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Hypnotic use and multiple sclerosis related fatigue: a forgotten confounder
Sleep Medicine 16 (2015) 319
Contents lists available at ScienceDirect
Sleep Medicine j o u r n a l h o m e p a g e : w w w. e l s e v i e r. c o m / l o c a t e / s l e e p
Editorial
Hypnotic use and multiple sclerosis related fatigue: a forgotten confounder
In the January issue of Sleep Medicine, Braley et al. [1] have published a cross-sectional study of 190 multiple sclerosis (MS) patients, showing that over-the-counter (OTC) hypnotic use, but not prescription hypnotic use, was independently associated with fatigue measured with the Fatigue Severity Scale (FSS) [2] after adjustment for insomnia (measured with the Insomnia Severity Index or [3]) and other clinical and sleep related confounds. Almost half (47%) of MS patients reported occasional or more frequent use of hypnotics, and the majority of them indicated the use of an OTC diphenhydramine-containing product. Diphenhydramine is a first generation H1-receptor antagonist with sedative effect and its elimination half-life is 4–9 hours for healthy adults [1]. It has been shown that antihistaminic drugs taken at night (ie, diphenhydramine) have carryover effects with impaired daytime functioning the day after drug administration [4]. To date, there is a lack of epidemiological data on the frequency of hypnotic use in MS compared with the general population. The research and therapy of MS related fatigue remain a challenging task because its mechanism is unknown [5,6] and treatment options are sparse (in particular there is no drug therapy approved by the Food and Drug Administration nor the European Medicines Agency) [7]). Moreover, there is an overlap between fatigue measured with the FSS and depression [2], and several other confounders described in this context such as cognitive deficits [8], disability [9,10], disease course [10], sleep disorders [7], and disease-modifying therapies [11–13]. In this trial [1], depression was assessed in a dichotomized manner, by the diagnosis of clinical depression or active symptoms of depression as documented by the treating physician. One limitation of the study is that no quantitative depression scale was used; however, despite this methodical limitation, the particular value of this work is to underline the significance of hypnotic use in this field and to introduce one more confounder in the research of MS-related fatigue: hypnotic use should be considered henceforth as a relevant confounder in all trials investigating MSrelated fatigue. Unfortunately, the large and increasing number of confounders taken into account makes research in this area more difficult, and future studies should accordingly include a large number of patients. On the other hand, the consideration of all these confounders could contribute to improved and more determined studies in order to elucidate what drives MS related fatigue – and finally lead us to treatment options in the future.
http://dx.doi.org/10.1016/j.sleep.2014.11.012 1389-9457/© 2014 Elsevier B.V. All rights reserved.
Conflict of interest The author reports no 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.2014.11.012.
References [1] Braley TJ, Segala BM, Chervin RD. Hypnotic use and fatigue in multiple sclerosis. Sleep Med 2014;doi:10.1016/j.sleep.2014.09.006. [2] Krupp LB, LaRocca NG, Muir-Nash J, Steinberg AD. The fatigue severity scale. Arch Neurol 1989;46:1121–3. [3] Bastien CH, Vallières A, Morin CM. Validation of the Insomnia Severity Index as an outcome measure for insomnia research. Sleep Med 2001;2:297–307. [4] Katayose Y, Aritake S, Kitamura S, Enomoto M, Hida A, Takahashi K, et al. Carryover effect on next-day sleepiness and psychomotor performance of nighttime administered antihistaminic drugs: a randomized controlled trial. Hum Psychopharmacol Clin Exp 2012;27(4):428–36. [5] Döring A, Pfueller CF, Paul F, Dörr J. Exercise in multiple sclerosis – an integral component of disease management. EPMA J 2012;3:2. [6] Multiple Sclerosis Council for Clinical Practice Guidelines. Fatigue and multiple sclerosis: evidence-based management strategies for fatigue in multiple sclerosis. Washington, DC: Paralyzed Veterans of America; 1998. [7] Veauthier C, Paul F. Sleep disorders in multiple sclerosis and their relationship to fatigue. Sleep Med 2014;15(1):5–14. doi:10.1016/j.sleep.2013.08.791. [8] Weinges-Evers N, Brandt AU, Bock M, Pfueller CF, Dörr J, Bellmann-Strobl J, et al. Correlation of self-assessed fatigue and alertness in multiple sclerosis. Mult Scler 2010;16:1134–40. [9] Patrick E, Christodoulou C, Krupp LB, New York State MS Consortium. Longitudinal correlates of fatigue in multiple sclerosis. Mult Scler 2009;15:258– 61. [10] Merkelbach S, Schulz H, Kölmel HW, Gora G, Klingelhöfer J, Dachsel R, et al. Fatigue, sleepiness, and physical activity in patients with multiple sclerosis. J Neurol 2011;258:74–9. [11] Jongen PJ, Lehnick D, Sanders E, Seeldrayers P, Fredrikson S, Andersson M, et al. Health-related quality of life in relapsing remitting multiple sclerosis patients during treatment with glatiramer acetate: a prospective, observational, international, multi-centre study. Health Qual Life Outcomes 2010;8:133. [12] Melanson M, Grossberndt A, Klowak M, Leong C, Frost EE, Prout M, et al. Fatigue and cognition in patients with relapsing multiple sclerosis treated with interferon beta. Int J Neurosci 2010;120(10):631–40. [13] Ziemssen T. Multiple sclerosis beyond EDSS: depression and fatigue. J Neurol Sci 2009;277(Suppl. 1):S37–41.
Christian Veauthier * Charité University Medicine Berlin, Interdisciplinary Center of Sleep Medicine, Berlin, Germany * Tel.: +49 30450513232; fax: +49 32122828668. E-mail address: [email protected] Available online 15 January 2015
Contents lists available at ScienceDirect
Sleep Medicine j o u r n a l h o m e p a g e : w w w. e l s e v i e r. c o m / l o c a t e / s l e e p
Editorial
Hypnotic use and multiple sclerosis related fatigue: a forgotten confounder
In the January issue of Sleep Medicine, Braley et al. [1] have published a cross-sectional study of 190 multiple sclerosis (MS) patients, showing that over-the-counter (OTC) hypnotic use, but not prescription hypnotic use, was independently associated with fatigue measured with the Fatigue Severity Scale (FSS) [2] after adjustment for insomnia (measured with the Insomnia Severity Index or [3]) and other clinical and sleep related confounds. Almost half (47%) of MS patients reported occasional or more frequent use of hypnotics, and the majority of them indicated the use of an OTC diphenhydramine-containing product. Diphenhydramine is a first generation H1-receptor antagonist with sedative effect and its elimination half-life is 4–9 hours for healthy adults [1]. It has been shown that antihistaminic drugs taken at night (ie, diphenhydramine) have carryover effects with impaired daytime functioning the day after drug administration [4]. To date, there is a lack of epidemiological data on the frequency of hypnotic use in MS compared with the general population. The research and therapy of MS related fatigue remain a challenging task because its mechanism is unknown [5,6] and treatment options are sparse (in particular there is no drug therapy approved by the Food and Drug Administration nor the European Medicines Agency) [7]). Moreover, there is an overlap between fatigue measured with the FSS and depression [2], and several other confounders described in this context such as cognitive deficits [8], disability [9,10], disease course [10], sleep disorders [7], and disease-modifying therapies [11–13]. In this trial [1], depression was assessed in a dichotomized manner, by the diagnosis of clinical depression or active symptoms of depression as documented by the treating physician. One limitation of the study is that no quantitative depression scale was used; however, despite this methodical limitation, the particular value of this work is to underline the significance of hypnotic use in this field and to introduce one more confounder in the research of MS-related fatigue: hypnotic use should be considered henceforth as a relevant confounder in all trials investigating MSrelated fatigue. Unfortunately, the large and increasing number of confounders taken into account makes research in this area more difficult, and future studies should accordingly include a large number of patients. On the other hand, the consideration of all these confounders could contribute to improved and more determined studies in order to elucidate what drives MS related fatigue – and finally lead us to treatment options in the future.
http://dx.doi.org/10.1016/j.sleep.2014.11.012 1389-9457/© 2014 Elsevier B.V. All rights reserved.
Conflict of interest The author reports no 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.2014.11.012.
References [1] Braley TJ, Segala BM, Chervin RD. Hypnotic use and fatigue in multiple sclerosis. Sleep Med 2014;doi:10.1016/j.sleep.2014.09.006. [2] Krupp LB, LaRocca NG, Muir-Nash J, Steinberg AD. The fatigue severity scale. Arch Neurol 1989;46:1121–3. [3] Bastien CH, Vallières A, Morin CM. Validation of the Insomnia Severity Index as an outcome measure for insomnia research. Sleep Med 2001;2:297–307. [4] Katayose Y, Aritake S, Kitamura S, Enomoto M, Hida A, Takahashi K, et al. Carryover effect on next-day sleepiness and psychomotor performance of nighttime administered antihistaminic drugs: a randomized controlled trial. Hum Psychopharmacol Clin Exp 2012;27(4):428–36. [5] Döring A, Pfueller CF, Paul F, Dörr J. Exercise in multiple sclerosis – an integral component of disease management. EPMA J 2012;3:2. [6] Multiple Sclerosis Council for Clinical Practice Guidelines. Fatigue and multiple sclerosis: evidence-based management strategies for fatigue in multiple sclerosis. Washington, DC: Paralyzed Veterans of America; 1998. [7] Veauthier C, Paul F. Sleep disorders in multiple sclerosis and their relationship to fatigue. Sleep Med 2014;15(1):5–14. doi:10.1016/j.sleep.2013.08.791. [8] Weinges-Evers N, Brandt AU, Bock M, Pfueller CF, Dörr J, Bellmann-Strobl J, et al. Correlation of self-assessed fatigue and alertness in multiple sclerosis. Mult Scler 2010;16:1134–40. [9] Patrick E, Christodoulou C, Krupp LB, New York State MS Consortium. Longitudinal correlates of fatigue in multiple sclerosis. Mult Scler 2009;15:258– 61. [10] Merkelbach S, Schulz H, Kölmel HW, Gora G, Klingelhöfer J, Dachsel R, et al. Fatigue, sleepiness, and physical activity in patients with multiple sclerosis. J Neurol 2011;258:74–9. [11] Jongen PJ, Lehnick D, Sanders E, Seeldrayers P, Fredrikson S, Andersson M, et al. Health-related quality of life in relapsing remitting multiple sclerosis patients during treatment with glatiramer acetate: a prospective, observational, international, multi-centre study. Health Qual Life Outcomes 2010;8:133. [12] Melanson M, Grossberndt A, Klowak M, Leong C, Frost EE, Prout M, et al. Fatigue and cognition in patients with relapsing multiple sclerosis treated with interferon beta. Int J Neurosci 2010;120(10):631–40. [13] Ziemssen T. Multiple sclerosis beyond EDSS: depression and fatigue. J Neurol Sci 2009;277(Suppl. 1):S37–41.
Christian Veauthier * Charité University Medicine Berlin, Interdisciplinary Center of Sleep Medicine, Berlin, Germany * Tel.: +49 30450513232; fax: +49 32122828668. E-mail address: [email protected] Available online 15 January 2015