TRESK background K+ channel deletion selectively uncovers enhanced mechanical and cold sensitivity.

KEY POINTS: TRESK background K+ channel is expressed in sensory neurons and acts as a brake to reduce neuronal activation. Deletion of the channel enhances the excitability of nociceptors. Skin nociceptive C-fibres show an enhanced activation by cold and mechanical stimulation in TRESK knockout animals. Channel deletion selectively enhances mechanical and cold sensitivity in mice, without altering sensitivity to heat. These results indicate that the channel regulates the excitability of specific neuronal subpopulations involved in mechanosensitivity and cold-sensing. ABSTRACT: Background potassium-permeable ion channels play a critical role in tuning the excitability of nociceptors, yet the precise role played by different subsets of channels is not fully understood. Decreases in TRESK (TWIK-related spinal cord K+ channel) expression/function enhance excitability of sensory neurons, but its role in somatosensory perception and nociception is poorly understood. Here, we used a TRESK knockout (KO) mouse to address these questions. We show that TRESK regulates the sensitivity of sensory neurons in a modality-specific manner, contributing to mechanical and cold sensitivity but without any effect on heat sensitivity. Nociceptive neurons isolated from TRESK KO mice show a decreased threshold for activation and skin nociceptive C-fibres show an enhanced activation by cold and mechanical stimulation that was also observed in behavioural tests in vivo. TRESK is also involved in osmotic pain and in early phases of formalin-induced inflammatory pain, but not in the development of mechanical and heat hyperalgesia during chronic pain. In contrast, mice lacking TRESK present cold allodynia that is not further enhanced by oxaliplatin. In summary, genetic removal of TRESK uncovers enhanced mechanical and cold sensitivity, indicating that the channel regulates the excitability of specific neuronal subpopulations involved in mechanosensitivity and cold-sensing, acting as a brake to prevent activation by innocuous stimuli.

The Background K+ Channel TRESK in Sensory Physiology and Pain.

TRESK belongs to the K2P family of potassium channels, also known as background or leak potassium channels due to their biophysical properties and their role regulating membrane potential of cells. Several studies to date have highlighted the role of TRESK in regulating the excitability of specific subtypes of sensory neurons. These findings suggest TRESK could be involved in pain sensitivity. Here, we review the different evidence available that involves the channel in pain and sensory perception, from studies knocking out the channel or overexpressing it to identified mutations that link the channel to migraine pain. In addition, the therapeutic possibilities are discussed, as targeting the channel seems an interesting therapeutic approach to reduce nociceptor activation and to decrease pain.

Call for Action: Benzodiazepine Prescription Prevalence Analysis Shows Off-Label Prescription in One in Eleven Citizens.

OBJECTIVE: Benzodiazepines have a good safety profile. Nevertheless, off-label use of these drugs may increase the risk of falls, dependence, and memory loss. Off-label prescription use is not highly prevalent. Studies have not researched the factors that influence off-label prescription use. We aim to identify the prevalence of off-label use of benzodiazepines in Barcelona and explore sociodemographic factors that may be involved for professionals and patients. METHOD: A cross-sectional study in Barcelona was carried out. Data from professionals were obtained from the Medical Official College of Barcelona. Patients' healthcare data were extracted from the electronic prescription system DataMart and from the Catalan Health System Observatory (catchment of 97% of the prescription system). Two multivariate analyses were performed to identify risk factors of off-label prescription use; one focused on the patients' characteristics and the other focused on professionals' characteristics. RESULTS: In total, 9.7% of Barcelona's citizens used benzodiazepine prescriptions; 96.1% of them were off-label uses. The most common reason was long-term use (95.8%). Elderly patients were the most common demographic that was exposed to off-label use (OR 1.05, 95% CI 1.04-1.05). Family doctors (B = 38.87, 95% CI 25.25-35.50) and psychiatrists (B = 16.93; 95% CI 11.50-22.35) were the largest groups of off-label prescribers. CONCLUSIONS: The prevalence of benzodiazepine off-label prescriptions in our environment is very high, especially when the length of the treatment is considered. Implementation of evidenced-based strategies to facilitate more effective prescription practices is required.

Antipsychotic polypharmacy in a regional health service: a population-based study.

BACKGROUND: To analyse the extent and profile of outpatient regular dispensation of antipsychotics, both in combination and monotherapy, in the Barcelona Health Region (Spain), focusing on the use of clozapine and long-acting injections (LAI). METHODS: Antipsychotic drugs dispensed for people older than 18 and processed by the Catalan Health Service during 2007 were retrospectively reviewed. First and second generation antipsychotic drugs (FGA and SGA) from the Anatomical Therapeutic Chemical classification (ATC) code N05A (except lithium) were included. A patient selection algorithm was designed to identify prescriptions regularly dispensed. Variables included were age, gender, antipsychotic type, route of administration and number of packages dispensed. RESULTS: A total of 117,811 patients were given any antipsychotic, of whom 71,004 regularly received such drugs. Among the latter, 9,855 (13.9%) corresponded to an antipsychotic combination, 47,386 (66.7%) to monotherapy and 13,763 (19.4%) to unspecified combinations. Of the patients given antipsychotics in association, 58% were men. Olanzapine (37.1%) and oral risperidone (36.4%) were the most common dispensations. Analysis of the patients dispensed two antipsychotics (57.8%) revealed 198 different combinations, the most frequent being the association of FGA and SGA (62.0%). Clozapine was dispensed to 2.3% of patients. Of those who were receiving antipsychotics in combination, 6.6% were given clozapine, being clozapine plus amisulpride the most frequent association (22.8%). A total of 3.800 patients (5.4%) were given LAI antipsychotics, and 2.662 of these (70.1%) were in combination. Risperidone was the most widely used LAI. CONCLUSIONS: The scant evidence available regarding the efficacy of combining different antipsychotics contrasts with the high number and variety of combinations prescribed to outpatients, as well as with the limited use of clozapine.

Gastrointestinal quality of life after laparoscopic Roux-en-Y gastric bypass.

BACKGROUND: Laparoscopic Roux-en-Y gastric bypass (LRYGBP) is a commonly performed bariatric surgical procedure for the treatment of morbid obesity (MO). Obesity-related co-morbidities reduce the quality and expectancy of life. We assessed gastrointestinal quality of life in patients following LRYGBP. METHODS: The Gastrointestinal Quality of Life Index (GIQLI test) was used in this study. A higher score correlates with better quality of life. The GIQLI test was administered to 3 non-selected groups: 100 morbidly obese patients (MO group), 100 patients who had undergone LRYGBP (LRYGBP group); and a control group of 100 individuals (CO group). The CO group was composed of healthy individuals with a BMI<30 kg/m2, consecutively recruited among the companions of patients who came for a surgery consultation for obesity or other pathologies. Overall test and specific dimensions scores were evaluated for each group. RESULTS: Overall test and specific dimensions scores were significantly lower in patients with MO when compared to the CO and LRYGBP groups. There were no differences between the CO and LRYGBP groups in the overall score with regard to disease-specific digestive symptoms and the psychological and social dimensions. CONCLUSIONS: The quality of life of morbidly obese patients is worsened not only because of the presence of digestive symptoms but also because of their emotional, physical and social impact. Patients operated on by LRYGBP experience an improvement in their quality of life, with good tolerance of the anatomical changes.

Policies to enhance the efficiency of prescribing in the Spanish Catalan region: impact and future direction.

AIM: To assess the impact of recent national and regional initiatives on the utilization and expenditure of four high-volume classes to provide future guidance. These were proton pump inhibitors, statins and ezetimibe, and renin-angiotensin drugs, as well as newer antidepressants. METHODS: An observational study of prescriptions dispensed in ambulatory care in Catalonia was conducted from 2003 to 2007. Utilization was converted into defined daily doses (DDDs) and DDDs per 1000 inhabitants per day, and compared over the study period, as well as with other European countries. RESULTS: As expected, there was increasing utilization of statins and renin-angiotensin drugs during the study period, as well as increased utilization of generics versus originators in each class; the latter figures were substantially greater than those published previously. There was also increased utilization of the proton pump inhibitors, which is a cause for concern. There were substantial reductions in the expenditure/DDDs of generics and originator products in 2007 versus 2003. For instance, expenditure/DDDs of generic and originator simvastatin were 81 and 72%, respectively, below 2003 originator prices. These reductions were much greater than those seen in previous publications. The increased utilization of generics, coupled with lower expenditure/DDDs for the classes, led to reduced reimbursed expenditure for the proton pump inhibitors, statins and newer antidepressants over time. CONCLUSION: The findings are in line with expectations and do provide direction to other European countries, especially those with higher expenditures/DDDs for generics. There is an opportunity for Catalonia to learn from other countries to further enhance the quality and efficiency of its prescribing, and possible initiatives are discussed.

Returned medicines in community pharmacies of Barcelona, Spain.

OBJECTIVE: To monitor the amount of unused drugs and the cost to the public health system. Setting A random sample of community pharmacies in Barcelona, Spain. Method The drugs were collected from 38 community pharmacies over a period of 7 consecutive working days (excluding Sundays). A questionnaire was designed to evaluate each returned medicine. The resulting data were analyzed and evaluated. MAIN OUTCOME MEASURE: The number of drugs collected at the pharmacy, the characteristics of the clients and the reasons why they returned the drugs, and finally the economic value of the drugs returned and the cost to the public health system. RESULTS: A total of 227 clients (54.6% women, 64 +/- 20 years-old) returned 1,176 packages to the pharmacy. The number of packages collected in one return ranged from 1 to 121. The number of packages collected per pharmacy ranged from 0 to 188. In more than half of the cases (52.4%) the patients returned their drug in person and in 32.2% of the cases a relative returned it on their behalf. The main reason (28.2%) why drugs were returned was the expiry date. In 24.9% of the cases the patient's condition had improved and there was no further need for the drug. In 20.8% the patient had died. The estimated total cost of the collected drugs was euro8,539.9. Over 75% of this amount (euro6,463.9) had been paid by the public health system. CONCLUSION: This study confirms the importance of analyzing the return of unwanted medicines to reduce unnecessary health expenditure. It also highlights the inadequacies of the Spanish health system in the areas of prescription, dispensing and use of medicines. Establishing strategies to reduce the wastage of unused medicines is necessary.