Nighttime Sleep and Respiratory Disturbances in Individuals Receiving Methadone to Treat Opioid Use Disorder.

ABSTRACT: Opioids are a leading cause of drug overdose deaths in the United States. Methadone used as medication for opioid use disorder (MOUD) reduces drug cravings and promotes abstinence. However, individuals in methadone-based MOUD treatment commonly report subjective sleep complaints and are at risk for respiratory depression from opioids. We investigated nighttime sleep and respiratory function in eight individuals (six women, two men; ages 31-68 years) in their first 90 days of methadone-based MOUD treatment. Participants underwent overnight cardiorespiratory polysomnography. Sleep and respiratory variables were characterized with descriptive statistics for comparison to reference data from similarly aged healthy adults. Although participants spent 8.1 ± 0.3 hours (mean ± SD ) in bed, their total sleep time was only 6.8 ± 1.3 hours. They exhibited longer sleep latency and intermittent wakefulness. Sleep structure was irregular, with disrupted sleep cycles. Participants also displayed a decreased amount of N1 sleep and an increased amount of N3 sleep, compared with reference data. Participants showed respiratory depression, with an average apnea-hypopnea index of 16.5 ± 8.9 events per hour. Central sleep apneas comprised 69.1% ± 20.9% of the respiratory events. A Cheyne-Stokes-like breathing pattern, consisting of 30-second cycles of three central sleep apneas, was observed in 75% of participants. Our results suggest that individuals early in methadone-based MOUD treatment experience disordered sleep and respiratory disturbances. Such nighttime physiological changes may have serious long-term health consequences and contribute to unintended overdose rates. Identifying and treating MOUD individuals with sleep apnea could reduce risk of death.

Co-consuming green tea with raloxifene decreases raloxifene systemic exposure in healthy adult participants.

Green tea is a popular beverage worldwide. The abundant green tea catechin (-)-epigallocatechin gallate (EGCG) is a potent in vitro inhibitor of intestinal UDP-glucuronosyltransferase (UGT) activity (Ki ~2 µM). Co-consuming green tea with intestinal UGT drug substrates, including raloxifene, could increase systemic drug exposure. The effects of a well-characterized green tea on the pharmacokinetics of raloxifene, raloxifene 4'-glucuronide, and raloxifene 6-glucuronide were evaluated in 16 healthy adults via a three-arm crossover, fixed-sequence study. Raloxifene (60 mg) was administered orally with water (baseline), with green tea for 1 day (acute), and on the fifth day after daily green tea administration for 4 days (chronic). Unexpectedly, green tea decreased the geometric mean green tea/baseline raloxifene AUC0-96h ratio to ~0.60 after both acute and chronic administration, which is below the predefined no-effect range (0.75-1.33). Lack of change in terminal half-life and glucuronide-to-raloxifene ratios indicated the predominant mechanism was not inhibition of intestinal UGT. One potential mechanism includes inhibition of intestinal transport. Using established transfected cell systems, a green tea extract normalized to EGCG inhibited 10 of 16 transporters tested (IC50 , 0.37-12 µM). Another potential mechanism, interruption by green tea of gut microbe-mediated raloxifene reabsorption, prompted a follow-up exploratory clinical study to evaluate the potential for a green tea-gut microbiota-drug interaction. No clear mechanisms were identified. Overall, results highlight that improvements in current models and methods used to predict UGT-mediated drug interactions are needed. Informing patients about the risk of co-consuming green tea with raloxifene may be considered.

Clinical Assessment of the Drug Interaction Potential of the Psychotropic Natural Product Kratom.

Oral formulations prepared from the leaves of the kratom (Mitragyna speciosa) plant are increasingly used for their opioid-like effects to self-manage opioid withdrawal and pain. Calls to US poison centers involving kratom exposures increased >50-fold from 2011-2017, one-third of which reported concomitant use of kratom with drugs of abuse. Many of these drugs are eliminated primarily via cytochrome P450 (CYP) 3A and CYP2D6, raising concerns for potential adverse pharmacokinetic kratom-drug interactions. The impact of a single low dose of kratom tea (2 g) on the pharmacokinetics of the CYP3A probe midazolam (2.5 mg) and CYP2D6 probe dextromethorphan (30 mg) were assessed in 12 healthy adult participants after oral administration. Kratom showed no effect on dextromethorphan area under the plasma concentration time-curve (AUC) and maximum concentration (Cmax ; geometric mean ratio (90% confidence interval) 0.99 (0.83-1.19) and 0.96 (0.78-1.19), respectively) but a modest increase in midazolam AUC and Cmax (1.39 (1.23-1.57) and 1.50 (1.32-1.70), respectively). Lack of change in midazolam half-life (1.07 (0.98-1.17)) suggested that kratom primarily inhibited intestinal CYP3A. This inference was further supported by a physiologically based pharmacokinetic drug interaction model using the abundant alkaloid mitragynine, a relatively potent CYP3A time-dependent inhibitor in vitro (KI , ~4 µM; kinact , ~0.07 min-1 ). This work is the first to clinically evaluate the pharmacokinetic drug interaction potential of kratom. Co-consuming kratom with certain drugs extensively metabolized by CYP3A may precipitate serious interactions. These data fill critical knowledge gaps about the safe use of this increasingly popular natural product, thereby addressing ongoing public health concerns.

Hyperbaric Oxygen Therapy for Pain, Opioid Withdrawal, and Related Symptoms: A Pilot Randomized Controlled Trial.

BACKGROUND: Pain, drug cravings, and opioid withdrawal symptoms can interfere with substance use disorder or opioid tapering treatment goals. AIM: This pilot study investigated the feasibility of a protocol designed to test opioid withdrawal symptom relief relative to a sham condition after two consecutive days of hyperbaric oxygen therapy (HBOT) for adults prescribed daily methadone for opioid use disorder. METHOD: Using a double-blind protocol, eight adults were randomized to receive either a full 90-minute HBOT dose in a pressurized chamber with 100% oxygen at 2.0 atmospheres absolute (ATA) or a sham condition receiving 21% oxygen (equivalent to room air within the chamber) at a minimal pressure of ≤1.3 ATA. Measures included study retention, treatment satisfaction, and pre- and post-intervention effects for opioid withdrawal symptoms, drug cravings, pain intensity and interference, sleep quality, and mood. RESULTS: Study retention and treatment satisfaction was high. All measurements improved more, on average, for participants receiving full-dose HBOT treatment than among participants receiving sham treatments except for clinically observed withdrawal symptoms. The largest positive effects were observed in measurements of pain intensity and drug craving. CONCLUSIONS: These pilot results provide evidence to support a fully powered study of HBOT as a potential treatment adjunct for adults receiving methadone for opioid use disorder. Trends towards symptom improvements were detected from pre- to post-HBOT in the full treatment arm versus sham condition. More research into novel non-pharmacologic options to relieve distressing symptoms related to pain and opioid use disorder is essential to improve clinical outcomes.

Clinical Pharmacokinetic Assessment of Kratom (Mitragyna speciosa), a Botanical Product with Opioid-like Effects, in Healthy Adult Participants.

Increasing use of the botanical kratom to self-manage opioid withdrawal and pain has led to increased kratom-linked overdose deaths. Despite these serious safety concerns, rigorous fundamental pharmacokinetic knowledge of kratom in humans remains lacking. We assessed the pharmacokinetics of a single low dose (2 g) of a well-characterized kratom product administered orally to six healthy participants. Median concentration-time profiles for the kratom alkaloids examined were best described by a two-compartment model with central elimination. Pronounced pharmacokinetic differences between alkaloids with the 3S configuration (mitragynine, speciogynine, paynantheine) and alkaloids with the 3R configuration (mitraciliatine, speciociliatine, isopaynantheine) were attributed to differences in apparent intercompartmental distribution clearance, volumes of distribution, and clearance. Based on noncompartmental analysis of individual concentration-time profiles, the 3S alkaloids exhibited a shorter median time to maximum concentration (1-2 vs. 2.5-4.5 h), lower area under the plasma concentration-time curve (430-490 vs. 794-5120 nM × h), longer terminal half-life (24-45 vs. ~12-18 h), and higher apparent volume of distribution during the terminal phase (960-12,700 vs. ~46-130 L) compared to the 3R alkaloids. Follow-up mechanistic in vitro studies suggested differential hepatic/intestinal metabolism, plasma protein binding, blood-to-plasma partitioning, and/or distribution coefficients may explain the pharmacokinetic differences between the two alkaloid types. This first comprehensive pharmacokinetic characterization of kratom alkaloids in humans provides the foundation for further research to establish safety and effectiveness of this emerging botanical product.

Sleep Deprivation and Sleep-Onset Insomnia are Associated with Blunted Physiological Reactivity to Stressors.

INTRODUCTION: Military operations often involve intense exposure to stressors combined with acute sleep deprivation, while military personnel also experience high prevalence of chronic sleep deficiency from insomnia and other sleep disorders. However, the impact of acute and chronic sleep deficiency on physiologic stressor responses is poorly understood. In a controlled laboratory study with normal sleepers and individuals with chronic sleep-onset insomnia, we measured responses to an acute stressor administered in a sleep deprivation condition or a control condition. METHODS: Twenty-two adults (aged 22-40 years; 16 females)-11 healthy normal sleepers and 11 individuals with sleep-onset insomnia-completed a 5-day (4-night) in-laboratory study. After an adaptation day and a baseline day, subjects were assigned to a 38-hour total sleep deprivation (TSD) condition or a control condition; the study ended with a recovery day. At 8:00 PM after 36 hours awake in the sleep deprivation condition or 12 hours awake in the control condition, subjects underwent a Maastricht Acute Stress Test (MAST). Salivary cortisol was measured immediately before the MAST at 8:00 PM, every 15 minutes after the MAST from 8:15 PM until 9:15 PM, and 30 minutes later at 9:45 PM. Baseline salivary cortisol was collected in the evening of the baseline day. Additionally, before and immediately upon completion of the MAST, self-report ratings of affect and pain were collected. RESULTS: The MAST elicited a stressor response in both normal sleepers and individuals with sleep-onset insomnia, regardless of the condition, as evidenced by increases in negative affect and pain ratings. Relative to baseline, cortisol levels increased immediately following the MAST, peaked 30 minutes later, and then gradually returned to pre-MAST levels. At the cortisol peak, there was a significant difference across groups and conditions, reflecting a pronounced blunting of the cortisol response in the normal sleepers in the TSD condition and the sleep-onset insomnia group in both the TSD and control conditions. CONCLUSIONS: Blunted stressor reactivity as a result of sleep deficiency, whether acute or chronic, may reflect reduced resiliency attributable to allostatic load and may put warfighters at increased risk in high-stakes, rapid response scenarios.

Assessing Transporter-Mediated Natural Product-Drug Interactions Via In vitro-In Vivo Extrapolation: Clinical Evaluation With a Probe Cocktail.

The botanical natural product goldenseal can precipitate clinical drug interactions by inhibiting cytochrome P450 (CYP) 3A and CYP2D6. Besides P-glycoprotein, effects of goldenseal on other clinically relevant transporters remain unknown. Established transporter-expressing cell systems were used to determine the inhibitory effects of a goldenseal extract, standardized to the major alkaloid berberine, on transporter activity. Using recommended basic models, the extract was predicted to inhibit the efflux transporter BCRP and uptake transporters OATP1B1/3. Using a cocktail approach, effects of the goldenseal product on BCRP, OATP1B1/3, OATs, OCTs, MATEs, and CYP3A were next evaluated in 16 healthy volunteers. As expected, goldenseal increased the area under the plasma concentration-time curve (AUC0-inf ) of midazolam (CYP3A; positive control), with a geometric mean ratio (GMR) (90% confidence interval (CI)) of 1.43 (1.35-1.53). However, goldenseal had no effects on the pharmacokinetics of rosuvastatin (BCRP and OATP1B1/3) and furosemide (OAT1/3); decreased metformin (OCT1/2, MATE1/2-K) AUC0-inf (GMR, 0.77 (0.71-0.83)); and had no effect on metformin half-life and renal clearance. Results indicated that goldenseal altered intestinal permeability, transport, and/or other processes involved in metformin absorption, which may have unfavorable effects on glucose control. Inconsistencies between model predictions and pharmacokinetic outcomes prompt further refinement of current basic models to include differential transporter expression in relevant organs and intestinal degradation/metabolism of the precipitant(s). Such refinement should improve in vitro-in vivo prediction accuracy, contributing to a standard approach for studying transporter-mediated natural product-drug interactions.

Robustness of inter-individual differences in slow wave sleep for daytime sleep periods after total sleep deprivation with or without caffeine administration: potential implications for around-the-clock operations.

There are large inter-individual differences in slow wave sleep, which constitute a trait or phenotype. We investigated whether the manifestation of this trait is impacted by daytime sleeping after sleep deprivation, and to what extent it is robust to prior caffeine intake. N = 12 subjects underwent three 48 h periods of total sleep deprivation with different caffeine dosing regimens. There were significant, considerable, and robust inter-individual differences in slow wave sleep across nighttime sleep opportunities before, and daytime sleep after, total sleep deprivation, regardless of caffeine dosing. The robustness of this phenotype may have functional implications for individuals in around-the-clock operational settings.

DRD2 C957T genotype modulates the time-on-task effect during total sleep deprivation.

Total sleep deprivation (TSD) and time-on-task (TOT), especially in combination, increase cognitive instability and cause performance impairment. There are large inter-individual differences in TSD and TOT effects which, in part, have a genetic basis. Here, we show that the dopamine receptor D2 C957T genetic polymorphism predicts the magnitude of the TOT effect on a psychomotor vigilance test (PVT) during 38 h of TSD. This finding indicates that dopamine availability in the striatum, where the dopamine receptor D2 is most prevalent, influences the TOT effect, suggesting a role for dopaminergic pathways in sustained attention deficits during sleep loss.

Speed/accuracy trade-off in the effects of acute total sleep deprivation on a sustained attention and response inhibition task.

Total sleep deprivation (TSD) is known to impair sustained attention. However, previously reported effects of TSD on response inhibition are mixed. We administered a "stop-signal" variation of the psychomotor vigilance test, which included 25% of trials requiring withholding of a response to assess response inhibition alongside sustained attention. Participants completed the task at baseline and after 34.5 h of wakefulness. Accuracy was not reduced during TSD. However, response times were significantly slower. A speed/accuracy trade-off allowed participants to effectively withhold responses on inhibition trials and conferred resilience of inhibitory control during TSD under conditions of relatively low time pressure.

Cannabis Use and Cognition in Adults Prescribed Opioids for Persistent Pain.

BACKGROUND: Adults with persistent pain frequently report cannabis use to help manage their symptoms. The impact of cannabis use on cognition in the presence of concurrent symptoms of depression and anxiety is poorly understood. AIMS: Our study explored how cannabis use affects relationships among symptoms of depression, anxiety, and cognition. DESIGN: A cross-sectional survey study was conducted. SETTINGS: Surveys were distributed at outpatient clinics treating adults for pain in the Pacific Northwestern United States. PARTICIPANTS: A total of 150 adults prescribed an opioid medicine for persistent pain were recruited. METHODS: A pencil and paper survey was used to collect several self-reported ratings of cognition, symptoms of depression and anxiety, and the average potency of cannabis consumed as measured by the percentage of delta-9-tetrahydrocannibinol (THC) and cannabidiol (CBD), as well as frequency of cannabis use. RESULTS: Depression, anxiety and cognition significantly worsened as the reported percentage of CBD, THC and overall frequency of cannabis use in the past 30 days increased. Depression and anxiety both significantly predicted worsening cognition in the sample. The relationship between depressive symptoms and cognition was strengthened as reported percentages of CBD use increased. The relationship was the same for anxiety and cognition, although not as strong. CONCLUSIONS: More cannabis use, particularly high CBD products, may be linked with increased symptom burdens and may strengthen relationships between negative affect and cognition. Further cannabis research within persistent pain populations is warranted to add evidence that can assist patients in managing mood and mental processes. Nurses should evaluate how negative affective health symptoms may impact cognition among adults with persistent pain using prescription opioid medications, especially in the context of concurrent cannabis use.

Psychomotor Vigilance Impairment During Total Sleep Deprivation Is Exacerbated in Sleep-Onset Insomnia.

PURPOSE: Individuals with primary insomnia frequently report cognitive impairment as a next-day consequence of disrupted sleep. Studies attempting to quantify daytime impairment objectively in individuals with insomnia have yielded mixed results, with evidence suggesting impairments in aspects of executive functioning but not psychomotor vigilance. It has been suggested that persons with insomnia may have latent performance deficits for which they would be able to compensate effectively under normal daytime circumstances - suggesting that any such deficits may be exposed through perturbation. In this context, we used a laboratory-based total sleep deprivation (TSD) paradigm to investigate psychomotor vigilance performance in individuals with chronic sleep-onset insomnia as compared to healthy normal controls. PARTICIPANTS AND METHODS: Fourteen participants, seven individuals with chronic sleep-onset insomnia (ages 24-40y) and seven age-matched, healthy normal sleepers completed a highly controlled in-laboratory study involving 38 h of TSD. A 10 min and a 3 min version of the psychomotor vigilance test (PVT) were administered every 3 h during TSD. RESULTS: In both the individuals with sleep-onset insomnia and the age-matched normal sleepers, lapses of attention and false starts on the PVT were relatively infrequent during the first 16 h of the TSD period, but increased significantly when wakefulness was extended beyond 16 h. However, the effects of TSD on PVT performance were considerably exacerbated in the sleep-onset insomnia group, which showed about twice as many lapses of attention, more than twice as many false starts, and approximately twice as big a time-on-task effect on the 10 min PVT as the age-matched normal sleepers group, with similar findings on the 3 min PVT. CONCLUSION: These findings indicate that daytime impairment reported by individuals with sleep-onset insomnia has an objective performance component that is exposed during TSD. Thus, persons with sleep-onset insomnia could be at increased risk of performance impairment in settings that involve extended wakefulness. This underscores the importance of treating insomnia and suggests that laboratory sleep deprivation studies could serve to document the effectiveness of treatment approaches.

Cardiac autonomic activity during sleep deprivation with and without caffeine administration.

Caffeine is often consumed to mitigate degraded alertness associated with sleep deprivation. Both caffeine and sleep deprivation have been implicated in cardiovascular disease, but evidence is largely anecdotal. We determined the effects of sleep deprivation and caffeine on markers of cardiac autonomic activity. Twelve healthy young adults completed an 18-day laboratory study. They were exposed to three 48 h sessions of acute total sleep deprivation (TSD), each separated by three recovery days. In randomized, counter-balanced order, subjects received 0 mg (placebo), 200 mg, or 300 mg of caffeine at 12 h intervals during each sleep deprivation session. Every 2 h during scheduled wakefulness, a 15-minute neurobehavioral task battery was administered, during which heart rate (HR) and the high frequency (HF) component of the HR variability power spectrum (HF-HRV) were measured. Caffeine administration decreased HR and increased HF-HRV, indicating elevated parasympathetic activity. The 300 mg caffeine dose did not significantly affect autonomic activity to a greater extent than the 200 mg dose. There was no significant effect of 48 h of TSD on HR, whereas there was a small increase across hours awake in HF-HRV. There was no significant interaction of TSD with caffeine. Circadian rhythmicity in HR and HF-HRV surpassed the magnitude of the effects of caffeine and TSD. Caffeine and acute TSD thus produced only modest changes in cardiac autonomic activity, unlikely to have immediate clinical implications in healthy young adults. However, further research is needed to determine the long-term effects of chronic exposure to sleep loss and/or caffeine on cardiac health, and to determine the generalizability of our findings to non-healthy populations.

Cardiac autonomic activity during simulated shift work.

Shift work leads to adverse health outcomes including increased risk of cardiovascular disease. Heart rate (HR) and heart rate variability (HRV) are measures of cardiac autonomic activity and markers of cardiovascular disease and mortality. To investigate the effects of shift work on cardiac autonomic activity, we assessed the influence of simulated night work on HR and HRV, and dissociated the direct effects of circadian misalignment from those of sleep displacement and altered physical activity patterns. A total of 29 subjects each participated in one of two in-laboratory, simulated shift work studies. In both studies, EKG was continuously monitored via Holter monitors to measure HR and the high frequency (HF) component of HRV (HF-HRV). We found endogenous circadian rhythmicity in HR and HF-HRV. Sleep and waking physical activity, both displaced during simulated night work, had more substantial, and opposite, effects on HR and HF-HRV. Our findings show systematic but complex, interacting effects of time of day, sleep/wake state, and physical activity on cardiac autonomic activity. These effects need to be taken into account when evaluating HR and HRV in shift work settings and when interpreting these measures of cardiac autonomic activity as markers of cardiovascular disease.

Randomized, double-blind, placebo-controlled, crossover study of the effects of repeated-dose caffeine on neurobehavioral performance during 48 h of total sleep deprivation.

RATIONALE: Caffeine is widely used as a countermeasure against neurobehavioral impairment during sleep deprivation. However, little is known about the pharmacodynamic profile of caffeine administered repeatedly during total sleep deprivation. OBJECTIVES: To investigate the effects of repeated caffeine dosing on neurobehavioral performance during sleep deprivation, we conducted a laboratory-based, randomized, double-blind, placebo-controlled, crossover, multi-dose study of repeated caffeine administration during 48 h of sleep deprivation. Twelve healthy adults (mean age 27.4 years, six women) completed an 18-consecutive-day in-laboratory study consisting of three 48 h total sleep deprivation periods separated by 3-day recovery periods. During each sleep deprivation period, subjects were awakened at 07:00 and administered caffeine gum (0, 200, or 300 mg) at 6, 18, 30, and 42 h of wakefulness. The Psychomotor Vigilance Test and Karolinska Sleepiness Scale were administered every 2 h. RESULTS: The 200 and 300 mg doses of caffeine mitigated neurobehavioral impairment across the sleep deprivation period, approaching two-fold performance improvements relative to placebo immediately after the nighttime gum administrations. No substantive differences were noted between the 200 mg and 300 mg caffeine doses, and adverse effects were minimal. CONCLUSIONS: The neurobehavioral effects of repeated caffeine dosing during sleep deprivation were most evident during the circadian alertness trough (i.e., at night). The difference between the 200 mg and 300 mg doses, in terms of the mitigation of performance impairment, was small. Neither caffeine dose fully restored performance to well-rested levels. These findings inform the development of biomathematical models that more accurately account for the time of day and sleep pressure-dependent effects of caffeine on neurobehavioral performance during sleep loss.

Sex differences in opioid use and medical issues during buprenorphine/naloxone treatment.

BACKGROUND: There are sex differences in buprenorphine/naloxone clinical trials for opioid use. While women have fewer opioid-positive urine samples, relative to men, a significant decrease in opioid-positive samples was found during treatment for men, but not women. In order to inform sex-based approaches to improve treatment outcomes, research is needed to determine if opioid use, and predictors of opioid use, differs between men and women during treatment. OBJECTIVES: To test for sex differences in opioid use during a buprenorphine/naloxone clinical trial and determine if sex differences exist in the associations between addiction-related problem areas and opioid use over the course of the trial. METHOD: This secondary data analysis of the National Drug Abuse Treatment Clinical Trials Network (CTN) 0003 examined sex differences (men = 347, women = 169) in opioid-positive samples in a randomized clinical trial comparing 7-day vs. 28-day buprenorphine/naloxone tapering strategies. Addiction-related problem areas were defined by Addiction Severity-Lite (ASI-L) domain composite scores. RESULTS: Women were more likely than men to use opioids during the course of the buprenorphine/naloxone clinical trial (B = .33, p = .01) and medical issues were positively related to submitting an opioid-positive sample during treatment for women (B = 1.67, p = .01). No ASI-L domain composite score was associated with opioid-positive samples during treatment for men. CONCLUSION: Women were more likely than men to use opioids during the course of the buprenorphine/naloxone clinical trial, and medical issues predicted opioid use during treatment for women but not men. Complementary treatment for medical problems during opioid replacement therapy may benefit women.

3-minute smartphone-based and tablet-based psychomotor vigilance tests for the assessment of reduced alertness due to sleep deprivation.

The psychomotor vigilance test (PVT) is widely used to measure reduced alertness due to sleep loss. Here, two newly developed, 3-min versions of the psychomotor vigilance test, one smartphone-based and the other tablet-based, were validated against a conventional 10-min laptop-based PVT. Sixteen healthy participants (ages 22-40; seven males, nine females) completed a laboratory study, which included a practice and a baseline day, a 38-h total sleep deprivation (TSD) period, and a recovery day, during which they performed the three different versions of the PVT every 3 h. For each version of the PVT, the number of lapses, mean response time (RT), and number of false starts showed statistically significant changes across the sleep deprivation and recovery days. The number of lapses on the laptop was significantly correlated with the numbers of lapses on the smartphone and tablet. The mean RTs were generally faster on the smartphone and tablet than on the laptop. All three versions of the PVT exhibited a time-on-task effect in RTs, modulated by time awake and time of day. False starts were relatively rare on all three PVTs. For the number of lapses, the effect sizes across 38 h of TSD were large for the laptop PVT and medium for the smartphone and tablet PVTs. These results indicate that the 3-min smartphone and tablet PVTs are valid instruments for measuring reduced alertness due to sleep deprivation and restored alertness following recovery sleep. The results also indicate that the loss of sensitivity on the 3-min PVTs may be mitigated by modifying the threshold defining lapses.

Sleep and performance in simulated Navy watch schedules.

To operate Navy ships 24h per day, watchstanding is needed around the clock, with watch periods reflecting a variety of rotating or fixed shift schedules. The 5/15 watch schedule cycles through watch periods with 5h on, 15h off watch, such that watches occur 4h earlier on the clock each day - that is, the watches rotate backward. The timing of sleep varies over 4-day cycles, and sleep is split on some days to accommodate nighttime watchstanding. The 3/9 watch schedule cycles through watch periods with 3h on, 9h off watch, allowing for consistent sleep timing over days. In some sections of the 3/9 watch schedule, sleep may need to be split to accommodate nighttime watchstanding. In both the 5/15 and 3/9 watch schedules, four watch sections alternate to cover the 24h of the day. Here we compared sleep duration, psychomotor vigilance and subjective sleepiness in simulated sections of the 5/15 and 3/9 watch schedules. Fifteen healthy male subjects spent 6 consecutive days (5 nights) in the laboratory. Sleep opportunities were restricted to an average of 6.5h daily. Actigraphically estimated sleep duration was 5.6h per watch day on average, with no significant difference between watch sections. Sleep duration was not reduced when sleep opportunities were split. Psychomotor vigilance degraded over watch days, and tended to be more variable in the 5/15 than in the 3/9 watch sections. These laboratory-based findings suggest that Navy watch schedules are associated with cumulative sleep loss and a build-up of fatigue across days. The fixed watch periods of the 3/9 watch schedule appear to yield more stable performance than the backward rotating watch periods of the 5/15 watch schedule. Optimal performance may require longer and more consistent daily opportunities for sleep than are typically obtained in Navy operations.

Pharmacokinetic analysis and comparison of caffeine administered rapidly or slowly in coffee chilled or hot versus chilled energy drink in healthy young adults.

CONTEXT: There is a paucity of data describing the impact of type of beverage (coffee versus energy drink), different rates of consumption and different temperature of beverages on the pharmacokinetic disposition of caffeine. Additionally, there is concern that inordinately high levels of caffeine may result from the rapid consumption of cold energy drinks. OBJECTIVE: The objective of this study was to compare the pharmacokinetics of caffeine under various drink temperature, rate of consumption and vehicle (coffee versus energy drink) conditions. MATERIALS: Five caffeine (dose = 160 mg) conditions were evaluated in an open-label, group-randomized, crossover fashion. After the administration of each caffeine dose, 10 serial plasma samples were harvested. Caffeine concentration was measured via liquid chromatography-mass spectrometry (LC-MS), and those concentrations were assessed by non-compartmental pharmacokinetic analysis. The calculated mean pharmacokinetic parameters were analyzed statistically by one-way repeated measures analysis of variance (RM ANOVA). If differences were found, each group was compared to the other by all pair-wise multiple comparison. RESULTS: Twenty-four healthy subjects ranging in age from 18 to 30 completed the study. The mean caffeine concentration time profiles were similar with overlapping SDs at all measured time points. The ANOVA revealed significant differences in mean Cmax and Vd ss/F, but no pair-wise comparisons reached statistical significance. No other differences in pharmacokinetic parameters were found. DISCUSSION: The results of this study are consistent with previous caffeine pharmacokinetic studies and suggest that while rate of consumption, temperature of beverage and vehicle (coffee versus energy drink) may be associated with slightly different pharmacokinetic parameters, the overall impact of these variables is small. CONCLUSION: This study suggests that caffeine absorption and exposure from coffee and energy drink is similar irrespective of beverage temperature or rate of consumption.

Examining the factor structure of the Clinical Opiate Withdrawal Scale: A secondary data analysis from the National Drug Abuse Treatment Clinical Trials Network (CTN) 0003.

BACKGROUND: The Clinical Opiate Withdrawal Scale (COWS) is used to assess withdrawal in clinical trials and practice. The aims of this study were to examine the inter-item correlations and factor structure of the COWS in opioid-dependent men and women. METHODS: This is a secondary data analysis of the National Drug Abuse Treatment Clinical Trials Network 0003, a randomized clinical trial that compared buprenorphine/naloxone tapering strategies. The trial included 11 sites in 10 US cities. Participants were opioid-dependent individuals (n=516) that had data on the COWS. The COWS at study baseline was analyzed in this study. RESULTS: Inter-item correlations showed weak to moderate relationships among the items. A 1-factor model did not fit the data for men (comparative fit index (CFI)=.801, root mean square error of approximation (RMSEA)=.073, weighted root mean square residual (WRMR)=1.132) or women (CFI=.694, RMSEA=.071, WRMR=.933), where resting pulse rate was not related to withdrawal for men, and yawning and gooseflesh skin was not related to withdrawal for women. A reduced model comprised of only the 8 items that were significantly related to the construct of withdrawal in both men and women, and an exploratory 2-factor model, were also assessed but not retained due to inconsistencies across gender. CONCLUSIONS: When traditional psychometric models are applied to the COWS, it appears that the scale may not relate to a single underlying construct of withdrawal. Further research testing the hypothesized factor structure in other opioid-dependent samples is needed.