348 Absence of Withdrawal Symptoms and Rebound Insomnia Upon Discontinuation of Daridorexant in Patients with Insomnia

SLEEP ◽  
2021 ◽  
Vol 44 (Supplement_2) ◽  
pp. A139-A139
Author(s):  
Damien Leger ◽  
Ingo Fietze ◽  
Scott Pain ◽  
Dalma Seboek Kinter ◽  
Bruno Flamion ◽  
...  
Keyword(s):  
Sleep Onset ◽  
Sleep Time ◽  
Withdrawal Symptoms ◽  
Double Blind ◽  
Rebound Effects ◽  
Rebound Insomnia ◽  
Abrupt Discontinuation ◽  
Placebo Trial ◽  
Benzodiazepine Withdrawal ◽  
To Receive

Abstract Introduction Abrupt discontinuation of sleep medications in patients with insomnia often causes withdrawal symptoms and rebound insomnia. In a Phase 3 program evaluating efficacy and safety of daridorexant on sleep and daytime functioning in patients with insomnia during 3 months of treatment, the risks of withdrawal symptoms and rebound insomnia were evaluated at treatment cessation. Methods In two randomized, double-blind, 3-month trials, adult (18–64 years) and elderly (≥65) patients with insomnia were assigned (1:1:1) to receive oral daridorexant 25mg, 50mg or placebo (Trial-1, NCT03545191) or 10mg, 25mg or placebo (Trial-2, NCT03575104) every evening. Each trial included a 7-day, single-blind, placebo run-out period following double-blind treatment to evaluate withdrawal symptoms and rebound insomnia. Withdrawal effects were assessed by the change in Benzodiazepine Withdrawal Symptom Questionnaire (BWSQ) total score, from last assessment on double-blind treatment to end of placebo run-out, and occurrence of relevant adverse events (AEs). Rebound insomnia was assessed objectively by change in wake-after-sleep-onset (WASO) and latency-to-persistent sleep (LPS), from baseline to first night of placebo run-out, and by subjective total-sleep-time (sTST), from baseline to end of run-out (mean of 7-days). Analyses included all patients who received ≥1 dose of placebo run-out treatment (Trial-1: N=852; Trial-2: N=851). Results No increase in mean BSWQ score from last assessment on double-blind treatment to end of placebo run-out was reported (Trial-1: 25mg, -0.6±2.3; 50mg, -0.6±2.3; placebo, -0.7±2.3; Trial-2: 10mg, -0.5±2.6; 25mg, -0.4±1.9; placebo, -0.4±1.4). No patients had a BWSQ score >20 at end of run-out. No AEs suggestive of withdrawal symptoms were reported. Mean WASO and LPS values (min) decreased from baseline to placebo run-out (WASO Trial-1: 25mg, -8.6±55.5; 50mg, -2.5±52.4; placebo, -20.4±45.8; Trial-2: 10mg, -11.6±58.3; 25mg, -5.1±57.9; placebo, -26.2±53.5; LPS Trial-1: 25mg, -17.2±56.7; 50mg, -15.0±55.8; placebo, -27.8±47.2; Trial-2: 10mg, -17.3±67.2; 25mg, -10.3±67.3; placebo, -18.3±63.8) while sTST values (min) increased (Trial-1: 25mg, 43.3±53.8; 50mg, 42.9±59.6; placebo, 42.3±52.7; Trial-2: 10mg, 43.3±52.9; 25mg, 46.8±55.4; placebo, 42.3±53.8) indicating absence of rebound effects. Conclusion Treatment with daridorexant for up to 3-months was not associated with any evidence of drug withdrawal or rebound insomnia upon abrupt discontinuation, indicating no safety concerns for patients should treatment be stopped. Support (if any) Funded by Idorsia Pharmaceuticals Ltd.

347 Daridorexant is Safe and Improves Both Sleep and Daytime Functioning in Elderly Patients with Insomnia

SLEEP ◽  
2021 ◽  
Vol 44 (Supplement_2) ◽  
pp. A138-A139
Author(s):  
Ingo Fietze ◽  
Claudio Bassetti ◽  
David Mayleben ◽  
Alberto Gimona ◽  
Scott Pain ◽  
...  
Keyword(s):  
Sleep Onset ◽  
Symptom Burden ◽  
The Elderly ◽  
Sleep Time ◽  
Least Square ◽  
Double Blind ◽  
Daytime Functioning ◽  
Sleep Behavior ◽  
Safety Risks ◽  
Benzodiazepine Withdrawal

Abstract Introduction Insomnia affects elderly more than younger adults, and comorbidities more prevalent in elderly populations can add to symptom burden and reduce therapeutic options. Drugs that improve insomnia symptoms with limited safety risks are needed to treat this patient group. We report elderly subgroup analyses from a Phase-3 registration trial with daridorexant. Methods In this multi-center, double-blind trial (NCT03545191), adult (18–64y) and elderly (≥65y) patients with insomnia were randomized (1:1:1) to receive oral daridorexant 25mg, 50mg or placebo every evening for 3 months. Month 3 endpoints were: change from baseline in polysomnography-measured wake-after-sleep-onset (WASO) and latency-to-persistent-sleep (LPS) (both primary endpoints), subjective total sleep time (sTST), and daytime functioning (Insomnia Daytime Symptoms and Impacts Questionnaire [IDSIQ] – sleepiness domain; with a lower score indicating improved daytime functioning). Safety endpoints included treatment emergent adverse events (TEAE), AEs of special interest (AESI; symptoms related to excessive daytime sleepiness or complex sleep behavior, and suicidal ideation/self-injury) and withdrawal effects upon treatment cessation (assessed by the Benzodiazepine Withdrawal Symptom Questionnaire total score and relevant AEs). Results Of the 930 patients randomized, 364 (39.1%) were ≥65y: daridorexant 25mg (n=121), 50mg (n=121) and placebo (n=122). In this subgroup, at Month 3, the placebo-corrected least-square mean of change from baseline [95%CL] for daridorexant 25mg and 50mg were: WASO -17.0[-27.0,-7.0] and -19.6[-29.5,-9.7] mins; LPS -7.8[-15.2,-0.4] and -14.9[-22.3,-7.5] mins; sTST 18.7[4.1,33.2] and 30.6[16.1,45.2] mins; IDSIQ sleepiness domain -0.6[-2.2,0.9] and -2.6[-4.1,-1.0], all respectively. TEAEs were reported in 32.2%, 35.3%, and 31.1% of patients ≥65y in the 25mg, 50mg and placebo groups, respectively. Falls (n=1,1,4 for 25mg, 50mg, placebo, respectively) and dizziness (n=4,1,1), both of particular interest in elderly, were least frequent in the 50mg group. Compared to placebo, somnolence was as frequent for 50mg daridorexant (n=6,1,1) while fatigue was more frequent in both daridorexant groups (n=4,3,1); incidence did not appear dose-related. AESI, of mild intensity, were reported in 2 patients ≥65y (one in each daridorexant group). There was no evidence of withdrawal symptoms. Conclusion Daridorexant is efficacious in the elderly population for improvements in sleep and daytime functioning. No safety concerns in this vulnerable population were identified at either dose. Support (if any) Funded by Idorsia Pharmaceuticals Ltd.

A Controlled Trial of Dothiepin and Placebo in Treating Benzodiazepine Withdrawal Symptoms

1996 ◽  
Vol 168 (4) ◽  
pp. 457-461 ◽  
Author(s):  
Peter Tyrer ◽  
Brian Ferguson ◽  
Cosmo Hallström ◽  
Marian Michie ◽  
Stephen Tyrer ◽  
...  
Keyword(s):  
Tricyclic Antidepressants ◽  
Drug Withdrawal ◽  
Controlled Trial ◽  
Statistical Significance ◽  
Withdrawal Symptoms ◽  
Antidepressant Effect ◽  
Double Blind ◽  
Benzodiazepine Dependence ◽  
Benzodiazepine Withdrawal ◽  
To Receive

BackgroundThe possibility that treatment with tricyclic antidepressants, in the form of dothiepin, might attenuate benzodiazepine withdrawal symptoms was investigated in a double-blind trial.MethodEighty-seven non-depressed psychiatric out-patients with putative normal dose benzodiazepine dependence had their benzodiazepines reduced in stepwise amounts of 20% of the original dose for eight weeks. The patients were randomised to receive dothiepin (with dosage increasing to 150 mg/day) or placebo as an aid to withdrawal before benzodiazepine reduction and these drugs were taken for four further weeks before being stopped.ResultsFewer patients entered and completed the study than expected and a Type II error was possible in the results. Although there was some evidence of withdrawal symptoms being less marked in those patients allocated to dothiepin this was independent of any antidepressant effect as depression scores were lower in the placebo group in the early phase of withdrawal (P<0.01). Of those completing the study, greater satisfaction (P=0.03) was recorded by those who had received dothiepin; no other differences reached statistical significance.ConclusionsDothiepin (and by implication other tricyclic antidepressants) might have some value in reducing benzodiazepine withdrawal symptoms but does not aid drug withdrawal.

scholarly journals The Effects of Quetiapine on Craving and Withdrawal Symptoms in Methamphetamine Abuse: A Randomized, Double-Blind, Placebo-Controlled Trial

2020 ◽  
Vol 10 (4) ◽  
pp. 29374.1-29374.7
Author(s):  
Najme Sadat Javdan ◽  
◽  
Amir Ghaderi ◽  
Hamid Reza Banafshe ◽  
◽  
...  
Keyword(s):  
Controlled Trial ◽  
Withdrawal Symptoms ◽  
Chi Square ◽  
Double Blind ◽  
Methamphetamine Abuse ◽  
Beneficial Effects ◽  
Amphetamine Withdrawal ◽  
Significant Difference ◽  
Chi Square Test ◽  
To Receive

Background: Patients with Methamphetamine Abuse (MA) are susceptible to many complications like craving, and withdrawal symptoms. These trials were designed to evaluate the effect of quetiapine administration on craving and withdrawal symptoms in MA abuse. Methods: This trial was conducted on 60 people with MA abuse to receive either 100 mg quetiapine (n=30), or placebo (n=30) every day for 2 months. The Desire for Drug Questionnaire (DDQ) and Amphetamine Withdrawal Questionnaire (AWQ) scores were evaluated at baseline and after 2 months’ intervention. For data analysis, t test, and the Chi-square test were applied in SPSS v. 18. Results: Quetiapine significantly decreased DDQ (P=0.002) and AWQ symptoms (P=0.001) compared to the placebo. Furthermore, there was a significant difference among groups in terms of the frequency of negative urine tests (P<0.001). Conclusion: This trial showed that administration of quetiapine supplements for 2 months in individuals with MA abuse had beneficial effects on craving and withdrawal syndrome.

Efficacy of zolpidem in insomnia

1997 ◽  
Vol 12 (S1) ◽  
pp. 4S-14S ◽  
Author(s):  
RG Priest ◽  
MG Terzano ◽  
L Parrino ◽  
P Boyer
Keyword(s):  
Sleep Onset ◽  
Sleep Time ◽  
Term Treatment ◽  
Sleep Onset Latency ◽  
Short Term Treatment ◽  
Sleep Physiology ◽  
Abrupt Discontinuation ◽  
Sleep Parameters ◽  
Hypnotic Agent ◽  
Hypnotic Efficacy

SummaryThe efficacy of zolpidem, a non benzodiazepine hypnotic agent with a short elimination half life, was reviewed, analysing more than 50 international clinical trials published since 1986. The hypnotic activity of zolpidem has been explored in different patient populations including normal volunteers, general practice outpatients and psychiatric out- or in-patients with varying sleep disorders; both transient and chronic. Assessment methods used have included objective and subjective measures of hypnotic efficacy for different treatment durations, with results confirming that 10 mg is superior to placebo. Zolpidem was shown to be superior in most trials on sleep parameters such as total sleep time, sleep onset latency and nocturnal awakenings, but total REM sleep and REM latency were usually unmodified. Zolpidem maintained normal sleep physiology as demonstrated by the preservation of slow wave stages and no, or minimal, effects on sleep architecture after abrupt discontinuation. Consequently, 10 mg is the recommended dose for the short-term treatment of insomnia in the non-elderly; in elderly patients 5 mg has been shown to be effective at inducing sleep whilst giving an optimum safety profile.

Effect on Primary Sleep Disorders When Children With ADHD Are Administered Guanfacine Extended Release

2014 ◽  
Vol 22 (1) ◽  
pp. 14-24 ◽  
Author(s):  
Thomas A. Rugino
Keyword(s):  
Extended Release ◽  
Slow Wave Sleep ◽  
Sleep Problems ◽  
Sleep Onset ◽  
Sleep Time ◽  
Outcome Variable ◽  
Controlled Study ◽  
Double Blind ◽  
Children With Adhd ◽  
Time Awake

Objective: To evaluate children with ADHD and sleep problems with polysomnography (PSG) after guanfacine extended-release (GXR) administration. Method: Double-blind, randomized, placebo-controlled study was terminated early due to treatment-emergent concerns after enrolling 29 children aged 6 to 12 years. After >4 weeks dose adjustment and >1 week dose stabilization, 11 children received GXR and 16 controls underwent analyses with PSG. Results: Although GXR improved ADHD symptoms, the primary outcome variable, total sleep time, was shorter in contrast to placebo (−57.32, SD = 89.17 vs. +31.32, SD = 59.54 min, p = .005). Increased time awake after sleep onset per hour of sleep was the primary factor for the reduction. Although rapid eye movement (REM), non-REM, and N3/slow wave sleep times were reduced, these were proportional to the overall sleep reduction. Sedation was common with GXR (73% vs. 6%). Conclusion: Morning-administered GXR resulted in decreased sleep and may contribute to sedation.

A Double-Blind Placebo-Controlled Study of Buspirone in Diazepam Withdrawal in Chronic Benzodiazepine Users

1990 ◽  
Vol 157 (2) ◽  
pp. 232-238 ◽  
Author(s):  
C. H. Ashton ◽  
M. D. Rawlins ◽  
S. P. Tyrer
Keyword(s):  
Controlled Trial ◽  
Dropout Rate ◽  
Withdrawal Symptoms ◽  
Controlled Study ◽  
Double Blind ◽  
Double Blind Placebo ◽  
Diazepam Withdrawal ◽  
Benzodiazepine Withdrawal

A double-blind placebo-controlled trial of 23 chronic benzodiazepine users showed that overall, buspirone did not appear to be helpful in alleviating benzodiazepine withdrawal symptoms. Buspirone (5 mg t.d.s.) or placebo was administered for four weeks before, during and after diazepam withdrawal. Patients taking buspirone had a markedly higher dropout rate (seven out of 11) than those taking placebo (one out of 12). Mean daily diazepam dosage at entry was significantly higher in the buspirone group, but overall initial diazepam dosage was not related to outcome. Higher subjectively rated anxiety at the start of withdrawal was significantly related to higher dropout rate, irrespective of treatment, and was greater (although not significantly so) in the buspirone group.

scholarly journals Oxytocin Blocks Opioid Withdrawal Symptoms Only When Combined with Group Therapy: A Double-Blind, Randomized Controlled Clinical Trial

2020 ◽  
Vol 14 (3) ◽  
Author(s):  
Shahram Naderi ◽  
Nasim Vousooghi ◽  
Nahid Sadighii ◽  
Seyed Amir Hossein Batouli ◽  
Fahimeh Mirzaii ◽  
...  
Keyword(s):  
Clinical Trial ◽  
Group Therapy ◽  
Methadone Maintenance ◽  
Opioid Withdrawal ◽  
Withdrawal Symptoms ◽  
Controlled Clinical Trial ◽  
Opioid Substitution Therapy ◽  
Double Blind ◽  
Group Interactions ◽  
Abrupt Discontinuation

Background: Oxytocin is a well-known central nervous system mediator in social-related behaviors and stress management. Oxytocin has also been shown to prevent withdrawal symptoms of opioids in animal studies. Group interactions with emotion sharing have been shown to result in an increase in endogenous oxytocin. Although abrupt discontinuation of methadone in opioid substitution therapy is not routinely recommended, it might result in severe withdrawal symptoms and relapse in cases that there is a clinical justification for quitting methadone. Objectives: To evaluate and compare the role of oxytocin and group interactions, combined or independently, in abrupt discontinuation of methadone in methadone maintenance treatment (MMT) cases, where there had been a reasonable clinical judgment to cease medication. Methods: In a double-blind randomized clinical trial, four groups of participants who were on methadone treatment for more than six months received either oxytocin or placebo and marathon group therapy or routine group therapy upon abrupt discontinuation of methadone. The participants were monitored for opioid withdrawal symptoms, depression, and anxiety during a four-month follow-up program. The participants were also screened by urine tests for lapses. Results: Administration of oxytocin combined with marathon group activity, with highly emotional content, resulted in less craving (P < 0.000) and withdrawal symptoms (P < 0.000) compared to placebo and non-marathon group intervention in different combinations, irrespective of methadone dose and age. The same combination also resulted in continued participation in group therapy for a longer period (P < 0.000). Additionally, the same combination was effective in improving mental health, as measured by the Beck Anxiety (P < 0.002) and Beck depression (P < 0.014) inventories. Conclusions: In order to prevent methadone craving and withdrawal symptoms and sustained abstinence, group therapy with a highly emotional theme appears to be an essential factor for the manifestation of oxytocin effects in the brain.

scholarly journals Distinct effects of orexin receptor antagonist and GABAA agonist on sleep and physical/cognitive functions after forced awakening

2019 ◽  
Vol 116 (48) ◽  
pp. 24353-24358 ◽  
Author(s):  
Jaehoon Seol ◽  
Yuya Fujii ◽  
Insung Park ◽  
Yoko Suzuki ◽  
Fusae Kawana ◽  
...  
Keyword(s):  
Energy Expenditure ◽  
Receptor Antagonist ◽  
Cognitive Functions ◽  
Sleep Latency ◽  
Sleep Time ◽  
Double Blind ◽  
Significant Difference ◽  
Placebo Trial ◽  
Eyes Open ◽  
Male Subjects

The majority of patients with insomnia are treated with hypnotic agents. In the present study, we evaluated the side-effect profile of an orexin receptor antagonist and γ-aminobutyric acid A (GABAA) receptor agonist on physical/cognitive functions upon forced awakening. This double-blind, randomized, placebo-controlled, cross-over study was conducted on 30 healthy male subjects. Fifteen minutes before bedtime, the subjects took a pill of suvorexant (20 mg), brotizolam (0.25 mg), or placebo and were forced awake 90 min thereafter. Physical- and cognitive-function tests were performed before taking the pill, after forced awakening, and the next morning. Polysomnographic recordings revealed that the efficacies of the hypnotic agents in prolonging total sleep time (∼30 min) and increasing sleep efficiency (∼6%) were comparable. When the subjects were allowed to go back to sleep after the forced awakening, the sleep latency was shorter under the influence of hypnotic agents (∼2 min) compared to the placebo trial (24 min), and the rapid eye movement latency was significantly shorter under suvorexant (98.8, 81.7, and 48.8 min for placebo, brotizolam, and suvorexant, respectively). Although brotizolam significantly impaired the overall physical/cognitive performance (sum of z score) compared with placebo upon forced awakening, there was no significant difference in the total z score of performance between suvorexant and placebo. Notably, the score for static balance with the eyes open was higher under suvorexant compared to brotizolam administration. The energy expenditure was lower under suvorexant and brotizolam compared with the placebo. The effect size of brotizolam (d = 0.24) to reduce the energy expenditure was larger than that of suvorexant (d < 0.01).

scholarly journals Glucocorticoid Replacement Is Permissive for Rapid Eye Movement Sleep and Sleep Consolidation in Patients with Adrenal Insufficiency1

2000 ◽  
Vol 85 (11) ◽  
pp. 4201-4206
Author(s):  
Diego GarcÍa-Borreguero ◽  
Thomas A. Wehr ◽  
Oscar Larrosa ◽  
Juan J. Granizo ◽  
Donna Hardwick ◽  
...  
Keyword(s):  
Rem Sleep ◽  
Sleep Onset ◽  
Sleep Time ◽  
Sleep Stages ◽  
Sleep Regulation ◽  
Double Blind ◽  
Rem Latency ◽  
Sleep Parameters ◽  
Sleep Consolidation ◽  
Permissive Role

There is a well described temporal relation between hormonal secretion and sleep phase, with hormones of the hypothalamic-pituitary-adrenal (HPA) axis possibly playing a role in determining entry into and duration of different sleep stages. In this study sleep features were studied in primary Addison’s patients with undetectable levels of cortisol treated in a double blind, randomized, cross-over fashion with either hydrocortisone or placebo supplementation. We found that REM latency was significantly decreased in Addison’s patients when receiving hydrocortisone at bedtime, whereas REM sleep time was increased. There was a trend toward an increase in the percentage of time in REM sleep and the number of REM sleep episodes. Waking time after sleep onset was increased, whereas no differences were observed between the two conditions when total sleep time or specific non-REM sleep parameters were evaluated. Our results suggest that in Addison’s patients, cortisol plays a positive, permissive role in REM sleep regulation and may help to consolidate sleep. These effects may be mediated either directly by the central effects of glucocorticoids and/or indirectly through CRH and/or ACTH.

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