TABLE 3.-Distribution of EEG patterns during barbiturate addiction, withdrawal, and recovery Electroencephalographic studies.-Electroencephalograms, consisting of bipolar and monopolar tracings from frontal, temporal, parietal, and occipital electrodes. were made on each of the 14 new subjects at weekly intervals during the period of chronic barbiturate intoxication, 2 to 4 times on the second day of abstinence and daily thereafter until the electroencephalographic pattern remained stable. An 8-channel Grass electroencephalograph was used. The analysis of 157 records of the last 14 cases is summarized in table 3. During chronic barbiturate intoxication, 98 percent of the electroencephalograms were decidedly abnormal. In most subjects mixed rhythmic fast and slow activity predominated, most conspicuously in the frontal and parietal tracings. Other patterns were also observed (table 3). However, it was not possible to establish a correlation between the specific electroencephalographic pattern and the degree of intoxication observed under clinical conditions. Very dramatic and abrupt changes in electroencephalograms occurred during the acute abstinence period. In the second day, background activity appeared to change in the direction of increasing normality (reappearance of well-sustained alpha rhythms). However, high-voltage paroxysmal discharges appeared suddenly in this background in over 40 percent of the records. Such paroxysmal activity consisted mainly or either high-voltage mixed spikes and slow waves or of welldefined 4 cycles per second spike-and-dome complexes. Almost as often, paroxysmal activity took the form of high-voltage sinusoidal 6 cycles per second discharges, similarly distributed. During the fourth to eighth day paroxysmal activity decreased, while continuous slow or random delta activity became more prominent in some records; in others, normal patterns were observed. By the ninth day of abstinence, when nearly all subjects began to improve markedly from the clinical standpoint, more than 72 percent were classified as normal. Biochemical studies.-The following biochemical studies were carried out on 15 of the patients: determinations of whole blood and serum nonprotein nitrogen and urea, serum uric acid, creatine, and creatinine. Eosinophile counts were made at appropriate intervals. Determinations were made during intoxication, withdrawal, and subsequent recovery. Typical results on subject 12 are shown in the chart. Creatine and creatinine values were not altered during any phase of the addiction cycle; consequently they are not illustrated. The other constituents were not affected by intoxication, since the intoxication values were the same as those observed during the recovery period. The effect of abrupt withdrawal is illustrated in the chart. Subsequent to four consecutive grand mal convulsions there was a precipitous rise in serum uric acid which was followed by a rise in nonprotein nitrogen. The rise in uric acid was accompanied by a concurrent fall in the eosinophile count from an average of 200 to 0 cells. The eosinophile count returned rapidly to normal even though delirium developed. The changes illustrated by this case were less dramatic in some of the other subjects, but there was usually a transient rise of from 1 to 23 milligrams in nonprotein nitrogen level, occurring any time during the third to eighth day of withdrawal. The increase in uric acid and the fall in eosinophile count were related in time to the incidence of grand mal seizures. Maximum changes were observed 2 to 5 hours after a convulsion. Unless reinforced by additional seizures, the uric acid level decreased sharply at first, then gradually declined to below control levels. Kidney function, as reflected by phenolsulfonphthalein excretion tests, was normal during withdrawal of barbiturates. Relation of (a) eosinophile count, (b) serum uric acid, and (c) nonprotein nitrogen to the clinical course in case 12 during intoxication with secobarbital (A) and during withdrawal and recovery (B). The question arose of whether the elevation of the uric acid level was specific to withdrawal from barbiturates or whether it was directly related to convulsive seizures. To investigate this point, four psychiatric patients who were receiving electroconvulsive therapy were studied. In a series of three electrically induced convulsions at 2- or 3-hour intervals the uric acid values rose about 6 milligrams after the second shock. The increase was further reinforced by the third shock of the series. The rise in uric acid was followed by elevation of the nonprotein nitrogen levels. It was concluded that the changes in the uric acid and nonprotein values were not specific to withdrawal of barbiturates but would occur after convulsions from any cause. COMMENT Judging from this experimental series of 19 cases, it is obvious that chronic barbiturate intoxication is a dangerous condition and that it resembles chronic alcoholism. Persons taking large amounts of barbiturates are confused and are unable to think clearly, have very poor judgment, and display marked emotional lability. The physician should suspect chronic barbiturate intoxication in a person who behaves like one intoxicated with alcohol but who has no odor of alcohol on the breath. The present additional series of 14 patients who received secobarbital confirms the previous observations that there is a considerable range among individual persons with respect to the amount of secobarbital required to produce equivalent degrees of intoxication. In this series the range was 0.9 to 2.2 grams daily. 2 Isbell, H.; Altschul, S.; Kornetsky, C. H.; Eisenman, A. J.; Flanary, H. G., and Fraser, H. F.: Chronic Barbiturate Intoxication; An Experimental Study, Arch. Neurol. & Psychiat. 64:1-28 (July) 1950. 4 This series of cases confirms the findings of many authors that convulsions and delirium will occur following abrupt withdrawal of barbiturates from persons who have been ingesting large amounts of these drugs. The constellation of signs and symptoms observed constitutes a distinct clinical entity, which is best termed the barbiturate-abstinence syndrome. This condition is self-limited, and the patient usually recovers even though no treatment is given. The development of the barbiturate-abstinence syndrome is not dependent on an underlying epileptic diathesis or on any peculiar predilection of morphine addicts to the development of a psychosis. The condition has been observed in many persons who were never addicted to morphine. Definite abstinence syndromes, including convulsions and very bizarre behavior, have been observed in dogs following withdrawal of sodium barbital after several months of chronic intoxication." Even though it is well established that dangerous symptoms follow abrupt withdrawal of barbiturates from persons who have been consuming 0.9 gram (131⁄2 grains) or more of these drugs daily, this fact should be kept in its proper perspective. It does not mean that patients who are taking ordinary therapeutic doses of barbiturates daily under proper medical supervision are addicted. In fact, all available information indicates that no significant degree of the abstinence syndrome occurs after abrupt withdrawal of barbiturates from nonepileptic patients who have been consuming 0.2 gram of these drugs nightly. 6 In an attempt to ascertain the minimum daily dose of secobarbital which will produce physical dependence, 0.6 gram of this drug was administered daily to 18 patients for 35 to 57 days. Two of these patients had one convulsion following abrupt withdrawal of secobarbital, but most of them had only mild or no significant abstinence symptoms." Very little is known concerning the incidence of symptoms following withdrawal of barbiturates from persons who have been consuming 0.3 to 0.5 gram of one of the potent barbiturates daily. Studies designed to shed light on this important quantitative aspect of the problem are being undertaken. The dangerous symptoms of intoxication caused by ingestion of large amounts of barbiturates, the danger of abrupt withdrawal, and the fact that chronic barbiturate intoxication is always associated with a psychiatric disorder mean that the treatment of chronic barbiturate intoxication must be patterned after the treatment of chronic alcoholism or morphine addiction. This implies that such patients should be hospitalized for detoxification and that prolonged psychotherapy is required during and after hospitalization. At the present time the only method for withdrawal of barbiturates which is known to be safe consists of gradual reduction of the dosage of barbiturates.? The importance of proper treatment has been emphasized by the occurrence of deaths during barbiturate withdrawal.8 SUMMARY AND CONCLUSION Fourteen men in good general health who were addicted to barbiturates volunteered for an experimental study of chronic barbiturate (secobarbital) intoxication. Barbiturates were administered orally in a dose sufficiently large to maintain continuous moderate to severe intoxication for 32 to 48 days and were then withdrawn abruptly. The clinical manifestations of chronic barbiturism resemble those of chronic alcoholism. After abrupt withdrawal of barbiturates, a definite abstinence syndrome developed. The barbiturate-abstinence syndrome is characterized by the disappearance of signs of intoxication, weakness, tremor, great anxiety, anorexia, nausea and vomiting, rapid loss of weight, fever, difficulty in making cardiovascular adjustments on standing, and convulsions of a grand mal type and/or psychosis which resembles alcoholic delirium tremens. Pohlisch, K., and Panse, F.: Schlafmittelmiszbrauch, Leipzig, Georg Thieme, 1934. Dunning, H. S.: Convulsions Following Withdrawal of Sedative Medication, Internat. Clin. 3: 255-264, Brownstein, S. R., and Pacella, B. L.: Convulsions Following Abrupt Withdrawal of Barbiturate: Isbell, H.: Treatment of Barbiturate Addiction, Postgrad. Med. 9: 256–258 (March) 1951. Fraser, H. F.; Shaver, M. R.; Maxwell, E. S., and Isbell, H.: Death Due to Withdrawal of Barbiturates, Ann. Int. Med. 38: 1319-1325 (June) 1953. Results of psychological, electroencephalographic, and biochemical studies are reported. Senator DANIEL. Do you have some other material for the record? Dr. FRASER. I have another paper on Death Due to Withdrawal of Barbiturates, if you wish that as part of the record. Senator DANIEL. Suppose you offer that for the files. We will make it a part of the record at this point. (The document referred to is as follows:) [From Annals of Internal Medicine, Vol. 38, No. 6, June, 1953] DEATH DUE TO WITHDRAWAL OF BARBITURATES 1 By H. F. Fraser, M. D., Lexington, Ky., M. R. Shaver, M. D., Topeka, Kans., E. S. Maxwell, M. D., and H. Isbell, M. D., F.A.C.P., Lexington, Ky. Although it is known that abrupt withdrawal of barbiturates from persons who have been chronically intoxicated with large amounts of these drugs may precipitate a serious abstinence syndrome,2 3 a review of the American literature revealed no report in which death was attributed to abstinence from barbiturates. Three cases in which death was associated with withdrawal of barbiturates were found in the German literature. Two of these cases were complicated by the presence of organic disease (Buerger's disease with gangrene, and acute yellow atrophy of the liver with blood dyscrasia), so that abstinence from barbiturates could be regarded only as a contributing factor to death. In the third patient no complicating disease was found on physical examination, and death was in all probability due to withdrawal of barbiturates. The usual course of the barbiturate abstinence syndrome may be described as follows: Upon abrupt withdrawal of barbiturates from individuals who have been ingesting 0.8 gram or more daily of one of the potent barbiturates (secobarbital, pentobarbital, amobarbital), signs of barbiturate intoxication disappear in the first 8 to 12 hours of abstinence, and, clinically, the patient seems to improve. Thereafter, increasing anxiety, insomnia, tremulousness, weakness, difficulty in making cardiovascular adjustments on standing, anorexia, nausea, and vomiting appear. One or more convulsions of grand mal type usually occur during the second or third day of abstinence. Following the seizures, a psychosis characterized by confusion, disorientation in time and place, agitation, tremulousness, insomnia, delusions, and visual and auditory hallucinations may supervene. psychosis clinically resembles alcoholic delirium tremens usually, begins and is worse at night, and terminates abruptly with a critical sleep. The With respect to the incidence of the various signs and symptoms, Fraser and Isbell found that all of 19 patients who had been ingesting 0.8 to 2.2 grams of amobarbital, secobarbital or pentobarbital chronically, exhibited anxiety, weakness, tremor, insomnia and paroxysmal bursts of abnormal waves in the elcetroencephalogram following abrupt withdrawal. Fifteen (or 80 percent) had 1 to 4 convulsions; 12 (or 60 percent) developed a delirium; 4 patients had seizures but no delirium; 1 patient had a delirium but no seizures, and 3 patients escaped both seizures and delirium, although they exhibited anxiety, weakness, and electroen-cephalographic abnormalities. These data indicate that the type with a delirium without a seizure is the least common variant of the barbiturate abstinence syndrome. In 17 of the 19 patients, symptoms disappeared within 10 to 14 days even though no treatment was given. The two remaining patients became so exhausted during the course of a protracted delirium that their lives were judged to be in danger; both were treated by rapid reintoxication with barbiturates, followed by gradual reduction 35 of barbiturates, with satisfactory results. The purpose of this communication is to present the clinical and pathologic findings in a case in which death was apparently due to the severe stress of the barbiturate abstinence syndrome superimpose on an already damaged cardiovascular system. 1 Received for publication December 13, 1952. From the National Institute of Mental Health, Addiction Research Center, Public Health Service Hospital, Lexington, Ky. 2 Pohlisch, K., and Panse, F.: Schlafmittelmissbrauch, 1934, Georg Thieme, Leipzig. 3 Isbell, H., Altschul, S., Kornetsky, C. H., Eisenman, A. J., Flanary, H. G., and Fraser, H. F.: Chronic barbiturate intoxication, Arch. Neurol, and Psychiat. 64: 1, 1950. Meyer, H. J.: Uber chronischen Schalfmittelmissbrauch und Phanodorn Psychosen, Psychiat.-neurol. Wchnschr. 41: 275, 1939. Fraser, H. F., and Isbell, H.: Unpublished data. CASE REPORT A white male physician, 49 years of age, was admitted to the USPHS hospital, Lexington, Ky., at 11 p. m. on June 21, 1951. He gave a history of intermittent addiction to codeine since 1942. The maximal codeine intake had been 360 milligrams daily, but this dose had been voluntarily reduced and no symptoms of abstinence from opiates were ever detected. He denied the use of barbiturates on admission, but 4 days later, while psychotic, admitted using 0.3 to 0.5 grams of secobarbital 4 times daily. When this information was obtained, the diagnosis of barbiturate abstinence syndrome was considered but could not be proved because of the unreliability of the patient's history. Subsequent to the patient's death a detailed history of secobarbital addiction was obtained from his wife. She stated that he had taken a high dose of barbiturates for 8 months, and for the 4 months prior to admission had been ingesting 5 grams (50 capsules) daily. The patient had had the usual cildhood diseases with no complications, and no adult diseases except appendicitis, with appendectomy in 1936. The only positive physical findings were obesity and a blood pressure of 170/90 mm. of Hg. The urinalysis, chest X-ray and blood Kahn were negative. Course in hospital. On admission the patient appeared to be in good physical condition; he had no signs of abstinence from codeine; he was cooperative in carrying out all admission procedures, talked coherently and wrote legibly. After 36 hours of hospitalization he still showed no opiate abstinence signs or other symptoms and was transferred to a convalescent ward. One hour later he vomited, became very nervous and perspired profusely. He was dizzy and refused lunch, and was given 0.2 gram of phenobarbital. At bedtime on the 2 previous days he had received 0.1 gram of pentobarbital. On June 23, at 3:30 p. m. (40 hours after admission), he developed auditory and visual hallucinations and was transferred to a ward for acutely disturbed patients. At this time his oral temperature was 99° F.; pulse was 80 per minute; respiratory rate was 20 per minute, and blood pressure was 162/90 mm. of Hg. He was perspiring profusely, his pupils were somewhat dilated and he had a slight facial tremor. He was very nervous and tremulous but had no complaints of pain. He ate no lunch or dinner. During the night he did not sleep, was disoriented in place, and said there were a lot of boys and girls having a party in his room. On June 24 his condition was unchanged; he was given 0.1 gram of Dilantin 3 times a day; he was oriented at intervals and confused at times. On June 25 these symptoms continued and the patient complained that his hometown neighbors were watching him. He was given 128 milligrams of phenobarbital at 8 p. m., and after 10:30 p. m. he slept fitfully. On June 26 the hallucinations continued and he was given 96 milligrams of phenobarbital at 9 p. m. He was quite nervous and restless and did not go to sleep until 3 a. m. On June 27 he appeared improved and was transferred from the disturbed ward to the convalescent psychotic ward, but during the evening meal he again became disturbed and attacked a fellow patient and had to be separated from him. Later in the evening he attacked another patient, and then was locked in his room. At 10:40 p. m., while still locked in his room, he had hallucinations and claimed that someone was being killed and cut up by the attendant. At 12:45 a. m. on June 28 he was put in a wetpack for 45 minutes but continued to be restless and noisy. The pulse rate declined from 120 at 1:15 a. m. to 64 per minute at 1:30 a. m., shortly before the patient was removed from the wetpack. He was rubbed down with a towel and returned to his room. At 2 a. m. the blood pressure was 90/70 mm. of Hg; at 2:15 a. m. patient had gross tremors, and was jerking and twitching and stuporous; axillary temperature was 107° F.; pulse volume was poor and the rate was 120 per minute; the extremities were cold and cyanotic. At 2:30 a. m. cyanosis was general; there was incontinence of feces, and the twitching continued in all extremities; the pulse was rapid (rate, 120 to 146 per minute), weak and thready. The respiratory rate was 44 to 48 per minute. The blood pressure could not be obtained because of the convulsive movements; the skin was hot and dry; the pupils were round, regular, and equal, and there was no nuchal rigidity. At 2:30 a. m. the patient was given 0.5 gram of sodium amytal intravenously, following which his color and pulse improved, and he became quieter. These effects wore off in about 45 minutes, but after repetition of the dose of sodium amytal he again improved temporarily. He was given 1 cubic centimeter of ephedrine and 300,000 units of penicillin G intramuscularly, and 1,000 cubic centimeters of 5 percent glucose with 10 units of insulin intravenously. At 4:15 a. m. the jerking and twitching recurred, and 0.5 gram of soidum amytal was given intramuscularly, but without any significant improvement. The axillary temperature continued at 107° F. The patient died at 4:37 a. m. on June 28, 6 days and 6 hours after admission to the hospital. |