Prediction of psychiatric comorbidity on premature death in a cohort of patients with substance use disorders: a 42-year follow-up.

BACKGROUND: We need to better understand how the use of different substances and psychiatric comorbidity influence premature death generally and cause-specific death by overdose, intoxication and somatic disorders in people with substance use disorders. METHOD: A cohort of 1405 patients consecutively admitted to a Swedish detoxification unit for substance use disorders in 1970-1995 was followed-up for 42 years. Substances were identified by toxicological analyses. Mortality figures were obtained from a national registry. Causes of death were diagnosed by forensic autopsy in 594 patients deceased by 2012. Predictions were calculated by competing risks analysis. RESULTS: Forty-two per cent of the cohort died during follow-up; more men than women (46.3% vs 30.4%). The standardised mortality ratio (SMR) was calculated as the ratio of observed deaths in males and females in specific age groups in the cohort versus expected deaths in corresponding groups in the general population. SMR was 5.68 for men (CI 95%; 5.04-6.11) and 4.98 (CI 95%; 4.08-5.88) for women. The crude mortality rate (number of deaths divided by number of person observation years) was 2.28% for men and 1.87% for women. Opiates predicted increased risk of premature death while amphetamine and cannabis predicted lower risk. Comorbid psychiatric disorders were identified in 378 cases and personality disorders in 763 cases. Primary psychoses or mood/depression and anxiety disorders predicted a higher risk of premature mortality. Death by overdose was predicted by male gender, younger age at admission to substance treatment, opiate use, and comorbid depression and anxiety syndromes. Cannabis and amphetamine use predicted a lower risk of overdose. Death by intoxication was predicted by male gender, use of sedatives/hypnotics or alcohol/mixed substances, primary psychoses and depression/anxiety syndromes. Premature death by somatic disorder was predicted by male gender and alcohol/mixed abuse. CONCLUSION: Psychiatric comorbid disorders were important risk factors for premature drug-related death. Early identification of these factors may be life-saving in the treatment of patients with substance use disorders.

Buprenorphine maintenance program with contracted work/education and low tolerance for non-prescribed drug use: a cohort study of outcome for women and men after seven years.

BACKGROUND: A seven-year follow-up of heroin dependent patients treated in a buprenorphine-maintenance program combining contracted work/education and low tolerance for non-prescribed drug use. Gender-specific differences in outcome were analysed. METHODS: A consecutively admitted cohort of 135 men and 35 women, with eight years of heroin abuse/dependence on average was admitted to enhanced buprenorphine maintenance treatment. Standardized interviews, diagnostic assessments of psychiatric disorders and psychosocial conditions were conducted at admission and at follow-ups. Outcome associated with gender was reported for abstinence, retention, psychiatric symptoms, employment and criminal convictions. RESULTS: 148 patients started treatment. After seven years, 94/148 patients (64%) were retained in the program, employed and abstinent from drugs and alcohol. Women had more continuous abstinence, retention and employment than men (76% versus 60%). After one year patients with a high-risk consumption of alcohol were no longer heavy consumers of alcohol and remained so throughout the study (p < .001). All women regained custody of their children. At admission, more women than men had been admitted for psychiatric disorders (70%/44%) and to compulsory care for substance abuse (30%/18%). Initial gender differences of psychiatric co-morbidity decreased and were no longer significant after one year. More men than women had been imprisoned (62% versus 27%) or in non-institutional care (80% versus 49%). Criminal convictions were reduced from 1751 convictions at admission to 742 (58%) after seven years. Eight patients in the entire cohort died over the 7 years (0.7% per year). One patient died in the completers group while still in the program (0.1% per year). CONCLUSIONS: After seven years, two thirds of the patients in the program were abstinent and employed. Convictions ceased in the completers group. One patient died in the completers group. Women had superior long-term outcome compared to men: more continuous abstinence, employment and fewer convictions. Women also lived with their children to a higher extent than men. The positive outcome highlights the importance of maintaining high structure in combining pharmacological treatment with a focus on employment and psychological treatment and low tolerance for non-prescribed drug use.

Substance abuse and psychiatric co-morbidity as predictors of premature mortality in Swedish drug abusers: a prospective longitudinal study 1970-2006.

BACKGROUND: Few longitudinal cohort studies have focused on the impact of substances abused and psychiatric disorders on premature mortality. The aim of the present study was to identify predictors of increased risk of drug related death and non drug related death in substance abusers of opiates, stimulants, cannabis, sedatives/hypnotics, hallucinogens and alcohol over several decades. METHODS: Follow-up study of a consecutive cohort of 561 substance abusers, admitted to a detoxification unit January 1970 to February 1978 in southern Sweden, and followed up in 2006. Demographic and clinical data, substance diagnoses and three groups of psychiatric diagnoses were identified at first admission. Causes of death were coded according to ICD-10 and classified as drug related deaths or non drug related deaths. To identify the incidence of some probable risk factors of drug related premature death, the data were subjected to a competing risks Cox regression analysis. RESULTS: Of 561 patients in the cohort, 11 individuals had either emigrated or could not be located, and 204/561 patients (36.4%) were deceased by 2006. The cumulative risk of drug related death increased more in the first 15 years and leveled out later on when non drug related causes of death had a similar incidence. In the final model, male gender, regular use of opiates or barbiturates at first admission, and neurosis were associated with an increased risk of drug related premature death, while cannabis use and psychosis were associated with a decreased risk. Neurosis, mainly depression and/or anxiety disorders, predicted drug related premature death while chronic psychosis and personality disorders did not. Chronic alcohol addiction was associated with increased risk of non drug related death. CONCLUSIONS: The cohort of drug abusers had an increased risk of premature death to the age of 69. Drug related premature death was predicted by male gender, the use of opiates or barbiturates and depression and anxiety disorders at first admission. The predicted cumulative incidence of drug related death was significantly higher in opiate and barbiturate abusers over the observed period of 37 years, while stimulant abuse did not have any impact. Alcohol contributed to non drug related death.

Causes of premature mortality in Swedish drug abusers: a prospective longitudinal study 1970-2006.

AIMS: To evaluate premature mortality and causes of death from young adulthood to middle age in a cohort of drug users followed during almost four decades. DESIGN: Follow-up study of a consecutive cohort of patients with drug abuse/dependence. METHODS: A cohort of 561 drug abusers, admitted to a detoxification and short-term rehabilitation unit 1970-1978 was followed to December 31st, 2006. Standardized interviews and hospital records with toxicological analyses were used for demographic data, substance use and psychiatric diagnoses at admission. For Follow-up analyses, autopsy protocols including toxicology tests and death certificates were obtained for assessment of causes of death which were coded according to ICD-10. Age-group standardized mortality ratios were calculated independently for both sexes. RESULTS: 204 persons (36.4%) were deceased by 2006. SMR was 5.94 for the cohort. Compared to an age- and gender-matched population, the risk of premature death was about eighteen times higher between the ages of 20-44 and about five times higher from 45 up to the age of 69. Of 120 (59%) drug-related deaths, 43 were opiate overdoses, and 3 were overdose from amphetamine. A total of 53 (26%) persons died violent deaths: 39 suicides, of which 25 were drug-related, 3 homicides and 12 accidents. The Swedish national causes of death register underestimated drug-related death by 37% and suicide by 85% compared to the results from this study. CONCLUSIONS: The cohort of drug abusers had an increased risk of premature often drug-related and violent death well into middle age, and to a great extent the drug addicts died from the same drug they had abused when they were first admitted for treatment. The underestimation of drug-related death and suicide in some national death cause registers could be reduced if the doctor routinely records ICD codes when issuing death certificates and autopsy protocols.

An evaluation of an optimal sampling strategy for meropenem in febrile neutropenics.

Optimal sampling design with nonparametric population modeling offers the opportunity to determine pharmacokinetic parameters for patients in whom blood sampling is restricted. This approach was compared to a standard individualized modeling method for meropenem pharmacokinetics in febrile neutropenic patients. The population modeling program, nonparametric approach of expectation maximization (NPEM), with a full data set was compared to a sparse data set selected by D-optimal sampling design. The authors demonstrated that the D-optimal sampling strategy, when applied to this clinical population, provided good pharmacokinetic parameter estimates along with their variability. Four individualized and optimally selected sampling time points provided the same parameter estimates as more intensive sampling regimens using traditional and population modeling techniques. The different modeling methods were considerably consistent, except for the estimation of CL(d) with sparse sampling. The findings suggest that D-optimal sparse sampling is a reasonable approach to population pharmacokinetic/pharmacodynamic studies during drug development when limited sampling is necessary.

Pharmacokinetics and pharmacodynamics of meropenem in febrile neutropenic patients with bacteremia.

BACKGROUND: Pharmacodynamic investigations with antimicrobials define the relationship between the infecting organism and achievable drug concentrations with clinical outcome. OBJECTIVE: To examine this relationship for meropenem in a population of patients who are at high risk of infection-related morbidity and mortality. METHODS: The study was a retrospective analysis of a multicenter, randomized, blinded clinical trial. A population-based predictive model was created using data from adults with febrile neutropenia and the nonparametric modeling program, NPEM. Patient age, body weight, and serum creatinine level were covariates in the model used to predict unbound concentrations for each patient. Pathogen susceptibility was estimated using product literature minimum inhibitory concentrations for effectiveness against 50% of microorganisms (MIC50) for specific organisms. The pharmacodynamic index of percent time above MIC (% T>MIC) was analyzed for its association with clinical outcome. RESULTS: A 2-compartment pharmacokinetic model using patient covariates of body weight and renal function best described the pharmacokinetics of meropenem in febrile neutropenic patients. Sixty patients with confirmed gram-positive or -negative bacteremia were studied. An average of 83% T>MIC was identified for the 42 clinical responders compared with 59% T>MIC for the 18 nonresponders (p = 0.04). An 80% clinical response rate was evident when the % T>MIC for meropenem exceeded 75% of the dosing interval (p = 0.01). CONCLUSIONS: To our knowledge, this is the first published report of a relationship between a pharmacodynamic index and clinical outcome in a febrile neutropenic population. Based on this relationship, dosing with intravenous meropenem 500 mg every 6 hours is predicted to be comparable to the currently recommended 1 g every 8 hours for serious infections. Our model provides further justification for a prospective clinical trial to evaluate a pharmacodynamically targeted meropenem dosing schedule as to its ability to improve clinical outcome in these patients.

Impact of combinations of antineoplastic drugs on intestinal microflora in 9 patients with leukaemia.

The impact of antineoplastic drugs on the intestinal microflora was studied in 9 patients with acute leukaemia during chemotherapy and in 5 patients also during chemotherapy-induced neutropenia. Quantitative and qualitative microbiological analyses of faecal samples obtained before and during chemotherapy showed significantly increased counts of Bacteroides spp. in 3/9 patients and, during neutropenia, significantly increased counts of yeasts in 2/5 patients; however, the intestinal microflora was stable in most patients.