Death from Therapeutic Doses of Morphine or Morphine-Scopolamine in Persons Affected by Alcohol or Barbituric Acid

Sections

METHODS, MATERIAL, ETC.
MORPHINE AND ALCOHOL
MORPHINE-SCOPOLAMINE AND ALCOHOL
MORPHINE PLUS SCOPOLAMINE BROMIDE PLUS ALCOHOL
MORPHINE-SCOPOLAMINE AND BARBITURATES
DISCUSSION
SUMMARY

Details

Author: Knud O. Müller
Pages: 11 to 19
Creation Date: 1953/01/01

Death from Therapeutic Doses of Morphine or Morphine-Scopolamine in Persons Affected by Alcohol or Barbituric Acid

Knud O. Müller

Dr. Knud O. Müller is Professor at the Institute of Pharmacology, University of Copenhagen. The editors of the Bulletin fell that, owing to the interest of the subject matter and the high reputation enjoyed by the author, the following article, already published in Danish in Ugeskrift for Leager (see bibliography at the end of this issue) should be brought to its readers.

Few medical practitioners realize that injection of therapeutic doses of morphine or morphine-scopolamine may be directly dangerous to life or fatal to persons seriously affected by alcohol or under the influence of moderate but toxic quantities of barbituric acid. I have found no mention of this in the literature.

My attention was first drawn to the problem by a fatal case which came to us for pharmaco-legal investigation at the Pharmacological Institute (see case 1, the first case here reported). Ascertainment of the cause of death from the results of chemical analysis of the organs, blood, urine, etc., may, through the nature of most of the cases, call for some degree of judgment. The correctness of the judgment will depend principally on the experience of the investigator derived from a long series of similar cases. Since the assessment of such cases may often have serious consequences for the persons concerned-e.g., for a physician who has given a patient a morphine injection-wide experience may be necessary to enable a worker to say with sufficient certainty whether, for example, an injection given by a physician has been the act which led to the death. Our volume of experience in the Medico-Legal Division of the Pharmacological Institute has only recently become large enough to enable us to state an opinion with the necessary certainty. In this paper an account will be given of the most typical cases of death from this cause that we have had to investigate. Space will not permit more than a brief summary of the reports, results of investigation and the like in each case. On the other hand, it has seemed to me necessary to make the case reports full enough to afford documentary support for the conclusions set forth below, so that the reader may to some extent be able to form his own judgment on these.

I should like to emphasize at the start that in most of the cases no blame was attached to the physician who gave the fatal injection, for - as I have already said - the literature has hitherto contained no information about the risk of administering morphine, etc., to persons affected by alcohol or barbituric acid.

METHODS, MATERIAL, ETC.

Except for one (case 5), all the cases were sent by the police to our Institute for pharmaco-legal examination, and the information given is derived from police reports, judicial autopsy reports, and the like.

Where any of the present case reports does not mention whether an injection was given intravenously, or by some other route, the reason is that no information was forthcoming.

A judicial autopsy was performed in all the cases, and often a histological examination as well, but the results are not given unless the autopsy or other examinations produced findings different from those usual in persons who have died of narcotic poisoning. The fact that an autopsy and other examinations were performed makes it most unlikely that in any of the reported cases the cause of death could have been other than the poisoning disclosed by the chemical analysis.

All the analyses were performed in the Medico-Legal Division (under Fanny Halström, Ph.D., forensic pharmacologist) of the Pharmacological Institute.

Barbiturates are determined by extraction from organs, isolation by sublimation, weighing, and identification by ascertainment of their micro melting-point (Halström, 1940), and sometimes by more special methods (Huang and Jereslev, 1951, and others). The method is quite specific and works with a very small loss. Only unaltered barbiturates are determined.

Alcohol is determined by a special variant of Zeisel's method, which gives very accurate values for alcohol concentration, even in much-decomposed cadaver blood, for which Widmark's method is well known to be useless. The method is controlled by the specific alcohol-dehydrogenization method (Bonnichsen and Theorell, 1950).

From the alcohol concentrations found in the cadaver blood was calculated the approximate alcohol concentration in the blood at the time of injection of the morphine or other substance. The alcohol concentration in the blood of man sinks at an average rate of about 0.15 parts per thousand per hour (between limits of 0.1 and 0.2 per thousand). In this paper, in calculating the earlier blood alcohol concentration we have in all cases allowed for a reduction in concentration of only 0.1 per thousand per hour, as alcohol combustion may be somewhat reduced in deeply unconscious persons.

Morphine is demonstrated by chemical and by biological methods (the mouse-tail reaction). Tropic alkaloids are demonstrated by a biological method (measurement of pupil diameter in a mouse; Tonnesen, 1948). Bromide is determined by the method of Behr, Palmer and Clarke (1930), which gives very accurate results.

The substances referred to in this paper are named as shown below. The list also shows the most important synonyms. "NFN" in the list means the name recognized by the Scandinavian Pharmacopoeia (NFN names). "INN" means International Non-proprietary Names, i.e., the names established by the International Sub-Committee on Nomenclature of WHO. (R) signifies a registered trademark. Morphine in this paper means the hydrochloride and scopolamine the hydrobromide of those substances.

Names used

Synonyms

Allypropymal (NFN)
Aprobarbital (INN) = Isonal (R)
Diemal (NFN)
Barbital (INN)= Veronal (R)
Fenemal (NFN)
Phenobarbital (INN) = Lu-minal (R)
Hexemal (NFN)
Cyclobarbital (INN) = Phanodorm (R) = Cyclodorm (R)
Hypnofen (NFN)
Somnifen (R)
Oxykon (NFN)
Oxykodon (INN) =Eukodal (R)
Pethidine
Pethidin (INN) = Dolantin (R) =Demerol (R)
Tetrapon (NFN)
Approximately = Pantopon (R)

For the sake of comparability, dosage of morphine and scopolamine is given in terms of kilogrammes of body weight. The following note may be of service in evaluating these figures. The usual therapeutic dose of morphine hydrochloride for an adult is 10-30 mg; if the weight is 70 kg, this corresponds to 0.14-0.43 mg per kg; thus the therapeutic dose of morphine hydrochloride is about 0.15- 0.4 mg/kg. The ordinary dose of scopolamine hydrobromide for an adult is 0.5 mg; the therapeutic dose of scopolamine hydrobromide, calculated in the same way, is about 7 µg/kg.

THE 1945 CASE: DEATH FROM POISONING BY A COMBINATION OF ALCOHOL, MORPHINE, SCOPOLAMINE AND BARBITURIC ACID

Case 1 (Ser. No. 875/1945). A., a wholesale dealer of 48, weight 86 kg.

A. lost his wife a few days before his death on 9 April. On that day his wife's body was taken to the chapel, and in the evening he had dinner with some friends and drank a large quantity of spirits. He was very excited, and his friends, thinking he needed a good sleep, called in a doctor for that purpose.

At 11.30 p.m. the doctor gave a slow intravenous injection of 0.25 g of diemal plus 0.25 g of allypropymal (in the form of hypnofen) plus 15-20 mg of morphine hydrochloride plus 0.4 mg of scopolamine hydrobromide, all mixed together in the syringe. The deceased immediately fell into a deep sleep.

About 1.30 a.m. one of the guests, Who had been a nurse, looked at him. He was then dying, and he died immediately afterwards, about two hours after the injection.

Chemical investigation. Barbiturates: Liver, 1.9 mg per cent, muscles, 1.0 mg per cent, urine, 12.3 mg per cent. The diemal was found mixed with another barbiturate. Alcohol: Blood, 1.59 per thousand, urine, 2.00 per thousand. Morphine demonstrated in the urine; no other poisonous substance could be detected.

Comment

The alcohol concentration in the deceased's blood at the time of the injection was presumably about 1.8 per thousand, a high concentration which probably produced a very powerful effect. The concentration of barbituric acid found in the organs can, according to our experience, be explained only by the injected barbiturate preparation, and by itself would not produce poisoning, let alone death.

An intravenous injection of 15-20 mg ( = 0.17-0.25 mg/kg) of morphine plus 0.4 mg ( = 4.7 µg/kg) of scopolamine in addition to the quantities of barbiturate given (0.5 g) into this intoxicated patient at once produced deep sleep, and death occurred two hours later. According to our present experience there can be no doubt that the injection given by the doctor caused the death. The aggregate dose of narcotic substances injected was very large, but not larger than that occasionally used in treatment; and in a person not affected by alcohol the injection would probably only have caused a deep and lengthy sleep without harmful after-effects. Even considering that the doctor did not know of the danger of injecting narcotics into a person affected by alcohol, it must nevertheless be regarded as very imprudent to inject that large a dose of narcotics directly into the bloodstream. The same facts appear in many of the subsequent cases of poisoning, and the assertion of the danger of intravenous injection therefore applies also to those cases.

MORPHINE AND ALCOHOL

The following cases occurred in persons affected by alcohol who were injected with morphine.

Case 2 (Ser. No. 1099/1947). B., a male factory worker of 48, weight 95 kg.

The history showed that on 25 May, B. drank with his lunch seven to ten glasses of Pilsner and one of brandy. In the evening he had an attack of renal colic, and at 7 p.m. he took two tablets of some unspecified hypnotic. The doctor who was summoned injected at 10 p.m., to treat the pain, 40 mg of morphine hydrochloride intravenously,after which B. fell asleep and snored loudly. Next morning (26 May) he could not be aroused, and was therefore admitted to hospital at 10 a.m. There the typical symptoms of morphine poisoning were found: pupils fully contracted and insensitive to light, marked cyanosis, and deep unconsciousness. He died at 4.50 p.m., almost nineteen hours after the injection.

Autopsyshowed that a renal calculus had been recently passed.

Chemical investigation. Alcohol: blood, 0.23 per thousand. Morphinedetected in liver and muscles. Barbiturates, bromine or other poisons could not be shown.

Comment

At the time of the morphine injection B. must have had at least 2.2 per thousand of alcohol in his blood. The failure to demonstrate barbiturates or bromide means that the hypnotics could not have contributed to the death. The dose of morphine given was very heavy, but the patient's weight (95 kg) must be allowed for; it was 0.42 mg/kg. When admitted to hospital twelve hours after the injection he showed the typical symptom picture of morphine poisoning: marked miosis with cyanosis, which is seen rarely if at all in any other condition. The dose of morphine given (0.42 mg/kg), though very large, will not cause the death of a person who is healthy except for renal colic. The conclusion is therefore that without any doubt the doctor's injection of morphine into a patient affected by alcohol was the direct cause of death.

Case 3(Ser. No. 1105/1947). C., an inspector aged 39, married, weight 87 kg.

On 6 June between 6 and 12 p.m. he had seven to nine drinks, and some more between midnight and 4 a.m. on 7 June. At about 5 a.m. he suffered from severe pains "inthe heart". The doctor who was called in judged that the pain was due to an attack of gallstone colic, and injected at about 6 a.m. 20 mg of morphine hydrochloride intramuscularly and then 10 mg more intravenously.C. promptly fell asleep. At 2.15 p.m. the other persons in the house noticed that he was snoring loudly and could not be awakened. He was admitted to hospital at 4.15 p.m. showing the typical symptoms of acute morphine poisoning described above. At 9.05 p.m. he died, 15 hours after the morphine injection.

The autopsyshowed gallstones, confirming the doctor's diagnosis.

Chemical investigation. Alcohol: blood, 0.68 per thousand. Barbiturates, bromine or other poisons could not be detected; no morphine could be detected in the organs; no urine was found in the body.

Comment

At the time of the morphine injection C. had presumably at least 2.2 parts per thousand of alcohol in his blood. The available methods of morphine determination are relatively so coarse that it is often impossible to show morphine in the organsif death occurs a long time after a therapeutic dose; but morphine can usually be found in the urine. The result of the chemical analysis does not therefore conflict with the doctor's report. The dose of morphine given, 0.35 mg/kg (30 mg in all) is within the therapeutic limits. Ten hours after the injection the typical symptoms of severe morphine poisoning were demonstrated in hospital. No other cause of death was shown, and there cannot be any doubt that the morphine injection was the direct cause of death.

Case 4.(Ser. No. 1345/1949). D., a woman of 35, married to a master baker, weight 65 kg.

D. was a troublesome patient, badly in need of treatment, a heavy drinker. She was in hospital a short time - about six months - before her death, with a diagnosis of abdominal colic, and was under observation for ulcer of the stomach, gallstones and misuse of pethidine, in other words, for some very indefinite complaints and for drug addiction. In the afternoon of 12 November she bought three half-bottles of brandy, and after her death one was found empty. The records do not show when she emptied it (see under Comment).

At about 6 p.m. on the same day she called to see a doctor. He was out, and she succeeded after a great deal of persuasion in inducing the doctor's wife at 6.15 p.m. to give her an injection of about 20 mg of morphine hydrochloride (presumably subcutaneous). The doctor's wife explained that D., when she came at 6 p.m., was swaying and had very flushed cheeks and bright eyes but did not smell of spirits.

At 8 p.m. D.'s husband found her unconscious; the doctor, who had by now returned home, was summoned and found her at about 9 p.m. dying, very cyanosed, with Cheyne-Stokes respiration and dilated pupils. She was dead on arrival at the hospital; i.e., death occurred about 3 hours after the morphine injection.

Autopsyshowed small stones in the gall bladder.

Chemical analysis. Alcohol: blood, 2.20 per thousand; urine, 2.70 per thousand; stomach contents, 2.90 per thousand. Morphinewas found in the liver and urine but not in the stomach contents. No barbiturates, bromine or other poison.

Comment

At the moment of the morphine injection D. presumably had about 2.5 parts per thousand of alcohol, perhaps slightly more, in her blood. The time when she took the alcohol is not stated. The description of her condition at 6 p.m. ("swaying, cheeks flushed") may signify that she had taken drink before 6 p.m. On the other side is the note that she did not smell of drink. The fact that the alcohol concentration in the stomach contents was only slightly higher than the probable concentration in the blood plasma (2.2 per thousand in whole blood corresponds to about 2.75 per thousand in the plasma), and that the concentration in the urine (2.7 per thousand) corresponds closely to the calculated plasma concentration, makes it most unlikely that alcohol was taken after 6.30 p.m. (she was observed between 6 and 6.30 p.m.). The overwhelming probability is that she was under the influence of alcohol when she received the injection but that, being used to drink, she could pull herself together when she was with the doctor's wife at 6 p.m. The doctor's wife left her alone for one minute in the consulting-room, where a bottle of tetrapon was standing in an open cupboard. The fact that no morphine was found in the stomach contents shows conclusively that D. did not take a drink from the bottle of tetrapon. The dose of morphine injected (0.31 mg/kg) is an ordinary therapeutic dose. There can, however, be no doubt that this dose caused the death of the very intoxicated patient. The question whether the alcohol was taken before or after the injection makes no difference to the toxicological conclusions, though it may have a legal bearing.

The wide dilation of D.'s pupils agrees with the general experience that the pupils are dilated before the terminal stage of morphine poisoning.

Case 5(Ser. No. 36/1939). E., a man of 54, an inmate of a charitable institution.

E. was brought to the police station on 23 December 1938 at 8.30 p.m. for brawling. In the cells he became very violent. Some time after 9 p.m. the doctor who was summoned gave an intravenousinjection of 10 mg of okykon. A few minutes later E. collapsed, with slowed respiration, deep cyanosis and irregular pulse; he died at 9.50 p.m., about half an hour after the injection.

The autopsyrevealed marked stasis in all organs but no cause of death.

Chemical analysis (at the University Medico-Legal Institute) showed 2.54 parts of alcoholper thousand in the serum and 2.89 in the urine. No special pharmaco-legal analysis was performed.

Comment

At the time of the injection E. presumably had about 2.6 parts of alcohol per thousand in his blood. He was a drinker and apparently a dissolute sort of person. His poor general condition may have contributed to his death. He lost consciousness almost immediately after the injection; this fact, although the dose was relatively small, makes it probable that the intravenousinjection was the direct cause of death in this highly-intoxicated person. That is all that can be said with certainty about this case.

MORPHINE-SCOPOLAMINE AND ALCOHOL

It is well known that scopolamine reinforces the depressive effect of morphine on the respiration. Our material also contains cases in which morphine-scopolamine was injected.

Case 6(Set. No. 1631/1952). F., male, a manager of 28, weighing 70 kg.

He was an alcoholic. On 10 November at 4 p.m. he returned home from a drinking bout. His wife telephoned to the doctor and said that her husband complained that he could not sleep. At 6 p.m. F. and his wife visited the doctor, who states that F. was obviously under the influence of alcohol. F. pestered the doctor to give him an injection to make him sleep; and the doctor yielded and gave him a subcutaneous injection (at about 6 p.m.) of 26 mg of morphine hydrochloride and 0.5 mg of scopolamine hydrobromide.

F. went straight home to bed. His wife went to look at him frequently, and he just lay and snored (nothing else is said about his condition). At 10 p.m. he stopped snoring and died at once, about 4 hours after the injection.

Chemical investigation. Alcohol: blood, 1.91 per thousand; in stomach contents, 2.19 per thousand; none in urine. Tropic alkaloids and morphine found, but not barbiturates, bromine or other poisons.

Comment

The alcohol concentration in F.'s blood at the time of the injection was probably at least about 2.3 per thousand - i.e., one which is not lethal by itself, especially in an alcoholic. He died about 4 hours after the injection of 0.38 mg/kg of morphine and 7.1 µg/kg of scopolamine, and there can be little doubt that the injection was the direct cause of death.

Case 7(Ser. No. 1629/1952). G., a farmer of 64, weight 80 kg.

He was an alcoholic, and was sometimes very violent and irresponsible. He had on several occasions assaulted women, and had once attempted rape. On 24 October he rose at 4 a.m., very restless and behaving aimlessly. After lunch he left home, to return about 4.30 p.m. very drunk, irritable and savage. His wife, who was afraid of him, called in a doctor, who, about 6 p.m., injected 20 cg of diemal, 20 cg of allypropymal, 7 mg of morphine hydro-chloride and 0.2 mg of scopolamine He at once became quiet, and it was decided to take him to the mental hospital. In the motor ambulance he lay and snored, dying in it at about 11 p.m., about five hours after the injection.

Autopsyshowed that he had moderate sclerosis of the coronary and cerebral arteries and the aorta, but 'did not show the direct cause of death.

Chemical analysis. Alcohol: blood, 2.23; urine, 3.06 per thousand. Tropic alkaloids shown in the urine; morphinewas not shown for certain. Traces only of barbiturates; bromine or other poisons not shown.

Comment

The alcohol concentration in G.'s blood at the time of the injection was probably at least about 2.7 per cent. He died about five hours after injection of about 0.1 mg/kg of morphine plus 2.5 µg/kg of scopolamine plus 40 cg of barbiturate (2 ml of hypnofen).

The alcohol concentration was very high, and his state of health (moderate coronary sclerosis) was not at all good. The autopsy, even if it could not demonstrate a direct cause of death, could not disprove that his death was chiefly due to the coronary sclerosis. According to our experience, however, I am much inclined to suppose that the injection of the narcotics was the direct cause of death, and that without it he would have survived his intoxication.

Case 8(Ser. No. 1634/1952). P., housewife of 33, married, weight 52 kg.

She was addicted to metadon (butalgin). During the previous eight days she had stayed in bed but had nothing the matter with her; her use of medicines during that time was supervised.

On 27 November in the evening she took 15 cg of fenemal, and on 28 November at 6 a.m. she obtained 15 cg of fenemal from the man she lived with, and he then went to work. At 8.45 a.m. he was called home, as she was complaining of severe pains in the back. A doctor was summoned and injected intramuscularly first 1 ml and then, ten to fifteen minutes later, about 0.35 ml of a mixture of tetrapon (for injection) and scopolamine (for injection) in all, that is 8.8 mg of morphine hydrochloride plus 0.68 mg of scopolamine hydrobromide.

Soon afterwards she fell aslep. The man stayed at home. At 3 p.m. she was still breathing, but at about 3.05 p.m. she died.

Autopsyrevealed no cause of death.

Chemical analysis: 1.20 per thousand alcoholin blood, 1.66 in urine and 1.48 in the stomach contents. Neither barbiturates nor any other narcotic was shown.

Comment

The alcohol concentration in P.'s blood at the time of the injection was probably at least 1.8 per thousand. There is nothing to show when she took the alcohol. She was somewhat underweight, and went to sleep immediately after an intramuscular injection of 0.17 mg/kg of morphine hydrochloride plus 13.1 µg/kg of scopolamine hydrobromide, dying six hours after the injection. The case strikingly resembles some of the previous ones (e.g., 6 and 7).

MORPHINE PLUS SCOPOLAMINE BROMIDE PLUS ALCOHOL

Chronic bromism is probably more wide-spread than is generally supposed. In chronic bromism with clear clinical symptoms, between about 130 and 500 mg per cent of bromine is found in the blood, and life is not endangered until the concentration becomes maximal (400 to 500 mg per cent) (Gundry, 1939; Müller, 1952).

Case 9(Ser. No. 1180/1948). H., a wholesaler's wife of 48, weight 41 kg.

She was unhappily married and drank, smoked and took hypnotics a great deal. She was always making scenes in the home. In the evening of 9 April she was very restless again. At 11 p.m. she took a little hexomal. She slept a few hours and became restless again, and threw china at her husband. On 10 April at 2.15 a.m. a doctor gave her an intramuscular injection of 15 mg of morphine hydrochloride plus 0.3 mg of scopolamine hydro-bromide, after which she was quiet. Her husband saw her at 4 a.m. and at midday; she was lying apparently asleep and was breathing. At 2 p.m. she was found dead and still warm; that is, death occurred about eleven hours after the injection.

Chemical analysis. Bromide: blood, 158 mg per cent; liver, 165 mg per cent, stomach contents 165 mg per cent. Organic compounds of bromine were not demonstrated, at any rate in the stomach contents. Alcohol:none in blood but 0.50 per thousand in the urine. Morphine and tropic alkaloids were shown in the urine. No other poison was found.

Comment

The urine contained 0.5 parts of alcohol per thousand, showing that the deceased had drunk an appreciable quantity. No alcohol was found in the blood; therefore the alcohol concentration in her blood at the time of the injection could not have been much more than one part per thousand. The urine concentration shows that she must at some time or another have had at least 0.6 per thousand in her blood. Nothing more precise can be said about the alcohol concentration. The blood contained 165 mg per cent of bromide. The ratio between the bromine concentrations in the blood, liver and stomach contents shows that there was an accumulation of bromine in the organism after prolonged use of bromides or of hypnotics containing bromine. Since, moreover, organic bromine compounds could not be shown, particularly in the digestive tract, it is certain that the bromine in the blood came from acute poisoning by a hypnotic containing bromine. The results of the analysis therefore permit the conclusion that H. was suffering from chronic bromism.

She died 11 hours after the injection of 0.37 mg/kg of morphine plus 7.3 µg/kg of scopolamine. The aggregate dose of these substances was not large, absolutely, but was large for a person whose weight was so low (41 kg). In view of these facts there can be little doubt that the injection of morphine and scopolamine caused the death of a person affected by chronic bromism and a moderate dose of alcohol and then by narcotics.

MORPHINE-SCOPOLAMINE AND BARBITURATES

We have had at the Pharmacological Institute during the past fifteen years to investigate an extraordinarily large number of cases of death from barbituric acid poisoning. We have thus gained a very large volume of case material - not yet published - on the connexion between the barbituric-acid concentration in the organs at death and the period elapsing between the time the hypnotic was taken and death. This material enables us to state with a considerable degree of certainty, for the various barbiturates, whether the barbituric-acid concentration found in the organs can be believed to have caused the death within the given period.

Except for one or two cases in which the dose was very large (and the barbituric-acid concentration in the organs correspondingly high) and death occurred in only a few hours, an untreated case of bar-bituric-acid poisoning will rarely end in death in the first twenty-four hours after the barbiturate is taken. That does not apply to cases in which the 'patient is exposed to severe chili - e.g., through lying in the open air; but even so the poisoning may occasionally extend over more than twenty-four hours. Nor does it apply where morphine or the like has been injected (or ingested). Some cases of this kind will now be reported.

Case 10 (Ser. No. 1484/1951). K., a workman's wife of 37, weight 45 kg.

K. had "bad nerves" and on this account took a good deal of fenemal. On 9 March at 8 a.m. she was still asleep when her husband left the house. At about 9 a.m. she took, in the presence of her son of 7, a "large number" of weak fenemal tablets (15 mg of fenemal each). At 10.30 a.m. her husband returned, summoned by a neighbour, and her usual doctor was called in.

The doctor arrived at 10.45 a.m. She was then not unconscious, but very excited. The doctor was shown a bottle which had contained 200 of the tablets (i.e., 3.5 g of fenemal) and was then empty. He had prescribed it for her ten days beforehand. (The number of tablets K. had taken during the previous ten days is not stated.) In spite of this demonstration the doctor injected 11 mg of morphine hydrochloride plus 0.4 mg of scopolamine hydrobromide. K. immediately fell asleep and at 3 p.m. she was found dead. Death therefore occurred six hours after the injection.

Autopsy revealed a few small infarcts in the lungs, but although thrombi were looked for none were found. The cause of death was not shown by the autopsy.

Chemical analysis. A barbiturate, identifiable as fenemal, was found: 5.0 mg per cent in the liver and 2.8 mg per cent in the muscles. Morphine could not be demonstrated (a chemical method only was used). The blood and organs contained a small amount of bromine (corresponding to about 5 per cent of the total halogens). There was no alcohol.

Comment

The amount of bromine found is quite insignificant (symptoms of chronic bromism do not appear until about 15 to 20 per cent of the total halogens consists of bromine). According to our experience, in cases of fenemal poisoning where death takes place in six hours or less the fenemal concentration found is considerably higher than in this case. It is therefore very improbable that the dose of fenemal taken by K. would have been fatal by itself. The presumption is, therefore, that death was caused by the injection of 0.25 mg/kg of morphine plus 8.9 µg/kg of scopolamine into a person already affected by a narcotic.

The case also shows the excitement which may supervene after the taking of barbiturates and before unconsciousness begins to set in. This was the symptom which induced the doctor to give the fatal injection.

Case 11 (Ser. No. 1252/1949). L., a woodman's wife of 45, weight 62 kg.

On 11 December L. was discharged from hospital, where she had been under observation for gallstones. She was then apparently quite fit. She was said to have been a heavy drinker and in the habit of taking hypnotics to excess.

On 25 December she had a severe attack of pain like those which had gone before. A doctor was called, and at 1 a.m. injected 20 mg of morphine hydrochloride. At 5 p.m. she got up, but at 6 p.m. she had more severe pains and got the doctor to inject 30 mg of morphine hydrochloride. At 9.30 p.m. she went back to bed. On 26 December at 12.45 a.m. her husband noticed that she could not be roused. She was at once taken to hospital, where she was found deeply unconscious with extremely contracted pupils, cyanosis and shallow breathing. She died at 4 a.m., or about ten hours after the last injection.

Autopsy showed no cause of death, and no gallstones or any other explanation of the attacks of pain.

Chemical analysis showed a mixture of fenemal and diemal 3.4 mg per cent was found in the liver, 2.3 mg per cent in the muscles, and 5.9 mg per cent in the stomach contents (total 28 mg). Morphine was demonstrated in the urine but not in the stomach contents. Neither alcohol nor any other poison was shown.

Comment

The effects of the first injection of morphine (1 a.m.) may be assumed to have substantially worn off, as she had a fresh injection of 30 mg, or 0.48 mg/ kg, of morphine at 6 p.m. As in the previous case (case 9), it is very unlikely that the fenemal and diemal she had taken could have caused death by themselves; it must be concluded that the death was due both to the morphine injection and to the barbiturates. In hospital she showed the typical symptoms of morphine poisoning about seven hours after the injection of morphine.

When she took the barbiturates is not known. There is no report that she was showing signs of narcotic poisoning when the doctor gave the injection, and there was therefore nothing to warn him against giving morphine for the severe pains of which she was complaining.

Case 12 (Ser. No. 1363/1950). M., a salesman of 40, weighing 68 kg.

M. had suffered for many years from the after-effects of a chronic encephalitis, and was almost mental and deeply addicted to narcotics. He was a thorn, in the side both of his wife and of his doctors. He took a great deal of morphine, as much as 70 mg in twenty-four hours, but during the last few weeks had only had chloral hydrate and some tablets of allypropymal daily.

In the forenoon of 4 January he had 1g of chloral hydrate. As he was particularly restless that day and was threatening to kill himself, the doctor injected at about 2 p.m. 30 mg of morphine hydrochloride. At 3 p.m. he had 0.30 g of allypropymal (prescribed by the doctor over the telephone), and at 6 p.m. the doctor injected 20 mg of morphine hydrochloride plus 0.4 mg of scopolamine hydrobromide. M. at once became quiet. On 5 January at 1 a.m. he was heard snoring. At 6.30 a.m. he was found dead in bed in exactly the same position as when he had fallen asleep after the injection . Rigor mortis had set in, meaning that death had presumably occurred not later than 1.30 to 2.30 a.m.

Autopsy. The clinical diagnosis of chronic encephalitis was confirmed by histological examination. No cause of death could be discovered.

Chemical analysis. Allypropymal 1.8 mg per cent in the liver, 1.9 mg per cent in the muscles, 5.7 mg per cent in the stomach contents. Morphine was shown in the urine but not in the liver. Alcohol or other poisons were not found.

Comment

The concentration of allypropymal in the organs was a good deal higher than would be expected after an injection of 0.30 g of allypropymal. It is therefore probable that M. afterwards took some, but not much, more allypropymal in addition to what the doctor prescribed at 3 p.m. The presence of allypropymal in the stomach contents bears this out. On the other hand, the concentration of allypropymal in the organs was so low that it is very unlikely that the allypropymal alone could have caused death so soon (presumably seven to eight hours after the last injection). It may therefore be assumed that death was due to the allypropymal in conjunction with the morphine (0.44 mg/kg plus 0.30 mg/kg) and scopolamine (5.9 µg/kg) injected by the doctor. The chloral hydrate can hardly have had any importance.

In addition to the cases just reported, a very short account will be given of four more cases in which it is extremely probable that death was due to morphine or to morphine-scopolamine given to patients under the influence of barbiturates.

I. The first case (Ser. No. 1210/1948) was a physically healthy but mentally unsound man who was given an injection of 0.25 mg/kg of morphine plus 6.2 µg/kg of scopolamine plus 20 cg of diemal plus 20 cg of allypropymal by a doctor before being taken to a mental hospital. Shortly before the injection the patient had taken fenemal (which was found in the stomach contents) without the knowledge of the doctor and without showing any sign of it at the time of the injection. He died five to six hours after the injection. The rapid death cannot be accounted for by the concentrations of barbiturates shown in the organs, and the injection may be presumed to have contributed to the death.

II. The second case (No. 1199/1948) occurred in a delicate, underweight woman (45 kg), a drug addict, who had been having large daily intravenous injections of morphine (150 to 200 mg, or 3.3 to 4.4 mg/ kg) and of barbiturates (0.4 g) from her doctor. She became more and more inert and helpless but still complained, and in the last few days could hardly lift an arm. Finally she became completely unconscious and died. It seems highly probable that death was due to the prolonged heavy dosage of morphine and barbiturates. Autopsy did not reveal any cause of death. The result of the chemical examination corresponded to the case history.

III. In this case (Ser. No. 1375/1950). a very restless male mental patient (in hospital) received every day for eight days 0.5 g diemal ( per os) plus 1.0 g chloral hydrate plus 0.25 mg/kg subcutaneous morphine hydrochloride plus 12.7 µg/kg subcutaneous scopolamine hydrobromide. He died five hours after the last injection. The case is made difficult to assess because the autopsy disclosed an infarct in a lung. No thrombi could be seen with the naked eye but a few appeared under the microscope. This might mean that a circulatory stimulus was present and caused the death. It is, however, fair to stress that there can be no proof that the heavy doses of narcotics led to the death, even if there was a circulatory stimulus. The chronic diemal poisoning which gradually set in (diemal is very cumulative) was reinforced by the injections of morphine-scopolamine.

This case should in my opinion suggest the query whether the "chemical strait-jacket" which has replaced the old mechanical strait-jacket for restless patients may not occasionally present a serious danger.

IV. This case (Ser. No. 1429/1950) is much like the previous one (No. III). A woman mental patient with a strong craving for drugs had been receiving fenemal for a considerable period. During the ten days before she was due to be admitted to the mental hospital she received every day an injection of 0.43 mg/kg of morphine hydrochloride plus 8.3 µg/kg of scopolamine hydrobromide (presumably subcutaneously). After the last injection she at once became very limp and fell asleep, dying about twenty minutes later. The cause of death was not shown at autopsy, and the result of the chemical examination corresponded to the ordinary findings in chronic fenemal poisoning. It may therefore be assumed that death was due to the injections of morphine and scopolamine in a person already suffering from chronic barbiturate poisoning.

In the last case of all the patient received a dosage of narcotics which it would be charitable to call injudicious.

Case 13. (Set. No. 1272/1949). N., a salesman's wife of 29, weight 78 kg.

N. had fallen from a horse five years before and suffered periodically from severe headaches. During the last month she had not felt well and had stayed in bed. On 14 February she got up.

During her earlier spells of illness she had received from her doctor injections of up to 60 to 70 mg of morphine and scopolamine, but not during the last time before 18 February.

On 18 February she fainted and had severe pains at her menstrual period. For the menstrual pains her doctor injected at 8.45 p.m. 35 mg of morphine hydrochloride plus 0.1 g of allypropymal plus 0.1 g of diemal (as hypnophen) intravenously. As at 10 p.m. the pains had not gone, the doctor injected, again intravenously, 15 mg of morphine hydrochloride plus 0.1 g of allypropymal plus 0.1 g of diemal. She then fell asleep. Details of her condition after the injection are lacking. Next morning, 19 December, at 8.30 a.m. a nurse who was summoned thought she could feel a weak pulse, but when very shortly afterwards a doctor arrived N. was dead, about ten and a half hours after the last injection.

The autopsy did not show anything in particular.

Chemical analysis. Barbiturates: Liver, 0.7 mg per cent, traces in muscle. Morphine was shown in the urine but not in the stomach contents. Alcohol was not found.

Comment

The autopsy did not reveal any morbid changes which could account for the death. The barbituric acid concentration in the organs corresponds closely to the information on the amount of barbiturates injected. Morphine was found but no alcohol. There was no indication that N. had been able to get at any morphine herself.

During 1? hours the doctor injected in all 50 mg, or 0.64 mg/kg, of morphine hydrochloride and 0.4 g of barbiturates, and death occurred about ten hours later. As no other cause of death could be shown, the reasonable explanation of the death is that it was due to the very large intravenous injections of morphine plus barbiturates. Even if N. had been supposed to be a drug addict, she could not be described as a real morphine taker, as she only received it periodically. That menstrual pain should never be an indication for morphine need merely be mentioned.

DISCUSSION

Morphine injected into a healthy adult in doses of 50 to 60 mg will usually produce a deep sleep lasting a variable time, from which the patient can be awakened only with difficulty if at all. To suppress the reflexes - heavy poisoning - often requires a dose, subcutaneous, of about 100 mg (about 1.4 mg/kg). It is usually agreed that the minimum lethal dose of morphine, given subcutaneously, is in the neighbourhood of 100 mg. Death most frequently occurs in ten to twenty-four hours. The toxic and lethal doses of scopolamine are difficult to determine, as the effect of this substance is so variable.

In all the seven cases of alcoholism the patient had had a high concentration of alcohol in the blood when the morphine, etc., was injected. In one case the concentration may be put at about 1.8 per thousand, and in the others between about 2.2 and 2.7 per thousand. As I said in more detail above, it may be presumed that the injections of morphine, etc., were the direct cause of death in all the six patients and probably in the seventh as well (case 5). This may signify that the morphine, etc., acted synergically with the alcohol.

The literature, as we know, records no investigations concerning synergism between alcohol and morphine (though it records some on synergism between alcohol and barbiturates, which will be dealt with in a later paper). Pharmacologically, alcohol is very closely related to ether and other narcotics; thus alcohol can produce a deep, reflexless anaesthesia. It is clinically well known that premedication with 10 to 20 mg of morphine reduces the amount or concentration of narcotic necessary to induce anaesthesia. I have found only one paper reporting a quantitative investigation carried out in man relating to this question. Turpeinen (1944) determined the ether concentration in the blood of persons in a precisely-defined stage of anaesthesia both with and without premedication, and found in patients who had received 10-12 mg of morphine hydro-chloride plus 0.15 mg of atropine sulphate an ether concentration of barely 25 per cent, and in patients who had received 20 mg of morphine hydrochloride plus 0.6 mg of scopolamine hydrobromide one about 50 per cent lower than in patients who had not received any morphine, etc. The author concludes from this that the synergy between morphine and ether is not additive but intensifying (for intensification, see, for example, Müller, pp. 9 and 214).

One would expect at first sight morphine and alcohol to be synergetic. Whether the synergy is intensifying we do not know, though Turpeinen's work suggests that it may be.

The reported cases show that in a certain number of these the injection of 0.3 to 0.4 mg/kg of morphine (cases 2, 3 and 4) caused death in persons with a blood-alcohol content of 2.2 to 2.5 per thousand. Fatal alcoholic poisoning (where no other narcotic is administered) may occur with an alcohol concentration of 3 to 4 per thousand,1 and fatal poisoning may result, as has been stated, from a concentration of about 1.4 mg/kg of morphine. If the minimum lethal concentration of alcohol is set at 3.5 per thousand, it may be very roughly reckoned that in the three cases mentioned (cases 2, 3 and 4) the blood-alcohol concentration reached about 62 to 70 per cent of the minimum lethal alcohol concentration and the injected dose of morphine about 20 to 25 per cent of the minimum lethal dose of morphine. These very rough calculations obviously do not permit a decision whether the synergy between morphine and alcohol is additive or intensifying. The answer may be given by future experiment.

My object in giving these very approximate calculations is to emphasize that pharmacologically it is by no means surprising to observe that therapeutic doses of morphine can cause death in persons heavily affected by alcohol. The thing to remember first and foremost is that the margin between the alcohol concentration that makes a person thoroughly drunk and that which kills him is very narrow. (It is well known that the concentration of ether, a close relative of alcohol, needed to produce not particularly deep anaesthesia is about 70 per cent of the concentration which will produce respiratory paralysis.)

We have had such cases in the Institute for investigation.

The fact of synergy between morphine and barbiturates is well known both in the practice of anesthesia and in the laboratory, but we know of no precise investigation of its nature. One case (case 8) shows that bromides also can act in synergy with morphine and the like.

The practical therapeutic conclusions of the material here presented should be carefully considered. The injection of morphine, etc., into persons affected by narcotics may be the last straw which breaks the camel's back.

If it is true that ordinary therapeutic doses of morphine or of morphine-scopolamine are dangerous to life and sometimes fatal if given to persons already under the influence of alcohol, barbiturates or bromides, the necessary conclusion must be that morphine and morphine-scopolamine, barbiturates and related substances are contra-indicated for persons under the influence of narcotic poisons. In other words, before a doctor 'gives or prescribes these substances he ought always to consider whether in the particular case there is reason to suppose that the patient is already under the influence of narcotics. It will naturally be impossible in every case to be certain that this contra-indication is not present. In the short case report No. I (Ser. No. 1210/1948) the patient had taken fenemal just before the doctor arrived and was showing no sign of it when the injection was given. On the other hand, in case No. 9 the doctor injected morphine-scopolamine although he had been expressly warned that the patient had taken fenemal; and in case No. 6 the patient was obviously intoxicated when the injection was given.

It appears from the case reports that in a relatively large number of cases the fatal morphine or morphine-scopolamine injections were given intravenously. There can be no doubt that the danger of poisoning from these substances is considerably greater when they are given intravenously than subcutaneously. The very high temporary concentration in the blood caused by an intravenous injection can have such a strong depressive effect on the respiratory and vasomotor centres that a vicious circle is set up which, assisted by the lower but persisting concentration of morphine, etc., in the blood, produces a fatal impairment of the vital functions.

Moreover, euphoria is specially intense after an intravenous injection, and an intravenous injection of morphine has in many cases led to morphine addiction. For the reasons given, morphine and related substances should be injected intravenously only in very rare cases, and then only in moderate doses. I derive the impression from many cases that intravenous morphine is given relatively often in Denmark.

I am well aware that this question will be asked: what is a doctor to do with a patient in a state of strong excitement caused by alcohol or barbiturates ? The only answer I can give is that the condition should never be treated with drugs; the only effective ones here are narcotics, and they endanger life and are sometimes fatal.

There remains, besides the problems dealt with here, the other problem of the simultaneous effect of alcohol and barbituric acid. This will be considered in another paper.

SUMMARY

1. An account is given of a series of cases showing that the injection of therapeutic doses of morphine or of morphine-scopolamine into persons already suffering from the effects of alcohol, barbiturates or bromides in non-lethal quantities may cause death, often with the characteristic symptoms of morphine poisoning.

2. Morphine works synergetically with alcohol, barbiturates and bromides.

BIBLIOGRAPHY

Behr, L. D., J. W. Palmer and H. T. Clarke: J. Biol. Chem. 88: 131, 1930.

Bonnichsen, R. K. and H. Theorell: Scand. J. Clin. and Lab. Invest. 3: 58, 1950.

Gundry, L. P.: J.A.M.A. 113, 466, 1939.

Halström, F.: "Om Stofidentifikation i den forensiske Kemi" (Identification of substances in forensic chemistry). Copenhagen, 1940.

Huang, Tso-Jueh and B. Jerslev: Acta pharmacol, et toxicol. 7: 227, 1951.

Müller, K. O.: Farmakologi, 4. publ. Copenhagen, 1952, p. 642.

Turpeinen, E.: "Etude sur la teneur en ether du sang chez l'homme pendant l'anesthésie générale combiniée avec la scopolamine- morphine" (Study of the blood-ether content in man during general anaesthesia combined with morphine-scopolamine). Acta chirurgica Scand. 1944, vol. 90, suppl. 87.

Tennesen, M.: Acta pharmacol, et toxicol. 4: 186, 1948.