Psychopharmacology (1992) 107:480-484
Psychopharmacology © Springer-Verlag 1992
Rebound insomnia and hypnotic self administration Timothy Roehrs, Lori Merlotti, Frank Zorick, and Thomas Roth
Henry Ford Hospital, 2921 West Grand Boulevard, Sleep Disorders and Research Center, Detroit, MI 48202, USA Received April 24, 1991 / Final version November 21, 1991 Abstract. Twenty-one (three groups of seven), men and women, 25-50 years of age were studied to determine whether or not rebound insomnia would increase the likelihood of self administering a benzodiazepine (triazolam 0°25 mg) hypnotic. The groups compared were patients with insomnia and disturbed sleep, insomnia and normal sleep, and healthy normals. Rebound insomnia, by both subjective and polysomnographic assessment, was induced. The experience of rebound insomnia did not increase the likelihood of self administering a benzodiazepine hypnotic in any of the groups. There were clear group differences in pill self administration with normals rarely and insomnia patients frequently, but not differentially (placebo versus active drug) self administering pills. Key words: Triazolam - Rebound insomnia - Insomnia patients - Normals - Dependence
The acknowledged drugs of choice for the pharmacological treatment of insomnia are the benzodiazepine (BZ) hypnotics, but the dependence liability of these drugs remains an unresolved issue (Consensus Conference 1984; American Psychiatric Association 1990). There are numerous documented clinical reports regarding the excessive use of and dependence on BZs (Marks 1978). However, daytime laboratory studies which have assessed the reinforcing and subjective effects of BZs using drug self administration procedures and mood questionnaires provide a somewhat different picture. These controlled studies suggest that the dependence liability of BZs is relatively low, particularly compared to other drug classes (Griffiths et al. 1979, 1983a, t985; Johanson and Uhlenhuth 1980a, b; Johanson et al. 1983; Griffiths and Roache 1985). But it is important to note that none of these studies have assessed the dependence liability of Offprint requests to:
T. Roehrs
BZs in the context of their use as hypnotics (i.e. in insomnia patients as pre-sleep medications). A recent American Psychiatric Association (APA) Task Force report identified the dependence liability of BZs as an important consideration in the treatment of insomnia (APA 1990). One condition which the APA Task Force suggested may place individuals at risk is the presence of a drug-related sleep disturbance which makes it difficult to discontinue hypnotic drug use. This sleep disturbance, termed rebound insomnia, appears when abruptly discontinuing the hypnotic and is characterized by a worsening of sleep beyond baseline levels (Kales et al. 1978). Previous evidence regarding the existence of rebound insomnia was inconsistent, due in part to methodological inadequacies (Roth et al. 1976; Bixler et al. 1978; Hartse et al. 1980; Kales et al. 1983). In studies designed to correct the inadequacies of the prior research, it was established that rebound insomnia is a consistent phenomenon (Roehrs et al. 1986; Merlotti et al. 1988). It occurs in healthy normals and in patients with insomnia as a reduction in total sleep time and increased awakening from sleep on one or two nights following administration of short and intermediate acting benzodiazepines (Roehrs et al. 1990). In addition, studies comparing doses have shown that rebound insomnia is related to dose, generally occurring with the abrupt discontinuation of a high dose, but not a low dose (Roehrs et al. 1986). No study has been conducted to determine whether or not rebound insomnia increases the likelihood of BZ hypnotic self administration. The purpose of the present study was to assess BZ hypnotic self administration following a hypnotic discontinuation likely to produce rebound insomnia (an abrupt discontinuation) and one unlikely (a tapered discontinuation) to do so (Greenblatt et al. 1987). The study was conducted in healthy normals and in patients with chronic insomnia complaints who do and do not have objectively disturbed sleep. This report focuses on the behavioral self administration data. The complete sleep data are presented in a companion paper.
481
Table 2. Study procedures and time line
Table 1. Characteristics of study groups Group
Normal
Subjective insomnia
Objective insomnia
Health screen and sleep disorders screen
Age m e a n ± SD
35.6 5.97
36.4 5.97
35.4 6.37
Sex females males Insomnia history Subj total sleep
4 3 Absent > 7
3 4 >_ 1 yr < 6.5 h
4 3 > 1 yr < 6.5 h
Condition 1 Adaptation Baseline Enforced pill administration Diseontinu(no pill) (no pill) (pill outlined by condition) ation (no pill) 1 nt 1 nt 6 nights 1 nt
Objective SE
> 90%
>_90%
>_85%
History of Bz use (# of Ss)
2
2
2
SE = sleep efficiency (sleep time/bed time)
Materials and methods Subjects. Twenty-one (three groups of seven), men and women, 25-50 years of age were studied (group demographics are presented in Table 1). All were in good health (except for an insomnia complaint) as determined by the screening procedures described below. All subjects signed a written, informed consent and received payment for their participation. Procedure. Subjects underwent a medical history, physical examination, and laboratory blood and urine tests prior to a screening nocturnal polysomnogram. Subjects were excluded if they had acute or chronic medical conditions that required treatment or were currently taking CNS acting drugs. The urine tests were also used to screen subjects for the current use of illicit drugs. Subjects with a current or past history of psychiatric disorders, drug addiction, and alcoholism were excluded based on a brief psychiatric screen, the Minnesota Multiphasic Personality Inventory and a urine drug screen. Finally, subjects who had taken BZ hypnotics within the past year were also excluded. The groups were matched as to previous experience with BZs (beyond the past year), which in the case of the normal group required recruiting subjects who had previously served in BZ hypnotic efficacy studies (not self administration studies). Each subject underwent a sleep disorders evaluation including a sleep history and a nocturnal polysomnogram. Table 1 outlines the sleep disorders history and entry criteria for the three groups. Subjects recruited as normals reported no history of insomnia, estimated their nightly sleep time as greater than 7 h, and had a sleep efficiency (sleep time per time in bed) on the nocturnal polysomnogram of 90% or greater. Subjects with objective insomnia had the complaint for at least 1 year, estimateA their nightly sleep time as less than 6.5 h, and had a sleep efficiency of 85% or less on the screening polysomnogram. Subjects qualifying as persons with insomnia complaints, but no objective sleep disturbance (subjective insomnia), had a 1 year history of insomnia, estimated their nightly sleep time as less than 6.5 h, and had a sleep efficiency of 90% or more on the polysomnogram while estimating that their sleep time for the screening night was at least 1 h less. All subjects had no evidence of apneas or periodic leg movements on the nocturnal polysomnogram. Each subject who passed the screening was exposed to three different conditions organized in a Latin Square design and administered in a double-blind fashion with seven nights between conditions. As outlined in Table 2, each condition consisted of t adaptation night and 1 baseline night with no pill administration then 6 nights of enforced pill administration consisting of 0.5 mg triazolam (abrupt condition), or 3 nights of 0.5 rag, 2 nights of 0.25 mg, and 1 night of 0.125 mg triazolam (taper condition), or 6 nights of placebo. Following the enforced administrations of each of the
1 week
Self administration At home (pill or no pill) (no pill) 3 nts 4 nts
Self administration (pill or no pill) 3 nts
1 week Condition 2
Adaptation (no pill) 1 nt
Baseline Enforced pill administration Diseontinu(no pill) (pill outlined by condition) ation (no pill) 1 nt 6 nights 1 nt
Self administration At home (pill or no pill) (no pill) 3 nts 4 nts
Self administration (pill or no pill) 3 nts
1 week Condition 3
Adaptation (no pill) 1 nt
Baseline Enforced pill administration Discontinu(no pill) (pill outlined by condition) ation (no pill) 1 nt 6 nights 1 nt
Self administration At home (pill or no pill) (no pill) 3 nts 4 nights
Self administration (pill or no pill) 3 nts
three conditions there was one night with no pill administration for the rebound insomnia induction. Then after the discontinuation night of each condition subjects were given the opportunity on 6 nights (3 nights immediately and 3 additional nights a week later) to self administer a pill, which they were told was the same as they had received during the enforced treatment period. In reality, during the abrupt and taper conditions the pill was always 0.25 mg triazolam (to avoid the possibility of rebound on other than the designated rebound night) and during the placebo condition it was placebo. All capsules were matched for appearance and given to the subject or self administered 30 min prior to lights out. To standardize self administration procedures, on each choice night subjects received a form on which they indicated their request for, or refusal of a pill. They also indicated why they made the choice and then signed the form. A technician then administered the pill, if requested. Each morning, the form and an appropriately opened or closed pill container was collected. On each study night subjects arrived at the sleep laboratory about 1.5 h before their usual bedtime which was held constant throughout the study. They were prepared for standard polysomnographic assessment (Rechtschaffen and Kales 1968). A standard all-night polysomnogram was obtained in each of the three conditions on the adaptation and baseline nights, the first, third, and last night of enforced pill administration, on the discontinuation night, and the 6 self administration nights. Subjects were awakened after 8 h in bed. After arising, each subject then completed a sleep questionnaire regarding the quantity and quality of the previous night's sleep. The complete polysomnographic data collected in this study are presented in a companion paper. The following study restrictions were adhered to by all subjects : 1) no alcoholic or caffeinated beverages after 4:00 p.m. on study nights, 2) no napping during the study, 3) no changes in bed or wake times during the study, 4) eight hours in bed each night during the
482 study and 5) no other medications without the approval of the investigator. Subjects were monitored by a periodic alcohol breath testing and self report of sleep schedules when sleeping at home. Each polysomnographic recording was scored manually in 30-s epochs according to the standards of Rechtschaffen and Kales (1968), maintaining an inter-rater reliability of 90% or better. Records were coded so that scorers were unaware of the treatment. Mixed design MANOVAs (SAS Institute) were conducted on the various polysomnographic, subjective sleep assessments, and self administration parameters with group as the between-subject factor and the three conditions (abrupt, taper and placebo) as the withinsubject factor, Conservative probability levels corrected by Greenhouse-Geisser procedure were used for all within subject comparisons. When :indicated pairwise post hoc comparisons (SAS Institute, Duncan) were conducted.
z L~J U~ 0 ]2
I ....
LJ
Z
Results
The effect of triazolam on sleep during the enforced pill administration period in the three groups is presented in Table 3. The mean of the 3 recorded treatment nights is presented as there were no effects of nights or night interactions. Compared to placebo both active drug conditions significantly increased total sleep time (F= 15.51, P
Psychopharmacology © Springer-Verlag 1992
Rebound insomnia and hypnotic self administration Timothy Roehrs, Lori Merlotti, Frank Zorick, and Thomas Roth
Henry Ford Hospital, 2921 West Grand Boulevard, Sleep Disorders and Research Center, Detroit, MI 48202, USA Received April 24, 1991 / Final version November 21, 1991 Abstract. Twenty-one (three groups of seven), men and women, 25-50 years of age were studied to determine whether or not rebound insomnia would increase the likelihood of self administering a benzodiazepine (triazolam 0°25 mg) hypnotic. The groups compared were patients with insomnia and disturbed sleep, insomnia and normal sleep, and healthy normals. Rebound insomnia, by both subjective and polysomnographic assessment, was induced. The experience of rebound insomnia did not increase the likelihood of self administering a benzodiazepine hypnotic in any of the groups. There were clear group differences in pill self administration with normals rarely and insomnia patients frequently, but not differentially (placebo versus active drug) self administering pills. Key words: Triazolam - Rebound insomnia - Insomnia patients - Normals - Dependence
The acknowledged drugs of choice for the pharmacological treatment of insomnia are the benzodiazepine (BZ) hypnotics, but the dependence liability of these drugs remains an unresolved issue (Consensus Conference 1984; American Psychiatric Association 1990). There are numerous documented clinical reports regarding the excessive use of and dependence on BZs (Marks 1978). However, daytime laboratory studies which have assessed the reinforcing and subjective effects of BZs using drug self administration procedures and mood questionnaires provide a somewhat different picture. These controlled studies suggest that the dependence liability of BZs is relatively low, particularly compared to other drug classes (Griffiths et al. 1979, 1983a, t985; Johanson and Uhlenhuth 1980a, b; Johanson et al. 1983; Griffiths and Roache 1985). But it is important to note that none of these studies have assessed the dependence liability of Offprint requests to:
T. Roehrs
BZs in the context of their use as hypnotics (i.e. in insomnia patients as pre-sleep medications). A recent American Psychiatric Association (APA) Task Force report identified the dependence liability of BZs as an important consideration in the treatment of insomnia (APA 1990). One condition which the APA Task Force suggested may place individuals at risk is the presence of a drug-related sleep disturbance which makes it difficult to discontinue hypnotic drug use. This sleep disturbance, termed rebound insomnia, appears when abruptly discontinuing the hypnotic and is characterized by a worsening of sleep beyond baseline levels (Kales et al. 1978). Previous evidence regarding the existence of rebound insomnia was inconsistent, due in part to methodological inadequacies (Roth et al. 1976; Bixler et al. 1978; Hartse et al. 1980; Kales et al. 1983). In studies designed to correct the inadequacies of the prior research, it was established that rebound insomnia is a consistent phenomenon (Roehrs et al. 1986; Merlotti et al. 1988). It occurs in healthy normals and in patients with insomnia as a reduction in total sleep time and increased awakening from sleep on one or two nights following administration of short and intermediate acting benzodiazepines (Roehrs et al. 1990). In addition, studies comparing doses have shown that rebound insomnia is related to dose, generally occurring with the abrupt discontinuation of a high dose, but not a low dose (Roehrs et al. 1986). No study has been conducted to determine whether or not rebound insomnia increases the likelihood of BZ hypnotic self administration. The purpose of the present study was to assess BZ hypnotic self administration following a hypnotic discontinuation likely to produce rebound insomnia (an abrupt discontinuation) and one unlikely (a tapered discontinuation) to do so (Greenblatt et al. 1987). The study was conducted in healthy normals and in patients with chronic insomnia complaints who do and do not have objectively disturbed sleep. This report focuses on the behavioral self administration data. The complete sleep data are presented in a companion paper.
481
Table 2. Study procedures and time line
Table 1. Characteristics of study groups Group
Normal
Subjective insomnia
Objective insomnia
Health screen and sleep disorders screen
Age m e a n ± SD
35.6 5.97
36.4 5.97
35.4 6.37
Sex females males Insomnia history Subj total sleep
4 3 Absent > 7
3 4 >_ 1 yr < 6.5 h
4 3 > 1 yr < 6.5 h
Condition 1 Adaptation Baseline Enforced pill administration Diseontinu(no pill) (no pill) (pill outlined by condition) ation (no pill) 1 nt 1 nt 6 nights 1 nt
Objective SE
> 90%
>_90%
>_85%
History of Bz use (# of Ss)
2
2
2
SE = sleep efficiency (sleep time/bed time)
Materials and methods Subjects. Twenty-one (three groups of seven), men and women, 25-50 years of age were studied (group demographics are presented in Table 1). All were in good health (except for an insomnia complaint) as determined by the screening procedures described below. All subjects signed a written, informed consent and received payment for their participation. Procedure. Subjects underwent a medical history, physical examination, and laboratory blood and urine tests prior to a screening nocturnal polysomnogram. Subjects were excluded if they had acute or chronic medical conditions that required treatment or were currently taking CNS acting drugs. The urine tests were also used to screen subjects for the current use of illicit drugs. Subjects with a current or past history of psychiatric disorders, drug addiction, and alcoholism were excluded based on a brief psychiatric screen, the Minnesota Multiphasic Personality Inventory and a urine drug screen. Finally, subjects who had taken BZ hypnotics within the past year were also excluded. The groups were matched as to previous experience with BZs (beyond the past year), which in the case of the normal group required recruiting subjects who had previously served in BZ hypnotic efficacy studies (not self administration studies). Each subject underwent a sleep disorders evaluation including a sleep history and a nocturnal polysomnogram. Table 1 outlines the sleep disorders history and entry criteria for the three groups. Subjects recruited as normals reported no history of insomnia, estimated their nightly sleep time as greater than 7 h, and had a sleep efficiency (sleep time per time in bed) on the nocturnal polysomnogram of 90% or greater. Subjects with objective insomnia had the complaint for at least 1 year, estimateA their nightly sleep time as less than 6.5 h, and had a sleep efficiency of 85% or less on the screening polysomnogram. Subjects qualifying as persons with insomnia complaints, but no objective sleep disturbance (subjective insomnia), had a 1 year history of insomnia, estimated their nightly sleep time as less than 6.5 h, and had a sleep efficiency of 90% or more on the polysomnogram while estimating that their sleep time for the screening night was at least 1 h less. All subjects had no evidence of apneas or periodic leg movements on the nocturnal polysomnogram. Each subject who passed the screening was exposed to three different conditions organized in a Latin Square design and administered in a double-blind fashion with seven nights between conditions. As outlined in Table 2, each condition consisted of t adaptation night and 1 baseline night with no pill administration then 6 nights of enforced pill administration consisting of 0.5 mg triazolam (abrupt condition), or 3 nights of 0.5 rag, 2 nights of 0.25 mg, and 1 night of 0.125 mg triazolam (taper condition), or 6 nights of placebo. Following the enforced administrations of each of the
1 week
Self administration At home (pill or no pill) (no pill) 3 nts 4 nts
Self administration (pill or no pill) 3 nts
1 week Condition 2
Adaptation (no pill) 1 nt
Baseline Enforced pill administration Diseontinu(no pill) (pill outlined by condition) ation (no pill) 1 nt 6 nights 1 nt
Self administration At home (pill or no pill) (no pill) 3 nts 4 nts
Self administration (pill or no pill) 3 nts
1 week Condition 3
Adaptation (no pill) 1 nt
Baseline Enforced pill administration Discontinu(no pill) (pill outlined by condition) ation (no pill) 1 nt 6 nights 1 nt
Self administration At home (pill or no pill) (no pill) 3 nts 4 nights
Self administration (pill or no pill) 3 nts
three conditions there was one night with no pill administration for the rebound insomnia induction. Then after the discontinuation night of each condition subjects were given the opportunity on 6 nights (3 nights immediately and 3 additional nights a week later) to self administer a pill, which they were told was the same as they had received during the enforced treatment period. In reality, during the abrupt and taper conditions the pill was always 0.25 mg triazolam (to avoid the possibility of rebound on other than the designated rebound night) and during the placebo condition it was placebo. All capsules were matched for appearance and given to the subject or self administered 30 min prior to lights out. To standardize self administration procedures, on each choice night subjects received a form on which they indicated their request for, or refusal of a pill. They also indicated why they made the choice and then signed the form. A technician then administered the pill, if requested. Each morning, the form and an appropriately opened or closed pill container was collected. On each study night subjects arrived at the sleep laboratory about 1.5 h before their usual bedtime which was held constant throughout the study. They were prepared for standard polysomnographic assessment (Rechtschaffen and Kales 1968). A standard all-night polysomnogram was obtained in each of the three conditions on the adaptation and baseline nights, the first, third, and last night of enforced pill administration, on the discontinuation night, and the 6 self administration nights. Subjects were awakened after 8 h in bed. After arising, each subject then completed a sleep questionnaire regarding the quantity and quality of the previous night's sleep. The complete polysomnographic data collected in this study are presented in a companion paper. The following study restrictions were adhered to by all subjects : 1) no alcoholic or caffeinated beverages after 4:00 p.m. on study nights, 2) no napping during the study, 3) no changes in bed or wake times during the study, 4) eight hours in bed each night during the
482 study and 5) no other medications without the approval of the investigator. Subjects were monitored by a periodic alcohol breath testing and self report of sleep schedules when sleeping at home. Each polysomnographic recording was scored manually in 30-s epochs according to the standards of Rechtschaffen and Kales (1968), maintaining an inter-rater reliability of 90% or better. Records were coded so that scorers were unaware of the treatment. Mixed design MANOVAs (SAS Institute) were conducted on the various polysomnographic, subjective sleep assessments, and self administration parameters with group as the between-subject factor and the three conditions (abrupt, taper and placebo) as the withinsubject factor, Conservative probability levels corrected by Greenhouse-Geisser procedure were used for all within subject comparisons. When :indicated pairwise post hoc comparisons (SAS Institute, Duncan) were conducted.
z L~J U~ 0 ]2
I ....
LJ
Z
Results
The effect of triazolam on sleep during the enforced pill administration period in the three groups is presented in Table 3. The mean of the 3 recorded treatment nights is presented as there were no effects of nights or night interactions. Compared to placebo both active drug conditions significantly increased total sleep time (F= 15.51, P
