At the intersection of sleep deficiency and opioid use: mechanisms and therapeutic opportunities

Due to the ongoing opioid epidemic, innovative scientific perspectives and approaches are urgently needed to reduce the unprecedented personal and societal burdens of nonmedical and recreational opioid use. One promising opportunity is to focus on the relationship between sleep deficiency and opioid use. In this review, we examine empirical evidence: (1) at the interface of sleep deficiency and opioid use, including hypothesized bidirectional associations between sleep efficiency and opioid abstinence; (2) as to whether normalization of sleep deficiency might directly or indirectly improve opioid abstinence (and vice versa); and (3) regarding mechanisms that could link improvements in sleep to opioid abstinence. Based on available data, we identify candidate sleep-restorative therapeutic approaches that should be examined in rigorous clinical trials

Anhedonia modulates benzodiazepine and opioid demand among persons in treatment for opioid use disorder

BACKGROUND: Benzodiazepine (BZD) misuse is a significant public health problem, particularly in conjunction with opioid use, due to increased risks of overdose and death. One putative mechanism underlying BZD misuse is affective dysregulation, via exaggerated negative affect (e.g., anxiety, depression, stress-reactivity) and/or impaired positive affect (anhedonia). Similar to other misused substances, BZD consumption is sensitive to price and individual differences. Although purchase tasks and demand curve analysis can shed light on determinants of substance use, few studies have examined BZD demand, nor factors related to demand. METHODS: This ongoing study is examining simulated economic demand for alprazolam (among BZD lifetime misusers based on self-report and DSM-5 diagnosis; n = 23 total; 14 male, 9 female) and each participant\u27s preferred-opioid/route using hypothetical purchase tasks among patients with opioid use disorder (n = 59 total; 38 male, 21 female) who are not clinically stable, i.e., defined as being early in treatment or in treatment longer but with recent substance use. Aims are to determine whether: (1) BZD misusers differ from never-misusers on preferred-opioid economic demand, affective dysregulation (using questionnaire and performance measures), insomnia/behavioral alertness, psychiatric diagnoses or medications, or urinalysis results; and (2) alprazolam demand among BZD misusers is related to affective dysregulation or other measures. RESULTS: Lifetime BZD misuse is significantly (p \u3c 0.05) related to current major depressive disorder diagnosis, opioid-negative and methadone-negative urinalysis, higher trait anxiety, greater self-reported affective dysregulation, and younger age, but not preferred-opioid demand or insomnia/behavioral alertness. Alprazolam and opioid demand are each significantly positively related to higher anhedonia and, to a lesser extent, depression symptoms but no other measures of negative-affective dysregulation, psychiatric conditions or medications (including opioid agonist therapy or inpatient/outpatient treatment modality), or sleep-related problems. CONCLUSION: Anhedonia (positive-affective deficit) robustly predicted increased BZD and opioid demand; these factors could modulate treatment response. Routine assessment and effective treatment of anhedonia in populations with concurrent opioid and sedative use disorder may improve treatment outcomes

Familial Childhood Sleep Apnea

We report four siblings who had polysomnographically documented sleep apnea. Two presented with the typical clinical picture of sleep apnea syndrome including daytime somnolence and snoring, had repetitive obstructive apneic episodes during sleep, and were effectively treated with upper airway surgery. The other two were asymptomatic and showed infrequent apneic episodes during sleep. This family illustrates the distinction between the sleep apnea syndrome and infrequent apneic episodes during sleep. The sleep apnea syndrome is associated with daytime symptomatology and requires treatment. The presence of apneic episodes during sleep in all four siblings has implications regarding the predisposing factors (eg, upper airway anatomy and central nervous system dysfunction) versus precipitating factors (eg, obesity, upper airway infection, and central nervous system depressants) in sleep apnea

Sleep-Wake Complaints and Their Relation to Sleep Disturbance

This report is a comparison of patients presenting with 1) an insomnia complaint diagnosed as no objective findings. 2) insomnia diagnosed as being associated with a psychiatric disorder, and 3) daytime sleepiness diagnosed as no objective findings. The sleep of patients with insomnia diagnosed as no objective findings is comparable to that of patients with daytime sleepiness diagnosed as no objective findings and is significantly better than that of patients with insomnia associated with a psychiatric disorder. Significant differences were found in sleep induction, sleep maintenance, and overall sleep efficiency. No major differences were found among any of the groups in terms of sleep staging. All groups showed signs of psychological distress, but as expected this was significantly higher in the patients with insomnia associated with a psychiatric disorder. The fact that patients may present with sleep complaints (either insomnia or daytime somnolence) despite essentially normal sleep has clinical implications. Adequate evaluation of sleep complaints and symptomatic treatment plans are discussed

Sleep Disturbance in Substance Use Disorders

This article discusses the role sleep and alertness disturbance plays in the initiation, maintenance and relapse of substance use disorders

Gender Differences in the Efficacy and Safety of Chronic Nightly Zolpidem

STUDY OBJECTIVES: Studies have shown pharmacokinetic differences for hypnotics in women compared to men, but few studies have assessed either short-or long-term differences in efficacy and safety. METHODS: To evaluate gender differences in the efficacy and safety of chronic nightly zolpidem (10 mg), we did a post hoc assessment of a large clinical trial. In the trial, participants with primary insomnia (n = 89), ages 23-70, meeting DSM-IV-TR criteria for primary insomnia were randomized, double blind, to nightly zolpidem, 10 mg (n = 47) or placebo (n = 42) 30 minutes before bedtime nightly for 12 months. Polysomnographic sleep on 2 nights in months 1 and 8 and likelihood of next-day sleepiness, rebound insomnia, and dose escalation were evaluated in months 1, 4, and 12. RESULTS: Relative to placebo, zolpidem significantly increased sleep efficiency and reduced sleep latency and wake after sleep onset assessed at months 1 and 8, with no differences in efficacy between women and men and no diminution of efficacy over months. On a next-day multiple sleep latency test (MSLT), no residual sedation was observed for either women or men. No rebound insomnia or dose escalation was seen with no gender differences in either. CONCLUSIONS: In adults with primary insomnia, nightly zolpidem administration showed no gender differences in acute or chronic efficacy or in next-day sleepiness. Zolpidem remained efficacious and safe across 12 months. CLINCIAL TRIALS REGISTRATION: ClinicalTrials.gov Identifier: NCT01006525; Trial Name: Safety and Efficacy of Chronic Hypnotic Use; http://clinicaltrials.gov/ct2/show/NCT01006525

Hyperarousal in insomnia: pre-sleep and diurnal cortisol levels in response to chronic zolpidem treatment

OBJECTIVES: To determine whether cortisol levels, both diurnal and pre-sleep, would vary as a function of MSLT and would be reduced by nightly placebo versus zolpidem 10 mg. METHODS: DSM-IVR diagnosed subjects with insomnia (N = 95), aged 32-70 yrs, having no other sleep disorder, unstable medical or psychiatric diseases or drug dependency served. On a screening MSLT 27 had MSLTs(Lo) and 42 \u3e 15 min (Hi). Participants took 10 mg zolpidem or placebo, double-blind, nightly for 12 months. In months one and 12 urine was collected over 24 h in 8 hr-aliquots and assayed for cortisol (Ward Laboratories, Ann Arbor, MI). Saliva samples were collected 35 min before bedtime and the 30 min drug administration in month one and eight, and analyzed for cortisol levels (Salimetrics, State College, PA). RESULTS: Pre-sleep salivary cortisol was higher in insomniacs than controls, but did not differ as a function of MSLT. Nightly zolpidem reduced pre-sleep cortisol relative to placebo on month one and eight, with no month effects or interaction. Diurnal (0700-1500 h) urinary cortisol was higher overall in the Hi vs Lo MSLT subjects with insomnia, was stable across months, and was not reduced with zolpidem. CONCLUSIONS: Hyperarousal among subjects with insomnia as operationalized by MSLT is associated with higher diurnal urinary cortisol than those without hyperarousal, but not differential pre-sleep salivary cortisol. Zolpidem relative to placebo reduced pre-sleep salivary cortisol in all subjects, but not diurnal urinary cortisol. CLINICAL TRIAL: Safety and Efficacy of Chronic Hypnotic Use: http://www.clinicaltrials.gov NCT01006525

Insomnia as a path to alcoholism: tolerance development and dose escalation

Study Objectives: To assess the risks associated with the use of alcohol as a sleep aid, we evaluated tolerance development to pre-sleep ethanol\u27s sedative-hypnotic effects, and subsequent ethanol dose escalation. Methods: Volunteers, 21-55 years old, with insomnia in otherwise good medical and psychiatric health and no history of alcoholism or drug abuse participated. In experiment 1 (n = 24) 0.0, 0.3, or 0.6 g/kg (n = 8 per dose) ethanol was administered before sleep and 8-hour nocturnal polysomnograms (NPSGs) were collected. In experiment 2, after six nights pretreatment with ethanol 0.45 g/kg (n = 6) versus placebo (n = 6), choice of pre-sleep ethanol or placebo was assessed over seven choice nights. Results: The 0.6 g/kg ethanol dose increased total sleep time and stage 3-4 sleep on night 2, but these effects were lost by night 6 (p \u3c .05). Six nights of ethanol pretreatment produced on the choice nights more self-administered ethanol refills than the placebo pretreatment (p \u3c .03). Conclusions: These are the first data to explicitly show the risks associated with the use of alcohol as a sleep aid among people with insomnia. Initially, a moderate dose of ethanol improved NPSG sleep, which was lost by night 6. Tolerance was associated with enhanced self-administration of pre-sleep ethanol

Hyperarousal in insomnia and hypnotic dose escalation

BACKGROUND: Given concerns about the abuse liability of hypnotics, this study assessed hyperarousal in people with insomnia and its relation to hypnotic self-administration over 12 months of nightly hypnotic use. METHODS: Ninety-five subjects with insomnia (age 32-64 years) underwent screening nocturnal polysomnogram (NPSG) and Multiple Sleep Latency Test (MSLT) the following day and, then, were randomized to receive zolpidem 10 mg or placebo nightly for 12 months. NPSGs and MSLTs were conducted and urine was collected (0700-1500 h) and analyzed for norepinephrine (NE) levels during months one and eight on study medication. A subset (n = 54) underwent hypnotic self-administration assessments in months one, four, and 12. RESULTS: Mean daily sleep latency on screening MSLT was distributed across the full range of MSLT latencies (2-20 min). The highest screening MSLT latencies were detected in subjects with higher NE levels, compared to those with the lowest MSLT latencies. In the subset undergoing self-administration assessment, those with the highest MSLT latencies chose more capsules (placebo and zolpidem) and increased the number of capsules chosen in months four relative to month one, compared to those with the lowest MSLT latencies. CONCLUSIONS: These data show that some insomniacs are hyperaroused with high MSLT/NE levels and, compared to low MSLT/NE insomniacs, they increase the number of capsules (zolpidem and placebo) self-administered on months four and 12 relative to Month one

Gender Differences in the Efficacy and Safety of Chronic Nightly Zolpidem

STUDY OBJECTIVES: Studies have shown pharmacokinetic differences for hypnotics in women compared to men, but few studies have assessed either short-or long-term differences in efficacy and safety. METHODS: To evaluate gender differences in the efficacy and safety of chronic nightly zolpidem (10 mg), we did a post hoc assessment of a large clinical trial. In the trial, participants with primary insomnia (n = 89), ages 23–70, meeting DSM-IV-TR criteria for primary insomnia were randomized, double blind, to nightly zolpidem, 10 mg (n = 47) or placebo (n = 42) 30 minutes before bedtime nightly for 12 months. Polysomnographic sleep on 2 nights in months 1 and 8 and likelihood of next-day sleepiness, rebound insomnia, and dose escalation were evaluated in months 1, 4, and 12. RESULTS: Relative to placebo, zolpidem significantly increased sleep efficiency and reduced sleep latency and wake after sleep onset assessed at months 1 and 8, with no differences in efficacy between women and men and no diminution of efficacy over months. On a next-day multiple sleep latency test (MSLT), no residual sedation was observed for either women or men. No rebound insomnia or dose escalation was seen with no gender differences in either. CONCLUSIONS: In adults with primary insomnia, nightly zolpidem administration showed no gender differences in acute or chronic efficacy or in next-day sleepiness. Zolpidem remained efficacious and safe across 12 months. CLINCIAL TRIALS REGISTRATION: ClinicalTrials.gov Identifier: NCT01006525; Trial Name: Safety and Efficacy of Chronic Hypnotic Use; http://clinicaltrials.gov/ct2/show/NCT01006525. CITATION: Roehrs TA, Roth T. Gender differences in the efficacy and safety of chronic nightly zolpidem. J Clin Sleep Med 2016;12(3):319–325