Psychophannacologia (Berl.) 43, 187-190 (1975) - 9 by Springer-Verlag 1975
Short Reports
The Actions of Flunitrazepam (Rohypnol on Heart and Respiratory Rates and Skin Potential Fluctuations during the Sleep Cycle in Normal Volunteers and Neurotic Patients with Insomnia JAIME M. MONTI*, HUMBERTO ALTIER, MIGUEL PRANDRO, and JUAN L. GIL Depto. de Farmacologfa y Terape6tica y Depto. de Psiquiatrfa, Hospital de Clhlicas, Montevideo, Uruguay Received January 1, 1975
Abstract. The actions of flunitrazepam (Rohypnol| were assessed on the sleep cycle, heart and respiratory rates and skin potential fluctuations of normal volunteers and neurotic patients with insomnia by means of all night recordings. The most conspicuous effect of flunitrazepam (2 mg p.o.) in the healthy subject's sleep cycle was an increase of the latency for the appearance of the first REM period. In the in-
somniacs the compound was effective in inducing and maintaining sleep. Flunitrazepam diminished heart rates during the REM phases and significantly decreased the variability indices, this effect being more prominent in the normal subjects. Skin potential fluctuations during stages 2 and REM sleep were also decreased although tolerance developed rapidly in this connection.
Key words: Psychopharmacology - Sleep - Insomnia - Flunitrazepam - Benzodiazepine - Skin Potential - Heart Rate.
Introduction We have previously shown that flunitrazepam (Rohypnol | is a clinically useful hypnotic which differs significantly from placebo (Monti and Altier, 1973; Monti et al., 1974). Insomnia and symptoms of the cardiac and respiratory sphere including dyspnea and palpitations are commonly referred by neurotic patients. It was our purpose to study the effects of flunitrazepam on heart and respiratory rates and the sinus arrhythmia observed during R E M sleep in normal volunteers and neurotic patients with insomnia. Increased number of skin potential fluctuations (SPF) occurs during wakefulness and sleep in anxiety states. Therefore, the action of flunitrazepam was assessed also on this variable. Material and Methods The study was performed on 5 healthy adult (4 male, 1 female) volunteers (age range 2 0 - 4 1 years) and 5 neurotic patients (4 female, 1 male, ages ranging * On sabattical leave. Present address: Depto. de Psicobiologia, Escola Paulista de Medicina, Sao Paulo, Brasil.
from 28 to 50 years) with a prevalent symptomatology of anxiety (n = 4) or hysteria (n = 1) associated with insomnia. Throughout the study they slept in a soundattenuated room for 7 hrs. During the habituation period they spent 2 nights in the laboratory receiving placebo in order to become accustomed to their new environment. The following variables were monitored: continuous electrocardiogram, respiration, 2 channels of electroencephalogram (right frontal and parietal), binocular electro-oculogram, electromyogram (chin muscles) and SPF. An 8-night schedule was used as follows: on night 1 a placebo was given and baseline measurements were obtained. During nights 2 to 6 subjects (Ss) were given the drug orally sleeping in the laboratory on nights 2, 4 and 6. The remaining nights they had the medication at home. A placebo was again administered on nights 7 and 8 and laboratory recordings taken on nights 8. During the recording nights a placebo or ftunitrazepam (2 mg p.o.) was given 30 min before bed time in identically matched tablets. The records were analyzed for wakefulness (W), slow wave sleep (SWS) and R E M sleep (REM) according to Rechtschaffen and Kales (1968). Baseline placebo nights were averaged and compared with the
188
Psychopharmacologia (Berl.), Vol. 43, Fasc. 2 (1975) B Heart 84
rate
82 80
ml A
76! 74 72
Heart rate
1!70++ +2 58 NIGHT
6 P
L_
D
I
P
P
L_
I
D
P
Fig. 1 A and B. Action of flunitrazepam on heart rate. A Normal volunteers. B Neurotics with insomnia. The hatched bars represent mean heart rates (+ 1 S.E.M.) from 20 rain samples of all REM periods of overnight recordings in 5 Ss. The open bars represent 20 min periods preceding and following REM episodes. Abscissa: recording nights. P placebo; D drug (flunitrazepam 2 mg p.o.)
X
1.2
~3
1.1
A
_z 1.o
>I-
.J
Short Reports
The Actions of Flunitrazepam (Rohypnol on Heart and Respiratory Rates and Skin Potential Fluctuations during the Sleep Cycle in Normal Volunteers and Neurotic Patients with Insomnia JAIME M. MONTI*, HUMBERTO ALTIER, MIGUEL PRANDRO, and JUAN L. GIL Depto. de Farmacologfa y Terape6tica y Depto. de Psiquiatrfa, Hospital de Clhlicas, Montevideo, Uruguay Received January 1, 1975
Abstract. The actions of flunitrazepam (Rohypnol| were assessed on the sleep cycle, heart and respiratory rates and skin potential fluctuations of normal volunteers and neurotic patients with insomnia by means of all night recordings. The most conspicuous effect of flunitrazepam (2 mg p.o.) in the healthy subject's sleep cycle was an increase of the latency for the appearance of the first REM period. In the in-
somniacs the compound was effective in inducing and maintaining sleep. Flunitrazepam diminished heart rates during the REM phases and significantly decreased the variability indices, this effect being more prominent in the normal subjects. Skin potential fluctuations during stages 2 and REM sleep were also decreased although tolerance developed rapidly in this connection.
Key words: Psychopharmacology - Sleep - Insomnia - Flunitrazepam - Benzodiazepine - Skin Potential - Heart Rate.
Introduction We have previously shown that flunitrazepam (Rohypnol | is a clinically useful hypnotic which differs significantly from placebo (Monti and Altier, 1973; Monti et al., 1974). Insomnia and symptoms of the cardiac and respiratory sphere including dyspnea and palpitations are commonly referred by neurotic patients. It was our purpose to study the effects of flunitrazepam on heart and respiratory rates and the sinus arrhythmia observed during R E M sleep in normal volunteers and neurotic patients with insomnia. Increased number of skin potential fluctuations (SPF) occurs during wakefulness and sleep in anxiety states. Therefore, the action of flunitrazepam was assessed also on this variable. Material and Methods The study was performed on 5 healthy adult (4 male, 1 female) volunteers (age range 2 0 - 4 1 years) and 5 neurotic patients (4 female, 1 male, ages ranging * On sabattical leave. Present address: Depto. de Psicobiologia, Escola Paulista de Medicina, Sao Paulo, Brasil.
from 28 to 50 years) with a prevalent symptomatology of anxiety (n = 4) or hysteria (n = 1) associated with insomnia. Throughout the study they slept in a soundattenuated room for 7 hrs. During the habituation period they spent 2 nights in the laboratory receiving placebo in order to become accustomed to their new environment. The following variables were monitored: continuous electrocardiogram, respiration, 2 channels of electroencephalogram (right frontal and parietal), binocular electro-oculogram, electromyogram (chin muscles) and SPF. An 8-night schedule was used as follows: on night 1 a placebo was given and baseline measurements were obtained. During nights 2 to 6 subjects (Ss) were given the drug orally sleeping in the laboratory on nights 2, 4 and 6. The remaining nights they had the medication at home. A placebo was again administered on nights 7 and 8 and laboratory recordings taken on nights 8. During the recording nights a placebo or ftunitrazepam (2 mg p.o.) was given 30 min before bed time in identically matched tablets. The records were analyzed for wakefulness (W), slow wave sleep (SWS) and R E M sleep (REM) according to Rechtschaffen and Kales (1968). Baseline placebo nights were averaged and compared with the
188
Psychopharmacologia (Berl.), Vol. 43, Fasc. 2 (1975) B Heart 84
rate
82 80
ml A
76! 74 72
Heart rate
1!70++ +2 58 NIGHT
6 P
L_
D
I
P
P
L_
I
D
P
Fig. 1 A and B. Action of flunitrazepam on heart rate. A Normal volunteers. B Neurotics with insomnia. The hatched bars represent mean heart rates (+ 1 S.E.M.) from 20 rain samples of all REM periods of overnight recordings in 5 Ss. The open bars represent 20 min periods preceding and following REM episodes. Abscissa: recording nights. P placebo; D drug (flunitrazepam 2 mg p.o.)
X
1.2
~3
1.1
A
_z 1.o
>I-
.J
