Pharmacokinetics of Sustained-Release and Transdermal Buprenorphine in G?ttingen Minipigs (Sus scrofa domestica)

The opioid buprenorphine has been shown to provide adequate postoperative analgesia in both companion and laboratory animals. However, its use is still hindered by the need for multiple parenteral injections to achieve continuous analgesia. The purpose of the current study was to conduct a pharmacokinetic analysis of 2 new long-acting formulations of buprenorphine—an injectable sustained-release buprenorphine (SRB) and a transdermal buprenorphine (TDB) patch—in healthy Göttingen minipigs by using liquid chromatography–electrospray ionization–tandem mass spectrometry. Administration of 0.18 mg/kg SC SRB and 30 μg/h TDB achieved AUC_0-Tlast of 221.6 ± 26.8 and 25.2 ± 3.9 ng × h/mL, respectively, compared with 9.7 ± 1.4 ng*h/mL for 0.02 mg/kg IV buprenorphine. By using a hypothesized therapeutic plasma buprenorphine concentration threshold of 0.1 ng/mL, therapeutic concentrations were achieved at the first study time point (5 to 30 min) and lasted an average of 8.0 ± 1.3 h for intravenous buprenorphine and 264.0 ± 32.2 h for SRB. TDB achieved therapeutic concentrations in 12 to 24 h after patch application, which lasted until the patch was removed at 72 h. The results of this study suggest that SRB and TDB are long-acting alternatives for pain management, and their use could decrease animal handling and stress, thereby simplifying pain management and improving welfare in laboratory swine.Abbreviation: AUC_0-Tlast, AUC to last quantifiable plasma concentration; C_max, peak plasma concentration; SRB, sustained-release buprenorphine; TDB, transdermal buprenorphine; T_max, time of peak plasma concentration; VAP, vascular access portBuprenorphine is a semisynthetic, partial µ-opioid receptor agonist used for analgesia in many companion and laboratory animal species.^7,29 Its popularity is due to a lower risk of respiratory depression and prolonged analgesia in comparison to pure µ-opioid agonists, such as fentanyl and hydromorphone.^7,29 Buprenorphine is often the analgesic of choice in swine because a single 0.01- to 0.1-mg/kg dose can provide analgesia for as long as 8 to 12 h with minimal adverse effects.^7,33Swine are valuable animal models for cardiovascular, digestive, urinary, and integumentary research.^32,33 As a result, laboratory swine often undergo major surgeries resulting in considerable postoperative pain. To provide analgesia of adequate efficacy and duration throughout the postoperative period, multiple injections of buprenorphine are necessary. Repeated injections and the associated handling and momentary pain can become increasingly stressful to swine with each subsequent injection. In addition, the recurrent peak and trough plasma concentrations associated with multiple parenteral injections potentially result in periods of inadequate pain relief at trough levels. A buprenorphine formulation that can be administered less frequently or in a noninjectable formulation but that can deliver a controlled and constant amount of drug over time potentially would eliminate the disadvantages of repeated dosing.Recently 2 new formulations of buprenorphine have become available: an injectable sustained-release buprenorphine (SRB) and a transdermal buprenorphine (TDB) patch. Both formulations are designed to provide a consistent, controlled release of buprenorphine over the course of several days after a single administration. Recent studies in mice,⁴ rats,⁸ cats,⁵ and dogs²⁴ support the ability of SRB to provide an extended duration of analgesia compared with that of the standard buprenorphine formulation. In addition, therapeutic plasma concentrations have been shown to last as long as 72 h in rats⁸ and 5 d in both macaques²³ and dogs.²⁴ Although SRB has been studied in several animal species, it has yet to be evaluated in swine.TDB has been extensively used in human medicine however, unlike SRB, there are relatively few studies evaluating the efficacy of TDB in animals. High-dose (35, 52.5, and 70 µg/h) and low-dose (5, 7.5, 10, 15, and 20 µg/h) TDB patches, lasting 3 and 7 d, respectively, have been used effectively in humans to treat moderate to severe, chronic pain such as lower back pain and that due to osteoarthritis or cancer.^{6,9,14,20,26,30,31,35} Currently, TDB studies in animals have only been performed by using high-dose patches and have been limited to dogs^1,21,25 and cats.²² In dogs, detectable plasma buprenorphine concentrations have been shown to last 72 h after the application of a single 52.5-µg/h TDB patch²⁵ and 108 h with a 70-µg/h patch.¹ In addition, a 70-µg/h TDB patch has been reported to provide equal postoperative analgesia in dogs that underwent an ovariohysterectomy when compared with 0.2 mg/kg of the standard formulation of buprenorphine administered subcutaneously every 6 h during the postoperative period. ²¹ To date, TDB has not been evaluated in swine.Because of the success seen with both SRB and TDB in other species, further investigation into the pharmacokinetics and clinical efficacy of SRB and TDB in swine is warranted. These buprenorphine formulations have the potential for extended drug delivery with a single administration and thus the potential to positively affect animal welfare by minimizing animal stress. The purpose of this study was to evaluate the pharmacokinetics of these 2 new formulations of buprenorphine compared with a standard dose of intravenous buprenorphine in Göttingen minipigs. We hypothesized that both SRB and TDB would achieve quantifiable plasma buprenorphine concentrations above an estimated therapeutic threshold of 0.1 ng/mL for a longer duration than that of a standard dose of intravenous buprenorphine, thus supporting the use of these new formulations as long-acting analgesics for pain management in swine.     

Resident‐staff interactions: a challenge for quality residential aged care

Objectives: This paper describes one facet of a study to develop and implement a “best practice model” of residential care for older people. The purpose of this facet of the larger study was to describe the current interactional context of a residential aged care facility. Method: A total of 2,848 observations of resident‐staff interactions were made and coded according to Baltes' observational schedule. Coder inter‐rater reliability was maintained at 90% (Cohen's Kappa). Results: Residents were alone 40% of the time they were observed. The dominant pattern of staff interaction with residents was to not engage in direct verbal or nonverbal communication or physical contact. The dominant response by staff to resident independence was to make no response. The dominant staff response to resident dependence was to support that dependence. Conclusions: Residential aged care practice continues to be focused on technology, and tasks and interactions between residents and staff continue to be dependency‐supporting.     

The role of cognitions in bulimia nervosa

This research investigated several characteristics of the cognitions of 15 bulimics, 15 repetitive dieters, and 15 nonbulimic, nondieting women using an in vivo thought-sampling procedure. Following training, subjects self-monitored their thoughts every 30 min for two randomly selected days. Subjects' cognitions were rated by independent raters on content, affective tone, accuracy, and adherence to a dichotomous thinking style. Results indicated bulimics reported significantly greater proportions of eating- and weight-related thoughts than non-eating-disordered control subjects and significantly greater proportions of negative affective thoughts than repetitive dieters and non-eating-disordered control subjects. Furthermore, bulimics were significantly more likely to report distorted eating- and weight-related thoughts than the remaining groups. While bulimics were not significantly more preoccupied with thoughts of food independent of eating, thoughts of weight and body shape composed a significantly greater proportion of their eating- and weight-related thoughts than those of the remaining groups. Theoretical and clinical implications of these findings are discussed.     

Understanding consumers' health information preferences: development and validation of a brief screening instrument

The impact of health communication is generally enhanced when it is targeted or tailored to the needs of a specific population or individual. In a segmentation analysis of the U.S adult population - using data from 2,636 respondents to a mail panel survey - we identified four segments of the adult population that vary significantly with regard to health information preferences based on their degree of engagement in health enhancement, and their degree of independence in health decision making. We also created a brief (10 item), easy-to-administer screening instrument that indicates into which segment people fall. The purpose of this article is to describe the segments, and the screening instrument, and to present initial tests of its validity. We believe this instrument offers a practical tool for differentiating motivationally coherent subgroups of the adult population with regard to their health information preferences, and therefore may have practical value in improving health communication and health services provision efforts. Additional research is needed to further validate the tool and test its utility in guiding the creation of targeted health messages and programs.     

The effects of varied extinction procedures on contingent cue-induced reinstatement in Sprague-Dawley rats

Rationale

Cue exposure therapy, which attempts to limit relapse by reducing reactivity to cocaine-paired cues through repeated exposures, has had limited success.

Objectives

The current experiments examined cocaine cue-induced anxiogenesis and investigated whether a model of cue exposure therapy would reduce reinstatement of cocaine seeking in rats with a history of cocaine self-administration.

Methods

Male rats experienced daily intravenous cocaine self-administration. Rats then experienced exposure to either the self-administration context or the context plus noncontingent presentations of cocaine-paired cues. Immediately following exposure, anxiety-like behavior was measured using elevated plus maze and defensive burying tests. In a second group of rats, self-administration was followed by 7 days of exposure to the context, context + noncontingent cue exposure, lever extinction, or cue + lever extinction. All animals then underwent two contingent cue-induced reinstatement tests separated by 7 days of lever extinction.

Results

Exposure to noncontingent cocaine-paired cues in the self-administration context increased anxiety-like behavior on the defensive burying test. Animals that experienced lever + cue extinction displayed the least cocaine seeking on the first reinstatement test, and lever extinction reduced cocaine seeking below context exposure or context + noncontingent cue exposure. All animals had similar levels of cocaine seeking on the second reinstatement test.

Conclusion

Noncontingent cue exposure causes anxiety, and noncontingent cue and context exposure are less effective at reducing contingent cue-induced reinstatement than lever or lever + cue extinction. These data indicate that active extinction of the drug-taking response may be critical for reduction of relapse proclivity in former cocaine users.     

Characterization of the corpus callosum in very preterm and full-term infants utilizing MRI

The corpus callosum is the largest white matter tract, important for interhemispheric communication. The aim of this study was to investigate and compare corpus callosum size, shape and diffusion characteristics in 106 very preterm infants and 22 full-term infants. Structural and diffusion magnetic resonance images were obtained at term equivalent. The corpus callosum was segmented, cross-sectional areas were calculated, and shape was analyzed. Fractional anisotropy, mean, axial and radial diffusivity measures were obtained from within the corpus callosum, with additional probabilistic tractography analysis. Very preterm infants had significantly reduced callosal cross-sectional area compared with term infants (p=0.004), particularly for the mid-body and posterior sub-regions. Very preterm callosi were more circular (p=0.01). Fractional anisotropy was lower (p=0.007) and mean (p=0.006) and radial (p=0.001) diffusivity values were higher in very preterm infants' callosi, particularly at the anterior and posterior ends. The volume of tracts originating from the corpus callosum was reduced in very preterm infants (p=0.001), particularly for anterior mid-body (p=0.01) and isthmus tracts (p=0.04). This study characterizes callosal size, shape and diffusion in typically developing infants at term equivalent age, and reports macrostructural and microstructural abnormalities as a result of prematurity.     

The relationship of character strengths to sexual behaviors and related risks among African American adolescents

Background: Relatively few studies have examined positive character traits that are associated with lower HIV/STD risks.Purpose: In the present study, the relationships of character strengths with sexual behaviors and attitudes were assessed among 383 African-American adolescents.Method: Character strengths were measured using the Values in Action Inventory of Strengths. Because the strengths were highly inter-correlated, stepwise discriminant function analyses were utilized to assess their independent associations with sexual behaviors and attitudes.Results: Greater Love of Learning was related to self-reported abstinence from sexual intercourse for boys and self-reported abstinence from drug use for boys and girls. Greater Love of Learning and Curiosity were related to the belief in no premarital sex for boys, whereas only Curiosity was significant for girls. Prudence was related to reported abstinence from sexual intimacy (e.g., touching or kissing). Judgment was related to sexual initiation efficacy for girls and boys, whereas Leadership was only significant for girls.Conclusions: The findings suggest that character strengths may be associated with lower levels of sexual behaviors and sex-related beliefs among a sample of African-American adolescents. The data for the present study were collected at Jackson State University. This research was supported by grants from the Values in Action Institute of the Mayerson Foundation and the National Institute of Child Health & Human Development (5R01HD039122-03).