Rebound Insomnia: Significance TIMOTHY ROEHRS,
PH.D. Detroit, Michigan
Its Determinants
GERALD VOGEL,
M.D. Atlanta,
Georgja THOMAS ROTH,
Rebound insomnia is a sleep disturbance that occurs on discontinuation of benzodiazepine hypnotic drugs. It has been reported in both patients and healthy normal subjects and is characterized by increased wakefulness above the person’s baseline levels. This article reviews the available information regarding determinants, possible mechanisms, and clinical significance of rebound insomnia. It is concluded that rebound insomnia is a disturbance of one or two nights’ duration that primarily follows discontinuation of short- to intermediate-acting benzodiazepines. It occurs at high doses of a given drug, beyond which no additional hypnotic efficacy is evident. There seem to be clear individual differences in the experience of rebound insomnia, but no prospective studies have established which differences predict rebound. It is likely to be avoided by initiating treatment with the lowest effective dose and tapering the dose upon discontinuation.
From the Henry Ford Hospital, Detroit, Michigan, and Emory University Medical School, Atlanta, Georgia. Requests for reprints should be addressed to Timothy Roehrs, Ph.D., Henry Ford Hospital, 2921 West Grand Boulevard, Detroit, Michigan 48202.
and PH.D. Detroit, nllichigan
ebound insomnia refers to the sleep disturbance R that follows discontinuation of hypnotic drugs and is characterized by a worsening of sleep beyond the baseline levels. It was initially reported as an observation in patients with insomnia who were participating in efficacy and safety studies of benzodiazepine hypnotics [1,2]. Although rebound insomnia now has been reported in other studies and from other laboratories, there still is little systematic and consistent information about the phenomenon. The present review will discuss the available information regarding the determinants, the possible mechanisms, and the clinical significance of rebound insomnia. However, before the relevant data are described, several important methodologic issues must be discussed. METHODOLOGIC CONSIDERATIONS Rebound insomnia has not been a consistent finding [3]. In earlier studies it was seen on some sleep parameters in one study, but not on others that logically should show it also [41, with the low dose but not the high dose of a drug [5], and when there was no evidence of prior pharmacologic activity [6]. These inconsistencies in earlier studies may be due in part to inadequate methodology. The initial report defined rebound insomnia as a significant increase in wake time during drug discontinuation compared with baseline, using standard all-night sleep recordings [l]. Later the criteria were extended to include a 40 percent increase above baseline in wake time (in the absence of a statistically significant increase) on a single recovery night or for the entire recovery period [‘71. These criteria presume that an adequate baseline or comparison has been established. Sleep, whether disturbed or normal, is a variable phenomenon night to night, but few studies have used a parallel placebo group to control for this variability [8]. An adequate assessment of rebound insomnia requires this minimal control. Most of the initial studies of rebound insomnia were cross-over studies in which patients are studied over a three- or four-day period of placebo treatment before being exposed to the active drug treatment. Rebound insomnia is assessed by comparing the baseline placebo period with the drug discontinuation period. The problem with such a design is that rebound effects are confounded with sequence effects. Furthermore, patients often must meet certain selection criteria during the placebo period (which then is the baseline against which sleep on drug discontinuation is compared) to be included in the study. If the entry criteria are extreme, later samples of the patients’ conditions will tend to regress from the extreme to the mean [91. Such regression to the mean will then bias the estimate of rebound insomnia. This is a further reason for the necessity of parallel placebo designs in the study of rebound insomnia. Finally, rebound insomnia has been studied almost
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gure 1. Sleep efficiency on first rebound night after one, six, and 12 nights of ,. ^W^ tnazolam u.su mg.
exclusively in patients with insomnia. There have been only a few studies in healthy subjects [lO,ll]. Thus, it is not clear whether rebound insomnia is primarily a clinical phenomenon, whether it has a pharmacologic basis, or whether it is the exacerbation in a clinical population of predictable and demonstrable pharmacologic effects. Further, as regards special populations, the elderly and women experience insomnia more often and also consume hypnotic drugs more frequently than other segments of the population, yet no studies have characterized rebound insomnia in such populations. The question arises whether rebound insomnia is more likely in such populations. DETERMINANTS Half-Life
The benzodiazepines, when classified in terms of half-life, are usually classified as short-acting (less than six hours), intermediate-acting (six to 24 hours), and long-acting (more than 24 hours) compounds. It has been argued that rebound insomnia is specific to short and intermediate half-life compounds [7]. Only a few studies have directly compared short and long half-life drugs; the inference regarding half-life and the probability of rebound insomnia is made based on comparisons across studies. Furthermore, only two studies have assessed patients for the necessary time period (four times the half-life) after discontinuing the long half-life drug, and these studies report contradictory results [12,13]. One study found rebound insomnia with triazolam (a short half-life drug) on the first two discontinuation nights and argued that rebound insomnia occurred with flurazepam (a long half-life drug) during the second week after drug discontinuation. The rebound insomnia after flurazepam occurred in six of the seven subjects studied? but it was experienced on different nights of discontinuation week 2 [12]. The other report studied two long half-life drugs for 15 nights after discontinuation and found no rebound insomnia, whereas in another study from the same laboratory, rebound was found on two nights after triazolam discontinuation [13,14]. In the 15-night discontinuation study, total wake time never increased above baseline after quazepam and never beyond 25 percent of baseline after flurazepam [131. Thus, comparing across studies, the authors conclude there is rebound after discontinuing the short-acting drug but not the long-acting ones. There are numerous reports of rebound insomnia 3A-4OS
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after discontinuation of short and intermediate halflife compounds. A recent comprehensive review presents the data for the many compounds that have been studied at a number of different laboratories [15]. To briefly summarize the information, the intermediateacting benzodiazepines that have been studied are alprazolam, estazolam, flunitrazepam, lormetazepam, loprazolam, lorazepam, nitrazepam, nordiazepam, and temazepam. Short-acting compounds studied include brotizolam, midazolamZ and triazolam. In some of the reports., sleep latency is increased, whereas in others wake time for the whole sleep period or number of awakenings is increased. But rebound insomnia, as reflected by some measurement, has been reported for each of the compounds studied. Thus, rebound insomnia does not appear to be specific to any one of the short and intermediate half-life compounds. Dose
Several of the early studies of rebound insomnia conducted in patients with insomnia included multiple doses of a particular compound [6,16]. These articles argued that the intensity of rebound insomnia following administration of midazolam [61 or lormetazepam [16] increased with increasing doses of the drugs. However, a recent study conducted in healthy normal subjects with the proper parallel placebo condition suggests that rebound insomnia is dose-specific, that is, rebound occurs only at doses beyond which there is no further increase in hypnotic efficacy [lo]. Over six nights of administration of triazolam, both the 0.25and 0.50-mg doses improved sleep compared with placebo administration (in a parallel design), but the 0.50mg dose did not improve sleep beyond the 0.25-mg dose. On the other hand, on the drug discontinuation night, wake time increased after 0.50 mg compared both with placebo and with 0.25 mg, whereas the 0.25mg dose did not differ from placebo. The data from this study therefore suggest that rebound is not doserelated but rather dose-specific. Duration of Administration
In the typical study reporting on rebound insomnia, drug is administered nightly for one, two, or four weeks [15]. There is one study showing rebound insomnia after three nights of administration of midazolam [6]. However, with one exception, no study has assessed the probability or intensity of rebound insomnia as a function of duration of administration. In that study, healthy normal subjects, compared with a parallel placebo condition, received 0.50 mg triazolam for one, six, or 12 consecutive nights; rebound insomnia was assessed on two discontinuation nights [17]. The results of the study are illustrated in Figure 1. The probability and intensity of rebound insomnia did not differ after one, six, or 12 nights of drug on either of the two discontinuation nights (the data for Night 1 are plotted in Figure 1). Although this study shows no effects of duration of administration on rebound, the possibility still exists that duration of administration will interact with dose or other determinants of rebound to alter the severity or probability of rebound. Individual Differences
There now are preliminary data that suggest individual differences in rebound insomnia. The data from the duration-of-administration study cited earlier showed that some of the healthy, normal subjects con-
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sistently had rebound insomnia, whereas others consistently had no rebound [17]. Specifically, subjects who had rebound insomnia after 12 nights of triazolam 0.5 mg also had it after one and six nights of drug. Those without rebound after 12 nights also had none after one and six nights of drug. Differences in baseline sleep and response to treatment characterized the groups. Subjects with rebound had poorer sleep efficiencies and longer sleep latencies at baseline, which then were improved with administration of the drug. Interestingly, a tendency to show tolerance to drug effects (i.e., a comparison of drug effects on the first versus the last night of drug administration) did not differentiate the two groups. Of course, prospective studies will be necessary to confirm these predictors of rebound insomnia. MECHANISMS A frequently offered explanation for rebound insomnia is that it is related to a rapid elimination of benzodiazepines, which results in a central nervous system deficiency in inhibitory neurons1 mechanisms [7]. Benzodiazepines are known to facilitate gammaaminobutyric acid-receptor function, which represents a major inhibitory system in the central nervous system. It is presumed that during the period of drug administration the production of endogenous benzodiazepines (if in fact such exist) has been suppressed by the exogenous benzodiazepine. For that reason, according to such a viewpoint, slowly eliminated benzodiazepines are not associated with rebound insomnia, whereas short-acting compounds are. In support of this viewpoint are data showing that gradual reduction of the dose of a short-acting benzodiazepine (i.e., the equivalent of the slow elimination that occurs with a long-acting drug) avoids the rebound insomnia seen with the abrupt discontinuation of a high dose of that compound [18]. Another hypothesis is that rebound insomnia is related to tolerance and involves the mechanisms of tolerance, specifically, decreased receptor density or sensitivity [7]. However, there are some facts that seem to contradict a tolerance-based explanation. First, the evidence, as noted earlier, indicates that duration of administration does not alter the intensity or probability of rebound insomnia, and it is generally accepted that tolerance is related to the duration of administration. More important, there are reports of rebound insomnia in the absence of evidence of tolerance, albeit these reports used subjective measures of sleep [191. Finally, the subjects showing rebound in the study cited earlier also did not show tolerance
[171.
Clinical explanations, not necessarily contradictory to the previous neuroblologic theories, have also been proposed. One of these is that rebound insomnia is associated with oversedation [lo], that is, rebound insomnia occurs only at doses that produce no increased hypnotic activity (doses at or beyond the asymptote on the dose-effect curve). At the neurobiologic level, rebound may reflect central nervous system excitation after elimination of drug due to oversuppression of endogenous benzodiazepine ligands or to down-regulation of benzodiazepine receptors. In support of this hypothesis at the clinical level are the previously described data showing rebound insomnia only at the high triazolam dose (a dose that produced no further hypnotic effect) [lo].
ON INSOMNIA/
ROEHRS ET AL
Finally, an alternative clinical explanation for rebound that has been suggested is that, on drug discontinuation, sleep is lessened (there is more wakefulness, hence rebound) because the sleep need has been satiated during the drug administration period [ZO]. Sleep need can be inferred based on sleep efficiency at night and sleepiness during the day. For example, in healthy normal subjects increased bed time and sleep time over successive nights are associated with progressive reductions in sleep efficiency [211. In addition, increasing bed time produces improvements in daytime function (i.e., reduced sleepiness and improved performance), whereas reducing nocturnal sleep time produces the opposite [SSI. In support of a sleep satiation hypothesis are the data showing that persons receiving hypnotic medication show reduced sleepiness during the day after nighttime use. This result has been reported in normal persons [2-31, in subjects with insomnia [24], in patients with transient insomnia 1251, and in elderly persons with insomnia PI. CLINICAL SIGNIFICANCE Duration of Rebound Insomnia
All of the studies of rebound insomnia report that the sleep disturbance endures for no more than one to two nights. After the one to two nights of rebound, sleep returns to the baseline condition for the patients with insomnia, and in those studies that have used healthy normal subjects, sleep returns to pretreatment normal levels. Clinically, rebound insomnia is likely to be avoided by initiating treatment with the lowest effective dose. Furthermore, the potentially disturbing effects of rebound insomnia on patients can be minimized by instructing them to expect one or two nights of poorer sleep after discontinuing the hypnotic treatment. Relation to the Withdrawal Syndrome
Although rebound insomnia is suggestive of a physiologic adaptation of the central nervous system, it cannot be likened to a withdrawal syndrome and evidence of physiologic dependence. The signs of physiologic dependence on benzodiazepines include nausea, muscle pains? tingling feelings, tremor, perspiration, loss of appetite, insomnia, anxiety, agitation, and, in severe forms, hallucinations and seizures. There have been reports of physiologic dependence at clinical doses of benzodiazepines, but after much longer durations of administration than those associated with rebound insomnia [27]. As noted earlier, rebound insomnia can occur after a single night and does not increase in probability or intensity with increased duration of administration (at least up to 12 nights). Rebound insomnia can be further differentiated from a withdrawal syndrome in that it is the expression of a single symptom or at most the experience of insomnia and increased levels of anxiety. It should be noted that there have been several reports of rebound anxiety, an analogue of rebound insomnia [7]. Abuse Potential
One particularly important clinical issue is the role of rebound insomnia in benzodiazepine abuse. Although clinical reports of excessive benzodiazepine use and dependence have received much attention, the epidemiologic and laboratory evidence suggests that benzodiazepines have a relatively low abuse liability [28,291. Yet, the fact that a small percentage of
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the duration of administration does not increase the probability’ or intensity of rebound, at least within 12 nights of administration. There also seem to be clear individual differences in the experience of rebound insomnia, which probably explains some of the inconsistency in the earlier data. Preliminary data do not seem to indicate that the experience of rebound insomnia increases the abuse liability of this class of drugs, that is, increases the probability of self-administering a benzodiazepine hypnotic.
20
15 35 10 8 i? 5
REFERENCES
0 TREATMENT
Placebo
1 Drug Nt
5 Drug Nts
DRUG ADMINISTRATION
12 Drug Nts
(1 ST NT)
gure 2. Percent pill choices on the six choice nights of the placebo (PLAC), abrupt discontinuation (REB), and tapered discontinuation (NREB) conditions.
persons may abuse benzodiazepines suggests that specific conditions and/or personality characteristics may increase the risk of dependence. It has been specifically suggested that rebound insomnia in combination with the development of tolerance will lead to drug dependence VI. There is only one study that has directly assessed the contribution of rebound insomnia to the probability of drug dependence [30].’ That study combined human drug self-administration techniques with concurrent evaluation of rebound insomnia and patient characteristics so as to assess the abuse liability of benzodiazepine hypnotic medication. As noted earlier, the likelihood of rebound insomnia is higher with abrupt discontinuation (six nights of 0.50 mg triazolam) than with tapered dose discontinuation (three nights of 0.50 mg, two nights of 0.25 mg, and finally 0.125 mg). Self-administration on six choice nights after placebo! abrupt discontinuation, and tapered discontinuation is illustrated in Figure 2; the likelihood of self-administration did not differ among these conditions. Two different subject groups have been studied using this design. Patients with insomnia complaints but normal sleep (as determined by standard sleep laboratory polysomnographic techniques) self-administered triazolam at a rate no greater than they did placebo (60 percent versus 67 percent, respectively). While taking pills frequently, these patients did not discriminate between the abrupt or the tapered discontinuation of triazolam. Healthy normal subjects also self-administered tri’azolam no more frequently than they did placebo (26 percent and 17 percent of nights, respectively). At this low overall rate of pilltaking there was a tendency to self-administer pills more frequently after abrupt discontinuation than after tapered discontinuation. COMMENTS The presently available information indicates that rebound insomnia, when studied using the proper controls, does occur in both healthy normal and patient populations. -Although the data are equivocal and incomplete, rebound insomnia is probably not likely to occur with long-acting benzodiazepines. Rebound insomnia has been reported for most’of the short- and intermediate-acting compounds and is not specific to any single compound. The data now suggest that rebound insomnia is dose-specific, occurring only at high doses of a given drug, beyond which additional hypnotic efficacy is not evident. One study has shown that 3A-42S
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1. Kales A, Scharf MB, Kales JD: Rebound insomnia: a new clinical syndrome. Science 1978; 201: 1039-1041. 2. Kales A, Scharf MB, Kales JD, Soldatos CR: Rebound insomnia: a potentral hazard following withdrawal of certain benzodiazepines. JAMA 1979; 241 (6): 1692-1695. 3. Hartse K, Roth T, Piccione P, Zorick F: Rebound Insomnia. Science 1980; 208: 423. 4. Roth T, Kramer M, Lutz T: lntermedrate use of triazolam: a sleep laboratory study. J lnt Med Res 1976; 4: 59-63. 5. Bixler E, Kales A, Soldatos C, Scharf M, Kales J: Effectiveness of temazepam wrth short-, intermediate., and long-term use. J Clin Pharmacol 1978; 18 (2,3): 110-118. 6. Kales A, Soldatos C, Bixler E, Goff P, Vela-Buena A: Midazolam: dose-response studies of effectiveness and rebound insomnra. Pharmacology 1983; 26: 138-149. 7. Kales A, Soldatos CR, Bixler EO, Kales JD Rebound insomnia and rebound anxrety: a review. Pharmacology 1983; 26 (3): 121-137. 8. Roth T, Kramer M, Roehrs T: The consistency of sleep measures. In: Proceedings of the 3rd European Congress on Sleep Research, Montpelier. Easel: Karger, 1977; 286-288. 9. RoehrsT, Vogel G, Vogel F, eta/: Eligrbility requrrements in hypnotic trials. Sleep 1985; 8 (1): 34-39. 10. Roehrs T, Zorick F, Wittig R, Roth T: Dose determrnants of rebound insomnia. Br J Clin Pharmacol 1986; 22: 143-147. 11. Vela-Buena A, Oliveros JC, Dobladez-Blanco B, Arrigain-ljurra S, Soldatos CR, Kales A: Brotizolam: a sleep laboratory evaluation. Eur J Clin Pharmacol 1983; 25: 53-56. 12. Mitler MM, Seidel WF, van den Hoed J, Greenblatt DJ, Dement WC: Comparative hypnotic effects of flurazepam, triazolam, and placebo: a long-term simultaneous nighttime and daytime study. J Clin Psychopharmacol 1984; 4 (1): 2-13. 13. Kales A, Bixler EO, Vela-Buena A, Soldatos C, Niklaus DE, Manfredi RL: Comparison of short and long half-life benzodiazepine hypnotics: triazolam and quazepam. Clin Pharmacol Ther 1986; 40 (4): 378-386. 14. Kales A, Bixler EO, Soldatos CR, Vela.Bueno A, Jacoby J, Kales JD: Quazepam and flurazepam. Clin Pharmacol Ther 1982; 32 (6): 781-788. 15. Lader M, Lawson C: Sleep studies and rebound insomnia: methodological problems, laboratory findings, and clinical implications. Clin Neuropharmacol 1987; 10 (4): 291-312. 16. Kales A, Bixler ED, Soldatos CR, Mitsky DJ, Kales JD: Dose-response studres of lormetazepam: efficacy, side effects, and rebound insomnia. J Clin Pharmacol 1982; 22: 520-530. 17. Merlotti L, Roehrs T, Zorick FJ, Stepanski E, Russo L, Roth T: Rebound insomnia, duration of administration, and individual differences. Sleep Res 1988; 17: 52. 18. Greenblatt DJ, Harmatz JS, Zinny MA, Shader RI: Effect of gradual withdrawal on the rebound sleep disorder after discontinuation of triazolam. N Engl J Med 1987; 317: 722778
19. Oswald I, French C, Adam K, Gilham J: Benzodiazepine hypnotics remain effective for 24 weeks. Br Med J 1982; 284: 860-863. 20. Allen RP, Mendels J, Nevins DB, Chernik DA, Hoddes E: Efficacy without tolerance or rebound insomnia for midazolam and temazepam after use for one to three months. J Clin Pharmacoi 1987; 27: 768-775. 21. Levine 8, Lumiey M, Roehrs T, Zorick F, Roth T: The effects of acute sleep restriction and extension on sleep efficiency. Int J Neurosci 1988: 43 (3,4): 139-143. 22. Roth T, Roehrs TA, Carskadon MA, Dement WC: Daytime sleepiness and alertness. In: Kryger MH, Roth T, Dement WC, eds. Principles and practice of sleep medicine. Philadelphia: W.B. Saunders Co., 1989; 433-441. 23. Serdel W, Ball S, Cohen S, Patterson N, Yost D, Dement W: Daytime alertness in relation to mood, performance, and nocturnal sleep in chronic insomniacs and noncomplainrng sleepers. Sleep 1984; 7 (3): 230-238. 24. Bliwise D, Serdel W, Karacan I, et al: Daytime sleepmess as a criterion rn hypnotic medication trials: comparison of triazolam and flurazepam. Sleep 1983; 6 (2): 156-163. 25. Seidel W, Roth T, Roehrs T, Zorick F, Dement W: Treatment of a 12.hour shift of sleep schedule with benzodiazepines. Science 1984; 224: 1262-1264. 28. Roehrs T, Zorick F, Wittig R, Roth T: Efficacy of a reduced triazolam dose in elderly insomniacs. Neurobiol Aging 1985; 6: 293-296. 27. Smith DE, Wesson DR (eds): Benzodrazepine dependency syndromes. In: The benzodiazeprnes: current standards for medical practice. Hrngham, Massachusetts: MTP Press, Ltd., 1985; 235-248. 28. Rrckles K: Are benzodiazepines overused and abused? Br J Clin Pharmacol 1981; 11: 715-83s. 29. Griffiths RR, Roache JD: Abuse liability of benzodiazepines: a review of human studies evaluating subjective and/or reinforcing effects. In: Smith DE, Wesson DR, eds. The benzodiazepines: current standards for medical practice, Hingham, Massachusetts: MTP Press Ltd., 1985; 209-225. 30. Roehrs TA, Merlott L, Rosenthal LD, Zorick FJ, Fortier J, Roth T: Benzodrazepine self administration in insomnia, Sleep Res 1989; 18: 70.
Volume 88 (suppl 3A)
PH.D. Detroit, Michigan
Its Determinants
GERALD VOGEL,
M.D. Atlanta,
Georgja THOMAS ROTH,
Rebound insomnia is a sleep disturbance that occurs on discontinuation of benzodiazepine hypnotic drugs. It has been reported in both patients and healthy normal subjects and is characterized by increased wakefulness above the person’s baseline levels. This article reviews the available information regarding determinants, possible mechanisms, and clinical significance of rebound insomnia. It is concluded that rebound insomnia is a disturbance of one or two nights’ duration that primarily follows discontinuation of short- to intermediate-acting benzodiazepines. It occurs at high doses of a given drug, beyond which no additional hypnotic efficacy is evident. There seem to be clear individual differences in the experience of rebound insomnia, but no prospective studies have established which differences predict rebound. It is likely to be avoided by initiating treatment with the lowest effective dose and tapering the dose upon discontinuation.
From the Henry Ford Hospital, Detroit, Michigan, and Emory University Medical School, Atlanta, Georgia. Requests for reprints should be addressed to Timothy Roehrs, Ph.D., Henry Ford Hospital, 2921 West Grand Boulevard, Detroit, Michigan 48202.
and PH.D. Detroit, nllichigan
ebound insomnia refers to the sleep disturbance R that follows discontinuation of hypnotic drugs and is characterized by a worsening of sleep beyond the baseline levels. It was initially reported as an observation in patients with insomnia who were participating in efficacy and safety studies of benzodiazepine hypnotics [1,2]. Although rebound insomnia now has been reported in other studies and from other laboratories, there still is little systematic and consistent information about the phenomenon. The present review will discuss the available information regarding the determinants, the possible mechanisms, and the clinical significance of rebound insomnia. However, before the relevant data are described, several important methodologic issues must be discussed. METHODOLOGIC CONSIDERATIONS Rebound insomnia has not been a consistent finding [3]. In earlier studies it was seen on some sleep parameters in one study, but not on others that logically should show it also [41, with the low dose but not the high dose of a drug [5], and when there was no evidence of prior pharmacologic activity [6]. These inconsistencies in earlier studies may be due in part to inadequate methodology. The initial report defined rebound insomnia as a significant increase in wake time during drug discontinuation compared with baseline, using standard all-night sleep recordings [l]. Later the criteria were extended to include a 40 percent increase above baseline in wake time (in the absence of a statistically significant increase) on a single recovery night or for the entire recovery period [‘71. These criteria presume that an adequate baseline or comparison has been established. Sleep, whether disturbed or normal, is a variable phenomenon night to night, but few studies have used a parallel placebo group to control for this variability [8]. An adequate assessment of rebound insomnia requires this minimal control. Most of the initial studies of rebound insomnia were cross-over studies in which patients are studied over a three- or four-day period of placebo treatment before being exposed to the active drug treatment. Rebound insomnia is assessed by comparing the baseline placebo period with the drug discontinuation period. The problem with such a design is that rebound effects are confounded with sequence effects. Furthermore, patients often must meet certain selection criteria during the placebo period (which then is the baseline against which sleep on drug discontinuation is compared) to be included in the study. If the entry criteria are extreme, later samples of the patients’ conditions will tend to regress from the extreme to the mean [91. Such regression to the mean will then bias the estimate of rebound insomnia. This is a further reason for the necessity of parallel placebo designs in the study of rebound insomnia. Finally, rebound insomnia has been studied almost
March 2, 1990
The American Journal of Medicine
Volume 88 (suppl 3A)
3A-39s
SYMPOSIUM
ON INSOMNIA / ROEHRS ET AL
gure 1. Sleep efficiency on first rebound night after one, six, and 12 nights of ,. ^W^ tnazolam u.su mg.
exclusively in patients with insomnia. There have been only a few studies in healthy subjects [lO,ll]. Thus, it is not clear whether rebound insomnia is primarily a clinical phenomenon, whether it has a pharmacologic basis, or whether it is the exacerbation in a clinical population of predictable and demonstrable pharmacologic effects. Further, as regards special populations, the elderly and women experience insomnia more often and also consume hypnotic drugs more frequently than other segments of the population, yet no studies have characterized rebound insomnia in such populations. The question arises whether rebound insomnia is more likely in such populations. DETERMINANTS Half-Life
The benzodiazepines, when classified in terms of half-life, are usually classified as short-acting (less than six hours), intermediate-acting (six to 24 hours), and long-acting (more than 24 hours) compounds. It has been argued that rebound insomnia is specific to short and intermediate half-life compounds [7]. Only a few studies have directly compared short and long half-life drugs; the inference regarding half-life and the probability of rebound insomnia is made based on comparisons across studies. Furthermore, only two studies have assessed patients for the necessary time period (four times the half-life) after discontinuing the long half-life drug, and these studies report contradictory results [12,13]. One study found rebound insomnia with triazolam (a short half-life drug) on the first two discontinuation nights and argued that rebound insomnia occurred with flurazepam (a long half-life drug) during the second week after drug discontinuation. The rebound insomnia after flurazepam occurred in six of the seven subjects studied? but it was experienced on different nights of discontinuation week 2 [12]. The other report studied two long half-life drugs for 15 nights after discontinuation and found no rebound insomnia, whereas in another study from the same laboratory, rebound was found on two nights after triazolam discontinuation [13,14]. In the 15-night discontinuation study, total wake time never increased above baseline after quazepam and never beyond 25 percent of baseline after flurazepam [131. Thus, comparing across studies, the authors conclude there is rebound after discontinuing the short-acting drug but not the long-acting ones. There are numerous reports of rebound insomnia 3A-4OS
March 2, 1990
The American Journal of Medicine
after discontinuation of short and intermediate halflife compounds. A recent comprehensive review presents the data for the many compounds that have been studied at a number of different laboratories [15]. To briefly summarize the information, the intermediateacting benzodiazepines that have been studied are alprazolam, estazolam, flunitrazepam, lormetazepam, loprazolam, lorazepam, nitrazepam, nordiazepam, and temazepam. Short-acting compounds studied include brotizolam, midazolamZ and triazolam. In some of the reports., sleep latency is increased, whereas in others wake time for the whole sleep period or number of awakenings is increased. But rebound insomnia, as reflected by some measurement, has been reported for each of the compounds studied. Thus, rebound insomnia does not appear to be specific to any one of the short and intermediate half-life compounds. Dose
Several of the early studies of rebound insomnia conducted in patients with insomnia included multiple doses of a particular compound [6,16]. These articles argued that the intensity of rebound insomnia following administration of midazolam [61 or lormetazepam [16] increased with increasing doses of the drugs. However, a recent study conducted in healthy normal subjects with the proper parallel placebo condition suggests that rebound insomnia is dose-specific, that is, rebound occurs only at doses beyond which there is no further increase in hypnotic efficacy [lo]. Over six nights of administration of triazolam, both the 0.25and 0.50-mg doses improved sleep compared with placebo administration (in a parallel design), but the 0.50mg dose did not improve sleep beyond the 0.25-mg dose. On the other hand, on the drug discontinuation night, wake time increased after 0.50 mg compared both with placebo and with 0.25 mg, whereas the 0.25mg dose did not differ from placebo. The data from this study therefore suggest that rebound is not doserelated but rather dose-specific. Duration of Administration
In the typical study reporting on rebound insomnia, drug is administered nightly for one, two, or four weeks [15]. There is one study showing rebound insomnia after three nights of administration of midazolam [6]. However, with one exception, no study has assessed the probability or intensity of rebound insomnia as a function of duration of administration. In that study, healthy normal subjects, compared with a parallel placebo condition, received 0.50 mg triazolam for one, six, or 12 consecutive nights; rebound insomnia was assessed on two discontinuation nights [17]. The results of the study are illustrated in Figure 1. The probability and intensity of rebound insomnia did not differ after one, six, or 12 nights of drug on either of the two discontinuation nights (the data for Night 1 are plotted in Figure 1). Although this study shows no effects of duration of administration on rebound, the possibility still exists that duration of administration will interact with dose or other determinants of rebound to alter the severity or probability of rebound. Individual Differences
There now are preliminary data that suggest individual differences in rebound insomnia. The data from the duration-of-administration study cited earlier showed that some of the healthy, normal subjects con-
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sistently had rebound insomnia, whereas others consistently had no rebound [17]. Specifically, subjects who had rebound insomnia after 12 nights of triazolam 0.5 mg also had it after one and six nights of drug. Those without rebound after 12 nights also had none after one and six nights of drug. Differences in baseline sleep and response to treatment characterized the groups. Subjects with rebound had poorer sleep efficiencies and longer sleep latencies at baseline, which then were improved with administration of the drug. Interestingly, a tendency to show tolerance to drug effects (i.e., a comparison of drug effects on the first versus the last night of drug administration) did not differentiate the two groups. Of course, prospective studies will be necessary to confirm these predictors of rebound insomnia. MECHANISMS A frequently offered explanation for rebound insomnia is that it is related to a rapid elimination of benzodiazepines, which results in a central nervous system deficiency in inhibitory neurons1 mechanisms [7]. Benzodiazepines are known to facilitate gammaaminobutyric acid-receptor function, which represents a major inhibitory system in the central nervous system. It is presumed that during the period of drug administration the production of endogenous benzodiazepines (if in fact such exist) has been suppressed by the exogenous benzodiazepine. For that reason, according to such a viewpoint, slowly eliminated benzodiazepines are not associated with rebound insomnia, whereas short-acting compounds are. In support of this viewpoint are data showing that gradual reduction of the dose of a short-acting benzodiazepine (i.e., the equivalent of the slow elimination that occurs with a long-acting drug) avoids the rebound insomnia seen with the abrupt discontinuation of a high dose of that compound [18]. Another hypothesis is that rebound insomnia is related to tolerance and involves the mechanisms of tolerance, specifically, decreased receptor density or sensitivity [7]. However, there are some facts that seem to contradict a tolerance-based explanation. First, the evidence, as noted earlier, indicates that duration of administration does not alter the intensity or probability of rebound insomnia, and it is generally accepted that tolerance is related to the duration of administration. More important, there are reports of rebound insomnia in the absence of evidence of tolerance, albeit these reports used subjective measures of sleep [191. Finally, the subjects showing rebound in the study cited earlier also did not show tolerance
[171.
Clinical explanations, not necessarily contradictory to the previous neuroblologic theories, have also been proposed. One of these is that rebound insomnia is associated with oversedation [lo], that is, rebound insomnia occurs only at doses that produce no increased hypnotic activity (doses at or beyond the asymptote on the dose-effect curve). At the neurobiologic level, rebound may reflect central nervous system excitation after elimination of drug due to oversuppression of endogenous benzodiazepine ligands or to down-regulation of benzodiazepine receptors. In support of this hypothesis at the clinical level are the previously described data showing rebound insomnia only at the high triazolam dose (a dose that produced no further hypnotic effect) [lo].
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Finally, an alternative clinical explanation for rebound that has been suggested is that, on drug discontinuation, sleep is lessened (there is more wakefulness, hence rebound) because the sleep need has been satiated during the drug administration period [ZO]. Sleep need can be inferred based on sleep efficiency at night and sleepiness during the day. For example, in healthy normal subjects increased bed time and sleep time over successive nights are associated with progressive reductions in sleep efficiency [211. In addition, increasing bed time produces improvements in daytime function (i.e., reduced sleepiness and improved performance), whereas reducing nocturnal sleep time produces the opposite [SSI. In support of a sleep satiation hypothesis are the data showing that persons receiving hypnotic medication show reduced sleepiness during the day after nighttime use. This result has been reported in normal persons [2-31, in subjects with insomnia [24], in patients with transient insomnia 1251, and in elderly persons with insomnia PI. CLINICAL SIGNIFICANCE Duration of Rebound Insomnia
All of the studies of rebound insomnia report that the sleep disturbance endures for no more than one to two nights. After the one to two nights of rebound, sleep returns to the baseline condition for the patients with insomnia, and in those studies that have used healthy normal subjects, sleep returns to pretreatment normal levels. Clinically, rebound insomnia is likely to be avoided by initiating treatment with the lowest effective dose. Furthermore, the potentially disturbing effects of rebound insomnia on patients can be minimized by instructing them to expect one or two nights of poorer sleep after discontinuing the hypnotic treatment. Relation to the Withdrawal Syndrome
Although rebound insomnia is suggestive of a physiologic adaptation of the central nervous system, it cannot be likened to a withdrawal syndrome and evidence of physiologic dependence. The signs of physiologic dependence on benzodiazepines include nausea, muscle pains? tingling feelings, tremor, perspiration, loss of appetite, insomnia, anxiety, agitation, and, in severe forms, hallucinations and seizures. There have been reports of physiologic dependence at clinical doses of benzodiazepines, but after much longer durations of administration than those associated with rebound insomnia [27]. As noted earlier, rebound insomnia can occur after a single night and does not increase in probability or intensity with increased duration of administration (at least up to 12 nights). Rebound insomnia can be further differentiated from a withdrawal syndrome in that it is the expression of a single symptom or at most the experience of insomnia and increased levels of anxiety. It should be noted that there have been several reports of rebound anxiety, an analogue of rebound insomnia [7]. Abuse Potential
One particularly important clinical issue is the role of rebound insomnia in benzodiazepine abuse. Although clinical reports of excessive benzodiazepine use and dependence have received much attention, the epidemiologic and laboratory evidence suggests that benzodiazepines have a relatively low abuse liability [28,291. Yet, the fact that a small percentage of
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the duration of administration does not increase the probability’ or intensity of rebound, at least within 12 nights of administration. There also seem to be clear individual differences in the experience of rebound insomnia, which probably explains some of the inconsistency in the earlier data. Preliminary data do not seem to indicate that the experience of rebound insomnia increases the abuse liability of this class of drugs, that is, increases the probability of self-administering a benzodiazepine hypnotic.
20
15 35 10 8 i? 5
REFERENCES
0 TREATMENT
Placebo
1 Drug Nt
5 Drug Nts
DRUG ADMINISTRATION
12 Drug Nts
(1 ST NT)
gure 2. Percent pill choices on the six choice nights of the placebo (PLAC), abrupt discontinuation (REB), and tapered discontinuation (NREB) conditions.
persons may abuse benzodiazepines suggests that specific conditions and/or personality characteristics may increase the risk of dependence. It has been specifically suggested that rebound insomnia in combination with the development of tolerance will lead to drug dependence VI. There is only one study that has directly assessed the contribution of rebound insomnia to the probability of drug dependence [30].’ That study combined human drug self-administration techniques with concurrent evaluation of rebound insomnia and patient characteristics so as to assess the abuse liability of benzodiazepine hypnotic medication. As noted earlier, the likelihood of rebound insomnia is higher with abrupt discontinuation (six nights of 0.50 mg triazolam) than with tapered dose discontinuation (three nights of 0.50 mg, two nights of 0.25 mg, and finally 0.125 mg). Self-administration on six choice nights after placebo! abrupt discontinuation, and tapered discontinuation is illustrated in Figure 2; the likelihood of self-administration did not differ among these conditions. Two different subject groups have been studied using this design. Patients with insomnia complaints but normal sleep (as determined by standard sleep laboratory polysomnographic techniques) self-administered triazolam at a rate no greater than they did placebo (60 percent versus 67 percent, respectively). While taking pills frequently, these patients did not discriminate between the abrupt or the tapered discontinuation of triazolam. Healthy normal subjects also self-administered tri’azolam no more frequently than they did placebo (26 percent and 17 percent of nights, respectively). At this low overall rate of pilltaking there was a tendency to self-administer pills more frequently after abrupt discontinuation than after tapered discontinuation. COMMENTS The presently available information indicates that rebound insomnia, when studied using the proper controls, does occur in both healthy normal and patient populations. -Although the data are equivocal and incomplete, rebound insomnia is probably not likely to occur with long-acting benzodiazepines. Rebound insomnia has been reported for most’of the short- and intermediate-acting compounds and is not specific to any single compound. The data now suggest that rebound insomnia is dose-specific, occurring only at high doses of a given drug, beyond which additional hypnotic efficacy is not evident. One study has shown that 3A-42S
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1. Kales A, Scharf MB, Kales JD: Rebound insomnia: a new clinical syndrome. Science 1978; 201: 1039-1041. 2. Kales A, Scharf MB, Kales JD, Soldatos CR: Rebound insomnia: a potentral hazard following withdrawal of certain benzodiazepines. JAMA 1979; 241 (6): 1692-1695. 3. Hartse K, Roth T, Piccione P, Zorick F: Rebound Insomnia. Science 1980; 208: 423. 4. Roth T, Kramer M, Lutz T: lntermedrate use of triazolam: a sleep laboratory study. J lnt Med Res 1976; 4: 59-63. 5. Bixler E, Kales A, Soldatos C, Scharf M, Kales J: Effectiveness of temazepam wrth short-, intermediate., and long-term use. J Clin Pharmacol 1978; 18 (2,3): 110-118. 6. Kales A, Soldatos C, Bixler E, Goff P, Vela-Buena A: Midazolam: dose-response studies of effectiveness and rebound insomnra. Pharmacology 1983; 26: 138-149. 7. Kales A, Soldatos CR, Bixler EO, Kales JD Rebound insomnia and rebound anxrety: a review. Pharmacology 1983; 26 (3): 121-137. 8. Roth T, Kramer M, Roehrs T: The consistency of sleep measures. In: Proceedings of the 3rd European Congress on Sleep Research, Montpelier. Easel: Karger, 1977; 286-288. 9. RoehrsT, Vogel G, Vogel F, eta/: Eligrbility requrrements in hypnotic trials. Sleep 1985; 8 (1): 34-39. 10. Roehrs T, Zorick F, Wittig R, Roth T: Dose determrnants of rebound insomnia. Br J Clin Pharmacol 1986; 22: 143-147. 11. Vela-Buena A, Oliveros JC, Dobladez-Blanco B, Arrigain-ljurra S, Soldatos CR, Kales A: Brotizolam: a sleep laboratory evaluation. Eur J Clin Pharmacol 1983; 25: 53-56. 12. Mitler MM, Seidel WF, van den Hoed J, Greenblatt DJ, Dement WC: Comparative hypnotic effects of flurazepam, triazolam, and placebo: a long-term simultaneous nighttime and daytime study. J Clin Psychopharmacol 1984; 4 (1): 2-13. 13. Kales A, Bixler EO, Vela-Buena A, Soldatos C, Niklaus DE, Manfredi RL: Comparison of short and long half-life benzodiazepine hypnotics: triazolam and quazepam. Clin Pharmacol Ther 1986; 40 (4): 378-386. 14. Kales A, Bixler EO, Soldatos CR, Vela.Bueno A, Jacoby J, Kales JD: Quazepam and flurazepam. Clin Pharmacol Ther 1982; 32 (6): 781-788. 15. Lader M, Lawson C: Sleep studies and rebound insomnia: methodological problems, laboratory findings, and clinical implications. Clin Neuropharmacol 1987; 10 (4): 291-312. 16. Kales A, Bixler ED, Soldatos CR, Mitsky DJ, Kales JD: Dose-response studres of lormetazepam: efficacy, side effects, and rebound insomnia. J Clin Pharmacol 1982; 22: 520-530. 17. Merlotti L, Roehrs T, Zorick FJ, Stepanski E, Russo L, Roth T: Rebound insomnia, duration of administration, and individual differences. Sleep Res 1988; 17: 52. 18. Greenblatt DJ, Harmatz JS, Zinny MA, Shader RI: Effect of gradual withdrawal on the rebound sleep disorder after discontinuation of triazolam. N Engl J Med 1987; 317: 722778
19. Oswald I, French C, Adam K, Gilham J: Benzodiazepine hypnotics remain effective for 24 weeks. Br Med J 1982; 284: 860-863. 20. Allen RP, Mendels J, Nevins DB, Chernik DA, Hoddes E: Efficacy without tolerance or rebound insomnia for midazolam and temazepam after use for one to three months. J Clin Pharmacoi 1987; 27: 768-775. 21. Levine 8, Lumiey M, Roehrs T, Zorick F, Roth T: The effects of acute sleep restriction and extension on sleep efficiency. Int J Neurosci 1988: 43 (3,4): 139-143. 22. Roth T, Roehrs TA, Carskadon MA, Dement WC: Daytime sleepiness and alertness. In: Kryger MH, Roth T, Dement WC, eds. Principles and practice of sleep medicine. Philadelphia: W.B. Saunders Co., 1989; 433-441. 23. Serdel W, Ball S, Cohen S, Patterson N, Yost D, Dement W: Daytime alertness in relation to mood, performance, and nocturnal sleep in chronic insomniacs and noncomplainrng sleepers. Sleep 1984; 7 (3): 230-238. 24. Bliwise D, Serdel W, Karacan I, et al: Daytime sleepmess as a criterion rn hypnotic medication trials: comparison of triazolam and flurazepam. Sleep 1983; 6 (2): 156-163. 25. Seidel W, Roth T, Roehrs T, Zorick F, Dement W: Treatment of a 12.hour shift of sleep schedule with benzodiazepines. Science 1984; 224: 1262-1264. 28. Roehrs T, Zorick F, Wittig R, Roth T: Efficacy of a reduced triazolam dose in elderly insomniacs. Neurobiol Aging 1985; 6: 293-296. 27. Smith DE, Wesson DR (eds): Benzodrazepine dependency syndromes. In: The benzodiazeprnes: current standards for medical practice. Hrngham, Massachusetts: MTP Press, Ltd., 1985; 235-248. 28. Rrckles K: Are benzodiazepines overused and abused? Br J Clin Pharmacol 1981; 11: 715-83s. 29. Griffiths RR, Roache JD: Abuse liability of benzodiazepines: a review of human studies evaluating subjective and/or reinforcing effects. In: Smith DE, Wesson DR, eds. The benzodiazepines: current standards for medical practice, Hingham, Massachusetts: MTP Press Ltd., 1985; 209-225. 30. Roehrs TA, Merlott L, Rosenthal LD, Zorick FJ, Fortier J, Roth T: Benzodrazepine self administration in insomnia, Sleep Res 1989; 18: 70.
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