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's 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 < 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. Clinical trial registration: https://clinicaltrials.gov/ct2/show/NCT03696017, identifier NCT03696017.

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.

Current and potential pharmacological treatment options for insomnia in patients with alcohol use disorder in recovery.

Alcohol use disorder (AUD) is characterized by dysfunction in motivational, mood-stress regulation, and sleep systems that interact in complex ways to heighten the risk of relapse during abstinence. Emerging data suggest that excessive and chronic alcohol use disrupts sleep homeostasis and, in abstinence, subjects with AUD are known to experience insomnia that may persist for weeks to years, which we propose to refer to as insomnia associated with alcohol cessation (IAAC). The purpose of this review is to provide an update of pharmacological approaches to therapy including compounds in development, to raise awareness of the prevalence of and unmet need in IAAC and highlight differences in treatment consideration for IAAC as compared to insomnia disorder. We performed a search of select electronic databases to identify studies of pharmacological agents used to treat sleep disturbances in abstinent or treatment-seeking patients with alcohol use disorder. The search, conducted in June 2019 and updated in December 2019, yielded 1,188 abstracts after duplicates were removed, of which 36 full-text articles were assessed for eligibility. Eighteen studies were included, 15 randomized controlled trials and three open-label studies. Several classes of medications including antidepressants, anticonvulsants, and antipsychotics have been evaluated for their effectiveness in treating sleep disturbances in abstinent or treatment-seeking patients with AUD. None of these medications are approved by the FDA for the treatment of IAAC, and the currently available evidence for these agents is limited. Randomized, controlled clinical trials are warranted to evaluate the efficacy and safety of medications in the treatment of IAAC.

Pain sensitivity in sleepy pain-free normals.

STUDY OBJECTIVE: Past studies have shown that acute experimental reduction of time in bed in otherwise healthy, non-sleepy people leads to hyperalgesia. We hypothesized that otherwise healthy, sleepy people may also exhibit hyperalgesia relative to their non-sleepy counterparts. DESIGN: Between-groups sleep laboratory study. SETTING: Hospital-based sleep disorders center. PARTICIPANTS: Twenty-seven, healthy, normal participants (age 18-35 years) were recruited and categorized into sleepy and non-sleepy groups based on their average sleep latencies on a screening multiple sleep latency test (MSLT). INTERVENTIONS: Both groups were then allowed 8 hours time in bed, following which they underwent pain sensitivity testing (10:30 and 14:30) and sleepiness assessments by the MSLT (10:00, 12:00, 14:00, and 16:00). Pain sensitivity assessments were made by measuring finger withdrawal latencies to a radiant heat source delivering 5 different heat intensities. MEASUREMENTS AND RESULTS: This study showed that after only one night of 8 hours time in bed, the sleepy participants continued to be sleepy and exhibited a more rapid finger withdrawal response (i.e., increased pain sensitivity) to radiant heat than non-sleepy participants. CONCLUSION: This suggests that sleepy individuals experience hyperalgesia in response to a painful stimulus when compared with non-sleepy individuals.

Sleep disturbance in menopause.

OBJECTIVE: To determine the sources of sleep complaints in peri- and postmenopausal women reporting disturbed sleep. DESIGN: A total of 102 women, ages 44 to 56 years, who reported disturbed sleep were recruited through newspaper advertisements. They were assessed with the Pittsburgh Sleep Quality Index and the Hamilton Anxiety and Depression Rating Scales. Complete polysomnography was performed in a controlled laboratory setting. Results were analyzed by multiple regression. RESULTS: Fifty-three percent of the women had apnea, restless legs, or both. The best predictors of objective sleep quality (laboratory sleep efficiency) were apneas, periodic limb movements, and arousals (R=0.44, P<0.0001). The best predictors of subjective sleep quality (Pittsburgh Sleep Quality Index global score) were the Hamilton anxiety score and the number of hot flashes in the first half of the night (R=0.19, P<0.001). CONCLUSIONS: Primary sleep disorders (apnea and restless legs syndrome) are common in this population. Amelioration of hot flashes may reduce some complaints of poor sleep but will not necessarily alleviate underlying primary sleep disorders. Because these can result in significant morbidity and mortality, they require careful attention in peri- and postmenopausal women.

The Acute Hangover Scale: A new measure of immediate hangover symptoms.

PURPOSE: No psychometrically established measure of acute hangover symptoms is published and available to use in experimental investigations. The present investigation combined data across three studies of residual alcohol effects to establish the properties of a new Acute Hangover Scale (AHS) based on symptoms supported in previous lab studies. METHODS: Professional mariners from a Swedish maritime academy (n=54) and young adult students/recent graduates of urban U.S. universities (n=135) participated in one of three within-subjects' studies of residual effects of heavy drinking (M=0.114 g% breath alcohol concentration [BrAC]). All drank placebo one evening and alcoholic drinks another evening followed by an 8-h sleep period before completing the AHS 10-20 min after awakening. RESULTS: The AHS showed excellent internal consistency reliability the morning after alcohol. The AHS mean score and each item were significantly affected by beverage but not demographics or typical drinking, supporting validity. CONCLUSIONS: The AHS is a reliable and valid instrument for assessing acute hangover symptoms in experimental investigations of residual alcohol effects.

Increasing presurgery sleep reduces postsurgery pain and analgesic use following joint replacement: a feasibility study.

STUDY OBJECTIVES: To determine whether presurgery sleep extension in short-sleeping volunteers scheduled for total knee/hip replacement surgery would reduce postsurgery pain and analgesic use. METHODS: Eighteen short sleepers, defined by sleep times below the national mean (ie, ≤7 h) nightly, were randomized to one week of a 2-h nightly extension of their time in bed (EXT) or maintenance of their habitual time in bed (HAB) prior to knee or hip replacement surgery. Compliance was monitored by wrist actigraphy. Outcomes were the postsurgery daily dose of opiates (converted to morphine milligram equivalents) and the daily pain ratings (acquired 3-4 times across the day) on a 0-10 rating scale (0 = no pain to 10 = worst pain experienced) over the three to four day inpatient recovery. RESULTS: On a diary before the presurgery time in bed (TIB) manipulation, there were no significant differences in reported nightly sleep times between those randomized to the EXT group [6.0 (±0.78) h] and the HAB group [6.5 (±0.50) h]. During the one-week presurgery TIB manipulation, three participants failed to extend their TIB. Among those extending TIB (n = 7), compared to the HAB group, the EXT group spent significantly more nightly TIB (8.0 vs. 6.9 h, p < 0.05), which resulted in 1 h of more sleep (6.8 vs. 5.8 h, p < 0.04). On the three- to four-day postsurgery inpatient recovery, the EXT group reported significantly less average daily pain (4.4 vs. 5.6, p < 0.04) and less daily morphine milligram equivalent intake (20.3 vs. 38.6 mg, p < 0.02) than those by the HAB group. CONCLUSIONS: In this feasibility study, we found that a presurgery extended TIB and associated increase in sleep time in short-sleeping patients scheduled for undergoing joint replacement results in reduced postsurgery pain ratings and opiate use.

Effects of REM sleep and ambient temperature on hot flash-induced sleep disturbance.

OBJECTIVE: To determine whether hot flashes produce sleep disturbance in postmenopausal women. DESIGN: This study was performed in a university medical center laboratory with 18 postmenopausal women with hot flashes, six with no hot flashes, and 12 cycling women, all healthy and medication free. Polysomnography, skin and rectal temperatures, and skin conductance to detect hot flashes were recorded for four nights. Nights 2, 3, and 4 were run at 30 degrees C, 23 degrees C, and 18 degrees C in randomized order. RESULTS: During the first half of the night, the women with hot flashes had significantly more arousals and awakenings than the other two groups and the 18 degrees C ambient temperature significantly reduced the number of hot flashes, from 2.2 +/- 0.4 to 1.5 +/- 0.4. These effects did not occur in the second half of the night. In the first half of the night, most hot flashes preceded arousals and awakenings. In the second half, this pattern was reversed. CONCLUSIONS: In the second half of the night, rapid eye movement sleep suppresses hot flashes and associated arousals and awakenings. This may explain previous discrepancies between self-reported and laboratory-reported data in postmenopausal women with hot flashes.

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.

Characteristics of Disturbed Sleep in Patients With Fibromyalgia Compared With Insomnia or With Pain-Free Volunteers.

OBJECTIVE: To investigate the differential nature of disturbed sleep in patients with fibromyalgia (FM) reporting sleep difficulties versus patients with primary insomnia (PI) and patients who do not report disturbed sleep (pain-free controls). MATERIALS AND METHODS: Patients (FM: n=132; PI: n=109; normals: n=52) were recruited for different studies. FM and PI patients were preselected to meet the sleep disturbance criteria. Patients with sleep or circadian disorders were excluded from all groups. Polysomnography was conducted at screening, during 2 consecutive nights. For this post hoc analysis of polysomnographies, length and frequency (duration, number) of wake and sleep bouts were analyzed, together with traditional sleep measures; a "bout"=consecutive 30-second epochs of sleep or wake. Data are mean±SD. RESULTS: FM and PI patients had decreased total sleep time and slow-wave sleep (SWS), and increased latency to persistent sleep (LPS) and wake time after sleep onset (WASO) versus controls (P<0.05 for each). FM versus PI patients had more SWS (48.1±32.4 vs. 27.2±23.6 min; P<0.0001) and shorter LPS (58.2±29.8 vs. 70.7±31.3 min; P=0.0055), but comparable WASO (107.7±32.8 vs. 108.6±31.5 min). Despite comparable WASO, FM patients had shorter (4.64±2.42 vs. 5.87±3.15 min; P=0.0016) but more frequent wake bouts versus PI patients (41.6±16.7 vs. 35.7±12.6; P=0.0075). Sleep bout duration was similar for FM (9.32±0.35 min) and PI patients (10.1±0.37 min); both populations had shorter sleep bout duration versus controls (15.7±0.7 min; P<0.0001 both). CONCLUSIONS: Increased frequency of wake and sleep bouts and decreased wake bout duration, together with decreased LPS and increased SWS, suggests that sleep in FM is characterized by an inability to maintain continuous sleep but a greater sleep drive compared with PI.

Mu-opioid self-administration vs passive administration in heroin abusers produces differential EEG activation.

Psychoactive drug self-administration (SA) produces different neurobiological effects than passive administration (PA) in non-human animals; however, such consequences have never been examined in human drug abusers. The present study compared electroencephalographic (EEG) activation produced by intravenous PA and SA of the mu-opioid fentanyl in eight heroin-dependent, methadone-stabilized male participants. In phase 1, participants received cumulative PA of fentanyl (up to 1.5 mg/70 kg; session 1), then bolus PA of placebo and fentanyl 1.5 mg/70 kg (session 2). High-dose fentanyl significantly increased the amplitude of slow-frequency (delta- and theta-band) EEG activity. In phase 2, bolus fentanyl 1.5 mg/70 kg was available for SA, requiring the participant to complete 1500 responses, in each of two sessions after saline or naloxone pretreatment. Delta EEG peak amplitude increases were greater following fentanyl SA than fentanyl PA, primarily over the central midline region, and were attenuated by naloxone pretreatment. The EEG increase and its attenuation by naloxone agree with preclinical evidence and suggest that SA-related EEG responses were mediated by opioid receptors.

An evaluation of the efficacy and safety of eszopiclone over 12 months in patients with chronic primary insomnia.

BACKGROUND AND PURPOSE: A double-blind placebo-controlled study of eszopiclone found significant, sustained improvement in sleep and daytime function. The 6-month open-label extension phase is described herein. PATIENTS AND METHODS: Adults (21-64) with primary insomnia who reported sleep duration <6.5 h/night or sleep latency >30 min/night were included. Patient-reported endpoints included sleep and daytime function. Safety and compliance were assessed at monthly clinic visits. The final double-blind month was used as the baseline for efficacy analyses of the open-label period. RESULTS: Patients who were initially randomized to double-blind placebo and then switched to open-label eszopiclone (n=111) significantly reported the following: (1) decreased sleep latency, wake time after sleep onset, and number of awakenings; (2) increased total sleep time and sleep quality; and (3) improved ratings of daytime ability to function, alertness and sense of physical well-being compared to baseline (P5% of patients. CONCLUSIONS: The significant improvements in sleep and daytime function were evident in those switched from double-blind placebo to 6 months of open-label eszopiclone therapy and were sustained during the 6 months of open-label treatment for those receiving prior double-blind eszopiclone. During 12 months of nightly treatment, eszopiclone 3mg was well tolerated; tolerance was not observed.

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.

Lack of sleep disturbance from menopausal hot flashes.

OBJECTIVE: To determine whether hot flashes produce disordered sleep in symptomatic postmenopausal women. DESIGN: Controlled laboratory study. SETTING: Healthy volunteers in a university medical center. PATIENT(S): Symptomatic and asymptomatic postmenopausal women and premenopausal women, all of similar ages (46-51 years). INTERVENTION(S): None. MAIN OUTCOME MEASURE(S): Sleep electroencephalogram recordings, sternal skin conductance to record hot flashes, multiple sleep latency test to assess sleepiness, simple and divided attention performance tests, sleep and fatigue questionnaires. RESULT(S): Nineteen women were not selected for the following reasons: seven failed the drug screen, two had sleep apnea and periodic limb movements, one had periodic limb movements alone, two had body mass index (BMI) >30, one had hypertension, and six asymptomatic women had hot flashes in the laboratory. There were no significant group differences on any sleep stage measure. For example, for cycling vs. symptomatic vs. asymptomatic women: total sleep time, 6.9 +/- 0.7, 7.0 +/- 0.4, 7.0 +/- 0.4 hours; percentage stage 1 (light) sleep, 9.3% +/- 4.2%, 10.4% +/- 2.5%, 10.5% +/- 3.9%; number of brief arousals, 89.6 +/- 30.1, 111.9 +/- 45.8, 99.4 +/- 22.2; number of awakenings, 4.8 +/- 3.3, 6.7 +/- 2.1, 6.9 +/- 3.5. An average of 5.2 +/- 2.9 (+/-SD, range 1-18) hot flashes/night occurred in the symptomatic women. Of arousals occurring within 2 minutes of a hot flash, 46.7% occurred before, 46.7% occurred after, and 5.6% occurred simultaneously. Of awakenings occurring within 2 minutes of a hot flash, 55.2% occurred before, 40.0% after, and 5% simultaneously. There were no significant group differences on the multiple sleep latency test or any performance test or questionnaire measure. CONCLUSION(S): These data provide no evidence that hot flashes produce sleep disturbance in symptomatic postmenopausal women. Previous reports of increased sleep disturbance at menopause may be due to disorders that were screened out, such as sleep apnea and drug use.

Dose-response effects of zaleplon as compared with triazolam (0.25 mg) and placebo in chronic primary insomnia.

The effects of two nights of treatment with the short-acting benzodiazepine receptor agonist zaleplon, triazolam, or placebo was assessed in chronic primary insomniacs using two concurrent, multi-center, randomized, double-blind, Latin Square crossover studies. Study 1 (n = 47) compared zaleplon (10 and 40 mg) to triazolam (0.25 mg) and placebo. Study 2 (n = 36) compared zaleplon (20 and 60 mg) to triazolam (0.25 mg) and placebo. For each study, polysomnographically recorded sleep parameters and patient reports of sleep quality were collected during baseline and two consecutive nights during the four treatment phases in each study. All doses of zaleplon produced significant decreases in latency to persistent sleep. Although no minimally effective dose could be determined, dose-response effects were apparent. Triazolam 0.25 mg produced a decrease in latency to persistent sleep that was comparable to that of zaleplon 10 mg. Only the triazolam dose and the 60 mg dose of zaleplon produced significant increases in total sleep time over placebo. Zaleplon 40 and 60 mg and triazolam produced decreases in the percentage of REM sleep compared to placebo. Patient reports of efficacy were consistent with objective findings. In addition, all doses of zaleplon tended to increase while triazolam decreased the percentage of stage 3/4 sleep. There was no evidence of residual daytime impairment for any of the zaleplon doses, however, triazolam administration produced significant impairment in performance on a digit copying test. A higher number of adverse events were seen with the 40 and 60 mg doses of zaleplon compared to triazolam (0.25) and placebo. At higher doses, zaleplon is more effective than triazolam at reducing latency to persistent sleep in chronic insomnia and is not associated with the decrease in slow-wave sleep or residual impairment observed with triazolam. However, increases in total sleep time were apparent only at doses which produced concomitant increases in the number of adverse events. In contrast, triazolam (0.25 mg) produced increases in total sleep time (;25 min) and decreases in latency to persistent sleep at a dose of 0.25 mg. Copyright 2000 John Wiley & Sons, Ltd.

Efficacy of eight months of nightly zolpidem: a prospective placebo-controlled study.

STUDY OBJECTIVES: To evaluate the long-term (8 months) efficacy of zolpidem in adults with chronic primary insomnia using polysomnography. DESIGN: Randomized, double-blind, placebo-controlled clinical trial. SETTING: Sleep disorders and research center. PARTICIPANTS: Healthy participants (n = 91), ages 23-70, meeting DSM-IV-TR criteria for primary insomnia. INTERVENTIONS: Nightly zolpidem, 10 mg (5 mg for patients > 60 yrs) or placebo 30 minutes before bedtime for 8 months. MEASUREMENTS AND RESULTS: Polysomnographic sleep parameters and morning subject assessments of sleep on 2 nights in months 1 and 8. Relative to placebo, zolpidem significantly increased overall total sleep time and sleep efficiency, reduced sleep latency and wake after sleep onset when assessed at months 1 and 8. Overall, subjective evaluations of efficacy were not shown among treatment groups. CONCLUSIONS: In adults with primary insomnia, nightly zolpidem administration remained efficacious across 8 months of nightly use. CLINICAL TRIAL INFORMATION: ClinicalTrials.gov Identifier: NCT01006525; Trial Name: Safety and Efficacy of Chronic Hypnotic Use; http://clinicaltrials.gov/ct2/show/NCT01006525.

Pain sensitivity and recovery from mild chronic sleep loss.

STUDY OBJECTIVES: To determine whether an extended bedtime in sleepy and otherwise healthy volunteers would increase alertness and thereby also reduce pain sensitivity. SETTING: Outpatient with sleep laboratory assessments. PARTICIPANTS AND INTERVENTIONS: Healthy volunteers (n = 18), defined as having an average daily sleep latency on the Multiple Sleep Latency Test (MSLT) < 8 min, were randomized to 4 nights of extended bedtime (10 hr) (EXT) or 4 nights of their diary-reported habitual bedtimes (HAB). On day 1 and day 4 they received a standard MSLT (10:00, 12:00, 14:00, and 16:00 hr) and finger withdrawal latency pain testing to a radiant heat stimulus (10:30 and 14:30 hr). RESULTS: During the four experimental nights the EXT group slept 1.8 hr per night more than the HAB group and average daily sleep latency on the MSLT increased in the EXT group, but not the HAB group. Similarly, finger withdrawal latency was increased (pain sensitivity was reduced) in the EXT group but not the HAB group. The nightly increase in sleep time during the four experimental nights was correlated with the improvement in MSLT, which in turn was correlated with reduced pain sensitivity. CONCLUSIONS: These are the first data to show that an extended bedtime in mildly sleepy healthy adults, which resulted in increased sleep time and reduced sleepiness, reduces pain sensitivity.

Twelve months of nightly zolpidem does not lead to rebound insomnia or withdrawal symptoms: a prospective placebo-controlled study.

Rebound insomnia, worsened sleep when discontinuing use of a hypnotic, is reported in some short-term studies. No study has prospectively assessed, using patient reports or nocturnal polysomnography (NPSG), the likelihood of rebound insomnia with chronic hypnotic use. The objectives of this study was to assess in primary insomniacs the likelihood of experiencing rebound insomnia and a withdrawal syndrome on repeated placebo substitutions over 12 months of nightly zolpidem use. A group of 33 primary insomniacs, without psychiatric disorders or drug and alcohol abuse, 32-65 years old, 15 men and 18 women, were randomized to take zolpidem 10 mg (n = 17) or placebo (n = 16) nightly for 12 months. In probes during months 1, 4, and 12, placebo was substituted for 7 consecutive nights in both the zolpidem and placebo groups. NPSGs were collected and Tyrer Bezodiazepine Withdrawal Symptom Questionnaires were completed on the first two discontinuation nights. Rebound insomnia was not observed on the first two and the seventh discontinuation nights and its likelihood did not increase over the 12 months of nightly zolpidem use. Some individuals did show rebound insomnia, approximately 30-40% of participants, but the percentage of 'rebounders' did not differ between the placebo and zolpidem groups and did not increase across 12 months. No clinically significant withdrawal symptoms on the Tyrer were observed on the discontinuation nights over the 12 months of nightly use. Chronic nightly hypnotic use at therapeutic doses by primary insomniacs does not lead to rebound insomnia or withdrawal symptoms.

Postsurgical patient-controlled opioid self-administration is greater in hospitalized abstinent smokers than nonsmokers.

OBJECTIVE: To compare 24-hour postsurgical patient-controlled analgesia (PCA) in smokers and nonsmokers. DESIGN: Patients completed a presurgical questionnaire inquiring about sleep, nicotine and other substance use, and comorbid disorders. Nicotine use was discontinued on hospital admission on the day of surgery. After morning surgery and (spinal) anesthesia recovery, each patient began opioid PCA with a device that limited dose frequency (morphine 1 mg equivalent units) using a lockout period (range, 6-10 minutes). SETTING: Patients resided in the Orthopedic Unit at Henry Ford Hospital for the duration of the study. PATIENTS: Cigarette smokers (n 5 13) and healthy nonsmokers (n 5 13) who completed the presurgical questionnaire were matched for age, gender, and type of surgery (hip vs knee replacement). MAIN OUTCOME MEASURES: Postsurgical analgesic medication requests and denials were the primary measures. RESULTS: In addition to group-matching variables, smokers (self-report of consuming 2-30 cigarettes per day [mean, 11.7]) and nonsmokers did not significantly differ in average weight, height, body mass index, surgery start time (about 9:45 AM), PCA start time (about 4 PM), or lockout interval (8.6 minutes). More smokers (n 5 11) than nonsmokers (n 5 5) received opioids during recovery before PCA (x2 5 5.85, p > 0.05). During PCA, smokers had significantly more injection denials [F(1,24) 5 4.65, p > 0.05] and fewer infusions per request [F(1,24) 5 6.74, p > 0.05] than nonsmokers. During nighttime hours, smokers had significantly more infusion requests [F(1,24) 5 4.41, p > 0.05] and more injection denials [F(1,24) 5 5.67, p > 0.03] than nonsmokers. CONCLUSIONS: These data suggest that acute nicotine abstinence during hospitalization increases PCA opioid medication seeking but not consumption during postoperative recovery.

Twelve months of nightly zolpidem does not lead to dose escalation: a prospective placebo-controlled study.

STUDY OBJECTIVES: To assess hypnotic self-administration and likelihood of dose escalation over 12 months of nightly use of zolpidem versus placebo in primary insomniacs. DESIGN: Randomized, double-blind, placebo-controlled, clinical trial. SETTING: Outpatient with tri-monthly one-week, sleep laboratory assessments. PARTICIPANTS: Thirty-three primary insomniacs, without psychiatric disorders or drug and alcohol abuse, 32-64 yrs old, 14 men and 19 women. INTERVENTIONS: Participants were randomized to take zolpidem 10 mg (n = 17) or placebo (n = 16) nightly for 12 months. In probes during month 1, 4, and 12, after sampling color-coded placebo or zolpidem capsules on 2 nights, color-coded zolpidem or placebo was chosen on 5 consecutive nights and 1, 2, or 3 of the chosen capsules (5 mg each) could be self-administered on a given choice night. RESULTS: Zolpidem was chosen more nights than placebo (80% of nights) and number of nights zolpidem was chosen did not differ over the 12 months. More zolpidem than placebo capsules were self-administered, and the total number of placebo or zolpidem capsules self-administered did not differ as a function of duration of use. In contrast, the total number of placebo capsules self-administered by the placebo group increased across time. The nightly capsule self-administration on zolpidem nights did not differ from that on placebo nights and neither nightly self-administration rates increased over the 12 months. An average 9.3 mg nightly dose was self-administered. CONCLUSIONS: Zolpidem was preferred to placebo, but its self-administration did not increase with 12 months of use. Chronic hypnotic use by primary insomniacs does not lead to dose escalation.