Forensic Science, 10 (1977) 127 - 132 @ Elsevier Sequoia S.A., Lausanne -Printed
in the Netherlands
ACCIDENTAL FATAL DRUG POISONING RENCE TO DEXTROPROPOXYPHENE
WITH PARTICULAR
127
REFE-
J@RN SIMONSEN University mark)
Institute
of Forensic
Medicine,
J. B. Winslbwsvej
17, DK 5000 Odense C (Den-
(Received January 12, 1977 ; accepted in revised form May 26,1977)
SUMMARY A rapid increase in fatal accidental dextropropoxyphene poisonings which is proportional to the increased use of the drug is reported. In 30 accidental poisonings dextropropoxyphene was responsible for 5O’F of the cases, and is the most common accidental medical poisoning at the present time. This is probably due to the unappreciated narrow margin between therapeutic and fatal dose and the simultaneous intake of alcohol which increases the resorbtion speed from the gastro-intestinal tract. In Denmark a slow-release preparation is frequently used, which is especially dangerous because of repeated dosage by the patient attempting to induce the therapeutic effect more quickly.
INTRODUCTION
Institutes of Forensic Medicine have a unique opportunity to determine and record the causes and the manners of death, and to issue statistics based on their observations. These institutes help guard the Public Health Standards of Society, in part by passing on their experience to the public with the purpose of warning against various potential dangers. This is one of the reasons why narcotic deaths, deaths during work, etc, are subjected to extensive police and medical investigations in most developed countries. One particular aspect of this problem is that of undesired side effects from new drugs used in medical treatment. Since the first fatal dextropropoxyphene poisoning was reported in the early sixties [l] an increasing number of fatalities due to this drug have been reported, especially from U.S.A. and Scandinavia [2-71 but not exclusively so [8]. Most reports have dealt with only one or a few cases, and these publications have almost exclusively dealt with accidental dextropropoxyphene poisonings amongst drug-addicts or drug-abusers, mainly administering the drug intravenously. Only a few suicidal poisonings have been reported. Recently, larger series have been reported from Sweden and Denmark [9, lo]. In a preliminary publication from this Institute [ll] the incidence of accidental fatal dextropropoxyphene cases was 41% of all accidental fatal drug poisonings. The first 7 cases in this series were collected over a period of 3 years, but the next 8 cases occurred over 1 year 9 months. Now the
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accidental fatal dextropropoxyphene cases have contributed to 50% of the number of accidental fatal drug-poisonings. Since this experience seems to be in accordance with that of other. institutes in this part of the world the author feels obliged to draw attention to the problems involved. MATERIAL
This report covers 30 cases of accidental death due to drug overdose between February 1, 1972 and September 30, 1976. This institute of Forensic Medicine serves a population of 0.7 million, and these cases amount to approximately 3.5% of the number of autopsies in the period concerned. Dextropropoxyphene analyses were carried out by the method described by Christensen [lo]. A poisoning was accepted as accidental only if there was no information about suicidal intensions, no psychiatric history and nothing at the scene which pointed towards suicide. The number of cases is without doubt a minimum since all doubtful cases have been excluded. The drugs involved, and relevant details of the cases are given in Table I. Sex distribution was equal and the average age was 42 years (youngest 19 years; oldest 84 years). In 15 cases (50%) dextropropoxyphene was involved; solely in 9 cases, in combination with alcohol in 4 cases and with barbiturates in 2 cases. Of the remaining 15 non-dextropropoxyphene cases, 6 were mainly due to barbiturate poisoning, 5 were due to morphine or morphinelike drugs, 2 cases were the result of an overdose with salicylic acid, and one case each of overdosage with chloroquine and orphenadine respectively. It is interesting to note that accidental fatal poisoning with dextropropoxyphene was responsible for almost three times as many cases as any of the other drugs. Also 11 (37%) of the subjects were drug-abusers or drug-addicts, 3 (10%) were alcoholics, and one occurred in an epileptic using barbiturates constantly. The remaining 15 cases had no evidence of heavy medication, but 5 of these were suffering from chronic diseases. Six typical fatal dextropropoxyphene cases are presented in detail below. Case histories Case 3
A 23 year old man who had become an abuser of light analgesics (salicylic acid combined with small amounts of codeine) after a severe accident 7 years previously. He took lo-12 tablets daily, but recently his physician changed to slow-release dextropropoxyphene capsules. He was found dead 3 days later. Toxicological examination revealed dextropropoxyphene poisoning as the cause of death. Case 12
A 51 year old female who had moderate drug abuse for the past 10 years was found depressed by her husband who immediately took her to hospital.
129 TABLE
I
Accidental 1976
fatal drug-poisonings
during the period February
1, 1972September
30,
No
Age/sex
Toxicology
Comments
1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30
38 57 23 57 63 30 41 53 36 84 39 51 19 70 31 30 36 27 63 24 43 27 65 19 21 19 54 34 57 57
Pethidine Dextropropoxyphene + barbiturate Dextropropoxyphene Barbiturate + alcohol Chloroquine Barbiturate Salicylic acid Morphine + gluthethimide Barbiturate Dextropropoxyphene Orphenadine Dextropropoxyphene Dextropropoxyphene + alcohol Dextropropoxyphene Dextropropoxyphene Barbiturate + alcohol Barbiturate Barbiturate Dextropropoxyphene Dextropropoxyphene Dextropropoxyphene + alcohol Dextropropoxyphene + barbiturate Dextropropoxyphene Methadone Dextropropoxyphene + alcohol Morphine + alcohol Salicylic acid + codeine Pethidine + alcohol Dextropropoxyphene + barbiturate Dextropropoxyphene + alcohol
Drug-addict Drug-abuse Drug-abuse
d d d
Q Q
d d
Q Q Q
d 0 d d
Q Q
d d
Q Q
d d d d d
Q Q d
Q Q
Arthritis
Alcoholic Drug-abuse
Epileptic Alcoholic Drug-addict Arthritis Drug-addict Drug-addict Drug-addict Renal failure Drug-addict Drug-addict Drug-addict Arthritis Alcoholic Arthritis
The duty physician confirmed her depressed state, but because she was able to react adequately to questions he considered that there was no cause for alarm and she was allowed to return home. There she immediately fell asleep, and when her husband found her unconscious 5 hours later he called a physician who pronounced her dead. A bottle containing slow-release dextropropoxyphene casules was found in the bedroom. Toxicological examination proved death due to dextropropoxyphene poisoning. Case 13 A 19 year old man, who was not an addict or a drug-abuser, bought several capsules of dextropropoxyphene and swallowed 8 during a short period of time due to their apparent lack of effect. After two hours he became comatose and one hour later he was found dead. Toxicological
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examination revealed the cause of death to be dextropropoxyphene poisoning and a blood alcohol concentration of 0.17%. The capsules were of the slow-release type. Case 15 A 31 year old obese female, not known as a drug-abuser by the family or the physician, was found on the floor convulsing and froth issuing from her mouth. The husband misinterpreted the attack as being an epileptic fit, which he was familiar with from his own family. However, there was no history of his wife ever having previously suffered from such an epileptic attack. When the convulsions stopped he covered her with a blanket and went to sleep. When he woke up 4 hours later her death was evident. In her room an empty bottle which had contained dextropropoxyphene capsules was found. A cause of death due to dextropropoxyphene poisoning was confirmed by toxicology. The house-physician did not remember that he had given her a prescription for the capsules a few weeks previously. 19 A 63 year old female who during the past 30 years had been confined to a wheel-chair because of chronic poly-arthritis. In spite of her severe handicap she was known to be a happy individual and had never shown signs of mental depression. One morning she was found dead in bed, apparently having been quite alert and happy the previous evening. Dextropropoxyphene medication had been prescribed for the poly-arthritis. Death was considered to be due to natural causes until toxicological examination revealed a fatal blood concentration of dextropropoxyphene. Case
Case 23 A 65 year old man, who received a head injury 7 years previously, known to be a drug-abuser, including the use of phenacetin. Because he developed mild renal failure his physician changed his medication to dextropropoxyphene capsules. Shortly after the patient was found dead. The cause of death was initially considered to be due to natural causes; however, toxicological analysis revealed a high dextropropoxyphene concentration in the blood.
DISCUSSION
In this series of cases the most common cause of fatal accidental drugpoisoning was dextropropoxyphene, accounting for 50% of the cases. Barbiturate poisonings were responsible for 20% of deaths, and morphine for 17% of the fatalities. The high incidence of dextropropoxyphene poisonings accords with the increased use of the drug, as has been found by other investigators [12, 131. The most common drugs used for suicide in Denmark are still the barbiturates; and the number of suicides due to barbiturates over the
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4% year period covered by this report were in excess of the number of accidental fatal barbiturate poisonings. Thus, over the same period of time, in which there were 15 accidental dextropropoxyphene poisonings, this institute investigated only 8 fatal dextropropoxyphene poisonings where suicide was questionable. Thus, the public apparently appreciate the hazards of barbiturates but not those of dextropropoxyphene. This conclusion was also reached by Finkle et al. [3]. Additionally, it appears that physicians are not aware of the dangers involved with dextropropoxyphene. In two of the cases reported here (3 and 23) the physician changed from a comparatively harmless drug, used heavily by the patient, to dextropropoxyphene. As a result the patients who continued to take the same number of tablets died within a short time of the change in medication. In such cases it seems reasonable to conclude that the physician himself was not aware of the narrow margin between the therapeutic and the fatal dose. The most interesting cases are numbers 19 and 23. In these 2 cases the deceased was elderly and suffering from chronic disease. The cause of death in both cases was considered natural until it was coincidently shown that there were high blood dextropropoxyphene levels, sufficient to account for death. The only reason that these cases came to medicolegal investigation was the fact that they died alone and for this reason required to be investigated according to the Danish law. If another person had been present at the time of death there is no doubt that a death certificate stating death as due to natural causes would have been issued. This raises the question of how many undiscovered cases of dextropropoxyphene poisoning are wrongly registered as due to natural death. This point has also been raised by Kaul and Harsfield [15]. This underlines the requirement for ready availability to toxicological examinations in connection with investigation of deaths in Denmark. The question has been raised, if fatal cases occurring in drug-addicts or drug-abusers could be avoided. The fact that dextropropoxyphene chloride is easily soluble in water whereas dextropropoxyphene napsylate is not could be relevant. Thus, studies in dogs using orally administered equimolar doses of the hydrochloride and napsylate showed a thirty fold increased plasma concentration of the former at one hour after administration [14]. Since the napsylate is more than 1300 times less soluble in water than the hydrochloride it should also be less attractive to drug-addicts for intravenous administration. Also, after oral intake the plasma concentration increases slower after intake of the napsylate than after hydrochloride intake [ 151. It has previously been pointed out that the slow-release dextropropoxyphene preparation is dangerous and has been responsible for the majority of fatal cases [ 10-121. In the present series slow-release capsules were involved in 8 cases, the standard preparation in 4 and in the remaining 3 cases the preparation could not be determined. The use of the slow-release dextropropoxyphene preparation combined with alcohol intake is considered extremely dangerous [g-12], since the release of the drug from the slow-release preparation is accelerated in the
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presence of alcohol [ 141. The number of cases reported here is too small to allow comment on this point. A further problem with the slow-release preparation is that the person may not exhibit severe signs of poisoning when examined by a physician. Several such cases with fatal outcome have been reported; in the present series Case 12 is typical. This patient was discharged from the hospital and found dead at home a few hours later. Probably because of the problems outlined above the Danish Drug Company responsible for the manufacture of the slow-release dextropropoxyphene capsules has printed a warning on the bottle against the repeated use of capsules and drawn attention to the fact that such repeated dosage can be dangerous. It is recommended that the label should bear a warning against taking alcohol with the drug.
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