Mayo Clinic Proceedings Home

Pharmacotherapeutic Failure in a Large Cohort of Patients With Insomnia Presenting to a Sleep Medicine Center and Laboratory: Subjective Pretest Predictions and Objective Diagnoses

Published:September 15, 2014DOI:https://doi.org/10.1016/j.mayocp.2014.04.032

      Abstract

      Objective

      To measure the frequency of pharmacotherapeutic failure and its association with the diagnosis of sleep-disordered breathing among patients with chronic insomnia disorder.

      Patients and Methods

      In a retrospective review of medical records from January 1, 2005, through December 31, 2012, we identified an inclusive, consecutive series of 1210 patients with insomnia disorder, 899 (74.3%) of whom used sleep aids either occasionally (168 [18.7%]) or regularly (731 [81.3%]). Patients presented to a community-based sleep medicine center in Albuquerque, New Mexico, with typical referral patterns: 743 (61.4%) were referred by primary care physicians, 211 (17.4%) by specialists, 117 (9.7%) by mental health professionals, and 139 (11.5%) by self-referral. Pharmacotherapeutic failure was assessed from subjective insomnia reports and a validated insomnia severity scale. Polysomnography with pressure transducer (an advanced respiratory technology not previously used in a large cohort of patients with insomnia) measured sleep-disordered breathing. Objective data yielded accuracy rates for 3 pretest screening tools used to measure risk for sleep-disordered breathing.

      Results

      Of the total sample of 1210 patients, all 899 (74.3%) who were taking over-the-counter or prescription sleep aids had pharmacotherapeutic failure. The 710 patients taking prescription drugs (79.0%) reported the most severe insomnia, the fewest sleep-associated breathing symptoms, and the most medical and psychiatric comorbidity. Of the 942 patients objectively tested (77.9%), 860 (91.3%) met standard criteria, on average, for a moderate to severe sleep-associated breathing disorder, yet pretest screening sensitivity for sleep-disordered breathing varied widely from 63.7% to 100%. Positive predictive values were high (about 90%) for all screens, but a tool commonly used in primary care misclassified 301 patients (32.0% false-negative results).

      Conclusion

      Pharmacotherapeutic failure and sleep-disordered breathing were extremely common among treatment-seeking patients with chronic insomnia disorder. Screening techniques designed from the field of sleep medicine predicted high rates for sleep-disordered breathing, whereas a survey common to primary care yielded many false-negative results. Although the relationship between insomnia and sleep-disordered breathing remains undefined, this research raises salient clinical questions about the management of insomnia in primary care before sleep center encounters.

      Abbreviations and Acronyms:

      AASM ( American Academy of Sleep Medicine), AHI ( apnea-hypopnea index), ISI ( Insomnia Severity Index), MSAS ( Maimonides Sleep Arts & Sciences, Ltd), NCPT ( nasal cannula pressure transducer), NPV ( negative predictive value), OSA ( obstructive sleep apnea), OTC ( over-the-counter), PAP ( positive airway pressure), PPV ( positive predictive value), PSG ( polysomnography), RDI ( respiratory disturbance index), RERA ( respiratory effort–related arousal), SDB ( sleep-disordered breathing), UARS ( upper airway resistance syndrome)
      To read this article in full you will need to make a payment

      References

        • American Academy of Sleep Medicine
        The International Classification of Sleep Disorders: Diagnostic & Coding Manual.
        2nd ed. American Academy of Sleep Medicine, Westchester, IL2005: 51-55
        • Buysse D.J.
        Insomnia.
        JAMA. 2013; 309: 706-716
        • Simon G.E.
        • VonKorff M.
        Prevalence, burden, and treatment of insomnia in primary care.
        Am J Psychiatry. 1997; 154: 1417-1423
        • Léger D.
        • Massuel M.A.
        • Metlaine A.
        • SISYPHE Study Group
        Professional correlates of insomnia.
        Sleep. 2006; 29: 171-178
        • Daley M.
        • Morin C.M.
        • LeBlanc M.
        • Grégoire J.P.
        • Savard J.
        • Baillargeon L.
        Insomnia and its relationship to health-care utilization, work absenteeism, productivity and accidents.
        Sleep Med. 2009; 10: 427-438
        • Crum R.M.
        • Storr C.L.
        • Chan Y.F.
        • Ford D.E.
        Sleep disturbance and risk for alcohol-related problems.
        Am J Psychiatry. 2004; 161: 1197-1203
        • Taylor D.J.
        • Lichstein K.L.
        • Durrence H.H.
        • Reidel B.W.
        • Bush A.J.
        Epidemiology of insomnia, depression, and anxiety.
        Sleep. 2005; 28: 1457-1464
        • Cappuccio F.P.
        • D'Elia L.
        • Strazzullo P.
        • Miller M.A.
        Quantity and quality of sleep and incidence of type 2 diabetes: a systematic review and meta-analysis.
        Diabetes Care. 2010; 33: 414-420
        • Gangwisch J.E.
        • Malaspina D.
        • Boden-Albala B.
        • Heymsfield S.B.
        Inadequate sleep as a risk factor for obesity: analyses of the NHANES I.
        Sleep. 2005; 28: 1289-1296
        • Elwood P.
        • Hack M.
        • Pickering J.
        • Hughes J.
        • Gallacher J.
        Sleep disturbance, stroke, and heart disease events: evidence from the Caerphilly cohort.
        J Epidemiol Community Health. 2006; 60: 69-73
        • Stoller M.K.
        Economic effects of insomnia.
        Clin Ther. 1994; 16: 873-897
        • Walsh J.K.
        • Engelhardt C.L.
        The direct economic costs of insomnia in the United States for 1995.
        Sleep. 1999; 22: S386-S393
        • Wilson J.F.
        Insomnia.
        Ann Intern Med. 2008; 148 (ITC13-1–ITC13-16)
        • Hamblin J.E.
        Insomnia: an ignored health problem.
        Prim Care. 2007; 34: 659-674
        • Benca R.M.
        Diagnosis and treatment of chronic insomnia: a review.
        Psychiatr Serv. 2005; 56: 332-343
        • Lande R.G.
        • Gragnani C.
        Nonpharmacologic approaches to the management of insomnia.
        J Am Osteopath Assoc. 2010; 110: 695-701
        • Papp K.K.
        • Penrod C.E.
        • Strohl K.P.
        Knowledge and attitudes of primary care physicians toward sleep and sleep disorders.
        Sleep Breath. 2002; 6: 103-109
        • Rosen R.C.
        • Rosekind M.
        • Rosevear C.
        • Cole W.E.
        • Dement W.C.
        Physician education in sleep and sleep disorders: a national survey of U.S. medical schools.
        Sleep. 1993; 16: 249-254
        • Ford D.E.
        • Kamerow D.B.
        Epidemiologic study of sleep disturbances and psychiatric disorders: an opportunity for prevention?.
        JAMA. 1989; 262: 1479-1484
        • Shochat T.
        • Umphress J.
        • Israel A.G.
        • Ancoli-Israel S.
        Insomnia in primary care patients.
        Sleep. 1999; 22: S359-S365
        • McCrae C.S.
        • Lichstein K.L.
        Secondary insomnia: diagnostic challenges and intervention opportunities.
        Sleep Med Rev. 2001; 5: 47-61
        • Sivertsen B.
        • Nordhus I.H.
        • Bjorvatn B.
        • Pallesen S.
        Sleep problems in general practice: a national survey of assessment and treatment routines of general practitioners in Norway.
        J Sleep Res. 2010; 19: 36-41
        • Hilty D.
        • Young J.S.
        • Bourgeois J.A.
        • Klein S.
        • Hardin K.A.
        Algorithms for the assessment and management of insomnia in primary care.
        Patient Prefer Adherence. 2009; 3: 9-20
        • Schutte-Rodin S.
        • Broch L.
        • Buysse D.
        • Dorsey C.
        • Sateia M.
        Clinical guideline for the evaluation and management of chronic insomnia in adults.
        J Clin Sleep Med. 2008; 4: 487-504
        • Chong Y.
        • Fryar C.D.
        • Gu Q.
        Prescription Sleep Aid Use Among Adults: United States, 2005-2010.
        National Center for Health Statistics, Hyattsville, MD2013 (NCHS data brief 127)
        • Bertisch S.M.
        • Herzig S.J.
        • Winkelman J.W.
        • Buettner C.
        National use of prescription medications for insomnia: NHANES 1999-2010.
        Sleep. 2014; 37: 343-349
        • Brandt N.J.
        • Piechocki J.M.
        Treatment of insomnia in older adults: re-evaluating the benefits and risks of sedative hypnotic agents.
        J Gerontol Nurs. 2013; 39: 48-54
        • Hajak G.
        • Geisler P.
        Experience with zolpidem 'as needed' in primary care settings.
        CNS Drugs. 2004; 18: 35-40
        • Omvik S.
        • Pallesen S.
        • Bjorvatn B.
        • Sivertsen B.
        • Havik O.E.
        • Nordhus I.H.
        Patient characteristics and predictors of sleep medication use.
        Int Clin Psychopharmacol. 2010; 25: 91-100
        • Randall S.
        • Roehrs T.A.
        • Roth T.
        Efficacy of eight months of nightly zolpidem: a prospective placebo-controlled study.
        Sleep. 2012; 35: 1551-1557
        • Krystal A.D.
        • Walsh J.K.
        • Laska E.
        • et al.
        Sustained efficacy of eszopiclone over 6 months of nightly treatment: results of a randomized, double-blind, placebo-controlled study in adults with chronic insomnia.
        Sleep. 2003; 26: 793-799
        • Krystal A.D.
        • Erman M.
        • Zammit G.K.
        • Soubrane C.
        • Roth T.
        • ZOLONG Study Group
        Long-term efficacy and safety of zolpidem extended-release 12.5 mg, administered 3 to 7 nights per week for 24 weeks, in patients with chronic primary insomnia: a 6-month, randomized, double-blind, placebo-controlled, parallel-group, multicenter study.
        Sleep. 2008; 31: 79-90
        • Ancoli-Israel S.
        • Richardson G.S.
        • Mangano R.M.
        • Jenkins L.
        • Hall P.
        • Jones W.S.
        Long-term use of sedative hypnotics in older patients with insomnia.
        Sleep Med. 2005; 6: 107-113
        • Mattila T.
        • Stoyanova V.
        • Elferink A.
        • Gispen-de Wied C.
        • de Boer A.
        • Wohlfarth T.
        Insomnia medication: do published studies reflect the complete picture of efficacy and safety?.
        Eur Neuropsychopharmacol. 2011; 21: 500-507
        • Kripke D.F.
        Chronic hypnotic use: deadly risks, doubtful benefit. REVIEW ARTICLE.
        Sleep Med Rev. 2000; 4: 5-20
        • Kripke D.F.
        • Klauber M.R.
        • Wingard D.L.
        • Fell R.L.
        • Assmus J.D.
        • Garfinkel L.
        Mortality hazard associated with prescription hypnotics.
        Biol Psychiatry. 1998; 43: 687-693
        • Chen H.C.
        • Su T.P.
        • Chou P.
        A nine-year follow-up study of sleep patterns and mortality in community-dwelling older adults in Taiwan.
        Sleep. 2013; 36 ([published correction appears in Sleep. 2013;36(10):1573]): 1187-1198
        • Brower K.J.
        • McCammon R.J.
        • Wojnar M.
        • Ilgen M.A.
        • Wojnar J.
        • Valenstein M.
        Prescription sleeping pills, insomnia, and suicidality in the National Comorbidity Survey Replication.
        J Clin Psychiatry. 2011; 72: 515-521
        • Zammit G.
        Comparative tolerability of newer agents for insomnia.
        Drug Saf. 2009; 32: 735-748
      1. Davy Z, Middlemass J, Siriwardena AN. Patients' and clinicians' experiences and perceptions of the primary care management of insomnia: qualitative study [published online ahead of print August 19, 2013]. Health Expect.

        • Lichstein K.L.
        Secondary insomnia: a myth dismissed.
        Sleep Med Rev. 2006; 10 ([editorial]): 3-5
        • American Psychiatric Association
        Diagnostic and Statistical Manual of Mental Disorders:DSM-5.
        5th ed. American Psychiatric Association, Washington, DC2013
        • Littner M.
        • Hirshkowitz M.
        • Kramer M.
        • et al.
        • American Academy of Sleep Medicine; Standards of Practice Committe
        Practice parameters for using polysomnography to evaluate insomnia: an update.
        Sleep. 2003; 26: 754-760
        • Wickwire E.M.
        • Collop N.A.
        Insomnia and sleep-related breathing disorders.
        Chest. 2010; 137: 1449-1463
        • Krakow B.
        • Ulibarri V.A.
        • Romero E.A.
        • McIver N.D.
        A two-year prospective study on the frequency and co-occurrence of insomnia and sleep-disordered breathing symptoms in a primary care population.
        Sleep Med. 2013; 14: 814-823
        • Luyster F.S.
        • Buysse D.J.
        • Strollo Jr., P.J.
        Comorbid insomnia and obstructive sleep apnea: challenges for clinical practice and research.
        J Clin Sleep Med. 2010; 6: 196-204
        • Benetó A.
        • Gomez-Siurana E.
        • Rubio-Sanchez P.
        Comorbidity between sleep apnea and insomnia.
        Sleep Med Rev. 2009; 13: 287-293
        • Lichstein K.L.
        • Riedel B.W.
        • Lester K.W.
        • Aguillard R.N.
        Occult sleep apnea in a recruited sample of older adults with insomnia.
        J Consult Clin Psychol. 1999; 67: 405-410
        • Fung C.H.
        • Martin J.L.
        • Dzierzewski J.M.
        • et al.
        Prevalence and symptoms of occult sleep disordered breathing among older veterans with insomnia.
        J Clin Sleep Med. 2013; 9: 1173-1178
        • Krakow B.
        • Melendrez D.
        • Pedersen B.
        • et al.
        Complex insomnia: insomnia and sleep-disordered breathing in a consecutive series of crime victims with nightmares and PTSD.
        Biol Psychiatry. 2001; 49: 948-953
        • Krakow B.
        • Ulibarri V.A.
        • Romero E.A.
        Patients with treatment-resistant insomnia taking nightly prescription medications for sleep: a retrospective assessment of diagnostic and treatment variables.
        Prim Care Companion J Clin Psychiatry. 2010; 12
        • Krakow B.
        • Ulibarri V.A.
        • Romero E.
        Persistent insomnia in chronic hypnotic users presenting to a sleep medical center: a retrospective chart review of 137 consecutive patients.
        J Nerv Ment Dis. 2010; 198: 734-741
        • Stone K.C.
        • Taylor D.J.
        • McCrae C.S.
        • Kalsekar A.
        • Lichstein K.L.
        Nonrestorative sleep.
        Sleep Med Rev. 2008; 12: 275-288
        • Sateia M.J.
        • Doghramji K.
        • Hauri P.J.
        • Morin C.M.
        Evaluation of chronic insomnia: an American Academy of Sleep Medicine review.
        Sleep. 2000; 23: 243-308
        • Kripke D.F.
        Who should sponsor sleep disorders pharmaceutical trials?.
        J Clin Sleep Med. 2007; 3: 671-673
        • Netzer N.C.
        • Stoohs R.A.
        • Netzer C.M.
        • Clark K.
        • Strohl K.P.
        Using the Berlin Questionnaire to identify patients at risk for the sleep apnea syndrome.
        Ann Intern Med. 1999; 131: 485-491
        • Chung K.F.
        Insomnia subtypes and their relationships to daytime sleepiness in patients with obstructive sleep apnea.
        Respiration. 2005; 72: 460-465
        • Krakow B.
        • Ulibarri V.A.
        Prevalence of sleep breathing complaints reported by treatment-seeking chronic insomnia disorder patients on presentation to a sleep medical center: a preliminary report.
        Sleep Breath. 2013; 17: 317-322
        • Bastien C.H.
        • Vallières A.
        • Morin C.M.
        Validation of the Insomnia Severity Index as an outcome measure for insomnia research.
        Sleep Med. 2001; 2: 297-307
        • Guilleminault C.
        • Eldridge F.L.
        • Dement W.C.
        Insomnia with sleep apnea: a new syndrome.
        Science. 1973; 181: 856-858
        • Guilleminault C.
        • Eldridge F.L.
        • Phillips J.R.
        • Dement W.C.
        Two occult causes of insomnia and their therapeutic problems.
        Arch Gen Psychiatry. 1976; 33: 1241-1245
      2. Sleep-related breathing disorders in adults: recommendations for syndrome definition and measurement techniques in clinical research; the report of an American Academy of Sleep Medicine task force.
        Sleep. 1999; 22: 667-689
        • Ong J.C.
        • Gress J.L.
        • Pedro-Salcedo M.G.
        • Manber R.
        Frequency and predictors of obstructive sleep apnea among individuals with major depressive disorder and insomnia.
        J Psychosom Res. 2009; 67: 135-141
        • Gooneratne N.S.
        • Gehrman P.R.
        • Nkwuo J.E.
        • et al.
        Consequences of comorbid insomnia symptoms and sleep-related breathing disorder in elderly subjects.
        Arch Intern Med. 2006; 166: 1732-1738
        • Krakow B.
        • Romero E.
        • Ulibarri V.A.
        • Kikta S.
        Prospective assessment of nocturnal awakenings in a case series of treatment-seeking chronic insomnia patients: a pilot study of subjective and objective causes.
        Sleep. 2012; 35: 1685-1692
        • Guilleminault C.
        • Palombini L.
        • Poyares D.
        • Chowdhuri S.
        Chronic insomnia, postmenopausal women, and sleep disordered breathing: part 1. Frequency of sleep disordered breathing in a cohort.
        J Psychosom Res. 2002; 53: 611-615
        • Guilleminault C.
        • Palombini L.
        • Poyares D.
        • Chowdhuri S.
        Chronic insomnia, premenopausal women and sleep disordered breathing, part 2: comparison of nondrug treatment trials in normal breathing and UARS post menopausal women complaining of chronic insomnia.
        J Psychosom Res. 2002; 53: 617-623
        • Iber C.
        • Ancoli-Israel S.
        • Chesson Jr., A.L.
        • Quan S.F.
        • American Academy of Sleep Medicine
        The AASM Manual for the Scoring of Sleep and Associated Events: Rules, Terminology and Technical Specifications.
        American Academy of Sleep Medicine, Westchester, IL2007
        • Collop N.
        I don't sleep because I can't breathe.
        Sleep Med. 2013; 14 ([editorial]): 807
        • Krakow B.
        • Melendrez D.
        • Warner T.D.
        • et al.
        Signs and symptoms of sleep-disordered breathing in trauma survivors: a matched comparison with classic sleep apnea patients.
        J Nerv Ment Dis. 2006; 194: 433-439
        • Heinzer R.C.
        • White D.P.
        • Jordan A.S.
        • et al.
        Trazodone increases arousal threshold in obstructive sleep apnoea.
        Eur Respir J. 2008; 31: 1308-1312
        • Guilleminault C.
        Benzodiazepines, breathing, and sleep.
        Am J Med. 1990; 88: 25S-28S
        • Kao C.H.
        • Sun L.M.
        • Liang J.A.
        • Chang S.N.
        • Sung F.C.
        • Muo C.H.
        Relationship of zolpidem and cancer risk: a Taiwanese population-based cohort study.
        Mayo Clin Proc. 2012; 87 ([published correction appears in Mayo Clin Proc. 2012;87(7):704]): 430-436
        • Phillips B.A.
        Insomnia, hypnotic drug use, and patient well-being: first, do no harm.
        Mayo Clin Proc. 2012; 87 ([editorial]): 417-418
        • Kushida C.A.
        • Littner M.R.
        • Morgenthaler T.
        • et al.
        Practice parameters for the indications for polysomnography and related procedures: an update for 2005.
        Sleep. 2005; 28: 499-521
        • Park J.G.
        • Ramar K.
        • Olson E.J.
        Updates on definition, consequences, and management of obstructive sleep apnea.
        Mayo Clin Proc. 2011; 86: 549-554
      3. Qaseem A, Holty JE, Owens DK, Dallas P, Starkey M, Shekelle P; Clinical Guidelines Committee of the American College of Physicians. Management of obstructive sleep apnea in adults: a clinical practice guideline from the American College of Physicians [published online ahead of print September 24, 2013]. Ann Intern Med.

        • Simpson L.
        • Hillman D.R.
        • Cooper M.N.
        • et al.
        High prevalence of undiagnosed obstructive sleep apnoea in the general population and methods for screening for representative controls.
        Sleep Breath. 2013; 17: 967-973
        • Thornton J.D.
        • Chandriani K.
        • Thornton J.G.
        • et al.
        Assessing the prioritization of primary care referrals for polysomnograms.
        Sleep. 2010; 33: 1255-1260
        • Webber M.P.
        • Lee R.
        • Soo J.
        • et al.
        Prevalence and incidence of high risk for obstructive sleep apnea in World Trade Center-exposed rescue/recovery workers.
        Sleep Breath. 2011; 15: 283-294
        • Cass A.R.
        • Alonso W.J.
        • Islam J.
        • Weller S.C.
        Risk of obstructive sleep apnea in patients with type 2 diabetes mellitus.
        Fam Med. 2013; 45: 492-500
        • Forrest C.B.
        • Nutting P.A.
        • von Schrader S.
        • Rohde C.
        • Starfield B.
        Primary care physician specialty referral decision making: patient, physician, and health care system determinants.
        Med Decis Making. 2006; 26: 76-85
        • Forrest C.B.
        • Shadmi E.
        • Nutting P.A.
        • Starfield B.
        Specialty referral completion among primary care patients: results from the ASPN Referral Study.
        Ann Fam Med. 2007; 5: 361-367
        • Lichstein K.L.
        • Thomas S.J.
        • Woosley J.A.
        • Geyer J.D.
        Co-occurring insomnia and obstructive sleep apnea.
        Sleep Med. 2013; 14: 824-829
        • Kendzerska T.
        • Mollayeva T.
        • Gershon A.S.
        • Leung R.S.
        • Hawker G.
        • Tomlinson G.
        Untreated obstructive sleep apnea and the risk for serious long-term adverse outcomes: a systematic review.
        Sleep Med Rev. 2014; 18: 49-59
        • Lévy P.
        • Pepin J.L.
        • McNicholas W.T.
        Should all sleep apnoea patients be treated? yes.
        Sleep Med Rev. 2002; 6: 17-26
        • Young T.
        • Finn L.
        • Peppard P.E.
        • et al.
        Sleep disordered breathing and mortality: eighteen-year follow-up of the Wisconsin sleep cohort.
        Sleep. 2008; 31: 1071-1078
        • Guilleminault C.
        • Stoohs R.
        • Kim Y.D.
        • Chervin R.
        • Black J.
        • Clerk A.
        Upper airway sleep-disordered breathing in women.
        Ann Intern Med. 1995; 122: 493-501
        • Krakow B.
        • Melendrez D.
        • Lee S.A.
        • Warner T.D.
        • Clark J.O.
        • Sklar D.
        Refractory insomnia and sleep-disordered breathing: a pilot study.
        Sleep Breath. 2004; 8: 15-29
        • Guilleminault C.
        • Davis K.
        • Huynh N.T.
        Prospective randomized study of patients with insomnia and mild sleep disordered breathing.
        Sleep. 2008; 31: 1527-1533
        • Krakow B.
        • Lowry C.
        • Germain A.
        • et al.
        A retrospective study on improvements in nightmares and post-traumatic stress disorder following treatment for co-morbid sleep-disordered breathing.
        J Psychosom Res. 2000; 49: 291-298
        • Krakow B.
        • Melendrez D.
        • Sisley B.
        • Warner T.D.
        • Krakow J.
        Nasal dilator strip therapy for chronic sleep maintenance insomnia: a case series.
        Sleep Breath. 2004; 8: 133-140
        • Guilleminault C.
        • Kirisoglu C.
        • Poyares D.
        • et al.
        Upper airway resistance syndrome: a long-term outcome study.
        J Psychiatr Res. 2006; 40: 273-279
        • Krakow B.
        • Ulibarri V.A.
        • Romero E.
        • Thomas R.J.
        • McIver N.
        Adaptive servo-ventilation therapy in a case series of patients with co-morbid insomnia and sleep apnea.
        J Sleep Disord Treat Care. 2013; 2: 1-10
        • Björnsdóttir E.
        • Janson C.
        • Sigurdsson J.F.
        • et al.
        Symptoms of insomnia among patients with obstructive sleep apnea before and after two years of positive airway pressure treatment.
        Sleep. 2013; 36: 1901-1909
        • Kushida C.A.
        • Littner M.R.
        • Hirshkowitz M.
        • et al.
        Practice parameters for the use of continuous and bilevel positive airway pressure devices to treat adult patients with sleep-related breathing disorders.
        Sleep. 2006; 29: 375-380