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STUDY OBJECTIVES: Patients with severe OSA consume greater amounts of cholesterol, protein, and fat as well as have greater caloric expenditure. However, it is not known whether their activity levels or diet change after treatment with CPAP. To investigate this issue, serial assessments of activity and dietary intake were performed in the Apnea Positive Pressure Long-term Efficacy Study (APPLES); a 6-month randomized controlled study of CPAP vs. sham CPAP on neurocognitive outcomes. METHODS: Subjects were recruited into APPLES at 5 sites through clinic encounters or public advertisement. After undergoing a diagnostic polysomnogram, subjects were randomized to CPAP or sham if their AHI was ≥ 10. Adherence was assessed using data cards from the devices. At the Tucson and Walla Walla sites, subjects were asked to complete validated activity and food frequency questionnaires at baseline and their 4-month visit. RESULTS: Activity and diet data were available at baseline and after 4 months treatment with CPAP or sham in up to 231 subjects (117 CPAP, 114 Sham). Mean age, AHI, BMI, and Epworth Sleepiness Score (ESS) for this cohort were 55 ± 13 [SD] years, 44 ± 27 /h, 33 ± 7.8 kg/m(2), and 10 ± 4, respectively. The participants lacking activity and diet data were younger, had lower AHI and arousal index, and had better sleep efficiency (p < 0.05). The BMI was higher among women in both CPAP and Sham groups. However, compared to women, men had higher AHI only in the CPAP group (50 vs. 34). Similarly, the arousal index was higher among men in CPAP group. Level of adherence defined as hours of device usage per night at 4 months was significantly higher among men in CPAP group (4.0 ± 2.9 vs. 2.6 ± 2.6). No changes in consumption of total calories, protein, carbohydrate or fat were noted after 4 months. Except for a modest increase in recreational activity in women (268 ± 85 vs. 170 ± 47 calories, p < 0.05), there also were no changes in activity patterns. CONCLUSION: Except for a modest increase in recreational activity in women, OSA patients treated with CPAP do not substantially change their diet or physical activity habits after treatment. .

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STUDY OBJECTIVE: To determine the impact of continuous positive airway pressure (CPAP) on weight change in persons with obstructive sleep apnea (OSA). DESIGN SETTING AND PARTICIPANTS: The Apnea Positive Pressure Long-term Efficacy Study (APPLES) was a 6-month, randomized, double-blinded sham-controlled multicenter clinical trial conducted at 5 sites in the United States. Of 1,105 participants with an apnea hypopnea index ≥ 10 events/ hour initially randomized, 812 had body weight measured at baseline and after 6 months of study. INTERVENTION: CPAP or Sham CPAP. MEASUREMENTS: Body weight, height, hours of CPAP or Sham CPAP use, Epworth Sleepiness Scale score. RESULTS: Participants randomized to CPAP gained 0.35 ± 5.01 kg, whereas those on Sham CPAP lost 0.70 ± 4.03 kg (mean ± SD, p = 0.001). Amount of weight gain with CPAP was related to hours of device adherence, with each hour per night of use predicting a 0.42 kg increase in weight. This association was not noted in the Sham CPAP group. CPAP participants who used their device ≥ 4 h per night on ≥ 70% of nights gained the most weight over 6 months in comparison to non-adherent CPAP participants (1.0 ± 5.3 vs. -0.3 ± 5.0 kg, p = 0.014). CONCLUSIONS: OSA patients using CPAP may gain a modest amount of weight with the greatest weight gain found in those most compliant with CPAP. COMMENTARY: A commentary on this article appears in this issue on page 995. CITATION: Quan SF; Budhiraja R; Clarke DP; Goodwin JL; Gottlieb DJ; Nichols DA; Simon RD; Smith TW; Walsh JK; Kushida CA. Impact of treatment with continuous positive airway pressure (CPAP) on weight in obstructive sleep apnea.

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Opioids induce respiratory depression via activation of µ-opioid receptors at specific sites in the central nervous system including the pre-Bötzinger complex, a respiratory rhythm generating area in the pons. Full opioid agonists like morphine and fentanyl affect breathing with onset and offset profiles that are primarily determined by opioid transfer to the receptor site, while the effects of partial opioid agonists such as buprenorphine are governed by transfer to the receptor site together with receptor kinetics, in particular dissociation kinetics. Opioid-induced respiratory depression is potentially fatal but may be reversed by the opioid receptor antagonist naloxone, an agent with a short elimination half-life (30 min). The rate-limiting factor in naloxone-reversal of opioid effect is the receptor kinetics of the opioid agonists that requires reversal. Agents with slow dissociation kinetics (buprenorphine) require a continuous naloxone infusion while agents with rapid kinetics (fentanyl) will show complete reversal upon a single naloxone dose. Since naloxone is non-selective and will reverse analgesia as well, efforts are focused on the development of compounds that reverse opioid-induced respiratory depression without affecting analgesic efficacy. Such agents include ampakines and serotonin agonists which are aimed at selectively enhancing central respiratory drive. A novel approach is aimed at the reduction of respiratory depression from opioid-activation of (micro-)glia cells in the pons and brainstem using micro-glia cell stabilizers. Since this approach simultaneously enhances opioid analgesic efficacy it seems an attractive alternative to the classical reversal strategies with naloxone.

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Morphine is the first choice of treatment of severe post-operative pain, despite the occurrence of often discomforting (post-operative nausea or vomiting (PONV)) and sometimes dangerous (sedation, respiratory depression) side effects. Literature data indicate that morphine's active metabolite, morphine-6-glucuronide (M6G), is a powerful analgesic with a possibly more favourable side-effect profile. In this multi-centre randomised controlled clinical trial patients undergoing major abdominal surgery were randomised to M6G or morphine treatment. Treatment started 30-60 min prior to the end of surgery and was continued postoperatively, after patients were titrated to comfort, via patient-controlled analgesia (PCA) for 24-48 h. Pain intensity, nausea, vomiting and sedation scores were collected at regular intervals. In the study 268 patients were randomised to M6G and 249 to morphine. Withdrawal due to insufficient pain relief occurred predominantly just after surgery and was higher in the M6G group (16.8%) than in the morphine group (8.8%), suggesting a slower onset of analgesia for M6G compared to morphine. Subjects who continued on PCA remained equi-analgesic throughout the study. During the first 24h, nausea levels showed a 27% difference in favour of M6G which narrowly failed to reach statistical significance (P=0.052). Sub-analysis showed a significant reduction in nausea levels in females on M6G (30% difference, P=0.034). In all patients, similar reductions of 30-35% were observed in anti-emetic use, vomiting, PONV (a combined measure of nausea and vomiting) in favour of M6G, persisting for the first 24h postoperatively. Reductions in sedation were observed in the first 4h post-operative period for M6G patients.

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BACKGROUND: Opioid-induced respiratory depression is antagonized effectively by the competitive opioid receptor antagonist naloxone. However, to fully understand the complex opioid agonist-antagonist interaction, the effects of various naloxone doses on morphine and morphine-6-glucuronide (M6G)-induced respiratory depression were studied in healthy volunteers. METHODS: Twenty-four subjects received 0.15 mg/kg morphine intravenously at t = 0 followed by placebo, 200 or 400 microg naloxone at t = 30 min. Thirty-two subjects received 0.3 mg/kg M6G intravenously at t = 0 followed by placebo, 25, 100, or 400 microg naloxone at t = 55 min. There were a total of 8 subjects per treatment group. Respiration was measured on a breath-to-breath basis at constant end-tidal Pco2. A mechanism-based pharmacokinetic-pharmacodynamic model consisting of a part describing biophase equilibration and a part describing receptor association-dissociation kinetics was used to analyze the data. RESULTS: Naloxone reversal of M6G-induced respiratory depression developed more slowly than reversal of the respiratory effect of morphine. A simulation study revealed that this was related to the slower receptor association-dissociation kinetics of M6G (koff M6G = 0.0327 +/- 0.00455 min versus morphine 0.138 +/- 0.0148 min; values are typical +/-SE). Duration of naloxone reversal was longer for M6G. This was related to the three- to fourfold greater potency of naloxone as an antagonist against M6G compared with morphine. Increasing the naloxone dose had no effect on the speed of reversal, but it did extend reversal duration. CONCLUSIONS: Naloxone reversal of the opioid effect is dependent on the receptor association-dissociation kinetics of the opioid that needs reversal with respect to the rate of reversal. The pharmacodynamics of naloxone determines reversal magnitude and duration.

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Opioid treatment of pain is generally safe with 0.5% or less events from respiratory depression. However, fatalities are regularly reported. The only treatment currently available to reverse opioid respiratory depression is by naloxone infusion. The efficacy of naloxone depends on its own pharmacological characteristics and on those (including receptor kinetics) of the opioid that needs reversal. Short elimination of naloxone and biophase equilibration half-lives and rapid receptor kinetics complicates reversal of high-affinity opioids. An opioid with high receptor affinity will require greater naloxone concentrations and/or a continuous infusion before reversal sets in compared with an opioid with lower receptor affinity. The clinical approach to severe opioid-induced respiratory depression is to titrate naloxone to effect and continue treatment by continuous infusion until chances for renarcotization have diminished. New approaches to prevent opioid respiratory depression without affecting analgesia have led to the experimental application of serotinine agonists, ampakines, and the antibiotic minocycline.

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The purpose of this study was to examine whether dietary habits and physical activity patterns were independently associated with severity of sleep disordered breathing (SDB) in adults diagnosed with obstructive sleep apnea. Data collected from 320 adults participating in an ancillary study of The Apnea Positive Pressure Long-term Efficacy Study were analyzed as a cross-sectional assessment at study baseline. The respiratory disturbance index (RDI) was used as a measure of the severity of sleep disordered breathing. Separate linear regression models were fitted using RDI as the independent variable and various preselected components of dietary intake and physical activity as the dependent variables. The results indicated that even after adjusting for BMI, age, and daytime sleepiness, subjects with very severe and extremely severe SDB (RDI > or =50) consumed a diet that was higher in cholesterol, protein, total fat, and total saturated fatty acids. These findings were most evident among women. For all participants, those with RDI > or =50 in comparison to those <50, on average consumed 88.16 more mg of cholesterol per day (95% CI: 44.45 to 131.86, p < 0.001). Among the women participants only, those with RDI > or =50 in comparison to those <50, on average consumed 21.96 more grams of protein (95% CI: 2.64 to 41.29, p = 0.026), 27.75 more grams of total fat (95% CI: 3.38 to 52.11, p = 0.026), and 9.24 more grams of saturated fatty acids (95% CI: 0.67 to 17.80, p = 0.035). Furthermore, those with an RDI > or =50 had a 224.58 greater caloric expenditure than those with RDI <50 from all activities including work and sleep (95% CI: 40.98 to 408.18, p = 0.017). Although significant results were seen in a reduction of physical activity from recreational activities, this finding was explained by the increase in BMI associated with higher levels of RDI.

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Morphine-6-glucuronide (M6G) appears to show equivalent analgesia to morphine but to have a superior side-effect profile in terms of reduced liability to induce nausea and vomiting and respiratory depression. The purpose of this review is to examine the evidence behind this statement and to identify the possible reasons that may contribute to the profile of M6G. The vast majority of available data supports the notion that both M6G and morphine mediate their effects by activating the micro-opioid receptor. The differences for which there is a reasonable consensus in the literature can be summarized as: (1) Morphine has a slightly higher affinity for the micro-opioid receptor than M6G, (2) M6G shows a slightly higher efficacy at the micro-opioid receptor, (3) M6G has a lower affinity for the kappa-opioid receptor than morphine, and (4) M6G has a very different absorption, distribution, metabolism, and excretion (ADME) profile from morphine. However, none of these are adequate alone to explain the clinical differences between M6G and morphine. The ADME differences are perhaps most likely to explain some of the differences but seem unlikely to be the whole story. Further work is required to examine further the profile of M6G, notably whether M6G penetrates differentially to areas of the brain involved in pain and those involved in nausea, vomiting, and respiratory control or whether micro-opioid receptors in these brain areas differ in either their regulation or pharmacology.

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