

warmed to 150°, hypochlorite of soda develops a carmine-red; and

chloride of iron, first a violet, then a cherry-red. The precipitants of

narcotine are--phosphomolybdic acid, picric acid, sulphocyanide of

potash, potassio cadmic iodide, mercuric chloride, platinic chloride,

auric chloride, and several other reagents.

From the brown mass left after heating narcotine above 200°,

hydrochloric acid extracts a small portion of a base but little studied.

The residue consists of humopic acid (C₄₀H₁₉O₁₄), which can be obtained

by dissolving in caustic potash, precipitating with HCl, dissolving the

precipitate in boiling alcohol, and finally throwing it down by water.

§ 367. =Effects.=--Narcotine in itself has toxic action only in rather

large doses; from 1 to 2 grms. have been given to man, and slight

hypnotic effects have followed. It is poisonous in very large doses; an

ordinary-sized cat is killed by 3 grms. The symptoms are mainly

convulsions.

§ 368. =Codeine= (=Codomethylene=), C₁₇H₁₇OCH₃(OH)NO + H₂O, is the

methyl of morphine; it is an alkaloid contained in opium in small

quantity only. Mulder, indeed, quotes ·66 to ·77 per cent. as present in

Smyrna opium, but Merck and Schindler give ·25 per cent. Schindler found

in Constantinople, ·5 per cent.; and Merck, in Bengal, ·5 per cent.

also.

Codeine crystallises out of dry ether in small, colourless, anhydrous,

crystals; but crystallised slowly from an aqueous solution, the crystals

are either in well-defined octahedra, or in prisms, containing one atom

of water, and melting in boiling-water to an oily fluid. The anhydrous

crystals have a melting-point of 150°, and solidify again on cooling.

Its watery solution is alkaline to litmus paper.

It requires 80 parts of cold, 17 of boiling water, 10 parts of benzole,

and 7 parts of amyl alcohol respectively, for solution. Alcohol,

benzene, ether, carbon disulphide, and chloroform freely dissolve it,

but in petroleum ether it is almost insoluble. Further, it is also

soluble in aqueous ammonia, and in dilute acids, but insoluble in

excess of caustic potash or soda, and may thus be thrown out of an

aqueous solution. A solution of codeine turns the plane of polarisation

to the left, [α]_r_ = 118·2°.

Concentrated sulphuric acid dissolves codeine without colour, but after

eight days the solution becomes blue; this reaction is quicker if the

acid contains a trace of nitric acid. If the sulphuric acid solution be

warmed to 150°, and a drop of nitric acid be added after cooling, a

blood-red colour is produced. Fröhde’s reagent produces a dirty green

colour, soon becoming Prussian blue, and terminating after twenty-four

hours in a pale yellow.

Cyanogen gas, led into an alcoholic solution of codeine, gives first a

yellow and then a brown colour; lastly, a crystalline precipitate falls.

On warming with a little sulphuric acid and ferric chloride, a blue

colour is produced. This blue colour is apparently common to all ethers

of the codeine class.

Of the group reagents, the following precipitate solutions of

codeine:--Mercuric potassium iodide, mercuric chloride, mercuric

bromide, picric acid, and tannin solutions. The following do not

precipitate:--Mercuric cyanide and potassium ferrocyanide solutions.

Potassium dichromate gives no immediate precipitate, but crystals form

on long standing. It does not give the reaction with iodic acid like

morphine; it is distinguished from narceine by dropping a small particle

of iodine into the aqueous solution, the iodine particle does not become

surrounded with fine crystals.

§ 369. =Effects.=--The physiological action of codeine on animals has

been investigated by Claude Bernard, Magendie, Crum Brown and Fraser,

Falck, and a large number of others.[405] It has also been administered

to man, and has taken in some degree the place of morphine. Claude

Bernard showed that, when given to dogs in sufficient quantity to

produce sleep, the sleep was different in some respects to that of

morphine sleep, especially in its after-effects. Thus, in his usual

graphic way, he describes the following experiment:--“Two young dogs,

accustomed to play together, and both a little beyond the average size,

received in the cellular tissue of the axillæ, by the aid of a

subcutaneous syringe, the one 5 centigrammes of morphine hydrochloride,

the other 5 centigrammes of codeine hydrochloride. At the end of a

quarter of an hour both dogs showed signs of narcosis. They were placed

on their backs in the experimental trough, and slept tranquilly for

three or four hours. When the animals woke, they presented the most

striking contrast. The morphine dog ran with a hyena-like gait

(_démarche hyénoid_), the eye wild, recognising no one, not even his

codeine comrade, who vainly bit him playfully, and jumped sportively on

his back. It was not until the next day that the morphine dog regained

his spirits and usual humour. A couple of days after, the two dogs being

in good health, I repeated the same experiment, but in an inverse

order--that is to say, I gave the codeine to that which previously had

the morphine, and _vice versâ_. Both dogs slept about as long as the

first time; but on waking the attitudes were completely reversed, just

as the administration of the two substances had been. The dog which, two

days before, after having been codeinised, woke lively and gay, was now

bewildered and half paralysed at the end of his morphine sleep; whilst

the other was wide awake and in the best spirits.”

[405] _Ann. Chem. Phys._ [5], 27, pp. 273-288; also, _Journ. Chem.

Soc._, No. ccxliv., 1883, p. 358.

Subsequent experimenters found what Bernard does not mention--viz., that

codeine produced epileptiform convulsions. Falck made some very careful

experiments on pigeons, frogs, and rabbits. To all these in high enough

doses it was fatal. Falk puts the minimum lethal dose for a rabbit at

51·2 mgrms. per kilo. Given to man, it produces a sleep very similar to

that described by Claude Bernard--that is, a sleep which is very

natural, and does not leave any after-effect. Therefore it is declared

to be the best alkaloid of a narcotic nature to give when lengthened

slumber is desired, more especially since it does not confine the

bowels, nor has it been found to produce any eruption on the skin.

Before it has a full narcotic effect, vomiting has often been excited,

and in a few cases purging. The maximum dose for an adult is about ·1

grm. (1·5 grain); three times this quantity, ·3 grms. (4-5 grains),

would probably produce unpleasant, if not dangerous, symptoms.[406]

[406] For further details as to the action of codeine, the reader is

referred to L. O. Wach’s monograph, _Das Codein_ (1868), which contains

reference to the earlier literature. See also Harley, _The Old Vegetable

Neurotics_, London.

§ 370. =Narceine=, C₂₃H₂₇NO₈ + 3H₂O.--Two of the three molecules of

water are expelled at 100°, the other molecule requires a higher

temperature; anhydrous narceine is hygroscopic, and melts in a tube

at about 140°; when exposed to air it unites with one molecule of

water, and then melts at about 160°.

The constitution of narceine is probably that of a substituted

phenylbenzylketone, and the following structural formula has been

attributed to it:[407]--

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

3 I:2 4 1’ 2’

COOH,C₆H₂-(OMe)₂CO-CH₂-C₆H(CH₂-CH₂NMe₂)

O

3 or 6/ \

OMe CH₂

\ /

O