Special article Acute overdosage with benzodiazepine derivatives* A total oi 773 admissions to Massachusetts General Hospital between 1962 and 1975 were due to acute overdosage with one or more psychotropic drugs. Benzodiazepine derivatives were involved in 99 oi these cases (13%), and the jrequency oi benzodiazepine overdosage, particularly with diazepam, increased relative to other psychotropic drugs over the years. Only 12 admissions were due to benzodiazepine overdosage alone, and none oi these patients were seriously ill or had significant complications. Multiple drugs were ingested in the other 87 cases, and the jrequency and severity oi complications among these individuals depended upon the type and quantity oi other nonbenzodiazepines taken. For example, 21 oi 31 patients who ingested benzodiazepines together with barbiturates experienced severe central nervous system (CNS) depression, and 14 oi 31 required assisted ventilation. However, the irequency oi such complications was nearly identical in a group oi patients who ingested barbiturates alone. This report and a review oi the literature suggest that serious intoxication iollowing overdosage with a benzodiazepine derivative alone is unusual. Ingestion oi benzodiazepines together with other drugs appears to be considerably more common than benzodiazepine overdosage alone as a cause oi intoxication. The severity oi intoxication in such cases oi multiple drug ingestion probably depends largely on the type and quantity oi nonbenzodiazepines.

David J. Greenblatt, M.D., Marcia D. Allen, R.N., Barbara J. Noel, B.S.N., and Richard I. Shader, M.D. Boston, Mass.

Clinical Pharmacology Unit, Massachusetts General Hospital, and Psychopharmacology Research Laboratory, Massachusetts Mental Health Center

Benzodiazepine derivatives are extensively used as sedative, hypnotic, and antianxiety drugs by adults throughout the world. 10, 39, 40, 45 An inevitable consequence of the widespread therapeutic use of benzodiazepines is their increasingly common implication in cases of deliberate or accidental overdosage. The social Supported in part by Grant MH·12279 fram the United States Public Health Service and by a Grant·in-Aid fram Hoffmann-La Roche Inc. Reprint requests to: Dr. David J. Greenblatt, Clinical Pharmacology Unit, Massachusetts General Hospital, Boston, Mass. 02114. 'Publication costs have been defrayed by support from Hoffmann-La Roche Inc.

and medical implications of this trend are of great importance and subject to considerable controversy. Many claim that benzodiazepine derivatives have a very low order of toxicity and are seldom responsible for serious or fatal intoxication. 25 , 39, 41, 42, 66, 71, 109 üthers, however, suggest that these drugs can and do cause death through overdosage. 5, 21 We investigated the incidence and consequences of benzodiazepine overdosage among patients admitted to Massachusetts General Hospital between 1962 and 1975. We also present a comprehensive review of the literature on the subject. 497

498

Greenblatt et al.

Clinical Pharmacology and Therapeutics

Table I. Benzodiazepine derivatives eneountered in the present clinieal study and literature review Generic name

Abbreviation

Trade name( s)

Chlordiazepoxide Diazepam Oxazepam Flurazepam CIorazepate Clonazepam Nitrazepam* Lorazepam*

CDX

Librium (many others) Valium Serax Dalmane Tranxene Clonopin Mogadon Ativan

DZ OXZ FLZ CZP CNZ NTZ LRZ

*Not currently available in the United States.

Table 11. Proportion of psyehotropie drug overdosage eases in whieh benzodiazepine derivatives were involved

Time period

Admissions due to psychotropic drug overdosage *

With benzodiazepines involved Number

1962-1966 1967-1971 1972-1975

226 297 178

18 40 35

I

%

8.0 13.6 19.7

*For patients with multiple admissions. only the first was tabulated.

Methods

The Massachusetts General Hospital is a 1089-bed general medical center. For all patients admitted between 1962 and 1975, diagnoses were coded descriptively and numerically and stored on magnetic tape. Patients whose diagnoses were consistent with self- infticted injury, deliberate or accidental self-poisoning, or attempted suicide were identified by computer. A research nurse (M. D. A. or B. J. N.) reviewed the medical records of all such patients 15 years of age or more. As in previous studies,37, 38 pertinent data were recorded on a standardized form, and the excerpted c1inical summaries were used to prepare this report. The severity of central nervous system depression was rated by the research nurse using the following system of Matthew and Lawson 72: grade 1, drowsy but response to verbal stimulation; grade 2, response to mild painful stimulation;

grade 3, minimum response to maximum painful stimulation; grade 4, no response to maximum painful stimulation. Results

The number of medical admissions to Massachusetts General Hospital between 1962 and 1975 was 97,994 (average, 7,538 per year). A total of 773 admissions (0.8% of the total), involving 701 patients, were attributable to accidental or deli berate overdosage with a psychotherapeutic drug. This total does not inc1ude 35 admissions for which the hospital record was lost, confidential, or otherwise unavailable for administrative reasons. Analysis of cases treated in the emergency room and discharged without hospital admission was not possible, since computerized records of the diagnoses of such patients are not available. Review of these records revealed 99 admissions, involving 93 patients, in whom c1inical findings or toxicolögic analyses indicated that a benzodiazepine derivative (Table I) was among the drugs ingested. Diazepam* was the most common (52 instances), followed by chlordiazepoxide (48 instances). Flurazepam was involved in 3 cases, oxazepam in 2, and c1orazepate in 1. In 7 cases more than one benzodiazepine was taken. Patient ages ranged from 15 to 80 years (mean, 35). Sixty of the pati~nts were female, and 33 were male. The mean ages of male and female patients were nearly identical (33 and 35 years). None of the patients died. Analysis of overdosage patterns over time indicated an increasing frequency of benzodiazepine ingestion relative to all cases of psychotropic drug overdosage (Table II). During the last five years diazepam became the most commonly used benzodiazepine derivative, consistent with its extensive availability and use for therapeutic purposes. In only 12 of the 99 cases was a benzodiazepine implicated as the only drug taken (Table 1II); multiple drug poisonings were much more common. In 50 cases, central nervous system depression reached grades 3 or 4, and in 32 cases assisted ventilation was re*See Table I for trade names of drugs.

Benzodiazepine overdosage

Volume 2/ Number 4

499

Table III. Summary of overdosage cases involving benzodiazepines admitted to Massachusetts General Hospital, /962-/975

Category Benzodiazepines alone Benzodiazepines with ethanol Benzodiazepines with other nondrug complications Benzodiazepines with analgesics* Benzodiazepines with nonbarbiturate sedative-hypnotics* Benzodiazepines with other psychotropic drugs* Benzodiazepines with barbiturates* Benzodiazepines with miscellaneous drug combinations* Total

Number requiring assisted ventilation

Number of patients

Number of admissions

Number with Grade 3 or 4 CNS depression

12 3 3

12 3 3

2

1

0

0

9 12

9 14

3 7

2 3

18

21

11

9

31 5

31

21

6

6

14 3

93

99

51

32

0

'With or without ethanol.

quired. However, the severity of the overdosage syndrome depended strongly on the drug or combination of drugs taken. Benzodiazepines alone. In 12 cases poisoning was attributed to one or more benzodiazepine derivatives alone (Table IV). The largest doses were approximately 2,500 mg of chlordiazepoxide and up to 400 mg of diazepam. Only one of the 12 patients reached stage 3 coma, and none required assisted ventilation. All patients were discharged without sequelae within 2 days of admission. Benzodiazepines with ethanol. In 3 cases a benzodiazepine was taken together with ethanol, but with no other drugs. Two of these patients reached grade 3 or 4 coma, and one required assisted ventilation. One patient (No. 15) developed hypotension that required treatment with pressor drugs. Benzodiazepines with nondrug substances or other complications. In 3 cases benzodiazepine overdosage was complicated by other methods of self-harm, including ingestion of pai nt thinner (No. 16), inhalation of carbon monoxide (No. 17), and a self-infticted abdominal gunshot wound. In none of these patients did coma exceed grade 1. Benzodiazepines with analgesics. Aspirin,

propoxyphene, or combination analgesics (Percodan) were taken together with benzodiazepines in 9 cases. In several of these instances, ethanol was also taken. Three of the patients reached grade 3 or 4 coma, and 2 required assisted ventilation. All patients were discharged within 3 days of admission. Benzodiazepines with nonbarbiturate sedative-hypnotics. Twelve patients, including two who were admitted twice, took benzodiazepines together with non barbiturate central nervous system depressants, such as methyprylon, chloral hydrate, meprobamate, glutethimide, promazine, or diphenhydramine. In many cases, ethanol was also taken. Grade 3 or 4 coma was reached in 7 instances, and in 3 cases assisted ventilation was required. The most seriously intoxicated of these patients (Nos. 31 and 36) ingested glutethimide and had plasma glutethimide levels exceeding 15 fLg/ml. One case (second admission of Patient 36) was deeply comatose, hypothermie, hypotensive, and required tracheostomy. This patient recovered after 19 days of hospitalization. Benzodiazepines with other psychotropic drugs. A variety of other psychotherapeutic drugs (antidepressants or antipsychotic drugs) were taken together with benzodiazepines in 21

500

Greenblatt et al.

Clinical Pharmacology and Therapeutics

Table IV. Cases of benzodiazepine overdosage

Case No.

Age/ sex

Benzodiazepines 1 26/F 2 40/F 3 31/M 4 48/F 5 20/F 47/M 6 29/F 7 33/F 8 56/M 9 10 31/F 11 39/F 12 16/F

13

61/M

14

30/M

15

32/F

Drug(s) ingested and dosage alone or with ethanol DZ, ~300 mg DZ, ~150 mg DZ, 200-400 mg CDX, ~2500 mg CDX, 100 mg CDX, 400 mg DZ, 38 mg CDX, 1200 mg CDX, 800 mg CDX, 2000 mg DZ, ~55-60 mg DZ, 120 mg FLZ, 60-90 mg CDX, 300-400 mg Ethanol CDX, ? dose Ethanol DZ, ? dose Ethanol

Deepest coma (grade)

0 0 0 0-1

1 1 2

I I

1 2

1 1 1 1 1 3

I

24

26/F

25

46/F

DZ, 150-250 mg Propoxyphene, 3250 mg CDX, 90 mg ASA, 19.5 gm ? Barbiturate

Comments

Transient hypotension (82/42 mm Hg)

I

1 2 I I

1 2 Assisted ventilation for 8 hr

3 4

Benzodiazepines with non-drug substances or other complications DZ, 500 mg 16 76/M FLZ, 300 mg Paint thinner DZ, 40 mg 17 46/F Carbon monoxide 18 CDX, 500 mg 23/F Benzodiazepines with analgesics* CDX, 600 mg 19 19/F ASA, 15 gm 20 CDX, 250 mg 21/F Darvon eompound, 10 eapsules DZ, 20 mg 21 16/F ASA-eontaining analgesie, 15 tablets 22 23/F CDX, 30 mg ASA, 16 gm DZ, 225 mg 23 45/F Propoxyphene, 1950 mg Ethanol

Duration of hospitalization

5

Blood alcohol level, 194 mg/100 ml Hypotension (60/0 mm Hg) requiring pressors

4

14

Self-inflicted abdominal gunshot wound requiring surgery

0 0 0

Blood salieylate level, 2 mg/100 ml

0

Blood salicylate level, 57 mg/ I 00 ml

2-3

3

2-3

2

0

Blood alcohol level, 296 mg/100 ml Hypotension (80/60 mm Hg) treated with eolloid Vomited and aspirated Assisted ventilation for 4 hr Transient hypotension (90/0 mm Hg) Assisted ventilation for I hr Blood salieylate level, 66.5 mg/100 ml; barbiturate level, 12 ILg/ml

Benzodiazepine overdosage

Votume 2/ Number 4

501

Table IV. Cont' d

Case No.

Age/ sex

26

17/M

27

30/F

Drug(s) ingested and dosage CDX, 200-300 mg Darvon compound, 11 capsules Ethanol DZ, 100-125 mg Percodan, 10 tablets Phenobarbital, ? dose

Benzodiazepines with nonbarbiturate sedative-hypnotics * 28 CDX, ~120 mg 23/F Methyprylon, ~360 mg Ethanol CDX, ? dose 29 35/F Chloral hydrate, 5-6 gm Ethanol CDX, 300 mg 30 30/F DZ, ? dose Chloral hydrate, 1.0 gm 31 CDX, 40 mg 15/M Glutethimide, 12 gm 32

29/F

32

34/F

33

27/M

34

42/F

35

35/M

36

CDX, ? dose Meprobamate, ? dose CDX, -100 mg Prornazine, ? dose CDX, 800 mg Meprobamate, 2.8-3.2 gm

Deepest coma (grade)

Duration 01 hospitalization

3-4

Comment Minor motor seizures

0

Apneic episodes

2-3 2-3

4

6

Blood glutethimide level, 34 fLg/ml on admission; later, 48 fLg/ml Assisted ventilation for ~8 hr Aspiration pneumonitis

8

Episode of oliguria (~30 ml/hr) treated with parenteral fluid Urinary retention

5

Blood glutethimide level, 24 fLg/ml; barbiturate level, 7 fLg/ml Grand mal seizures during recovery Blood barbiturate level, 16 fLg/ml; glutethimide level, 10 fLg/ml Transient hypotension (82/50 mm Hg) Assisted ventilation for -18 hr Blood glutethimide level, 17 fLg/ml Hypotenstion (70/0 mm Hg) requiring colloid and pressors Hypothermia (temperature, 94° F) Assisted ventilation for ~4 days Laryngeal edema requiring tracheostomy Gastrointestinal bleeding Delirium during recovery

0 3 0

CDX, ? dose Meprobamate, ? dose ? Barbiturate CDX, ? dose Glutethimide, ? dose

3

44/F

DZ, ? dose Glutethimide, ? dose Chlorpheniramine, ? dose

3

4

36

44/F

DZ, ? dose Glutethimide, ? dose

4

19

37

23/F

CDX, -50 mg Diphenhydramine, - 100 mg Ethanol

4

502

Greenblatt et al.

Clinical Pharmacology and Therapeutics

Table IV. Cant' d

Case No.

Age/ sex

Drug(s) ingested and dosage

38

33/M

39

27/M

CDX, 750 mg Chloral hydrate, 4-5 gm Ethanol ? Barbiturate CDX, 300 mg Diphenhydramine, 1000 mg Ornade, 30 capsules ? Barbiturate

Benzodiazepines with other psychotropic drugs* 40 DZ, 190 mg 66/F Perphenazine, 120 mg Amitriptyline, 625 mg 41 DZ, 50 mg 32/M Imipramine, 500 mg ASA, 15 gm Ethanol 42 CDX, 1500-2000 mg 21/M Amitriptyline, 250-300 mg 43 CDX, ? dose 59/F Amitriptyline, ? dose 44 CDX, 2000 mg 40/F Haloperidol, 3-6 mg Amitriptyline, 300 mg ASA, ? dose 45 CDX, ? dose 31/F Amitriptyline, ~ 1250 mg Ethanol 46

49/F

47

34/M

47

34/M

48

27/M

49

39/F

50

27/F

51

34/M

Deepest coma (grade)

Duration oi hospitaliza!ion 3

1-2

Comment Blood barbiturate level, 6 p,g/ml Pneumonia

3

3 3

Blood salicylate level, 23.5 mg/lOO ml Pneumonia

2

7

Blood salicylate level, 44.5 mg/lOO ml Tachycardia (l20/min) Aspiration pneumonitis

2-3

2

DZ, 30-35 mg Amitriptyline, 500 mg ASA,1.5gm CDX, 250 mg Doxepin, 450 mg Triavil, 8 tablets Ethanol CDX, ? dose Doxepin, ? dose Triavil, ? dose Ethanol

2-3

3

3

4

Blood CDX level, 7.6 p,g/ml; alcohol level, 160 mg/lOO ml Assisted ventilation for ~ 18 hr Tachycardia and ECG abnarmalities Blood salicylate level, 14.5 mg/lOO ml Hypothermia (rectal temperature, 95° F) Assisted ventilation for ~ 2 days Blood alcohol level, 230 mg/lOO ml Assisted ventilation for ~2 days Pneumonia

3

5

Blood alcohollevel, 268 mg/lOO ml Hypotension (80/50 mm Hg) treated with colloid and pressors Assisted ventilation for ~ 2 days Pneumonia

DZ, 350 mg Triavil, ? dose OXZ, 300 mg Amitriptyline, 500 mg Ethanol DZ, ? dose Etrafon, ? dose

3 2-3

2

Blood alcohollevel, 63 mg/lOO ml Assisted ventilation for 12 hr

4

8

Hypotension (60/20 mm Hg) Assisted ventilation far ~ 2 days Pneumonia Transient hypotension (90/0 mm Hg) Urinary retention

DZ, ? dose Chlorpromazine, 5 gm

0-1

1-2

Benzodiazepine averdasage

Va/urne 2/ Number 4

503

Table IV. Cant' d

Case No.

Age/ sex

52

35/M

53

40/F

53

41/F

53

41/F

54

26/F

55

43/M

56

59/F

57

42/F

Drug(s) ingested and dosage

CDX, 1200 mg Methylphenidate, 300 mg DZ, 460 mg Imipramine, 1125 mg ? Barbiturate ? DZ ? Imipramine Ethanol DZ, 100 mg Imipramine, 250 mg CDX, ? dose Amitriptyline, -2000 mg Ethanol ? Barbiturate CDX, ? dose Hydroxyzine, ? dose Chlorpromazine, ? dose ? Meprobamate ? ASA ? Glutethimide DZ, 60 mg Amitriptyline, 750 mg ? Barbiturate DZ, -500 mg FLZ, ? dose Unidentified tricyclic antidepressant, 2500 mg ? Phenothiazine

Benzodiazepines with barbiturates* DZ, 10-15 mg 58 20/F Meprobamate, 1200 mg Phenytoin, 300-400 mg Desbutal, t 2-3 tablets 59 CDX, 150 mg 34/M Secobarbital, 200 mg Fiorinal, 20 tablets Ethanol 60 DZ, -70 mg 36/F Secobarbital, ? dose Propoxyphene, ? dose 61 CDX, ? dose 21/M DZ, ? dose Tuinal, ? dose Chlorprornazi ne, 2000 mg

Deepest coma (grade)

Duration 01 hospitalization

Comment

6

Blood barbiturate level, 14 p.g/ml

3

4

Blood alcohollevel, 278 mg/100 ml Assisted ventilation for -24 hr

2

2

3

3

4

4

6

Blood barbiturate level, 6 p.g/ml Hypothermia (rectal temperature, 95.6° F) Assisted ventilation for -48 hr Aspiration pneumonia Hypotension (0 mm Hg) requiring colloid Hypothermia (rectal temperature less than 93° F) Assisted ventilation for - 3 days Toxic delirium during recovery

Blood barbiturate level, 12 p.g/ml; phenytoin level, 6 p.g/ml

0-1

0-1

3 2

3

Blood barbiturate level, 10 p.g/ml Aspiration pneumonia ECG abnormalities

504

Greenblatt et al.

Clinical Pharmacology and Therapeutics

Table IV. Cant' d

Drug(s) ingested and dosage

Deepest coma (grade)

Dura!ion 0/ hospitalization 5

Blood barbiturate level, 34 f.Lg/ml Assisted ventilation for -72 hr Hypothermia (rectal temperature, 95.2° F) Tracheobronchitis Blood barbiturate level, 6 f.Lg/ml

3

2

Insulin-dependent diabetic Blood barbiturate level, 11 f.Lg/ml

3

6

Blood barbiturate level, 16 f.Lg/ml; ethanol level, 75 mg/100 ml Assisted ventilation for 15 hr Hypothermia (rectal temperature, 95° F) Cardiac arrhythmias Blood barbiturate level, 8 f.Lg/ml Transient hypotension (86/52 mm Hg) Assisted ventilation for 15 hr Blood barbiturate level, 112 f.Lg/ml

Case No.

Age/ sex

62

22/M

DZ, ? dose Tuinal, -60 capsules Methadone, ? dose

2-3

63

25/F

2-3

64

24/F

65

23/F

DZ, ? dose Butabarbital, ? dose Butiserpazide, ? dose DZ, 40 mg Pento barbital, 1000-1500 mg DZ, 15 mg Amobarbital, 600 mg Ethanol

66

40/M

DZ, ? dose Phenobarbital, ? dose

3

67

63/F

3

3

68

42/M

4

3

69

43/M

DZ, 20 mg Phenobarbital, 60 mg Barbital, ? dose Amobarbital, ? dose CDX, ? dose Pentobarbital, -1200 mg Ethanol CDX, 250 mg Secobarbital, 2500 mg

3-4

3

70

38/M

4

7

71

36/F

DZ, 34 mg Butabarbital, 900 mg CDX, -160 mg Tuinal, ? dose Ethanol

4

3

72

18/M

4

2

73

37/F

74

26/F

DZ, ? dose Pentobarbital, ? dose Carbromal, ? dose Methaqualone, ? dose CDX, ? dose Carbromal, ? dose Ethanol DZ, ? dose Secobarbital, 2500 mg

Blood barbiturate level, 5 f.Lg/ml Assisted ventilation for 7 hr Aspiration pneumonia Blood barbiturate level, 40 f.Lg/ml; ethanol level, 63 mg/100 ml Assisted ventilation for -48 hr Pulmonary edema Aspiration pneumonia Blood barbiturate level, 16 f.Lg/ml Blood barbiturate level, 18 f.Lg/ml; a!cohol level, 49.4 mg/100 ml Assisted ventilation for 27 hr Transient hypotension (78/56 mm Hg) Blood barbiturate level, 10 f.Lg/ml Hypothermia (rectal temperature, 96° F) Assisted ventilation for 18 hr Blood barbiturate level, 10 f.Lg/ml

4 4

Comments

9

Blood barbiturate level, 15 f.Lg/ml Assisted ventilation for -48 hr Aspiration pneumonia Decubitus u!cers

Benzodiazepine overdosage

Vo/ume 2/ Number 4

505

Table IV. Cont' d

Drug(s) ingested and dosage

Deep est coma (grade)

Duration of hospitalization

Case No.

Age/ sex

75

42/F

DZ, 30-40 mg Pentobarbital, ? dose

4

13

76

17/M

4

3

77

60/F

4

6

78

34/M

4

2

79

28/F

DZ, 35 mg Unknown barbiturate, ? dose DZ, ? dose Amobarbital, 4000 mg Phenobarbital, ? dose CDX, 20 mg Pentobarbital, 300 mg Ethanol CDX, 120 mg Pentobarbital, 1800 mg Mephenesin, 8.5 gm

80

20/F

CDX, ? dose Unknown barbiturate, ? dose

4

2-3

CDX, 125 mg Imipramine, 50 mg Tuinal, ~ 18 capsules 82 64/F DZ, ? dose 3 Secobarbital, ? dose 4 DZ, ? dose 83 31/F CZP, ~ 125 mg Ethinamate, 12.5 gm ? Barbiturate 84 28/F DZ, ? dose 0 ? Barbiturate 85 51/M CDX, ? dose ? Barbiturate 2 86 CDX, ? dose 15/M ? Barbiturate CDX, ~IOOO mg 2 87 35/F ? Barbiturate DZ, ~150 mg 0-1 88 38/F CDX, ? dose Unknown barbiturate, ? dose Benzodiazepines and miscellaneous drug mixtures* 4 DZ, 95 mg 89 38/F Codeine, ? dose Theophylline, 10 gm Ethanol 81

2

24/M

4

Comments

Blood barbiturate level, 50 p,g/ml Hypothermia (rectal temperature, 95° F) Hypotension (0 mm Hg) requiring colloid and pressors Assisted ventilation for ~4 days Pneumonia Blood barbiturate level, 206 p,g/ml Aspiration pneumonia Assisted ventilation for ~4 days Hypotension requiring pressors Blood barbiturate level, 12 p,g/ml Hypotension (86/60 mm Hg) Blood barbiturate level, 11 p,g/ml Hypotension requiring colloid and pressars Assisted ventilation far ~ 24 hr Pneumonia and/or pulmonary edema Blood barbiturate level, 14 p,g/ml Assisted ventilation for less than 24 hr Transient hypotension (92/80 mm Hg) Blood barbiturate level, 24 p,g/ml Assisted ventilation for ~ 12 hr Pneumonia Hypothermia (rectal temperature, 96° F)

2

Blood barbiturate level, 12 p,g/ml Assisted ventilation for ~2 days Hypotension 01iguria Trace barbiturate level in blood

3

Blood barbiturate level, 22 p,g/ml

2

Trace barbiturate level in blood Transient hypotension (90/50 mm Hg) Blood barbiturate level, 12 p,g/ml Transient hypotension (70/0 mm Hg) Blood barbiturate level, 5 p,g/ml

3

IO

Cardiopulmonary arrest Multiple cardiac arrhythmias Assisted ventilation for ~ 1 day Pneumonia Possible cerebral embolus

506

Greenblatt et al.

Clinical Pharmacology and Therapeutics

Table IV. Cant' d

Case No.

Age/ sex

90

181M

90

181M

91

80/F

92

22/F

93

36/F

Deepest coma (grade)

Duration of hospitalization

DZ, ? dose Methaqualone, ? dose ? Methadone DZ, 400 rng Methaqualone, 1050 rng Methadone, ? dose OXZ, ? dose Methyldopa, ? dose Chloral hydrate, ? dose ? Barbiturate

4

5

DZ, ? dose Nine other drugs detected in blood DZ, ? dose Six other drugs detected

3

Drug(s) ingested and dosage

4 3

11

3

5

Comment

Blood diazepam level, 10 JLg/rnl Assisted ventilation for -48 hr Aspiration pneurnonia Responded to intravenous naloxone Hypotension (70/50 rnrn Hg) requiring pressors Cardiac arrhythrnias Pulrnonary ederna Pneurnonia

Assisted ventilation for -4 days Pneurnonia

'With or without ethanol. tCombination preparation containing methamphetamine and pentobarbital.

admissions involving 18 patients. Ethanol was also taken in many instances. Eleven patients reached grade 3 or 4 coma, and 9 required assisted ventilation. Cardiac arrhythmias or disturbances of temperature regulation, often observed due to antidepressant or antipsychotic drugs taken alone,25, 42 occurred in many of these cases. Agitated delirium was noted during the recovery phase of one patient who had taken a large dose of an unidentified tricyclic antidepressant, together with two benzodiazepine derivatives and possibly a phenothiazine. Benzodiazepines with barbiturates. The most seriously intoxicated subgroup were the 31 patients who took barbiturates (with or without alcohol) together with benzodiazepines. More than two-thirds of the patients reached grade 3 or 4 coma, and half required assisted ventilation. In most of these cases, dosage of the implicated benzodiazepine was not excessive. In contrast, barbiturate dosage, as weIl as blood barbiturate levels, was often very high. The findings suggest that the barbiturate was the major contributor to central nervous system depression. Benzodiazepines and miscellaneous drug mixtures. Six admissions, involving 5 patients,

were due to benzodiazepine ingestion together with other miscellaneous drugs. All of these patients reached grade 3 or 4 coma, and 3 required assisted ventilation. The most seriously intoxicated patient (No. 89), who took a large dose of theophylline, had cardiopulmonary arrest from wh ich resuscitation was successful. Patient 91, who took oxazepam together with chloral hydrate and methyldopa, had cardiac arrhythmias and severe hypotension requiring treatment with pressor drugs. Discussion

Our investigation surveyed all adult patients admitted since 1962 to a large urban medical center because of psychotropic drug overdosage. Benzodiazepine derivatives were implicated in 13% of the 773 cases. Year-by-year analysis, however, indicates that the use of benzodiazepines as agents of self-poisoning is increasing, consistent with the increase in their availability and therapeutic use. Similar findings are described in the medical literature. 2,8, 14, 16,29,33,49,56,59,64,69, 71, 73, 75, 76, 82, 87, 90, 91, 94, 104, 108, 110, 113 Despite substantial differences in characteristics of the patient populations and in criteria for inclusion, numerous clinical studies of the incidence and

Benzodiazepine overdosage

Vo/ume 2/ Number 4

507

Table V. Epidemiology of benzodiazepine overdosage

Reference

Location

49 108

USA (San Francisco-Anned Forces) USA (Baltimore)

56 104 8 2 94 87 82 64

USA (Dallas) USA (Pennsylvania) USA (Cleveland) USA (Los Angeles) Canada Canada Canada Scotland

73 75 14 33 77 16 29 113

Scotland Scotland Australia Australia Australia Australia Australia (Armed Forces) New Zealand

91 76 69 59

New Zealand England Italy Denmark

Year(s) 1957-1966 1963-1967 1968-1970 1967-1971 1969-1970 1969-1972 Not stated 1966-1967 1972 1973 1960-1965 1966-1971 1968 1969 1963-1964 1968-1969 1969-1974 1970-1971 1970-1972 1963 1973 1971 1963-1967 1963-1964 (?) 1973

Number of poisoning cases 605 234 285 195t 1,003 71:j: 208:j: 297 108 61 361 580 1,067 1,174 100 333 15911 20 142** 43 217 1,181** 415 72 112

Cases with benzodiazepines implicated No. 54* 6 11 8 58 1 8 50§ 35 30 11 115 153 211 7* 53 4~

6 35~

2 69 177 14 5 15

j

% 9 3 4 4 6 1 4 17 32 49 3 20 14 18 7 16 3 30 25 5 32 15 3 7 13

*CDX only. t All patients admitted to an intensive care uni!. :j:Comatose patients onl y. §Includes only CDX and DZ. IIAll patients admitted to an intensive care unit and requiring assisted ventilation.

only. **Includes patients not hospitalized.

~DZ

consequences of acute overdosage from around the world indicate that benzodiazepine ingestion accounts for a substantial proportion of cases of drug overdosage in adults (Table V). Findings from series describing time-related changes in patterns of drug ingestion 64 , 73, 75, 82, 87, 113 strongly suggest that the relative incidence of benzodiazepine overdosage is increasing. In some recent surveys, benzodiazepine derivatives have been implicated in 25% to 50% of poisoning cases. 29, 82, 87, 90, 113 Reports of benzodiazepine overdosage likewise commonly reach poison control centers. 68, 106 The frequency of identification of benzodiazepines in toxicologic specimens is variable from center to

center (Table VI), but in the most recent survey from an urban laboratory, 84 benzodiazepines were identified in 16% of 2,500 blood specimens from patients in whom drug overdosage was suspected. C onsequences of benzodiazepine overdosage. Self-poisoning with multiple drugs is more common than overdosage with a single drug. Patients who are at risk for suicide generally have access to numerous drugs, and alcohol is ubiquitous. Our series is consistent with this experience. Although benzodiazepines were implicated in 99 admissions due to acute overdosage, multiple drugs were ingested in all but 12 of the cases. Since we did not have access to

508

Greenblatt et al.

Clinical Pharmacology and Therapeutics

Table VI. Identification 01 benzodiazepines in toxicologic specimens Benzodiazepines detected

Re/erence 65 52 84 63

Location

Year(s)

Los 1972 Angeles Detroit 19741975 Buffalo 1975 Bethesda 19691971

Number 0/ blood specimens analyzed* No.

I%

24,205

492

2

1,013

56

6

2,500 74t

388 7

16 9

'Not equal to the number of patients, since more than one speci· men per patient may have been analyzed. tlncludes specimens of blood, urine, and gastric contents.

records of patients treated in the emergency room without hospital admission, we cannot determine whether the small number of benzodiazepine-alone admissions actually reflects a relative infrequency of poisonings with benzodiazepines alone, or whether a substantial number of patients who took a benzodiazepine derivative by itself were not sufficiently ill to require hospitalization. In any case, it appears that understanding of the consequences of overdosage of benzodiazepines together with other drugs is at least as important as that of the benzodiazepines alone. Benzodiazepines alone. None of the 12 patients in our series who were hospitalized due to ingestion of one or more benzodiazepine derivatives experienced serious intoxication. Our findings are consistent with reported series of intoxication with chlordiazepoxide,19, 36, 114 nitrazepam,20, 47, 74 and diazepam,61 and with case reports of poisoning in adults (Table VII) and children (Table VIII). Complications such as hypotension and respiratory failure do occur,20, 61, 74 but they are relatively uncommon, particularly in comparison with a similar group of patients poisoned with other drugs such as barbiturates and methaqualone. 74 Of interest are several case reports in which central nervous system (CNS) depression due to diazepam was reversed by physostigmine or naloxone. 7, 15, 27 The mechanism of this interaction is not established, since diazepam appears to have little if any anticholinergic or opiate agonist properties of clinical importance.

Although "toxic" and "lethai" blood concentrations of benzodiazepines have been described,6, 111 reliable data are fragmentary. Cate and Jatlow 19 assessed chlordiazepoxide blood levels in 60 cases of acute poisoning with this drug. Levels exceeding 20 p,g/ml tended to be associated with grade 2 or 3 central nervous system depression, but deep coma was not observed even with levels exceeding 60 p,g/ml. Therapeutic dosage of chlordiazepoxide usually produces concentrations between 0.5 and 3 p,g/ml. 39, 41. 43, 44, 46, 99

Benzodiazepines combined with other drugs. The incidence of serious intoxication when benzodiazepines are ingested together with other drugs considerably exceeds that of the benzodiazepines per se. This is clearly evident from case reports (Table VII) and from larger series in the literature. 19 , 20 In our series, combination of benzodiazepines with almost any other drug, whether ethanol, analgesics, other sedative-hypnotics, tricyclic antidepressants, antipsychotic agents, or barbiturates, substantially increased the likelihood of serious intoxication (Tables III and IV). Benzodiazepines with barbiturates appeared to be a dangerous combination; 21 of the 31 patients reached grade 3 or 4 central nervous system depression, and 14 required assisted ventilation. We emphasize, however, that neither our series nor others establish whether benzodiazepines "potentiate" CNS depression due to other drugs, whether the effects are simply "additive," or whether the poisoning syndrome is largely attributable to the other drugs taken. Circumstantial evidence suggests that the last possibility is usually correct. Controlled clinical studies indicate that benzodiazepines add very little to the cardiovascular and respiratory depressant effects of other drugs such as opiates. 39 Among the 701 MGH patients with drug overdosage reviewed for this series, 82 took either secobarbital or pentobarbital alone. Grade 3 or 4 coma was reached in 52 of these patients, and assisted ventilation was required in 41. These frequencies of complications attributable to barbiturate overdosage alone are comparable to those associated with benzodiazepines combined with barbiturates. Benzodiazepine fatalities. Wh ether benzodiazepine overdosage as such can produce

Benzodiazepine overdosage

Volume 21 Number 4

509

Table VII. Case reports of benzodiazepine overdosage in adults Reference

Drug(s)* ingested and dosage

Benzodiazepines alone 22 44/F 22/M 103 ? 101 ?

CDX, CDX, CDX, CDX,

875 mg 1630 mg 190 mg 385 mg

60 80 58

30/F 32/F 23/F

CDX, 625 mg CDX, 600 mg CDX, 1850 mg

78

44/M

CDX, ? dose

95 50 15

45/F ? 23/M

CDX, 250 mg DZ, 250 mg DZ, ? dose

115

45/M

OXZ, ? dose

34 85

16/M 24/F

OXZ, 900 mg NTZ, 500 mg

4 48

23/F 26/F

NTZ, 180 mg CZP, 600 mg

Benzodiazepines with other drugs 70 45/M CDX, 200-250 mg Chlorpromazine, 3125 mg Amobarbital, 1250 mg 35 38/F CDX, 1250 mg Ethanol 23 18/F CDX, 400-500 mg Desipramine, 1000- 1200 mg 42/F CDX, 480 mg 3 Amobarbital, 1000 mg Phenelzine, 600 mg 96 47/F CDX, 1150 mg Ethanol 107 56/F CDX, 120 mg Ethchlorvynol, 4 gm 17

68/F

24

43/F

CDX, 400 mg Pentobarbital, 600 mg CDX, ? dose Pentobarbital, 4000 mg Tuinal, ? dose Ethchlorvynol, ? dose Propoxyphene, ? dose Ethanol

Comment Ataxia, dysarthria Ataxia, somnolence Drowsiness Recovered without sequelae (no other details available) Not hospitalized Coma Blood CDX level, 8 fLg/ml Somnolence Coma Death attributable to sickle cell crisis Somnolence Ataxia, dysarthria, somnolence Lethargy and somnolence reversed by physostigmine Coma Required tracheostomy Recovered following peritoneal dialysis and exchange transfusion Somnolence Unconscious for 36 hr Bullous skin lesions Ataxia, dysarthria, somnolence Drowsiness, ataxia, and somnolence Blood desmethyldiazepam level as high as 5.3 fLg/ml Coma

Coma Semicoma Cardiac toxicity inciuding ventricular tachycardia Coma Required assisted ventilation and pressors Somnolence, ataxia, dysarthria Blood ethchlorvynol level, 30 fLg/ml Coma Required assisted ventilation "Complete recovery" (no other details available) Blood levels: CDX plus desmethyl metabolite, 24 fLg/ml Barbiturate, 45 fLg/ml Alcohol, 140 mg/100 ml CDX elimination apparently enhanced by dialysis Death attributable to pulmonary infection

510

Greenbiatt et ai.

Clinical Pharmacology and Therapeutics

Table VII. Cont' d Reference

Drug(s)* ingested and dosage

89

21/F

93

25/F

97

27/F

102

44/F

112

42/F

62

37/F

31

38/F

54

40/F

32

32/F

89

44/M

18

20/F

86

66/F

79

20/F

53

16/F

CDX, 45 mg Nortriptyline, 1250 mg CDX, ? dose Phenobarbital, ? dose DZ, 100 mg Amitriptyline, 1000 mg DZ, 250 mg Ethchlorvynol, 25 gm DZ, 200 mg Meprobamate, 150 mg Diphenhydramine, 2000 mg Quinidine sulfate, 20 gm DZ, ~100 mg lmipramine, 2500 mg Propranolol, 800 mg DZ, ? dose Glutethimide, 7.5 gm DZ, ? dose Meprobamate, ? dose DZ, ? dose Amitriptyline, ? dose Nortriptyline, ? dose DZ, ? dose Amitriptyline, ? dose DZ, 1400 mg Methaqualone, 10 gm Diphenhydramine, 1000 mg FLZ, ? dose Glutethimide, ? dose FLZ, 360 mg DZ, 100 mg Metronidazole, 15 gm Penicillin V, 14 gm FLZ, ? dose Amitriptyline, ? dose Orphenadrine, ? dose

Comment

Death attributable to cardiac toxicity Coma Shock Death Coma reversed by physostigmine Blood ethchlorvynollevel, 29 fLg/ml Death following prolonged coma Hypotension and cardiac toxicity attributable to quinidine Recovered following hemodialysis Coma Hypotension reversed by glucagon Coma, shock, required assisted ventilation Hypothermia (rectal temperature, 85° F) Coma Hypotension requiring pressors Coma Death attributable to cardiac toxicity Death attributable to cardiac toxicity Coma, moderate hypotension, hypothermia Blood glutethimide level, 25 fLg/ml Coma Recovered following resin hemoperfusion Semicoma

Coma Gastric retention and dilatation

'See Table I far abbreviations.

fatal CNS depression is an important and controversial issue. There were no deaths in the present MGH series. Fatalities reported in case studies (Table VII) were due either to multiple drug ingestion or to other causes. The same is true for larger reviews of benzodiazepine overdosage. 19 Chapallaz,20 however, reported one fatality apparently due to diazepam combined with nitrazepam and chlordiazepoxide. Other sources of data on drug-related fatalities inc1ude autopsy reports and statistics from official sources such as coroners' offices.

Some of these reports do not implicate benzodiazepines in any drug-related deaths. 51, 55, 67 Others do report fatalities, but these were probably or definitely due to drug combinations.1, 13, 30, 81 Several reports implicate benzodiazepines as contributing to death,5, 12, 21, 26, 83, 105 but sufficient data are not available to ruIe out multiple drug ingestion, or to establish that the benzodiazepine overdosage was the cause of death. Dinovo and associates 28 surveyed 2,000 drugrelated deaths that were confirmed by toxicologic analyses. Diazepam was involved in a

Valurne 2/ Number 4

Benzodiazepine overdosage

511

Table VIII. Case reports of benzodiazepine overdosage in children Reference

Drug(s)* ingested and dosage

II 98 100

2V2/? 2/M 2/F

CNZ, 60 mg DZ, 20-24 mg DZ, 300 mg

88

Il/M

CDX, 425 mg Seeobarbital, 100 mg

9

2/F

DZ, 70 mg

7 92

2/F 2/F

DZ, 200 mg OXZ, 90 mg

27 57

2/F 6/M

DZ, 80 mg LRZ, ? dose

Comment Drowsiness, ataxia Lethargy, ataxia Coma Reeovered in 3 days Blood level of CDX plus metabolites, 9 Mg/mi Coma Reeovered in 2-3 days Lethargy Episodes of sinus arrest Coma reversed by naloxone Blood OXZ level, 13 Mg/mi Somnolenee Coma reversed by physostigmine Drowsiness, hallueinations

'See Table I for abbreviations.

total of 67 cases (mean blood level, 18 J.Lg/ml), of which 3 involved diazepam alone (mean blood level, 4.8 J.Lg/ml) and 5 involved diazepam plus ethanol (mean diazepam blood level, 5.2 J.Lg/ml). Flurazepam was involved in 8 fatal multiple drug ingestions (mean blood level, 13 J.Lg/ml) and chlordiazepoxide in 21 multiple ingestions (mean blood level, 6.9 J.Lg/ ml). It appears that benzodiazepines may produce fatal intoxication, but few if any welldocumented and adequately studied cases are available. We are grateful for the assistanee of Drs. Donald Green and L. R. Hines and Ms. Ann Werner.

References 1. Anonymous: Inereasing deaths from drugs noted in state, Texas Med. 68:22, Oetober, 1972. 2. Arieff, A. I., and Friedman, E. A.: Coma following nonnareotie drug overdosage: Management of 208 adult patients, Am. J. Med. Sei. 266:405-426, 1973. 3. Austin, T. R.: Mixed drug overdosage with phenelzine, Amytal and ehlordiazepoxide, Anaesthesia 21:249-252, 1966. 4. Bardhan, K. 0.: Cerebellar syndrome after nitrazepam overdosage, Laneet 1:1319-1320, 1969. 5. Barraclough, B. M.: Are there safer hypnoties than barbiturates? Laneet 1:57-58, 1974. 6. Baselt, R. c., Wright, J. A., and Cravey, R. H.: Therapeutie and toxie eoneentrations of more than 100 toxieologieally signifieant drugs in blood, plasma, or serum: A tabulation, Clin. Chem. 21:44-62, 1975.

7. Bell, E. F.: The use of naloxone in the treatment of diazepam poisoning, J. Pediatr. 87:803-804, 1975. 8. Benjamin, S. P., Willis, C. E., Tytko, S., and Miklieh, P.: The eoma profile, Cleve. Clin. Q. 40:57-61, 1973. 9. Berger, R., Green, G., and Melniek, A.: Cardiae arrest eaused by oral diazepam intoxieation, Clin. Pediatr. 14:842-844, 1975. 10. Blaekwell, B.: Minor tranquilizers: Use, misuse or overuse? Psyehosomaties 16:28-31, 1975. 11. Bladin, P. F.: The use of clonazepam as an antieonvulsant-clinical evaluation, Med. J. Aus!. 1:683-688, 1973. 12. Blanke, R. V.: Role of toxicology in suicide evaluation, J. Forensie Sei. 19:284-291, 1974. 13. Bonniehsen, R., Maehly, A. c., and Sko1d, G.: Areport on autopsy cases involving amitriptyline and nortriptyline, Z. Reehtsmed. 67:190-200, 1970. 14. Boxall, J. S., and Chauve1, P. J.: Attempted suieide: A review of 100 conseeutive eases at a distriet hospital, Med. J. Aus!. 1:264-266, 1966. 15. Brashares, Z. A., and Conley, W. R.: Physostigmine in drug overdose, J. Am. Coll. Emergency Physieians 4:46-48, 1975. 16. Bridges-Webb, C.: Attempted suieide by drug overdose in a eountry town, Med. J. Aus!. 2:782-783, 1973. 17. Burston, G. R.: Self-poisoning in elderiy patients, Gerontol. Clin. 11:279-289, 1969. 18. Carroll, B. J.: Attempted suicide: Hypnoties and sedatives, Med. 1. Aust. 2:806, 1970. 19. Cate, J. C., and Jat10w, P. I.: Chlordiazepoxide overdose: Interpretation of serum drug eoneentrations, Clin. Toxieol. 6:553-561, 1973. 20. Chapallaz, S.: Intoxieations aigues par le ni-

512

21. 22.

23.

24. 25. 26. 27.

28.

29.

30. 31.

32.

33.

34. 35. 36. 37.

Greenblatt et al.

trazepam (Mogadon R), Schweiz. ApothekerZeitung 111:95-99, 1973. Christopoulos, G. N., Toman, A. J., and Stein, R. J.: Drugs and fatality levels found in overdose cases, Ill. Med. 1. 147:133-136, 1975. Clarke, T. P., Simpson, T. R., and Wise, S. P.: Two unsuccessful suicidal attempts with a new drug: Methaminodiazepoxide (Librium), Texas State J. Med. 57:24-26, 1961. Colvard, C., Jr.: Overdosage of desipramine hydrochloride with marked electrocardiographic abnormalities, South. Med. J. 61:1218, 1222, 1968. Cruz, I. A., Cramer, N. C., and Parrish, A. E.: Hemodialysis in chlordiazepoxide toxicity, J. A. M. A. 202:438-440, 1967. Davis, J. M., Bartlett, E., and Termini, B. A.: Overdosage of psychotropic drugs: A review, Dis. Nerv. Syst. 29:157-164, 1968. Detre, T. P., and Jarecki, H. G.: Modern psychiatric treatment, Philadelphia, 1971, J. B. Lippincott Co., p. 617. DiLiberti, J., O'Brien, M. L., and Turner, T.: The use of physostigmine as an antidote in accidental diazepam intoxication, J. Pediatr. 86:106-107, 1975. Dinovo, E. c., Gottschalk, L. A., McGuire, F. L., Birch, H., and Heiser, J. F.: Analysis of results of toxicological examinations performed by coroners' or medical examiners' laboratories in 2,000 drug-involved deaths in nine major U. S. cities, Clin. Chem. 22:847-850, 1976. Duncan, D. R., O'Gorman, J. G., Fleming, K. J. A., and Salas, R. G.: Suicidal behaviour in the Australian army: Incidence, methods, and outcome, Med. J. Aust. 2:736-739, 1974. Fatteh, A., and Hayes, B.: Poisons that killed: An analysis of 300 cases, N. C. Med. J. 35:227-229, 1974. Fell, R. H., and Dendy, P. R.: Severe hypothermia and respiratory arrest in diazepam and glutethimide intoxication, Anaesthesia 23:636-640, 1968. Freeman, J. W., Mundy, G. R., Beattie, R. R., and Ryan, c.: Cardiac abnormalities in poisoning with tricyclic antidepressants, Br. Med. J. 2:610-611, 1969. Freeman, J. W., Ryan, C. A., and Beattie, R. R.: Epidemiology of drug overdosage in southern Tasmania, Med. J. Aust. 2: 1168-1172, 1970. Ganguli, L. K., Sen, D., Chatterjee, P., and Mandal,1. N.: Oxazepam overdosage, J. Indian Med. Assoc. 54:424-425, 1970. Gilbert, J. E.: Ingestion of a massive dose of Librium, South Dakota J. Med. Pharm. 14:307-309, 1961. Gjerris, F.: Poisoning with chlordiazepoxide (Librium R ), Dan. Med. Bull. 13:170-172, 1966. Greenblatt, D. 1., Allen, M. D., and KochWeser, 1.: Accidenta1 poisoning with psycho-

Clinical Pharmacology and Therapeutics

38.

39. 40.

41.

42.

43.

44.

45.

46.

47.

48. 49. 50. 51.

tropic drugs in children, Am. J. Dis. Child. 130:507-511, 1976. Greenblatt, D. J., Allen, M. D., and KochWeser, J.: Accidental iron poisoning: Six cases including one fatality, Clin. Pediatr. 15:835838, 1976. Greenblatt, D. J., and Shader, R. 1.: Benzodiazepines in clinical practice, New York, 1974, Raven Press. Greenblatt, D. J., and Shader, R. 1.: Psychotropic drugs, medical disease, and other medical therapies, in Greenblatt, M., editor: Seminars in psychiatry: Drugs in combination with other therapies, New York, 1975, Grune & Stratton, Inc., pp. 83-99. Greenblatt, D. J., and Shader, R. 1.: Bloou levels of benzodiazepines: Applications in medicine and toxicology, in SeHers, E. M., editor: Clinical pharmacology of psychoactive drugs, Toronto, 1975, Addiction Research Foundation of Ontario, pp. 87-104. Greenblatt, D. J., and Shader, R. 1.: Psychotropic drug overdosage, in Shader, R. 1., editor: Manual of psychiatric therapeutics, Boston, 1975, Little, Brown & Co., pp. 237-268. Greenblatt, D. J., Shader, R. 1., Harmatz, J. S., Franke, K., and Koch-Weser, J.: Inftuence of magnesium and aluminum hydroxide mixture on chlordiazepoxide absorption, CLiN. PHARMACOL. THER. 19:234-239, 1976. Greenblatt, D. 1., Shader, R. 1., Harmatz, J. S., Franke, K., and Koch-Weser, J.: Absorption rate, blood concentrations, and early responses to oral chlordiazepoxide: Subjective manifestations of a pharmacokinetic interaction, Am. J. Psychiatry. (In press.) Greenblatt, D. J., Shader, R. 1., and KochWeser, 1.: Psychotropic drug use in the Boston area: Areport from the Boston Collaborative Drug Surveillance Program, Arch. Gen. Psychiatry 32:518-521,1975. Greenblatt, D. J., Shader, R. 1., Koch-Weser, J., and Franke, K.: Clinical pharmacokinetics of chlordiazepoxide, in Gottschalk, L. A., and Merlis, S., editors: Pharmacokinetics of psychoactive drugs: Blood levels and clinical response, Flushing, N. Y., 1976, Spectrum Publications, pp. 127-139. Haider, 1., Matthew, H., and Oswald, I.: Electroencephalographic changes In acute drug poisoning, Electroencephalogr. Clin. Neurophysiol. 30:23-31, 1971. Hancock, B. W., and Martin, 1. F.: Attempted suicide with potassium clorazepate, Br. J. Clin. Pharmacol. 1:512-513, 1974. Hauschild , T. B.: Suicidal population of a military psychiatric center: A review of ten years, Milit. Med. 133:425-436, 1968. Hillyer, D. M.: An overdose of "Valium," Med. J. Aust. 1:565, 1965. Holland, J., Massie, M. J., Grant, c., and

Volume 21 Number 4

52.

53. 54.

55. 56.

57. 58. 59. 60.

61.

62.

63. 64. 65.

66. 67.

68.

Plumb, M. M.: Drugs ingested in suicide attempts and fatal outcome, N. Y. State J. Med. 75:2343-2349, 1975. Horwitz, J. P., Hills, E. B., Andrzejewski, D., Brukwinski, W., Penkala, J., and Albert, S.: Adjunct hospital emergency toxicology service: A model for a metropolitan area, J. A. M. A. 235:1708-1712,1976. How, J., and Strachan, R. W.: Acute dilatation of stornach as late complication of drug overdose, Br. Med. J. 1:563-564, 1976. Hulting, J., and Thorstrand, C.: Hemodynamic effects of norepinephrine in severe hypnotic drug poisoning with arterial hypotension, Acta Med. Scand. 192:447-453, 1972. Irey, N. S., and Froede, R. c.: Evaluation of deaths from drug overdose: A clinicopathologic study, Am. J. Clin. Pathol. 61:778-784, 1974. Jay, S. J., Johanson, W. G., Jr., and Pierce, A. K.: Respiratory complications of overdose with sedative drugs, Am. Rev. Respir. Dis. 112: 591-598, 1975. Jeffrey, D. 1., and Whitfield, M. F.: Lorazepam poisoning, Br. Med. J. 4:719, 1974. Jenner, F. A., and Parkin, D.: A large overdose of chlordiazepoxide, Lancet 2:322-323, 1961. Jensen, K.: The poisoning treatment centre of Copenhagen, Resuscitation 3: 199-204, 1974. Kinross-Wright, J., Cohen, 1. M., and Knight, J. A.: The management of neurotic and psychotic states with Ro 5-0690 (Librium), Dis. Nerv. Syst. 21(Suppl):23-26, 1960. Kop, P., Cosic, V., Simic, B., Andelski, A., and Brdjovic, P.: Analysis of the clinical experience in 100 cases of acute intoxication with Apaurin (diazepam), Bull. Med. Leg. Toxicol. 15:243-251, 1972. Kosinski, E. J., and Malindzak, G. S., Jr.: Glucagon and isoproterenol in reversing propranolol toxicity, Arch. Intern. Med. 132:840843, 1973. Law, N. c., FaIes, H. M., and Milne, G. W. A.: Identification of drugs taken in overdose cases, Clin. Toxicol. 5:17-21, 1972. Lawson, A. A. H., and MitchelI, I.: Patients with acute poisoning seen in a general medical unit (1960-71), Br. Med. J. 4:153-156, 1972. Lundberg, G. D., Walberg, C. B., and Pantlik, V. A.: Frequency of clinical toxicology testordering (primarily overdose cases) and results in a large urban general hospital, Clin. Chem. 20:121-125, 1974. McBay, A. J.: Toxicological findings in fatal poisonings, Clin. Chem. 19:361-365, 1973. McBay, A. J., and Hudson, P.: Drug deaths in North Carolina: Abrief survey of deaths attributed to drugs in North Carolina, 1973, N. C. Med. 1. 35:542-544, 1974. MacEachen, A. J., Crawford, J. N., Willard, 1. W., Napke, E., Adams, D. M., and Fournier, L.deG.: Canadian poison control program statis-

Benzodiazepine overdosage

513

tics, 1965, Clin. Toxicol. 1:91-131, 1968. 69. Malizia, E., Bertolini, G., and Venturi, V. M.: Comparison between experimental responses and clinical intoxications caused by central nervous system depressants and by antihistaminic drugs, in Proceedings of the European Society for the Study of Drug Toxicity, Experimental studies and clinical experience-the assessment of risk, Amsterdam, 1965, Excerpta Medica Foundation, vol. 6, pp. 179-184. 70. Master, R. S.: An attempted suicide with a chlorpromazine cocktail, Am. J. Psychiatry 120: 1126-1128, 1964. 71. Matthew, H.: Are there safer hypnotics than barbi turates? Lancet 1: 224, 1974. 72. Matthew, H., and Lawson, A. A. H.: Acute barbiturate poisoning: A review of two years experience, Q. J. Med. 35:539-552, 1966. 73. Matthew, H., Proudfoot, A. T., Brown, S. S., and Aitken, R. C. B.: Acute poisoning: Organization and work-Ioad of a treatment centre, Br. Med. J. 3:489-493, 1969. 74. Matthew, H., Roscoe, P., and Wright, N.: Acute poisoning. A comparison of hypnotic drugs, Practitioner 208:254-258, 1972. 75. Matthew, H., and Wright, N.: The management of acute poisoning, Br. J. Clin. Pract. 25:303310, 1971. 76. Mawer, G. E., Smith, P. H., and Yuill, G. M.: The management of acute poisoning in a provincial teaching hospital, Clin. Toxicol. 4:409-417, 1971. 77. Morgan, E. B.: Severe drug overdose: Results of treatment, Anaesth. Intensive Care 3:131-138, 1975. 78. Mullick, F. G., Delage, C., and Irey, N. S.: Sickle cell crisis associated with drugs, Arch. Environ. Health 26:221-222, 1973. 79. O'Neil, J. T., and Pogge, R. C.: Relative safety of self inflicted overdose with re1atively newer medications, Ariz. Med. 30:484-485, 1973. 80. Pennington, G. W., and Synge, V. M.: Chlordiazepoxide ("Librium") overdosage, J. Ir. Med. Assoc. 49:187-188, 1961. 81. Rada, R. T., Kellner, R., and Buchanan, J. G.: Chlordiazepoxide and alcohol: A fataloverdose, J. Forensic Sci. 20:544-547, 1975. 82. Rangno, R. E.: Epidemiology and therapy of suicidal drug intoxication, in Seilers, E. M., editor: Clinical pharmacology of psychoactive drugs, Toronto, 1975, Addiction Research Foundation of Ontario, pp. 43-54. 83. Rehling, C. J.: Poison residues in human tissues, in Stolman, A., editor: Progress in chemical toxicology, New York, 1967, Academic Press, Inc., vol. 3, pp. 363-386. 84. Rejent, T. A., and Wahl, K. c.: Diazepam abuse: Incidence, rapid screening, and confirming methods, Clin. Chem. 22:889-891, 1976. 85. Ridley, C. M.: Bullous lesions in nitrazepam overdosage, Br. Med. 1. 3:28, 1971.

514

Greenblatt et al.

86. Rosenbaum, J. L., Kramer, M. S., and Raja, R.: Resin hemoperfusion for acute drug intoxication, Arch. Intern. Med. 136:263-266, 1976. 87. Ruedy, J.: Acute drug poisoning in the adult, Can. Med. Assoc. 1. 109:603-606, 1973. 88. Schaefer, S.: Toxicity from drug overdosage in an eleven-year-old boy: Case report, Clin. Pediatr. 1: 103-104, 1962. 89. Sedal, L., Korman, M. G., WiHiams, P. 0., and Mushin, G.: Overdosage of tricyclic antidepressants: Areport of two deaths and a prospective study of 24 patients, Med. J. Aust. 2:74-79, 1972. 90. SeHers, E. M.: Factors influencing the interpretation of drug concentration in acute drug overdose, in SeHers, E. M., editor: Clinical pharmacology of psychoactive drugs, Toronto, 1975, Addiction Research Foundation of Ontario, pp. 73-86. 9l. Sharman, J. R., Taylor, H. W., and Scott, R. D.: Drug overdosages and poisonings in Christchurch during 1971, N. Z. Med. J. 76:402-404, 1972. 92. Shimkin, P. M., and Shaivitz, S. A.: Oxazepam poisoning in a child, J. A. M. A. 196:154-155, 1966. 93. Shubin, H., and Weil, M. H.: The mechanism of shock following suicidal doses of barbiturates, narcotics and tranquilizer drugs, with observations on the effects of treatment, Am. J. Med. 38:853-863, 1965. 94. Sims, M., Purdy, M., and Devenyi, P.: Drug overdoses in a Canadian city, Am. J. Public Health 63:215-226, 1973. 95. Singh, H., and Gupta, V. K.: Chlordiazepoxide poisoning: A case report, Curr. Med. Pract. 7:519-520, 1963. 96. Smith, M. E.: Suicidal attempt by oral ingestion of chlordiazepoxide (Librium), Clin. Med. 8:72-74, January, 1961. 97. Snyder, B. D., Blonde, L., and McWhirter, W. R.: Reversal of amitriptyline intoxication by physostigmine, J. A. M. A. 230: 14331434, 1974. 98. Spark, H., and Goldman, A. S.: Diazepam intoxication in a child, Am. J. Dis. Child. 109:128-129, 1965. 99. Stanski, D. R., Greenblatt, D. J., Selwyn, A., Shader, R. 1., Franke, K., and Koch-Weser, J.: Plasma and cerebrospinal fluid concentrations of chlordiazepoxide and its metabolites in surgical patients, CUN. PHARMACOL. THER. 20:571-578, 1976. 100. Tanner, T. B., and Moorhead, S. H.: High

Clinical Pharmacology and Therapeutics

1Ol. 102.

103. 104.

105. 106.

107.

108.

109. 110. 111. 112. 113. 114.

115.

dose poisoning with diazepam (Valium) and survival in a two-year-old child, J. Med. Assoc. Ga. 57:534-536, 1968. Taylor, M. A., Spero, M., Simeon, 1., and Fink, M.: High dose chlordiazepoxide therapy of anxiety, Curr. Ther. Res. 11:9-14, 1969. Teehan, B. P., Maher, J. F., Carey, J. J. H., Flynn, P. D., and Schreiner, G. E.: Acute ethchlorvynol (PlacidyIR) intoxication, Ann. Intern. Med. 72:875-882, 1970. Thomson, J., and Gien, A. 1. M.: A large overdose of chlordiazepoxide, Lancet 2:722723, 1961. Tokuhata, G. K., and Anderson, R. E.: Hospital emergency cases of poisonings and other injuries caused by ingestion, H. S. M. H. A. Health Reports 86: 1042-1049, 1971. Torry, J. M.: A case of suicide with nitrazepam and alcohol, Practitioner 217:648-649, 1976. Verhulst, H. L., and Crotty, J. J.: Survey of products most frequently named in ingestion accidents in 1965, J. Clin Pharmacol. 7:9-16, 1967. Westervelt, F. B., Jr.: Ethchlorvynol (PlacidylR) intoxication: Experience with live patients, including treatment with hemodialysis, Ann. Intern. Med. 64: 1229-1236, 1966. Whelton, A., Snyder, D. S., and Walker, W. G.: Acute toxic drug ingestions at the Johns Hopkins Hospital, 1963 through 1970, Johns Hopkins Med J. 132: 157 -167, 1973. Whitlock, F. A.: Suicide in Brisbane, 1956 to 1973: The drug-death epidemic, Med. J. Aust. 1:737-743, 1975. Wiltbank, T. B., Sine, H. E., and Brody, B. B.: Are emergency toxicology measurements reaHy used? Clin. Chem. 20:116-120, 1974. Winek, C. L.: Tabulation of therapeutic, toxic, and lethai concentrations of drugs and chemicals in blood, Clin. Chem. 22:832-836, 1976. Woie, L., and Oyri, A.: Quinidine intoxication treated with hemodialysis, Acta Med. Scand. 195:237-239, 1974. Wright-St. Clair, R. E.: Poisoning and overdosage, N. Z. Med. J. 81:193-195, 1975. Zbinden, G., Bagdon, R. E., Keith, E. F., PhiHips, R. D., and Randall, L. 0.: Experimental and clinical toxicology of chlordiazepoxide (Librium R), Toxicol. Appl. Pharmacol. 3:619-637, 1961. Zileli, M. S., Telatar, F., Deniz, S., liter, E., and Adalar, N.: Pseudohyperosmolar nonketoacitotic coma due to oxazepam intoxication, Clin. Toxicol. 5:337-341, 1972.