Will peripherally restricted kappa-opioid receptor agonists (pKORAs) relieve pain with less opioid adverse effects and abuse potential?

WHAT IS KNOWN AND OBJECTIVE: Optimal utilization of opioid analgesics is significantly limited by the central nervous system adverse effects and misuse/abuse potential of currently available drugs. It has been postulated that opioid-associated adverse effects and abuse potential would be greatly reduced if opioids could be excluded from reaching the brain. We review the basic science and clinical evidence of one such approach - peripherally restricted kappa-opioid receptor (KOR) agonists (pKORAs). METHODS: Published and unpublished literature, websites and other sources were searched for basic science and clinical information related to the potential benefits and development of peripherally restricted kappa-opioid receptor agonists. Each source was summarized, reviewed and assessed. RESULTS: The historical development of pKORAs can be traced from the design of increasingly KOR-selective agonists, elucidation of the pharmacologic attributes of such compounds and strategies to restrict passage across the blood-brain barrier. Novel compounds are under development and have progressed to clinical trials. WHAT IS NEW AND CONCLUSIONS: The results from recent clinical trials suggest that peripherally restricted opioids can be successfully designed and that they can retain analgesic efficacy with a more favourable adverse effect profile.

The effects of temporally secondary co-morbid mental disorders on the associations of DSM-IV ADHD with adverse outcomes in the US National Comorbidity Survey Replication Adolescent Supplement (NCS-A).

BACKGROUND: Although DSM-IV attention deficit hyperactivity disorder (ADHD) is known to be associated with numerous adverse outcomes, uncertainties exist about how much these associations are mediated temporally by secondary co-morbid disorders. METHOD: The US National Comorbidity Survey Replication Adolescent Supplement (NCS-A), a national survey of adolescents aged 13-17 years (n = 6483 adolescent-parent pairs), assessed DSM-IV disorders with the World Health Organization (WHO) Composite International Diagnostic Interview (CIDI). Statistical decomposition was used to compare direct effects of ADHD with indirect effects of ADHD through temporally secondary mental disorders (anxiety, mood, disruptive behavior, substance disorders) in predicting poor educational performance (suspension, repeating a grade, below-average grades), suicidality (ideation, plans, attempts) and parent perceptions of adolescent functioning (physical and mental health, interference with role functioning and distress due to emotional problems). RESULTS: ADHD had significant gross associations with all outcomes. Direct effects of ADHD explained most (51.9-67.6%) of these associations with repeating a grade in school, perceived physical and mental health (only girls), interference with role functioning and distress, and significant components (34.5-44.6%) of the associations with school suspension and perceived mental health (only boys). Indirect effects of ADHD on educational outcomes were predominantly through disruptive behavior disorders (26.9-52.5%) whereas indirect effects on suicidality were predominantly through mood disorders (42.8-59.1%). Indirect effects on most other outcomes were through both mood (19.8-31.2%) and disruptive behavior (20.1-24.5%) disorders, with anxiety and substance disorders less consistently important. Most associations were comparable for girls and boys. CONCLUSIONS: Interventions aimed at reducing the adverse effects of ADHD might profitably target prevention or treatment of temporally secondary co-morbid disorders.

A case-control study of erectile dysfunction among men diagnosed with panic disorder.

The association between panic disorder and erectile dysfunction (ED) among men was examined in the Integrated Healthcare Information Services National Managed Care Benchmark Database (IHCIS). The IHCIS is a fully de-identified, HIPAA compliant database and includes complete medical history for more than 17 million managed care lives; data from more than 30 US health plans, covering seven census regions; and patient demographics, including morbidity, age and gender. A total of 60,949 ED cases and 243,796 controls were included for analysis. Unconditional logistic regression analyses were first performed to assess the crude risk of ED, and adjusted risks of ED that accounted for comorbid conditions and comedications. A second set of analyses measured the crude and adjusted risks after restricting the patient population to men who were diagnosed with panic disorder at least 1 month prior to an ED diagnosis. In the first set of analyses, men with panic disorder were observed to have more than a two-fold increase in risk for ED (OR=2.29, 95% CI=2.03, 2.58). After adjusting for comorbid conditions, a 52% increase in risk of ED was observed (OR=1.52, 95% CI=1.34, 1.72). Following subsequent adjustment for comorbidities and comedications, a 33% increased risk of ED was detected (OR=1.33, 95% CI=1.17, 1.51). In the second set of analyses studying panic disorder that preceded ED, only a 13% higher risk was noted (OR=1.13, 95% CI=0.97, 1.31). However, after adjusting for comorbid conditions, a 25% reduction in risk was observed (OR=0.75, 95% CI=0.64, 0.88). A 35% risk reduction was seen after adjusting for comorbidities and comedications (OR=0.65, 95% CI=0.56, 0.77).

12-Month comorbidity patterns and associated factors in Europe: results from the European Study of the Epidemiology of Mental Disorders (ESEMeD) project.

OBJECTIVE: Comorbidity patterns of 12-month mood, anxiety and alcohol disorders and socio-demographic factors associated with comorbidity were studied among the general population of six European countries. METHOD: Data were derived from the European Study of the Epidemiology of Mental Disorders (ESEMeD), a cross-sectional psychiatric epidemiological study in a representative sample of adults aged 18 years or older in Belgium, France, Germany, Italy, the Netherlands and Spain. The diagnostic instrument used was the Composite International Diagnostic Interview (WMH-CIDI). Data are based on 21 425 completed interviews. RESULTS: In general, high associations were found within the separate anxiety disorders and between mood and anxiety disorders. Lowest comorbidity associations were found for specific phobia and alcohol abuse-the disorders with the least functional disabilities. Comorbidity patterns were consistent cross-nationally. Associated factors for comorbidity of mood and anxiety disorders were female gender, younger age, lower educational level, higher degree of urbanicity, not living with a partner and unemployment. Only younger people were at greater risk for comorbidity of alcohol disorder with mood, anxiety disorders or both. CONCLUSION: High levels of comorbidity are found in the general population. Comorbidity is more common in specific groups. To reduce psychiatric burden, early intervention in populations with a primary disorder is important to prevent comorbidity.

Sampling and methods of the European Study of the Epidemiology of Mental Disorders (ESEMeD) project.

OBJECTIVE: The European Study of Epidemiology of Mental Disorders (ESEMeD) project was designed to evaluate the prevalence, the impact and the treatment patterns in Europe. This paper presents an overview of the methods implemented in the project. METHOD: ESEMeD is a cross-sectional study in a representative sample of 21 425 adults, 18 or older, from the general population of Belgium, France, Germany, Italy, the Netherlands and Spain. The Composite International Diagnostic Interview (WMH-CIDI) was administered by home interviews from January 2001 to August 2003 using Computer Assisted Personal Interview (CAPI) technology. Data quality was controlled to ensure reliability and validity of the information obtained. RESULTS: Response rate varied from 78.6% in Spain to 45.9% in France. Less than 4% of the individuals had errors in the checking procedures performed. CONCLUSION: The sampling methodologies, comprehensive psychiatric instruments and quality control procedures used have rendered the ESEMeD database a unique and important source of information about the prevalence, the disability burden and unmet medical needs of mental disorders within Europe.

Prevalence of mental disorders in Europe: results from the European Study of the Epidemiology of Mental Disorders (ESEMeD) project.

OBJECTIVE: To describe the 12-month and lifetime prevalence rates of mood, anxiety and alcohol disorders in six European countries. METHOD: A representative random sample of non-institutionalized inhabitants from Belgium, France, Germany, Italy, the Netherlands and Spain aged 18 or older (n = 21425) were interviewed between January 2001 and August 2003. DSM-IV disorders were assessed by lay interviewers using a revised version of the Composite International Diagnostic Interview (WMH-CIDI). RESULTS: Fourteen per cent reported a lifetime history of any mood disorder, 13.6% any anxiety disorder and 5.2% a lifetime history of any alcohol disorder. More than 6% reported any anxiety disorder, 4.2% any mood disorder, and 1.0% any alcohol disorder in the last year. Major depression and specific phobia were the most common single mental disorders. Women were twice as likely to suffer 12-month mood and anxiety disorders as men, while men were more likely to suffer alcohol abuse disorders. CONCLUSION: ESEMeD is the first study to highlight the magnitude of mental disorders in the six European countries studied. Mental disorders were frequent, more common in female, unemployed, disabled persons, or persons who were never married or previously married. Younger persons were also more likely to have mental disorders, indicating an early age of onset for mood, anxiety and alcohol disorders.

Disability and quality of life impact of mental disorders in Europe: results from the European Study of the Epidemiology of Mental Disorders (ESEMeD) project.

OBJECTIVE: This manuscript examines the impact of mental health state and specific mental and physical disorders on work role disability and quality of life in six European countries. METHOD: The ESEMeD study was conducted in: Belgium, France, Germany, Italy, the Netherlands and Spain. Individuals aged 18 years and over who were not institutionalized were eligible for an in-home computer-assisted interview. Common mental disorders, work loss days (WLD) in the past month and quality of life (QoL) were assessed, using the WMH-2000 version of the CIDI, the WHODAS-II, and the mental and physical component scores (MCS, PCS) of the 12-item short form, respectively. The presence of five chronic physical disorders: arthritis, heart disease, lung disease, diabetes and neurological disease was also assessed. Multivariate regression techniques were used to identify the independent association of mental and physical disorders while controlling for gender, age and country. RESULTS: In each country, WLD and loss of QoL increased with the number of disorders. Most mental disorders had approximately 1.0 SD-unit lower mean MCS and lost three to four times more work days, compared with people without any 12-month mental disorder. The 10 disorders with the highest independent impact on WLD were: neurological disease, panic disorder, PTSD, major depressive episode, dysthymia, specific phobia, social phobia, arthritis, agoraphobia and heart disease. The impact of mental vs. physical disorders on QoL was specific, with mental disorders impacting more on MCS and physical disorders more on PCS. Compared to physical disorders, mental disorders had generally stronger 'cross-domain' effects. CONCLUSION: The results suggest that mental disorders are important determinants of work role disability and quality of life, often outnumbering the impact of common chronic physical disorders.

Use of mental health services in Europe: results from the European Study of the Epidemiology of Mental Disorders (ESEMeD) project.

OBJECTIVE: Comprehensive information about access and patterns of use of mental health services in Europe is lacking. We present the first results of the use of health services for mental disorders in six European countries as part of the ESEMeD project. METHOD: The study was conducted in: Belgium, France, Germany, Italy, the Netherlands and Spain. Individuals aged 18 years and over who were not institutionalized were eligible for an computer-assisted interview done at home. The 21 425 participants were asked to report how frequently they consulted formal health services due to their emotions or mental health, the type of professional they consulted and the treatment they received as a result of their consultation in the previous year. RESULTS: An average of 6.4% of the total sample had consulted formal health services in the previous 12 months. Of the participants with a 12-month mental disorder, 25.7% had consulted a formal health service during that period. This proportion was higher for individuals with a mood disorder (36.5%, 95% CI 32.5-40.5) than for those with anxiety disorders (26.1%, 95% CI 23.1-29.1). Among individuals with a 12-month mental disorder who had contacted the health services 12 months previously, approximately two-thirds had contacted a mental health professional. Among those with a 12-month mental disorder consulting formal health services, 21.2% received no treatment. CONCLUSION: The ESEMeD results suggest that the use of health services is limited among individuals with mental disorders in the European countries studied. The factors associated with this limited access and their implications deserve further research.

Psychotropic drug utilization in Europe: results from the European Study of the Epidemiology of Mental Disorders (ESEMeD) project.

OBJECTIVE: To assess psychotropic drug utilization in the general population of six European countries, and the pattern of use in individuals with different DSM-IV diagnoses of 12-month mental disorders. METHOD: Data were derived from the European Study of the Epidemiology of Mental Disorders (ESEMeD/MHEDEA 2000), a cross-sectional psychiatric epidemiological study in a representative sample of 21 425 adults aged 18 or older from six European countries (e.g. Belgium, France, Germany, Italy, the Netherlands and Spain). Individuals were asked about any psychotropic drug use in the past 12 months, even if they used the drug(s) just once. A colour booklet containing high-quality pictures of psychotropic drugs commonly used to treat mental disorders was provided to help respondents recall drug use. RESULTS: Psychotropic drug utilization is generally low in individuals with any 12-month mental disorder (32.6%). The extent of psychotropic drug utilization varied according to the specific DSM-IV diagnosis. Among individuals with a 12-month diagnosis of pure major depression, only 21.2% had received any antidepressants within the same period; the exclusive use of antidepressants was even lower (4.6%), while more individuals took only anxiolytics (18.4%). CONCLUSION: These data question the appropriateness of current pharmacological treatments, particularly for major depression, in which under-treatment is coupled with the high use of non-specific medications, such as anxiolytics.

Three fatalities involving phosphine gas, produced as a result of methamphetamine manufacturing.

In August of 1996, Sheriff's deputies investigated the deaths of three individuals suspected to have been overcome by phosphine gas. Phosphine is an extremely toxic gas, and is generally seen in the farming industry where it is used as a grain fumigant. It can also be generated as a by-product during the manufacturing of methamphetamine. Chemicals and equipment consistent with the manufacturing of methamphetamine were noted at the location, as well as an apparent reaction mixture heated to near dryness. Dräger tubes detected an atmospheric phosphine concentration in excess of 0.3 parts per million (ppm), the Threshold Limit Value. Deputies had initially assessed the scene with no protective equipment, raising concerns about phosphine toxicity and the effects of exposure. The objectives of this paper are to describe how phosphine is formed during the manufacture of methamphetamine, to review the toxicity, health effects and symptoms of exposure, to address the safety concerns regarding potential exposure to law enforcement personnel, and to describe the protective equipment available for personnel who respond to clandestine laboratories.

A long-term analysis of 620 patients with malignant melanoma at a major referral center.

BACKGROUND: A univariate and multivariate statistical analysis of a single surgeon's experience with resectable malignant melanoma during 26 years (November 1970 to August 1996) was conducted. METHODS: Six hundred twenty consecutive patients were registered. Univariate analysis of disease-free survival (DFS) and melanoma survival (MS) was calculated by the Kaplan-Meier method and correlated to American Joint Committee on Cancer stage, thickness, ulceration, site, lymph node involvement, age, sex, type, and excision margins. Linear trends, log-rank test, and pairwise comparisons were used to discriminate differences in survival curves. A Cox proportional hazards model was used for multivariate analysis and determination of relative risk. RESULTS: Univariate analysis of stage, thickness (in millimeters), ulceration, lymph node involvement, age, type, and margins of excision were predictive of DFS (5 years, 85.7%; 10 years, 82.5%) and MS (5 years, 92.2%; 10 years, 87.8%) (P < .01). Multivariate analysis revealed correlations with thickness, ulceration, and age in predicting DFS (relative risk = 2.75, 2.21, and 1.47, respectively) and MS (relative risk = 2.66, 2.47, and 1.48, respectively). The 5-year MS rate was 73.3% and 93.3% for patients with positive and negative lymph nodes, respectively. Of 133 patients who underwent lymph node dissection, 28 (21.1%) had nodal metastases. Patients with primary melanomas thicker than 4 mm had 50% metastatic involvement of their lymph nodes. CONCLUSIONS: Our findings reveal that thickness, ulceration, and age are the most important predicting factors in DFS and MS. The data support including ulceration and age in modifying American Joint Committee on Cancer staging for melanoma.

In vivo effect of human growth hormone on hepatic adenylate cyclase activity.

Significant increases in basal, and glucagon and fluoride stimulated adenylate cyclase activity were observed in liver plasma membranes of hypophysectomized rats compared to normal adult and weanling rats. The fluoride stimulated adenylate cyclase activity was 2-3 fold greater in the membranes from hypophysectomized animals while the glucagon stimulated activity was 5-7 fold greater, and the basal activity was approximately double that of membranes from normal adult animals. Administration of growth hormone to hypophysectomized rats by an intramuscular or intravenous route decreased adenylate cyclase activity to levels equivalent to those in normal adult rats. Estradiol and thyroxine replacement did not alter the adenylate cyclase activity of the membranes from hypophysectomized animals. The fluoride or epinephrine stimulated adenylate cyclase activity of rat diaphragm homogenates was not affected by hypophysectomy.