Attitudes towards a maintenance (-agonist) treatment approach in high-dose benzodiazepine-dependent patients: a qualitative study

BACKGROUND High-dose benzodiazepine dependence constitutes a major clinical concern. Although withdrawal treatment is recommended, it is unsuccessful for a significant proportion of affected patients. More recently, a benzodiazepine maintenance approach has been suggested as an alternative for patients' failing discontinuation treatment. While there is some data supporting its effectiveness, patients' perceptions of such an intervention have not been investigated. METHODS An exploratory qualitative study was conducted among a sample of 41 high-dose benzodiazepine (BZD)-dependent patients, with long-term use defined as doses equivalent to more than 40 mg diazepam per day and/or otherwise problematic use, such as mixing substances, dose escalation, recreational use, or obtainment by illegal means. A qualitative content analysis approach was used to evaluate findings. RESULTS Participants generally favored a treatment discontinuation approach with abstinence from BZD as its ultimate aim, despite repeated failed attempts at withdrawal. A maintenance treatment approach with continued prescription of a slow-onset, long-acting agonist was viewed ambivalently, with responses ranging from positive and welcoming to rejection. Three overlapping themes of maintenance treatment were identified: "Only if I can try to discontinue…and please don't call it that," "More stability and less criminal activity…and that is why I would try it," and "No cure, no brain and no flash…and thus, just for everybody else!" CONCLUSIONS Some patients experienced slow-onset, long-acting BZDs as having stabilized their symptoms and viewed these BZDs as having helped avoid uncontrolled withdrawal and abstain from criminal activity. We therefore encourage clinicians to consider treatment alternatives if discontinuation strategies fail.

Alfaxalone versus alfaxalone-dexmedetomidine anaesthesia by immersion in oriental fire-bellied toads (Bombina orientalis)

OBJECTIVE To determine a dexmedetomidine concentration, to be added to an alfaxalone-based bath solution, that will enhance the anaesthetic and analgesic effects of alfaxalone; and to compare the quality of anaesthesia and analgesia provided by immersion with either alfaxalone alone or alfaxalone with dexmedetomidine in oriental fire-bellied toads (Bombina orientalis). STUDY DESIGN Pilot study followed by a prospective, randomized, experimental trial. ANIMALS Fourteen oriental fire-bellied toads. METHODS The pilot study aimed to identify a useful dexmedetomidine concentration to be added to an anaesthetic bath containing 20 mg 100 mL(-1) alfaxalone. Thereafter, the toads were assigned to one of two groups, each comprising eight animals, to be administered either alfaxalone (group A) or alfaxalone-dexmedetomidine (group AD). After immersion for 20 minutes, the toads were removed from the anaesthetic bath and the righting, myotactic and nociceptive reflexes, cardiopulmonary variables and von Frey filaments threshold were measured at 5 minute intervals and compared statistically between groups. Side effects and complications were noted and recorded. RESULTS In the pilot study, a dexmedetomidine concentration of 0.3 mg 100 mL(-1) added to the alfaxalone-based solution resulted in surgical anaesthesia. The toads in group AD showed higher von Frey thresholds and lower nociceptive withdrawal reflex scores than those in group A. However, in group AD, surgical anaesthesia was observed in two out of eight toads only, and induction of anaesthesia was achieved in only 50% of the animals, as compared with 100% of the toads in group A. CONCLUSIONS AND CLINICAL RELEVANCE The addition of dexmedetomidine to an alfaxalone-based solution for immersion anaesthesia provided some analgesia in oriental fire-bellied toads, but failed to potentiate the level of unconsciousness and appeared to lighten the depth of anaesthesia. This limitation renders the combination unsuitable for anaesthetizing oriental fire-bellied toads for invasive procedures.

Alfaxalone-butorphanol versus alfaxalone-morphine combination for immersion anaesthesia in oriental fire-bellied toads (Bombina orientalis)

Oriental fire-bellied toads (Bombina orientalis) are small semi-aquatic anuran species popular as both pets and laboratory animals. Although they are commonly anaesthetized to undergo clinical and experimental procedures, very little is known about their anaesthetic management. The aims of this prospective, randomized, cross-over experimental trial were to establish effective butorphanol and morphine concentrations to be added to alfaxalone for immersion anaesthesia (pilot study), and to compare the anaesthetic and antinociceptive effects of the two drug mixtures (alfaxalone-butorphanol and alfaxalone-morphine), in Bombina orientalis toads. For the actual trial, the toads were randomly assigned to one of two treatment groups: AB and AM, with seven animals in each group, which received alfaxalone-butorphanol and alfaxalone-morphine combinations, respectively, at the concentrations established during the pilot study. Heart rate, respiratory rate, von Frey filament threshold and response to nociceptive withdrawal (NWR), righting and myotactic reflexes were measured at 5 min intervals until return of righting reflex was observed. The investigator who carried out all the measurements was blinded to the treatment. Any undesired effect or complication was noted and recorded. The two treatments were found to be comparable in terms of onset and duration of anaesthesia, and occurrence of undesired effects. However, group AM resulted in lower NWR scores and higher von Frey filament thresholds than group AB. It is concluded that, at the investigated concentrations and in combination with alfaxalone by immersion, morphine provides better antinociception than butorphanol in oriental fire-bellied toads.

The Role of Autophagy in Cancer and Chemotherapy

Resistance to current chemo- and radiation therapy is the principal problem in anticancer treatment. Although intensively investigated, the therapeutic outcome is still far from satisfactory. Among the multiple factors which contribute to the drug resistance in cancer cells, the involvement of autophagy is becoming more and more evident. Autophagy describes a cellular self-digestion process, in which cytoplasmic elements can be selectively engulfed and finally degraded in autophagolysosomes to supply nutrients and building blocks for the cells. Autophagy controls cellular homeostasis and can be induced in response to stresses, like hypoxia and growth factor withdrawal. Since the essential physiological function of autophagy is to maintain cellular metabolic balance, dysregulated autophagy has been found associated with multiple diseases, including cancer. Interestingly, the role of autophagy in cancer is two-sided; it can be pro- or antitumor. Autophagy can suppress tumor formation, for example, by controlling cell proliferation and the production of reactive oxygen species. On the other hand, autophagy can provide nutrients to the tumor cells to support tumor growth under nutrition-limiting conditions, thereby promoting tumor development. This ambivalent behavior is also evident in anticancer therapy: By inducing autophagic cell death, autophagy has been shown to potentiate the cytotoxicity of chemotherapeutic drugs, but autophagy has also been linked to drug resistance, since inhibiting autophagy has been found to sensitize tumor cells toward anticancer drug-induced cell death. In this chapter, we will focus on the dual role of autophagy in tumorigenesis and chemotherapy, will classify autophagy inducers and inhibitors used in anticancer treatment, and will discuss topics related to future drug development which have arisen.

Pharmacokinetics and pharmacodynamics of γ-hydroxybutyrate in healthy subjects.

AIMS γ-Hydroxybutyrate (GHB) is used as a treatment for narcolepsy and alcohol withdrawal and as recreational substance. Nevertheless, there are limited data on the pharmacokinetics and pharmacokinetic-pharmacodynamic relationship of GHB in humans. We characterized the pharmacokinetic profile and exposure-psychotropic effect relationship of GHB in humans. METHODS Two oral doses of GHB (25 and 35 mg/kg) were administered to 32 healthy male subjects (16 for each dose) using a randomized, placebo-controlled, cross-over design. RESULTS Maximal concentrations of GHB were (geometric mean and 95%CI): 218 (176-270) nmol/ml and 453 (374-549) nmol/ml for the 25 and 35 mg/kg GHB doses, respectively. The elimination half-lives (mean ± SD) were 36 ± 9 and 39 ± 7 min and the AUC∞ values (geometric mean and 95%CI) were 15,747 (12,854-19,290) and 40,113 (33,093-48,622) nmol∙min/ml for the 20 and 35 mg/kg GHB doses, respectively. Thus, plasma GHB exposure (AUC0-∞ ) rose disproportionally (+40%) with the higher dose. γ-Hydroxybutyrate produced mixed stimulant-sedative effects, with a dose-dependent increase in sedation and dizziness. It did not alter heart rate or blood pressure. A close relationship between plasma GHB exposure and its psychotropic effects was found, with higher GHB concentrations associated with higher subjective stimulation, sedation, and dizziness. No clockwise hysteresis was observed in the GHB concentration effect plot over time (i.e., no acute pharmacological tolerance). CONCLUSION Evidence was found of a non-linear dose-exposure relationship (i.e., no dose proportionality) at moderate doses of GHB. The effects of GHB on consciousness were closely linked to its plasma exposure and exhibited no acute tolerance. This article is protected by copyright. All rights reserved.

Pain hypersensitivity and spinal nociceptive hypersensitivity in chronic pain: prevalence and associated factors.

Hypersensitivity of pain pathways is considered a relevant determinant of symptoms in chronic pain patients, but data on its prevalence are very limited. To our knowledge, no data on the prevalence of spinal nociceptive hypersensitivity are available. We studied the prevalence of pain hypersensitivity and spinal nociceptive hypersensitivity in 961 consecutive patients with various chronic pain conditions. Pain threshold and nociceptive withdrawal reflex threshold to electrical stimulation were used to assess pain hypersensitivity and spinal nociceptive hypersensitivity, respectively. Using 10th percentile cutoff of previously determined reference values, the prevalence of pain hypersensitivity and spinal nociceptive hypersensitivity (95% confidence interval) was 71.2 (68.3-74.0) and 80.0 (77.0-82.6), respectively. As a secondary aim, we analyzed demographic, psychosocial, and clinical characteristics as factors potentially associated with pain hypersensitivity and spinal nociceptive hypersensitivity using logistic regression models. Both hypersensitivity parameters were unaffected by most factors analyzed. Depression, catastrophizing, pain-related sleep interference, and average pain intensity were significantly associated with hypersensitivity. However, none of them was significant for both unadjusted and adjusted analyses. Furthermore, the odds ratios were very low, indicating modest quantitative impact. To our knowledge, this is the largest prevalence study on central hypersensitivity and the first one on the prevalence of spinal nociceptive hypersensitivity in chronic pain patients. The results revealed an impressively high prevalence, supporting a high clinical relevance of this phenomenon. Electrical pain thresholds and nociceptive withdrawal reflex explore aspects of pain processing that are mostly independent of sociodemographic, psychological, and clinical pain-related characteristics.