Continuous positive airway pressure in cluster headache: A randomized, placebo-controlled, triple-blind, crossover study.

BACKGROUND: Oxygen inhalation aborts cluster headache attacks, and case reports show the effect of continuous positive airway pressure. The aim of this study was to investigate the prophylactic effect of continuous positive airway pressure in chronic cluster headache. METHODS: This was a randomized placebo-controlled triple-blind crossover study using active and sham continuous positive airway pressure treatment for chronic cluster headache. Patients entered a one month's baseline period before randomly being assigned to two months' active continuous positive airway pressure treatment followed by a four weeks' washout period and two months' sham continuous positive airway pressure or vice versa. Primary outcome measure was number of cluster headache attacks/week. RESULTS: Of the 30 included participants (12 males, median age 49.5 years, min-max 20-66 years), 25 completed both treatment/sham cycles (two discontinued, three lost to follow-up). The median number of cluster headache attacks per week was reduced from 8.25 (0.75-89.75) attacks to 6.25 (0-56.00) attacks for active continuous positive airway pressure and to 7.50 (0.50-43.75) attacks for sham continuous positive airway pressure, but there was no difference in active versus sham (p = 0.904). One patient had a serious adverse event during active treatment, none occurred during sham treatment. CONCLUSIONS: Continuous positive airway pressure treatment did not reduce the number of cluster headache attacks compared to sham treatment in chronic cluster headache patients. TRIAL REGISTRATION CLINICALTRIALS.GOV: NCT03397563.

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

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

Exercise and obstructive sleep apnoea: a 24-week follow-up study.

Objective: Report on long-term follow-up results in the apnoea hypopnea index (AHI) and self-reported daytime sleepiness in participants with moderate to severe obstructive sleep apnoea at 12 weeks after completion of a high-intensity exercise training or control intervention. Methods: Twenty-six participants with obstructive sleep apnoea (body mass index (BMI) 37 (36-39) kg/m, age 52 (49-55) years, apnoea-hypopnoea index 40.5 (31.3-50.2) events/hour), randomised to either 12 weeks of supervised high-intensity interval training (HIIT) (4×4 min of treadmill running or walking at 90%-95% of maximal heart rate) or no intervention (control), underwent a sleep evaluation follow-up 24 weeks after intervention initiation. Respiratory measures during sleep were registered at baseline, 12 weeks (postintervention) and 24 weeks (long-term follow-up). Results: At the 24-week follow-up, there were no statistically significant differences between the groups in the AHI (HIIT 30.7 (17.2-44.1) and control 38.7 (22.8-54.5) events/hour), Epworth score (HIIT 7.0 (4.7-9.3) and control 5.5 (3.9-7.0)), mean oxygen saturation (HIIT 93.2 (92.5-93.9) and control 92.0 (91.1-92.8)) or oxygen desaturation events (HIIT 32.9 (20.4-45.4) and control 44.3 (27.3-61.3) n/hour). BMI remained unchanged from the baseline in both groups. In the HIIT group, only two participants reported having continued with HIIT at 24 weeks. Conclusion: The effect of 12 weeks of supervised high-intensity exercise training on AHI and self-reported daytime sleepiness was lost at the 24-week follow-up.

Contact-free radar recordings of body movement can reflect ultradian dynamics of sleep.

This work aimed to evaluate if a contact-free radar sensor can be used to observe ultradian patterns in sleep physiology, by way of a data processing tool known as Locomotor Inactivity During Sleep (LIDS). LIDS was designed as a simple transformation of actigraphy recordings of wrist movement, meant to emphasise and enhance the contrast between movement and non-movement and to reveal patterns of low residual activity during sleep that correlate with ultradian REM/NREM cycles. We adapted the LIDS transformation for a radar that detects body movements without direct contact with the subject and applied it to a dataset of simultaneous recordings with polysomnography, actigraphy, and radar from healthy young adults (n = 12, four nights of polysomnography per participant). Radar and actigraphy-derived LIDS signals were highly correlated with each other (r > 0.84), and the LIDS signals were highly correlated with reduced-resolution polysomnographic hypnograms (rradars >0.80, ractigraph >0.76). Single-harmonic cosine models were fitted to LIDS signals and hypnograms; significant differences were not found between their amplitude, period, and phase parameters. Mixed model analysis revealed similar slopes of decline per cycle for radar-LIDS, actigraphy-LIDS, and hypnograms. Our results indicate that the LIDS technique can be adapted to work with contact-free radar measurements of body movement; it may also be generalisable to data from other body movement sensors. This novel metric could aid in improving sleep monitoring in clinical and real-life settings, by providing a simple and transparent way to study ultradian dynamics of sleep using nothing more than easily obtainable movement data.

Sleep restriction alters cortical inhibition in migraine: A transcranial magnetic stimulation study.

OBJECTIVE: Migraine is a primary headache disorder with a well-known association with insufficient sleep. However, both the underlying pathophysiology of the disease and the relationship with sleep is still unexplained. In this study, we apply transcranial magnetic stimulation to investigate possible mechanisms of insufficient sleep in migraine. METHODS: We used a randomised, blinded crossover design to examine 46 subjects with migraine during the interictal period and 29 healthy controls. Each subject underwent recordings of cortical silent period, short- and long-interval intracortical inhibition, intracortical facilitation and short-latency afferent inhibition after both two nights of habitual eight-hour sleep and two nights of restricted four-hour sleep. RESULTS: We found reduced cortical silent period duration after sleep restriction in interictal migraineurs compared to controls (p = 0.046). This effect was more pronounced for non-sleep related migraine (p = 0.002) and migraine with aura (p = 0.017). The sleep restriction effect was associated with ictal symptoms of hypersensitivity such as photophobia (p = 0.017) and overall silent period was associated with premonitory dopaminergic symptoms such as yawning (p = 0.034). CONCLUSIONS: Sleep restriction reduces GABAergic cortical inhibition during the interictal period in individuals with migraine. SIGNIFICANCE: Sleep related mechanisms appear to affect the pathophysiology of migraine and may differentiate between migraine subgroups.

Validation of questionnaires for restless legs syndrome in the general population: the Trøndelag Health Study (HUNT).

Questionnaires for restless legs syndrome have rarely been validated against face-to-face interviews in the general population. We aimed to validate the modified Norwegian, seven-item Cambridge-Hopkins restless legs syndrome questionnaire and a single diagnostic question for restless legs syndrome. We also aimed to stratify validity at 65 years of age. Among a random sample of 1,201 participants from the fourth wave of the Trøndelag Health Study, 232 (19%) agreed to participate, out of whom 221 had complete data for analyses. Participants completed the questionnaires for restless legs syndrome immediately before attending a face-to-face interview using the latest diagnostic criteria. We calculated sensitivity, specificity, and Cohen's kappa statistic (κ) of questionnaire- versus interview-based diagnoses. We found acceptable validity of the seven-item modified Cambridge-Hopkins diagnostic questionnaire for restless legs syndrome (κ = 0.37, 95% confidence interval [CI] 0.23-0.51) and good validity of the single diagnostic question (κ = 0.47, 95% CI 0.35-0.58). We also found good validity through the combination of modified Cambridge-Hopkins diagnostic questionnaire for restless legs syndrome items 2 and 5, while item 1 or 2 alone showed only acceptable validity. The single diagnostic question was significantly more valid among those aged <65 years (κ = 0.60 versus κ = 0.26). Both single- and two-item questionnaire-based diagnoses overestimated interview-based restless legs syndrome prevalence. The seven-item modified Cambridge-Hopkins diagnostic questionnaire for restless legs syndrome will be useful for epidemiological studies although low sensitivity may cause underestimation of true restless legs syndrome prevalence in the general population, especially among elderly. Brief questionnaire-based diagnoses of up to three items seem best utilised as an initial screen. Future studies should identify brief and even more valid questionnaire-based diagnoses for restless legs syndrome in order to estimate prevalence accurately in large epidemiological studies.

Pain thresholds and suprathreshold pain after sleep restriction in migraine - A blinded crossover study.

OBJECTIVE: There is an unexplained association between disturbed sleep and migraine. In this blinded crossover study, we investigate if experimental sleep restriction has a different effect on pain thresholds and suprathreshold pain in interictal migraineurs and controls. METHODS: Forearm heat pain thresholds and tolerance thresholds, and trapezius pressure pain thresholds and suprathreshold pain were measured in 39 interictal migraineurs and 31 healthy controls after two consecutive nights of partial sleep restriction and after habitual sleep. RESULTS: The effect of sleep restriction was not significantly different between interictal migraineurs and controls in the primary analyses. Pressure pain thresholds tended to be lower (i.e., increased pain sensitivity) after sleep restriction in interictal migraineurs compared to controls with a 48-hour preictal-interictal cut-off (p = 0.061). We found decreased pain thresholds after sleep restriction in two of seven migraine subgroup comparisons: heat pain thresholds decreased in migraineurs with lower pain intensity during attacks (p = 0.005) and pressure pain thresholds decreased in migraineurs with higher severity of photophobia during attacks (p = 0.031). Heat pain thresholds tended to decrease after sleep restriction in sleep-related migraine (p = 0.060). Sleep restriction did not affect suprathreshold pain measurements in either group. CONCLUSION: This study could not provide strong evidence for an increased effect of sleep restriction on pain sensitivity in migraineurs compared to healthy controls. There might be a slightly increased effect of sleep restriction in migraineurs, detectable using large samples or more pronounced in certain migraine subgroups.

Distinguishing sleep from wake with a radar sensor: a contact-free real-time sleep monitor.

This work aimed to evaluate whether a radar sensor can distinguish sleep from wakefulness in real time. The sensor detects body movements without direct physical contact with the subject and can be embedded in the roof of a hospital room for completely unobtrusive monitoring. We conducted simultaneous recordings with polysomnography, actigraphy, and radar on two groups: healthy young adults (n = 12, four nights per participant) and patients referred to a sleep examination (n = 28, one night per participant). We developed models for sleep/wake classification based on principles commonly used by actigraphy, including real-time models, and tested them on both datasets. We estimated a set of commonly reported sleep parameters from these data, including total-sleep-time, sleep-onset-latency, sleep-efficiency, and wake-after-sleep-onset, and evaluated the inter-method reliability of these estimates. Classification results were on-par with, or exceeding, those often seen for actigraphy. For real-time models in healthy young adults, accuracies were above 92%, sensitivities above 95%, specificities above 83%, and all Cohen's kappa values were above 0.81 compared to polysomnography. For patients referred to a sleep examination, accuracies were above 81%, sensitivities about 89%, specificities above 53%, and Cohen's kappa values above 0.44. Sleep variable estimates showed no significant intermethod bias, but the limits of agreement were quite wide for the group of patients referred to a sleep examination. Our results indicate that the radar has the potential to offer the benefits of contact-free real-time monitoring of sleep, both for in-patients and for ambulatory home monitoring.

The evening light environment in hospitals can be designed to produce less disruptive effects on the circadian system and improve sleep.

STUDY OBJECTIVES: Blue-depleted lighting reduces the disruptive effects of evening artificial light on the circadian system in laboratory experiments, but this has not yet been shown in naturalistic settings. The aim of the current study was to test the effects of residing in an evening blue-depleted light environment on melatonin levels, sleep, neurocognitive arousal, sleepiness, and potential side effects. METHODS: The study was undertaken in a new psychiatric hospital unit where dynamic light sources were installed. All light sources in all rooms were blue-depleted in one half of the unit between 06:30 pm and 07:00 am (melanopic lux range: 7-21, melanopic equivalent daylight illuminance [M-EDI] range: 6-19, photopic lux range: 55-124), whereas the other had standard lighting (melanopic lux range: 30-70, M-EDI range: 27-63, photopic lux range: 64-136), but was otherwise identical. A total of 12 healthy adults resided for 5 days in each light environment (LE) in a randomized cross-over trial. RESULTS: Melatonin levels were less suppressed in the blue-depleted LE (15%) compared with the normal LE (45%; p = 0.011). Dim light melatonin onset was phase-advanced more (1:20 h) after residing in the blue-depleted LE than after the normal LE (0:46 h; p = 0.008). Total sleep time was 8.1 min longer (p = 0.032), rapid eye movement sleep 13.9 min longer (p < 0.001), and neurocognitive arousal was lower (p = 0.042) in the blue-depleted LE. There were no significant differences in subjective sleepiness (p = 0.16) or side effects (p = 0.09). CONCLUSIONS: It is possible to create an evening LE that has an impact on the circadian system and sleep without serious side effects. This demonstrates the feasibility and potential benefits of designing buildings or hospital units according to chronobiological principles and provide a basis for studies in both nonclinical and clinical populations.

The short-term impact of methylprednisolone on patient-reported sleep in patients with advanced cancer in a randomized, placebo-controlled, double-blind trial.

PURPOSE: Although corticosteroids are frequently used in patients with advanced cancer, few studies have examined the impact of these drugs on patient-reported sleep. We aimed to examine the short-term impact of methylprednisolone on patient-reported sleep in patients with advanced cancer. METHODS: Patient-reported sleep was a predefined secondary outcome in a prospective, randomized, placebo-controlled, double-blind trial that evaluated the analgesic efficacy of corticosteroids in advanced cancer patients (18+), using opioids, and having pain ≥ 4 past 24 h (NRS 0-10). Patients were randomized to the methylprednisolone group with methylprednisolone 16 mg × 2/day or placebo for 7 days. The EORTC QLQ-C30 (0-100) and the Pittsburgh Sleep Quality Index questionnaire (PSQI) (0-21) were used to assess the impact of corticosteroids on sleep at baseline and at day 7. RESULTS: Fifty patients were randomized of which 25 were analyzed in the intervention group and 22 in the control group. Mean age was 64 years, mean Karnofsky performance status was 67 (SD 13.3), 51% were female, and the mean oral daily morphine equivalent dose was 223 mg (SD 222.77). Mean QLQ-C30 sleep score at baseline was 29.0 (SD 36.7) in the methylprednisolone group and 24.2 (SD 27.6) in the placebo group. At day 7, there was no difference between the groups on QLQ-C30 sleep score (methylprednisolone 20.3 (SD 32.9); placebo 28.8 (SD 33.0), p = 0.173). PSQI showed similar results. CONCLUSIONS: Methylprednisolone 16 mg twice daily for 7 days had no impact on patient-reported sleep in this cohort of patients with advanced cancer. TRIAL REGISTRATION: Clinical trial information NCT00676936 (13.05.2008).

Validation of insomnia questionnaires in the general population: The Nord-Trøndelag Health Study (HUNT).

The primary aim was to validate questionnaire-based insomnia diagnoses from a modified Karolinska Sleep Questionnaire (KSQ) and the Insomnia Severity Index (ISI), by age category (< or >65 years), against a semi-structured face-to-face interview. Secondary aims were to split validity by diagnostic certainty of the interview and to compare prevalence estimates of questionnaire- and interview-based diagnoses. A total of 232 out of 1,200 invited (19.3%) from the fourth Nord-Trøndelag Health Study (HUNT4) completed questionnaires, including the KSQ and ISI, shortly before attending a face-to-face diagnostic interview for insomnia based on the fifth edition of the Diagnostic and Statistical Manual of Mental Disorders (DSM-5). Both a tentative (DSM-5 criteria A-E) and a definite (criteria A-H) interview diagnosis was evaluated. Cohen's kappa statistic quantified questionnaire validity. In all, 33% (95% confidence interval 27-39%) of participants had definite insomnia: 40% of women and 21% of men. The ISI (cut-off 12) and several KSQ-based diagnoses showed very good validity (κ ≤0.74) against the tentative, versus good validity (κ ≤0.61) against the definite interview diagnosis. Short questionnaires, requiring a daytime symptom at least three times a week, may underestimate insomnia prevalence. Validity was consistently higher for persons aged below versus above 65 years (definite insomnia: κ ≤0.64 vs. κ ≤0.56). Our results have implications for epidemiological population-based studies utilising insomnia questionnaires.

Sleep Characteristics in Adults With and Without Chronic Musculoskeletal Pain: The Role of Mental Distress and Pain Catastrophizing.

OBJECTIVES: Sleep disturbance is associated with persistence and exacerbation of chronic pain. As this relationship seems to be bidirectional, factors underpinning sleep disturbance may prove important in multimodal rehabilitation approaches. The aim of this cross-sectional study was to examine the impact of psychological symptoms on subjective and objective sleep measures in patients with chronic musculoskeletal pain (CMP), as compared with pain-free controls. MATERIALS AND METHODS: Sleep was assessed by self-report questionnaires, actigraphy, and polysomnography recordings in 56 patients (75.0% female; M age=41.7 y, SD=10.8 y) with CMP and compared with 53 matched pain-free controls (71.7% female; M age=41.8 y, SD=10.7). Mental distress (Hopkins Symptoms Checklist [HSCL]) and Pain Catastrophizing Scale (PCS) were tested as predictors of objective and subjective sleep measures in multiple regression models, and their indirect effects were tested in bootstrapped mediation models. RESULTS: The sleep data revealed substantially more subjective sleep disturbance (Hedge g: 1.32 to 1.47, P<0.001), moderately worse sleep efficiency in the actigraphy measures (Hedges g: 0.5 to 0.6, P<0.01), and less polysomnography measured slow wave sleep (Hedges g: 0.43, P<0.05) in patients, as compared with controls. HSCL was strongly associated with the self-reported measures Insomnia Severity Index (ISI) and Pittsburgh Sleep Quality Index (PSQI). HSCL also partially explained the association between pain and sleep, but HSCL was not associated with any of the objective sleep measures. More pain catastrophizing was related to less slow wave sleep. DISCUSSION: The differences in subjective and objective sleep measures indicate that they probe different aspects of sleep functioning in patients with musculoskeletal pain, and their combined application may be valuable in clinical practice. Self-reported sleep disturbance seems to overlap with affective dimensions reflected by the HSCL questionnaire.

Sleep quality in hospitalized patients with advanced cancer: an observational study using self-reports of sleep and actigraphy.

PURPOSE: Although patients with advanced cancer report poor sleep quality, few studies have assessed sleep quality with a combination of subjective and objective measures. We aimed to examine sleep quality in hospitalized patients with advanced cancer by combining patient-reported outcome-measures (PROMs) and polysomnography (PSG) or actigraphy. METHODS: A one-night prospective observational study of sleep in hospitalized patients with metastatic cancer using WHO step III opioids was conducted. Total sleep time, sleep onset latency, number of awakenings, and wake after sleep onset were assessed by PROMs and actigraphy. Sleep quality was assessed by the Pittsburgh Sleep Quality Index (PSQI) (range; 0-21), where higher scores indicate worse sleep quality. RESULTS: Forty patients were monitored. Median age was 70, median oral morphine equivalent dose was 80 mg/24 h (10-1725), median Karnofsky Performance Score was 50 (20-90), and median time to death from inclusion was 38 days (4-319). Mean PSQI score was 6.5 (SD ± 3.4). PROMs and actigraphy of mean (SD) sleep onset latency were 46 (± 64) and 35 min (± 61), respectively, while mean time awake at night was 37 (± 35) and 40 min (± 21). PROMs and actigraphy differed on number of awakenings (mean 2 (± 1) vs. 24 (± 15), p Ë‚ 0.001). Bland-Altman plots showed large individual differences between PROMs and actigraphy. PSG was not feasible. CONCLUSIONS: PROMs and actigraphy documented poor sleep quality, but a lack of agreement across methods. The study demonstrates a need to improve assessment of sleep quality and treatment of sleep disturbance in hospitalized patients with advanced cancer near end of life.

Atypical event-related potentials revealed during the passive parts of a Go-NoGo task in autism spectrum disorder: a case-control study.

Background: The core features of autism spectrum disorder (ASD) are easily recognizable in non-structured clinical and real-life situations. The features are often difficult to capture in structured laboratory settings, and the results from tests do not necessarily reflect symptom severity. We investigated neurophysiological processing in the passive parts of a cued Go-NoGo task, using the active parts of the test as a comparator. Methods: Forty-nine adolescents diagnosed with ASD and 49 typically developing (TD) adolescents (age 12-21 years) were included. Daily life executive function was assessed with the Behavior Rating Inventory of Executive Function (BRIEF). We applied a visual cued Go-NoGo task and recorded event-related potentials (ERPs). We investigated occipital N1, a component related to early perception of visual stimuli, and P3a, a fronto-central component related to switching of attention, in the passive and active parts of the test. Results: During the passive parts, the ASD group had statistically significantly longer N1 latency (p < 0.001, Cohens d = 0.75) and enhanced amplitude of P3a (p = 0.002, Cohens d = 0.64) compared to the TD, while no significant differences were observed in the active parts. Both components correlated significantly with the Behavioral Regulation Index of the BRIEF (partial correlation r = 0.35, p = 0.003). Conclusion: Delayed N1 response, indicating altered visual perception, and enhanced P3a response, indicating increased neural activation related to attention allocation, were found during the passive parts of a Go-NoGo task in ASD participants. These abnormal ERP signals in the non-structured settings were associated with everyday executive function, suggesting that neurophysiolocal measures related to atypical control of alertness and "hyper-awareness" underlie daily life dysfunction in ASD. Assessments during passive settings have a potential to reveal core neurobiological substrates of ASD.

Sleep quality with WHO Step III opioid use for cancer pain.

OBJECTIVE: Sleep is often disturbed in patients with advanced cancer. There is limited knowledge about sleep in patients with cancer treated with strong opioids. This study examines sleep quality in patients with advanced cancer who are treated with a WHO Step III opioid for pain. METHODS: An international, multicentre, cross-sectional study with 604 adult patients with cancer pain using WHO Step III opioids. Sleep quality was assessed by the Pittsburgh Sleep Quality Index (PSQI) global score (range; 0-21; score >5 indicates poor sleep). PSQI includes sleep quality, sleep latency, sleep duration, sleep efficiency, sleep disturbances, use of sleep medications and daytime dysfunction. Pain and quality of life were assessed by Brief Pain Inventory and European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire Core30. RESULTS: The median age was 62 years, 42% were female, mean Karnofsky performance score (KPS) was 62.5 (±14.2) and mean oral daily morphine equivalent dose was 303 mg/24 hours (±543.8 mg). The mean PSQI global score was 8.8 (±4.2) (range 0-20). Seventy-eight per cent were poor sleepers. All PSQI components were affected, and 44% reported trouble sleeping caused by pain. In the multiple regression model, predictors of PSQI global scores were pain intensity, emotional function, constipation, financial difficulties and KPS (adjusted R2=0.21). CONCLUSION: The majority (78%) of these patients with cancer treated with Step III opioids experienced poor sleep quality. Pain intensity, emotional function, constipation, financial difficulties and KPS predicted poor PSQI global scores. The clinical implication is that healthcare personnel should routinely assess and treat sleep disturbance in patients with advanced cancer disease.

Zopiclone versus placebo for short-term treatment of insomnia in patients with advanced cancer: study protocol for a double-blind, randomized, placebo-controlled, clinical multicenter trial.

BACKGROUND: Despite the high prevalence of insomnia in patients with advanced cancer, there are no randomized controlled trials on pharmacological interventions for insomnia in this group of patients. A variety of pharmacological agents is recommended to manage sleep disturbance for insomnia in the general population, but their efficacy and safety in adults with advanced cancer are not established. Thus, there is a need to evaluate the effectiveness of medications for insomnia in order to improve the evidence in patients with advanced cancer. One of the most used sleep medications at present in patients with cancer is zopiclone. METHODS: This is a randomized, double-blind, placebo-controlled, parallel-group, multicenter trial. A total of 100 patients with metastatic cancer who report insomnia will be randomly allocated to zopiclone or placebo. The treatment duration with zopiclone/placebo is 6 consecutive nights. The primary endpoint is patient-reported sleep quality during the final study night (night 6) assessed on a numerical rating scale of 0-10, where 0 = Best sleep and 10 = Worst possible sleep. Secondary endpoints include the mean patient-reported total sleep time and sleep onset latency during the final study night (night 6). DISCUSSION: Results from this study on treatment of insomnia in advanced cancer will contribute to clinical decision-making and improve the treatment of sleep disturbance in this patient cohort. TRIAL REGISTRATION: ClinicalTrials.gov, NCT02807922 . Registered on 21 June 2016.