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Association Between Cardiorespiratory Fitness and Incident Purchase of Hypnotic Drugs in Adults: The HUNT Study

Published:October 13, 2022DOI:



      To assess whether cardiorespiratory fitness (CRF) is associated with first purchase of a prescribed hypnotic drug in the adult population.


      A total of 34,357 adult participants (53.9% women) with a mean age of 51.5 years (SD 15.6 years) from the third Trøndelag Health Study (HUNT) of 2006 to 2008 were observed until January 1, 2018. Cardiorespiratory fitness was estimated from a validated nonexercise algorithm. Data on first hypnotics prescription were obtained through linkage to the National Norwegian Prescription Database. Cox regression with 95% CIs was used to estimate hazard ratios (HRs).


      After 304,899 person-years of follow-up, 5791 participants had their first registered purchase of prescribed hypnotics, corresponding to an incidence rate of 1.90 per 100 person-years. Each 1–metabolic equivalent of task increase in CRF was significantly associated with 5% (HR, 0.95; 95% CI, 0.91 to 0.99; P=.02) and 4% (HR, 0.96; 95% CI, 0.92 to 1.00; P=.046) risk reduction for incident use of hypnotics in men and women, respectively. When CRF was categorized into tertiles with lowest CRF as the reference group, reduced risk was 13% (HR, 0.87; 95% CI, 0.79 to 0.96; P=.006) and 15% (HR, 0.85; 95% CI, 0.77 to 0.95; P=.003) for men in the intermediate and highest CRF category, respectively. In women with highest CRF, the reduced risk was 5% (HR, 0.95; 95% CI, 0.87 to 1.03; P=.22).


      Cardiorespiratory fitness in adulthood is associated with incident purchase of prescription medication commonly used for sleep problems. These findings suggest that fitness should be considered a target for preventing sleep problems in adults.

      Abbreviations and Acronyms:

      ATC (Anatomical Therapeutic Chemical classification system), CRF (cardiorespiratory fitness), CVD (cardiovascular disease), HUNT (Trøndelag Health Study), HR (hazard ratio), MET (metabolic equivalent of task), NorPD (Norwegian Prescription Database), PA (physical activity), rHR (resting heart rate), WC (waist circumference), Z-drugs (benzodiazepine-related drugs)
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        • Centers for Disease Control and Prevention
        Unhealthy sleep-related behaviors—12 states, 2009.
        MMWR Morb Mortal Wkly Rep. 2011; 60: 233-238
        • Olesen J.
        • Gustavsson A.
        • Svensson M.
        • et al.
        The economic cost of brain disorders in Europe.
        Eur J Neurol. 2012; 19: 155-162
        • Medic G.
        • Wille M.
        • Hemels M.E.
        Short- and long-term health consequences of sleep disruption.
        Nat Sci Sleep. 2017; 9: 151-161
        • Zhang X.
        • Zhang R.
        • Cheng L.
        • et al.
        The effect of sleep impairment on gestational diabetes mellitus: a systematic review and meta-analysis of cohort studies.
        Sleep Med. 2020; 74: 267-277
        • Javaheri S.
        • Redline S.
        Insomnia and risk of cardiovascular disease.
        Chest. 2017; 152: 435-444
        • Sofi F.
        • Cesari F.
        • Casini A.
        • Macchi C.
        • Abbate R.
        • Gensini G.F.
        Insomnia and risk of cardiovascular disease: a meta-analysis.
        Eur J Prev Cardiol. 2020; 21: 57-64
        • Baglioni C.
        • Battagliese G.
        • Feige B.
        • et al.
        Insomnia as a predictor of depression: a meta-analytic evaluation of longitudinal epidemiological studies.
        J Affect Disord. 2011; 135: 10-19
        • Shi L.
        • Chen S.J.
        • Ma M.Y.
        • et al.
        Sleep disturbances increase the risk of dementia: a systematic review and meta-analysis.
        Sleep Med Rev. 2018; 40: 4-16
        • American Psychiatric Association
        Diagnostic and Statistical Manual of Mental Disorders.
        Fifth Edition. DSM-V. American Psychiatric Publishing, 2013
        • Riemann D.
        • Baglioni C.
        • Bassetti C.
        • et al.
        European guideline for the diagnosis and treatment of insomnia.
        J Sleep Res. 2017; 26: 675-700
        • Dopheide J.A.
        Insomnia overview: epidemiology, pathophysiology, diagnosis and monitoring, and nonpharmacologic therapy.
        Am J Manag Care. 2020; 26: S76-S84
        • Cao X.L.
        • Wang S.B.
        • Zhong B.L.
        • et al.
        The prevalence of insomnia in the general population in China: a meta-analysis.
        PLoS One. 2017; 12e0170772
        • Morin C.M.
        • Jarrin D.C.
        • Ivers H.
        • Mérette C.
        • LeBlanc M.
        • Savard J.
        Incidence, persistence, and remission rates of insomnia over 5 years.
        JAMA Netw Open. 2020; 3e2018782
        • Deoras K.S.
        • Moul D.E.
        in: Aminoff M.J. Daroff R.B. Encyclopedia of the Neurological Sciences. 2nd ed. Academic Press, 2014: 646-649
        • Kaufmann C.N.
        • Spira A.P.
        • Alexander G.C.
        • Rutkow L.
        • Mojtabai R.
        Trends in prescribing of sedative-hypnotic medications in the USA: 1993-2010.
        Pharmacoepidemiol Drug Saf. 2016; 25: 637-645
        • Ford E.S.
        • Wheaton A.G.
        • Cunningham T.J.
        • Giles W.H.
        • Chapman D.P.
        • Croft J.B.
        Trends in outpatient visits for insomnia, sleep apnea, and prescriptions for sleep medications among US adults: findings from the National Ambulatory Medical Care Survey 1999-2010.
        Sleep. 2014; 37: 1283-1293
        • Estrela M.
        • Herdeiro M.T.
        • Ferreira P.L.
        • Roque F.
        The use of antidepressants, anxiolytics, sedatives and hypnotics in Europe: focusing on mental health care in Portugal and prescribing in older patients.
        Int J Environ Res Public Health. 2020; 17: 8612
        • Begum M.
        • Gonzalez-Chica D.
        • Bernardo C.
        • Woods A.
        • Stocks N.
        Trends in the prescription of drugs used for insomnia: an open-cohort study in Australian general practice, 2011-2018.
        Br J Gen Pract. 2021; 71: e877-e886
        • Tannenbaum C.
        • Diaby V.
        • Singh D.
        • Perreault S.
        • Luc M.
        • Vasiliadis H.M.
        Sedative-hypnotic medicines and falls in community-dwelling older adults: a cost-effectiveness (decision-tree) analysis from a US Medicare perspective.
        Drugs Aging. 2015; 32: 305-314
        • Li C.T.
        • Bai Y.M.
        • Lee Y.C.
        • et al.
        High dosage of hypnotics predicts subsequent sleep-related breathing disorders and is associated with worse outcomes for depression.
        Sleep. 2014; 37: 803-809
        • Harbourt K.
        • Nevo O.N.
        • Zhang R.
        • Chan V.
        • Croteau D.
        Association of eszopiclone, zaleplon, or zolpidem with complex sleep behaviors resulting in serious injuries, including death.
        Pharmacoepidemiol Drug Saf. 2020; 29: 684-691
        • Aschenbrenner D.S.
        Common insomnia drugs receive black box warning.
        AJN Am J Nurs. 2019; 119: 22
        • Sateia M.J.
        • Buysse D.J.
        • Krystal A.D.
        • Neubauer D.N.
        • Heald J.L.
        Clinical practice guideline for the pharmacologic treatment of chronic insomnia in adults: an American Academy of Sleep Medicine clinical practice guideline.
        J Clin Sleep Medicine. 2017; 13: 307-349
        • Yang P.Y.
        • Ho K.H.
        • Chen H.C.
        • Chien M.Y.
        Exercise training improves sleep quality in middle-aged and older adults with sleep problems: a systematic review.
        J Physiother. 2012; 58: 157-163
        • Amiri S.
        • Hasani J.
        • Satkin M.
        Effect of exercise training on improving sleep disturbances: a systematic review and meta-analysis of randomized control trials.
        Sleep Med. 2021; 84: 205-218
        • Kovacevic A.
        • Mavros Y.
        • Heisz J.J.
        • Fiatarone Singh M.A.
        The effect of resistance exercise on sleep: a systematic review of randomized controlled trials.
        Sleep Med Rev. 2018; 39: 52-68
        • Edinger J.D.
        • Arnedt J.T.
        • Bertisch S.M.
        • et al.
        Behavioral and psychological treatments for chronic insomnia disorder in adults: an American Academy of Sleep Medicine systematic review, meta-analysis, and GRADE assessment.
        J Clin Sleep Med. 2021; 17: 263-298
        • Stubbs B.
        • Vancampfort D.
        • Mänty M.
        • Svärd A.
        • Rahkonen O.
        • Lahti J.
        Bidirectional longitudinal relationship between leisure-time physical activity and psychotropic medication usage: a register linked follow-up study.
        Psychiatry Res. 2017; 247: 208-213
        • Ross R.
        • Blair S.N.
        • Arena R.
        • et al.
        Importance of assessing cardiorespiratory fitness in clinical practice: a case for fitness as a clinical vital sign: a scientific statement from the American Heart Association.
        Circulation. 2016; 134: e653-e699
        • Imboden M.T.
        • Harber M.P.
        • Whaley M.H.
        • et al.
        The influence of change in cardiorespiratory fitness with short-term exercise training on mortality risk from the Ball State Adult Fitness Longitudinal Lifestyle Study.
        Mayo Clin Proc. 2019; 94: 1406-1414
        • Zhang Y.
        • Zhang J.
        • Zhou J.
        • et al.
        Nonexercise estimated cardiorespiratory fitness and mortality due to all causes and cardiovascular disease: the NHANES III study.
        Mayo Clin Proc Innov Qual Outcomes. 2017; 1: 16-25
        • Dishman R.K.
        • Sui X.
        • Church T.S.
        • Kline C.E.
        • Youngstedt S.D.
        • Blair S.N.
        Decline in cardiorespiratory fitness and odds of incident sleep complaints.
        Med Sci Sports Exerc. 2015; 47: 960-966
        • Schuch F.B.
        • Vancampfort D.
        • Sui X.
        • et al.
        Are lower levels of cardiorespiratory fitness associated with incident depression? A systematic review of prospective cohort studies.
        Prev Med. 2016; 93: 159-165
        • Shigdel R.
        • Stubbs B.
        • Sui X.
        • Ernstsen L.
        Cross-sectional and longitudinal association of non-exercise estimated cardiorespiratory fitness with depression and anxiety in the general population: the HUNT study.
        J Affect Disord. 2019; 252: 122-129
        • Carlsen T.
        • Salvesen Ø.
        • Sui X.
        • et al.
        Long-term changes in depressive symptoms and estimated cardiorespiratory fitness and risk of all-cause mortality: the Nord-Trøndelag Health Study.
        Mayo Clin Proc. 2018; 93: 1054-1064
        • Zotcheva E.
        • Pintzka C.W.
        • Salvesen O.
        • Selbaek G.
        • Haberg A.K.
        • Ernstsen L.
        Associations of changes in cardiorespiratory fitness and symptoms of anxiety and depression with brain volumes: the HUNT study.
        Front Behav Neurosci. 2019; 13: 53
        • DeFina L.F.
        • Willis B.L.
        • Radford N.B.
        • et al.
        The association between midlife cardiorespiratory fitness levels and later-life dementia: a cohort study.
        Ann Intern Med. 2013; 158: 162-168
        • Harber M.P.
        • Metz M.
        • Peterman J.E.
        • Whaley M.H.
        • Fleenor B.S.
        • Kaminsky L.A.
        Trends in cardiorespiratory fitness among apparently healthy adults from the Ball State Adult Fitness Longitudinal Lifestyle STudy (BALL ST) cohort from 1970-2019.
        PLoS One. 2020; 15e0242995
        • Holmen J.
        • Midthjell K.
        • Bjartveit K.
        • et al.
        The Nord-Trøndelag Health Survey 1984-86. Purpose, Background and Methods. Participation, Non-participation and Frequency Distributions.
        (Issues 4-90 of Rapport) National Institute of Public Health, Unit for Health Services Research, 1990
        • Holmen J.
        • Midthjell K.
        • Krüger Ø.
        • et al.
        The Nord-Trøndelag Health Study 1995-97 (HUNT 2): objectives, contents, methods and participation.
        Norsk Epidemiologi. 2003; 13: 19-32
        • Krokstad S.
        • Langhammer A.
        • Hveem K.
        • et al.
        Cohort profile: the HUNT Study, Norway.
        Int J Epidemiol. 2013; 42: 968-977
      1. Åsvold BO, Langhammer A, Rehn TA, et al. Cohort profile update: the HUNT Study, Norway. Int J Epidemiol. Published online May 17, 2022. doi:10.1093/ije/dyac095

        • Sommerschild T.H.
        • Berg C.L.
        • Jonasson C.
        • Husabø K.J.
        • Sharikabad M.N.
        Data resource profile: Norwegian Database for Drug Utilization and Pharmacoepidemiology.
        Norsk Epidemiologi. 2021; 29
        • von Elm E.
        • Altman D.G.
        • Egger M.
        • Pocock S.J.
        • Gotzsche P.C.
        • Vandenbroucke J.P.
        • STROBE Initiative
        The Strengthening the Reporting of Observational Studies in Epidemiology (STROBE) statement: guidelines for reporting observational studies.
        J Clin Epidemiol. 2008; 61: 344-349
        • Norwegian Institute of Public Health
        Welcome to the Norwegian Prescription Database.
        (Accessed August 1, 2021)
        • Norwegian Institute of Public Health
        WHO Collaborating Centre for Drug Statistics Methodology.
        (Accessed August 1, 2021)
        • Nes B.M.
        • Janszky I.
        • Vatten L.J.
        • Nilsen T.I.
        • Aspenes S.T.
        • Wisloff U.
        Estimating {Vdot}O2peak from a nonexercise prediction model: the HUNT Study, Norway.
        Med Sci Sports Exerc. Nov 2011; 43: 2024-2030
        • Kurtze N.
        • Rangul V.
        • Hustvedt B.E.
        • Flanders W.D.
        Reliability and validity of self-reported physical activity in the Nord-Trøndelag Health Study: HUNT 1.
        Scand J Public Health. 2008; 36: 52-61
        • Zigmond A.
        • Snaith R.
        The Hospital Anxiety and Depression Scale.
        Acta Psychiatr Scand. 1983; 67: 361-370
        • Bjelland I.
        • Dahl A.A.
        • Haug T.T.
        • Neckelmann D.
        The validity of the Hospital Anxiety and Depression Scale: an updated literature review.
        J Psychosom Res. 2002; 52: 69-77
        • Patel D.
        • Steinberg J.
        • Patel P.
        Insomnia in the elderly: a review.
        J Clin Sleep Med. 2018; 14: 1017-1024
        • Kleinbaum D.G.
        Survival Analysis: A Self-Learning Text.
        2nd ed. Springer, 2006: 590
        • Putter H.
        • Sasako M.
        • Hartgrink H.H.
        • van de Velde C.J.
        • van Houwelingen J.C.
        Long-term survival with non-proportional hazards: results from the Dutch Gastric Cancer Trial.
        Stat Med. 2005; 24: 2807-2821
        • Sloan R.A.
        • Kim Y.
        • Sawada S.S.
        • Asakawa A.
        • Blair S.N.
        • Finkelstein E.A.
        Is less sedentary behavior, more physical activity, or higher fitness associated with sleep quality? A cross-sectional study in Singapore.
        Int J Environ Res Public Health. 2020; 17: 1337
        • Mochón-Benguigui S.
        • Carneiro-Barrera A.
        • Castillo M.J.
        • Amaro-Gahete F.J.
        Role of physical activity and fitness on sleep in sedentary middle-aged adults: the FIT-AGEING study.
        Sci Rep. 2021; 11: 539
        • Osailan A.M.
        • Elnaggar R.K.
        • Alsubaie S.F.
        • Alqahtani B.A.
        • Abdelbasset W.K.
        The association between cardiorespiratory fitness and reported physical activity with sleep quality in apparently healthy adults: a cross-sectional study.
        Int J Environ Res Public Health. 2021; 18: 4263
        • Li S.
        • Li Z.
        • Wu Q.
        • et al.
        Effect of exercise intervention on primary insomnia: a meta-analysis.
        J Sports Med Phys Fitness. 2021; 61: 857-866
        • Lahti J.
        • Lallukka T.
        • Lahelma E.
        • Rahkonen O.
        Leisure-time physical activity and psychotropic medication: a prospective cohort study.
        Prev Med. 2013; 57: 173-177
        • Bjorvatn B.
        • Meland E.
        • Flo E.
        • Mildestvedt T.
        High prevalence of insomnia and hypnotic use in patients visiting their general practitioner.
        Fam Pract. 2016; 34: 20-24
        • Miner B.
        • Kryger M.H.
        Sleep in the aging population.
        Sleep Med Clin. 2020; 15: 311-318
        • Kocevska D.
        • Lysen T.S.
        • Dotinga A.
        • et al.
        Sleep characteristics across the lifespan in 1.1 million people from the Netherlands, United Kingdom and United States: a systematic review and meta-analysis.
        Nat Hum Behav. 2021; 5: 113-122
        • Milani S.A.
        • Raji M.A.
        • Chen L.
        • Kuo Y.F.
        Trends in the use of benzodiazepines, Z-hypnotics, and serotonergic drugs among US women and men before and during the COVID-19 pandemic.
        JAMA Netw Open. 2021; 4e2131012
        • Thompson K.N.
        • Hübel C.
        • Cheesman R.
        • et al.
        Age and sex-related variability in the presentation of generalized anxiety and depression symptoms.
        Depress Anxiety. 2021; 38: 1054-1065
        • Nauman J.
        • Nes B.M.
        • Lavie C.J.
        • et al.
        Prediction of cardiovascular mortality by estimated cardiorespiratory fitness independent of traditional risk factors: the HUNT Study.
        Mayo Clin Proc. 2017; 92: 218-227
        • Shigdel R.
        • Dalen H.
        • Sui X.
        • Lavie C.J.
        • Wisloff U.
        • Ernstsen L.
        Cardiorespiratory fitness and the risk of first acute myocardial infarction: the HUNT Study.
        J Am Heart Assoc. 2019; 8e010293
        • Tari A.R.
        • Nauman J.
        • Zisko N.
        • et al.
        Temporal changes in cardiorespiratory fitness and risk of dementia incidence and mortality: a population-based prospective cohort study.
        Lancet Public Health. 2019; 4: e565-e574
        • Kaminsky L.A.
        • Imboden M.T.
        • Arena R.
        • Myers J.
        Reference standards for cardiorespiratory fitness measured with cardiopulmonary exercise testing using cycle ergometry: data from the Fitness Registry and the Importance of Exercise National Database (FRIEND) Registry.
        Mayo Clin Proc. 2017; 92: 228-233