A narrative review of the epidemiology and economics of chronic wounds.

Chronic wounds have a debilitating effect on the quality of life of many individuals, and the large economic impact on health system budgets warrants greater attention in policy making and condition management than is currently evident. The aim of this narrative review is to summarize the nature and extent of the chronic wound problem that confronts health systems across the world. The first section is used to highlight the underlying epidemiology relating to chronic wounds, while the second explores the economic costs associated with them and the relative efficiency of measures designed to manage them.

Attributable Length of Stay, Mortality Risk, and Costs of Bacterial Health Care-Associated Infections in Australia: A Retrospective Case-cohort Study.

BACKGROUND: Unbiased estimates of the health and economic impacts of health care-associated infections (HAIs) are scarce and focus largely on patients with bloodstream infections (BSIs). We sought to estimate the hospital length of stay (LOS), mortality rate, and costs of HAIs and the differential effects on patients with an antimicrobial-resistant infection. METHODS: We conducted a multisite, retrospective case-cohort of all acute-care hospital admissions with a positive culture of 1 of the 5 organisms of interest (Escherichia coli, Klebsiella pneumoniae, Pseudomonas aeruginosa, Staphylococcus aureus, or Enterococcus faecium) from 1 January 2012 through 30 December 2016. Data linkage was used to generate a data set of statewide hospital admissions and pathology data. Patients with bloodstream, urinary, or respiratory tract infections were included in the analysis and matched to a sample of uninfected patients. We used multistate survival models to generate LOS, and logistic regression to derive mortality estimates. RESULTS: We matched 20 390 cases to 75 635 uninfected control patients. The overall incidence of infections due to the 5 studied organisms was 116.9 cases per 100 000 patient days, with E. coli urinary tract infections (UTIs) contributing the largest proportion (51 cases per 100 000 patient days). The impact of a UTI on LOS was moderate across the 5 studied pathogens. Resistance significantly increased LOS for patients with third-generation cephalosporin-resistant K. pneumoniae BSIs (extra 4.6 days) and methicillin-resistant S. aureus BSIs (extra 2.9 days). Consequently, the health-care costs of these infections were higher, compared to corresponding drug-sensitive strains. CONCLUSIONS: The health burden remains highest for BSIs; however, UTIs and respiratory tract infections contributed most to the health-care system expenditure.

Best practice perioperative strategies and surgical techniques for preventing caesarean section surgical site infections: a systematic review of reviews and meta-analyses.

BACKGROUND: Surgical site infection (SSI) following caesarean section is a problem for women and health services. Caesarean section is a high volume procedure and the estimated incidence of SSI may be as high as 9%. OBJECTIVES: The objective of this study was to identify a suite of perioperative strategies and surgical techniques that reduce the risk of SSI following caesarean section. SEARCH STRATEGY: Six electronic databases were searched to systematically review literature reviews, systematic reviews and meta-analyses published from 2006 to 2016. Search terms included: endometritis, SSI, caesarean section, meta-analysis, review, systematic. SELECTION CRITERIA: Studies were sought in which competing perioperative strategies and surgical techniques relevant for caesarean section were identified and quantifiable infection outcomes were reported. General infection control strategies were excluded. DATA COLLECTION AND ANALYSIS: Data on study characteristics and clinical effectiveness were extracted. Quality, including bias within individual studies, was examined using a modified A Measurement Tool to Assess Systematic Reviews (AMSTAR) checklist. Recommendations for SSI risk-reducing strategies were developed using the Grading of Recommendations Assessment, Development and Evaluation (GRADE) approach. MAIN RESULTS: Of 466 records retrieved, 44 studies were selected for the evidence synthesis. Recommended strategies were: administer pre-incision antibiotic prophylaxis, prepare the vagina with iodine-povidone solution and spontaneous placenta removal. CONCLUSIONS: We recommend clinicians implement pre-incision antibiotic prophylaxis, vaginal preparation and spontaneous placenta removal as an infection control bundle for caesarean section. FUNDING: Queensland University of Technology. TWEETABLE ABSTRACT: Infection control for caesarean: pre-incision AB prophylaxis, vaginal prep, spontaneous placenta removal.

Impact of central-line-associated bloodstream infections and catheter-related bloodstream infections: a systematic review and meta-analysis.

BACKGROUND: Accurate effect estimates are needed to inform input parameters of health economic models. Central-line-associated bloodstream infections (CLABSIs) and catheter-related bloodstream infections (CRBSIs) are different definitions used for central-line bloodstream infections and may represent dissimilar patients, but previous meta-analyses did not differentiate between CLABSIs/CRBSIs. AIM: To determine outcome effect estimates in CLABSI and CRBSI patients, compared to uninfected patients. METHODS: PubMed, Embase, and CINAHL were searched from January 2000 to March 2024 for full-text studies reporting all-cause mortality and/or hospital length of stay (LOS) in adult inpatients with and without CLABSI/CRBSI. Two investigators independently reviewed all potentially relevant studies and performed data extraction. Odds ratio for mortality and mean difference in LOS were pooled using random-effects models. Risk of study bias was assessed using ROBINS-E. FINDINGS: Thirty-six studies were included. Sixteen CLABSI and 12 CRBSI studies reported mortality. The mortality odds ratios of CLABSIs and CRBSIs, compared to uninfected patients, were 3.19 (95% CI: 2.44, 4.16; I2 = 49%) and 2.47 (95% CI: 1.51, 4.02; I2 = 82%), respectively. Twelve CLABSI and eight CRBSI studies reported hospital LOS; only three CLABSI studies and two CRBSI studies accounted for the time-dependent nature of CLABSIs/CRBSIs. The mean differences in LOS for CLABSIs and CRBSIs compared to uninfected patients were 16.14 days (95% CI: 9.27, 23.01; I2 = 91%) and 16.26 days (95% CI: 10.19, 22.33; I2 = 66%), respectively. CONCLUSION: CLABSIs and CRBSIs increase mortality risk and hospital LOS. Few published studies accounted for the time-dependent nature of CLABSIs/CRBSIs, which can result in overestimation of excess hospital LOS.

Cost-effectiveness of a real-time spatiotemporal mapping surveillance system for meticillin-resistant Staphylococcus aureus prevention.

OBJECTIVES: An infection surveillance system based on a hospital's digital twin [4D-Disease Outbreak Surveillance System (4D-DOSS)] is being developed in Singapore. It offers near-real-time infection surveillance and mapping capabilities. This early economic modelling study was conducted, using meticillin-resistant Staphylococcus aureus (MRSA) as the pathogen of interest, to assess the potential cost-effectiveness of 4D-DOSS. METHODS: A Markov model that simulates the likelihood of MRSA colonization and infection was developed to evaluate the cost-effectiveness of adopting 4D-DOSS for MRSA surveillance from the hospital perspective, compared with current practice. The cycle duration was 1 day, and the model horizon was 30 days. Probabilistic sensitivity analysis was conducted, and the probability of cost-effectiveness was reported. Scenario analyses and a value of information analysis were performed. RESULTS: In the base-case scenario, with 10-year implementation/maintenance costs of 4D-DOSS of $0, there was 68.6% chance that 4D-DOSS would be cost-effective. In a more pessimistic but plausible scenario where the effectiveness of 4D-DOSS in reducing MRSA transmission was one-quarter of the base-case scenario with 10-year implementation/maintenance costs of $1 million, there was 47.7% chance that adoption of 4D-DOSS would be cost-effective. The value of information analysis showed that uncertainty in MRSA costs made the greatest contribution to model uncertainty. CONCLUSIONS: This early-stage modelling study revealed the circumstances for which 4D-DOSS is likely to be cost-effective at the current willingness-to-pay threshold, and identified the parameters for which further research will be worthwhile to reduce model uncertainty. Inclusion of other drug-resistant organisms will provide a more thorough assessment of the cost-effectiveness of 4D-DOSS.

Community Opioid Dispensing after Injury (CODI): Cohort characteristics and opioid dispensing patterns.

BACKGROUND: Despite a focus of opioid-related research internationally, there is limited understanding of long-term opioid use in adults following injury. We analysed data from the 'Community Opioid Dispensing after Injury' data linkage study. AIMS: This paper aims to describe the baseline characteristics of the injured cohort and report opioid dispensing patterns following injury-related hospitalisations. METHODS: Retrospective cohort study of adults hospitalised after injury (ICD-10AM: S00-S99, T00-T75) in Queensland, Australia between 1 January 2014 and 31 December 2015, prior to implementation of opioid stewardship programs. Data were person-linked between hospitalisation, community opioid dispensing and mortality collections. Data were extracted for 90-days prior to the index hospital admission, to establish opiate naivety, to 720 days after discharge. Median daily oral morphine equivalents (i.e., dose) were averaged for each 30-day interval. Cumulative duration of dispensing and dose were compared by demographic and clinical characteristics, stratified by drug dependency status. RESULTS: Of the 129,684 injured adults, 61.3 % had no opioids dispensed in the 2-year follow-up period. Adults having any opioids dispensed in the community (38.7 %) were more likely older, female, to have fracture injuries and injuries with a higher severity, compared to those with no opioids dispensed. Longer durations and higher doses of opioids were seen for those with pre-injury opioid use, more hospital readmissions and repeat surgeries, as well as those who died in the 2-year follow-up period. Median dispensing duration was 24-days with a median daily end dose of 13 oral morphine equivalents. If dispensing occurred prior to the injury, duration increased 10-fold and oral morphine equivalents doubled. Adults with a documented dependency prior to, or after, the injury had significantly longer durations of use and higher doses than the rest of the cohort receiving opioids. Approximately 7 % of the total cohort continued to be dispensed opioids at 2-years post injury. CONCLUSION: This is a novel population-level profile of opioid dispensing patterns following injury-related hospitalisation, described for the time period prior to the implementation of opioid stewardship programs and regulatory changes in Queensland. Detailed understanding of this pre-implementation period is critical for evaluating the impact of these changes moving forward.

Comparison of multistate model, survival regression, and matched case-control methods for estimating excess length of stay due to healthcare-associated infections.

BACKGROUND: A recent systematic review recommended time-varying methods for minimizing bias when estimating the excess length of stay (LOS) for healthcare-associated infections (HAIs); however, little evidence exists concerning which time-varying method is best used for HAI incidence studies. AIM: To undertake a retrospective analysis of data from a one-year prospective incidence study of HAIs, in one teaching hospital and one general hospital in NHS Scotland. METHODS: Three time-varying methods - multistate model, multivariable adjusted survival regression, and matched case-control approach - were applied to the data to estimate excess LOS and compared. FINDINGS: The unadjusted excess LOS estimated from the multistate model was 7.8 (95% confidence interval: 5.7-9.9) days, being shorter than the excess LOS estimated from survival regression adjusting for the admission characteristics (9.9; 8.4-11.7) days, and the adjusted estimates from matched case-control approach (10; 8.5-11.5) days. All estimates from the time-varying methods were much lower than the crude time-fixed estimates of 27 days. CONCLUSION: Studies examining LOS associated with HAI should consider a design which addresses time-dependent bias as a minimum. If there is an imbalance in patient characteristics between the HAI and non-HAI groups, then adjustment for patient characteristics is also important, where survival regression with time-dependent covariates is likely to provide the most flexible approach. Matched design is more likely to result in data loss, whereas a multistate model is limited by the challenge in adjusting for covariates. These findings have important implications for future cost-effectiveness studies of infection prevention and control programmes.

Impact of the COVID-19 pandemic on a tertiary care public hospital in Singapore: resources and economic costs.

BACKGROUND: The COVID-19 pandemic has prompted hospitals to respond with stringent measures. Accurate estimates of costs and resources used in outbreaks can guide evaluations of responses. We report on the financial expenditure associated with COVID-19, the bed-days used for COVID-19 patients and hospital services displaced due to COVID-19 in a Singapore tertiary hospital. METHODS: We conducted a retrospective cost analysis from January to December 2020 in the largest public hospital in Singapore. Costs were estimated from the hospital perspective. We examined financial expenditures made in direct response to COVID-19; hospital admissions data related to COVID-19 inpatients; and the number of outpatient and emergency department visits, non-emergency surgeries, inpatient days in 2020, compared with preceding years of 2018 and 2019. Bayesian time-series was used to estimate the magnitude of displaced services. RESULTS: USD $41.96 million was incurred in the hospital for COVID-19-related expenses. Facilities set-up and capital assets accounted for 51.6% of the expenditure; patient-care supplies comprised 35.1%. Of the 19,611 inpatients tested for COVID-19 in 2020, 727 (3.7%) had COVID-19. The total inpatient- and intensive care unit (ICU)-days for COVID-19 patients in 2020 were 8009 and 8 days, respectively. A decline in all hospital services was observed from February following a raised disease outbreak alert level; most services quickly resumed when the lockdown was lifted in June. CONCLUSION: COVID-19 led to an increase in healthcare expenses and a displacement in hospital services. Our findings are useful for informing economic evaluations of COVID-19 response and provide some information about the expected costs of future outbreaks.

Time-dependent analysis of extra length of stay and mortality due to ventilator-associated pneumonia in intensive-care units of ten limited-resources countries: findings of the International Nosocomial Infection Control Consortium (INICC).

Ventilator-associated pneumonias (VAPs) are a worldwide problem that significantly increases patient morbidity, mortality, and length of stay (LoS), and their effects should be estimated to account for the timing of infection. The purpose of the study was to estimate extra LoS and mortality in an intensive-care unit (ICU) due to a VAP in a cohort of 69,248 admissions followed for 283,069 days in ICUs from 10 countries. Data were arranged according to the multi-state format. Extra LoS and increased risk of death were estimated independently in each country, and their results were combined using a random-effects meta-analysis. VAP prolonged LoS by an average of 2·03 days (95% CI 1·52-2·54 days), and increased the risk of death by 14% (95% CI 2-27). The increased risk of death due to VAP was explained by confounding with patient morbidity.

The cost-effectiveness of temporary single-patient rooms to reduce risks of healthcare-associated infection.

BACKGROUND: The use of single rooms for patient isolation often forms part of a wider bundle to prevent certain healthcare-associated infections (HAIs) in hospitals. Demand for single rooms often exceeds what is available and the use of temporary isolation rooms may help resolve this. Changes to infection prevention practice should be supported by evidence showing that cost-effectiveness is plausible and likely. AIM: To perform a cost-effectiveness evaluation of adopting temporary single rooms into UK National Health Service (NHS) hospitals. METHODS: The cost-effectiveness of a decision to adopt a temporary, single-patient, isolation room to the current infection prevention efforts of an NHS hospital was modelled. Primary outcomes are the expected change to total costs and life-years from an NHS perspective. FINDINGS: The mean expected incremental cost per life-year gained (LYG) is £5,829. The probability that adoption is cost-effective against a £20,000 threshold per additional LYG is 93%, and for a £13,000 threshold the probability is 87%. The conclusions are robust to scenarios for key model parameters. If a temporary single-patient isolation room reduces risks of HAI by 16.5% then an adoption decision is more likely to be cost-effective than not. Our estimate of the effectiveness reflects guidelines and reasonable assumptions and the theoretical rationale is strong. CONCLUSION: Despite uncertainties about the effectiveness of temporary isolation rooms for reducing risks of HAI, there is some evidence that an adoption decision is likely to be cost-effective for the NHS setting. Prospective studies will be useful to reduce this source of uncertainty.

Impact of healthcare-associated infection on length of stay.

BACKGROUND: Increased length of stay (LOS) for patients is an important measure of the burden of healthcare-associated infection (HAI). AIM: To estimate the excess LOS attributable to HAI. METHODS: This was a one-year prospective incidence study of HAI observed in one teaching hospital and one general hospital in NHS Scotland as part of the Evaluation of Cost of Nosocomial Infection (ECONI) study. All adult inpatients with an overnight stay were included. HAI was diagnosed using European Centres for Disease Prevention and Control definitions. A multi-state model was used to account for the time-varying nature of HAI and the competing risks of death and discharge. FINDINGS: The excess LOS attributable to HAI was 7.8 days (95% confidence interval (CI): 5.7-9.9). Median LOS for HAI patients was 30 days and for non-HAI patients was 3 days. Using a simple comparison of duration of hospital stay for HAI cases and non-cases would overestimate the excess LOS by 3.5 times (27 days compared with 7.8 days). The greatest impact on LOS was due to pneumonia (16.3 days; 95% CI: 7.5-25.2), bloodstream infections (11.4 days; 5.8-17.0) and surgical site infection (SSI) (9.8 days; 4.5-15.0). It is estimated that 58,000 bed-days are occupied due to HAI annually. CONCLUSION: A reduction of 10% in HAI incidence could make 5800 bed-days available. These could be used to treat 1706 elective patients in Scotland annually and help reduce the number of patients awaiting planned treatment. This study has important implications for investment decisions in infection prevention and control interventions locally, nationally, and internationally.

Bed-days and costs associated with the inpatient burden of healthcare-associated infection in the UK.

BACKGROUND: Healthcare-associated infection (HAI) is associated with increased morbidity and mortality resulting in excess costs. AIM: To investigate the impact of all types of HAI on the inpatient cost of HAI using different approaches. METHODS: The incidence, types of HAI, and excess length of stay were estimated using data collected as part of the Evaluation of Cost of Nosocomial Infection (ECONI) study. Scottish NHS reference costs were used to estimate unit costs for bed-days. Variable (cash) costs associated with infection prevention and control (IPC) measures and treatment were calculated for each HAI type and overall. The inpatient cost of HAI is presented in terms of bed-days lost, bed-day costs, and cash costs. FINDINGS: In Scotland 58,010 (95% confidence interval: 41,730-74,840) bed-days were estimated to be lost to HAI during 2018/19, costing £46.4 million (19m-129m). The total annual cost in the UK is estimated to be £774 million (328m-2,192m). Bloodstream infection and pneumonia were the most costly HAI types per case. Cash costs are a small proportion of the total cost of HAI, contributing 2.4% of total costs. CONCLUSION: Reliable estimates of the cost burden of HAI management are important for assessing the cost-effectiveness of IPC programmes. This unique study presents robust economic data, demonstrating that HAI remains a burden to the UK NHS and bed-days capture the majority of inpatient costs. These findings can be used to inform the economic evaluation and decision analytic modelling of competing IPC programmes at local and national level.

Evaluating the post-discharge cost of healthcare-associated infection in NHS Scotland.

BACKGROUND: Whereas the cost burden of healthcare-associated infection (HAI) extends beyond the inpatient stay into the post-discharge period, few studies have focused on post-discharge costs. AIM: To investigate the impact of all types of HAI on the magnitude and distribution of post-discharge costs observed in acute and community services for patients who developed HAI during their inpatient stay. METHODS: Using data from the Evaluation of Cost of Nosocomial Infection (ECONI) study and regression methods, this study identifies the marginal effect of HAI on the 90-daypost-discharge resource use and costs. To calculate monetary values, unit costs were applied to estimates of excess resource use per case of HAI. FINDINGS: Post-discharge costs increase inpatient HAI costs by 36%, with an annual national cost of £10,832,437. The total extra cost per patient with HAI was £1,457 (95% confidence interval: 1,004-4,244) in the 90 days post discharge. Patients with HAI had longer LOS if they were readmitted and were prescribed more antibiotics in the community. The results suggest that HAI did not have an impact on the number of readmissions or repeat surgeries within 90 days of discharge. The majority (95%) of the excess costs was on acute care services after readmission. Bloodstream infection, gastrointestinal infection, and pneumonia had the biggest impact on post-discharge cost. CONCLUSION: HAI increases costs and antibiotic consumption in the post-discharge period. Economic evaluations of IPC studies should incorporate post-discharge costs. These findings can be used nationally and internationally to support decision-making on the impact of IPC interventions.

Who bears the cost of healthcare-acquired surgical site infection?

The aim of this study was to estimate the economic costs of healthcare-acquired surgical site infection (HA-SSI) and show how they are distributed between the in-hospital and post-discharge phases of care and recovery. A quantitative model of the epidemiology and economic consequences of HA-SSI was used, with data collected from a prospective cohort of surgical patients and other relevant sources. A logical model structure was specified and data applied to model parameters. A hypothetical cohort of 10 000 surgical patients was evaluated. We found that 111 cases of infection would be diagnosed in hospital and 784 cases would first appear after discharge. Of the total costs incurred, either 31% or 67% occurred during the hospital phase, depending on whether production losses incurred after discharge were included. Most of the costs incurred by the hospital sector arose from lost bed-days and only a small proportion arose from variable costs. We discuss the issues relating to the size of these costs and provide data on where they are incurred. These results can be used to inform subsequent cost-effectiveness analyses that evaluate the efficiency of programmes to reduce the risks of HA-SSI.

Make economics your friend.

In this essay I define the discipline of economics and say why it's useful. I review methods for measuring economic outcomes relevant to those working to prevent infections, and review how decision-makers should use the information to help choose the best among competing programmes. I finish by arguing that good economics can improve the amount of health gained from an infection prevention service working under conditions of scarce resources.

Cost-effectiveness of interventions to improve hand hygiene in healthcare workers in middle-income hospital settings: a model-based analysis.

BACKGROUND: Multi-modal interventions are effective in increasing hand hygiene (HH) compliance among healthcare workers, but it is not known whether such interventions are cost-effective outside high-income countries. AIM: To evaluate the cost-effectiveness of multi-modal hospital interventions to improve HH compliance in a middle-income country. METHODS: Using a conservative approach, a model was developed to determine whether reductions in meticillin-resistant Staphylococcus aureus bloodstream infections (MRSA-BSIs) alone would make HH interventions cost-effective in intensive care units (ICUs). Transmission dynamic and decision analytic models were combined to determine the expected impact of HH interventions on MRSA-BSI incidence and evaluate their cost-effectiveness. A series of sensitivity analyses and hypothetical scenarios making different assumptions about transmissibility were explored to generalize the findings. FINDINGS: Interventions increasing HH compliance from a 10% baseline to ≥20% are likely to be cost-effective solely through reduced MRSA-BSI. Increasing compliance from 10% to 40% was estimated to cost US$2515 per 10,000 bed-days with 3.8 quality-adjusted life-years (QALYs) gained in a paediatric ICU (PICU) and US$1743 per 10,000 bed-days with 3.7 QALYs gained in an adult ICU. If baseline compliance is not >20%, the intervention is always cost-effective even with only a 10% compliance improvement. CONCLUSION: Effective multi-modal HH interventions are likely to be cost-effective due to preventing MRSA-BSI alone in ICU settings in middle-income countries where baseline compliance is typically low. Where compliance is higher, the cost-effectiveness of interventions to improve it further will depend on the impact on hospital-acquired infections other than MRSA-BSI.

Estimating excess length of stay due to healthcare-associated infections: a systematic review and meta-analysis of statistical methodology.

BACKGROUND: Healthcare-associated infection (HCAI) affects millions of patients worldwide. HCAI is associated with increased healthcare costs, owing primarily to increased hospital length of stay (LOS) but calculating these costs is complicated due to time-dependent bias. Accurate estimation of excess LOS due to HCAI is essential to ensure that we invest in cost-effective infection prevention and control (IPC) measures. AIM: To identify and review the main statistical methods that have been employed to estimate differential LOS between patients with, and without, HCAI; to highlight and discuss potential biases of all statistical approaches. METHODS: A systematic review from 1997 to April 2017 was conducted in PubMed, CINAHL, ProQuest and EconLit databases. Studies were quality-assessed using an adapted Newcastle-Ottawa Scale (NOS). Methods were categorized as time-fixed or time-varying, with the former exhibiting time-dependent bias. Two examples of meta-analysis were used to illustrate how estimates of excess LOS differ between different studies. FINDINGS: Ninety-two studies with estimates on excess LOS were identified. The majority of articles employed time-fixed methods (75%). Studies using time-varying methods are of higher quality according to NOS. Studies using time-fixed methods overestimate additional LOS attributable to HCAI. Undertaking meta-analysis is challenging due to a variety of study designs and reporting styles. Study differences are further magnified by heterogeneous populations, case definitions, causative organisms, and susceptibilities. CONCLUSION: Methodologies have evolved over the last 20 years but there is still a significant body of evidence reliant upon time-fixed methods. Robust estimates are required to inform investment in cost-effective IPC interventions.

A randomized double-blind study of carbamazepine in the treatment of cocaine abuse.

A 12-week, randomized, double-blind, placebo-controlled, fixed-dose outpatient study of carbamazepine (400 mg and 800 mg) in the treatment of cocaine dependence was performed. Data were analyzed with respect to both treatment condition and carbamazepine serum levels. Outcome variables included subject retention, cocaine urinalysis, self-reported cocaine use, cocaine craving, patient and clinical global impressions, the Drug Impairment Rating Scale for Cocaine, and side effects. Compared with placebo, the 400 mg treatment condition exhibited a greater decrease in the rate of positive cocaine urinalyses and a reduction in intensity and duration of craving over the course of the study. Higher serum carbamazepine levels were associated with a lower rate of positive cocaine urinalysis, fewer days of self-reported cocaine use, briefer craving episodes, and greater subject interval retention. The clinical and methodologic implications of these findings and of the study design are discussed.

Phenytoin in the treatment of cocaine abuse: a double-blind study.

OBJECTIVES: To evaluate the effectiveness of phenytoin in the treatment of cocaine abuse. SUBJECTS AND METHODS: A 12-week, double-blind, placebo-controlled outpatient study of phenytoin in the treatment of cocaine abuse was conducted. Sixty cocaine-using subjects were randomly assigned to a daily fixed dose of 300 mg phenytoin or placebo. Forty-four subjects initiated treatment and returned for weekly visits. Primary measures of outcome included weekly quantitative and qualitative cocaine urinalysis, self-reported cocaine use, global functioning and improvement, craving intensity, and subject retention. RESULTS: Cocaine use, as measured both by weekly urinalysis and self-report, was significantly lower in the phenytoin group. The phenytoin group was also rated as significantly less impaired and more improved than the placebo group. Craving intensity was lower in the phenytoin group, but the difference was not statistically significant. Among phenytoin subjects, serum phenytoin levels above 6.0 micrograms/ml were associated with lower rates of positive cocaine urine specimens and longer cocaine-free periods. No differences were observed between groups in study retention. CONCLUSIONS: These findings suggest that phenytoin may be useful in the treatment of cocaine abuse. Further studies are needed to replicate these findings.

Effect of felbamate on carbamazepine and its major metabolites.

Felbamate is a novel antiepileptic drug that is now available in the United States. During a previous double-blind, crossover, placebo-controlled safety and efficacy study, concomitant phenytoin concentrations increased, whereas carbamazepine concentrations decreased. We evaluated the effect of felbamate on the concentrations of carbamazepine and of its major metabolites, carbamazepine-10,11-epoxide (epoxide) and carbamazepine-trans-10,11-diol (diol) in 26 patients. After the addition of felbamate, mean epoxide concentrations increased from 1.8 micrograms/ml during placebo or baseline periods to 2.4 micrograms/ml during felbamate treatment (p < 0.05); there was no significant change in diol concentrations. Mean carbamazepine concentrations decreased from 7.5 micrograms/ml during placebo treatment to 6.1 micrograms/ml during felbamate treatment (p < 0.05). Mechanisms that could account for the increase in steady-state epoxide concentrations are induction of carbamazepine metabolism to epoxide, inhibition of the conversion of epoxide to diol, or both.