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Cost effectiveness of disulfiram: treating cocaine use in methadone-maintained patients |
Jofre-Bonet M, Sindelar J L, Petrakis I L, Nich C, Frankforter T, Rounsaville B J, Carroll K M |
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Record Status This is a critical abstract of an economic evaluation that meets the criteria for inclusion on NHS EED. Each abstract contains a brief summary of the methods, the results and conclusions followed by a detailed critical assessment on the reliability of the study and the conclusions drawn. Health technology The study compared two strategies for the treatment of cocaine dependence in methadone-maintained (MM) opiate addicts. One strategy was the standard MM programme with an average daily dose of 70 mg of methadone. The other strategy was the disulfiram-enhanced (DE) programme, in which 250 mg/day disulfiram was added to the standard MM programme.
Economic study type Cost-effectiveness analysis.
Study population The population comprised individuals recruited from a community-based MM programme. According to the inclusion criteria of the selected clinical trial (Petrakis et al., see Other Publications of Related Interest), the individuals were required to have been stabilised on MM for a minimum of 3 months, to meet current DSM-III-R criteria (American Psychiatric Association, 1987) for cocaine dependence (assessed through structured clinical interviews; SCID), and to have had 3 out of 4 urine screens test positive for cocaine in the last month. Individuals who had psychotic or bipolar disorders or medical problems that would contraindicate disulfiram treatment were excluded.
Setting The setting was tertiary care (an urban methadone maintenance clinic). The economic study was carried out in the USA.
Dates to which data relate The effectiveness data were derived from a completed study published in 2000. However, the dates to which the effectiveness data related were not reported. The date to which the resource use data related appears to have been 1999. The price year was 1999.
Source of effectiveness data The effectiveness data were derived from a parent study (Petrakis et al., see Other Publications of Related Interest).
Link between effectiveness and cost data The costing was undertaken retrospectively from a provider after the effectiveness results were known.
Study sample The authors did not report whether the sample size was determined in the planning phase of the study. They also did not report any retrospective power calculations. Of the 95 individuals screened, 13 were not eligible because of medical problems, while a further 13 were not randomised because of repeated missed intake appointments, termination from the MM programme, or inability to attend the programme. Therefore, 69 individuals were randomised. After 2 patients dropped out there were 67 in the study, of which 32 were in the standard MM group and 35 in the DE group. Fifty-two per cent of the sample was female, 51% Caucasian, 25% married, 20% working, and 25% had less than a high school degree. The mean age of the patients was 33 years in the DE group and 33.97 years in the MM group. More detailed information can be found in the primary report of the clinical trial (Petrakis et al.).
Study design This study was based on a randomised, double-blinded, placebo-controlled trial that had 12 weeks' follow-up and was conducted in a single centre (an urban methadone maintenance clinic). In the parent study, following baseline assessment, the patients were randomly assigned to one of two 12-week treatment programmes (the standard MM programme or the DE programme). The standard MM programme was defined as conventional clinical practice. It involved identical treatment in all respects to the DE programme, except for disulfiram. The group assigned to the DE programme had a daily dose of disulfiram dissolved directly into the methadone to insure compliance. An inert substance was added to the methadone of the standard MM group to ensure blinding. More detailed information can be found in the primary report of the clinical trial (Petrakis et al.).
Analysis of effectiveness The primary health outcomes used in this study were the days of cocaine use during the past 30 days and the mean grams of cocaine consumed in the previous week. The frequency and quantity of cocaine use were obtained weekly by a research assistant using the Time Line Follow-Back (calendar) method. Patients' self-reports of drug use were verified through urine toxicology screens collected twice weekly. For each outcome variable, an effectiveness measure was obtained, which was the change in the outcome variable from baseline to follow-up, by treatment group. The analysis was conducted on an intention to treat basis. The DE group reported somewhat higher weekly cocaine use than the MM group. There were no significant differences between the groups for the rest of the baseline demographic or substance use variables.
Effectiveness results The number of days of cocaine use in the past 30 days (+/- standard deviation, SD) was 16.74 (+/- 9.78) pre-treatment and 6.68 (+/- 7.03) at the end of treatment for the MM group (n=32), and 19.65 (+/- 9.86) pre-treatment and 4.96 (+/- 7.50) at the end of treatment for the DE group (n=35). The gain in reduced days of cocaine use was 10.06 in going from "no care" to standard MM care, and 14.06 in going from "no care" to MM enhanced with disulfiram treatment.
The mean grams of cocaine used weekly (+/- SD) was 1.46 (+/- 1.92) pre-treatment and 0.41 (+/- 0.51) at the end of treatment for the MM group, and 3.16 (+/- 5.07) pre-treatment and 0.59 (+/- 1.28) at the end of treatment for the DE group. The gain in reduced grams of cocaine used during the previous week was 1.05 in going from "no care" to standard MM care, and 2.57 in going from "no care" to MM enhanced with disulfiram treatment.
The gain in going from standard MM care to MM enhanced with disulfiram treatment was 4.63 days of cocaine use out of the last 30 days, and 1.52 grams cocaine used during the previous week.
There was a significant disulfiram multiplied by time effect for both frequency (Z=1.97; p=0.04) and quantity (Z=2.23; p=0.02) of cocaine use, with patients assigned to disulfiram reporting less cocaine use over time compared with the methadone only group.
Clinical conclusions DE treatment achieved greater reductions in the use of cocaine (days and grams) compared with standard MM care.
Measure of benefits used in the economic analysis The measure of benefits used was the gains, that is, the reduction in days of cocaine use in the last 30 days and grams of cocaine used in the previous week. This was derived directly from the effectiveness results.
Direct costs The direct programme costs for both strategies included medication costs, breathalyser readings, urine screens, medical care, individual counselling, group therapy, pharmacist and medical staff costs, and other related expenses. The authors also included overhead costs and fringe benefits. An alternative cost estimate, which excluded research costs corresponding to the additional procedures included in the MM programme, was also calculated. The quantities and the costs were analysed separately. The quantities and costs were estimated from actual data and were obtained from the provider, a non-profit university-affiliated substance abuse treatment centre. The quantity of resource use was measured retrospectively, and the price year was 1999. Discounting was not carried out, which was appropriate given the short term horizon of the study. The authors stated that possible cost offsets were not considered. The authors also excluded the costs associated with an adverse event for two reasons. One, the adverse event could not definitively be attributed to disulfiram and, two, the associated costs could not reasonably be determined.
Statistical analysis of costs The costs were treated deterministically (i.e. only point estimates were reported).
Indirect Costs No indirect costs were reported.
Sensitivity analysis To provide a more realistic estimate of the actual cost of the MM programme, the authors provided an alternative scenario of cost estimates that eliminated those costs which arose only from research needs, and which would not be incurred in a typical MM clinical setting. The alternative cost scenario assumed that only those patients taking disulfiram received a second blood test, breathalyser readings, and a second medical visit at the end of the 4th or 6th week. This "Real World Cost Scenario" compared the cost of standard methadone, delivered without the extra costs of the research protocol, with the costs of disulfiram as carried out in the trial. The authors stated that this reflected how it might be carried out in standard clinical practice.
Estimated benefits used in the economic analysis See the "Effectiveness Results" section.
Cost results The standard MM treatment cost was $1,015.34 per 12 weeks of treatment, or $84.61 per patient per week. The DE treatment cost was $1,070.23 per 12 weeks, or $89.19 per patient per week. Therefore, the incremental cost of adding disulfiram to the standard MM treatment was $54.89.
Under the assumptions of the real world cost scenario, the standard MM treatment cost was $732.07 per 12 weeks of treatment, or $61.01 per patient per week. The DE treatment cost was $1,070.23 per 12 weeks, or $89.19 per patient per week. Therefore, the incremental cost of adding disulfiram to standard MM treatment was $338.16.
Synthesis of costs and benefits The incremental cost-effectiveness ratio (ICER) was $101 for standard MM treatment compared with "no care", and about $12 for disulfiram compared with MM treatment, when effectiveness is measured by days of drug use and using the actual study scenario for the costs.
When grams of cocaine were used as the benefit measure, the ICERs were $967 for MM treatment compared to "no care" and $36 for disulfiram compared with MM treatment.
An additional set of adjusted ICERs was provided for using the estimated 3-month improvements instead of using just the last month for the number of days of cocaine use, and for using the estimated 12-week improvements instead of using just the previous week for the grams of cocaine used. The authors assumed that the reduction is stable over treatment, and it is therefore possibly a lower bound of the ICER. The corresponding ratios for MM treatment and disulfiram were, respectively, about $34 and $4 per reduced day of cocaine use and $81 and $3 per reduced grams of cocaine used.
Under the real world scenario, the ICER for MM treatment declined, while that of disulfiram increased. The ICERs for days of cocaine use were $73 for MM treatment compared with "no care" and $73 for disulfiram compared with MM treatment (the adjusted ICERs were $24 for both treatments). For grams of cocaine, the ICER for MM treatment was $697 and that of disulfiram was $222 (the adjusted ICERs with the adjusted effectiveness measures were $58 and $19, respectively).
Authors' conclusions The addition of disulfiram is likely to be more cost-effective in reducing cocaine use than methadone-maintained (MM) treatment alone. Even though disulfiram increases the cost of methadone treatment slightly, its increase in effectiveness may be sufficient to warrant its addition for treating cocaine dependence in MM opiate addicts.
CRD COMMENTARY - Selection of comparators The choice of the comparator was explicitly justified by the authors, who stated that cocaine is a pervasive problem in MM programmes, and that recent evidence has suggested the effectiveness of disulfiram for cocaine dependence in a range of settings including these programmes. Disulfiram will be most likely to be adopted in a MM programme as they have medical staff to prescribe it. In contrast, drug-free programmes are less likely to have the requisite medical staff. You should judge if this is relevant to your own setting.
Validity of estimate of measure of effectiveness The analysis was based on a randomised controlled trial, which was adequate for the study question. Only a small number of individuals from the study population were finally included in the original study. This small sample size may restrict the generalisability of these findings, as stated in the original study and by the authors. Further, it is not clear whether these results would be generalisable to treatment in other settings. The comparability of the study groups was reasonable. No statistical analyses were performed, but a real world scenario was used for the sensitivity analysis.
Validity of estimate of measure of benefit The estimation of benefit was measured in natural units (days and grams of cocaine use) and was obtained from the trial results. This choice of specific benefit measure may limit the comparability to other cost-effectiveness studies in other health fields.
Validity of estimate of costs The study had a detailed and explicit costing section, with all relevant categories and items included from the adopted health provider perspective, following methods recommended by published literature. As the authors stated, the study overestimated the costs of the MM programme in order to maintain blindness, but they reported a real world scenario in order to assess the costs as might be carried out in standard clinical practice. The study had a very short-term time horizon and excluded possible differences in costs that might be incurred following the intervention, such as additional diagnostic testing or other treatment services. The costs and the quantities were reported separately and the price date was also reported. These facts will enhance the generalisability of the study and will facilitate any future reflation exercises. Discounting was unnecessary since the costs referred to a period of time shorter than a year, and was appropriately not performed.
Other issues The authors made appropriate comparisons with other similar studies and published literature, explicitly stating similarities and differences in the results and methodology. They also discussed the generalisability of the study to other settings. The authors acknowledged some limitations of their study:
the small sample size;
not considering a broader (i.e. societal) perspective;
not including the impact of the treatments on other illicit drugs used (especially heroin and alcohol), medical care used outside the MM programme, and crime-related expenses among other factors;
not comparing the cost-effectiveness of disulfiram with other possible methods of addressing cocaine use (e.g. counselling only);
assuming no change from baseline to follow-up for those not in treatment;
not collecting costs simultaneously with the effectiveness measures; and
not considering a longer time horizon, meaning that the findings could not necessarily be extrapolated beyond this period.
An important issue that could be somewhat misleading is the omission of the report of the weak dominance of disulfiram compared with MM treatment, making disulfiram a more cost-effective strategy, even when compared with the "no care" strategy (ICER $76.1 per reduced day of cocaine use and $416.4 per reduced gram of cocaine used). This means that disulfiram could be more cost-effective than MM treatment in obtaining a unit of benefit (in terms of days of cocaine use or grams consumed) and could be an efficient way to replace current care (MM treatment).
Implications of the study The authors stated that the benefits associated with the use of disulfiram might be even higher than the estimated, as they did not consider the broader impacts of cocaine use on society (e.g. crime and worsened health). The authors also mentioned that while the broader use of disulfiram for the treatment of cocaine dependence would require multiple supportive trials in a range of settings and populations, these findings suggested that the added costs of disulfiram may be justified in an MM programme.
Source of funding Supported by grants from the APT foundation.
Bibliographic details Jofre-Bonet M, Sindelar J L, Petrakis I L, Nich C, Frankforter T, Rounsaville B J, Carroll K M. Cost effectiveness of disulfiram: treating cocaine use in methadone-maintained patients. Journal of Substance Abuse Treatment 2004; 26(3): 225-232 Other publications of related interest Carroll KM, Nich C, Ball, SA, McCance, E, Rounsaville BJ. Treatment of cocaine and alcohol dependence with psychotherapy and disulfiram. Addiction 1998;93:713-28.
George TP, Chawarski MC, Pakes J, Carroll KM, Kosten TR, Schottenfeld RS. Disulfiram versus placebo for cocaine dependence in buprenorphine-maintained subjects: a preliminary trial. Biological Psychiatry 2000;47:1080-6.
Petrakis IL, Carroll KM, Nich C, Gordon LT, McCance-Katz EF, Frankforter T, et al. Disulfiram treatment for cocaine dependence in methadone maintained opioid addicts. Addiction 2000;95:219-28.
Indexing Status Subject indexing assigned by NLM MeSH Adult; Analgesics, Opioid /economics /therapeutic use; Cocaine-Related Disorders /drug therapy; Connecticut; Cost-Benefit Analysis; Disulfiram /economics /therapeutic use; Drug Therapy, Combination; Enzyme Inhibitors /economics /therapeutic use; Female; Health Care Costs; Humans; Male; Methadone /economics /therapeutic use; Opioid-Related Disorders /drug therapy; Treatment Outcome AccessionNumber 22004006409 Date bibliographic record published 31/07/2005 Date abstract record published 31/07/2005 |
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