***TASK*** the task is to summarize an input biomedical literature in six sentences 
    ***INPUT*** the input is a biomedical literature 
    ***OUTPUT*** the output is the summary of an input biomedical literature in six sentences 
    ***DOCUMENTATION*** 
    ***EXAMPLES*** 
    Input: This study examined the reinforcing effects of hydromorphone ( HYD ) ( 0 , 4 , 8 , and 16 mg/70 kg i.m . ) in heroin-dependent outpatient volunteers maintained on buprenorphine ( BUP ) at doses of 2 , 4 , and 8 mg , each for 2 weeks . Following a week of maintenance at each dose , volunteers received injections of one of the four HYD doses under double-blind conditions . Eight volunteers ( abstainers ) were heroin-free during HYD test weeks , whereas six volunteers remained heroin-positive ( nonabstainers ) . Among abstainers , HYD had minimal reinforcing value , whereas in nonabstainers there were marked dose-related increases in  HYD reinforcing value , which were not attenuated by increasing doses of BUP . A similar pattern was found for HYD subjective agonist effects . Heroin craving among nonabstainers was significantly higher compared with abstainers , and was reduced in a dose-related manner by HYD . Although BUP and HYD produced dose-related miosis , abstinence status had no differential effect . In summary , BUP  effects on opioid reinforcement were consistent from outpatient setting ( heroin abstinence ) to laboratory setting ( decreased HYD reinforcement ) , supporting the validity of this laboratory model It is estimated that more than 500 000 people in the United States are dependent on opioids [ 1 , 2 ] . Methadone , a synthetic opioid first reported as a treatment agent for opioid dependence by Dole and Nysw and er in 1965 [ 3 ] , is the most widely used pharmacologic treatment for opioid dependence . The National Drug and Alcoholism Treatment Unit Survey ( NDATUS ) determined a point prevalence of 92 715 opioid abusers treated in 758 methadone treatment programs on 30 September 1989 [ 4 ] . When used in conjunction with counseling services , methadone treatment has been associated with reduced rates of criminal activity , illicit drug use , and needle sharing and with improved rates of employment [ 5 - 9 ] . With the recognition of intravenous drug use as a primary risk factor for infection with human immunodeficiency virus ( HIV ) , improved access to methadone treatment has been identified as an important means for reducing the risk of HIV infection [ 10 , 11 ] . Although methadone treatment is effective in decreasing opioid use , recent studies have reported considerable variability across clinics in rates of continued intravenous drug use during treatment [ 12 ] . One aspect of this problem is that intravenous use of cocaine has become a serious problem among  methadone treatment patients [ 13 - 16 ] . Few systematic studies have addressed the efficacy of  methadone treatment since the onset of the cocaine epidemic [ 17 ] . Such research could re-evaluate in a contemporary population sample methadone 's specific pharmacologic efficacy in decreasing opioid use [ 18 - 20 ] while providing new information about any potential effect of methadone treatment on concurrent cocaine use . The issue of appropriate methadone dosing levels is highly pertinent because low-dose treatment has been strongly associated with poor drug use outcomes in descriptive clinical studies [ 12 , 21 ] and because a substantial number of clinics continue to use low doses of methadone [ 22 ] . For example , a report prepared by the General Accounting Office ( GAO ) that summarized the dosing practice s of 24 methadone programs in eight states found that doses ranged widely ( from 21 to 68 mg ) and 29 % had a mean dose of less than 40 mg [ 23 ] . Thus , despite more than 25 years of clinical experience , optimal dosing levels of methadone remain controversial [ 24 , 25 ] . Previous studies of methadone dosing have either surveyed clinics for their dosing practice and related doses to clinic-wide outcomes or have r and omly assigned patients to a specific predetermined dose of methadone using clinical trial methods . Naturalistic survey studies [ 5 , 6 , 12 , 21 , 26 ] , although valuable for identifying associations between dose and outcome , are method ologically compromised by confounding factors that differ across the clinics surveyed . Previous early clinical trials of methadone dosing [ 27 - 29 ] are also method ologically compromised ( for example , being single-blinded ) or only tested higher doses of methadone [ 30 ] . Thus there is a need for well-controlled research on methadone dosing reflecting doses in common use and incorporating the changing patient population . In this controlled clinical trial we compared moderate and low methadone dosing to methadone-free treatment , providing data in a contemporary population sample of opioid addicts and examining the effect of methadone dose on cocaine as well as opioid use . Methods Participants were 247 persons who had consecutive admissions to a methadone research clinic from September 1988 through July 1990 . The mean age was 34 years , 70 % were male , and 50 % were black . Most were unmarried ( 84 % ) and unemployed ( 62 % ) . They had an average of 11 years of education , were generally legally free ( 72 % ) , and had a mean of two previous admissions for drug abuse treatment . Their primary drug of choice was intravenous heroin , and 47 % reported using cocaine in the 30 days before their application to treatment . Eligibility criteria for study participation were age between 18 and 50 years , history of intravenous opioid dependence ( including documentation of previous treatment for opioid dependence or legal involvement secondary to opioid use , a urine sample positive for opioids , and physical examination consistent with acute and chronic needle use ) , no chronic medical illnesses , absence of a major mental illness , a negative pregnancy test for women , and at least 3 months since the patient 's last treatment at the clinic . Applicants who failed to fulfill the study 's eligibility criteria were assisted in seeking an alternate treatment program . The study was approved by the institutional review board , and informed consent was obtained from each patient at the time of admission to the study . Study Procedures Applicants who fulfilled the eligibility criteria were admitted to a 6-month short-term methadone treatment program .  Participants were stratified as to race and sex and were assigned to one of three fixed-dose methadone schedules ( Figure 1 ) . Treatment group assignment , stabilization doses , and dosing schedules were double-blind for all patients and the clinic staff who had patient contact . All patients received a minimum of 35 days of active methadone during the first 5 weeks of treatment ; this was followed by a 15-week stabilization period at either 50 , 20 , or 0 mg of methadone . Thus , patients assigned to the 0-mg treatment group received 35-day methadone detoxification . During weeks 21 through 26 , the methadone dose was gradually tapered for those patients still receiving active medication because this was a short-term ( 182-day ) treatment episode . A sub sample of patients ( n = 44 ) assigned to the 0-mg treatment group received a more prolonged ( 8-week ) induction period , reaching 0 mg at the start of week 9 to compare the effects of a faster to a slower detoxification protocol . In this report data for patients in the alternate 0-mg treatment groups are collapsed . Figure 1 . Dosing schedule . Treatment Procedures Patients were assigned an individual counselor who set treatment goals and developed an individualized treatment plan . Patients were given weekly group therapy focusing on relapse prevention . On-site medical services were provided by a full-time internist and a part-time nurse practitioner . Take-home medication was provided only on legal holidays and for documented extenuating circumstances ( for example , funeral out of town for a death in the family ) . Patients who failed to attend the clinic for 3 consecutive days were discharged from treatment . Outcome Measures Treatment Retention and Compliance Treatment retention was calculated as the total number of days between the day of admission and the day of discharge , or the last day of the stable dosing period ( day 140 ) if the patient remained in treatment beyond the stable dosing period . Compliance with treatment was assessed through treatment attendance , the number of days medicated divided by days in treatment , and counseling contacts , which were based on the length ( minutes ) and number of contacts the patient had with either individual or group treatments . Urine Testing Patients provided a supervised urine sample for toxicology screening three times per week . Sample s were tested on-site using EMIT ( Syva Corporation , Palo Alto , California ) for the presence of opioids , cocaine , and benzodiazepines ; and cut-off calibration concentrations were set at 300 g/mL for each test ( morphine , benzoylecgonine , oxazepam ) . The specificity of the EMIT system ranges from 96 % to 100 % . One sample each week was r and omly selected to be sent to an outside laboratory for thin-layer chromatography analysis , which detects these same compounds and a wide variety of other less commonly abused substances . Data Analysis Retention to week 20 , days in treatment , percentage of days attended , and amount of counseling contact time were analyzed with a one-way analysis of variance with methadone dose as the grouping factor and the Tukey Honestly Significant Difference ( HSD ) test was used for post hoc analyses . Comparisons for which the critical difference value corresponding to P < 0.05 are reported as significant for this and all subsequently described analyses . Treatment survival curves were compared using the Lee-Desu statistic , with pairwise comparisons between each of the three treatment groups . The percentages of urine positive for opioids , cocaine , benzodiazepines , and any other drugs were calculated for each patient through the end of the stable dosing period . A one-factor analysis of variance with methadone dose as the grouping factor was used for each of these analyses . Results Table 1 shows the demographic features of the 247 patients enrolled in the study . The only difference across the three treatment groups on any variable was marital status ; 8 % of the patients in the 50-mg treatment group were married compared to 17 % in the 20-mg and 25 % in the 0-mg groups . Table 1 . Demographic Characteristics for Patients ( n = 247 ) Assigned to Different Methadone Doses * Treatment Retention and Compliance Orderly dose effects were seen for survival in treatment ( Figure 2 ) . Although the three treatment groups had similar rates of retention during the first 4 weeks of treatment , when all participants were receiving active methadone , retention rates diverged between weeks 4 and 8 and dose effects were seen from weeks 8 through 20 . In the survival analysis , there was an overall difference between the three curves ( P < 0.01 ) , and pairwise comparison between the 50-mg and 0-mg treatment groups differed significantly ( P < 0.01 ) ; the differences between the 50-mg and 20-mg , and 20-mg and 0-mg treatment groups approached significance ( P = 0.1 and P = 0.08 , respectively ) . At week 20 , the end of the stable dosing period , retention was 52.4 % for the 50-mg , 41.5 % for the 20-mg , and 21.0 % for the 0-mg groups ( 50 versus 0 and 20 versus 0 , P < 0.05 ; 50 versus 20 , P > 0.05 ) . Figure 2 . Retention in treatment . n The number of days retained in treatment was also dose related ( P < 0.01 ) ; Buprenorphine at 2 mg and 6 mg daily was compared with methadone at 35 mg and 65 mg during 24 weeks of maintenance among 125 opioid-dependent patients . As hypothesized , 6 mg of buprenorphine were superior to 2 mg of buprenorphine in reducing illicit opioid use , but higher dosage did not improve treatment retention . Self-reported illicit opioid use declined substantially in all groups , but by the third month , significantly more heroin abuse was reported at 2 mg than at 6 mg of buprenorphine or of methadone . From an initial average of $ 1860/month , month 3 usage dropped to $ 41 ( methadone 65 mg ) , $ 73 ( methadone 35 mg ) , $ 118 ( buprenorphine 6 mg ) , and $ 35I/month ( buprenorphine 2 mg ) . Days of use also dropped from 29 days to 1.7 ( methadone 65 mg ) , 2.8 ( methadone 35 mg ) , 4.0 ( buprenorphine 6 mg ) , and 6.6 days/month ( buprenorphine 2 mg ) . This relatively low efficacy for 2 mg of buprenorphine persisted through month 6 of the trial , with 7.2 days/month and $ 235/month of use for buprenorphine at 2 mg versus 1.9 days/month and $ 65/month for the other three groups . Increased opioid abuse also was associated with significantly greater and persistent opioid withdrawal symptoms . Our secondary hypothesis , that buprenorphine would be equivalent to methadone in efficacy , was not supported . Treatment retention was significantly better on methadone ( 20 us . 16 weeks ) , and methadone patients had significantly more opioid-free urines ( 51 % 
    Output:
    
The evidence indicated that higher doses of methadone and buprenorphine are associated with better treatment outcomes .
Low-dose methadone ( 20 mg per day ) is less effective than buprenorphine ( 2 - 8 mg per day ) .
Higher doses of methadone ( > 50 - 65 mg per day ) are slightly more effective than buprenorphine ( 2 - 8 mg per day ) .
There was some evidence that primary care could be an effective setting to provide this treatment , but such evidence was sparse .
The literature supports the effectiveness of substitute prescribing with methadone or buprenorphine in treating opiate dependence .
Evidence is also emerging that the provision of methadone or buprenorphine by primary care physicians is feasible and may be effective