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Kappa-opioid induced regulation of mu-opioid mediated effects on EEG power spectra and behavior in ratsThe regulatory effects of kappa-opioid ligands on mu-opioid induced changes in EEG power spectra and behavior were evaluated in rats receiving various acute and chronic treatments. Rats were implanted with cortical EEG electrodes and i.c.v. and/or intravenous (i.v.) cannulae. EEG spectral parameters were derived from digitized EEG samples with spectral analysis techniques. Pretreatment with intracerebroventricular (i.c.v.) injection of dynorphin, morphine and dynorphin/morphine resulted in quantitative and qualitative changes in EEG power spectra in rats given i.c.v. morphine 24 hr later. I.c.v. injections of morphine (20 {dollar}\mu{dollar}g/rat) produced high-voltage, slow-wave EEG bursts (1-10 Hz). Injections of i.c.v. morphine in rats pretreated with i.c.v. dynorphin (20 {dollar}\mu{dollar}g/rat), morphine (20 {dollar}\mu{dollar}g/rat) or dynorphin/morphine twenty-four hours earlier, produced quantitative increases in absolute EEG spectral power. Injections of i.c.v. morphine in rats pretreated with i.c.v. dynorphin/morphine 24 hr earlier, also produced qualitatively different EEG power spectra with a predominant peak in the 4-6 Hz band, similar to the EEG power spectra seen after acute administration of kappa opioids. Correlated changes in sensitivity to antagonism of these EEG effects by naloxone were also found. Thus, Dynorphin may act as a possible regulator of certain {dollar}\mu{dollar}-opioid receptor-associated phenomena, such as morphine-induced EEG bursts at a binding site which is nor-BNI insensitive. Chronic administration of morphine, a {dollar}\mu{dollar}-opioid selective agonist, for seven days resulted in tolerance development to EEG bursts and EEG absolute power, but not to latency to onset of slow-wave sleep (SWS). Chronic morphine administration was also associated with increases in the duration of hyperexcitability. Chronic administration of U-50,488H, a selective {dollar}\kappa{dollar}-agonist, was not associated with any changes in the duration of EEG bursts, latency to onset of SWS or duration of sedation. The coadministration of U-50,488H and morphine produced no significant tolerance development to the duration of EEG bursts and latency to onset of sleep, but increased the duration of sedation. Morphine or ethylketocyclazocine (EKC) challenges before and after chronic treatment with either morphine or U-50,488H resulted in greater tolerance development to the duration of EEG bursts and to increases in EEG absolute spectral power compared to the group receiving chronic coadministration. (Abstract shortened with permission of author.)
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Predictors and subsequent healthcare utilization associated with CDC-guideline opioid thresholds among commercially insured new chronic opioid usersBackground: The receipt and subsequent healthcare utilization surrounding new chronic opioid users (NCOUs) is multifactorial and includes clinical, demographic, and state-level factors. This study evaluated i) predictors for receipt of chronic opioid therapy informed by CDC-guideline morphine milligram equivalent (MME)/day recommendations and the short-term healthcare utilization measured by ii) total healthcare costs and iii) all-cause hospitalization after new chronic opioid use. Methods: We conducted a retrospective cohort study using IQVIA PharMetrics® Plus for Academics commercial claims with NCOUs identified between January 2014 through March 2015. NCOUs were defined as having at least 60-days coverage of opioids within a 90-day period with at least a 30-day opioid-free period prior to the date of the first qualifying opioid prescription. The short-term healthcare observation period began the 91st day or the day after last day coverage of the chronic opioid period, whichever is sooner. We placed NCOUs in one of three-tiered risk-based opioid thresholds categories: low (> 0 to < 50 MME/day), medium (≥ 50 to < 90 MME/day), and high (≥ 90 MME/day). A multinomial logistic regression was used to evaluate the impact of prescription drug monitoring program (PDMP) rigor on the receipt of respective opioid thresholds. A generalized linear model and multivariable logistic regression was utilized to evaluate the incremental total healthcare costs (ITHC) and odds of incurring a hospitalization between the thresholds, respectively. Results: A total of 16,684 NCOUs were identified. Among the NCOUs, a state with high PDMP robustness had lower odds of receiving medium (0.74; 0.62-0.90) and high (0.74; 0.59-0.92) thresholds when compared to low. When compared to low, medium and high were found to have higher ITHC, (US$, 95% Confidence Interval [CI]) $1,429 (947-1,911) and $1,775 (1,183-2,368), respectively. When compared to medium, the ITHC for high $267 (-310-844) was non-significant. When evaluating odds of all-cause hospitalization (adjusted odds; 95% CI), when compared to low, no difference was identified with medium (1.01; 0.94-1.28) or high (1.01; 0.84-1.22). Conclusion: Among NCOUs, PDMP robustness was found to decrease the odds of subsequent receipt of higher thresholds. However, short-term healthcare costs and all-cause hospitalization did not differ among the thresholds.
