Prospective Randomized Controlled Trial on the Efficacy of Continuous Positive Airway Pressure and Adaptive Servo-Ventilation in the Treatment of Chronic Complex Insomnia

Abstract

Background: Complex insomnia, the comorbidity of chronic insomnia and obstructive sleep apnea (OSA), is a common sleep disorder, but the OSA component, whether presenting overtly or covertly, often goes unsuspected and undiagnosed due to a low index of suspicion. Among complex insomniacs, preliminary evidence demonstrates standard CPAP decreases insomnia severity. However, CPAP causes expiratory pressure intolerance or iatrogenic central apneas that may diminish its use. An advanced PAP mode-adaptive servo-ventilation (ASV)-may alleviate CPAP side-effects and yield superior outcomes.

Methods: In a single-site protocol investigating covert complex insomnia (ClinicalTrials.gov identifier: NCT02365064), a low index of suspicion for this comorbidity was confirmed by exclusion of 455 of 660 eligible patients who presented during the study period with overt OSA signs and symptoms. Ultimately, stringent inclusion/exclusion criteria to test efficacy yielded 40 adult, covert complex insomnia patients [average Insomnia Severity Index (ISI) moderate-severe 19.30 (95% CI 18.42-20.17)] who reported no definitive OSA symptoms or risks and who failed behavioral or drug therapy for an average of one decade. All 40 were diagnosed with OSA and randomized (using block randomization) to a single-blind, prospective protocol, comparing CPAP (n = 21) and ASV (n = 19). Three successive PAP titrations fine-tuned pressure settings, facilitated greater PAP use, and collected objective sleep and breathing data. Patients received 14 weeks of treatment including intensive biweekly coaching and follow-up to foster regular PAP use in order to accurately measure efficaciousness. Primary outcomes measured insomnia severity and sleep quality. Secondary outcomes measured daytime impact: OSA-induced impairment, fatigue severity, insomnia impairment, and quality of life. Performance on these seven variables was assessed using repeated measures ANCOVA to account for the multiple biweekly time points.

Findings: At intake, OSA diagnosis and OSA as a cause for insomnia were denied by all 40 patients, yet PAP significantly decreased insomnia severity scores (p = 0.021 in the primary ANCOVA analysis). To quantify effect sizes, mean intake vs endpoint analysis was conducted with ASV yielding nearly twice the effects of CPAP [- 13.2 (10.7-15.7), Hedges' g = 2.50 vs - 9.3 (6.3-12.3), g = 1.39], and between mode effect size was in the medium-large range 0.65. Clinically, ASV led to remission (ISI < 8) in 68% of cases compared to 24% on CPAP [Fisher's exact p = 0.010]. Two sleep quality measures in the ANCOVA analysis again demonstrated superior significant effects for ASV compared to CPAP (both p < 0.03), and pre- and post-analysis demonstrated substantial effects for both scales [ASV (g = 1.42; g = 1.81) over CPAP (g = 1.04; g = 0.75)] with medium size effects between modes (0.54, 0.51). Measures of impairment, residual objective sleep breathing events, and normalized breathing periods consistently demonstrated larger beneficial effects for ASV over CPAP.

Interpretation: PAP therapy was highly efficacious in decreasing insomnia severity in chronic insomnia patients with previously undiagnosed co-morbid OSA. ASV proved superior to CPAP in this first efficacy trial to compare advanced to traditional PAP modes in complex insomnia. Future research must determine the following: pathophysiological mechanisms to explain how OSA causes chronic insomnia; general population prevalence of this comorbidity; and, cost-effectiveness of ASV therapy in complex insomnia. Last, efforts to raise awareness of complex insomnia are urgently needed as patients and providers appear to disregard both overt and covert signs and symptoms of OSA in the assessment of chronic insomnia.

Keywords: Adaptive servo-ventilation; Apnea; Complex insomnia; Continuous positive airway pressure; Efficacy trial; Hypopnea; Insomnia; Obstructive sleep apnea; Respiratory effort-related arousals; Sleep fragmentation; Sleep quality; Upper airway resistance syndrome.

Conflict of interest statement

Authors NDM, VAU, JK, and RMS report grants from ResMed Sciences during the conduct of the study. Additionally, author JK is the CEO of the commercial sleep center, Maimonides Sleep Arts & Sciences, where the study was conducted in part; Barry and Jessica Krakow are married. Author BK reports: 6 main activities related to his work in sleep medicine. For websites, Dr. Krakow owns and operates 6 sites that provide education and offer products and services for sleep disorders patients: www.nightmaretreatment.com, www.ptsdsleepclinic.com, www.sleeptreatment.com, www.sleepdynamictherapy.com, www.soundsleepsoundmind.com, and www.nocturiacures.com. For other professional services, he is the medical director of a national DME company Classic SleepCare for which his sole functions are consultation and QA; he has neither patient encounters nor does he benefit from the sale of any DME equipment. For intellectual property, Dr. Krakow markets and sells 3 books for sleep disorders patients: Insomnia Cures, Turning Nightmares into Dreams, and Sound Sleep, Sound Mind. For clinical services, he owns and operates one commercial sleep center: Maimonides Sleep Arts & Sciences, Ltd. For educational and consulting services: Dr. Krakow conducts CME/CEU educational programs for medical and mental health providers to learn about sleep disorders. Sometimes these programs involve the attendee paying a fee directly to Maimonides Sleep Arts & Sciences. Other times, he conducts the workshops at other locations, which may be paid for by vendors such as Respironics and ResMed or other institutions such as the AMEDDC&S, VAMC, and regional sleep center conferences. He is also president and principal investigator of a non-profit sleep research center, the Sleep & Human Health Institute (www.sleepingresearch.org, www.shhi.org) that occasionally provides consultation services or receives grants for pilot studies, the most recent: ResMed ~$400,000 January 2015 (funding for this randomized control trial of treatment in insomnia patients). Recently, and after this research had been conducted, he provided a brief consultation to ASOCorp, a medical supply company that manufactures nasal strips.

Figures

Fig. 1

Flowchart showing a) eligibility and final sample of chronic insomnia disorder patients presenting with chief complaint of chronic psychophysiological insomnia attributed to behavioral, psychological, psychiatric, and environmental factors, and b) excluded patients' details. Abbreviations: ISI — Insomnia Severity Index; ITT — intent to treat; Dx — diagnosis; BMI — body mass index; ESS — Epworth Sleepiness Scale; PSG — Polysomnography Sleep Test; Rx — prescription; OSA — obstructive sleep apnea; UARS — upper airway resistance syndrome; ASV — adaptive servo-ventilation; CPAP — continuous positive airway pressure; RLS — restless leg syndrome; PLMD — periodic limb movement disorder. Footnote: aChronic insomnia disorder as defined by the AASM: chief complaint of insomnia, ISI ≥ 15, impairment due to insomnia, and duration of at least 6 months. bRandomization reset halfway through sample collection due to exclusion of ASV participants secondary to disproportionate leg movement disorders in this group. cWithdrawn patients after randomization and completion of first exposure to PAP treatment; chose not to pursue research without offering explanation. dIntercurrent medical/psychiatric patients developed medical or psychiatric issues that required immediate attention and subsequent removal from the study due to treatment plan. eFinal ITT included all eligible randomized patients, total n = 61. fThe 17 exclusions were eligible for the study and completed the informed consent and randomization process. However, during a titration study they exhibited independent RLS/PLMD and were excluded as post-randomization exclusions. gUnable/unwilling: patients with scheduling conflicts or no interest in participation; comorbidities/urgent care required: patients with multiple health issues that may have confounded research or patients who needed immediate treatment of their sleep-disordered breathing; unstable Rx dose: patients working with doctors to titrate medication dosage; no diagnosis of OSA: did not meet requirements for OSA/UARS.

Fig. 2

Protocol timeline: patient pathway from referral through study exit. Abbreviations: MSAS — Maimonides Sleep Arts & Sciences; OSA — obstructive sleep apnea; UARS — upper airway resistance syndrome; PSG — Polysomnography Sleep Test; ISI — Insomnia Severity Index; ESS — Epworth Sleepiness Scale; III — Insomnia Impairment Index; FSS — Fatigue Severity Scale; FOSQ-10 — Functional Outcomes of Sleep Questionnaire Short Form; QLESQ — Quality of Life Enjoyment and Satisfaction Questionnaire Summary; DxPSG — Diagnostic Polysomnography Sleep Test; MD — medical director; CPAP — continuous positive airway pressure; ASV — adaptive servo-ventilation; SQ-Lik — sleep quality (Likert scale); SQ-Pct — sleep quality (percent scale); ODD — objective data download. Footnote: aIntake included ISI, ESS, III, FSS, FOSQ-10, QLESQ. Potentially eligible patients were informed “the protocol does not involve drugs, placebos or deception; it is a randomized controlled trial of two different techniques to treat chronic insomnia,” but no further details were provided about treatment. bOnline sleep diary completed daily via home computer or smart phone throughout the study and included two questions regarding subjective sleep quality, SQ-Lik and SQ-Pct, as well as subjective sleep indices. Pre-treatment sleep diary completed for 7 consecutive days prior to first titration. cPatients encouraged to use PAP nightly; the protocol was designed for patients to quickly attain or approach standard PAP compliance metrics to ensure final results would measure efficacy among two samples of regular users. Adaptation to CPAP and ASV may follow different courses, because CPAP users must contend with EPI and central apneas from the outset; whereas ASV patients may experience immediate alleviation of EPI as well as fewer or no central apneas. However, ASV patients may struggle with the constant auto-adjusting changes embedded within this technology, which makes some individuals feel as if they are losing control over their breathing. dCompletion of protocol granted patient ownership of the PAP device and transportation reimbursement ($85).

Fig. 3

Categories of failed a) all insomnia treatments and b) pharmacologic insomnia treatments at intake. Abbreviations: OTC — over the counter; CBT — cognitive-behavioral therapy; SSRI — selective serotonin reuptake inhibitor; SSNRI — selective serotonin and norepinephrine reuptake inhibitor. Footnote: aPatients suffered from insomnia for an average of 10 years and reported multiple attempts at insomnia treatment [mean 4.48 (3.61–5.34)]. bOTC supplements and herbal remedies. cEducation from books, articles, magazines, etc. dCBT does not refer to CBT-I. No patient was introduced to or attempted CBT-I. eMeditation, acupuncture, other alternative therapies. fBenzo: lorazepam, alprazolam, clonazepam, triazolam, temazepam; SSRI & SSNRI: sertraline, escitalopram, fluoxetine, duloxetine, paroxetine; OTC supplement: melatonin, 5-htp; Sedating anti-depressant: mirtazapine, doxepin, trazodone; Z drug: eszopiclone, zolpidem; Gaba agonist: gabapentin; Antihistamine: diphenhydramine, chlorpheniramine, doxylamine; Muscle relaxant: baclofen, chlorzoxazone; Illicit drugs: tetrahydrocannabinol (THC).

Fig. 4

Improvement in (a) insomnia, (b, c) sleep quality, (d–f) daytime impairment, and (g) quality of life over 14 weeks of therapy by mode. a. Insomnia Severity Index (ISI) b. Sleep quality – Likert (SQ-Lik) c. Sleep quality – percent (SQ-Pct) d. Insomnia Impairment Index (III) e. Fatigue Severity Scale (FSS) f. Functional Outcomes of Sleep Questionnaire Short Form (FOSQ-10) g. Quality of Life Enjoyment and Satisfaction Questionnaire Summary Form (QLESQ) Estimated trajectories for primary outcomes of each mode are shown along with 95% confidence intervals for average scores at each time point. Overlap in the band indicates intersection of confidence intervals. (a) Average ISI scores for ASV patients drop below clinical threshold for insomnia (ISI = 8) by week 7 and statistical separation between modes occurred at week 11. (b) Mean SQ-Lik scores were consistently higher for ASV shortly after baseline, with statistically significant separation by the third week. (c) Mean SQ-Pct scores were consistently higher for ASV reaching nearly 80% at final follow-up with significant separation between the modes by the second week. (d) III mirrored the changes in ISI but significant separation between the modes did not occur until week 13. (e–g) No statistical separation between modes occurred, although there was a trend for between mode separation in QLESQ scores.

Fig. 5

Improvement in (a) Respiratory Effort-Related Arousal (RERA) Index, (b) percent Normal Sleep Breathing Time, and (c) Normal Sleep Breathing Time in minutes, over 14 weeks of therapy by mode. Estimated trajectories for outcomes of each mode are shown along with 95% confidence intervals for average scores at each time point. Overlap in the band indicates intersection of confidence intervals. (a) RERA index improved for the ASV group at first encounter with PAP therapy and remained low for the duration of the study whereas the CPAP group increased in RERA index at first encounter with PAP and then gradually decreased back to baseline RERA index. (b) Percent time with Normal Sleep Breathing improved at first encounter with PAP and remained relatively consistent for the remainder of the study with ASV demonstrating nearly 20% more time with normal sleep breathing throughout treatment. (c) Minutes spent with Normal Sleep Breathing improved for both groups at first encounter with PAP therapy and continued to improve for the ASV group.