Letters to the Editor/Sleep Medicine 15 (2014) 1168–1172
References [1] Mayer G, Wang-Weigand S, Roth-Schechter B, Lehmann R, Staner C, Partinen M. Efficacy and safety of 6-month nightly ramelteon administration in adults with chronic primary insomnia. Sleep 2009;32:351–60. [2] Ancoli-Israel S, Krystal AD, McCall WV, Schaefer K, Wilson A, Claus R, et al. A 12-week, randomized, double-blind, placebo-controlled study evaluating the effect of eszopiclone 2 mg on sleep/wake function in older adults with primary and comorbid insomnia. Sleep 2010;33:225–34. [3] Sunovion. NCT003386334. ; 2010 [accessed 10.09.09]. [4] Michelson D, Snyder E, Paradis E, Chengan-Liu M, Snavely DB, Hutzelmann J, et al. Safety and efficacy of suvorexant during 1-year treatment of insomnia with subsequent abrupt treatment discontinuation: a phase 3 randomised, doubleblind, placebo-controlled trial. Lancet Neurol. 2014;13:461–71. doi:10.1016/ S1474-4422(14)70053-5.
Daniel F. Kripke * Viterbi Family Sleep Center, Scripps Clinic W-207, 10666 North Torrey Pines Road, La Jolla, CA 92037, USA * Address: Viterbi Family Sleep Center, Scripps Clinic W-207, 10666 North Torrey Pines Road, La Jolla, CA 92037, USA. Tel.: +1 858 554 8845; fax: +1 858 554 8492. E-mail address: [email protected]
http://dx.doi.org/10.1016/j.sleep.2014.08.001 1389-9457/© 2014 Published by Elsevier B.V.
Response to Dr. Kripke’s letter In his letter Dr. Kripke raises the question if hypnotics can cause insomnia. At first glance it seems like a contradiction in itself that hypnotics might cause insomnia due to rebound. At second glance the idea sounds challenging, because this has never been directly addressed by studies. Thinking further about this idea makes us wonder if this thought might just serve as another argument supporting the public condemnation of hypnotics. But before drawing final conclusions, methodological aspects have to be considered. One of the methodological key issues is if results during withdrawal period should be compared to baseline or to the end of treatment data. Another is the crucial question whether the assessment of rebound should be done by means or by single patient comparisons resulting in percentages of patients with rebound. Let’s discuss these issues point by point. The contradiction: A World Health Organization (WHO) study recently reported that insomnia is the most frequent co-morbidity concerning health impact [1]. It is well known that benzodiazepines initially shorten sleep latency (SL), but do not increase sleep length or duration of slow wave sleep [2]. On the other hand, total sleep time (TST) becomes shorter and worsens after withdrawal. Nevertheless benzodiazepines do not cause insomnia; they simply do not heal insomnia and can cause dependency. There is ample evidence that insomnia decreases quality of life strongly and that many patients suffer chronically without getting help (cognitive behavioral therapy [CBT] not being paid for, hypnotics being considered to be too dangerous). Would anyone with pain be left alone because opioids are dangerous and may cause addiction? Do insomniacs have to suffer until they get the ‘right’ support, if ever? There must be a balance of pro and cons that needs to be considered, which should also be done with hypnotics. The study protocols: In most short and long term studies the primary study goals were to determine the efficacy and safety of hypnotics. Very few studies have looked at rebound after the hypnotic had been withdrawn. In those studies that looked at post treatment effects 1 day to 2 months after withdrawal, the assess-
1169
ment was mostly done at one or few time points only, either with questionnaires and/or with polysomnography. Even then an immense improvement of up to 60% (TST, SL) was seen in patients and controls. There are strong patient benefits from the study visits, study inherent patient care, and considerable day-to-day variations of the evaluation of sleep quality and other sleep parameters [3,4]. Rebound versus withdrawal insomnia: Kales et al. [5] introduced ‘drug-withdrawal insomnia’ for disturbed sleep, more frequent and intense dreams, and occasional nightmares after abrupt withdrawal of drugs (barbiturates) administered in multiple nightly doses over a long time. Withdrawal insomnia “results from both psychological factors and physiological changes” [5]. In contrast ‘rebound insomnia’ consists of “a marked worsening of sleep following the abrupt withdrawal of benzodiazepine drugs administered in only single doses nightly for short periods” indicated by a significant worsening of sleep latency, wake after sleep onset, and total wake time beyond baseline [6] i.e., an increase of at least 40% of total wake time in the mean group value [7]. Later on this definition was also used for other sleep parameters including subjective assessments and daytime performance. Roehrs et al. [8] have found a difference between pretreatment sleep and sleep during discontinuation of benzodiazepines, regardless of the type of treatment with active drug or placebo, suggesting that pill discontinuation itself might cause rebound insomnia in the sense of a placebo effect. Considering the high day-by-day variation of sleep parameters in insomnia, it seems reasonable to assess both baseline sleep and possible rebound effects over longer time intervals than several days, e.g., in the study of Hajak et al. [9] on 1507 insomnia patients the rebound rates were lower on day 1 of discontinuation than on day 31. Therefore in studies using polysomnographic evaluations the comparison of one or two nights at baseline, end of treatment, and withdrawal is highly questionable to assess rebound insomnia. Dr. Kripke re-evaluated long term studies, which have very different study designs and goals, and either use subjective sleep logs, questionnaires, polysomnography or a combination. All studies he cited had different rebound definitions. The methods show statistically significant differences of SL and TST at different time points of evaluation. The ramelteon study [10] defined rebound as a mean sleep latency during placebo run-out equal to or worse than mean sleep latency at baseline (both in diaries and PSG). The suvorexant [11] study defined rebound as “exploratory endpoints in the first 3 days of discontinuation phase”. This study is the only one that presents the rebound rate (number of patients affected by rebound) in percent. The statistics in different insomnia studies use comparison of baseline to endpoint or discontinuation mean values, which raises two problems: Presenting mean values without giving the range does not allow discrimination of good from poor responders. Secondly, the number of patients from start to end diminishes up to 50%. Therefore comparing mean values at any point of the study does not allow seeing inter-individual changes of sleep parameters. Since rebound (worsening beyond baseline levels) affects single patients, it is not appropriate to use this method to assess withdrawal or rebound insomnia, but this is what is done in nearly all studies. At least the baseline mean of patients who reached the withdrawal study phase must be given. For example: independently of exactly equal TSTs in placebo and treatment groups at study start patients are lost from baseline to end of study (around 25% in both groups of the eszopiclone study [12], 4% in the suvorexant study, and 30% in the ramelteon study). Except for the suvorexant study, we do not know if the dropouts had been good or poor responders. Therefore these data must be interpreted with caution, leaving more patients in the ongoing study with mild and moderate insomnia [12] than
1170
Letters to the Editor/Sleep Medicine 15 (2014) 1168–1172
at baseline. The published data provided means over all patients enclosed per time point including withdrawal period. The comparisons between baseline and end of treatment data clearly indicated in all mentioned studies that both placebo and treatment groups benefited from the treatment with greater improvements for active treatment. Baseline means of those patients who reached the discontinuation phase were given only as additional online material for the eszopiclone [13] and suvorexant [11] study. Based on the published data none of the studies showed a rebound insomnia referring to the definitions presented above. However the results of a therapeutic benefit in the placebo group over time supports the current treatment guidelines that request every medical treatment of insomnia to be supported by behavioral therapy. The application of Kales et al. rebound definition of a 40% decrease of sleep parameters for the data of the ramelteon study would have required a decrease in TST from 381.4 min (end of treatment) to 228.8 min. Instead, TST decreased to 372.9 min during discontinuation in the ramelteon group and increased slightly from 380 to 383 min in the placebo group. Thus, the slight improvement of TST in the placebo group at run-out and reduced TST in the ramelteon group could be interpreted as an effect proving that medication had been helpful instead of causing withdrawal. In contrast, Dr. Kripke indicated that the between group difference at withdrawal is significant. This is correct, but is not within the scope of rebound definitions. Rebound could be concluded in a subgroup of the eszopiclone study which had actigraphy [13]. There was a decrease of 0.6 ± 56.17 min TST in the eszopiclone group compared to baseline and an increase of 15.4 ± 51.75 min in the placebo group. However, the high standard deviation of the delta values between run-out and baseline indicated that rebound only affects single patients and not all treated patients per se. In the suvorexant study the analysis of rebound insomnia was based on all patients who entered the discontinuation phase. This is the only study that gives the proportion of patients in each treatment group with worsening between baseline TST and SL compared to each of the first three nights of the discontinuation phase and to any of the first three nights. The “primary comparison of interest was between the suvorexant-placebo group and the placebo– placebo group”. Figure 2 of this study shows a sudden drop in TST with slow adaptation to the level of placebo after switching patients from suvorexant to placebo. SL in the suvorexant group was 15 min longer than in the baseline and did not reach the levels of the placebo group. Sticking to the study’s rebound definition patients did not have a rebound because they stayed below the baseline values. Going away from the mean values, the individual values (supplementary table e6 [11]) revealed that for discontinuation nights 1–3, 51% patients had rebound in the TST and 40.8% in the SL [40.1% (TST) and 36.2% (SL), respectively, in the placebo–placebo group [11]] which revealed indeed a significant difference for TST. The authors actually discuss if this worsening is a rebound effect or a withdrawal effect or combination of both. The authors themselves conclude that “symptom return did not exhibit a spike with subsequent resolution, and the persistence of effects over the discontinuation phase, suggests that symptom return probably represents an unmasking of the underlying disorder rather than a drug-related rebound” [11]. In conclusion, definitions of rebound or withdrawal of hypnotics and methods are very different throughout various studies, making it difficult to draw conclusions. It certainly is Dr. Kripke’s merit to uncover the flaws of presentation and statistics in studies cited in his letter. However, in the end Dr. Kripke’s interpretations are a result of insufficient presentation of the study data and the use of immanent statistical methods. Insomnia is not the conse-
quence of hypnotics. Rather, insomnia is the cause for treating patients with hypnotics. The presentation of insomnia studies should all refer to the same withdrawal/rebound paradigm. They should give the raw data or rebound rates instead of the means or log transformed data only, which would make it much easier for the reader to understand the interpretations and figures. Nevertheless, it must be considered that withdrawal or rebound insomnia is a key issue which may lead physicians to continue drug administration. Therefore it is necessary to inform patients prior to treatment about the risk of rebound after discontinuation or to choose intermittent drug therapy regimes if a non-pharmacological therapy is not available.
Conflict of interest The ICMJE Uniform Disclosure Form for Potential Conflicts of Interest associated with this article can be viewed by clicking on the following link: http://dx.doi.org/10.1016/j.sleep.2014.08.002.
References [1] Alonso J, Vilagut G, Chatterji S, Heeringa S, Schoenbaum M, Bedirhan Üstün T, et al. Including information about co-morbidity in estimates of disease burden: results from the World Health Organization World Mental Health Surveys. Psychol Med 2011;41:873–86. [2] Riemann D, Perlis ML. The treatments of chronic insomnia: a review of benzodiazepine receptor agonists and psychological and behavioral therapies. Sleep Med Rev 2009;13:205–14. [3] Hohagen F, Kappler C, Schramm E, Riemann D, Weyerer S, Berger M. Sleep onset insomnia, sleep maintaining insomnia and insomnia with early morning awakening – temporal stability of subtypes in a longitudinal study on general practice attenders. Sleep 1994;17:551–4. [4] Roth T, Kramer M, Roehrs T. The consistency of sleep measures. In: Koella W, Levin P, editors. Sleep 1976. Basel: Karger; 1977. p. 286–8. [5] Kales A, Bixler EO, Tan T-L, Scharf MB, Kales JD. Chronic hypnotic-drug use. Ineffectiveness, drug-withdrawal insomnia, and dependence. JAMA 1974;227:513–17. [6] Kales A, Scharf MB, Kales JD. Rebound insomnia: a new clinical syndrome. Science 1978;201:1039–41. [7] Kales A, Soldatos CR, Bixler EO, Kales JD. Rebound insomnia and rebound anxiety: a review. Pharmacology 1983;26:121–37. [8] Roehrs T, Merlotti L, Zorick F, Roth T. Rebound insomnia and hypnotic selfadministration. Psychopharmacology 1992;107:480–4. [9] Hajak G, Clarenbach P, Fischer W, Rodenbeck A, Bandelow B, Broocks A, et al. Rebound insomnia after hypnotic withdrawal in insomniac outpatients. Eur Arch Psychiatry Clin Neurosci 1998;248:148–56. [10]Mayer G, Wang-Weigand S, Roth-Schechter B, Lehmann R, Staner C, Partinen M. Efficacy and safety of 6-month nightly ramelteon administration in adults with chronic primary insomnia. Sleep 2009;32:351–60. [11]Michelson D, Snyder E, Paradis E, Chengan-Liu M, Snavely DB, Hutzelmann J, et al. Safety and efficacy of suvorexant during 1-year treatment of insomnia with subsequent abrupt treatment discontinuation: a phase 3 randomised, doubleblind, placebo-controlled trial. Lancet Neurol 2014;13:461–71; published online March 27, 2014. [12]Ancoli-Israel S, Krystal AD, McCall WV, Schaefer K, Wilson A, Claus R, et al. A 12-week, randomized, double-blind, placebo-controlled study evaluating the effect of eszopiclone 2 mg on sleep/wake function in older adults with primary and comorbid insomnia. Sleep 2010;33:225–34. [13]Sunovion. Supplementary data to Ancoli-Israel et al. 2010. NCT00386334. 2010. Available from: [accessed September 9, 2010].
G. Mayer * Hephata Klinik, Schimmelpfengstr 6, 34613 Schwalmstadt, Germany Department of Neurology, Philipps University Marburg, Rudolf-Bultmann-Straße 8, 35039 Marburg, Germany Studienzentrum Wilhelmshöhe, Wilhelmshöher Allee 259, 34131 Kassel, Germany * Address: Hephata Klinik, Schimmelpfengstr 6, 34613 Schwalmstadt, Germany. Tel.: +496691182002; fax: +496691182040. E-mail address: [email protected]
M. Terzaghi et al./Sleep Medicine 15 (2014) 1168–1172
A. Rodenbeck Studienzentrum Wilhelmshöhe, Wilhelmshöher Allee 259, 34131 Kassel, Germany Institute of Physiology, Charité-Universitätsmedizin Berlin, St.-Hedwig Krankenhaus, Große Hamburger Str. 5-11, 10115 Berlin, Germany Department of Pneumology, Evangelisches Krankenhaus Weende gGmbH, An der Lieth 5, 37120 Bovenden, Germany
http://dx.doi.org/10.1016/j.sleep.2014.08.002 1389-9457/© 2014 Published by Elsevier B.V.
Multiple sleep latency test may be not sensitive in obstructive sleep apnea with comorbid narcolepsy revealed by low cerebrospinal fluid orexin levels To the Editor: We describe a 38-year-old man referred to our sleep center complaining of excessive daytime sleepiness (EDS) and subtle episodes of knee weakness, elicited by laughing. His Epworth Sleepiness Scale (ESS) score was 17. Polysomnography (PSG) documented severe obstructive sleep apnea (OSA) with apnea–hypopnea index (AHI) of 57.9/h. Multiple sleep latency test (MSLT) showed a mean sleep latency (MSL) of 8 min without sleep onset REM periods (SOREMPs). He started continuous airway positive pressure (CPAP) treatment, but at the follow-up he complained of worsening EDS (ESS 21), despite good compliance. PSG under CPAP therapy documented AHI of 3.2/h. MSLT showed MSL of 2.7 min without SOREMPs, but during each nap several obstructive apneas were observed with sudden awakenings and arousals. Since the cataplectic-like attacks endured, we performed brain magnetic resonance imaging, which was unremarkable, and lumbar puncture to quantify cerebrospinal fluid (CSF) orexin level, which was 45.6 pg/mL (orexin deficiency
References [1] Mayer G, Wang-Weigand S, Roth-Schechter B, Lehmann R, Staner C, Partinen M. Efficacy and safety of 6-month nightly ramelteon administration in adults with chronic primary insomnia. Sleep 2009;32:351–60. [2] Ancoli-Israel S, Krystal AD, McCall WV, Schaefer K, Wilson A, Claus R, et al. A 12-week, randomized, double-blind, placebo-controlled study evaluating the effect of eszopiclone 2 mg on sleep/wake function in older adults with primary and comorbid insomnia. Sleep 2010;33:225–34. [3] Sunovion. NCT003386334. ; 2010 [accessed 10.09.09]. [4] Michelson D, Snyder E, Paradis E, Chengan-Liu M, Snavely DB, Hutzelmann J, et al. Safety and efficacy of suvorexant during 1-year treatment of insomnia with subsequent abrupt treatment discontinuation: a phase 3 randomised, doubleblind, placebo-controlled trial. Lancet Neurol. 2014;13:461–71. doi:10.1016/ S1474-4422(14)70053-5.
Daniel F. Kripke * Viterbi Family Sleep Center, Scripps Clinic W-207, 10666 North Torrey Pines Road, La Jolla, CA 92037, USA * Address: Viterbi Family Sleep Center, Scripps Clinic W-207, 10666 North Torrey Pines Road, La Jolla, CA 92037, USA. Tel.: +1 858 554 8845; fax: +1 858 554 8492. E-mail address: [email protected]
http://dx.doi.org/10.1016/j.sleep.2014.08.001 1389-9457/© 2014 Published by Elsevier B.V.
Response to Dr. Kripke’s letter In his letter Dr. Kripke raises the question if hypnotics can cause insomnia. At first glance it seems like a contradiction in itself that hypnotics might cause insomnia due to rebound. At second glance the idea sounds challenging, because this has never been directly addressed by studies. Thinking further about this idea makes us wonder if this thought might just serve as another argument supporting the public condemnation of hypnotics. But before drawing final conclusions, methodological aspects have to be considered. One of the methodological key issues is if results during withdrawal period should be compared to baseline or to the end of treatment data. Another is the crucial question whether the assessment of rebound should be done by means or by single patient comparisons resulting in percentages of patients with rebound. Let’s discuss these issues point by point. The contradiction: A World Health Organization (WHO) study recently reported that insomnia is the most frequent co-morbidity concerning health impact [1]. It is well known that benzodiazepines initially shorten sleep latency (SL), but do not increase sleep length or duration of slow wave sleep [2]. On the other hand, total sleep time (TST) becomes shorter and worsens after withdrawal. Nevertheless benzodiazepines do not cause insomnia; they simply do not heal insomnia and can cause dependency. There is ample evidence that insomnia decreases quality of life strongly and that many patients suffer chronically without getting help (cognitive behavioral therapy [CBT] not being paid for, hypnotics being considered to be too dangerous). Would anyone with pain be left alone because opioids are dangerous and may cause addiction? Do insomniacs have to suffer until they get the ‘right’ support, if ever? There must be a balance of pro and cons that needs to be considered, which should also be done with hypnotics. The study protocols: In most short and long term studies the primary study goals were to determine the efficacy and safety of hypnotics. Very few studies have looked at rebound after the hypnotic had been withdrawn. In those studies that looked at post treatment effects 1 day to 2 months after withdrawal, the assess-
1169
ment was mostly done at one or few time points only, either with questionnaires and/or with polysomnography. Even then an immense improvement of up to 60% (TST, SL) was seen in patients and controls. There are strong patient benefits from the study visits, study inherent patient care, and considerable day-to-day variations of the evaluation of sleep quality and other sleep parameters [3,4]. Rebound versus withdrawal insomnia: Kales et al. [5] introduced ‘drug-withdrawal insomnia’ for disturbed sleep, more frequent and intense dreams, and occasional nightmares after abrupt withdrawal of drugs (barbiturates) administered in multiple nightly doses over a long time. Withdrawal insomnia “results from both psychological factors and physiological changes” [5]. In contrast ‘rebound insomnia’ consists of “a marked worsening of sleep following the abrupt withdrawal of benzodiazepine drugs administered in only single doses nightly for short periods” indicated by a significant worsening of sleep latency, wake after sleep onset, and total wake time beyond baseline [6] i.e., an increase of at least 40% of total wake time in the mean group value [7]. Later on this definition was also used for other sleep parameters including subjective assessments and daytime performance. Roehrs et al. [8] have found a difference between pretreatment sleep and sleep during discontinuation of benzodiazepines, regardless of the type of treatment with active drug or placebo, suggesting that pill discontinuation itself might cause rebound insomnia in the sense of a placebo effect. Considering the high day-by-day variation of sleep parameters in insomnia, it seems reasonable to assess both baseline sleep and possible rebound effects over longer time intervals than several days, e.g., in the study of Hajak et al. [9] on 1507 insomnia patients the rebound rates were lower on day 1 of discontinuation than on day 31. Therefore in studies using polysomnographic evaluations the comparison of one or two nights at baseline, end of treatment, and withdrawal is highly questionable to assess rebound insomnia. Dr. Kripke re-evaluated long term studies, which have very different study designs and goals, and either use subjective sleep logs, questionnaires, polysomnography or a combination. All studies he cited had different rebound definitions. The methods show statistically significant differences of SL and TST at different time points of evaluation. The ramelteon study [10] defined rebound as a mean sleep latency during placebo run-out equal to or worse than mean sleep latency at baseline (both in diaries and PSG). The suvorexant [11] study defined rebound as “exploratory endpoints in the first 3 days of discontinuation phase”. This study is the only one that presents the rebound rate (number of patients affected by rebound) in percent. The statistics in different insomnia studies use comparison of baseline to endpoint or discontinuation mean values, which raises two problems: Presenting mean values without giving the range does not allow discrimination of good from poor responders. Secondly, the number of patients from start to end diminishes up to 50%. Therefore comparing mean values at any point of the study does not allow seeing inter-individual changes of sleep parameters. Since rebound (worsening beyond baseline levels) affects single patients, it is not appropriate to use this method to assess withdrawal or rebound insomnia, but this is what is done in nearly all studies. At least the baseline mean of patients who reached the withdrawal study phase must be given. For example: independently of exactly equal TSTs in placebo and treatment groups at study start patients are lost from baseline to end of study (around 25% in both groups of the eszopiclone study [12], 4% in the suvorexant study, and 30% in the ramelteon study). Except for the suvorexant study, we do not know if the dropouts had been good or poor responders. Therefore these data must be interpreted with caution, leaving more patients in the ongoing study with mild and moderate insomnia [12] than
1170
Letters to the Editor/Sleep Medicine 15 (2014) 1168–1172
at baseline. The published data provided means over all patients enclosed per time point including withdrawal period. The comparisons between baseline and end of treatment data clearly indicated in all mentioned studies that both placebo and treatment groups benefited from the treatment with greater improvements for active treatment. Baseline means of those patients who reached the discontinuation phase were given only as additional online material for the eszopiclone [13] and suvorexant [11] study. Based on the published data none of the studies showed a rebound insomnia referring to the definitions presented above. However the results of a therapeutic benefit in the placebo group over time supports the current treatment guidelines that request every medical treatment of insomnia to be supported by behavioral therapy. The application of Kales et al. rebound definition of a 40% decrease of sleep parameters for the data of the ramelteon study would have required a decrease in TST from 381.4 min (end of treatment) to 228.8 min. Instead, TST decreased to 372.9 min during discontinuation in the ramelteon group and increased slightly from 380 to 383 min in the placebo group. Thus, the slight improvement of TST in the placebo group at run-out and reduced TST in the ramelteon group could be interpreted as an effect proving that medication had been helpful instead of causing withdrawal. In contrast, Dr. Kripke indicated that the between group difference at withdrawal is significant. This is correct, but is not within the scope of rebound definitions. Rebound could be concluded in a subgroup of the eszopiclone study which had actigraphy [13]. There was a decrease of 0.6 ± 56.17 min TST in the eszopiclone group compared to baseline and an increase of 15.4 ± 51.75 min in the placebo group. However, the high standard deviation of the delta values between run-out and baseline indicated that rebound only affects single patients and not all treated patients per se. In the suvorexant study the analysis of rebound insomnia was based on all patients who entered the discontinuation phase. This is the only study that gives the proportion of patients in each treatment group with worsening between baseline TST and SL compared to each of the first three nights of the discontinuation phase and to any of the first three nights. The “primary comparison of interest was between the suvorexant-placebo group and the placebo– placebo group”. Figure 2 of this study shows a sudden drop in TST with slow adaptation to the level of placebo after switching patients from suvorexant to placebo. SL in the suvorexant group was 15 min longer than in the baseline and did not reach the levels of the placebo group. Sticking to the study’s rebound definition patients did not have a rebound because they stayed below the baseline values. Going away from the mean values, the individual values (supplementary table e6 [11]) revealed that for discontinuation nights 1–3, 51% patients had rebound in the TST and 40.8% in the SL [40.1% (TST) and 36.2% (SL), respectively, in the placebo–placebo group [11]] which revealed indeed a significant difference for TST. The authors actually discuss if this worsening is a rebound effect or a withdrawal effect or combination of both. The authors themselves conclude that “symptom return did not exhibit a spike with subsequent resolution, and the persistence of effects over the discontinuation phase, suggests that symptom return probably represents an unmasking of the underlying disorder rather than a drug-related rebound” [11]. In conclusion, definitions of rebound or withdrawal of hypnotics and methods are very different throughout various studies, making it difficult to draw conclusions. It certainly is Dr. Kripke’s merit to uncover the flaws of presentation and statistics in studies cited in his letter. However, in the end Dr. Kripke’s interpretations are a result of insufficient presentation of the study data and the use of immanent statistical methods. Insomnia is not the conse-
quence of hypnotics. Rather, insomnia is the cause for treating patients with hypnotics. The presentation of insomnia studies should all refer to the same withdrawal/rebound paradigm. They should give the raw data or rebound rates instead of the means or log transformed data only, which would make it much easier for the reader to understand the interpretations and figures. Nevertheless, it must be considered that withdrawal or rebound insomnia is a key issue which may lead physicians to continue drug administration. Therefore it is necessary to inform patients prior to treatment about the risk of rebound after discontinuation or to choose intermittent drug therapy regimes if a non-pharmacological therapy is not available.
Conflict of interest The ICMJE Uniform Disclosure Form for Potential Conflicts of Interest associated with this article can be viewed by clicking on the following link: http://dx.doi.org/10.1016/j.sleep.2014.08.002.
References [1] Alonso J, Vilagut G, Chatterji S, Heeringa S, Schoenbaum M, Bedirhan Üstün T, et al. Including information about co-morbidity in estimates of disease burden: results from the World Health Organization World Mental Health Surveys. Psychol Med 2011;41:873–86. [2] Riemann D, Perlis ML. The treatments of chronic insomnia: a review of benzodiazepine receptor agonists and psychological and behavioral therapies. Sleep Med Rev 2009;13:205–14. [3] Hohagen F, Kappler C, Schramm E, Riemann D, Weyerer S, Berger M. Sleep onset insomnia, sleep maintaining insomnia and insomnia with early morning awakening – temporal stability of subtypes in a longitudinal study on general practice attenders. Sleep 1994;17:551–4. [4] Roth T, Kramer M, Roehrs T. The consistency of sleep measures. In: Koella W, Levin P, editors. Sleep 1976. Basel: Karger; 1977. p. 286–8. [5] Kales A, Bixler EO, Tan T-L, Scharf MB, Kales JD. Chronic hypnotic-drug use. Ineffectiveness, drug-withdrawal insomnia, and dependence. JAMA 1974;227:513–17. [6] Kales A, Scharf MB, Kales JD. Rebound insomnia: a new clinical syndrome. Science 1978;201:1039–41. [7] Kales A, Soldatos CR, Bixler EO, Kales JD. Rebound insomnia and rebound anxiety: a review. Pharmacology 1983;26:121–37. [8] Roehrs T, Merlotti L, Zorick F, Roth T. Rebound insomnia and hypnotic selfadministration. Psychopharmacology 1992;107:480–4. [9] Hajak G, Clarenbach P, Fischer W, Rodenbeck A, Bandelow B, Broocks A, et al. Rebound insomnia after hypnotic withdrawal in insomniac outpatients. Eur Arch Psychiatry Clin Neurosci 1998;248:148–56. [10]Mayer G, Wang-Weigand S, Roth-Schechter B, Lehmann R, Staner C, Partinen M. Efficacy and safety of 6-month nightly ramelteon administration in adults with chronic primary insomnia. Sleep 2009;32:351–60. [11]Michelson D, Snyder E, Paradis E, Chengan-Liu M, Snavely DB, Hutzelmann J, et al. Safety and efficacy of suvorexant during 1-year treatment of insomnia with subsequent abrupt treatment discontinuation: a phase 3 randomised, doubleblind, placebo-controlled trial. Lancet Neurol 2014;13:461–71; published online March 27, 2014. [12]Ancoli-Israel S, Krystal AD, McCall WV, Schaefer K, Wilson A, Claus R, et al. A 12-week, randomized, double-blind, placebo-controlled study evaluating the effect of eszopiclone 2 mg on sleep/wake function in older adults with primary and comorbid insomnia. Sleep 2010;33:225–34. [13]Sunovion. Supplementary data to Ancoli-Israel et al. 2010. NCT00386334. 2010. Available from: [accessed September 9, 2010].
G. Mayer * Hephata Klinik, Schimmelpfengstr 6, 34613 Schwalmstadt, Germany Department of Neurology, Philipps University Marburg, Rudolf-Bultmann-Straße 8, 35039 Marburg, Germany Studienzentrum Wilhelmshöhe, Wilhelmshöher Allee 259, 34131 Kassel, Germany * Address: Hephata Klinik, Schimmelpfengstr 6, 34613 Schwalmstadt, Germany. Tel.: +496691182002; fax: +496691182040. E-mail address: [email protected]
M. Terzaghi et al./Sleep Medicine 15 (2014) 1168–1172
A. Rodenbeck Studienzentrum Wilhelmshöhe, Wilhelmshöher Allee 259, 34131 Kassel, Germany Institute of Physiology, Charité-Universitätsmedizin Berlin, St.-Hedwig Krankenhaus, Große Hamburger Str. 5-11, 10115 Berlin, Germany Department of Pneumology, Evangelisches Krankenhaus Weende gGmbH, An der Lieth 5, 37120 Bovenden, Germany
http://dx.doi.org/10.1016/j.sleep.2014.08.002 1389-9457/© 2014 Published by Elsevier B.V.
Multiple sleep latency test may be not sensitive in obstructive sleep apnea with comorbid narcolepsy revealed by low cerebrospinal fluid orexin levels To the Editor: We describe a 38-year-old man referred to our sleep center complaining of excessive daytime sleepiness (EDS) and subtle episodes of knee weakness, elicited by laughing. His Epworth Sleepiness Scale (ESS) score was 17. Polysomnography (PSG) documented severe obstructive sleep apnea (OSA) with apnea–hypopnea index (AHI) of 57.9/h. Multiple sleep latency test (MSLT) showed a mean sleep latency (MSL) of 8 min without sleep onset REM periods (SOREMPs). He started continuous airway positive pressure (CPAP) treatment, but at the follow-up he complained of worsening EDS (ESS 21), despite good compliance. PSG under CPAP therapy documented AHI of 3.2/h. MSLT showed MSL of 2.7 min without SOREMPs, but during each nap several obstructive apneas were observed with sudden awakenings and arousals. Since the cataplectic-like attacks endured, we performed brain magnetic resonance imaging, which was unremarkable, and lumbar puncture to quantify cerebrospinal fluid (CSF) orexin level, which was 45.6 pg/mL (orexin deficiency
