Patients' perspectives about the role of primary healthcare providers in long-term opioid therapy: a qualitative study in Dutch primary care.

BACKGROUND: Over the past decade, long-term use of prescription opioids for chronic non-cancer pain has risen globally despite the associated risks. Most opioid users receive their first prescription in primary care. AIM: To investigate the perspective of patients who are long-term opioid users in primary care regarding the role of healthcare providers (HCPs) in their prolonged opioid use. DESIGN AND SETTING: Semi-structured interviews in Dutch primary care. METHOD: We recruited patients who were long-term users of opioids for chronic non-cancer pain from seven community pharmacies in the Netherlands. In-depth, semi-structured interviews focused on patients' experiences with long-term opioid use, access to opioids, and the guidance of their HCPs (primarily their GPs and pharmacists). A directed content analysis was conducted on the transcribed interviews using NVivo. RESULTS: Participants (n = 25) described ways in which HCPs impacted their long-term use of opioids. These encompassed the initiation of treatment, chronic use of opioids, and discontinuation of treatment. Participants stressed the need for risk counselling during initial prescribing, ongoing medication evaluations including tapering conversations, and more support from their HCP during a tapering attempt. CONCLUSION: Patients' perspectives illustrate the important role of HCPs across the spectrum of opioid use - from initiation to tapering. The results of this study underscore the importance of clear risk counselling starting at initial prescribing, repeated medication assessments throughout treatment, addressing tapering at regular intervals, and strong support during tapering. These insights carry significant implications for clinical practice, emphasising the importance of informed and patient-centred care when it comes to opioid use for chronic non-cancer pain management.

Patients' Perspectives on the Development of Prescription Opioid Use Disorder in Patients with Chronic Non-Cancer Pain.

INTRODUCTION: In the past decade, prescription opioid use increased exponentially and concomitantly opioid use disorders (OUD) are becoming more common. Several risk factors for developing OUD have been identified, but little is known regarding the patients' perspective on developing a prescription OUD. METHODS: We recruited 25 adults undergoing treatment for prescription OUD. In-depth, semi-structured interviews focussed on experiences with long-term opioid use, knowledge and attitudes regarding opioids, and access to opioids. A directed content analysis was conducted on the transcribed interviews using NVivo. RESULTS: Participants showed that the development of an OUD is affected by various factors which could be grouped into three themes: (1) experiences driving initiation, (2) experiences driving continuation, and (3) experiences with prescription OUD. Besides the need for pain management, the dynamics of patient-provider communication, care coordination, provider vigilance, and environmental support all contributed to the way patients used their opioids. CONCLUSION: Patients' experiences illustrate that the first stage of the development of prescription OUD differs from the development of other substance addictions. Negative reinforcement might play a more prominent role in the early phase of prescription opioid use. Patients expressed a lack of guidance, both at the start of use and long-term use, easy access to new prescriptions and a lack of monitoring as main drivers of the development. Poorly controlled pain and subjective stress fuelled continuous opioid use.

The Association Between Tobacco Outlet Density and Smoking Among Young People: A Systematic Methodological Review.

AIM: Evidence on the association between tobacco outlet density and proximity and smoking behavior among youth is inconsistent, which may be due to methodological problems in some studies. We assessed the association of outlet density or proximity with smoking behavior among young people while taking into account the methodological quality of studies. METHODS: MEDLINE, EMBASE, and Google Scholar were systematically searched for studies on the relationship between outlet density or proximity and smoking behavior among 12- to 25-year-olds, published between 1997 and 2017. Methodological quality of the included studies was evaluated independently by two reviewers. RESULTS: Twenty studies were included in the review. The quality assessment identified five primary sources of potential bias: overadjustment for mediators (problems identified in 14 studies), underadjustment for confounders (six studies), poor statistical model fit (four studies), selection bias (three studies), and misclassification of exposure measurements (eight studies). Four studies were of high methodological quality. In studies with relatively high quality, 10 associations were reported, of which seven were nonsignificant, two positive, and one negative. Similarly, the complete body of evidence demonstrated mostly nonsignificant associations, but a larger proportion of positive associations than negative. CONCLUSION: Although there is some support for a positive direction, current literature does not provide consistent evidence for a positive association between outlet density and smoking among youth. This is not necessarily due to bias in specific studies, but more to fundamental challenges in study design and exposure measurements. These issues need to be addressed in future studies using more rigorous methods. IMPLICATIONS: Our findings suggest that, although there is some evidence for a positive association, current scientific literature does not provide consistent support to claim an effect of tobacco outlet density or proximity on youth smoking. This underlines the need for more research with improved methodology. There is a need for quasiexperimental studies, in which the outlet density changes substantially, studies measuring the actual exposure of youth to tobacco outlets, and qualitative research on the mechanisms underlying any association.

Low-dose oral theophylline combined with inhaled corticosteroids for people with chronic obstructive pulmonary disease and high risk of exacerbations: a RCT.

BACKGROUND: Despite widespread use of therapies such as inhaled corticosteroids (ICSs), people with chronic obstructive pulmonary disease (COPD) continue to suffer, have reduced life expectancy and utilise considerable NHS resources. Laboratory investigations have demonstrated that at low plasma concentrations (1-5 mg/l) theophylline markedly enhances the anti-inflammatory effects of corticosteroids in COPD. OBJECTIVE: To determine the clinical effectiveness and cost-effectiveness of adding low-dose theophylline to a drug regimen containing ICSs in people with COPD at high risk of exacerbation. DESIGN: A multicentre, pragmatic, double-blind, randomised, placebo-controlled clinical trial. SETTING: The trial was conducted in 121 UK primary and secondary care sites. PARTICIPANTS: People with COPD [i.e. who have a forced expiratory volume in 1 second (FEV1)/forced vital capacity (FVC) of < 0.7] currently on a drug regimen including ICSs with a history of two or more exacerbations treated with antibiotics and/or oral corticosteroids (OCSs) in the previous year. INTERVENTIONS: Participants were randomised (1 : 1) to receive either low-dose theophylline or placebo for 1 year. The dose of theophylline (200 mg once or twice a day) was determined by ideal body weight and smoking status. PRIMARY OUTCOME: The number of participant-reported exacerbations in the 1-year treatment period that were treated with antibiotics and/or OCSs. RESULTS: A total of 1578 people were randomised (60% from primary care): 791 to theophylline and 787 to placebo. There were 11 post-randomisation exclusions. Trial medication was prescribed to 1567 participants: 788 in the theophylline arm and 779 in the placebo arm. Participants in the trial arms were well balanced in terms of characteristics. The mean age was 68.4 [standard deviation (SD) 8.4] years, 54% were male, 32% smoked and mean FEV1 was 51.7% (SD 20.0%) predicted. Primary outcome data were available for 98% of participants: 772 in the theophylline arm and 764 in the placebo arm. There were 1489 person-years of follow-up data. The mean number of exacerbations was 2.24 (SD 1.99) for participants allocated to theophylline and 2.23 (SD 1.97) for participants allocated to placebo [adjusted incidence rate ratio (IRR) 0.99, 95% confidence interval (CI) 0.91 to 1.08]. Low-dose theophylline had no significant effects on lung function (i.e. FEV1), incidence of pneumonia, mortality, breathlessness or measures of quality of life or disease impact. Hospital admissions due to COPD exacerbation were less frequent with low-dose theophylline (adjusted IRR 0.72, 95% CI 0.55 to 0.94). However, 39 of the 51 excess hospital admissions in the placebo group were accounted for by 10 participants having three or more exacerbations. There were no differences in the reporting of theophylline side effects between the theophylline and placebo arms. LIMITATIONS: A higher than expected percentage of participants (26%) ceased trial medication; this was balanced between the theophylline and placebo arms and mitigated by over-recruitment (n = 154 additional participants were recruited) and the high rate of follow-up. The limitation of not using documented exacerbations is addressed by evidence that patient recall is highly reliable and the results of a small within-trial validation study. CONCLUSION: For people with COPD at high risk of exacerbation, the addition of low-dose oral theophylline to a drug regimen that includes ICSs confers no overall clinical or health economic benefit. This result was evident from the intention-to-treat and per-protocol analyses. FUTURE WORK: To promote consideration of the findings of this trial in national and international COPD guidelines. TRIAL REGISTRATION: Current Controlled Trials ISRCTN27066620. FUNDING: This project was funded by the National Institute for Health Research (NIHR) Health Technology Assessment programme and will be published in full in Health Technology Assessment; Vol. 23, No. 37. See the NIHR Journals Library website for further project information.

Chronic obstructive pulmonary disease (COPD) is a long-term lung disease that cannot be cured. The main symptom is shortness of breath on exertion. In the UK, about 1.2 million people have COPD. It is a major cause of death and costs the NHS > £1B a year. Sudden 'flare-ups' of symptoms often need emergency treatment, shorten life expectancy and reduce people's ability to get on with their lives. Theophylline is a drug that has been around for decades. In the past, it was used in high doses to treat COPD by opening up airways. However, its benefits were limited and it often caused unpleasant side effects. High-dose theophylline has been replaced by drugs administered by inhalers, such as inhaled corticosteroids (ICSs). Recent work in the laboratory and in animal models suggests that, at low dose, theophylline could make ICSs work better in COPD with none of the side effects of high-dose theophylline. The Theophylline With Inhaled CorticoSteroid (TWICS) trial tested whether or not adding low-dose theophylline reduces flare-ups in people with COPD taking ICSs. A total of 1578 people with COPD from 121 centres all over the UK took part. Participants were randomly divided into two groups: one group took low-dose theophylline and the other took dummy placebo pills. Participants were asked to attend visits at 6 and 12 months. A total of 791 participants were prescribed low-dose theophylline and 787 were prescribed dummy placebo pills. Although not everyone took the tablets for a whole year, it was possible to count the number of flare-ups in 98% of those taking part. In total, there were 3430 flare-ups. On average, the people taking low-dose theophylline had 2.24 flare-ups and the people taking placebo had 2.23 flare-ups. Overall, the trial showed that, for people with COPD, taking low-dose theophylline on top of steroid inhalers makes no real difference.

Effect of Theophylline as Adjunct to Inhaled Corticosteroids on Exacerbations in Patients With COPD: A Randomized Clinical Trial.

Importance: Chronic obstructive pulmonary disease (COPD) is a major global health issue and theophylline is used extensively. Preclinical investigations have demonstrated that low plasma concentrations (1-5 mg/L) of theophylline enhance antiinflammatory effects of corticosteroids in COPD. Objective: To investigate the effectiveness of adding low-dose theophylline to inhaled corticosteroids in COPD. Design, Setting, and Participants: The TWICS (theophylline with inhaled corticosteroids) trial was a pragmatic, double-blind, placebo-controlled, randomized clinical trial that enrolled patients with COPD between February 6, 2014, and August 31, 2016. Final follow-up ended on August 31, 2017. Participants had a ratio of forced expiratory volume in the first second to forced vital capacity (FEV1/FVC) of less than 0.7 with at least 2 exacerbations (treated with antibiotics, oral corticosteroids, or both) in the previous year and were using an inhaled corticosteroid. This study included 1578 participants in 121 UK primary and secondary care sites. Interventions: Participants were randomized to receive low-dose theophylline (200 mg once or twice per day) to provide plasma concentrations of 1 to 5 mg/L (determined by ideal body weight and smoking status) (n = 791) or placebo (n = 787). Main Outcomes and Measures: The number of participant-reported moderate or severe exacerbations treated with antibiotics, oral corticosteroids, or both over the 1-year treatment period. Results: Of the 1567 participants analyzed, mean (SD) age was 68.4 (8.4) years and 54% (843) were men. Data for evaluation of the primary outcome were available for 1536 participants (98%) (772 in the theophylline group; 764 in the placebo group). In total, there were 3430 exacerbations: 1727 in the theophylline group (mean, 2.24 [95% CI, 2.10-2.38] exacerbations per year) vs 1703 in the placebo group (mean, 2.23 [95% CI, 2.09-2.37] exacerbations per year); unadjusted mean difference, 0.01 (95% CI, -0.19 to 0.21) and adjusted incidence rate ratio, 0.99 (95% CI, 0.91-1.08). Serious adverse events in the theophylline and placebo groups included cardiac, 2.4% vs 3.4%; gastrointestinal, 2.7% vs 1.3%; and adverse reactions such as nausea (10.9% vs 7.9%) and headaches (9.0% vs 7.9%). Conclusions and Relevance: Among adults with COPD at high risk of exacerbation treated with inhaled corticosteroids, the addition of low-dose theophylline, compared with placebo, did not reduce the number COPD exacerbations over a 1-year period. The findings do not support the use of low-dose theophylline as adjunctive therapy to inhaled corticosteroids for the prevention of COPD exacerbations. Trial Registration: isrctn.org Identifier: ISRCTN27066620.

The role of self-control and cognitive functioning in educational inequalities in adolescent smoking and binge drinking.

BACKGROUND: Large differences in substance use between educational levels originate at a young age, but there is limited evidence explaining these inequalities. The aim of this study was to test whether a) smoking and binge drinking are associated with lower levels of self-control and cognitive functioning, and b) associations between educational track and smoking and binge drinking, respectively, are attenuated after controlling for self-control and cognitive functioning. METHODS: This study used cross-sectional survey data of 15 to 20-year-olds (N = 191) from low, middle, and high educational tracks. We measured regular binge drinking and regular smoking (more than once a month), cognitive functioning (cognitive ability, reaction time and memory span), and self-control. Logistic regression models were used to assess the associations between educational track and smoking and binge drinking controlled for age, gender and social disadvantage, and for self-control and cognitive functioning. RESULTS: According to models that controlled for age, gender and social disadvantage only, respondents in the low educational track were more likely to drink heavily (OR = 3.25, 95% CI = 1.48-7.17) and smoke (OR = 5.74, 95% CI = 2.31-14.29) than adolescents in the high educational track. The association between educational track and binge drinking was hardly reduced after adjustment for self-control and cognitive ability (OR = 2.88, 95% CI = 1.09-7.62). Adjustment for self-control and cognitive functioning, especially cognitive ability, weakened the association between education and smoking (OR = 3.40, 95% CI = 1.11-10.37). However, inequalities in smoking remained significant and substantial. CONCLUSIONS: In this study population, pre-existing variations between adolescents in terms of self-control and cognitive functioning played a minor role in educational inequalities in smoking, but not in binge drinking.

A Screening Study to Determine the Prevalence of Airway Disease in Heroin Smokers.

Over the last 20 years smoking has become the most common method of heroin use and increasing numbers of heroin smokers are presenting to local medical services, before the age of 40 years, with severe airway disease. To determine COPD prevalence we recruited 129 subjects from two local community drug services, of whom 107 were heroin smokers. We collected demographic, medical and treatment data, smoking history (including cannabis and opiates) and details of symptoms including MRC dyspnoea. Subjects completed the COPD Assessment Tool and spirometry. Thirty heroin smokers were identified as having COPD resulting in a COPD prevalence of 28%. Mean age was 43 (4) years and FEV1 was 2.71 (0.98) L; 70 (23) %predicted. Breathlessness and wheeze were more common in subjects with COPD (p < 0.04 and p < 0.05) but symptoms were common in all heroin smokers. MRC score was higher (3 vs. 2.4; p < 0.04) in those with COPD and health status appeared poorer (CAT 20.4 vs. 15.8; p < 0.07). Only 4 (11%) had previously been diagnosed with COPD and only 16 (53%) received any inhaled medication. Asthma prevalence was also high at 33% and asthmatic subjects had similar symptoms and health status compared with the COPD subjects, and were also significantly undertreated. COPD and asthma are common in current and former heroin smokers. They are often present at a young age and are underdiagnosed and undertreated. Awareness of this issue should be highlighted within drug services and in particular to heroin smokers. Screening this high-risk population with spirometry should be considered.

Use of low-dose oral theophylline as an adjunct to inhaled corticosteroids in preventing exacerbations of chronic obstructive pulmonary disease: study protocol for a randomised controlled trial.

BACKGROUND: Chronic obstructive pulmonary disease (COPD) is associated with high morbidity, mortality, and health-care costs. An incomplete response to the anti-inflammatory effects of inhaled corticosteroids is present in COPD. Preclinical work indicates that 'low dose' theophylline improves steroid responsiveness. The Theophylline With Inhaled Corticosteroids (TWICS) trial investigates whether the addition of 'low dose' theophylline to inhaled corticosteroids has clinical and cost-effective benefits in COPD. METHOD/DESIGN: TWICS is a randomised double-blind placebo-controlled trial conducted in primary and secondary care sites in the UK. The inclusion criteria are the following: an established predominant respiratory diagnosis of COPD (post-bronchodilator forced expiratory volume in first second/forced vital capacity [FEV1/FVC] of less than 0.7), age of at least 40 years, smoking history of at least 10 pack-years, current inhaled corticosteroid use, and history of at least two exacerbations requiring treatment with antibiotics or oral corticosteroids in the previous year. A computerised randomisation system will stratify 1424 participants by region and recruitment setting (primary and secondary) and then randomly assign with equal probability to intervention or control arms. Participants will receive either 'low dose' theophylline (Uniphyllin MR 200 mg tablets) or placebo for 52 weeks. Dosing is based on pharmacokinetic modelling to achieve a steady-state serum theophylline of 1-5 mg/l. A dose of theophylline MR 200 mg once daily (or placebo once daily) will be taken by participants who do not smoke or participants who smoke but have an ideal body weight (IBW) of not more than 60 kg. A dose of theophylline MR 200 mg twice daily (or placebo twice daily) will be taken by participants who smoke and have an IBW of more than 60 kg. Participants will be reviewed at recruitment and after 6 and 12 months. The primary outcome is the total number of participant-reported COPD exacerbations requiring oral corticosteroids or antibiotics during the 52-week treatment period. DISCUSSION: The demonstration that 'low dose' theophylline increases the efficacy of inhaled corticosteroids in COPD by reducing the incidence of exacerbations is relevant not only to patients and clinicians but also to health-care providers, both in the UK and globally. TRIAL REGISTRATION: Current Controlled Trials ISRCTN27066620 was registered on Sept. 19, 2013, and the first subject was randomly assigned on Feb. 6, 2014.

Feasibility and impact of a computer-guided consultation on guideline-based management of COPD in general practice.

BACKGROUND: Applying guidelines is a universal challenge that is often not met. Intelligent software systems that facilitate real-time management during a clinical interaction may offer a solution. AIMS: To determine if the use of a computer-guided consultation that facilitates the National Institute for Health and Clinical Excellence-based chronic obstructive pulmonary disease (COPD) guidance and prompts clinical decision-making is feasible in primary care and to assess its impact on diagnosis and management in reviews of COPD patients. METHODS: Practice nurses, one-third of whom had no specific respiratory training, undertook a computer-guided review in the usual consulting room setting using a laptop computer with the screen visible to them and to the patient. A total of 293 patients (mean (SD) age 69.7 (10.1) years, 163 (55.6%) male) with a diagnosis of COPD were randomly selected from GP databases in 16 practices and assessed. RESULTS: Of 236 patients who had spirometry, 45 (19%) did not have airflow obstruction and the guided clinical history changed the primary diagnosis from COPD in a further 24 patients. In the 191 patients with confirmed COPD, the consultations prompted management changes including 169 recommendations for altered prescribing of inhalers (addition or discontinuation, inhaler dose or device). In addition, 47% of the 55 current smokers were referred for smoking cessation support, 12 (6%) for oxygen assessment, and 47 (24%) for pulmonary rehabilitation. CONCLUSIONS: Computer-guided consultations are practicable in general practice. Primary care COPD databases were confirmed to contain a significant proportion of incorrectly assigned patients. They resulted in interventions and the rationalisation of prescribing in line with recommendations. Only in 22 (12%) of those fully assessed was no management change suggested. The introduction of a computer-guided consultation offers the prospect of comprehensive guideline quality management.

New mutations in the Wilson disease gene, ATP7B: implications for molecular testing.

Wilson disease (WND), an autosomal recessive disorder of copper transport with a broad range of genotypic and phenotypic characteristics, results from mutations in the ATP7B gene. ATP7B encodes a copper transporting P-type ATPase involved in the transport of copper into the plasma protein ceruloplasmin, and for excretion of copper from the liver. Defects in ATP7B lead to copper storage in liver, brain and kidney. Mutation analysis was carried out on 300 WND patients of various origins, and new mutations not previously reported were identified: European white (p.L217X, c.918_931, c.1073delG, c.3082_3085delAAGAinsCG, p.V536A, p.S657R, p.A971V, p.T974M, p.Q1004P, p.D1164N, p.E1173G, p.I1230V, p.M1359I, c.2355+4A>G), Sephardic Jewish (p.Q286X), Filipino (p.G1149A), Lebanese (p.R1228T), Japanese (p.D1267V) and Taiwanese (p.A1328T). All but one missense variant have strong evidence for classification as disease-causing mutations. In the patients reported here, we also identified 20 nucleotide substitutions, six not previously reported, which cause silent amino acid changes or intronic changes. Documentation and characterization of all variants is essential for accurate DNA diagnosis in WND because of the wide range of clinical and biochemical variability.

Cirugía para la enfermedad de parkinson: la nueva cara de una vieja moneda: comentarios sobre técnicas actuales en neurocirugía funcional (talamotomías y palidotomías) y experiencia en 65 pacientes / Surgery to the parkinson's disease: the new face of an old coin: commentaries about the present tecnics in funtional neurosurgery (thalamotomy and pallidotomy) and experience in 65 patients

La enfermedad de Parkinson (EP) es una enfermedad neurodegenerativa común, progresiva, cuyo manejo terapéutico puede llegar a ser muy complicado y exigente. Los pacientes después de un tiempo, frecuentemente presentan fallas en responder a las drogas anti-parkisonianas y se convierten en dependientes funcionales de las actividades diarias más comunes. La constante búsqueda de nuevas perspectivas terapéuticas, el entendimiento actual de los mecanismos neurales en la EP sugieren que una lesión adecuadamente colocada en el tálamo (talamotomía) y en el pallidum medial (palidotomía) deberían aliviar síntomas de temblor, rigidez, bradikinesias así como diskinesias inducidas por drogas. La clave para el éxito de esta cirugía y para evitar sus complicaciones, es la correcta colocación de los blancos a lesionar. Aun cuando la mejor forma de lograr esto es todavía controversial, la tecnología actual ha permitido diseñar programas computarizados que fusionan las imágenes cerebrales de la TAC con las de RMN, para definir en forma más precisa la anatomía de los ganglios basales, y con ello el blanco a lesionar en las talamotomías y palidotomías para parkinsonismo y temblor. Presentamos nuestra experiencia con esta técnica en 65 pacientes