Movement Termination of Slow-Wave Sleep-A Potential Biomarker?

The duration of slow-wave sleep (SWS) is related to the reported sleep quality and to the important variables of mental and physical health. The internal cues to end an episode of SWS are poorly understood. One such internal cue is the initiation of a body movement, which is detectable as electromyographic (EMG) activity in sleep-electroencephalography (EEG). In the present study, we characterized the termination of SWS episodes by movement to explore its potential as a biomarker. To this end, we characterized the relation between the occurrence of SWS termination by movement and individual characteristics (age, sex), SWS duration and spectral content, chronotype, depression, medication, overnight memory performance, and, as a potential neurological application, epilepsy. We analyzed 94 full-night EEG-EMG recordings (75/94 had confirmed epilepsy) in the video-EEG monitoring unit of the EpiCARE Centre Salzburg, Austria. Segments of SWS were counted and rated for their termination by movement or not through the visual inspection of continuous EEG and EMG recordings. Multiple linear regression was used to predict the number of SWS episodes that ended with movement by depression, chronotype, type of epilepsy (focal, generalized, no epilepsy, unclear), medication, gender, total duration of SWS, occurrence of seizures during the night, occurrence of tonic-clonic seizures during the night, and SWS frequency spectra. Furthermore, we assessed whether SWS movement termination was related to overnight memory retention. According to multiple linear regression, patients with overall longer SWS experienced more SWS episodes that ended with movement (t = 5.64; p = 0.001). No other variable was related to the proportion of SWS that ended with movement, including no epilepsy-related variable. A small sample (n = 4) of patients taking Sertraline experienced no SWS that ended with movement, which was significant compared to all other patients (t = 8.00; p < 0.001) and to n = 35 patients who did not take any medication (t = 4.22; p < 0.001). While this result was based on a small subsample and must be interpreted with caution, it warrants replication in a larger sample with and without seizures to further elucidate the role of the movement termination of SWS and its potential to serve as a biomarker for sleep continuity and for medication effects on sleep.

Co-prescribing of opioids and benzodiazepines/Z-drugs associated with all-cause mortality-A population-based longitudinal study in primary care with weak opioids most commonly prescribed.

Introduction: The risk of mortality associated with the co-prescribing of benzodiazepines and opioids has been explored in a number of papers mainly focusing on strong opioids. The mortality risk associated with the use of weak opioids has not been dealt with to a similar extent. Objective: To assess the mortality risk in primary care patients with consistent 3-year co-prescribing of benzodiazepine/Z-drugs (benzodiazepine receptor modulators) and mainly weak opioids (codeine, tramadol). Methods: Of 221,804 patients contacting the primary healthcare centres, 124,436 were selected for further analysis, 88,832 participants fulfilled the inclusion criteria, aged 10-69 years and were divided into four groups with neither any use of benzodiazepines/Z-drugs nor opioids as Group 1, 3 years' use of opioids and no/minimal benzodiazepines/Z-drugs as Group 2, with benzodiazepines/Z-drugs and no/minimal opioids as Group 3, and finally both benzodiazepines/Z-drugs and opioids as Group 4. Hazard ratios were calculated with the no-drug group as a reference, using Cox proportional hazards regression model adjusted for age, sex, number of chronic conditions and cancer patients excluded (n = 87,314). Results: Hazard ratios for mortality increased both in Group 3 where it was 2.66 (95% CI 2.25-3.09) and in Group 4 where it was 5.12 (95% CI 4.25-6.17), with increased dose and higher number of chronic conditions. In Group 4 an opioid dose-dependent increase in mortality among persons using >1000 DDDs benzodiazepines/Z-drugs was observed when those on less than ≤300 DDDs of opioids with HR 4.94 (95% CI 3.54-6.88) were compared to those on >300 DDDs with HR 7.61/95% CI 6.08-9.55). This increase in mortality was not observed among patients on <1000 DDDs of benzodiazepines/Z-drugs. Conclusion: The study supports evidence suggesting that mortality increases in a dose-dependent manner in patients co-prescribed benzodiazepines/Z-drugs and weak opioids (codeine, tramadol). An association between the number of chronic conditions and a rise in mortality was found. Long-term use of these drugs should preferably be avoided. Non-pharmacological therapy should be seriously considered instead of long-term use of benzodiazepines/Z-drugs, and deprescribing implemented for chronic users of these drugs when possible.

Association between prescription of hypnotics/anxiolytics and mortality in multimorbid and non-multimorbid patients: a longitudinal cohort study in primary care.

OBJECTIVES: To assess the risk of mortality in primary care patients, multimorbid (≥2 chronic conditions) or not, prescribed hypnotics/anxiolytics. DESIGN: A longitudinal cohort study SETTING: Primary healthcare in the Reykjavik area. PARTICIPANTS: 114 084 individuals (aged 10-79 years, average 38.5, SD 18.4) contacting general practitioners during 2009-2012 (mortality follow-up to 31 December 2016). Of those, the reference group comprised 58 560 persons who were neither multimorbid nor had redeemed prescriptions for hypnotics/anxiolytics. Participants (16 108) redeeming prescriptions for hypnotics/anxiolytics on a regular basis for 3 consecutive years were considered as consistent, long-term users. They were subdivided into low-dose (1-300 defined daily doses (DDD)/3 years), medium-dose (301-1095 DDDs/3 years) and high-dose users (>1095 DDDs/3 years). All six groups taking these drugs were compared with the reference group. MAIN OUTCOME MEASURES: All-cause mortality. RESULTS: HRs were calculated with the no multimorbidity-no drug group as a reference, using Cox proportional hazards regression model adjusting for age, sex and the number of chronic conditions (n=111 767), patients with cancer excluded. During follow-up, 516 358 person-years in total, 1926 persons died. Mean follow-up was 1685 days (4.6 years), range 1-1826 days (5.0 years). For all multimorbid patients who took no drugs the HR was 1.14 (95% CI 1.00 to 1.30) compared with those without multimorbidity. HRs in the non-multimorbid participants varied from 1.49 to 3.35 (95% CI ranging from 1.03 to 4.11) with increasing doses of hypnotics/anxiolytics, and correspondingly from 1.55 to 3.52 (1.18 to 4.29) in multimorbid patients. CONCLUSIONS: Mortality increased in a dose-dependent manner among both multimorbid and non-multimorbid patients taking hypnotics/anxiolytics. This increase was clearly associated with prescribing of these drugs. Their use should be limited to the recommended period of 2-4 up to 6 weeks; long-term use may incur increased risk and should be re-examined.